PH26585A - N-substituted-arylalkyl and arylalkylene aminoheterocyclics as cardiovascular antihistamic and antisecretory agents - Google Patents

N-substituted-arylalkyl and arylalkylene aminoheterocyclics as cardiovascular antihistamic and antisecretory agents Download PDF

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Publication number
PH26585A
PH26585A PH38517A PH38517A PH26585A PH 26585 A PH26585 A PH 26585A PH 38517 A PH38517 A PH 38517A PH 38517 A PH38517 A PH 38517A PH 26585 A PH26585 A PH 26585A
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Philippines
Prior art keywords
bis
mole
pharmaceutically acceptable
acceptable salt
mixture
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PH38517A
Inventor
Shanklin James Robert Jr
Anthony George Proakis
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Robins Co Inc A H
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Publication of PH26585A publication Critical patent/PH26585A/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D227/00—Heterocyclic compounds containing rings having one nitrogen atom as the only ring hetero atom, according to more than one of groups C07D203/00 - C07D225/00
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

Cy
N-SUBSTITUTED-ARYLALKYL AND ARYLALKYLENE
AMINOHETEROCYCLICS AS CARDIOVASCULAR ANTIHISTAMINIC
AND ANTISECRETORY AGENTS
This application is a continuation-in-part of a copending Philippine Patent
Application Serial No. 34083 filed on July 30, 1986.
BACKGROUND OF THE INVENTION : 1. Field of Invention.
This invention relates to certain N-substituted arylalkyl and arylalkylenepyrrolidines, piperidines and homopiperidines useful in methods of treating cardiovascular disfunctions, countering effects of histamine in allergies and countering gastric secretion excesses. Certain of the com- - | pounds are novel and certain intermediates useful in their preparation are . novel and all the methods of treatment novelly use the compounds.
Co 2. Information Disclosure Statement.
LEE oo U.S. Patent 3,956,296 and a divisional patent thereof, U.S.
So © 4,032,642, disclose pertinent compounds, among which some would fall oo within a generic structure as follows: . A y
Ae cena OY
R : wherein Ar is phenyl, p-fluorophenyl or m-trifluorophenyl; R is phenyl, p- fluoropheny! or cyclohexyl; A is hydrogen or hydroxy; X is hydrogen or acetyl; and Y is hydrogen or loweralkoxy, the coinpounds having utility as anti-inflammatory agents, sedatives and tranquilizers and pharmaceutical compositions therefor. The compounds of this structure are within the scope oo | -2- of novel treatment methods of the present invention but are excluded from formulas representing novel compounds. . ‘ U.S. Patent 3,922,276 discloses compounds, among which would fall within a generic structure as follows: 5 .
Y
Ar-C=( eno Ox
R wherein Ar is phenyl or p-fluorophenyl and R is phenyl, p-flucrophenyl, m- trifluorophenyl or cyclohexyl; X is hydrogen or acetyl; and Y is hydrogen or loweralkoxy, the compounds having utility as anti-inflammatory agents and tranquilizers and pharmaceutical compositions therefor. The compounds of this structure are within the scope of novel treatment methods of the present : invention but are excluded form formulas representing novel compounds.
U.S. Patent 4,163,790 discloses compounds which fall within a generic structure as follows:
A peed wherein Ar and R are phenyl and p-fluorophenyl and Z is hydrogen, acetyl, p- fluorobenzoylpropyl, carbamoyl, N-methylearbamoyl, N,N-dimethylcarba- moyl, phenylcarbamoyl, or N-(@-morpholinoethyl)carbamoyl; A is hydrogen, _ hydroxy or forms a double bond as indicated by the dotted line. The com- pounds were active in increasing coronary blood flow; however, the com- pounds while substituted in the 4-piperidine position and also disclosed in the above-mentioned patents, differ substantially in structure from the com- pounds of the present invention in the substitution in the 1-position of the piperidine radical and are not within the scope of generic formulas hereof of compounds for novel treatment methods or novel compounds.
U.S. Patent No. 4,632,925 discloses compounds wt generic structure . 2
R N-Ry-Het
PN
Re wherein R3 and Rq are hydrogen, halogen or loweralkoxy: R is CH, C=CH or CH-CHg; Ra is alkylene or -C(O)-(CH2),, where nis 0-11: and Het is pyridinyl, pyrimidinyl or imidazoyl. The compounds are disclosed to have insulin lowering activity and to be usefn) as antiobesity agents. Certain of the compounds disclosed in U.S. 4,632,925, i.e., wherein R} is C =CH or CH-
CH are encompassed by Formulas [ and Ia. 1.Benzyl-(a,a-diphenyl)-4-benzylidinepiperidines of the formula (phenyl),-C = N-CH ,-phenyl are disclosed in Ger. Offen. 2,800,919 as having anticonvulsant and vaso- dilating properties. Similar 1-benzyl-(a,a-diphenyl)-4-benzylidine- fea. piperidines of the formula (phenyl),-CH von O ym : + aredisclosed in U.S. Patent No. 4,035,372 as having vasedilating properties.
The compounds are excluded from the present invention by proviso. 1-Benzyl-(a,a-diphenyl)-4-benzylpiperidines of the general formula
X 0 1 (pheny!),-C-~ N-T ne OF are disclosed in U.S. 3,965,257 as having antihistaminic activity. The compounds are ketones and, as contrasted to the ethers, useful in the present methods. 4-(Diphenylmethylene)-1-benzylpiperidines of the general formula
Ol. R? having hemodynamic, antiarrhythmic and antihistaminic activities are disclosed in U.S. Patent 3,759,928 and are excluded from the present invention by proviso.
The compound 4-diphenylmethylene-1-benzyl piperidine maleate is disclosed in Japanese kokai 62,145,018 to be an antiallergy agent not liberating histamine. The compound is not encompassed by Formulas or Ia.
Lo : U.S. Patent 3,984,557 discloses compounds which fall within a generic structure as follows: ©
Y—
N
R wherein R represents loweralkyl, lowercycloalkyl or phenylloweralkyl and Y is carbamoyl, cyano or hydrogen, the compoupds having utility as antiar- rhythmic agents. In the compounds of the present invention, the radical on the 1-position of the cycloalkylamino moiety has an aryloxy, arylamino or an aryl group other than phenyl on the alkyl chain.
An application, Serial No. 34072, directed to the use of certain com- pounds of Formula I as anti-allergy agents wherein (B)z is confined to oxygen and A is hydrogen, hydroxy, cyano or forms a double bond has been filed on
July 28, 1986 the specification of which is hereby incorporated by - reference.
SUMMARY OF THE INVENTION
The present invention is concerned with methods of correcting cardio- vascular disturbances, and antihistiminic and antisecretory agents in animals and humans utilizing heterocyclic amines of the general formula I, and certain novel compounds thereof as composition of matter. The com- pounds useful in the methods of the invention have the formula: (A)
Ar | J \
F === (Qn=={ N~(CHy)m-(B)z-D (CHy) rR” Ze Pp) Formula l
E © wherein; : , © Piszero,oneor two; : 0 Oo Oo : n _R' Nn ~ Aishydrogen, -O-R!,-C=N, -C-N\ po ,-C-R!,-C-O-R!, - -O-C-R!, -CH,OR!, -CH,-N. po -N “Rg? °F -NHC(O)CH,; ) 25 m is zero to six inclusive:
OH
Qis-CH-,-CH,- or “0 © H d,eand n are selected from zero or one and the dotted lines represent double bonds which may form consistent with the valence of carbon:
Ar, D and R are selected from the group consisting of
Y
© Owe z N 3 ° O and in addition, R may have the values of cycloalkyl or loweralkyl; and D may have additionally the values:
I 9 { 0 \ ' o o 0 0 0 ' \ - or Ar(CH,),.4-; X, Y, and Z are selected from the group consisting of hydrogen, loweralkyl, halogen, ’ OH i. | A RE , -NO,, -O-R1, .C-R:, -CF,, -C=N, COW, , N , -CH-loweralkyl, -C(O)OR!, -CH,C(0)- : : : I" o 0 R2 R2? : 0 oo Re rn A ; OR, S(0),Rs, -SR¢, S(O)R¢, GRY -CH.C(O)YOM, SOWN , ASOLCH,, ey .
I
Ce R10 R2 Rt Rt Re 0 i , lowerhydroxyaltkanyl, N-ClOIC(O)-O-laweralkyl, or TE-OR®: Biaselected from O, S,
H Rt 00 0
TT In -S-,-S-, N- or -N-C-O-R%; " oO R zis one or zero with the proviso that z cannot be zero at tk zero when one of the following occurs at the same time that D is phenyl or substituted phenyl: (A)d is hydrogen, (A)q is cyano, (A)d is aminocarbonyl, or a double bond forms between the a carbon and a carbon of the central 6 | heterocyclic amine ring.
R!"R? and R?, same or different, are selected from hydrogen, lower- alkyl, phenyl or phenylloweralkyl; R* is selected from loweralkyl, phenyl or phenylloweralkyl; M is a pharmaceutically acceptable metal ion; and the pharmaceutically acceptable salts thereof, including acid addition salts, quaternary salts, and hydrates and alcoholates thereof.
In the further definition of symbols in the formulas hereof and where they appear elsewhere throughout this specification and in the claims, the terms have the following significance.
The term “loweralkyl” as used herein, unless otherwise specified, includes straight and branched chain radicals of up to eight carbons inclusive and is exemplified by such groups as methyl, ethyl, propyl, isopropyl, butyl, : sec-butyl, tert-butyl, amyl, isoamyl, hexyl, heptyl, and octyl radicals and the like. The term "loweralkoxy” has the fomula -O-loweralkyl. The term “lowerhydroxyalkanyl” refers to loweralkyl radicals carrying a hydroxy radical. ; a
The term “cycloalkyl” as used herein includes primarily cyclic alkyl radicals containing 3-7 carbon atoms inclusive and includes such groups as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and methylcyclo- ‘hexyl and the like.
The term “halo” or “halogen” when referred to herein includes fluorine, chlorine, bromide and iodine unless otherwise stated. oo :
The term “central heterocyclic amine ring” refers to that portion of Formula I represented by x p) wherein the dotted line may represent a double bond. The tern "saturated . central heterocyclic amine ring” refers to the foregoing radical having no double bond.
The term “"phenylloweralkyl” includes phenyl connected hy hydro- carbon chains exemplified hy lnwernik yl above and wherein phenyl may be substituted by non-reactive or non-interfering radicals such as halo, lower- alkyl, loweralkoxy and the like. . *Pharmaceutically acceptable salts” include acid addition salts, hydrates, alcoholates and quaternary salts of the compounds of Formula I which are physiologically compatible in warm-blooded animals. The acid addition salts may be formed by either strong or weak acids. Representative of strong acids are hydrochloric, hydraebromic, sulfuric and phosphoric acids.
Representative of weak acids are fumaric, maleic, mandelic, tartaric, citric, oxalic, succinic, hexamic and the like. Suitable quaternary salts include the loweralkyl halides and loweralkyl sulfates.
The compounds of Formula I have been found to be calcium antagonists with potential use as coronary vasodilators, antihypertensives, antiarrhyth- mic, antiallergy, antihistaminic and antisecretory agents. As stated above, an application directed to use of certain compounds of Formula I as anti- allergy agents where (B)z is confined to oxygen and A is hydrogen, hydroxy, cyano or forms a double bond has been filed on July 28, 1986 is hereby incorporated by reference and serves to demonstrate utility of those com- pounds as antiallergy agents.
Pharmacological testing methods used for }creening in support of methods of treatment of this invention excluding antiallergy method of treat- ment as described herein below.
Certain compounds encompassed by Formula I are novel as represented by Formula Ia. (AM
Ar] p prea Secnsnms
Wa Pp) Ia wherein p,m, e, d, Q,n,AAr,D,R,m,B and z are as defined under Formula . I with the followjng additional proviso: (B)z canngt represent oxygen at the same time D is phenyl or : substituted phenyl when n is zero and (A)q is hydrogen or hydraxyl; or when d is zero and a double bond forms between the a-carbon of a saturated central heterocyclic amine ring.
.
Certain intermediate compounds useful in the preparauvi ve c.... pounds of Formula I wherein (A)q is amino and are represented by formula rR? rR! : y a (CHy)e p) Formula : wherein Ar, e, Rl, RZ n and p are as defined under Formula [ and the dotted lines represent double bonds which may form consistent with the valence of carbon: and wherein Ris defined as under Formula I except loweralkyl.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of Formula I may be prepared by methods described in "U.S. Patents 3,922,276 and 4,032,642 and as set forth in Charts I, IT, TTT, IV and V, VI, VII and VIII, which give a description of the preparation of ~~ Intermediates, Preparations and Examples contained herein. One of the general methods used is outlined by equations in Chart I. This reaction can be carried out in alcoholic solvents, preferably refluxing butanol, or in
CL ~ dimethylformamide or dimethoxyethane in the presence of an acid receptor, ) as for example, an alkali-metal carbonate and preferably using potassium iodide catalyst. The reaction time may vary from a few hours to 24 hr, depending on reactivity of the aryloxyalkyl halide and temperature. 28 Temperature can vary from about 80°C to 125°C. Products are isolated, . usually by partitioning in a solvent such as methylene chloride, chloroform or benzene and the like and a weak basic aqueous solution and washing, drying and concentrating the organic layer to give the free base which may . then be converted, if desired, to an acid addition salt in a conventional manner.
Alternate Method B is shown by equation in Chart Il. This reaction : may be carried out in a suitable snlvent such as tetrahydrofuran at room temperature for several hours. Prrpar tion and isolation of the fren base and a salt is typically described in F xz mple 4.
Alternate Method C is shown by equation in Chart... «..___. : suitable only when there is no other hydroxy radical present. .
Mesylation or tosylation with such as mesyl or tosyl chloride is conducted in the presence of an acid receptor such as a tertiary amine; e.g, triethylamine, while cooling. The final reaction of the mesylate or tosylate with the DO®M® is conducted in a suitable organic solvent and the product free base is isolated by conventional means such as washing, extracting with an acid solution and an organic solvent and evaporating the solvent. Salts may be prepared as described hereinabove.
Alternate Method D is shown by equation in Chart ITV. When the halo compound is reacted with the DO®M® compound, a suitable solvent is dimethylsulfoxide and a suitable temperature is about 25°C. When the halo compound is reacted with the H N-1) compound, excess HN. compound
R R may be used as solvent and a temperature of about 100°C or above is suitable.
Alternate Method E is shown by euqation in Chart V. The method is - limited to preparation of certain derivatives such as wherein D is 2-pyridinyl
Co or 2-quinolinyl. Dimethyl sulfoxide is a suitable solventand 80°Cisa + 70 suitable temperature for the reaction.
Method F is shown by equation in Chart VI, the method is limited to preparation of derivatives wherein (A){ is -O-R! and Rlis other than hydro- gen, from Formula I compounds wherein (A) is hydroxy. N,N-dimethyl- formamide is a suitable solvent and 80°C is a suitable temperature for the reaction. The reactant RX is advantageously used at about 10-100% excess to enhance desired product yield.
Method G is shown by equation in Chart VII, the method is limited to - preparation of Formula I compounds wherein (A)d is aminomethyl from
Formula I compounds wherein (A)d is cyano, tetrahydrofuran is a suitable solvent and 25-60°C is a suitable temperature for the reaction.
Method H is also shown by equation in Chart VII, the method is limited to the preparation of Formula I compounds wherein (A)d is -C(0)-OH from compounds of Formula I wherein (A)d is cyano, ethanol is a suitable solvent, and 78°C is a suitable temperature for the reaction.
Method I is shown by equation in Chart VIII, the method is limited to no 26585
I the preparation of compounds of Formula I wherein (Ad is loweralkyl-C-O- from compounds wherein (A){ is hydroxyl, by reaction of the desired hydroxyl compound with an appropriate acid anhydride. Methylene chloride isa suitable reaction mixture solvent and room temperature is a suitable temperature to carry out the reaction. 5
C30 a 35 i
CHART1
Preparation of Compounds nf Formula I:
Method A. (A)
Ar | d -
SC e=m== (Qin === . ‘ H + "X-(CH,}n-(BY;-D (He o
R
Acid Receptor, eg,
Solvent, e.g., Na,CO,, butanol, DMF, NaHCo,, etc. K,CO, + KI Catalyst {optinnal) (A)
Ar_ | d .
Ss @nee ’ N-(CH)m@-0-D (CH,e b
R
Optionally when
A=0H and n=1zero
H*, . A
Ar ~cC aznk ‘ ‘ N - (CH, m-(B)z-D (CH,e F 3 y p
R
*X = halide
CHARTII
Alternate Preparation of Compounds of Formula I:
Method B.
Ar UH (R = Ar, nof (Q)p is zero) \ _ (CH yp (B),-D
Ar y p
H,, Pt : : Ar . > NACH)m-(BY, D
Ar _ J + -\ / ( . H+ - (CH, -(B),-D + 2A1 MgX . )
EtO,C p qu \ ’ Ar—(C : [ N -(CH,)m-(B);-D *X = halo Ar /\ p v
CHART II :
Alternate Preparation of Compounds of Formula U:
Method C. (A)
Ar__ | d ;
C==mes (Qin === i -(CH,)m-OH when no other {CH,)e ) hydroxyl is
R p present
WNT 4 acid receptor . (A)
Ar | d : 0) a ci ko - _O.S-W* (CH e 2m os
R p 0 (A) / won
Ar__ | d n tee
Gen NC CHImOD (CH,)e vm )p
R .
Footnotes: *X = hale. **W = mesyl], tosyl, etc. *+¢M = alkali-metal ion.
CHARTI1V
Alternate Preparation of Compounds of Formula I:
Method D. (A)
Ar | d
Gem ===7 N (CH OD . py LTH Im U- (CT e J
R p
DOSMB eo (A)
Ar | d
TSC ===22 (Qin === -(CH);m-X* (CH,e ) 1
R P 1
A n (A)
Ar_ | d R! . } TSC a====(Q), === \ . i ’ N -(CH,\n-N-D (CH,)e ) *X = halo R : : p **M = alkali-metal ion.
CHARTYV
Alternate Preparation of Certain Compounds of Formula:
Method E. (A)
Ar] d
C=====(Q)p ===5 i " (CH m-0OM®. (CHje , )p
R
NN Kore N Xeoe (A)
Ar] d oo Ce C=====(Q)n ==" bee . eee i " A(CH,Jm-0- Das (CH,)e )
B p *M® = alkali-metal cation . **D = pyridin-2-vl or quinolin-2-yL. **+X = halo (Br, Cl).
CHART VI :
Method F.
Certain compounds of Formula [ wherein (A)q is hydroxyl may be converted to compounds of Formula I wherein (A)q is -O-R! when desired (when no other hydroxyl is present), as is illustrated by the following equation:
OH
Ar_
I (CH,)m-(B)z-D (Cte - 2)m-{D)z-
R P :
NaH
R'X* (X* = halogen) \
R! DMF 0
Ar
Gres Qa N- (CH) (B)z-D * (CH.)e 7m z
R Pp
R!is not hydrogen, and R1X is reacted in about 10-100% molar excess.
When Rl is phenyl or phenyl loweralkyl, phenyl substitution is restricted to electron withdrawing groups, e.g., nitro radicals.
CHART VII
Method G.
Certain compounds of Formula I wherein (A){ is aminomethyl may be prepared via compounds of Formula I wherein (A)d is cyano, and is illustrated by the following equation;
N
Il
Cc : Ar_
DD N (CH mB); D (CH,e me
R 'p
NH, .
LiAIH,
CH,
Ar_ “SC as=es (Qn ===3 | -(CH)m-(R)z-D (CH))e y
R p
Method H.
Certain compounds of Formula I wherein (A){ is cyano, may be v hydrolized to compounds wherein (A)d is -C-OH, as illustrated by the following equation: i
C
Ar_ geese @n=s (CH,)m-(B)z-D (CH,)e / Tm )
R p 0 | 1. KOH, H,0,A
I 2. H+
C-OH
Ar_ gress @n== N - (CH,)m-(B)y-D (CHye , crm
R p
CHART VII
Method I. 0 1
Certain compounds of Formula I wherein (A)d is R1-C-O- may be prepared from compounds of Formula I wherein (A)d is hydroxyl when desired, as is illustrated by the following equation:
OH?* :
Ar_
Cams (Qin ress -(CHy)y-(B)z-D (CH,)e rm ] )
R p 0 Oo i 16 | ¥ R'C-O-C-R'* * 5 oo | Ar
LL I (CH m-(B)z-D ; : (CH,e rma
J i )p ’ R - *No other hydroxyl present ** R!is loweralkyl : 25
To prepare acid addition salt, the free base is reacted with the calcu- lated amount of organic or inorganic acid in aqueous miscible solvent such as ethanol or isopropanol, with isolation by concentrating and/or cooling, or the base is reacted with an excess of the acid in aqueous immiscible solvent such as diethyl ether or isopropyl ether, with the desired salt separating directly.
Exemplary of such organic salts are those formed with oxalic, maleic, fum- aric, benzoic, ascorbic, pamoic, succinic, methanesulfonie, acetic, propionic, tartaric, citric, lactic, malic, citraconic, itaconic, hexamie, p-aminobenzoic,
glutamic and stearic acid and the like. Exemplary of such inorganic salts are those formed with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids.
To prepare quaternary salts the free base of a formula I compound may be reacted with a loweralkyl halide, preferably methyl iodide or methylbro- mide, or may be reacted with a loweralkyl sulfate, preferably methyl sulfate.
If desired, the free base may be regenerated by proportioning the acid addition salt between an organic solvent such as methylene chloride and a weakly basic aqueous solution of, for example, sodium bicarbonate and separating the methylene chloride layer and evaporating it.
Precursors (Chemical Intermediates) used in the synthesis of compounds of Formula I are prepared in a number of ways as illustrated by the following 1 to 13 sets of equations which are also applicable to pyrrolidinyl and homopiperidinyl derivatives. (See also U.S. Patents 3,922,276 and 3,956,296). \
? oH 0
ArMgX I
NO)-¢oee —5 KO)-c an ArMeX | NO) Ear
He PAC HI, HOAC, A * H,. Pd/C
HOAC, 25° 10AC, HCI ST or a NO cian,
H,, Rhodium/ Al
HOAC, 90°C . H.. Pd/C
HOAC, A
OH
[ HI, P, HOAC a :
HN Ar, STAT T= HN -CH Ar,
HS, A
Ar H,, Pd/C
HN Y=C HOAC, A ’ ~
Ar (2) ax co CX phoH,N (X = Cl, Br) To 0.5 [vex / HI OH . PhCH,N ferrari. v ' {onan — PRIN Cr ' A rae
H,, Pd/C or
HN »C.Ar,
HDA
H,; Pd/C: HOAC: A ~~ Ar
HN —CHAr, or HI, P,HOAC: A HN zc” ( N
Ar
H.: 1 AC; HCI
Ph = phenyl. HOAC: A '
Hy cot PhSO,CI PhSOyN )}-CO,Et
Pyridine
MgXAr J
OH LiAll
Ar aM OH ay cl Fhe mo Jean Tug ha ~-I\Ty
Ar A AN
HI, P,HOAC,
HI, P, a
HOAC, A
HN )-CHAr, (4) — nN cok HO. om )-comu,
Arnie
Ar HCI, H,0 OH : - mms r— . HN T.,. A crn Can \ : HI, P, HOAC HN “HAT, (5) 0 ;
Ar-H ..Pd/
XO)-Ln Ho. XO)-cn Ar, H2PYC oun cua,
H HOAC or
H® alcohol : (6) on
HN 0,Et + D-O-(CH,)m-X —» D 0 (CH,)m-N CO,Et
X = Cl, Br ArMgBr (2 fi
Ar — OH / H,S0, /
D-O-(CH,)m-N =C tt —— D.O(CHIm N ~C.Ar, “Ar Nee.
H,, Pd/C / ee D.O-(CH.)m- Y-C- :
HOAC D-0-(CH.)m N C-Ar,
Ph = phenyl.
~, -23. ™ R Ar :
O=H cu eit . — RACHM: Ci
O CHOH eT In
N RArCHCOW _— O + N *M — ®
So —tWRAC—CH, @H® ,, Pt.
O cu,
N R Ar ( ) NS ©) CH
N i *M®Ocy, CHO
Strong base,
O e.g., BuLi
N I
1) and 2) H
In sequence | H* A 1) R-COAr ' 2) H ! R GH Ar R Ar
NL NS
C g
OH i
ROTA : CH, i.
C
! H® A
CH, H,, Pt 0) — 0) rr . .
QO ! I
H H
N H,. Pd
ALP | (high pressure, a .
R_ " Ar H,, Pd, A H high temp.)
To AN A
CH, CH
CH
© H,, Pt 2 -- TTTe— — “N ~~ T—— : “~ ‘MP = 1Li®or MgBr ® hy
AM ’ ? Ms
HCH=( N Ph-0-C-Cl_ NaOH HCH=( N-H
Ar” A" TTT Ar”
Cie oP
Pt 0) Base _ LLL a HCI
Ww SN “NT .
N N N RE
Ph Ph Ph . : Pon. ATi (ro vo 0 Ar
Ar 1
CH-C-H { H / 2
Ar Pt
Ar ~ cro, CHCH NH
Ar
H,,
Pt
Ar NaOH
CHCH,OH* 7
Ar 0 fl
PCJ, Ph-0O-C-Cl
Ph — —\
Ar PPh Ar N° “CHCH,Cl ——2» Base, CH-C=PPh, ————
A / Ar” r H
Ar *Commercially available A ener <
Ph = phenyl r Ph
N
-25. 9) (pa
Ar—(C===== (Qn =====¢ {
H + X-(CH,)p-OH
He Y
R fd
Ar—C===2=(q) = )
Wn (CH pm OH
X = halo. (ie )p
R
N
]
C
(10) 0 (CHp)g-O-S.R (CHan-C- ~<O)- M:
I
0 . 1 CL
P N > N
Na-C-( F) \ lO)
C l 0 :
N Ci & 0-H
RN
=0,1 " (CH,)n-C- ~O) Pn,
H,0, NaOH or H®
C=0 0 ; (CH,)n-C- ~O)- F),
I = phenyl
H
. N * -26- (11) H Li® o
Ar—C—(A)g* - Ar—C— (A) lithium dipropylamine (Hine (CH)e
R : (Md (Ma ~\ wl on ~~“ Arg Jen
H/Pd io " Li " =
R 0 0 R :
Il ] *(A)d is -C-O-R! or -C-R! » Bie td ne Tan eed ae aR Ph = phenyl A vist y Coach ae Le Lo med thew WO :
Ts = tosyl (12) 0 { i )p + R-CH,-MgBr
OH
ArC {js
Hs p
HI R
HOA, NA
A
© QOH popu en ned
CH, Pp cw, ‘Pp
R b
(13) N fH : i
Ar—CH {J
P
Butyllithium
N R-CH,Br fn i i
Are — _ 0 ! 7 J N I Ar—C NH - ) Ph C1 C-O-Ph NaOH
CH, p ——— —— )
H,0 {He p
R R
The method of preparation of certain starting materials wherein D is phenyl substituted by hydroxy is illustrated by the following equation:
OH OH
Na,CO,
HO O C— CH, + Br(CH,)n-ClI Cl(CH,YO C— CH, i I 0 0
The preparation of other hydroxyphenyl intermediates and compounds isillustrated by the following equation: »
OCH, @
OCH, ¢
Cl- (CHp)m-Cl O(CH,)mCI
Na l asin
Chart
OCH. oH 2
H,,
Pd/C OH ' 2 & = phenyl.
The preparation of certain substituted phenol starting materials is illustrated by the following equations: sano{O)- NH, (1)CISO,CH, ys NHSO,CH, . ’ mere fin. . 0 i (2)CH,N=C=0 en, nb son, : ——— 0 0 . . " Il (3) CI-C-OEt weno {O) y-snbon — - | Pd/C
H, (1) 10-{O y-wsacn, 0 n (2) 0={() =r sen
ST 9 & = phenyl. @ Ho —{ (_) > NHC-OEt
: : ~ 29.
The preparation of chemical intermediates is further illustrated in the following Preparations 1 to 192, Examples 1 to 232 illustrate the synthesis methods for preparing compounds of Formula I. The scope of the invention is not limited by the descriptive methods and procedures of the preparations and examples, however. ! : ‘
Preparation 1 4-Diphenylmethylenepiperidine.
A solution of 7.0 g of 1-acetyl-4-diphenylhydroxymethylpiperidine in 30 ml of absolute alcohol and 76 ml of concentrated hydrochloric acid was heated at reflux for seven hours, cooled and made basic with 50% sodium hydroxide. The oil which separated was extracted with benzene and the combined extracts washed with water. After drying over magnesium sulfate the solvent was evaporated at reduced pressure. The residual oil which crystallized on cooling was recrystallized twice from petroleum ether to give 4.0 g (73.0%) of white crystals, m.p. 85-86°C.
Analysis: Calculated for CygH1gN: C, 86.70; H, 7.68; N, 5.62
Found + C,86.70; H, 7.83; N,5.73
Preparation 2 [a,a-Bis(p-fluorophenyl)}-4-pipeidinemethanol hydrochloride hydrate {1:1:0.5].
This compound was prepared by the method described in Preparation 1 of U.S. Patent 4,032,642, m.p. 243-243.5°C from the Grignard reagent formed with p-fluorobromobenzene and 1-acetyl-4-(p-fluorobenzoyl)piperidine followed by hydrolysis and conversion to the salt.
Preparation 3 1-(Phenylmethyl)-4-piperidinecarboxylic acid ethyl ester hydrochloride
A mixture of 100 g (0.637 mole) of ethyl isonipecotate, 80.64 g (0.64 mole) of benzyl chloride and 67.84 g (0.64 mole) of sodium carbonate in 1 liter of absolute ethanol was refluxed for 8 hours and then was stirred at room temperature for 10 hours. The solvent was removed in vacuo, and the residue was partitioned between methylene chloride and dilute sodium hydroxide.
The methylene chloride phase was dried over magnesium sulfate, and the solvent was removed in vacuo to give the free base of the title compound as a liquid. The free base was converted to the hydrochloric acid salt, and the salt was recrystallized from ethanol-ether to give 89.33 g (49.7%) of white crystalline solid, m.p. 154-155°C.
. ~N -31-
Analysis: Calculated for CjsH2oNO2Cl: C, 63.48; H, 7.81; N, 4.94
Found : C,63.07;H,7.82;: N,4.91 .
Preparation 4 a,0-Bis-(4-fluorophenyl)-1-(phenylmethyl)-4-piperidinemethanol.
To a 6.08 g (0.25 mole) of magnesium turnings and an iodine crystal in 600 ml of dry tetrahydrofuran and under an atmosphere of nitrogen was . added, dropwise, a solution of p-bromofluorohenzene in 125 ml of tetrahydro- furan. The temperature of the reaction was kept below 10°C by cooling in an ice-methanol bath. The mixture was stirred at room temperature for 1.5 hours. A solution of 24.7 g (0.10 mole) of 1-(phenylmethyl)-4-piperidine- carboxylic acid ethyl ester hydrochloride in tetrahydrofuran was added, and the mixture was stirred at room temperature for 17 hours. The reaction was poured into an icy, aqueous solution of ammonium chloride, and the resulting solution was extracted with methylene chloride. The methylene chloride solution was extracted with dilute sodium hydroxide and was dried over magnesium sulfate. The solvent was removed in vacuo to give an oil. This was crystallized from ether-hexane to give 19.87 g (51%) of the title compound, m.p. 113-115°C.
Analysis: Calculated for CosHo5NOF9: C, 76.31: H, 6.40; N, 3.56
Found : C,76.24; H,6.38; N, 3.50
Preparation 5 [a.a-Bis(p-fluorophenyl)]-4-piperidinemethanol.
A solution of 31.2 g (0.079 mole) of a,a-bis-(4-fluorophenyl)-1- (phenylmethyl)-4-piperidinemethanol in 400 m] of absolute ethanol was hydrogenated at 50 psi and 70°C over 5% palladium on carbon over the weekend. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a gum as residue. Methylene chloride was added to the residue, and the gum crystallized. The mixture was diluted with petroleum ether, and the solid was collected by filtration, washed with petroleum ether, and dried to yield 22 g (92%) of white solid which was : recrystallized from 2-propyl ether/2-propanol, m.p. 159.5-160.5°C.
Analysis: Calculated for C gil gF3NO: C, 71.27; H, 8.31; N, 4.62
Found : C,70.93;H,6.71; N, 4.38
Preparation 6 . 1-(Phenylsulfonyl)-4-piperidinecarboxylic acid, ethyl ester.
To a solution of 10.1 g (0.0642 mole) of ethyl isonipecotate in 300 ml of pyridine and cooled in an ice bath was added 13.2 g (0.075 mole) of benzene sulfonyl chloride. The mixture was stirred for 2 hours at room temperature, and the solvent was removed in vacuo. The residue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene chloride solution was dried over magnesium sulfate, and the solvent was removed in vacuo to give a solid. This was recrystallized from ethanol-ether to give 4.59 g (24.1%) of crystalline solid; m.p. 85-86.5°C.
Analysis: Calculated for C14H19NO4S: C, 56.55; H, 6.44; N, 4.71
Found : C,5653;H,6.55N, 4.67
In another preparation, 100 g (0.634 mole) of ethyl nipecotate and 130.4 g (0.74 mole) of benzene sulfonyl chloride were reacted by the above procedure for 4.5 hrs to give the title product in 78.1% yield.
Preparation 7 a,a-Bis(4-fluorophenyl)-1-(phenylsulfonyl)-4-piperidinemethanol.
To a suspension of 33.78 g (1.39 mole) of magnesium trimmings in 1 liter of tetrahydrofuran (dried over molecular sieves 5A) under an atmo- sphere of nitrogen and cooled in an ice bath was added dropwise a solution of 243.25 g (1.39 mole) of p-bromofluorobenzene in 150 ml of tetrahydrofuran.
The mixture was stirred for 2 hr after the addition was completed. To this mixture was added 103 g (0.346 mole0 of 1-(phenylsulfonyl)-4-piperidine- 25 . carboxylic acid ethyl ester as a solid, and the solution was stirred at ambient temperature for 5 hr. The reaction mixture was poured into an icy aqueous solution of ammonium chloride. The phases were separated, and the solvent was removed in vacuo from the organic phase. The residue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene chloride solution was dried over magnesium sulfate and was reduced in vacuo to =1 liter volume. The title compound was obtained by adding hexane and cooling, recrystallizing the precipitate from ethyl acetate and hexane and drying the solid under high vacuum at 130°C for 45 min at which time the product had partially melted. m.p. 142.5-144°C.
\ -33-
Analysis: Calculated for Co4H23NO3SFa: C, 65.00; H,5.23; N, 3.16
Found : C,65.21; H,5.30;N, 3.10 .
Preparation 8 4-[Bis(4-fluorophenyl)methylene]-1-(phenylsulfonyl)piperidine.
A solution of 5.23 g (0.0118 mole) of a,a-bis(4-fluorophenyl)-1- (phenylsulfonyl)-4-piperidinemethanol in 100 ml of acetic acid and 20 ml of 2M sulfuric acid was refluxed for 2-1/2 hours and then poured over ice. The mixture was made basic with 50% sodium hydroxide, and the basic mixture was extracted with methylene chloride. The methylene chloride solution was dried (anhydrous sodium sulfate), and the solvent was removed in vacuo. The residue was recrystallized from ether-hexane to give 3.23 g (64.4%) of white crystalline solid, m.p. 90-92.5°C.
Analysis: Calculated for C24H21NO2SFo: C, 67.75; H, 4.98; N, 3.29
Found : C,67.73; H,5.00; N, 3.21
Preparation 9 4-[Bis(4-fluorophenyl)methylene]piperidine hydrobromide [1:1].
A mixture of 164 g (0.342 mole) of a,a-bis(4-fluorophenyl)-1- (phenylsulfonyl)-4-piperidinemethanol and 80 g (0.85 mole) of phenol in 700 co ml of 48% hydrobromic acid was refluxed for 7 hr and then was stirred at room temperature for 9 hr. The hydrobromic acid solution was decanted from
I a gum in the bottom of the reaction flask. The gum was triturated with ~1 yt 25 liter of ether, and a tan solid formed. The solid was washed with several oo portions of ether and was dried under high vacuum to give 9.13 g (73%) of : slightly impure title product, m.p. 211-215°C. A small sample of this solid . . | was recrystallized from methanol to give an analytically pure sample asa : crystalline solid; m.p. 216-218°C. - C30 Analysis: Calculated for CigH1sNBrFy: C, 59.03; H, 4.95; N, 3.82
Found : C,58.96;H,4.98;N, 3.76
Preparation 10 4-(Bis(4-fluorophenyl)methyl piperidine fumarate hydrate [1:0.5:0.5]. © 35 - A mixture of 30.6 g (0.99 mole) of phosphorous and 15.1 g (0.059 mole) nf : iodine in 90 ml of glacial acetic acid was stirred for 20 nin at room tempera-
ture. A mixture of 6 ml of water, 70 ml of methanesulfonic acid, 56.19 g (0.197 mole) of 4-[bis(4-Mluorophenyl)methylene)piperidine and 110 ml of glacial acetic acid was added, and the mixture was refluxed for 7 hr. The solvent was removed in vacuo, and the resulting viscous liquid was poured over ice. The icy mixture was made basic with 50% sodium hydroxide, and the basic suspension was extracted with methylene chloride. The methylene “chloride solution was extracted with an aqueous solution of sodium thio- sulfate and was dried over anhydrous sodium sulfate, and the solution was filtered through Celite®. The solvent was removed in vacuo to give a gum.
The gum was dissolved in 400 ml of hot methanol, and 4.25 g of an unknown tan solid was collected from the warm solution. Fumaric acid (22 g, 0.190 mole) was added to the methanolic solution followed by the addition of ether.
A white precipitate was collected to give 22.55 g (32.3%) of crystalline solid; m.p. 208-209°C.
Analysis: Calculated for C2oH22NO2 5F2: C,67.78; H,6.26; N, 3.95
Found : C,67.86;H,6.12; N, 3.81
Preparation 11 4-[a-(p-Fluorophenyl)-a-phenyl}methylpiperidine hydrochloride [1:1].
This compound was prepared as described in U.S. Patent 4,032,642 by hydrogenation of a-(p-fluorophenyl)benzylidinepiperidine over palladium charcoal catalyst, m.p. 81-82°C.
Analysis: Calculated for C3gHg CIFN: C, 70.69; H,6.92;N, 4.58
Found : C,70.69:H,6.93; N, 4.52 : Preparation 12 1-[4-(3-Chloropropoxy)-3-methoxyphenyllethanone.
To a mixture of 15.15 kg (96.26 mole) of 1-bromo-3-chloropropane and 25 liter of water heated to 86°C was added a solution of 8 kg (48.13 mole) of acetovanillone in 3.93 kg (48.6 mole) of 50% aqueous sodium hydroxide and 89 liter of water over a 2.5 hr period. The mixture was heated at 80-85°C for 2.5 hr after addition was complete. The mixture was cooled and extracted twice with 49 kg portions of toluene. The combined extracts were washed once with 1.9 kg of 50% sodium hydroxide diluted to 5 gal, and once with 5 gal of water. The toluene layer was dried over 3 1b of anhydrous sodium sulfate and concentrated under reduced pressure. The residue was heated to reflux in 15 gal of diisopropylether, filtered, and the filtrate cooled. The crystallized ; title compound obtained by filtration together with additional compound obtained by concentrating the filtrate to 25% of its original volume amounted to 4.2 kg (36%). Acetovanillone recovered was 3.4 kg. The product was recrystallized twice from cyclohexane and twice from ligroin, m.p. 57.8- 58.5°C. : Analysis: Calculated for C12H15C103: C, 59.39; H, 6.23
Found : C,59.07; H,6.22 - 10
Preparation 13 1-(3-Phenoxypropyl)-4-piperidinecarboxylic acid ethyl ester oxalate
A mixture of ethyl isonipecotate (35.5 g, 0.226 mole) 3-phenoxy-1- bromopropane (51.6 g, 0.24 mole) and sodium carbonate (25.4 g, 0.24 mole) in 500 ml of absolute ethanol was refluxed for 16 hr. The solvent was removed oo in vacuo, and the residue was partitioned between methylene chloride and dilute sodium hydroxide. The solution was dried over anhydrous sodium sulfate and the solvent was removed in vacuo to give a liquid. The liquid was dissolved in absolute ethanol, and a solution of oxalic acid (~0.23 mole) in absolute ethanol was added. The product 73.43 g (87.7%) precipitated asa white, crystalline solid, m.p. 180-181.5°C.
Analysis: Calculated for C;gH27NO7: C, 59.83; H, 7.14; N, 3.67 26 Found : C,59.76:H, 7.17; N, 3.64
Preparation 14 4-[Bis(4-fluorophenyl)methylenel-1-(phenylmethyl)piperidine maleate
A mixture of a-a-bis(4-fluorophenyl)-1-(phenylmethyl)-4-piperidine- methanol (5.09 g, 0.013 mole) in 200 ml of acetic acid and 10 ml of 2M sulfuric acid was refluxed for 2 hr. The solvent was removed in vacuo, and the residue was partitioned between methylene chloride and dilute sodium hydroxide. ~The methylene chloride solution was dried over magnesium sulfate and the : solvent was removed in vacuo to give the free base of the title compound as a solid. The free base was dissolved in methanol-diethylether and maleic acid
(excess) was added. The product (5.24 g, 82.1%) precipitated as a white, crystalline solid, m.p. 180-181.5°C. .
Analysis: Calculated for CogH27NF204: C, 70.86; H, 5.54; N, 2.85
Found : C,70.80;:H,545:N,2.79
Preparation 15 a-a-Bis(4-fluorophenyl)-4-pyridinemethanol.
The Grignard reagent was prepared from 4-bromofluorobenzene (66.6 g, 0.381 mole) and magnesium (9.13 g, 0.381 mole) in tetrahydrofuran (ice bath). The Grignard reagent was stirred at room temperature for 1.5 hr and transferred (under nitrogen) to an addition funnel. This solution was added dropwise to a tetrahydrofuran solution of ethyl isonicotinate (25.0 g, 0.165 mole) (ice bath cooling). The reaction mixture was stirred 3 hr at room temperature and poured onto ice containing ammonium chloride (28 g, 0.5 mole). The mixture was allowed to stand overnight. The reaction mixture was diluted to 3 liter with water and extracted with chloroform. The chloroform layer was back extracted with dilute sodium hydroxide. Removal of chloroform gave a gummy brown solid. The brown solid was triturated with methanol-diethyl ether (10-120 v/v) and placed in the refrigerator freezer. Solid was filtered off and dried overnight in vacuo at 80°C to give 11.86 g (24%) of white crystalline product, m.p. 185-189°C
Analysis: Calculated for CygH13NOFg: C, 72.72; H,4.41; N, 4.71
Found : C,72.76: H,4.39;: N, 4.67
Preparation 16 4-[Bis(4-fluorophenyl)methyll-1-(phenylmethyl)piperidine, furnarate
A mixture of 4.3 g (0.139 mole) of phosphorous, 44 g (0.196 mole) of a 75% aqueous solution of hydrogen iodide and 4.15 g (0.0106 mole) of 4-[bis(4- fluorophenyl)methylenel-1-(phenylmethyl)piperidine in 60 ml of glacial acetic acid was refluxed for 1 hr. The mixture was poured over ice and was made basic with 50% sodium hydroxide. The aqueous mixture was extracted with methylene chloride. The methylene chloride solution was extracted with an aqueous solution of sodium =ulfite and was dried over magnesium sulfate. The solvent was removed in vacuo to give 3.89 g (89%) of the free [J base of the title compound. The free base was converted to the fumarate salt, and the salt was recrystallized from methanol-ether to give 3.62 g (69.3%) white solid; m.p. 201-202°C.
Analysis: Calculated for CogHogNO4F9: C, 70.57; H, 5.92; N, 2.84
Found : C,70.69; H,5.95;N, 2.81
Preparation 17 4-(2-Chloroethoxy)benzoic acid ethyl ester.
A mixture of 71.7 g (0.5 mole) of 1-bromo-2-chloroethane, 83.1 g (0.5 mole) of ethyl p-hydroxybenzoate and 69.1 g (0.5 mole) of potassium carbonate in 200 ml of acetone was heated at reflux for 40 hr, The solids were removed by filtration and the filtrate was evaporated under reduced pressure to leave a semi-solid residue. The residue was triturated with 200 ml of 5% sodium hydroxide solution and filtered.! The filter cake was washed with water (100 ml) and dried to give 42.4 g (80%)2 of a solid. A sample was recrystallized from benzene-petroleum ether (30-60°C) to give white solid, - m.p.74-76°C.
Analysis: Calculated for C;;H;3C103: C, 57.78: H, 5.73
Co | Found : C,57.87;H,5.82 oo ~~ The filtrate pH was adjusted to 2 with concentrated hydrochloric acid. The oo oo - resulting solid was collected by filtration, washed with water (100 ml) and - dried to give 44.4 g of ethyl p-hydroxybenzoate. wo 2The yield is based on unrecovered starting material.
I
: Preparation 18 1.[4-(2-Chloroethoxy)-3-methoxyphenyllethanone. oo To a solution of 12.7 g (0.55 mole) of sodium metal in 750 ml of absolute ethanol was added 83.1 g (0.5 mole) of acetovanillone to give a slurry. This slurry was then added over a 3-hr period to a solution of 107.6 g (0.75 mole) of 1-bromo-2-chloroethane in 500 ml of absolute ethanol at reflux. An addi- tional 250 ml of ethanol was used to wash the slurry into the reaction mix- ture. The mixture was heated at reflux overnight and then concentrated under reduced pressure to give a solid as residue. The solid was partitioned between 1 liter of benzene and 1 liter of water. The aqueous layer was extracted with 500 ml of benene and the combined organic layers were washed successively with three 200 m} portions of a 5% sodium hydroxide solution, once with water and once with brine. The benzene solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give an oil which gradually crystallized. The solid was triturated with petroleum ether, collected by filtration and recrystallized from 2- propanol to yield 48.5 g (42%) of off-white solid. An analytical sample was prepared from isopropyl ether, m.p. 69-71°C.
Analysis: Calculated for C11H13C103: C, 57.78; H,5.73
Found : C,57.55;H,5.74
Preparation 19 1-{4-(4-Bromobutoxy)-3-methoxyphenyllethanone. ~ To a warm solution of 12.7 g (0.55 mole) of sodium metal in 500 ml of absolute ethanol was added a slurry of 83.1 g (0.5 mole) of acetovanillone in . 250 ml of absolute ethanol. All solids dissolved and then a solid precipitated.
The mixture was stirred at.ambient temperature for 1 hr and.then added over . a 3-hr period to a solution at reflux of 177 g (0.82 mole) of 1,4-dibromobutane in 500 ml of absolute ethanol. After addition was complete, the mixture was heated at reflux overnight. The mixture was concentrated under reduced pressure, and the residue was partitioned between 1.5 liter of benzene and 1 liter of water. The mixture was filtered to remove undesirable insoluble material. The filtrate layers were separated, and the organic layer was washed with four 300 m! portions of a 5% sodium hydroxide solution, once with water, and once with brine, dried over anhydrous sodium sulfate and : concentrated under reduced pressure to give 138 g of gummy solid as residue.
This solid was purified by column chromatography on 1 kg of silica gel, eluting with 2% ethyl acetate in benzene to yield 69.6 g (46%) of title compound as an off-white solid. The solid was recrystallized from isopropyl ether, m.p. 52-54°C.
Analysis: Calculated for C13H17BrO3: C,51.84; H,5.69
Found : C,52.03;H,5.76
Wn) -39-
Preparation 20 4-(Diphenylmethyl)pyridine. : : A mixture of 99 g (0.379 mole) of diphenyl-4-pyridylmethanol, 50 ml of conc. hydrochloric acid, 200 ml of 57% hydroiodic acid and 200 ml of glacial : 5 acetic acid was refluxed for 4-1/2 hr and then was stirred at room tempera- ture for 12 hr. The reaction mixture was poured over ice and was made basic with 50% sodium hydroxide. An aqueous solution of sodium thiosulfate was added, and the mixture was extracted with methylene chloride. The methylene chloride solution was dried over magnesium sulfate, and the solvent was removed in vacuo. The residue was recrystallized from a mixture : of methylene chloride-ether-hexane to give two crops of crystalline solids:
Crop1, 40.87 g (44.0%), m.p. 124-126°C; Crop II, 25.38 g (27.3%), m.p. 123- 125°C. Analysis of the mixture of the Crops J and IT was as follows:
Analysis: Calculated for CigH sN: C, 88.13: H,6.16;N,5.71
Found : C,87.67;H,6.01;N, 5.56 - Preparation 21 1-(3-Chloropropoxy)-4-methoxybenzene.
A solution of sodium hydroxide 20.0 g (0.5 mole) in 300 ml of water and p-methoxyphenol, 62.1 g (0.5 mole) in 300 ml of dioxane was stirred for 1 hour at room temperature. 1-Chloro-3-bromopropane (472.35 g, 3.0 mole) in 100 ml of dioxane was added, and the reaction mixture was stirred overnight at 80°C. The lower layer was separated, and the aqueous layer extracted with hexane. The lower layer and hexane layer were combined, dried, and solvent was removed in vacuo. The residue was dissolved in chloroform and extracted with 5% sodium hydroxide; removal of chloroform by evaporation gave a yellow oil. A 10-g sample of the oil was subjected to column chromato- graphy on silica gel with an elution'series composed of hexane-methylene chloride-methanol. This furnished 9.64 g (79.3% based on the aliquot taken) of pure clear oil.
Analysis: Calculated for C1gH1302Cl: C, 59.86; H, 6.53
Found : C,59.39;H,6.56 | :
\ -40-
Preparation 22 1-[4-(3-Chloropropoxy)phenyljethanone. ‘
The sodium salt of p-hydroxyacetophenone was prepared in 200 ml of dioxane-400 ml of water from p-hydroxyacetophenone (68.08 g, 0.5 mole) and sodium hydroxide (20.0 g, 0.5 mole). The reaction mixture was stirred 3/4 hr at room temperature. Next, chlorobromopropane, (472.35 g, 3.0 mole) was added along with 200 ml of dioxane, and the mixture was heated at 80-90°C overnight with stirring. The mixture was diluted to 4 liters with water; the aqueous phase was extracted with hexane and chloroform. These were com- bined and back extracted with 5% sodium hydroxide. The solvent was removed in vacuo with heating. A 10-g sample of the oil was subject to column chromatography on silica gel using hexane-methylene chloride- methanol. Fractions with similar TLCs were combined, and solvent re- moved. The oil from the column did not analyze, therefore a short-path bulb-
Co 15 bulb distillation was carried out. This produced 4.38 g (37.9%) of clear oil.
Analysis: Calculated for C;1H;302Cl: C, 62.12; H, 6.16
Cena ives Found : ~~. t+ GC,6170;H,6.17 ~~ 0 1 1H NMR (CDCl3) Analysis: §8.1 doublet aromatic portons 2H 5 6.8-7.0 doublet aromatic portons 2H : + 84.1-4.3 triplet CHgy 2H §3.6-3.8 triplet -CHo- 2H §2.5 singlet -C-CHz or COCH3 3H h 862-24 triplet -CHo- 2H
Preparation 23 4-(Diphenylmethyl)piperidine hydrochloride [1:1].
A mixture of 62.69 g (0.256 mole) of diphenyl-4-pyridylmethane and 6.4 g of 10% palladium on carbon (0.0060 mole) in 300 ml of glacial acetic acid and under an atmosphere of hydrogen (44 psi) was shaken on a Parr apparatus at 85° for 4 days. The reaction mixture was filtered, and the solvent was removed in vacuo from the filtate. The residue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene
. \ 41- chloride solution was dried over magnesium sulfate, and the solvent was removed in vacuo to give a solid. This was dissolved in a mixture of ' methanol-acetonitrile, and excess ethereal hydrogen chloride was added. A precipitate was collected to give 59.13 g (80.3%) of slightly impure title compound as a white crystalline solid, m.p. 273-274°C. Part of this was recrystallized from methanol-ether to give an analytically pure sample, m.p. 275.5-277°C.
Analysis: Calculated for C1gH22NCl: C, 75.11; H, 7.70; N, 4.87
Found : C,75.03; H,7.73; N, 4.93
Preparation 24 a-(4-Fluorophenyl)-a-phenyl-4-pyridinemethanol.
To a suspension of 18.5 g (0.761 mole) of magnesium turnings and several crystals of iodine in 800 ml of anhydrous ether, cooled in an ice bath and under an atmosphere of argon, was slowly added a solution of p- bromofluorobenzene in 200 ml of ether. The solution was stirred for 2 hr at 25°C and 97.02 g (0.530 mole) of 4-benzoylpyridine was added as a solid. An ro a additional 1 liter of anhydrous ether was added, and the solution was stirred
IE at 25°C for 3 hr. The reaction mixture was poured into an icy, aqueous
Co 20 solution of ammonium chloride. The mixture stood in the hood overnight and
N So a white solid was collected. The solid was dissolved in a mixture of methanol eo methylene chloride. The solution was filtered and the solvent was removed \ Cy in vacuo. The residue was crystallized from chloroform-hexane to give 66.68 oo g (45%) of title compound as a white, crystalline solid, m.p. 189-192°C. Part oo 25 of this was recrystallized from methylene chloride-acetonitrile-hexane, m.p.
Lo . 190-192°C.
Analysis: Calculated for CjgH4NOF: C, 77.40; H, 5.05; N, 5.02 - Found Co C,77.24;H,5.03; N. 4.90
Preparation 25 a,a-Bis(4-chlorophenyl)-1-(phenylsulfonyl)-4-piperidinemethanol.
Following the procedure of Preparation 7, but substituting p- bromochlorobenzene for p-bromofluorobenzene, the title compound was : prepared. ,
Preparation 26 4-[Bis( 4-chlorophenylmethylene |piperidine hydrobromide hydrate
A mixture of 69.33 g (0.146 mole) of «.a-bis(4-chlorophenyl)-1-(phenyl- sulfonyl)-4-piperidinemethanol and 26 g (0.277 mole) of phenol in 400 ml of 48% hydrobromic acid was refluxed for 6 hr and then was stirred at room temperature for 10 hr. The reaction solution was decanted from a gum which had formed in the bottom of the reaction flask. The gum was washed with several portions of water and then was crystallized from ether to give a solid.
The solid was recrystallized from a mixture of methanol-diethyl ether to give 26.52 g (43.6%) of white crystalline solid, m.p. 106-109°C.
Analysis: Calculated for C18H20NBrCl20: C,51.83; H, 4.83; N, 3.36
Found . C,52.13; H, 4.62; N,3.38
Preparation 27 1-Chloro-4-(3-chloropropoxy )benzene.
A mixture of 77.2 g (0.60 mole) of p-chlorophenol, 189 g (1.2 mole) of 1- bromo-3-chloropropane, 249 g (1.8 mole) of anhydrous potassium carbonate, and 600 ml of acetone was stirred vigorously and heated to reflux for 16 hr
Co 20 "under a nitrogen atmosphere. The potassium carbonate was removed by . Wo "suction filtration, and the acetone and excess bromochloropropane were ro "* removed by heating under reduced pressure. The residue was dissolved in - oo petroleum ether, and the resulting solution was cooled in an ice-isopropyl alcohol bath to produce a white solid. The solid was collected by filtration and washed with cold petroleum ether. The filtrate was concentrated and cooled to yield two more crops of white crystals. The combined solids were dried under vacuum at ambient temperature to yield 107 g (87%) of white, flaky solid, m.p. 35-36°C.
Analysis: Calculated for CgH100Cl2: C,52.71; H, 4.92
Found . C,52.99;H,4.87
Preparation 28 4-(3-Chloropropoxy)benzoic acid methyl ester.
Ethyl 4-hydroxybenzoate 83.1 g (0.50 mole), 107 ml (1.0 mole) of 1- bromo-3-chloropropane, and potassium carbonate (1.5 mole, 207.3 g) were
A . -43- mechanically stirred in 600 ml of refluxing acetone under nitrogen over- night. The potassium carbonate was removed by filtration, and the filtrdte was evaporated under reduced pressure to give 122 g of a liquid. This liquid was dissolved in 250 ml of petroleum ether and with stirring and cooling in an ice/2-propanol bath. A white precipitate formed and was collected by filtration and washed with cold petroleum ether to yield 108 g of a solid. An additional 6 g of the product was obtained from the mother liquor. A small sample of the solid was dissolved in petroleum ether at room temperature.
The solution was stirred and cooled in an ice bath. White crystals were collected by filtration, washed with cold petroleum ether and dried under vacuum at room temperature, m.p. 24-25°C.
Analysis: Calculated for C19H;503Cl: C, 59.39; H, 6.23
Found : C,59.69;H,6.30
Preparation 29 1-(3-Chloropropoxy)-4-nitrobenzene. i
A mixture of 7.0 g (0.05 mole) of 4-nitrophenol, 15.7 g (0.1 mole) of 1- bromo-3-chloropropane and 20.7 g (0.15 mole) of anhydrous potassium carbonate in 350 ml of acetone was heated at reflux for 17 hr. The mixture | was cooled, filtered, and the filtrate was concentrated to give an oil which crystallized. The solid was collected by filtration, washed with petroleum ether, and dried to yield 10.1 g (94%) of the title compound. An analytical sample was prepared from ethyl ether-petroleum ether, m.p. 37-39°C.
Analysis: Calculated for CsH1gCINO3: C, 50.13; H, 4.67; N, 6.50
Found : C,49.95;H,4.71; N, 6.51
Preparation 30 4-(Bis(4-fluorophenyl)methyl]1-1piperidinepropanol oxalate - hydrate[1:1:1]. - :
A mixture of 10.67 g (0.0372 mole) of 4-(bis(4-fluorophenyl)methyl]- piperidine, 5.42 g (0.039 mole) of 3-bromo-1-propanol and 8 g (0.095 mole) of sodium bicarbonate in 400 ml of 1-butanol was refluxed for 21 hr. The solvent was removed in vacuo, and the residue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene chloride
Co 35 solution was dried over magnesium sulfate, and the solvent was removed in vacuo to give 8.88 g (67.3%) of oil, the free base of the title compound. A small sample of this oil was converted to the oxalate salt, and the salt was recrystallized from methanol-ether to give a white solid, m.p. 89-94°C.
Overall yield was calculated to be 75.1%. 8 Analysis: Calculated for C23Ha9NOgF2: C, 60.92; H, 6.45; N, 3.09 : Found : C,61.49;H,6.15;N, 3.03
Preparation 31 4-(3-Chloropropoxy)-3-methoxybenzoic acid methyl ester.
A mixture of 100 g (0.549 mole) of methyl vanillate, 172.8 g (1.1 mole) of 1-bromo-3-chloropropane and 228 g (1.65 mole) of anhydrous potassium carbonate in 1 liter of acetone was heated at reflux for 20 hr. The mixture was cooled, filtered, and the filtrate concentrated to give a white solid as residue. The solid was triturated with petroleum ether, collected by filtration, and dried to yield 137.8 g (97%) of white powder which was recrystallized from isopropyl alcohol, m.p. 104-105°C.
Analysis: Calculated for C12H15C104: C,55.71; H, 5.84
Found : C,55.87;H,5.94 \
Preparation 32 4-[Bis(4-methoxyphenyl)methyl]pyridine.
Anisole, 108.13 g (1.0 mole) was cooled in an ice bath. Concentrated sulfuric acid, 115.3 ml (2.0 mole) was added while stirring the mixture in an © ice bath. The temperature rose to 55°C. The reaction was then cooled in the ice bath. To this solution was added 4-pyridine carboxaldehyde, 53.5 g (0.5 - mole). The temperature rose to 95°C and further cooling and stirring brought . the temperature down to 20°C. The reaction mixture was heated at 70°C for 3-1/2 hr. The red gel was made alkaline with 50% sodium hydroxide-ice mix.
The alkaline phase was extracted with toluene and the toluene extracted : 30 with a saturated sodium chloride solution. The product crystallized from the toluene solution while standing at room temperature. The white solid can be recrystallized from hot hexane-isopropyl alcohol. : A small 2.2 g sample of the product was recrystallized from methylene ~ chloride-hexanes (1:9 v/v) and dried overnight at 80°C in vacuo. This
« | A ’ 45. furnished 1.08 g (48.6% yield based on the aliquot taken) of white crystalline product, m.p. 111.5-113.5°C. ’
Analysis: Calculated for CooH1gNOy: CC, 78.66; H, 6.27; N, 4.59
Found : C,78.14;H,6.24; N, 4.54 5 .
Preparation 33 4-[Bis(4-methoxyphenyl)methyllpiperidine hydrochloride hydrate
The precursor pyridine derivative 4-[bis-4-methoxyphenyl)methyl}- pyridine was prepared from the reaction of anisole and 4-pyridine carboxaldehyde in the presence of sulfuric acid.
To prepare the title compound, a solution of 4-[bis(4-methoxyphenyl)- methyl]pyridine (70.8 g, 0.232 mole) in 350 ml of acetic acid was hydro- genated with 5% palladium on carbon (7.08 g) for five hours with heat. The hydrogenation was continued overnight at room temperature. The reaction mixture was filtered and rinsed with methanol. The filtrate was stripped of oe solvent via a rotary evaporator, and the residue was partitioned between 5% ; oo Cy sodium hydroxide and toluene. The aqueous layer was back extracted with : SEE toluene. The organic layer was dried over anhydrous sodium sulfate and 200 filtered. Removal of solvent by means of a rotary evaporator gave 64 g - (88.6%) of white solid, the free base. The free base was then converted to the oo | * hydrochloride salt by dissolving it in methanol and treating with ethereal
Co ~- hydrogen chloride. The white solid was filtered off and dried overnight at 80°C in vacuo in the amount of 2.08 g, m.p. 132-135°C.
Analysis: Calculated for C20H2sNO3Cl: C, 65.65; H, 7.71; N, 3.83
Found : C, 65.63; H, 7.53; N, 3.90 ‘Preparation 34 4-[Bis(4-methylphenyl)methyl]piperidine hydrochloride [1:1). 30 . The free base of the title compound was prepared by hydrogenation of 4- [(bis-4-methylpenyl)methyl]pyridine in acetic acid using palladium on carbon as catalyst and converted to the hydrochloride salt in methanol- diethyl ether. The salt was recrystallized from methanol-diethyl ether and isopropanol-diethyl ether and dried overnight in vacuo at 80°C. White solid amounting to 46% yield, m.p. 232°C was obtained.
. } A -46-
Analysis: Calculated for CogHog¢NCl: C, 76.05; H, 8.30; N, 4.43 ‘
Found : C,75.51;H,8.33; N, 4.33
Preparation 35
N-[4-(3-Chloropropoxy)phenyllacetamide.
A mixture of 4-acetamidophenol, (182.2 g, 1.2 mole), 1-bromo-3-chloro- propane, 157.4 g (1.0 mole), and potassium carbonate 145.0 g (1.05 mole) was refluxed overnight in 700 ml of acetone. The acetone solution was refrig- erated overnight and white crystals formed. This white solid was filtered and washed with acetone. The filtrate was stripped to dryness, and the residue was dissolved in chloroform and extracted with 5% sodium hydroxide.
Removal of chloroform gave an oil. The white solid was also dissolved in chloroform and extracted with 5% sodium hydroxide. Removal of chloroform gave a white solid. The white solid and oil were combined and placed in acetone in the refrigerator; white crystals were obtained. The white crystals were recrystallized twice from acetone. A 5-g sample of the white crystals oo was recrystallized from acetone. This furnished 1.76 g after drying in vacuo oo overnight at 80°C (23%) of white crystalline product; m.p. 125-127°C. oo oo Analysis: Calculated for C11 Hi4NO2Cl: C, 58.03; H, 6.20; N, 6.15 | | - Found | : C,58.21;H,6.28;N,6.15
SE oo RE Preparation 36 co ~ 1-(3-Chloropropoxy)-3,5-dimethoxybenzene.
A mixture of 3,5-dimethoxyphenol (100.0 g, 0.6486 mole) chlorobromo- ~~. propane 148.0 g (0.96 mole) and potassium carbonate (89.6 g, 0.96 mole) was heated overnight at gentle reflux in 600 m! of acetone. The reaction mixture was cooled at room temperature, filtered, and stripped to dryness via a rotary evaporator. The resulting oil was dissolved in chloroform, and the solution extracted with 5% aqueous sodium hydroxide; removal of chloroform gave 122.62 g (82.2%) of a dark brown oil. A 5-g sample of the oil was pumped in vacuo overnight at 80°C. This produced 3.23 g (53.2% yield based on the aliquot taken) of dark brown oil.
H! NMR(CDCl3): 6 2-2.4 (quintuplet, center methylene protons, 2H), 3.6-4.2 (m, aliphatic protons, 4H), 3.8 (s, OCH3, 6H), 6.1 (s, aromatic protons, 3H).
Analysis: Calculated for C1 H1503Cl: C, 57.27; H, 6.56
Found + C,56.96;H,6.49 ‘
Preparation 37 ° 4-(3-Chloropropoxy)benzonitrile.
A mixture of 4-cyanophenol (125.0 g, 1.05 mole) bromochloropropane (189.0 g, 1.2 mole) and potassium carbonate (145.0 g, 1.05 mole) was heated overnight at reflux in 750 ml of acetone. The reaction mixture was filtered and stripped to dryness. The resulting residue was dissolved in chloroform and extracted with 5% sodium hydroxide. Removal of chloroform gave 205.1 g (100%) of an oil which crystallized to a white solid. A 5-g sample was recrystallized from isopropyl ether. This furnished 1.22 g (24.4%) of white solid, m.p. 40-44°C which contained a dimer impurity.
Analysis: Calculated for C1gHogNOCl: C,61.39;H,5.15;N, 7.16
Found : C,61.57;H,5.14; N, 7.20
Preparation 38 1-[4-(3-Chloropropoxy)-3-methylphenyl]ethanone.
A mixture of 25 g (0.166 mole) of 4-hydroxy-3-methylacetophenone, 45.8 g (0.33 mole) of 1-bromo-3-chloropropane and 69.1 g (0.5 mole) of anhydrous potassium carbonate in 500 ml of acetone was heated at reflux for "20 hr. The mixture was cooled, filtered, and the filtrate concentrated under reduced pressure to give an oil as residue. The oil was crystallized in petro- oo leum ether. The solid was collected by filtration, washed with petroleurn ether and dried to yield 35.8 g (95%) of an off-white powder. An analytical «sample, m.p. 41.5-42.5°C was prepared from petroleum ether.
Analysis: Calculated for C12H15C102: C, 63.58; H, 6.67 ‘
Found ~~: C,63.40;H,6.64
Preparation 39 4-(3-Chloropropoxy)benzamide.
A mixture of 50 g (0.365 mole) of 4-hydroxybenzamide, 114.8 g (0.729 : : mole) of 1-bromo-3-chloropropane and 151.3 g (1.1 mole) of anhydrous i” 0 3s potassium carbonate in 1 liter of acetone was heated at reflux for 20 hr. The
Ch | ‘mixture was concentrated under reduced pressure, and the residue was stirred with 1.2 liter of water to remove inorganic solids. The mixture was . filtered and the filter cake was washed with water and petroleum ether and dried to yield 75.5 g (97%) of white solid. The solid was recrystallized from ethyl acetate, m.p. 142-145°C. : 5 Analysis: Calculated for C1gH2CINOg: C, 56.22; H, 5.66; N, 6.56
Found : C,55.92;:H,561;N,5.56
Preparation 40 1-[4-(5-Chloropentoxy)-3-methoxyphenyllethanone.
A mixture of 59.7 g (0.36 mole) of acetovanillone, 100 g (0.539 mole) of 1-bromo-5-chloropentane and 138 g (1 mole) of anhydrous potassium carbo- nate in 1 liter of acetone was heated at reflux for 20 hr. The mixture was filtered and the filtrate was concentrated under reduced pressure to give an oil which crystallized in petroleum ether (30-60°C). The solid was collected by filtration, washed with petroleum ether and dried to yield 81.4 g (84%) of fluffy, white solid. The solid was recrystallized from isopropyl ether, m.p. 57- 58°C.
Analysis: Calculated for C14H19C103: C, 62.11; H, 7.07
Found : C,62.14;H,7.10 20 .
Preparation 41 : 4-(3-Chloropropoxy)-3-methoxybenzeneacetic acid ethyl ester.
A mixture of 50 g (0.238 mole) of ethyl homovanillate, 75 g (0.476 mole) of 1-bromo-3-chloropropane and 98.7 g (0.71 mole) of anhydrous potassium carbonate in 1 liter of acetone was heated at reflux for 24 hr. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give an oil which gradually crystallized to a semi-solid. The solid was recrystal- : lized from ethyl ether-petroleum ether (30-60°C) to yield 44.4 g (65%) of white solid, m.p. 36-38°C.
Analysis: Calculated for C14H19ClO4: C,58.64; H, 6.68
Found + C,58.74;H,6.74
S35
Preparation 42 1-(3-Chloropropoxy)-4-(methylsulfonyl)benzene. ‘
To a solution of 21.7 g (0.1 mole) of 1-(3-chloropropoxy)-4-(methylthio)- benzene in 100 ml of chloroform was cautiously added a slurry of 51.8 g (0.3 mole) of m-chloroperbenzoic acid in 450 ml of chloroform. The mixture was stirred at ambient temperature for 2 days and then filtered. The filtrate was washed with four portions of a solution comprised of 110 ml of saturated sodium bicarbonate, 110 ml of water, and 30 ml of 20% sodium hydroxide, once with brine, dried (sodium sulfate) and concentrated under reduced pressure to give a solid as residue. The solid was triturated with petroleum ether, collected by filtration and air dried to yield 24.3 g (98%) of white solid.
An analytical sample, m.p. 84-86°C was recrystallized from 2-propanol.
Analysis: Calculated for C1gH13C103S: C, 48.29; H, 5.27
Found : C,48.38;H,5.30
Preparation 43 } ~ 5-Oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylic acid, methyl ester. : ~ Asolution of 158.2 g (1.0 mole) of dimethylitaconate and 107.2 g (1.0 mole) of benzylamine in 750 ml of methanol was let stand at ambient tem-
ERE 20. perature over the weekend. The solution was filtered, and the filtrate was concentrated under reduced pressure to give an oil as residue. The oil ~ crystallized when it was triturated with petroleum ether (30-60°C). The solid was collected by filtration and dried to yield 225.5 g (97%) of white powder.
An analytical sample, m.p. 63-65°C was prepared from diisopropyl ether.
Analysis: Calculated for C13H15NO3: C,66.94; H, 6.48; N,6.01
Found : C,66.82;H,6.48;N,6.01 : ‘Preparation 44 : 1-Benzyl-3-(hydroxymethyl)-pyrrolidine oxalate [1:1].
A solution of (60.0 g, 0.2553 mole) 5-oxo-1-(phenylmethyl)-3-pyrroli- dinecarboxylic acid methyl ester in dry dimethoxyethane was added to a mixture of dimethoxyethane and 47.0 g (1.23 mole) of lithium aluminum hydride. The reaction mixture was stirred 2 hrs at room temperature and then heated at reflux 2 hrs. The mixture was then stirred overnight at room temperature, then quenched by the slow addition of ethyl acetate. More ethyl acetate was added and the use of Celite® allowed the solid material to be separated from filtrate by filtration. The filtrate was stripped to dryness and dissolved in chloroform. The chloroform layer was extracted with 10% sodium hydroxide. The chloroform layer was dried, filtered, and solvent removed to give an oil. A portion of the oil was converted to the oxalate salt.
The salt was recrystallized from methanol-diethyl ether and dried at 80°C in vacuo overnight to give 2.27 g, 39.4% yield of white crystalline solid, m.p. 98- 102°C.
Analysis: Calculated for C{4H;gNOs: C, 59.78; H, 6.81; N, 4.98 | Found : C,59.43;H,6.79; N, 4.95
Preparation 45 1-[4-(6-Chlorohexyloxy)-3-methoxyphenyllethanone.
A mixture of 41.6 g (0.25 mole) of acetylvanillone, 76 g (0.375 male) of 1- bromo-6-chlorohexane and 103.7 g (0.75 mole) of anhydrous potassium carbonate in 750 ml of acetone was heated at reflux 20 hr. The mixture was cooled, filtered, and the filter cake washed with acetone. The combined
Co filtrates were concentrated under vacuum pump pressure at 90°C to give an oil which gradually crystallized. The residue was triturated with petroleum ether (30-60°C), collected by filtration, and dried to yield 59.6 g (84%) of off-
Lo white solid. An analytical sample, m.p. 35-38°C, was prepared from isopropyl oo © ether.
Analysis: Calculated for C15H21C103: C, 63.26; H, 7.43
Found : C,63.50;H,7.60
Preparation 46 4-(3-Chloropropoxy)benzenesulfonamide.
A mixture of 25 g (0.144 mole) of p-hydroxybenzenesulfonamide, 45.5 g (0.289 mole) of 1-bromo-3-chloropropane and 59.7 g (0.432 mole) of anhydrous potassium carbonate in 500 ml of acetone was heated at reflux for 24 hr. The
Co mixture was cooled, filtered and the filtrate concentrated under vacuum pump pressure at 90°C to give 32.2 g of tan gum as residue. The gum was purified by column chromatography on 600 g of silica gel. Fractions containing the title compound eluted with 8% acetone in benzene were combined and concentrated under reduced pressure to yield 12.2 g (34%) of white solid, m.p. 106-107.5°C on recrystallization from 2-propanol. ‘
Analysis: Calculated for CH 9NO3S: C, 43.29; H, 4.84; N, 5.61
Found : C,43.48; H,4.92; N, 5.62
Preparation 47 7-(3-Chloropropoxy)-2H-1-benzopyran-2-one.
A mixture of 16.8 g (0.104 mole) of 7-hydroxycoumarin, 31.6 g (0.2 mole) of 1-bromo-3-chloropropane and 41.5 g (0.3 mole) of anhydrous potassium carbonate in 500 ml of acetone was heated at reflux for 24 hr. The mixture was filtered with difficulty to give a milky filtrate. The filtrate was treated with charcoal and filtered through Celite® to give a clear filtrate. The filtrate was concentrated under reduced pressure to give a solid residue. The solid was triturated with petroleum ether (30-60°C), collected by filtration, and dried to yield 19.1 g (77%) of fluffy, white solid. An analytical sample, m.p. 100-102°C, was obtained on recrystallization from 2-propanol.
Analysis: Calculated for C12H1Cl03: C, 60.39; H, 4.65
Found : C,60.35; H, 4.68
Preparation 48 Co 7-(3-Chloropropoxy)-4-oxo-4H-1-benzopyran-2-carboxylic acid ethyl © ester. :
A mixture of 23.4 g (0.1 mole) of 7-hydroxy-4-oxo-4H-1-benzopyran-2- carboxylic acid ethyl ester, 31.6 g (0.2 mole) of 1-bromo-3-chloropropane and 41.5 g (0.3 mole) of anhydrous potassium carbonate in 500 ml of acetone was heated at reflux for 20 hr. The mixture was cooled and filtered through
Celite®. The filtrate was concentrated under reduced pressure to give a solid residue. The solid was triturated with petroleum ether (30-60°C), collected by filtration, and recrystallized from 2-propanol to yield 22.5 g (73%) of white solid, m.p. 107-108°C.
Analysis: Calculated for C;5H5C10s: C, 57.98; H, 4.87
Found : C.58.21:H,4.88
Preparation 49 1-[4-(3-Chloropropoxy)-2-methoxyphenyljethanone. ‘
A mixture of 10.6 g (0.637 mole) of 1-(4-hydroxy-2-methoxyphenyl)- ethanone, 20 g (0.127 mole) of 1-bromo-3-chloropropane and 26.4 g (0.19 mole) of anhydrous potassium carbonate in 250 ml of acetone was heated at reflux for 20 hr. The mixture was cooled, filtered, and the filtrate concen- trated under vacuum pump pressure at 90°C to give an oil which gradually crystallized. The solid was triturated with petroleum ether (30-60°C), collected by filtration, and dried to yield 14.6 g (94%) of white solid, m.p. 47- 49°C on recrystallizing from isopropyl ether. :
Analysis: Calculated for C12H5Cl103: C,59.39; H, 6.23
Found : C,59.32;H,6.26
Preparation 50 1-(3-Chloropropoxy)-4-methylsulfinylbenzene.
The title compound is prepared by treating 1-(3-chloropropoxy)-4- methylthiobenzene with sodium perborate in glacial acetic acid. t .
Preparation 51 2-(3-Chloropropoxy)benzonitrile.
A mixture of 2-cyanophenol (50.0 g, 0.42 mole), 1-bromo-3-chloro- . propane (67.7 g, 0.43 mole), and potassium carbonate (58.0 g, 0.42 inole) was heated overnight at gentle reflux in 500 ml of acetone. The reaction mixture was stripped to dryness and the residue was dissolved in chloroform. The chloroform layer was extracted several times with 5% sodium hydroxide. The chloroform layer was dried (anhydrous sodium sulfate), filtered, and the solvent was removed, to give a brown oil (80.09 g, 95.6%). A ten gram portion of this oil was subjected to flash chromatography on silica gel with 10% ethyl acetate-hexanes and 20% ethyl acetate-hexanes used for elution. Fractions were combined, and solvent removed in vacuo. The clear oil obtained was dried 18 hrs in vacuo at room temperature and 8 hrs at 80°C in vacuo. This furnished 5.24 g (50.0% yield - based on aliquot taken) of clear oil. Hl NMR (CDCl3);82.1-2.5(q, 2,-CH2), 3.8(t, 2,-CICHg),4.2(t, 2,-OCHy), 6.9 (m, 2,
Lo aromatic protons ortho and para to ether), 7.5 (m, 2, aromatic protons ortho 3 and para to CN group).
ND
53.
Analysis: Calculated for CjgH1gNOCI: C, 61.39; H,5.15;N, 7.16
Found : C,61.27;H,5.15;N, 7.14
Preparation 52 1-Phenylmethyl-3-pyrrolidinemethanol methanesulfonate (ester) oxalate [1:1].
A solution of 113.80 g (0.596 mole) of 1-benzyl-3-(hydroxymethyl)pyr- rolidine and triethylamine, (66.6 g, 0.66 mole) in 600 ml of acetonitrile was prepared. This solution was cooled in an ice bath. A solution of tosyl chloride (125.9 g, 0.66 mole) in 300 ml of acetonitrile was added dropwise with stirring. The solution was allowed to stir overnight at room temperature. A solid precipitated, and the solution was filtered. The solvent was removed by rotary evaporator, and the residue was dissolved in chloroform. The chloroform layer was extracted with 5% sodium hydroxide and water. The chloroform layer was dried (anhydrous sodium sulfate), filtered, and solvent
Ce removed to give 232.9 g of a dark brown oil. This oil was converted to the oxalate salt and recrystallized from methanol-diethyl ether. After drying at 80°C in vacuo overnight, 181.63 g (88.4%) of white crystalline solid was obtained. A five gram sample was recrystallized again from methanol- diethyl ether and dried at 80°C in vacuo overnight. A yield of 1.41 g (19.7% overall adjusted for the aliquot taken) of white crystalline solid, m.p. 147- 149°C was obtained.
Analysis: Calculated for Co; HosNO7S: C, 57.92; H, 5.79; N, 3.22 . Found : C,57.62;H,5.82; N, 3.22 : Preparation 53 a,a-Diphenyl-3-pyrrolidineacetamide maleate [1:1]..
A 1.13 g sample of 1-benzyl-a,a-diphenyl-3-pyrrolidineacetamide dissolved in 50 ml of methanol was hydrogenated with 0.5 g of 10% palladium-on-charcoal catalyst at 75°C overnight in a Parr hydrogenation apparatus. After removal of the catalyst by filtration the filtrate was concentrated to give 0.783 g (80%) of light tan gum. The mass spectra and infrared spectra were consistent with its structure. A sample of this free base in methanol was treated with one molar equivalent of a solution of maleic acid in methanol. After evaporation of the methanol, the residue crystallized and was recrystallized twice from isopropanol-ether. The material was dried at 100°C/0.1 mm for 3 hr, m.p. 110-145°C (softens and turns liquid). The: material appears to be an amorphous solid.
Analysis: Calculated for Co2H24N205: C, 66.65; H, 6.10; N, 7.07
Found : C,66.79: H,6.05;N, 7.04
Preparation 54 a,a-Diphenyl-3-pyrrolidineacetamide N-cyclohexylsulfamate hydrate [1:1:1.5].
A 1.15 g sample of free base of the above compound (obtained by pro- portioning a,a-diphenyl-3-pyrrolidineacetamide maleate in chloroform and aqueous basic solution and evaporating the chloroform layer) and 0.735 g of hexamic acid were dissolved in 10 ml of ethanol. The solvent was evaporated, the residue crystallized, and then was recrystallized from ethanol, m.p. 103- 106°C.
Analysis: Calculated for Co4H33N3S04¢1.5 H20: C,59.24; H, 7.46; N, 8.64
Found : C,58.97;H,6.98;,N,8.51 \
Preparation 55 1-(Phenylmethyl)-4-piperidinol ester with 4-methylbenzenesulfonic acid maleate [1:1].
A solution of 100 g (0.524 mole) of N-benzyl-4-hydroxypiperidine and 13 g (0.684 mole) of tosylchloride in 600 ml of pyridine was stirred at room temperature overnight. One liter of methylene chloride and 500 ml of 0.5 M aqueous sodium hydroxide were added to the reaction mixture. The reaction : mixture was stirred for 10 min, and the phases were separated. The methylene chloride layer was extracted with several portions of the dilute sodium hydroxide, dried over magnesium sulfate and evaporated in vacuo to give an oil, the free base of the title compound. The free base was converted to the maleate salt, which was recrystallized from methylene chloride-diethyl ether to give white crystalline solid, m.p. 159-160°C.
Analysis: Calculated for CoaH7NOS: C, 59.86; H,5.90; N, 3.04
Found + C.59.79; H, 5.86; N, 2.95
Preparation 56 1-{2-(Phenylthio)ethyl]-4-piperidinecarboxylic acid ethyl ester ~~ - hydrochloride [1:1].
A mixture of 69.3 g (0.40 mole) of 2-chloroethylphenylsulfide, 61.65 g (0.393 mole) of ethyl isonipecotate and 53 g (0.50 mole) of sodium carbonate in 1 liter of absolute ethanol was refluxed for 30 hr in the presence of molecular 3A sieves. The reaction mixture was filtered, and the solvent was removed in vacuo from the filtrate. The residue was partitioned between methylene chloride and dilute sodium hydroxide, and the methylene chloride solution was dried over anhydrous sodium sulfate. The solvent was removed in vacuo to give the free base of the title compound as an oil. The free base was converted to the hydrochloride salt, and the salt was recrystallized from absolute ethanol-ether to give 38.62 g (29.8%) of white crystalline solid, m.p. 125-126°C.
Analysis: Calculated for C1gH24NO,SCl: C, 58.26; H,7.33; N, 4.25
Found : C,58.11;H, 7.32; N, 4.20 i
Preparation 57 1-[(4-Methylphenyl)sulfonyl]-4-piperidinol ester with 4- methylbenzenesulfonic acid.
A solution of 1.63 g (0.016 mole) of 4-hydroxypiperidine and 13.9 g (0.0732 mole) of tosyl chloride in 80 ml of pyridine was stirred overnight at 25°C. The mixture was quenched in 200 ml of water, and the aqueous mixture was extracted with several portions of methylene chloride. The combined methylene chloride layer was extracted with several portions of 1M sulfuric acid followed by 1M sodium hydroxide and dried over magnesium sulfate. The solvent was removed in vacuo to give a solid. This was recrystal- : lized from methylene chloride-diethyl ether to give 4.82 g (73.3%) of the product, m.p. 140.5-141°C. ~~ ° 0 Analysis: Calculated for C1gHg3NOsSg: C, 55.73; H, 5.66; N, 3.42
Found : C,55.60;H,5.64;N, 3.39
. | ~ -56-
Preparation 58 1-[(4-Methylphenyl)sulfonyl}-a,a-diphenyl-4-piperidine-acetonitrile. ~The sodium salt of diphenylacetonitrile was formed in toluene from diphenylacetonitrile, (94.5 g, 0.488 mole) and sodium hydride, (19.6 g, 0.488 mole). The reaction mixture was heated at reflux for approximately two hours. A color change from green to brown was detected during the reaction. 1-[(4-Methylphenyl)sulfonyl]-4-piperidinol ester with methylbenzenesulfonic acid (200.0 g, 0.488 mole) was added in small portions as a solid while stirring the reaction mixture under nitrogen at room temperature. The solution became green. The solution/mixture was stirred overnight at 100°C. The mixture was filtered and the toluene was removed by rotary evaporation.
The filter cake and the residue from removal of toluene were combined and dissolved in chloroform. The chloroform was extracted several times with 5% sodium hydroxide followed by extraction with 1N sulfuric acid and sodium hydroxide. The chloroform was removed in vacuo to give a reddish- brown oil (193, 98 g, 92.4%).
A sample of the oil was crystallized from toluene. The solid obtained was then recrystallized from methylene chloride-hexanes and dried at 80°C \ in vacuo overnight to give white solid title compound in 26.7% yield based on aliquot taken, m.p. 183-184°C. | ;
Analysis: Calculated for CoeHoeN202S: C, 72.53; H,6.09;N, 6.51
Found . C,72.11;H,6.07;N, 6.45
Preparation 59 a,a-Diphenyl-4-piperidineacetonitrile oxalate [2:1].
A solution of 1-[(4-methylphenyl)sulfonyl]-a,a-diphenyl-4-piperidine- acetonitrile (183.83 g, 0.428 mole) and phenol (150.0 g, 1.60 mole) in 750 ml of 48% hydrobromic acid was stirred vigorously and heated at reflux for 3-1/2 hrs. The reaction mixture was cooled and made alkaline with ice/50% sodium hydroxide. The reaction mixture was extracted with chloroform, and the chloroform layer was back extracted with 5% sodium hydroxide. The chloro- form layer was dried, filtered over anhydous sodium sulfate and solvent . removed to furnish a red oil (150.55 g, quantitative). This oil, the free base of "the title compound, was converted to the oxalate salt using a methanol-
diethyl ether mixture. A sample of the oxalate salt was recrystallized from methanol-diethyl ether to give white crystalline product, m.p. 275-276°C.
Analysis: Calculated for CogH2; N20: C,74.74; H, 6.59; N, 8.72
Found : C,74.51; H,6.52; N, 8.60
Preparation 60 a,a-Diphenyl-4-piperidineacetamide fumarate [2:3]. a,a-Diphenyl-4-piperidineacetonitrile oxalate [2:1] (60.34 g, 0.165 mole) was converted to the free base by partitioning in 5% sodium hydroxide and chloroform. Removal of chloroform from the chloroform layer gave an oil which was then dissolved in a mixture of 280 ml concentrated sulfuric acid and 30 ml of water. The solution was stirred overnight at 90°C. The reaction mixture was poured into ice and carefully made alkaline with 50% sodium hydroxide. The aqueous layer was extracted several times with chloroform.
The chloroform layer was dried over anhydrous sodium sulfate, filtered, and solvent removed to give an oil (32.36 g, 66.7%) which crystallized. A two , . gram sample of the oil was converted to the fumarate salt and the salt was ~~. - recrystallized from methanol-diethyl ether. A white solid was obtained (47.9% yield based on aliquot taken) which was dried overnight in vacuo at 80°C, m.p. 234-235°C. ~ Analysis: Calculated for CgsHogN207: C,64.09;H,6.02; N, 5.98
Found : C,63.82;:H,6.14; N, 5.82
Preparation 61 1-[(4-Methvlphenvl)sulfonyl]-a-a-diphenyl-3-piperidinepropanenitrile.
The sodium salt of diphe:iylacetonitrile was formed in 400 ml of dimethylsulfoxide from sodium hydride (60%, 39.0 g, 0.975 mole) and diphenylacetonitrile (188.90 g, 0.975 mole). The resulting solution was stirred under nitrogen for 1 hr at room temperature. A 90-10 mixture of 3- (chloromethyl)-1-[(4-methylphenyl)sulfonyl)piperidine and 4-methyl- benzenesulfonic acid 1-[(4-methylphenyl)sulfonyl]piperidin-3-yl methyl ester (221.42 g, 0.975 mole) dissolved in 400 ml of dimethylsulfoxide was added.
The reaction mixture was heated to 85°C and stirred overnight at 73'C. The : dimethylsulfoxide was removed in vacuo, and the residue obtained was : 35 dissolved in chloroform. The chloroform layer was extracted with 1N sulfuric acid. The chloroform layer was dried, filtered, and the chloroform was removed by rotary evaporator. A brown residue was obtained which was triturated with isopropyl ether to give a brown solid. A 5-g sample was recrystallized from ethyl acetate-isopropyl ether. This gave 4 g (56.8% based on aliquot taken) of white solid, m.p. 136.5-137°C.
Analysis: Calculated for Co7H28N202S: C,72.94;H,6.35;N,6.30
Found : C,72.82;H,6.36; N, 6.29
Preparation 62 a,a-Diphenyl-3-piperidinepropanenitrile fumarate [1:1].
A mixture of 1-[(4-methylphenyl)sulfonyl}-a,a-diphenyl-3-piperidine- propanenitrile (302.41 g, 0.68 mole), hydrogen bromide (48%, 750 ml), and phenol (260 g, 2.76 mole) was stirred vigorously while heating at reflux for 3- 1/2 hr. The reaction mixture was cooled to room temperature and made alkaline with 50% hydroxide-ice. The aqueous phase was extracted several times with chloroform, and the chloroform layer was back extracted with 5% sodium hydroxide. The chloroform layer was dried, filtered, and solvent removed. NMR showed about 80% product was obtained. The same sequence was repeated. The chloroform layer gave a brown oil which was converted to the oxalate salt (148.8 g, 75.5%). A portion of this oxalate salt was converted to the free base by partitioning in chloroform and dilute aqueous sodium hydroxide and separating and evaporating the chloroform layer. The free base was converted to the fumarate salt. This salt was recrystallized from methanol-diethyl ether and dried in vacuo at 80°C overnight to give 6.53 g white crystals, m.p. 181-182°C. : Analysis: Calculated for Ca4HggN904: C,7092; H,6.45; N, 6.89
Found : C,70.46;H,6.41; N, 6.86
Preparation 63 a,a-Diphenyl-3-piperidinepropanamide maleate [1:1].
A solution of 52.01 g (0.179 mole) of a,a-diphenyl-3-piperidinepropane- nitrile was stirred overnight at 85°C in 280 ml of 90% sulfuric acid. The reaction mixture was allowed to cool to room temperature and then poured into 50% sodium hydroxide/ice mix. The basic layer was extracted with the solvent removed to give 52.1 g (94.4%) of a fluffy solid, the free base of the
. , : -59- title compound. A 3 g portion of the free base was converted to the maleate salt and recrystallized from methanol-diethyl ether. The salt obtained was dried in vacuo overnight at 80°C. This furnished 2.15 g of white crystalline product, m.p. 177-179°C.
Analysis: Calculated for C24H2sN205: C, 67.91; H, 6.65; N, 6.60
Found : C,67.85; H, 6.85; N, 6.55
Preparation 64 1-{(2-Chloroethyl)sulfonyl}-4-fluorcbenzene.
A solution of 30% hydrogen peroxide (153 g, 1.34 mole) in 400 ml of glacial acetic acid was prepared. To this ice cooled solution was added a solution of 2-chloroethyl p-fluorophenylsulfide (70.11 g, 0.369 mole) in 200 ml of glacial acetic acid. The resulting solution was stirred 72 hours at room temperature. The volume of acetic acid was concentrated on a rotary evaporator. The residual material was dissolved in chloroform and extracted with a solution of sodium bicarbonate and sodium sulfite. The chloroform layer was then dried, filtered, and solvent removed to give a white solid. A ’ 5 g portion of this white solid was recrystallized from methylene chloride- isopropyl ether. The white solid was dried in vacuo at 80°C overnight. This furnished 1.84 g (32.6% yield base on aliquot taken) of white crystalline solid, m.p. 72.5-74°C. "Analysis: Calculated for CgHgSO2FCl: C,43.15;H,3.62
Found : C, 43.52: H, 3.66
Preparation 65 i 4-Fluoro-a-(4-fluorophenyl)benzeneacetonitrile. : 4-Fluorophenylacetonitrile (70.0 g, 62.2 ml, d=1.126, 0.518 mole) was heated to 120°C, Bromine (83.0 g, 26:6 ml, d=3.119, 0.525 mole) was added dropwise over 1 hr while maintaining a temperature of 120°C. The solution was stirred for 1/2 hr at 120°C and then flushed vigorously with nitrogen for 3/4 hr (solution A). .
In a separate 2-liter flask was placed aluminum chloride (85.0 g, 0.644 mole). Fluorobenzene (200 g, 2.08 mole, d =1.024, 195.3 ml) was added dropwise with stirring over 1/2 hr while flushing with nitrogen (Mixture B).
. oN ~ -60-
Solution A was added dropwise to mixture B starting at room tempera- ture. The temperature rose to 50°C. The reaction mixture was stirred at this temperature for 1/3 hr. The temperature was raised to 70°C and maintained there for 1/3 hr. At this point the reaction became uncontrollable and part of the mixture was lost. The remainder was added to ice/75 ml of concentrated hydrochloric acid. The aqueous phase was extracted several times with chloroform. The solvent layer was dried, filtered, and solvent removed to give a green solid. The solid was recrystallized from isopropanol; the solid was washed with cold isopropanol twice and dried in vacuo at 55°C overnight.
This produced 29.72 g (25.1%) of light yellow solid, m.p. 62-63.5°C.
Analysis: Calculated for C14HgNFy: C, 73.36; H, 3.96; N, 6.11
Found : C,73.55;H,3.88;N,6.10
Preparation 66 a,a-Bis(4-fluorophenyl)-1-[(4-methylphenyl)sulfonyl]-4-piperidine- acetonitrile.. oo oo oo The sodium salt of 4-fluoro-a-(4-fluorophenyl)benzeneacetonitrile was prepared in dimethyl sulfoxide from its free base, 28.0 g (0.1223 mole) and 4.90 g of 60% sodium hydride (0.1227 mole). The salt was stirred for 1 hr at room temperature. To the mixture was added 50.0 g (0.1223 mole) of 1-[(4- methylphenyl)sulfonyl]-4-piperidinol ester with 4-methylbenzenesulfonic acid over five minutes in solid form while stirring under nitrogen. The resulting solution was stirred 15 hours at 65°C and then allowed to stand at room temperature for 72 hours. The solution was stripped to dryness, the residue was dissolved in chloroform, and the solution was extracted several : times with 5% sodium hydroxide. The chloroform layer was dried (anhydrous sodium sulfate), filtered, and solvent removed to give 111.36 g of solid. The solid was triturated with isopropyl ether and placed in the freezer. After washing the solid several times with isopropyl ether, 55.41 g (97.2%) of white solid was obtained. A 3 g sample was then triturated with 50-50 (v/v) hot isopropyl alcohol-methanol and placed in the freezer. The white solid collected was washed with isopropyl ether and dried in vacuo at 80°C overnight. This produced 2.28 g of white crystalline product, m.p. 180-191°C.
Analysis: Calculated for CogH24N209SFy: C, 66.94; H,5.18; N, 6.00 3 Found : C,66.92;H,5.17;N, 5.99
Preparation 67 ’ a,a-Bis(4-fluorophenyl)-4-piperidineacetonitrile oxalate, diethyl ether [1:1:0.5].
A solution of 52.41 g (0.1125 mole) of a,a-bis-(4-fluorophenyl)-1-[(4- methylphenyl)sulfonyl]-4-piperidine acetonitrile was heated at reflux for 3- 1/2 hr in 200 ml of 48% hydrobromic acid with phenol (50.0 g, 0.53 mole). The reaction mixture was cooled to room temperature and then made alkaline with ice/50% sodium hydroxide mixture. The alkaline phase was extracted several times with chloroform. The chloroform layer was back extracted with 5% sodium hydroxide. The chloroform layer was dried (anhydrous sodium sulfate), filtered, and solvent removed to give 34.24 g of dark brown oil. The entire oil was converted to the oxalate salt and recrystallized from methanol- diethyl ether. The salt obtained was dried in vacuo overnight at 80°C to give 34.24 g (69.3%) of white crystalline solid, m.p. 124-127°C.
Analysis: Calculated for Cog3HosNoF2045: C, 62.86; H,5.73: N, 6.37 .
Ce Found oo - .:.C;62.80;H,5.78: N; 6.17 re \
Preparation 68
N-[3-(3-Chloropropoxy)phenyl]urea.
A mixture of 45.6 g (0.3 mole) of 1-(3-hydroxyphenyl)urea, 94.5 g (0.6 * mole) of 1-bromo-3-chloropropane, 124.4 g (0.9 mole) of anhydrous potassium carbonate and 1 liter of acetone was heated at reflux with mechanical stir- ring for 20 hr. The mixture was concentrated and the residue was slurried with 1.5 liters of water. The mixture was filtered and the filter cake was _ recrystallized from isopropanol to yield 57.0 g (83%) of off-white solid, m.p. 141-143°C. , Analysis: Calculated for C;pH3CIN9QO3: C,52.52; H,5.73; N, 12.25 ~ Found : C,5237;H,5.79;N, 12.17
Preparation 69
N-[4-(3-Chloropropoxy)phenyljcarbamic acid ethyl ester.
A mixture of 6.6 g (0.036 mole) of (4-hydroxyphenyl)carbamic acid ethyl ester, 11.5 g (0.072 mole) of 1-bromo-3- chloropropane, 13.8 g (0.10 mole) of anhydrous potassium carbonate and 150 ml of acetone was heated at reflux for 21 hr. The mixture was cooled and filtered. The filtrate was concentrated under reduced pressure to give a solid residue. The solid was triturated with petroleum ether (30-60°C) collected by filtration and recrystallized from isopropanol to yield 7.7 g (83%) of white solid, m.p. 91-93°C.
Analysis: Calculated for C12H1gCINO3: C,55.93; H,6.26; N, 5.43
Found : C,55.93;H,6.28; N, 5.46
Preparation 70 a-(4-Fluorophenyl)-2-pyridineacetonitrile.
A sample of sodium hydride (60%, 1.60 g, 0.04 mole) was washed with dry hexanes. After removal of hexanes a 100 ml portion of dimethyl sulfoxide was added. To this mixture was added a solution of 4-fluorophenylaceto- nitrile (5.41 g, 0.04 mole). The mixture was stirred 3 hrs at room tempera- 16 ture under nitrogen. 2-Bromopyridine (6.32 g, 0.04 mole) was added to the mixture, the reaction mixture was then stirred overnight at 65°C. The
Co ~~ reaction mixture was poured into 1200 ml of water und'the aqudsiis phase " was extracted several times with chloroform (the chloroform layer was filtered using Celite®). The combined chloroform layer was extracted with water and 5% sodium hydroxide. The chloroform layer was dried over sodium sulfate, filtered, and solvent removed to give a red oil. The oil was subjected + to flash chromatography on silica gel using 10% ethylacetate-90% hexanes and 20% ethylacetate-80% hexanes for elution. Fractions of similar purity was combined and solvent removed in vacuo. The oil obtained was dried in vacuo overnight at 80°C to give 2.43 g (28.6%) of clear oil. 1H (CDCl3): 68.5 (m, 1, proton adjacent to N in pyridine nucleus), 6.8-7.8 (m, 7, aromatics), 5.3 (s, 1, methine). :
Analysis: Calculated for C13HoNgF: C, 73.57; H, 4.27; N, 13.20
Found . C,73.23;H,4.23;N,13.12
Preparation 71 a-(4-Fluorophenyl)-a-[1-](4-methylphenyl)sulfonyl}-4-piperidinyl]-2- pyridineacetonitrile hydrate [1:0.5).
The sodium salt of the free base of a-(4-fluorophenyl)-2-pyridine- acetonitrile was formed in dimethylsulfoxide from sodium hydride (60%, 5.16 g, 0.129 mole) and the free base of a-(4-fluorophenyl)-2-pyridine- acetonitrile (27.36 g, 0.129 mole). The salt was stirred in dimethylsulfoxide for 4-1/2 hr at room temperature. Next, 4-methylphenylsulfonic acid ester with 1-[(4-methylbenzene)sulfonyl)-4-piperidinol (52.8 g, 0.129 mole) was added and the reaction mixture was stirred 2 hr at room temperature. The reaction mixture was stirred overnight at 80°C. The solvent was removed in vacuo and the residue obtained was dissolved in chloroform. The chloroform was extracted with water and 5% sodium hydroxide. The chloroform layer was dried over sodium sulfate and filtered. Solvent was removed to give a dark brown residue. This material was triturated with acetone to give 36.2 ¢ of white solid. A one gram portion was triturated with acetone and then recrystallized from methylene chloride-acetone. The solids were dried in vacuo overnight at 80°C to give 0.74 g (62.4% based on aliquot taken) of white crystals, m.p. 228-229°C.
Analysis: Calculated for CosHosN302 5SF: C, 65.90; H, 5.49: N, 9.16 : Found : C,65.86;H,5.27;N, 9.16
Preparation 72 a-(4-Fluorophenyl)-a-(4-piperidinyl)-2-pyridineacetonitrile oxalate © [2:3].
A solution of a-(4-fluorophenyl)-a-[1-[(4-methylphenyl)sulfonyl]-4- piperidinyl]-2-pyridineacetonitrile (30.86 g, 0.0687 mole) and phenol (75 g, 0.8 mole) in 200 ml of 48% hydrobromic acid was heated at reflux for 3 hrs. ~The resultant was cooled in ice and made alkaline with ice-50% sodium hydroxidé. The aqueous layer was extracted with chloroform and the chloro- form layer was extracted with 5% sodium hydroxide. The chloroform layer i was dried over sodium sulfate, filtered, and solvent removed to give a dark brown 0il (26.35 g, 89.1%). The entire oil was converted to the oxalate salt in methanol-diethyl ether. A one gram portion was taken and recrystallized from methanol-diethyl ether and dried in vacuo at 80°C overnight. This furnished 0.90 g (80.2% based on aliquot taken) of white crystalline product, m.p. 98°C (soften, 70°C).
Analysis: Calculateed for Co) Hg N3OgF: C, 58.60; H,492;N,9.76
: Found : C,58.77; H,5.01; N, 10.04
Preparation 73 3-(8-Quinolinyloxy)-1-propanol.
A solution of 8-hydroxyquinoline (36.0 g, 0.25 mole) and potassium tert- butoxide (28.0 g, 0.25 mole) in 80 ml of dimethyl sulfoxide was stirred for 1 hr at room temperature. 3-Chloro-1-propanol (24.0 g, 0.25 mole) was added and the solution was heated overnight at 70°C. The solution was poured into 500 ml of water. A brown solid/mass was obtained. The solid was washed with several portions of water and then triturated with acetone. The solid was filtered and dried in vacuo at 80°C overnight to give 35.67 g (70.3%) of light brown solid, m.p. 126-127°C.
Analysis: Calculated for C12H13NOg: C,70.92;: H,6.45; N, 6.89 5 Found ..: ..C,70.94;H,6.49; N, 6.87
Preparation 74 fo ne eee BY 3-CHloropropoxy)quinoline.t © pe cube vs a 8 Cn
A solution of 3-(8-quinolinyloxy)-1-propanol (32.0 g, 0.158 mole) and thionyl chloride (24.0 g, 0.203 mole) was heated at reflux for 5 hours in 300 ml of dry benzene (dried over 4A molecular sieves). The reaction mixture was cooled to room temperature and then stripped to dryness. The residue * was treated with potassium carbonate solution (30 g in 500 ml of water). The gummy residue was dissolved in chloroform and extracted with the potas- sium carbonate solution. The chloroform layer was dried over anhydrous sodium sulfate, filtered, and solvent removed to give a dark mass which crystallized. The mass was treated with 500 ml of boiling hexane. The hexane layer was decanted off from insoluble oil. A white solid crystallized on cooling, the hexane layer was filtered off. The solid was dried in vacuo at room temperature overnight to give 26.69 g (76.2%) of white crystalline solid, m.p. 69-T1°C.
Analysis: Calculated for C12H2NOCI: C, 65.02; H, 5.45; N, 6.32 :
Found : C,65.19;H,5.51;N, 6.27
0 -65-
Preparation 75 a,a-Bis(4-fluorophenyl)-1-[(4-methylphenyl)sulfonyl}-3-piperidine- acetonitrile..
The sodium salt of 4-fluoro-a-(4-fluorophenyl)benzeneacetonitrile was formed in 500 ml of dimethylsulfoxide from (39.42 g, 0.172 mole) of its free base and sodium hydride (60%) (6.88 g, 0.172 mole). The reaction mixture was stirred for one hour at room temperature. 1-[(4-Methylphenylsulfonyl]- 3-piperidinol-4-methylphenylsulfonate ester (70.4 g, 0.172 mole) was added, and the solution was stirred overnight at 65°C. The solution was stripped to dryness on a rotary evaporator. The residue obtained was dissolved in chloroform and the chloroform layer was extracted with 5% sodium hydrox- ide and also water. Removal of chloroform gave a dark brown oil. Aneight : gram portion of this oil was subjected to flash chromatography on silica gel : using 15% ethyl acetate-85% hexane for elution. Fractions of similar purity were combined and solvent was removed in vacuo. The residue was dried in : vacuo overnight at 80°C to give 4.75 g (45.9% based on aliquot taken) of white amorphous material. 1H NMR (CDCl3): 6.9-7.6 8 (m, 12, aromatic), 3.7-4.0 (m, 2, protons adjacent to sulfonamide nitrogen), 2.4 (5, 3, methyl), 1.3-2.9 (m, 7, aliphatics).
Analysis: Calculated for CogH24N20,SFg: C, 66.93; H, 5.18; N, 6.00
Found : C,66.62;H, 5.20; N, 5.89 \ : Preparation 76 a.a-Bis(4-fluorophenvl)-3-piperidineacetonitrile maleate [1:1].
A solution of a,a-bis(4-fluocrophenyl)-1-[(4-methylphenylsulfonyl]-3- . piperidineacetonitrile (25.00 g, 0.0536 mole) in 125 ml of 48% hydrobromic acid containing phenol (25.00 g, 0.2657 mole) was heated at reflux for 3-1/2 hours. The solution was cooled to room temperature and diluted to 1 liter with ice while being made alkaline with 50% sodium hydroxide. The purple aqueous phase was extracted with three 300 ml portions of chloroform. The chloroform layer was back extracted with two 150 ml portions of 1N sodium hydroxide. The chloroform layer was dried over anhydrous sodium sulfate, filtered, and solvent removed to give a light brown oil. The oil was converted to the maleate salt which was recrystallized from methanol-diethyl ether.
The precipitate was dried in vacuo overnight at 80°C to give 13.05 g (56.8%) of white crystals, m.p. 115-118°C. .
Analysis: Calculated for Co3HgaNgO4Fg: C, 64.48, H, 5.18; N, 6.54
Found : C,64.04;H,5.15;N, 6.50
Preparation 77 4-| Bis(4-fluorophenyl)methyl]-1-(3-chloropropyl)piperidine.
A solution of 4-[bis(4-fluorophenyl)methyl]-1-piperidinepropanol (40.27 g, 0.117 mole free base) and thionyl chloride (17.90 g, 0.150 mole) in 350 ml of chloroform was stirred at room temperature for 1/2 hour. The solution was heated at reflux for 6 hours, cooled to room temperature, and then stripped to dryness. The gum obiained was dissolved in chloroform and extracted with saturated sodium bicarbonate. The chloroform layer was dried (anhydrous sodium sulfate), filtered, and solvent removed to give a reddish-brown oil (42.11 g). An eight gram sample was subjected to flash chromatography on silica gel using 50-50 v/v of ethyl acetate-hexane for elution. After combining fractions, removing solvent and drying the oilin vacuo, 6.84 g (84.6% yield-based on aliquot) of brown oil was obtained. : Analysis: Calculated for Co; HgsNOFoClg: C, 69.32; H, 6.65; N, 3.85
Found . C, 69.09; H,6.60;N, 3.84
Preparation 78 7-Hydroxv-4-oxo-4H-1-benzopyran-2-carboxylic acid ethyl ester.
To a warm, stirred solution of (18.4 g, 0.8 mole) sodium metal in 250 ml of absolute ethanol was added dropwise a solution of 30.4 g (0.2 mole) of 2,4- . dihydroxyacetophenone and 58.5 g (0.4 mole) of diethyloxalate in 50 ml of absolute ethanol and 50 ml of absolute ethyl ether over a 30-min period. The mixture was heated at reflux for 4 hr and then poured into a solution of 200 ml of concentrated hydrochloric acid and 1.8 liter of water. The mixture was extracted with two 500-m) portions of ethyl ether and the combined extracts were concentrated under reduced pressure to give a solid residue.
The solid was dissolved in a mixture of 250 ml of ethanol and 3 ml of concentrated hydrochloric acid and heated at reflux for 2 hr. The mixture was concentrated under reduced pressure and the solid residue was triturated with ethyl ether, collected by filtration, and recrystallized from 95% ethanol to yield 28.1 g (60%) of tan powder, m.p. 217-221°C.
Analysis: Calculated for C12H1005: C, 61:54; H, 4.30
Found : C,61.68;H,4.34
Preparation 79 a,a-Diphenyl-1-(phenylmethyl)-4-piperidineacetonitrile hydrochloride : To a prewashed slurry of 8.00 g (0.19 mole), 57% sodium hydride in 300 ml of dimethylsulfoxide was added 32.80 g (0.17 mole) diphenylaceto- nitrile. The solution was heated at 65°C for 1 hr during which time the solution became deep red. 1-(Phenylmethyl)-4-piperidinol ester with benzenesulfonic acid (0.17 mole) was then added in 50 ml of dimethyl- sulfoxide and the solution stirred overnight at 60°C. The solution was cooled and poured into 1 liter of water. The aqueous solution was extracted with toluene (3 x 150 ml). The toluene extracts were treated with 500 ml of sulfuric acid which caused a gummy residue to precipitate. The residue was taken up in a mixture of methylene chloride and 10% sodium hydroxide. The " layers were separated, the aqueous layer extracted with methylene chloride 2 and the combined extracts dried over magnesium sulfate. Concentration gave 35.0 g (57%) of a tan solid, m.p. 138-142°C.
A small portion was converted to the hydrochloride salt which was recrystallized from methanol/diethyl ether to give white powder, m.p. > 250°C. : Analysis: Calculated for CogH27CINg: C, 77.50; H, 6.75; N, 6.95
BEE = Found : C,71.09;H, 6.76; N, 7.04 - : . Preparation 80 oo a,a-Diphenyl-1-(phenylmethy!)-3-piperidinepropanenitrile hydroc- : 30 - hloride [1:1].
A mixture of (7.25 g, 0.025 mole) a,a-diphenyl-3-piperidinepropane- nitrile, 4.28 g, (0.025 mole) of benzyl bromide and potassium carbonate (5.53 g, 0.04 mole) was stirred overnight at room temperature in 300 ml of acetonitrile containing potassium iodide (0.3 g). The reaction mixture was : 35 stripped to dryness, and the resulting residue was dissolved in chloroform.
The chloroform layer was extracted several times with water, dried, filtered, and solvent removed to give an oil. The oil was converted to the hydro- chloride salt via ethereal hydrogen chloride. The white solid was recrystallized from methanol-diethyl ether and dried in vacuo at 80°C overnight. A yield of 7.04 g (67.5%) of white solid, m.p. 243-246°C with decomposition was obtained.
Analysis: Calculated for Co7H29N2Cl: C, 77.77; H, 7.01; N, 6.72
Found : C,77.36;H,6.97; N, 6.67
Preparation 81 a,a-Diphenyl-1-(phenylmethyl)-4-piperidineacetamide fumarate [1:1 ].
A solution of (5.88 g, 0.02 mole) a,a-diphenyl-4-piperidineacetamide in acetonitrile was prepared by warming with a heat gun. To this solution was added (3.42 g, 0.02 mole) of benzyl bromide and potassium carbonate (6.91 g, 0.05 mole). This mixture was stirred ovrnight at room temperature and then heated at reflux for 5 hours. The reaction mixture was stripped to dryness, - and the residue obtained was partitioned between chloroform-water and chloroform-5% sodium hydroxide. Removal of chloroform gave an oil which was subjected to column chromatography on silica gel using mixtures of ethyl acetate-dimethoxyethane for elution. Suitable fractions were combined and . converted to the fumarate salt. The salt was recrystallized from methanol- diethyl ether and dried overnight at 80°C in vacuo. A yield of 1.65 g (10%) of white crystalline material, m.p. 218-220°C was obtained.
Analysis: Calculated for C30H32N20s5: C, 71.98; H, 6.44; N, 5.60 ~ Found + C,71.60;H,6.47;N, 5.51
Preparation 82 a,a-Diphenyl-1-(phenylmethyl)-3-piperidinepropanamide hydrate 3% A mixture of (7.70 g, 0.025 mole) a,a-diphenyl-3-piperidinepro- panamide, 4.28 g (0.025 mole) of benzyl bromide and potassium carbonate (5.54 g, 0.04 mole) was heated overnight at gentle reflux in 300 ml of acetonitrile containing potassium iodide (0.3 g). The reaction mixture was : Co ' stripped to dryness and partitioned between chloroform-water and chloro- 3 form 5% sodium hydroxide. Removal of chloroform gave an oil. This oil was
Ce) . -69- subjected to column chromatography on silica gel using dimethoxyethane and ethyl acetate for elution. A yield of 3.34 g (32.8%) of yellow amorphous solid, after combining column fractions and drying at 80°C in vacuo over- night was obtained. 1H NMR (CDCl) 8 7.1-7.6 (m, 15, aromatic), 5.5-6.0 (br, s, 2, NH9), 3.4 (s, 2,
CH»), 3.1(s, 1,1/2 H20) 1.0-2.7 (m, 11, alphatic).
Analysis: Calculated for Co7H3;N2015: C, 79.57; H,7.67; N, 6.87
Found : C,79.65;H,67.46;N,6.88
Preparation 83 a,a-Bis(4-fluorophenyl)-1-(phenylmethyl)-4-piperidineacetonitrile hydrochloride hydrate [1:1:0.5].
A mixture of a,a-bis(4-fluorophenyl)-4-piperidineacetonitrile (6.05 g, 0.019 mole), benzyl bromide (3.32 g, 0.019 mole), and potassium carbonate : 15 (5.53 g, 0.04 mole) was heated overnight at gentle reflux in 350 ml of aceto- nitrile containing potassium iodide. The reaction mixture was stripped to : dryness and partitioned between chloroform and water. The chloroform layer was dried over anhydrous sodium sulfate, filtered, and solvent removed to give 7.55 g of light yellow oil. The oil was converted to the hydrochloride salt using ethereal hydrogen chloride, and the salt was recrystallized from . methanol-diethyl ether. The white solid obtained by filtration was washed with diethyl ether and dried in vacuo overnight at 80°C. A yield of 3.85¢g (45.2%) of white crystals, m.p. 283°C with decomposition was obtained.
Analysis: Calculated for CogHogN20g sF2Cl: C, 69.71; H, 5.85; N,6.25
Found : C,70.07;H,5.68; N, 6.25
Preparation 84 a,a-Bis( 4-fluorophenyl)-1-(phenylmethyl)-3-pyrrolidinepropanenitrile hydrate [1:0.5]. oo
The sodium salt of 4-fluoro-a-(4-fluorophenyl)benzeneacetonitrile was prepared in dimethyl sulfoxide from 41.9 g (0.183 mole) of the free base and 7.32 g (0.183 mole) of 60% sodium hydride. After stirring at room tempera- ture for 3 hrs, a solution of (63.18 g, 0.183 mole) 1-phenylmethyl-3-pyr- rolidinemethanol methanesulfonate ester in dimethylsulfoxide was added.
The resulting solution was stirred overnight at 60°C. The solvent was removed in vacuo via a rotary evaporator. The oil obtained was dissolved in chloroform and the solution was extracted several times with 1N sulfuric acid. The chloroform layer was extracted with 5% sodium hydroxide, dried over anhydrous sodium sulfate, filtered, and solvent removed to give 59.6 g (81%) of dark brown oil. A 10 g fraction was subjected to flash chromatog- raphy on silica gel using 50-50 v/v ethyl acetate-hexane and 100% ethyl acetate for elution. Fractions of similar purity were combined, and sovlent was removed in vacuo. A dark brown oil was obtained and dried at 80°C in vacuo overnight. A yield of 4.13 g (33.5% based on aliquot used) of dark brown oil was obtained.
IH NMR (CDCl3): 8 6.8-7.4 (m, 13 aromatic), 3.5 (s, 2, N-CHp ~O 1.1-2.8 (m, 9, aliphatic).
Analysis: Calculated for Cag 25N200 5F2: C,75.89;H,6.12; N, 6.81
Found + C, 75.93; H,6.00; N, 6.55
Preparation 85 a-(4-Fluorophenyl)-a-[1-(phenylsulfonyl )-4-piperidinyl]-2-pyridine- methanol. !
A solution of 2-bromopyridine (9.26 g, 0.059 mole) in 250 ml of tetra- hydrofuran was prepared and cooled to -65°C in an acetone/dry ice bath. To . this solution was added n-buty! lithium (10.5 M in hexane, 5.60 ml, 0.05 mole) while maintaining a temperature of -45°C to -65°C. The solution was stirred for 2 hr at -65°C. A tetrahydrofuran solution of (4-fluoropheny)[1- 28 (phenylsulfonyl)-4-piperidinyllmethanone (18.2 g, 0.0525 mole) was added dropwise while maintaining a temperature of -65°C. The solution was stirred 72 hr while reaching room temperature. The solution was stripped to dry- ness. The residue was dissolved in chloroform and extracted with several portions of water. The chloroform layer was dried over sodium sulfate and | solvent was removed in vacuo tn give a brown oil. This oil was subjected to flash chromatography on silica gel using 30% &thyl acetate/hexanes and 40% ethyl acetate/hexanes for elutinn. Fractions of similar purity were combined and solvent removed to give a white crystalline solid. This solid was tritur- ated with diethyl ether and chilled in the freezer for 12 hr. The solid was £35 isolated and dried at 80°C in vacuo overnight. This process provided ig.12g (54.1% yield) of white crystalline solid, mp 160-163°C.
Analysis: Calculated for C23H23N203SF: C, 64.78; H, 5.44; N, 6.57
Found : C,64.74;H,543:N, 6.49 .
Preparation 86 2-[(4-Fluorophenyl)(4-piperidinyl)methyl]pyridine hydrochloride hydrate [1:2:0.5].
A mixture of a-(4-fluorophenyl)-a-[1-(phenylsulfonyl)-4-piperidinyl]-2- pyridinemethanol (62.0 g, 2.0 mole) and 500 ml of 57% hydriodic acid was heated at reflux for 6 hours. The reaction mixture was concentrated and then filtered with Celite®. The filtrate obtained was stripped to dryness. Ice/ water was added, and the mixture was made alkaline with 50% sodium hydroxide. The aqueous phase was extracted several times with chloroform.
The chloroform layer was dried over sodium sulfate, filtered, and solvent removed to obtain an oil which crystallized on standing at room temperature.
The oil was converted to the hydrochloride salt and the salt was recrystal- lized from methanol-diethyl ether. A white solid was obtained which was dried at 80°C in vacuo overnight. This furnished 15.45 g (71.9% yield) of yellow solid, mp 182-185°C.
Analysis: Calculated for C17H21N20g sFCl: C, 57.96: H,6.30; N, 7.95
Found : C,57.46; H, 6.26; N, 7.88
Preparation 87 ) a,a-Diphenyl-1-(phenylmethyl)-4-piperidinemethanol. 3 BE - “A Grignard solution was prepared by the addition of 94.2 g (0.6 mole) of bromobenzene in 250 ml of dry (freshly distilled from lithium aluminum hydride) tetrahydrofuran to a mixture of (12.5 g, 0.5 mole) magnesium chips in 500 ml of dry tetrahydrofuran. After the addition was complete, the mixture was heated at reflux for 15 min to complete formation. To this 0 Grignard reagent at ambient temperature, was added a solution (44.2 g, 0.179 mole) of the base of 1-(phenylmethyl)-4-piperidinecarboxylic acid ethyl ~ esterin 250 ml of tetrahydrofuran in a stream. The solution was stirred : overnight at ambient temperature and then poured into 2.5 liters of a saturated ammonium chloride solution. The layers were separated and the aqueous layer was extracted once with 500 ml of methylene chloride and twice with 250 ml of methylene chloride. The combined organic layers were washed successively with 500 ml of water, 750 ml of a 3% sodium hydroxide solution, 250 ml of water and 250 ml of brine. The organic layer was dried over sodium sulfate and concentrated to give a gum as residue. The gum was dissolved in 500 ml of ethyl ether, and the solution was treated with activated charcoal, filtered through Celite®, and then concentrated to give a gum as residue. The gum crystallized when triturated with petroleum ether (30- 60°C). The solid was collected by filtration and dried to yield 49.0 g (77%) of title compound as a white solid. An analytical sample, mp 89.5-90.5°C, was prepared by recrystallization from isopropanol.
Analysis: Calculated for Co5H27NO: C, 83.99; H,7.61;N, 3.92
Found : C,B4.09;H,7.63;N,3.97 :
Preparation 88 a,a-Dipheyl-4-piperidinemethanol.
A mixture of 35.8 g (0.1 mole) of a,a-Diphenyl-1-(phenylmethyl)-4- piperidinemethanol and 5% palladium on carbon catalyst in 500 ml of absolute ethanol was hydrogenated at 60°C in a Parr apparatus for 3 days. !
The mixture was filtered through Celite® and the filtrate was concentrated to give a solid residue. The solid was triturated with petroleum ether (30-60°C), . collected by filtration and dried to give 26.7 g of title compound as a white solid. An analytical sample was obtained by recrystallization from 2- : propanol-isopropyl ether, mp 160-161°C.
Analysis: Calculated for C1gH21NO: C, 80.86; H,7.92; N, 5.24
Found | . C,80.98;H,7.96;N,5.30
Preparation 89 oF a-(4-Fluorophenyl)-a-methyl-4-piperidinemethanol. : - To a solution of 49.9 g (0.2 mole) of 1-acetyl-4-(p-fluorobenzoyl)- piperidine in 500 ml of tetrahydrofuran was added dropwise 110 ml (0.35 mole) of a 3.2 molar solution of methylmagnesium bromide in ethyl ether* at "ambient temperature. After addition was complete, the mixture was heated : at reflux for 1 hr and then at ambient temperature overnight. The mixture was poured into 1.5 liters of a saturated ammonium chloride solution with vigorous stirring. The layers were separated and the aqueous layer was extracted twice with 300 ml portions of methylene chloride. The combined organic layers were washed successively with 250 ml of water, 250 ml of a 40% sodium hydroxide solution, 250 ml of water and 250 ml of brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give 37.3 g (70% yield) of crude alcohol as a gum.
The gum was dissolved in 400 ml of 95% ethanol and the solution was heated with a solution of 22.4 g (0.4 mole) potassium hydroxide in 100 ml of water and then heated at reflux overnight. The solution was concentrated under reduced pressure, and the residue was triturated with water. The resulting solid was collected by filtration and recrystallized from 2-propanol to yield 19.8 g (44%) of title compound as an off-white powder, mp 184-186°C.
Analysis: Calculated for C;3H1gFNO: C, 69.93; H, 8.13; N, 6.27
Found : C,70.00;H,8.21;N, 6.27 *Available commercially, e.g., Aldrich Chemical Co., Inc., 940 West Saint
Paul Avenue, Milwaukee, Wisconsin 53233 USA.
Preparation 90 \ a,a-Bis(4-methylphenyl)-1-(phenylmethyl)-4-piperidinemethanol.
A Grignard solution was prepared by the addition of 102.6 g (0.6 mole) of 4-bromotoluene in 500 ml of dry tetrahydrofuran to a mixture of 12.5 g (0.5 mole) of magnesium chips in 250 ml of tetrahydrofuran. After the addition © was complete, the mixture was heated at reflux for 1 hr to complete forma- tion. To this Grignard reagent at ambient temperature was added-in a stream 42.9 g (0.173 mole) of 1-(phenylmethyl)-4-piperidinecarboxylic acid ethyl ester in 250 ml of dry tetrahydrofuran. The solution was stirred at ambient temperature and then poured into 2.5 liters of a saturated ammonium chloride solution. The layers were separated, and the aqueous layer was extracted twice with 375 ml portions of methylene chloride. The combined organic layers were washed successively with 500 ml of water, 750 ml of a 3% sodium hydroxide solution, 250 ml of water and 250 ml of brine.
The organic layer was dried over sodium sulfate and concentrated under pressure to give a gum as residue. The gum gradually crystallized. The solid was triturated with petroleum ether (30-60°C), collected by filtration and dried to yield 63.6 g (95%) of title coinpound as a white solid. An analytical sample was recrystallized from 2-propanol, mp 115-117°C.
Analysis: Calculated for Cg7H3;NO: C, 84.11; H,8.10;N, 3.63 . Found : C,84.23;H,8.13; N, 3.66 :
Preparation 91 a,a-Bis(4-methylphenyl)-4-piperidinemethanol.
A solution of 38.5 g (0.1 mole) of a,a-bis(4-methylphenyl)-4-piperidine- methanol in 500 ml of absolute ethanol was hydrogenated at 50 psi and 60°C over one 5% palladium on carbon catalyst in a Parr apparatus for 3 days. The cooled mixture was filtered through Celite® and the filtrate was concentrated under reduced pressure to give a glass as residue. The glass was crystallized from 2-propanol to yield 17.7 g (60%) of title compound as a white solid, mp 150-153°C.
Analysis: Calculated for C2oHosNO: C, 81.31; H, 8.53; N, 4.74
Found : C,81.18;H,8.62;N,4.72
Preparation 92 a,a-Bis(4-methoxyphenyl)-1-(phenylmethyl)-4-piperidinemethanol oxlate hydrate [1:1:0.5] compound with ethanol [1:0.5].
A Grignard reagent was prepared by the addition of a solution of 112.2 g (0.6 mole) of 4-bromoanisole in 500 ml of dry tetrahydrofuran to a mixture of . 12.5 g (0.5 mole) of magnesium chips in 250 ml of tetrahydrofuran. After the additon was complete, the mixture was heated at reflux for 0.5 hr to complete formation. To this Grignard reagent at ambient temperature was added a solution of 42.8 g (0.173 mole) of the base of 1-(phenylmethyl)-4-piperidine- carboxylic acid ethyl ester in 250 ml of tetrahydrofuran in a stream. The mixture was stirred at ambient temperature overnight and then poured into 2.5 liters of a saturated ammonium chloride solution. The layers were separated and the aqueous layer was exracted twice with 375 ml portions of methylene chloride. The combined organic layers were washed successively with 500 ml of water, 750 ml of a 3% sodium hydroxide solution, 250 ml of water and 250 ml of brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give a gum as residue. The gum was dissolved in 2-propanol and converted to the oxalic acid salt. The solid =. was collected by filtration, washed with 2-propanol and ethyl ether and dried to yield 84.8 g (97%) of title compound as a white powder. An analytical sample was recrystallized from absolute ethanol, mp 128-131°C (with - decomposition) (slow heating; rapid heating gives mp ~110°C).
Analysis: Calc’d for CogH33NO7.50.5CoHsOH: C, 66.74; H, 6.91; N, 2.60
Found : C,67.08,H,6.77; N, 2.67
Preparation 93 4-(3-Chloropropoxy)benzoic acid methyl ester.
A mixture of 30.4 g (0.2 mole) of methyl-4-hydroxybenzoate*, 63 g (0.4 mole) of 1-bromo-3-chloropropane and 82.9 g (0.6 mole) of anhydrous potas- sium carbonate in 1 liter of acetone was heated at reflux for 20 hr. The mixture was cooled and filtered, and the filtrate concentrated to give an oil as residue. The oil crystallized when triturated with cold petroleum ether (30- 60°C). The solid was collected by filtration and recrystallized from petroleum ether (60-110°C) to yield 42.9 g (94%) of title compound as a white solid, mp 56.5-59°C. : Analysis: Calculated for C11 H3ClO03: C,57.78;H,5.73 oo Found : C,57.91; H,5.80
Co *Available commercially, e.g., Aldrich Chemical Co., Inc., 940 West Saint
AE 20 Paul Avenue, Milwaukee, Wisconsin 53233 USA.
Preparation 94
Co | a.a-Bis (4-methoxyphenvl)-4-piperidinemethanol. : A solution of 36.7 g (0.088 mole) of a,a-bis(4-methoxyphenyl)-1- (phenylmethyl)-4-piperidinemethanol in 500 ml of absolute ethanol was - hydrogenated over 5% palladium on carbon catalyst at 60°C in a Parr apparatus for 3 days. The mixture was cooled, filtered through Celite®, fresh catalyst added to the filtrate and the mixture hydrogenated. This process was repeated until no starting material was present by mass spectral analysis. The filtrate was concentrated, and the residue was partitioned between methylene chloride and a 5% sodium hydroxide solution. The organic layer was dried over sodium sulfate and concentrated to give a solid residue. The solid was recrystallized from 2-propanol to yield 8.6 g (30%) of title compound as a white solid, mp 153-155°C.
we) -76-
Analysis: Calculated for C2oH25NO3: C,73.37; H,7.70; N, 4.28
Found : C,73.42;H,7.72; N, 4.30 .
Preparation 95 4-(3-Chloropropoxy)-1,1'-biphenyl.
A mixture of 34 g (0.2 mole) of 4-phenylphenol, 63 g (0.4 mole) of 1- bromo-3-chloropropane and 82.9 g (0.6 mole) of anhydrous potassium carbonate in 1 liter of acetone was heated at reflux for 17 hr. The mixture was cooled and filtered, and the filtrate concentrated under reduced pressure.
The residue was triturated with petroleum ether (30-60°C), and a solid crystallized. The solid was collected by filtration and was subjected to flash chromatography on 400 g of silica gel on a 10-cm diameter column to remove starting phenol. The column was eluted with a 1:2 mixture of benzene and cyclohexane, and fractions containing title compound were combined and concentrated to give a solid residue. The solid was triturated with petroleum ether (30-60°C), collected by filtration, and dried to yield 35.1 g (71%) of title compound as a white solid. An analytical sample was recrystallized from petroleum ether (60-110°C), mp 65-66°C.
Analysis: Calculated for C15H5Cl0O: C, 73.02; H,6.13
Found : C, 73.08; H,6.12
Preparation 96 1-[4-(3-Chloropropoxy)phenyl]-1-propanone.
A mixture of 37.6 g (0.25 mole) of 4'-hydroxypropiophenone (97%)*, 718.7 g (0.5 mole) of 1-bromo-3-chloropropane and 103.5 g (0.75 mole) of anhydrous potassium carbonate in 1 liter of acetone was heated at reflux for 18 hr. The mixture was cooled, filtered, and the filtrate concentrated under reduced pressure. The oily residue was dissolved in 500 ml of benzene, and the solu- tion stirred with potassium hydroxide pellets for 1.5 hr to remove unreacted phenol. The mixture was filtered, and the filtrate was concentrated to give 56.1 g (99% yield) of title compound as an oil. The oil gradually crystallized and a portion of the solid was recrystallized from petroleum ether (60-1 10°C) to yield title compound as a fluffy, white solid, mp 41-43°C.
N
-77-
Analysis: Calculated for C12H;5C102: C, 63.58; H, 6.67
Found + (,63.46;H, 6.82 . *Available commercially, e.g., Aldrich Chemical Co., Inc., 940 West Saint
Paul Avenue, Milwaukee, Wisconsin 53233 USA. 5 .
Preparation 97 4-[Bis(4-chlorophenyl)hydroxymethyl]-N,N-diethyl-1-piperidine- carboxamide.
A Grignard solution was prepared by the treatment of a slurry of 8.5 g (0.35 mole) of magnesium chips in 200 ml of dry tetrahydrofuran with a solution of 72.8 g (0.38 mole) of 1-bromo-4-chlorobenzene in 400 ml of tetra- hydrofuran. After the addition was complete, the mixture was heated at reflux for 15 min to complete formation. To the Grignard solution at ambient temperature was added a solution of 38.4 g (0.15 mole) of 1-{(diethylamino)- carbonyl]-4-piperidine carboxylic acid ethyl ester in 200 m! of tetrahydro- furan in a stream. The solution was stirred at ambient temperature over- night and poured into 2.5 liters of a saturated ammonium chloride solution.
The layers were separated, and the aqueous layer was extracted once with 500 ml of methylene chloride and once with 250 ml of methylene chloride.
The combined organic layers were filtered through Celite® and the filtrate was washed successively with 500 ml of water, 750 ml of a 4% sodium hydroxide solution, 250 ml of water and 250 ml of brine. The solution was dried over sodium sulfate and concentrated under reduced pressure to give a gum which gradually crystallized. The solid was triturated with petroleum 26 ether (30-60°C), collected by filtration, and dried to yield 56.7 g (87%) of title compound as a white solid. An analytical sample was recrystallized from isopropanol, mp 172-175°C.
Analysis: Calculated for Co3HogClgN9Og: C, 63.54; H, 6.48; N, 6.43
Found : C,63.60;H,6.64;N,6.25
Preparation 98 3-Methoxy-4-(phenylmethyloxy)benzaldehyde.
A mixture of 4-hydroxy-3-methoxybenzaldehyde (100.0 g, 0.657 mole), benzyl bromide (112.4 g, 0.657 mole), and potassium carbonate (90.8 g, 0.657 3 35 mole) was heated overnight at reflux in 600 ml of dry acetonitrile (dried over
4A molecular sieves). The reaction mixture was stripped to dryness on a rotary evaporator. A white solid was obtained which was recrystallized form ethanol and dried in vacuo overnight at 80°C, to give 147.45 g (92.6% yield) of white crystalline product , mp 58-63°C.
Analysis: Calculated for CisH 403: C,74.36;H,5.83
Found : (C,74.36;H,5.78
Preparation 99 5-Methoxy-2-nitro-4-(phenylmethoxy)benzaldehyde.
Reference: J. Med. Chem. 1977, Vol. 20, No. 1, p. 147 3-Methoxy-4-(phenylmethyloxy)benzaldehyde (48.0 g, 0.198 mole) was added in small portions over 0.5 hour to 200 ml of concentrated nitric acid cooled to 0°C in an acetone-dry ice bath. The temperture was maintained at 0-1°C for ten minutes. The temperature was allowed next to reach 15°C and suddenly but briefly allowed to rise to 45°C. The temperature was cooled to 20°C and then the reaction mixture was poured in ice/water. A yellow solid was obtained and filtered and washed with diethyl ether. A two gram sample was recrystallized from isopropanol. The light yellow solid isolated was dried in vacuo overnight at 80°C to give 0.92 g (32.5% yield) of light yellow solid, mp 122-124°C.
Analysis: Calculated for C15H13NOs: C, 62.72; H, 4.56; N, 4.88
Found : C,62.42;H,457;N,5.17
Preparation 100 5-Methoxy-2-nitro-4-(phenylmethyloxy)benzoic acid.
A solution of 5-methoxy-2-nitro-4-(phenylmethyloxy)benzaldehyde (45.11 g, 0.157 mole) in 600 ml of acetone was prepared. To this solution was added 400 ml of 10% potassium permanganate solution over 1 hr. The resultant mixture was stirred for 1 hr at room temperature. The reaction mixture was cooled to room temperature and filtered with Celite®, acetone was removed. The resulting material was made acidic with concentrated hydrochloric acid. A yellow solid formed and was separated from aqueous solution, and air dried. The yellow solid was dissolved in ethyl acetate, and filtered through sodium sulfate to remove traces of manganese dioxide, after which 25.84 g of yellow solid was obtained. A 2 g sample was recrystallized
: \ . . -79- from isopropyl alcohol. The yellow solid isolated was dried in vacuo over- night at 80°C, to give 1.85 g (50% yield) of yellow solid, mp 188°C (with . decomposition).
Analysis: Calculated for CysH13NOg: C,59.41; H, 4.32; N, 4.62
Found : C,59.27;H, 4.40; N, 4.46
Preparation 101 4-(4-Chlorobutoxy)benzoic acid methyl ester. ’
A mixture of 30.4 (0.2 mole) of methyl-4-hydroxybenzoate, 68.6¢g(0.4 mole) of 1-bromo-4-chlorobutane and 82.9 g (0.6 mole) of anhydrous potas- sium carbonate in 1 liter of acetone was heated at reflux for 17 hr. The mixture was cooled and filtered, and the filtrate concentrated under reduced pressure to give an oil which crystallized. The solid was triturated with cold petroleum ether (30-60°C), collected by filtration, and dried to yield 44.3 g : 15 (92%) of title compound as a white solid. An analytical sample, mp 28.5-29°C, oo was prepared from petroleum ether (30-60°C). a Analysis: Calculated for C12H5C103: C, 59.39; H, 6.23 . Vv | “Found : C,59.30;H,6.34 \ : 2 Preparation 102 ’ 1-[4-(4-Chlorobutoxy)-3-methoxyphenyljethanone.
A mixture of 16.6 g (0.1 mole) of acetovanillone, 34.3 g (0.2 mole) of 1- bromo-4-chlorobutane and 41.4 g (0.3 mole) of anhydrous potassium carbo- : : nate in 500 ml of acetone was heated at reflux for 18 hr. The mixture was cooled, filtered, and the filtrate concentrated under reduced pressure to give } an oil which readily crystallized. The solid was triturated with petroleum ether (30-60°C), collected by filtration, and dried to yield 24.4 g (95%) of title compound as an off-white solid. An analytical sample, mp 68.5-70.5°C, was : prepared from isopropyl ether. cr
Analysis: Calculated for C13H7C103: C, 60.82; H, 6.67
Found : C,60.83;H,6.91
Preparation 103 1. Acetyl-a-(4-fluorophenyl)-a-phenyl-4-piperidinemethanol. .
A solution (667 ml, 2 mole) phenylmagnesium bromide* (3 molar in ethyl ether) was diluted with 2 liters of anhydrous ethyl ether, cooled to 0- 10°C, and treated with a solution of 148 g (0.6 mole) of 1-acetyl-4-(p-fluoro- benzoyl)piperidine in 1.5 liters of anhydrous tetrahydrofuran dropwise over a 1.5 hr period. The mixture was stirred at ambient temperature overnight and then poured into a solution of 107 g (2 mole) of ammonium chloride in 2 liters of cold water. The mixture was extracted thrice with 1 liter portions of benzene. The combined extracts were washed with water, dried over magne- sium sulfate, and concentrated to give a semi-solid as residue. The semi-solid was triturated with isopropyl ether, and the mass crystallized. The solid was collected by filtration and dried to yield 87.8 g (45%) of title compound asa white solid. An analytical sample was recrystallized from 2-propanol, mp 173-175°C. -
Analysis: Calculated for CpoH22FNOg: C, 73.37; H,6.77;N, 4.28
Found St iC, 73.20: H, 6.93; N; 4.22 * Available commercially, e.g., Morton Thiokol, Inc., Alpha Products, 152
Andover Street, Danvers, Mass. 01923 USA.
Preparation 104 a,a-Bis(4-chlorophenyl)-4-piperidinemethanol.
To a slurry of 8.5 g (0.225 mole) of lithium aluminum hydride in 400 ml of anhydrous tetrahydrofuran was added a solution of 39.2 g (0.09 mole) of 4- [bis(4-chlorophenyDhydroxymethyl]-N,N-diethyl-1-piperidinecarboxamide in 400 ml of tetrahydrofuran in a stream over a 15 min period. The mixture was heated at reflux for 24 hr, cooled, and treated successively with 8.5 ml of water, 25 ml of a 3 N sodium hydroxide solution and 8.5 ml of water. The mixture was stirred for 0.5 hr and then filtered. The filtrate was concen- trated under reduced pressure to give a gum which crystallized. The solid was triturated with petroleum ether (30-60°C), collected by filtration and recrystallized from benzene to yield 10.5 g (35%) of title compound as a white solid. An analytical sample was recrystallized from 2-propanol, mp 184- 188°C.
MN
.81- : Analysis: Calculated for C1gH19CIgNO: C, 64.30; H, 5.70; N, 4.17 : Found : C,64.59;H,5.79;N,4.16 .
Preparation 105 a,a-Bis(4-fluorophenyl)-4-pyridineethanol.
A solution of 27.8 g (0.30 mole) of 4-picoline in 400 ml of tetrahydro- furan and under an atmosphere of nitrogen was cooled to -30°C in a dry-ice acetone bath. A solution of 2.5 moles n-butyllithium in hexane (119 ml, 0.30 mole) was added over 1 hr and the mixture was stirred for an additoinal 30 min at -30°C. The reaction mixture was allowed to warm to room tempera- : ture over 1.5 hr, and 66.7 g (0.30 mole) of 4,4'-difluorobenzophenone in 100 ml of tetrahydrofuran was added. The mixture was stirred for 2 hr and then was poured into an icy solution of ammonium chloride. A white solid wascol- lected. The aqueous mixture was extracted with several portions of methy- lene chloride and the methylene chloride then removed in vacuo to give additional solid. The solid fractions were combined and recrystallized from a mixture of ether-hexane to give 63.14 g (67.9% yield) of title compound as a white crystalline solid: mp 158-159.5°C. \
Analysis: Calculated for C1gH5NOF3: C, 73.30; H, 4.86; N, 4.50
Found : C,73.27; H, 4.79; N, 4.51
Preparation 106 a.a-Bis(4-fluorophenvl)-4-piperidineethanol..
A mixture of 12.25 g (0.0394 mole) of a,a-bis(4-fluorophenyl)-4- 26 pyridineethanol and 1.3 g of 5% platinum on carbon catalyst in 250 ml of - acetic acid was shaken under an atmosphere of hydrogen (53 psi) for 9 hr.
The solution was filtered through Celite®, and the solvent was removed in vacuo. The residue was partitioned between methylene chloride and dilute sodium hydroxide. The solvent was removed in vacuo to give a solid.
Recrystallization from acetonitrile gave 10.62 g (85.0% yield) of title compound as a white crystalline solid: mp 169-171°C.
Analysis: Calculated for CjgHo)NF20: CC, 71.90; H, 6.67; N, 4.41
Found + C,71.98;H,6.75; N, 4.54
TN
-82-
Preparation 107 a-(4-Fluorophenyl)-a-phenyl-4-piperidinemethanol. :
A mixture of 16.3 g (0.05 mole) of 1-acetyl-a-(4-fluorophenyl)-a-phenyl- 4-piperidinemethanol and 5.6 g (0.1 mole) of potassium hydroxide in 150 ml of 95% ethanol and 20 ml of water was heated at reflux for 18 hr. The mix- ture was poured into 1.5 liters of ice-water and a solid precipitated. The gum- my solid was collected by filtration and dried. The solid was dissolved in ethyl ether, filtered, and the filtrate slowly evaporated to 50 ml. The result- ing solid was collected by filtration and recrystallized from isopropanol-iso- propyl ether to yield 3.5 g (25%) of title compound as a white solid, m.p. 144.5-146°C. ‘ Analysis: Calculated for C1gH2oFNO: C, 76.76; H, 7.06; N, 4.91
Found : C,75.91; H, 7.20; N, 4.93 16 Preparation 108 } 4-[2-2,Bis(4-fluorophenyl)ethyllpyridine hydrochloride [1:1].
A mixture of 15.05 g (0.0484 mole) of a, a-bis(4-fluorophenyl)ethyl]-4- pyridineethanol, 3.2 g (0.10 mole) of phosphorus and 50 ml of 56.9% hydrogen iodide in 150 ml of glacial acetic acid was refluxed for 11 hr. The solvent was removed in vacuo, and the residue was partitioned between methylene chlor- "ide and dilute sodium hydroxide. The methylene chloride solution was dried over magnesium sulfate, and the solvent was removed in vacuo to give an oil.
This was dissolved in a mixture of methanol and ether, and an excess of ethereal hydrogen chloride was added. The solvent was removed in vacuo, and the residue was recrystallized from a mixture of acetonitrile and ether to give 13.89 g (86.7% yield) of title compound as a white crystalline solid, m.p. 197-199°C.
Analysis: Calculated for C1gH1gNF2Cl: C, 68.78; H,4.86:N, 4.22
Found : C,68.58;H,5.17; N, 4.23
Preparation 109 4-[2.2-Bis(4-fluorophenylethyl]piperidine hydrochloride hydrate [1:1:0.5].
A mixture of 10.0 g (0.30 mole) a,a-bis(4-fluoropheny)-4-pyridineetha- nol and 1.2 g of 5% platinum on carbon catalyst in 200 ml of acetic acid was
4 L .83- shaken under an atomsphere of hydrogen (49 psi) for 16 hr. The solution was filtered through Celite®, and the solvent was removed in vacuo. The residue was partitioned between methylene chloride and dilute sodium hydroxide.
The solvent was removed in vacuo to give an oil. This was dissolved in methanol, an excess of ethereal hydrogen chloride was added and ether was added. A precipitate was collected to give 7.58 g (72.4%) as a white crystalline solid, m.p. 171-173°C.
Analysis: Calculated for C1gHo3NF2ClOg 5. C, 65.80; H, 6.68; N, 4.04
Io Found : C,65.79; H, 6.80; N, 4.05
Preparation 110 4-[2,2-Bis(4-fluorophenyl)ethylene]piperidine oxalate [1:1].
A mixture of 8.44 g (0.0266 mole) of a,a-bis(4-fluorophenyl)-4-piperi- dineethanol and 25 ml of concentrated sulfuric acid in 200 ml of glacial acetic acid was refluxed for 4 hr. The solvent was removed in vacuo, and the residue ~ was made basic with 50% sodium hydroxide. The basic mixture was
Ce extracted with methylene chloride, and the methylene chloride solution was
Co dried over magnesium sulfate. The solvent was removed in vacuo to give an
EE | oil. The oil was dissolved in a mixture of methanol ether, and a slight excess
BEL | of oxalic acid was added. Ether as added, and a precipitate was collected to give 8.79 g (85.0% yield) of title compound as a white crylstalline solid, m.p. 225-225.5°C with decomposition.
Analysis: Calculated for Co1H9)NF204 : C,64.78; H,5.44; N, 3.60 - Found : C,64.95:H,5.56; N, 3.61
Preparation 111 4-[Bis(4-chlorophenyl)methyl)piperidine oxalate hydrate {1:1:0.5].
A mixture of 4-[bis(4-chlorophenyl)methylene]piperidine (13.05 g, 0.041 mole), phosphorus (45.0 g, 1.45 mole), glacial acetic acid (300 ml) and 57% hydriodic acid (230 ml) was heated at reflux for 72 hr. The mixture was cooled to room temperature, stirred 5 min with Celite®, and filtered. The filtrate was made basic with ice/50% sodium hydroxide. The alkaline layer was extracted with chloroform. The chloroform layer was dried over sodium sulfate and filtered, and solvent removed to give a brown oil. A 0.65 g portion of the oil was converted to the oxalate salt and the salt was recrystallized
. N .84- from ethanol-diethyl ether. A white solid was isolated and dried in vacuo overnight at 80°C. This provided 0.46 g (59.1% yield) of white crystalline : solid, m.p. 219-220°C.
Analysis: Calculated for C29H22NO4 5Cl2: C, 57.29: H, 5.29; N, 3.34
J Found : C, 57.26; H,4.99; N, 3.36
Preparation 112
Cyclohexyl[1-(phenylsulfonyl)-4-piperidinyljmethanone. . To a solution of 25.1 g (0.085 mole) of 1-(phenylsulfonyl)-4-piperidine- carboxylic acid, ethyl ester in 500 ml of dry, cooled to 0°C and under an atmosphere of nitrogen, was added 95 ml of a 2 molar solution (0.19 mole) of cyclohexylmagnesium bromide in ether. The mixture was stirred for 2 hr at ambient temperature and then was quenched on an icy solution of ammon- ium chloride. The mixture was extracted with methylene chloride. The methylene chloride solution was dried over magnesium sulfate, and the solvent was removed in vacuo to give a semisolid material. This was recrystallized from ethanol to give 8.50 g (29.8% yield) of title compound as a white crystalline solid, m.p. 141-143°C.
Analysis: Calculated for C1gH2sNO3S: C, 64.45; H, 7.51; N, 4.18
Found ©: C,64.39;H,7.82;N,4.20°
Preparation 113 4-[2.2-Bis(4-fluorophenyllethvlenelpyridine.
A mixture of 1.57 g (0.0050 mole) of a,a-bis(4-fluorophenyl)-4-pyridine- ethanol, 10 ml of concentrated sulfuric acid and 80 ml of glacial acetic acid . was heated at reflux for 2 hr. The solvent was removed in vacuo, and the residue was made basic with an icy solution of dilute sodium hydroxide. The aqueous mixture was extracted with methylene chloride, and the methylene chloride extract was dried over magnesium sulfate. The solvent was removed in vacuo to give a colorless oil. This was crystallized from ether-hexane to give 0.74 g (50% yield) of title compound as a white crystalline solid, m.p. 111-112.5°C.
Analysis: Calculated for CjgH13NF2: C, 77.80; H, 4.47; N, 4.78
Found - + C,77.78;H,4.42; N, 4.74
Preparation 114 a-Cyclohexyl-a-(4-fluorophenyl)-1-(phenylsulfonyl)-4-piperidine- - methanol.
A solution of (4-fluorophenyl)[1-(phenylsulfonyl)-4-piperidinylJmetha- none (20.8 g, 0.06 mole) in 250 ml of tetrahydrofuran (dried over 4A sieves) was prepared. This solution was stirred 0.5 hr under nitrogen atmosphere in an ice bath. Next, cyclohexylmagnesium chloride (35 ml of 2 molar in diethyl ether, 0.070 mole) was added dropwise with a syringe (under nitrogen atmos- phere). The resulting solution was stirred for 48 hr allowing the reaction solution to cool to room temperature. The reaction mixture was stripped to dryness and treated with aqueous ammonium chloride. The aqueous solution was extracted with chloroform, and the chloroform layer was back extracted with water. The chloroform layer was dried over sodium sulfate and filtered, and solvent removed to give a fluffy white residue. This material was sub- jected to flash chromatography on silica gel using 20% ethyl acetate-80% hexanes, and 30% ethyl acetate-70% hexanes for elution. Fractions contain- ing a single spot were combined, and solvent was removed in vacuo. A fluffy white residue was obtained and dried in vacuo overnight at 80°C in the presence of phosphorus pentoxide. This procedure produced 16.72 g (64.7% yield) of the title compound as a white crystalline solid, m.p. 106-109°C.
Analysis: Calculated for Co4H30NO3SF : C, 66.79; H, 7.01; N, 3.24
Found : C,66.78;H,7.09;N, 3.21
Preparation 115 a,a-Bis(3-fluorophenyl)-1-(phenylsulfonyl)-4-piperidinemethanol. : To a suspension of 7.78 g (0.33 mole) of magnesium turnings and a crystal of iodine in 800 ml of anhydrous ether under an atmosphere of nitro- gen was slowly added a solution of 3-bromofluorobenzene in 200 ml of ether.
The mixture was stirred for 1.5 hr and 30.6 g (0.103 mole) of ethyl 1-benzene- - 30 sulfonylisonipecotate was added as a solid. Tetrahydrofuran (300 ml) was added, and the mixture was stirred at room temperature for 12 hr. The mix- ture was poured into an icy solution of ammonium chloride. The aqueous mixture was extracted with methylene chloride, and the resulting residue
Co was recrystallized from ether to give 24.14 g (52.9%) of the title compound as a white crystalline solid, m.p. 183-185°C.
h -86-
Analysis: Calculated for C24H23NO3SF3 : C,65.00; H,5.23; N, 3.16
Found : C,6495;H,5.38;N,3.15 .
Preparation 116 4-[Bis(3-fluorophenylmethyl]piperidine hydrochloride [1:1].
A mixture of 15.25 g (0.0344 mole) of a,a-bis(3-fluorophenyl)-1-phenyl- sulfonyl-4-piperidinemethanol, 50 ml of 57% hydrogen iodide and 3.4 g (0.11 mole) of phosphorous in 300 ml of glacial acetic acid was heated at reflux for 40 hr. The reaction mixture was filtered, and the solvent was removed from the filtrate in vacuo. The residue was partitioned between methylene chlor- ide and dilute sodium hydroxide. The methylene chloride solution was dried over magnesium sulfate, and the solvent was removed in vacuo. The residue was dissolved in methanol, excess ethereal hydrogen chloride was added and anhydrous ether was added. A white precipitate was collected to give 7.04 g (63.2% yield) of title compound as a white crystalline solid, m.p. 260-262°C.
Analysis: Calculated for C1gH2oNF2Cl C,66.77; H,6.23; N, 4.33
Found + C,66.45;H,6.26; N, 4.28
Preparation 117 5-Methoxy-2-nitro-4-(phenylmethoxy)benzamide. : A solution of 5-methoxy-2-nitro-4-(phenylmethoxy)benzoic acid (25.84 g, 0.085 mole) and thionyl chloride (200 ml) was heated overnight at gentle reflux in 100 ml of methylene chloride. The reaction mixture was stripped to dryness and dried in vacuo. To this residue was added 200 ml of dioxane (dried over molecular sieves). Ammonia was slowly added to the soution with constant agitation. A brown solid was formed and the mixture was filtered.
The brown solid was washed with dioxane, water, and isopropanol. The grey solid thus obtained was dried in vacuo at room temperature (23.2g). A2g portion was triturated in refluxing ethanol and then cooled to room tempera- ture. A white solid was filtered and dried in vacuo at 80°C overnight. This furnished 1.72 g (77.5% yield) of white crystalline solid, m.p. 222-223.5°C with decomposition.
Analysis: Calculated for C15H14N20s: C, 59.60; H, 4.67; N, 9.27
Found : C,59.48; H, 4.68; N,9.19
Preparation 118 4-] (Cyclohexyl)(4-fluorophenyl )methyllpyridine. .
A mixture of the free base of a-cyclohexyl-a-(4-fluorophenyl)-4-piperi- dinemethanol (16.54 g, 0.058 mole), 57% hydrogen iodide (250 ml), glacial acetic acid (250 ml), and phosphorus (50.0 g) was heated overnight at reflux.
The reaction mixture was cooled and filtered with Celite®. The volume of the filtrate was concentrated to 100 ml. Ice/50% sodium hydroxide was added, and the aqueous phase was extracted with chloroform. The chloroform layer was back extracted with 5% sodium hydroxide and water. The organic layer was dried over sodium sulfate and filtered, and solvent removed to give a green oil. A 4 g portion of this oil was subjected to flask chromatography on silica gel using 20% ethyl acetate-hexanes for elution. Fractions of similar purity were combined and solvent removed to give an oil. This oil was dried in vacuo overnight at 80°C. The oil crystallized to give 2.95 g (18.9% yield) of white crystalline solid, m.p. 78-81°C. } Analysis: Calculated for C1gHzoNF : C,80.26; H, 7.48; N, 5.20
Found . C,79.96;H,7.45;N,5.23
Preparation 119 4-[(Cyclohexyl )(4-fluorophenyl)methyl |piperidine. : A mixture of 4-[(cyclohexyl)(4-fluorophenyhmethyllpiperidine (10.42 g, 0.039 mole), platinum oxide (1.5 g), and 10 drops of concentrated hydrochloric acid in 200 ml of glacial acetic was subjected to hydrogenation at 80°C and 300 p.s.i. overnight, after which NMR analysis showed 50% desired product and 50% starting material. The reaction was repeated using 5% platinum on carbon at 85°C and 1400 p.s.i. overnight. The reaction mixture was then “cooled to room temperature and filtered. Solvent was removed by rotary - evaporator. The oil obtained was dissolved in chloroform and the solution was extracted with 5% sodium hydroxide and water. The chloroform layer was dried over sodium sulfate and filtered, and the solvent removed to give 9.94 g of brown oil. NMR analysis showed a 75%-25% mixture of product and starting material. The 9.94 g of oil obtained was dissolved in methanol and : subjected to flash chromatography on silica gel using methanol and ammo- nium hydroxide - methanol for elution. Fractions of similar purity were combined and solvent removed. The clear oil obtained was dried in vacuo overnight at 80°C, to give 5.86 g (59.6% yield) of title compound as a clear oil.
H! NMR (CDCl3): 56.9-7.2(d, 7, aromatic), §0.8-3.3(m, 22, alaphatics)
Analysis: Calculated for C1gHggNF : C, 78.50; H,9.52; N, 5.09
Found : C,78.26;H,9.41; N, 5.06
Preparation 120 1-Acetyl-4-(p-fluorobenzoyl)piperidine.
A mixture of 93 g (0.7 mole) of aluminum chloride in 150 ml of fluoro- benzene was stirred while 70 g (0.37 mole) of 1-acetylisonipecotic acid chloride was added in small portions. After the addition was complete, the mixture was refluxed for 1 hr. The mixture was poured onto ice and the2 resulting layers were separated. The aqueous layer was extracted twice with chloroform, and the chloroform extracts were added to the fluorobenzene which was separated previously. The organic solution was dried over anhy-- drous sodium sulfate and filtered. The filtrate was concentrated, and 73.7 g (80% yield) of 1-acetyl-4-(p-fluorobenzoyl)-piperidine was obtained asa crystalline residue. Recrystallization from ligroin-isopropyl ether gave a white crystalline product melting at 75-78°C.
Analysis: Calculated for C14H16FNO2: C, 67.45; H, 6.47; N, 5.62
Found : C,67.26;H,6.50; N, 5.54
Preparation 121 (4-Fluorophenvl){ 1-(phenylsulfonyl)-4-piperidinyl methanone.
A mixture of 4-(4-fluorobenzoy!)piperidine hydrochloride (53.30, 0.219 mole) and benzenesulfonyl chloride (44 g, 0.25 mole) in 500 ml of pyridine | was stirred at room temperature overnight. The solvent was removed in vacuo, and the residue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene chloride solution was extracted with dilute sulfuric acid and then dried over magnesium sulfate. The volume was reduced to 400 ml, hexane was added and 39.20 g (50.6%) of title com- pound was collected as a white, crystalline solid, m.p. 156.5-158°.
Analysis: Calculated for C1gHgNO3SF: C, 62.23: H, 5.22; N, 4.03 .
Found : C,62.13; H,5.20; N, 4.13
Preparation 122 4-[Bis(4-fluorophenyl)methyl]-1-(3-chloropropyl)piperidine.
A solution of 4-[bis(4-fluorophenyl)methyl}-1-piperidinepropanol (40.27 g, 0.117 mole) and thionyl chloride (17.90 g, 0.150 mole) in 350 mL of chloroform was stirred at room temperature for 0.5 hr. The solution was heated at reflux for 6 hr, cooled to room temperature, and then stripped to dryness. The gum obtained was dissolved in chloroform and extracted with saturated sodium bicarbonate. The chloroform layer was dried (anhydrous ‘sodium sulfate) and filtered, and solvent removed to give a reddish-brown oil (42.11 g, 99%). An 8 gram sample was subjected to flash chromatography on or silica gel using 50-50 v/v of ethyl acetate-hexanes for elution. After com-
Bh 5 .. .. bining fractions, removing solvent, and drying the oil obtained in vacuo, . 6.84 g (84.6% yield) of brown oil was obtained, the title compound.
H1 NMR (CDCl3) 8: 6.7-7.3 (m, 8, aromatics), 3.4-3.7 (m, 3, methine adjacent to aromatics and methylenes adjacent to Cl), 1.0-3.0 (m, 13, remaining -alaphatics).
Analysis: Calculated for C19Hg4NF3Cl : C, 69.32; H, 6.65; N, 3.85
Found : C,69.09;H,6.60; N, 3.84 : Preparation 123 (4-Fluorophenyl) (4-pyridinyl)methanone.
A solution of 4-cyanopyridine (20.8 g, 0.2 mole) in 300 ml of tetrahydro- furan was cooled in an ice bath. Next, a 100 ml soution of p-fluorophenyl magnesium bromide (2 moles in diethyl ether) was added with a syringe under nitrogen atmosphere with stirring. The resulting solution was stirred at room temperature for 1 hr and then heated at reflux for 6 hr. The solution was stripped to dryness and then transferred (via chloroform) to a mixture of ice and concentrated hydrochioric acid (100 ml). The aqueous phase was made alkaline (using 5% sodium hydroxide solution) and the chloroform 3 layer separated with the aidof Celite®. The chloroform layer was dried over
. N\ -90- sodium sulfate and filtered, and solvent removed to give a dark brown oil (33.1 g, 82.3%). The oil was subjected to flash chromatography on silica gel using 40% ethyl acetate-hexanes and 50% ethyl acetate-hexanes for elution.
Fractions of similar purity were combined and solvent removed to give a yellow solid (25.81 g). A 2 g portion was recrystallized from 100 ml of hexanes. A light yellow solid was isolated and dried in vacuo overnight at room temperature, to give 1.88 g (77.3% yield) of light yellow solid, m.p. 85- 88°C.
Analysis: Calculated for C12HgNOF : C, 71.64; H,4.01;N, 6.96
Found :C, 71.83; H, 3.95; N, 6.99
Preparation 124 a-(3,4-Difluorophenyl)-a-(4-fluorophenyl)-1-(phenylsulfonyl).4- piperidinemethanol. ;
A three-necked round bottom flask, equipped with a mechanical stirrer, oo flushed with nitrogen, and containing 3.74 g (0.154 mole) of magnesium turnings, was dried with a bunsen burner. After the flask had cooled, 600 ml of tetrahydrofuran was added. To this mechanically stirred mixture was slowly added a solution of 29.4 g (0.152 mole) of 4-bromo-1,2-difluorobenzene in 50 ml of tetrahydrofuran. The mixture was stirred for 1 hour, and 45.11 ¢g (0.13 mole) of (4-fluorophenyl)[1-(phenylsulfonyl)-4-piperidinyllmethanone "was added as a solid. The solution was stirred at ambient temperatures for 3 hours and was poured into an icy aqueous solution of ammonium chloride.
The aqueous mixture was extracted with methylene chloride, the methylene chloride solution was dried (magnesium sulfate), and the solvent was . removed in vacuo. The residue was recrystallized from methylene chloride- hexane to give 58.89 g (82.9%) of title compound. A small sample was recrystallized from a mixture of methylene chloride-ether-hexane to give an analytically pure sample of the title compound: mp 97-99°C.
Analysis: Calculated for C24H29NO3SF3: C, 62.46; H,4.81; N, 3.04
Found : (C,62.63;H, 4.86; N,3.02
Preparation 125 4-{(3,4-Difluorophenyl)(4-fluorophenyl)methylene piperidine oxalate
A mixture of 30.19 g (0.065 mole) of a-(3,4-difluorophenyl)-a-(4-fluoro- phenyl)-1-phenylsulfonyl-4-piperidine methanol, 4.0 g (0.125 mole) of phos- phorus and 160 ml of 47% hydriodic acid in 400 ml of glacial acetic acid was refluxed for 52.5 hours. The solvent was removed in vacuo, and the residue was partitioned between methylene chloride and dilute sodium hydroxide.
The methylene chloride solution was dried over sodium sulfate and was filtered through a sentered glass funnel (fine porosity), and the solvent was removed in vacuo. The residue was flash chromatographed (silica gel, elution with methanol and then with a 99/1 mixture of methanol/ammonium hydrox- ide) to give two separate products: the non-salt forms of the title compoynd + rom rs mins and 4-((3,4-difluorophenyl)(4-fluorophenyl)methyl}piperidine. Both of these were converted to the oxalate salts. The title compound was recrystallized
Ca el _ from methanol ether to give 0.47 g (0.24%) of product as a white crystalline solid, mp 195-198°C.
Analysis: Calculated for CooHgNF304 : C, 61.07; H,4.61;N, 3.56
Found : C,60.88; H,4.57: N, 3.57
Preparation 126 : 4-[(3.4-Difluorophenyl)(4-fluorophenyl)methyllpiperidine oxalate hvdrate [1:1:0.5].
A mixture of 30.19 g (0.065 mole) of a-(3,4-difluoropheny)-a-(4-fluoro- phenyl)-1-phenylsulfonyl-4-piperidinemethanol, 14.0 g (0.125 mole) of phos- + phorus and 160 ml of 47% hydriodic acid in 400 ml of glacial acetic acid was refluxed for 52.5 hours. The solvent was removed in vacuo, and the residue was partitioned between methylene chloride and dilute sodium hydroxide.
The methylene chloride solution was dried over sodium sulfate and was fil- tered through a sentered glass funnel (fine porosity), and the solvent was removed in vacuo. The residue was flash chromatographed (silica gel, elution with methanol and then with a 99/1 mixture of methanol/ammonium : hydroxide) to give the non-salt forms of 4-[(3,4-difluorophenyl)(4-fluoro- phenyl)methylene]piperidine and the title compound. The title compound was recrystallized from acetonitrile to give 5.64 g (21.5%) of a white solid, m.p. 78-83°C. .
Analysis: Calculated for C2oH21NF3045: C, 59.40; H,5.23; N, 3.46
Found : C,59.58;H,5.05; N, 3.48
Preparation 127 1-[(4-Methylphenyl)sulfonyl]-3-pyrrolidinol (4-methylphenyl)sulfonate ester.
A solution of N-benzyl-3-pyrrolidinol (50.0 g, 0.282 mole) and triethyl- amine (100 ml) in 300 ml of acetonitrile (dried over 4A molecular sieves) was prepared and chilled in an ice bath. A solution of tosyl chloride (88.6 g, 0.465 mole) in 300 ml of acetonitrile was prepared and added dropwise with stirring to the prior solution. The solution obtained was stirred overnight and allowed to reach room temperature. The reaction mixture was filtered, and the solvent was removed by rotary evaporator. The residue obtained was dissolved in chloroform, and the organic layer extracted successively with 5% sodium hydroxide and water. The chloroform layer was dried (sodium sul- fate) and filtered, and solvent was removed to give a dark brown oil. This oil was stirred overnight at room temperature in isopropanol. A brown oil crystallized, and the solid was separated by filtration and washed with isopropanol. The brown solid was dried in vacuo (27.67 g, 24.8%). A one gram sample of this material was recrystallized from ethyl acetate; a light brown solid was isolated and dried at 80°C overnight in vacuo. This procedure furnished 0.13 g (3.2% yield based on aliquot) of light brown solid, mp 121-122°C. "Analysis: Calculated for C1gH21NO5S2: CC, 54.67; H, 5.35; N, 3.54
Found : C,54.71;H,5.41; N, 3.52
Preparation 128 a,a-Bis(4-fluorophenyl)-1-[(4-methylphenyl)sulfony! ]-3-pyrrolidine- acetonitrile.
The sodium salt of 4-fluoro-a-(4-fluorophenyl)benzeneacetonitrile was prepared in dimethylsulfoxide from 4-fluoro-a-(4-fluorophenyl)benzeneaceto- nitrile (11.60 g, 0.0506 mole) and sodium hydride (60%, 2.02 g, 0.0506 mole).
Next, 1-[(4-methylphenyl)sulfonyl]-3-pyrrolidinol (4-methylphenyl)sulfonate
N
-93- ester (20.0 g, 0.0506 mole) in 200 ml of dimethyl sulfoxide was added. The solution was stirred overnight at 55°C. The solvent was then removed. A dark brown oil was obtained and dissolved in chloroform. The organic layer was extracted with 1N sulfuric acid and 5% sodium hydroxide. The chloro- form layer was dried (over sodium sulfate) and filtered; solvent was removed to give a dark brown oil. The oil was triturated with isopropanol and placed in the freezer over the weekend. A brown solid was separated by filtration (18.33 g, 80.1%). A one gram sample of the solid was recrystallized from isopropanol. A light brown solid was separated and dried in vacuo overnight at 80°C in the presence of phosphorus pentoxide. This process furnished 0.57 g (45.7% based on aliquot taken) of light brown solid, m.p. 181-183°C based upon the aliquot taken.
Analysis: Calculated for CosHo9N2O9SFg: C, 66.36; H, 4.90; N, 6.19
Found : C,65.80;H,4.91;N, 6.03
Preparation 129 a,a-Bis(4-fluorophenyl)-3-pyrrolidineacetonitrile oxalate hydrate [1:1:0.5].
A mixture of a,a-bis(4-fluorophenyl)-1-{(4-methylphenyl)sulfonyl]-3- pyrrolidineacetonitrile (16.6 g, 0.0367 mole), phenol (50 g, 0.53 mole) and 300 - ml of 48% hydrobromic acid was heated at reflux for two hours. The reaction mixture was cooled to room temperature and made alkaline with ice/50%
Co sodium hydroxide. The aqueous layer was extracted with chloroform. The chloroform layer was back extracted with 5% sodium hydroxide, dried over sodium sulfate, filtered, and solvent removed to produce a dark brown oil. oo * The dark brown oil was dissolved in chloroform and extracted with 1N : sulfuric acid. This acidic layer was discarded. The chloroform layer was extracted with base and solvent was removed to give a dark brown oil. This oil was converted to the oxalate salt, and the salt was recrystallized from methanol-diethylether. A white solid was isolated and dried in vacuo co overnight at 80°C, to give 7.17 g (49.2%) of the title compound as an off-white solid, mp 88.5-90°C.
Analysis: Calculated for CooH9N9oO4 5Fy: C, 60.45; H,4.82; N, 7.05
Found : C,60.52,H,4.56;N,7.01 :
.04.
Preparation 130 1-[(4-Methylphenylsulfonyl]-3-piperidinemethanol (4-methylphenyl)- sulfonate ester.
A solution of 3-piperidinemethanol {50.0 g, 0.434 mole) in 300 ml of acetonitrile (dried over 4A molecular sieves) was prepared. This solution was cooled in an ice bath, and a solution of triethylamine (150 ml in 200 ml of acetonitrile) was added while simultaneously adding a solution of p-toluene- sulfonyl chloride (191 g, 1.0 mole) in 300 ml of acetonitrile. After the addi- tions were complete, the resulting solution was stirred 3.5 hours at room tem- perature. The mixture was filtered and solvents were removed by a rotary evaporator to give a dark brown oil. The oil was dissolved in chloroform and extracted with 5% sodium hydroxide and also IN sulfuric acid. The chloro- form layer was dried over sodium sulfate and filtered, and solvent was removed to give a dark brown oil. This oil was triturated with isopropyl ether to give a brownish-white solid. This light brown solid was separated and then triturated with hot isopropanol. The mixture was chilled in the freezer and filtered. A light brown solid was isolated and dried in vacuo overnight at 65°C (142.29 g, 77.5%). A give gram sample of this material was recrystal- lized from isopropyl alcohol, and the brown solid isolated was dried overnight in vacuo at 80°C. This provided 3.55 g (55% yield based on aliquot taken) of ~ light brown solid, m.p. 108-109°C.
Analysis: Calculated for CooHo5NO5S9: C, 56.72; H, 5.95; N, 3.31
Found + C,56.43; H,6.00; N, 3.32
Preparation 131 a,a-Bis(4-fluorophenyl)-1-[(4-methylphenyl)sulfonyl}-3-piperidine- propanenitrile.
The sodium salt of 4-fluoro-a-(4-fluorophenyl)benzeneacetonitrile was prepared in 350 ml of dimethyl sulfoxide (dried over 4A molecular sieves) from sodium hydride (60% 4.37 g, 0.109 mole) and 4-fluoro-a-(4-fluoro- phenyl)benzeneacetonitrile (25.0 g, 0.109 mole). The resulting dark brown solution was stirred at room temperature for 1 hour. 1-((4-Methylphenyl)- sulfonyllpiperidinemethanol (4-methylphenyl)sulfonate ester (46.18 g, 0.109 mole) was added and the resulting solution was stirred for 2 hours at roorn temperature. The solution was then stirred overnight at 60°C. The dimethyl sulfoxide was removed by rotary evaporator. A dark brown residue was obtained which was dissolved in chloroform. The chloroform layer was - extracted several times with water. The chloroform layer was dried over sodium sulfate, filtered, and solvent removed to give a thick brown oil. The oil was triturated with isopropyl ether to give a white solid (46.54 g, 82.7%). : A 5 g portion of this solid was recrystallized from isopropanol to give a white solid and was isolated and dried in vacuo overnight at 80°C. This furnished : 3.96 g (70.4% yield) of the title compound as a white crytalline product, m.p. 142-143 °C.
Analysis: Calculated for Cg7H26N202SF3 : C, 67.48; H, 5.45; N, 5.83
Found : C,67.17;H,5.46: N, 5.75
Preparation 132 a,a-Bis(4-fluorophenyl)-3-piperidinepropanenitrile.
A mixture of a,a-bis(4-fluorophenyl)-1-[(4-methylphenyl)sulfonyl]-3- piperidinepropanenitrile (41.21 g, 0.0858 mole) and phenol (100 g, 1.06 mole) in 200 ml of 48% HBr was heated at reflux for 2 hours. The reaction mixture “was cooled to room temperature and made alkaline with ice and 50% sodium hydroxide. The aqueous layer was extracted with chloroform. The chloro- form layer was back extracted with 5% sodium hydroxide. The organic layer * was then dried over sodium sulfate and filtered, and solvent was removed to give a dark brown oil. This oil was subjected to flash chromatography on ‘silica gel using methanol for elution. Fractions of similar purity were com- bined and solvent removed. The oil obtained was dried in vacuo overnight at 80°C, to give 18.83 g (67.2% yield) of brown oil.
H!NMR (CDCl3): 6 6.9-7.6 (m, 8, aromatics), 1.1-3.1 (m, 12, aliphatics)
Analysis: Calculated for CogHogN9Fg : C, 73.60; H, 6.18: N, 8.58
Found : C,73.19;H,6.11;: N, 8.56 ‘ Preparation 133 a,a-Bis(4-flurophenyl)-4-piperidineacetamide hydrochloride [1:1].
A solution of a,a-bis(4-fluorophenyl)-4-piperidineacetonitrile (free base of Preparation 67) (9.31 g, 0.0298 mole) in 100 ml of 90% sulfuric acid solu- tion was heated overnight at 85°C. The solution was cooled to room tempera-
NN
-96- ture and made basic with 50% sodium hydroxide solution/ice. The aqueous layer was extracted with chloroform. The chloroform layer was dried over sodium sulfate, filtered, and solvent removed in vacuo. A white solid was obtained upon removal of solvent (9.19 g, 92.4%). A portion (2.25 g) of the white solid was converted to the hydrochloride salt and recrystallized from isopropyl alcohol/diethyl ether to give a white solid which was dried in vacuo overnight at 80°C. This provided 0.54 g (20.3% yield) of title compound as a white crystalline solid; mp 328°C with decomposition.
Analysis: Calculated for C1gH9)NoOF2Cl: C,62.21: H,5.77, N, 7.64
Found : C,6181;H,5.89;N, 7.45
Preparation 134 4-[Bis(3,4-diflurophenyl)methyllpiperidine hydrochloride [1:1].
A mixture of 4-a,a-bis(3,4-difluorophenyl}methyllpyridine (20.05 g, 0.063 mole) in glacial acetic acid (200 m)), concentrated hydrochloric acid (8 ml) and 5% platinum on carbon catalyst (3.0 g) was subjected to hydrogena- Co tion for 3 days at 60°C. The reduction mixture was filtered through Celite®, and the solvent removed in vacuo. The residue obtained was partitioned between methylene chloride and dilute sodium hydroxide. The solvent was dried over magnesium sulfate, filtered, and solvent removed to give an oil.
The oil was pumped in vacuo to a weight of 19.18 g (clear oil). The oil was first dissolved in methanol and a white solid crystallized. Methanol was removed by a rotary evaporation, and the white solid was dissolved in a small amount of methylene chloride and placed on a flash-chromatography column.
The column was eluted with methanol and 1/99 ammonium hydroxide/ * methanol. Fractions of similar purity were combined, and solvent removed to . give a clear 0il (15.30 g, 67.5% yield). A 2-g portion of the oil was dissolved in isopropyl alcohol and treated with ethereal hydrogen chloride. A white solid was isolated and dried in vacuo overnight at 80°C to give 1.35 g (41% yield) of white crystalline solid, m.p. 263-268°C.
Analysis: Calculated for C1gH1aNF4Cl: C,60.09; H, 5.04; N, 3.89
Found : C,59.71; H, 5.01; N, 3.87
Preparation 135
When in the procedure of Preparation 1 and substituting the following for 1-acetyl-4-diphenylhydroxymethylpiperidine: (a) a,a-bis(3,4-difluorophenyl)-4-piperidinemethanol, (b) a,a-bis(2,5-difluorophenyl)-4-piperidinemethanol, (¢) a,a-bis(2,4-difluorophenyl)-4-piperidinemethanol, (d) a,a-bis(3-trifluoromethylphenyl)-4-piperidinemethanol, and (e) a,a-bis(4-trifluoromethylphenyl)-4-piperidinemethanol. there are obtained: (a) 4[a,a-bis(3,4-difluorophenyl)methylene]piperidine, (b) 4[a,a-bis(2,5-difluorophenyl)methylene]piperidine, (c) 4[a,a-bis(2,4-difluorophenyl)methylenelpiperidine, (d) 4[a,a-bis(3-trifluoromethylphenyl)methylenelpiperidine, and (e) 4[a,a-bis(4-trifluoromethylphenyl)methylene]piperidine. 4 : Preparation 136
When in the procedure of Preparation 15 and substituting the following ©. for 4-bromoflurobenzene:
A , (a) 1-bromo-3,4-difluorobenzene, (b) 1-bromo-2,5-difluorobenzene, 1 (c) 1-bromo-2,4-difluorobenzene, (d) 3-bromobenzotrifluoride, and (e) 4-bromobenzotrifluoride.
There are obtained the following: (a) a,a-bis(3,4-difluorophenyl)-4-pyridinemethanol, (b) a,a-bis(2,5-difluorophenyl)-4-pyridinemethanol, (¢) a,a-bis(2,4-difluorophenyl)-4-pyridinemethanol, (d) a,a-bis(3-trifluoromethylphenyl)-4-pyridinemethanol, and (e) a,a-bis(4-trifluoromethylphenyl)-4-pyridinemethanol.
) 98.
Preparation 137 :
When in the procedure of Preparation 106 and substituting the follow- ing for a,a-bis(4-fluorophenyl)-4-pyridineethanol: (a) a,a-bis(3,4-difluorophenyl)-4-pyridinemethanol, (b) a,a-bis(2,5-difluorophenyl)-4-pyridinemethanol, (¢) a,a-bis(2,4-difluorophenyl)-4-pyridinemethanol, (d) a,a-bis(3-trifluoromethylphenyl)-4-pyridinemethanol, (e) a,a-bis(4-trifluoromethylphenyl)-4-pyridinemethancl, and (HD a,a-bis(4-fluorophenyl)-4-pyridinemethanol. there are obtained the following: (a) a,a-bis(3,4-difluorophenyl)-4-piperidinemethanol, (b) a,a-bis(2,5-difluorophenyl)-4-piperidinemethanol, (¢) a,a-bis(2,4-difluorophenyl)-4-piperidinemethanol, \ (d) a,a-bis(3-trifluoromethylphenyl)-4-piperidinemethanol, (e) a,a-bis(4-trifluoromethylphenyl)-4-piperidinemethanol, and 2 () a,a-bis(4-fluorophenyl)-4-piperidinemethanol.
Preparation 138
When in the procedure of Preparation 16 and substituting the following for 4-[bis(4-fluorophenyl)methylene]-1-(phenylmethyl)piperidine: (a) a,a-bis(3,4-difluorophenyl)-4-methylenepiperidine, (b) - a,a-bis(2,5-difluorophenyl)-4-methylenepiperidine, (¢) a,a-bis(3-difluorophenyl)-4-methylenepiperidine, and : (d) a,a-bis(4-trifluoromethylphenyl)-4-methylenepiperidine. there are obtained the following free bases before optional conversion to their fumaric salts: (a) 4-[a,a-bis(3,4-difluorophenyl)methyllpiperidine, (b) 4-[a,a-bis(2,5-difluorophenyl)methyl]piperidine, (¢) 4-{a,a-bis(3-trifluoromethylphenyl)methyllpiperidine, and (d) 4-[a,a-bis(4-trifluoromethylphenyl)methyl]piperidine.
~ -99-
Preparation 139 . a-(3,4-Difluorophenyl)-a-(4-fluorophenyl)-4-piperidinemethanol.
A solution of a-(3,4-difluorophenyl)-a-(4-fluorophenyl)-1- (phenylsulfonyl)-4-piperidinemethanol (obtained in Preparation 124) and lithium aluminum hydride in tetrahydrofuran is refluxed for approximately 8 to 18 hr. The reaction mixture is filtered, filtrate dried over sodium sulfate, and the filtrate concentrated to a residue. The residue is partitioned between an alkaline aqueous solution of sodium hydroxide and water, and chloroform.
The chloroform layer is dried, filtered and solvent evaporated to give the title compound as an oil which may or may not crystallize upon standing.
Preparation 140 4-Ethyl-2-methoxyphenol.
A mixture of zinc powder, 150 ml of water and 49.9 g (0.3 mole) of acetovanillone was stirred and treated dropwise with 150 ml of concentrated hydrochloric acid. The solution was heated at reflux for 3.5 hr, during which time, after each hour 10 ml of addtional concentrated hydrochloric acid was added. After 3.5 hr the solution was diluted with ethyl alcohol and treated with aqueous ferric chloride solution. The mixture was cooled and filtered and the filter cake washed with water, and the combined filtrates saturated with sodium chloride and extracted with diethyl ether (3 x 150 ml). The combined extracts were dried over sodium sulfate and concentrated to yield 1.4 gof a pink oil. The filter cake was washed with 250 ml of diethyl ether.
The mixture was filtered and the filtrate dried over sodium sulfate and "concentrated to a gum residue. The above obtained pink oil and gum residue were combined and chromatographed on a 750 g column of silica gel using 1:1 benzene:ligroin as the eluting solvent. Appropriate fractions were combined and concentrated to give 13.2 g (29% yield) of the title compound as an oil. 0 Preparation 141 4-[a,a-Bis(4-fluorophenyl)methyl}-1-(3-chloropropyl)piperidine.
A solution of 4-[a,a-bis(4-fluorophenyl)methyllpiperidine, 3-bromo- - propanol and potassium carbonate in acetonitrile is refluxed for 12 hr to give 4-[a,a-bis(4-fluorophenyl)methyl]-1-piperidinepropanol, which is then reacted neat for approximately 2 hr with thionyl chloride to give the hydro- chloride salt of the title compound; which is reacted with sodium bicarbonate in chloroform to give the title compound.
Preparation 142 3-(3-Chloropropoxy)benzoic acid ethyl ester.
A mixture of 25 g (0.149 mole) of ethyl-3-hydroxybenzoate, 46.9 g (0.3 mole) of 1-bromo-3-chloropropane and 62 g (0.45 mole) of anhydrous potas sium carbonate is one liter of acetone was heated at reflux for ~23 hr. The mixture was cooled, filtered, and the filtrate concentrated to give an oil as residue. The oil was dissolved in 200 ml of benzene, treated with potassium hydroxide pellets and stirred for 1 hr. The mixture was filtered through
Celite® and the filtrate was concentrated lo give 36.5 g of oil as residue.
NMR analysis showed it was the desired product.
Preparation 143 1-[(Diethylamino)carbonyl]-4-piperidine carboxylic acid ethyl ester.
To a solution of 72.4 g (0.46 mole) of ethylisonipecotate and 46.5 g (0.46 mole) of triethylamine in 400 ml of methylene chloride was added dropwise with stirring a solution of diethylcarbamyl chloride 62.4 g (0.46 mole} in 100 ml of methylene chloride. The reaction was exothermic, and the reaction mixture began to reflux during addition of the diethylcarbamyl chloride solution. The mixture was allowed to stir at ambient temperature for 24 hr and then treated with 50 ml of water. The layers were separated, and the orgaqic layer washed with 25 ml of a 2N hydrochloric acid (twice), 50 ml of a "saturated sodium bicarbonate solution, 100 ml of a saturated sodium chloride solution and dried over sodium sulfate and finally concentrated to give a tan oil. The oil was subjected to vacuum distillation and appropriate fractions (0.2-0.5 mmHg, bp 112-118°C) collected to give 100.6 g (85% yield) of the desired product. " Preparation 144 3-(4-Ethyl-2-methoxyphenoxy)propyl chloride.
A mixture of 13.2 g (0.87 mole of 4-ethyl-2-methoxyphenol, 27.3 g (0.173 mole) of 1-bromo-3-chloropropane, 35.9 g (0.26 mole) of anhydrous potassium
A
-101- carbonate and 500 ml of acetone was heated at reflux for 20 hr. The reaction mixture was cooled, filtered and the filtrate concentrated to give 18.7 g (94% yield) of oil as a residue. The oil was chromatographed on a 400 g silica gel column using 2:1 benzene:ligroin as the eluting solvent and appropriate sol- vents collected. NMR indicated approximately 10-15% nf the starting phenol compound remained. The oil was dissolved in 250 ml of benzene and stirred with potassium hydroxide pellets for approximately 4 hr. The mixture was filtered through Celite® and filtrate concentrated to give 10.3 g (52% yield) of the desired product.
Preparation 145 1-Chloro-3-(4-isopropylphenoxy)propane.
A mixture of 27.4 g (0.2 mole) of p-isopropylphenol, 63 g (0.4 mole of 1- bromo-3-chloropropane and 82.9 g (0.6 mole) of anhydrous potassium carbo- nate in 1 liter of acetone was heated at reflux for 24 hr. The reaction mixture was cooled, filtered and filtrate concentrated. The residue was dissolved in "200 m! of benzene and treated with potassium hydroxide pellets to remove oo . excess starting phenol. The mixture was stirred at ambient temperature for
Ca : 0.5 hr, filtered through Celite® and the filtrate concentrated to give 36.4 g
So 20 ~ (87% yield) of the title compound as an oil residue. , Co Preparation 146 a - 1-Chloro-3-(4-methviphenoxy)propane. : A mixture of 27 g (0.25 mole) of p-cresol, 78.7 g (0.5 mole) of 1-bromo-3- chloropropane and 103.7 g (0.75 mole) of anhydrous potassium carbonate in 1 "liter of acetone was heated at reflux for 24 hr. The reaction mixture was “cooled, filtered and concentrated in vacuo at 90°C to give 47.1 g of an oil residue. The oil was subjected to vacuum distillation to give 39.3 g (85%) of : clear oil, bp 85-90°C at 0.1 mmHg.
Preparation 147 3-(2-Benzyloxyphenoxy)propy! chloride.
A mixture of 50 g (0.25 mole) of o-benzyloxyphenol, 78.7 g (0.5 mole) of 1-bromo-3-chloropropane and 103.7 g of anhydrous potassium carbonate in 1 3 liter of acetone was heated at reflux for 24 hr. The reaction mixture was cooled, filtered and concentrated in vacuo to give 67.2 g of a tan oil as residue.
The oil was dissolved in 300 ml of diethyl ether and washed with 100 ml of a 5% sodium hydroxide solution. A solid precipitated, about 200 ml of water was added and the precipitated sold redissolved. Solvent layers were sepa- rated and the diethyl ether layer washed twice with a 5% sodium hydroxide solution. The organic layer was next washed with water, brine, and dried over sodium sulfate and concentrated to give 58.4 g (84%) of oil as product.
Preparation 148 1-[4-(3-Chloropropoxy)-2-methoxyphenyljethanone.
A solution of 4-hydroxy-2-methoxyacetophenone, 1-bromo-3-chloro- propane and potassium carbonate in acetone is heated at reflux for about 12 hr to give the title compound.
Preparation 149 1-[4-(3-Chloropropoxy)-3-methoxyphenyl]ethanone. Ca
A solution of acelovanillone, 1-bromo-3-chloropropane and potassium carbonate in acetone is refluxed for about 12 hr to give the title compound. | Preparation 150 4-[Bis(2,4-difluorophenyl)methyl]pyridine hydrochloride [1:1].
Sulfuric acid (40 ml) was cooled in an acetone-dry ice bath. 1,3-difluoro- benzene (45.6 g, 0.4 mole) was added with stirring while maintaining a temperature of 0°C. The resulting soluton was stirred until room tempera- ture was obtained. 4-Pyridinecarboxaldehyde (21.4 g, 0.2 mole) was added dropwise while maintaining a temperature of 0°C. The reaction mixture was stirred until room temperature was obtained, and the reaction mixture was then stirred overnight at 70°C. The mixture was cooled to room temperature and made alkaline with ice/50% sodium hydroxide. The aqueous layer was extracted several times with chloroform, and the organic layer was back extracted with 5% sodium hydroxide. The chloroform layer was dried over sodium sulfate and filtered. The organic solvent was removed in vacuo to give a clear oil (28.30 g, 44.6%). A 1 g portion of the clear oil was dissolved in isopropanol and treated with ethereal hydrogen chloride. A white crystalline
\ oo -103- solid formed and was separated. The solid was dried in vacuo overnight at ~ 80°C. This furnished 0.97 g (39%) of white crystalline solid mp 218-222°C.
Analysis: Calculated for CgHoNF4Cl: CC, 61.12; H, 3.42; N, 3.96 : Found : C,61.00;H,3.32;N, 3.94 5 .
Preparation 151 4-[Bis(2,4-difluorophenyl)methyl]piperidine hydrochloride [1:1].
A mixture of 4-[bis(2,4-difluorophenyl)methyl]pyridine (23.84 g, 0.0752 mole) and 5% platinum on carbon (2.0 g) was subjected to hydrogenation for three days at 60°C in 400 ml of glacial acetic acid containing 3 ml of con- centrated hyrochloric acid. Following hydrogenation the reaction mixture was cooled to room temperature and dissolved in chloroform and extracted with 5% sodium hydroxide. The chloroform laver was dried over sodium sulfate and filtered. The chloroform layer was removed by rotary evaporator ” to give a dark residue (24.40 g). A one gram sample of this material was converted to the hydrochoride salt and recrystallized from methanol-diethyl : ether. A white solid was obtained and dried in vacuo overnight at 80°C. This provided 1.06 g (95.2%) of white crystalline solid, mp 215-217°C.
Analysis: Calculated for CygHsNF4Cl: C, 60.09; H,5.04: N, 3.89
Found : : C,59.77: H,5.02;: N, 3.87
Preparation 152
Utilizing the procedure of Preparation 65 and substituting the following reactants for the reactants 4-fluorophenylacetonitrile and - | fluorobenzene: : (a) 3,4-difluorophenylacetonitrile and 1,2-difluorobenzene, (b) 2,5-difluorophenylacetonitrile and 1,4-difluorobenzene, (¢) 2,4-difluorophenylacetonitrile and 1,3-difluorobenzene, (d) 3-trifluoromethylphenylacetonitrile and trifluoromethylbenzene, i and (e) 4-trifluoromethylphenylacetonitrile and trifluoromethylbenzene,
So there are obtained: co - (a) 3,4-difluorophenyl-a-(3,4-difluorophenyl)benzeneacetonitrile, : ie 5 (b) 2,5-difluorophenyl-a-(2,5-difluorophenyl)benzeneacetonitrile,
(c) 2.4-difluorophenyl-a-(2,4-difluorophenyl)benzeneacetonitrile, (d) 3-trifluoromethylphenyl-a-(3-trifluoromethylphenyl)benzene- acetonitrile, and (e) 4-trifluoromethylphenyl-a-(4-trifluoromethylphenyl)benzene- acetonitrile.
Preparation 153
Utilizing the procedure of Preparation 66 and substituting the following for 4-fluoro-a-(4-fluorophenyl)benzeneacetonitrile: (a) 3,4-difluorophenyl-a-(3,4-difluorophenyl)benzeneacetonitrile, (b) 2,5-difluorophenyl-a-(2,5-difluorophenyl)benzeneacetonitrile, (¢) 2,4-difluorophenyl-a-(2,4-difluorophenyl)benzeneacetonitrile, (d) 3-trifluoromethylphenyl-a-(3-trifluoromethylphenyl)benzene- acetonitrile, and (e) 4-trifluoromethylphenyl-a-(4-trifluoromethylphenyl)benzene- acetonitrile, i} I Ce Pe co there are obtained: \ (a) a,a-bis(3,4-difluorophenyl)-1-{(4-methylphenyl)sulfonyl]-4- piperidineacetonitrile, (b) a,a-bis(2,5-difluorophenyl)-1-[(4-methylpheny!)sulfonyl]-4- piperidineacetonitrile, (¢) a,a-bis(2,4-difluorophenyl)-1-[(4-methylphenyl)sulfonyl]-4- piperidineacetonitrile, (d) a,a-bis(3-trifluoromethylphenyl)-1-[(4-methylphenylsulfonyl]-4- piperidineacetonitrile, and (e) a,a-bis(4-trifluoromethylphenyl)-1-[(4-methylphenyl)sulfonyl]-4- piperidineacetonitrile.
Preparation 154
Utilizing the procedure of Preparation 67 and substituting the following for a,a-bis(4 fluorophenyl)-1-[(4-methyiphenyl)sulfonyl]-4- piperidineacetonitrile: (a) a,a-bis(3,4-difluorophenyl)-1-[(4-methylphenyl)sulfonyl]-4- piperidineacetonitrile,
(b) a,a-bis(2,5-difluorophenyl)-1-[(4-methylphenyl)sulfonyl}-4- piperidineacetonitrile, . (¢) a,a-bis(2,4-difluorophenyl)-1-[(4-methylphenyl)sulfonyl}-4- piperidineacetonitrile, (d) a,a-bis(3-trifluoromethylphenyl)-1-[(4-methylphenyl)sulfonyl]-4- piperidineacetonitrile, and (e) a,a-bis(4-trifluoromethylphenyl)-1-{(4-methylphenyl)sulfonyl)-4- piperidineacetonitrile, there are obtained: (a) a,a-bis(3,4-difluorophenyl)-4-piperidineacetonitrile oxalate, (b) a,a-bis(2,5 diftuorophenyD-4.piperidineacetonitrile oxalate, (c) a,a-bis(2,4 difluorophenyl) .4-piperidineacetonitrile oxalate, (d) a,a-bis(3-trifluoromethylphenyl)-4-piperidineacetonitrile oxalate, and
Co . (e) a,a-bis(4-trifluoromethylphenyl)-4-piperidineacetonitrile oxalate. ) Co Preparation 155 : oo oo The following compounds: (a) 3,4-difluoro-a-(3,4-difluorophenyl)benzeneacetic acid ethyl ester, ~~ (b) 2,5-difluoro-a-(2,5-difluorophenyl)benzeneacetic acid ethyl ester, (¢) 2.4-difluoro-a-(2 4-difluorophenyl)benzeneacetic acid ethyl ester, a (d) 3-trifluoromethyl-a-(3-trifluoromethylphenyl)benzeneacetic acid . ethyl ester, (e) 4-trifluoromethyl-a-(4-trifluoromethylphenyl)benzeneacetic acid : ethyl ester, (Hh 1,1-bis[3,4-difluorophenyl]-2-butanone, (g) 1,1-bis[2,5 difluorophenyl]-2-butanone, (h) 1,1-bis[2,4-difluorophenyl]-2-butanone, (i) 1,1-bis[3-(trifluoromethyl)phenyl]-2-butanone, and (G) 1,1-bis[4-(trifluoromethyl)phenyl]-2-butanone, are reacted stepwise with (1) lithium dipropylamine (2) 4-[(4-phenylmethyl)sulfonyloxy]-1-(phenylmethyl)piperidine and hydrogenated over palladium catalyst to give the following ~~ compounds: (a) a,a-bis(3,4-difluorophenyl)-4-piperidineacetic acid ethyl ester, (b) a,a-bis(2,5-difluorophenyl)-4-piperidineacetic acid ethyl ester, (c) a,a-bis(2,4-difluorophenyl)-4-piperidineacetic acid ethyl ester, (d) a,a-bis((3-trifluoromethyl)phenyl]-4-piperidineacetic acid ethyl ester, (e) a,a-bis{(4-trifluoromethyl)phenyl]-4-piperidineacetic acid ethyl ester, (H 1,1-bis(3,4-difluorophenyl)-1-(4-piperidinyl)-2-butanone, (g) 1,1-bis(2,5-difluorophenyl)-1-(4-piperidinyl)-2-butanone, (h) 1,1-bis(2.4 difluorophenyl)-1-(4-piperidinyl)-2-butanone, : : (i) 1,1-bis[(3-trifluoromethyl)phenyl]-1-(4-piperidinyl)-2-butanone, and . 15 (Gg) 1,1-bis[(4-trifluoromethyl)phenyl}-1-(4-piperidinyl):2-butanone.
Preparation 156 1-[4-(3-Chloropropoxy)-3-methoxyphenvljethanone.
A solution of acelovanillone, 1-bromo-3-chloropropane and potassium carbonate in acetone is refluxed for about 12 hr to give the title compound.
Preparation 157 1-(Phenylmethyl)-4-piveridinol 4-methvlbenzenesulfonate (ester) hydrochloride [1:1]. | A solution of 1-benzyl-4-hydroxypiperidine (95.6 g, 0.5 mole) in 500 mL of pyridine was cooled in an ice bath. To this solution was added dropwise a solution of tosyl chloride (133.5 g, 0.7 mole) in 400 mL of acetonitrile (dried over 4A molecular sieves). Upon the addition to the second solution, a color change from yellow to dark-red was observed. The resulting solution was stirred at room temperature for 4.5 hours. The reaction mixture was stripped to dryness, and a dark-brown masz was obtained. This material was dissolved in chloroform and extracted with 5% sodium hydroxide. The chloroform layer was dried over sodium sulfate and filtered. The chloroform layer was removed in vacuo to give a dark brown mass. This material was converted to the hydrochloride salt, and the salt was recrystallized from - methanol-diethyl ether. A light brown solid was isolated and dried in vacuo overnight at 80°C. This procedure provided 68.17 g (35.8%) of light brown solid, mp 169-171.5°C. }
Analysis: Calculated for C1gH24NO3SCl: CC, 59.75: H, 6.33; N, 3.67
Found : C,59.74; H,6.38; N, 3.69
Preparation 158 a,a-Bis(3,4-Difluorophenyl)-4-pyridinemethanol. : To a magnetically stirred solution of ethyl isonicotinate in dry tetra- hydrofuran at 0°C and under an atmosphere of nitrogen is slowly added a solution 2.2 equivalents of 3,4-difluorophenyl magnesium bromide in tetra- hydrofuran. The solution is stirred at ambient temperature for 4 h and is poured into an icy solution of ammonium chloride. The mixture is extracted with methylene chloride, and the organic phase was dried over sodium sul- fate. The solvent was removed in vacuo to give a solid. This was recrystal- lized from ethylene chloride/hexane to give the title compound as a white crystalline solid, mp 147-149°C.
Analysis: Calculated for C1gH|NOF4: C, 64.84; H, 3.33: N, 4.20
Found : C,64.54; H,3.22; N, 4.20
Preparation 159 4-[Bis-(4-fluorophenvl)methyl]-1-(phenylsulfonvl)piperidine.
A solution of 15.18 g (0.0529 mole) of 4-[bis(4-fluorophenyl)methylene]- . piperidine and 10.89 g (0.0617 mole) of benzenesulfonyl chloride in 350 mL of . pyridine was stirred at room temperature for 16 hr. The solvent was removed in vacuo, and the residue was partitioned between methylene chloride and dilute sulfuric acid. The methylene chloride solution was extracted with dilute sodium, and the methylene chloride solution was dried over sodium sulfate. The solvent was removed in vacuo, and the residue was dissolved in 200 mL of methanol. A precipitate was collected. This was recrystallized from methylene chloride - methanol to give 11.14 g (49.3%) of the title ~~.“ compound as a white solid, mp 180-184°C.
: SN -108-
Analysis: Calculated for Co4H3NO9SFg : C,67.43; H, 5.42; N, 3.28
Found + C,67.17:H,542:N,3.27 .
Preparation 160 a,a-Bis(3,4-difluorophenyl)-4-piperidinemethanol oxalate hydrate [1:0.5:0.5].
A solution of 4.02 g (0.012 mole) of a,a-bis(3,4-difluoropheny!)-4-pyri- dinemethanol in 150 mL of glacial acetic acid was subjected to catalytic hydrogenation with 0.70 g of 5% platinum on carbon (Parr hydrogenation apparatus; 53 psi of hydrogen) at room temperature for 70 hr. The solution was filtered through Celite®, and the solvent was removed in vacuo.
The residue was partitioned between methylene chloride and dilute sodium hydroxide, and the methylene chloride solution was dried sodium sulfate. The solvent was removed in vacuo to give a white solid. This was dissolved in methanol, 1.0 g (0.011 mole) of oxalic acid was added, and anhydrous ether was added. After being cooled in the freezer, the solution produced 0.51 g (10.9%) of the title compound as a white crystalline solid. )
Anhydrous either was added to the filtrate, and the solution was placed in the freezer. An additional 2.70 g (57.3%) of the title compound was collected as a white solid, mp 278-279°C with decomposition.
Analysis: Calculated for C;oH gNO35F : C,58.02;H,4.87;N,3.56
Found : (C,5842;H,.4.66;N,3.61
Preparation 161 a-(4-Fluorophenyl)-a-(4-piperidinyl)-2-pyridinemethanol. : To a stirred solution of 36.3 g (0.23 mole) of 2-bromopyridine in 500 mL of anhydrous tetrahydrofuran (THF) at -65°C was added 88 mL (0.22 mole) of a commercial solution of 2.5 molar n-butyllithium in hexane at such a rate that the temperature did not exceed -60°C. The dark solution was stirred at - 65°C for 1 hr and then treated dropwise with a solution of 24.9 g (0.1 mole) of 1-acetyl-4-(p-fluorobenzoyl)piperidine in 250 mL of THF at such a rate that the temperature did not exceed -60°C. The mixture was stirred for 1 hr at -65°C and overnight at ambient temperature. The dark mixture was poured into 2 liters of a saturated ammonium chloride solution. The layers were separated, and the aqueous layer was extracted once with a 500-ml portion of
2D -109- methylene chloride. The combined organic layers were washed successively with 500 ml of water, 500 ml of a 4% sodium hydroxide solution, 250 ml] of water, and 250 ml of brine.
All of the aqueous layers were combined and allowed to stand in a filter flask for several weeks. As the soluble nrganic solvents in the aqueous solution evaporated, a solid precipitated. The aqueous solution was decanted, and the solid was slurried with water, collected by filtration, and dried. The solid was recrystallized from absolute ethanol-pyridine to yield 4.5 g (14%) of the title compound as an off-white solid, mp 228-230°C (dec.)
Analysis: Calculated for C;7HgFNoO : C,71.31:H,6.69; N, 9.78
Found : C,71.43;H,6.54; N,9.52
Preparation 162 a,a-Bis(4-fluorophenyl)-1-(phenylmethyl)-3-piperdinemethanol. ~The title compound was synthesized by the procedure described in
Preparation 4 except that 1-phenylmethyl-3-piperidine carboxylic acid ethyl 3 Co ‘ester was used in place of 1-(phenylmethyl)-4-piperidinecarboxylic acid ethyl
Co : ester hydrochloride. The melting range of the white solid thus obtained was ; | 104-111.5°C. vo
Analysis: Calculated for CogsHosNOFg : CC, 76.31; H, 6.40; N, 3.55
Found : C,76.75;H, 6.46; N, 3.55 : Preparation 163 [a.a-Bis(4-fluorophenvl)]-3-pvridineethanol.
A Grignard solution was prepared from 19.4 g (0.8 mole) of magnesium ~ chips and 148.8 g (0.85 mole) of 1-bromo-4-fluorobenzene in 1.25 liters of dry tetrahydrofuran (THF). To this solution was added in a stream a solution of 41.3 g (0.25 mole) of ethyl-3-pyridylacetate (Aldrich) on 2560 ml of THF. The mixture was stirred at ambient temperature overnight and then poured into 2.5 liters of a saturated ammonium chloride solution. The layers were sepa- rated and the aqueous layer was extracted once with 500 mL of methylene chloride and twice with 250 m] of inethylene chloride. The combined organic layers were washed successively with 250 ml water, 250 m) of a 4% sodium hydroxide solition, 250 ml of water and 250 ml of brine. The organic layer was dried over sodium sulfate and concentrated to give a gum which crystal-
lized when triturated with a mixture of 100 ml of petroleum ether (30-60°C) and 100 m] of isopropyl ether. The solid was collected by filtration, dried and slurried with 500 ml of water.
The solid was collected by filtration, washed with petroleum ether and dried to yield 32.5 g of tan solid. Mass spec shows m/e = 312. The solid was slurried with 500 ml of water, collected by filtration and dried.
The solid was next heated to reflux in ~300 ml] of 2-propanol and filtered to remove insolubles. The filtrate was concentrated to give a solid residue.
The solid was recrystallized from cyclohexane-benzene to yield 24.3 g (31%) of off-white solid, mp 137-141°C.
Analysis: Calculated for C1gH15F2NO : C,73.30; H, 4.86; N, 4.50
Found : C,73.42;H,4.77,N, 451
Preparation 164 : [a,a-Bis(4-fluorophenyl)]-3-piperidinethanol hydrochloride | 1:1]. ’
A mixture of 23.8 g (0.076 mole) of [a,a-bis(4-fluorophenyl)]-3-pyri- dineethanol hydrochloride [1:1] in 500 ml of glacial acetic acid was hydro- genated over 2.4 g of 5% platinum on carbon in a Parr apparatus for 24 hr.
The mixture was filtered through Celite®, and the filtrate was concentrated to give a gummy residue. The residue was partitioned between 300 ml of methylene chloride and 300 ml of a 5% sodium hydroxide solution and a solid precipitated. The solid was collected by filtration and partitioned between 200 ml of methylene chloride and 100 ml of a 5% sodium hydroxide solution.
The organic layer was washed with brine, dried over sodium sulfate and concentrated to give a gum as residue. The gum was dissolved in ethyl ether - and converted to the hydrochloride salt. The solid was collected by filtration and dried to yield 19.2 g (71%) of the title compound as a white solid, mp 248°C (dec) (absolute ethanol).
Analysis: Calculated for C1gHg2CIFgNO : C, 64.50; H,6.27: N, 3.96
Found . C,64.30;H,6.28;N, 3.98
Preparation 165 1-(Phenylmethyl)-3-piperidinécarboxylic acid ethyl ester hydrobromide
To a stirred mixture of 35.4 g (0.225 mole) of (+) ethylnipecotate (Aldrich) and 31.8 g (0.3 mole) of anhydrous sodium carbonate in 300 ml of absolute ethanol was added dropwise 41 g (0.24 mole) of benzylbromide and the mixture was stirred at ambient temperature for 24 hr. The mixture was filtered and the filtrate was concentrated. The residue was partitioned between 250 ml of methylene chloride and 250 ml of a 5% sodium hydroxide solution. The organic layer was washed with brine, dried over sodium sulfate and concentrated to give a gummy residue. The residue was triturated with ethyl ether, filtered, and the filtrate treated with hydrogenbromide gas. The solid which precipitated was collected by filtration and recrystallized from 2. propanol to yield 35.0 g (47%) of the title compound as a white solid, mp 148- 152°C.
Analysis: Calculated for C1sHo2BrNOg : C,54.89:H,6.76; N, 4.27
Found : C,54.83;H,6.83; N, 4.30
A
: Preparation 166 [a,a-Bis(4-fluorophenyl)]-3-piperidinemethanol.
A solution of 26.6 g (0.0676 mole) of a,a-bis(4-fluorophenyl)-1-(phenyl- methyl)-3-piperidinemethanol in 750 ml of absolute ethanol was hydro- genated at 60°C and 50 psi over 5% palladium on carbon in a Parr apparatus for 18 hr. The mixture was filtered through Celite®, and the filtrate was 2 concentrated to give a gum which crystallized when triturated with petro- " leum ether (30-60°C). The solid was collected by filtration and recrystallized from cyclohexane to yield 14.8 g (72%) of the title compound as a white solid, mp 114.5-115.5°C.
Analysis: Calculated CigH19FoNO : C,71.27;H,6.31;N, 4.62 10 Found : C,71.43;H,6.33; N, 4.64
Preparation 167 3 1-Chloro-3-[(2-phenylmethoxy)phenoxy]propane. -
A mixture of 50 g (0.25 mole) of 0-benzyloxyphenol (Aldrich), 78.7 g (0.5 mole) of 1-bromo-3-chloropropane and 103.7 g (0.75 mole) of anhydrous potassium carbonate in one liter of acetone was heated at reflux for ~24 hr.
The mixture was worked up to give 67.2 g of tan oil as residue. The oil was dissolved in ~300 ml of diethyl ether and washed with 100 ml of 5% sodium hydroxide solution and a solid precipitated. Approximately 200 ml of water was added and the solid dissolved. The layers were then separated. This : process was repeated twice with 100 ml of 5% sodium hydroxide solution.
The organic layer was washed with water and brine, dried over sodium car- bonate, and concentrated to give 58.4 g (84%) of oil as residue. NMR was consistent for the title compound.
Preparation 168 1-Chloro-3-[2,6-(dimethoxy)phenoxy]propane.
A reaction mixture consisting of the following was heated for about 18 hr at gentle reflux in 750 ml of acetone: 1. 2,6-dimethoxyphenol (154.17 g, 1 mole), 2. 1-bromo-3-chloropropane (314.8 g, 2 mole), and 3. potassium carbonate (290.0 g, 2.1 mole).
The reaction mixture was filtered and stripped to dryness to give a dark brown oil which was dissolved in chloroform and extracted with dilute (5%) sodium hydroxide solution. An emulsion resulted, which was broken by the addition of saturated sodium chloride. The aqueous layer was extracted several times with chloroform. The chloroform layer was back extracted with 5% sodium hydroxide. Removal of chloroform gave a dark brown oil (83.55 g, 36.3% yield). NMR analysis was consistent with the desired product.
Preparation 169 1-Chloro-3-{(2-methoxy-4-methyl)phenoxy]propane.
A mixture of 50 g (.362 mole) of 2-methoxy-4-methylphenol (Lancaster), 113.9 g (.72 mole) of 1-bromo-3-chloropropane and 150 g (1.1 mole) of anhy- drous potassium carbonate in one liter of acetone was heated at reflux with stirring for ~20 hr. The mixture was cooled, filtered, and the filtrate concentrated lo yield 66.3 g of vil as residue. NMR showed 75% product, and 25% phenol present.
The oil was dissolved in 500 m| nf acetone and treated with 28 g of 1- bromo-3-chloropropane and 35 g of anhydrous potassium carbonate, and the mixture was heated at reflux for ~16 hr. The mixture was worked up as above to yield 67 gof an oil. NMR indicated it was mostly product, but that some replaceable proton was still present.
The oil was dissolved in 300 ml of benzene and stirred with potassium hydroxide pellets for 21 hr. The mixture was filtered through Celite® and the filtrate was concentrated to yield 54.7 g (70%) of clear oil. NMR was consistent with the title compound.
Preparation 170 1-[2-(3-Chloropropoxy)phenyljethanone.
A mixture of 40.8 g (.3 mole) of o-hydroxyacetophenone (97%, Aldrich), 94.4 g (.6 mole) of 1-bromo-3-chloropropane and 124.4 g (.9 mole) of anhy- drous potassium carbonate in one liter of of acetone was heated at reflux for
Co ~18 hr. The mixture was cooled to’robm temperature, filtered dnd the filtrate concentrated under vacuum pump pressure to give ~45 g of oil as residue. The
Ce oil was dissolved in 200 ml of benzene and stirred with potassiym hydroxide pellets for ~2 hr. The mixture was filtered through Celite® and the filtrate was concentrated to yield 29.6 g (46%) of light yellow oil. NMR was consistent for 2 desired product. Mass Spectra Analysis shows m/e = 213.
Preparation 171 1-[3-(3-Chloropropoxy)phenylljethanone.
A mixture of 40.8 g (.3 mole) of m-hydroxyacetophenone (95%, Aldrich), 94 4 g (.6 mole) of 1-bromo-3-chloropropane and 124.4 g (.9 mole) of anhy- drous potassium carbonate in one liter of acetone was heated at reflux for ~20 hr. The mixture was worked up to yield 61.4 g (96%) of dark oil as residue.
NMR analysis was consistent for the desired product. Mass Spectra Analysis showed m/e = 213.
Preparation 172 1-Chloro-3-[(3-methoxy)phenoxylpropane.
A mixture of 37.2 g (.3 mole) of m-methoxyphenol (Pfaltz & Bauer), 94.4 g (.6 mole) of 1-bromo-3-chloropropane and 124.4 g (.9 mole) of anhydrous potassium carbonate in one liter of acetone was heated at reflux for ~20 hr (the reaction mixture turned a dark color when the potassium carbonate was added). The mixture was worked-up to give 57.7 g (96%) of yellow oil as residue. NMR analysis was perfect for desired compound. Mass Spectra -
Analysis showed m/e = 201.
Preparation 173 1-Chloro-3-(4-ethylphenoxy)propane.
A mixture of 36.6 g (.3 mole) of 4-ethylphenol (99%, Aldrich), 94.4 g (.6 mole) of 1-bromo-3-chloropropane and 124.4 g (.9 mole) of anhydrous potas- sium carbonate in one liter of acetone was heated at reflux for ~24 hr. The mixture was worked-up to yield 48 g (81%) of pale yellow oil. NMR was perfect for desired product. Mass Spectra Analysis showed m/e = 199.
Preparation 174 4-(3-Chloropropoxy)benzeneacetic acid methyl ester.
A mixture of 24.3 g (.146 mole) of methyl-4-hydroxyphenylacetate (99%,
Aldrich), 47.2 g (.3 mole) of 1-bromo-3-chloropropane and 62.1 g (.45 mole) of anhydrous potassium carbonate in 500 ml of acetone was heated at reflux for ~24 hr. The mixture was cooled, filtered and the filtrate concentrated to give 34.8 g (98%) of oil as residue. Mass Spectra Analysis showed m/e = 243.
NMR was consistent for the desired product.
Preparation 175 1-Chloro-3-(2-methylphenoxy)propane.
A mixture of 32.4 g (.3 mole) of o-cresol, 94.4 g (.6 mole) of 1-bromo-3- chloropropane and 124.4 g (.9 mole) of anhydrous potassium carbonate in one . liter of acetone was heated at reflux for ~24 hr. The mixture was worked-up to yield 34.5 g (62%) of pale yellow oil. NMR looked perfect for the desired product. Mass Spectra Analysis showed m/e = 185.
Preparation 176 1-Chloro-3-(2-ethoxyphenoxy)propane.
A mixture of 41.5 g (.3 mole) of o-ethoxyphenol (Eastman), 94.4 g(.6 mole) of 1-bromo-3-chlorophenol and 124.4 g (.9 mole) of anhydrous potassium carbonate in one liter of acelone was heated at reflux for ~20 hr.
The mixture was worked-up to give 34.3 g (53%) of clear oil as residue. NMR was perfect for the desired product. Mass Spectra showed m/e = 215.
Preparation 177 ° 1-Chloro-3-(3-methylphenoxy)propane.
A mixture of 32.4 g (3 mole) of m-cresol (Fisher), 94.4 g (.6 mole) of 1- bromo-3-chloropropane and 124.4 g (.9 mole) of anhydrous potassium carbo- nate in one liter of acetone was heated at reflux for ~20 hr. The mixture was 0 worked-up to yield 45 g (81%) of pale yellow oil as residue. NMR was con- sistent for desired product. Mass Spectra Analysis showed m/e = 185.
Preparation 178 1-Chloro-3-{2-(1-methylethoxy)phenoxy]propane. 15 A mixture of 25 g (.164 mole) of 2-isopropoxyphenol (97%, Aldrich), 51.7 g (.33 mole) of 1-bromo-3-chloropropane, and 67.9 g (.49 mole) of anhydrous potassium carbonate in 500 ml acetone was heated at reflux for ~20 hr. The mixture was cooled and filtered, and the filtrate concentrated. The residue was dissolved in 200 ml of benzene, treated with potassium hydroxide pellets 20 and stirred overnight. The mixture was filtered through Celite® and the : filtrate concentrated to yield 23.2 g (62%) of oil as residue. NMR was perfect for desired product. Mass Spectra Analysis showed m/e = 229.
Prepartion 179 [4-(3-Chloroprovoxy)phenvl]phenylmethanone.
A mixture of 49.7 g (.20 mole) of 4-hydroxybenzophenone, 78.7 g (0.5 - mole) of 1-bromo-3-chloropropane and 103.5 g (.75 mole) of anhydrous potas- sium carbonate in one liter of acetone was heated at reflux for 20 hr. The mixture was cooled to room temperature, filtered and the filtrate concen- trated to give a dark oil as residue. Mass Spectra Analysis showed m/e = 275. The oil was dissolved in 300 ml of benzene and stirred with potassium hydroxide pellets over the weekend. The mixture was filtered through
Celite® and the filtrate was concentrated to give 67.4 g (98%) of reddish- brown oil as residue. NMR was perfect for the desired compound.
™N -116-
Preparation 180 5-Oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylic acid methyl ester. -
A solution of 158.2 g (1.0 mole) of dimethylitaconate and 107.2 g (1.0 mole) of benzylamine in 750 ml of methanol was let stand at ambient tem- perature over the weekend. The solution was filtered, and the filtrate was concentrated under reduced pressure to give an oil as residue. The oil crystallized when it was triturated with petroleum ether (30°-60°C). The solid was collected by filtration and dried to yield 225.5 g (97%) of the title compound as a white powder. An analytical sample, m.p. 63-65°C, was prepared from 2-propyl ether.
Analysis: Calculated for C13H, sNO3 : (C,66.94:H,6.48;N,6.01
Found : C,66.82;H,6.48: N, 6.01
Preparation 181 4-(Bis(4-fluorophenyl)hydroxymethyl]-1-(phenylmethyl)-2-pyrrolidi- none.
A Grignard solution was prepared by the addition of 96.3 g (0.55 mole) of 4-bromofluorobenzene in 150 ml of dry tetrahydrofuran to a mixture of 12.2 g (0.5 mole) of magnesium chips in 250 ml of tetrahydrofuran. After the reaction had subsided, the mixture was diluted with 350 ml of tetrahydro- furan and heated at reflux for 15 min to complete formation.
The Grignard solution was added to a solution of 46.7 g (0.2 mole) of 5- oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylic acid methyl ester in 250 ml of tetrahydrofuran, and the mixture was stirred at ambient temperature over- night. The solution was poured into 2.5 liters of a cold ammonium chloride * solution. The layers were separated, and the aqueous layer was extracted once with 500 ml of methylene chloride and once with 250 ml of methylene chloride. The combined organic layers were washed once with 250 ml of water, once with 250 ml of a 4% sodium hydroxide solution, once with 250 ml of water and once with 250 ml of brine, dried over sodium sulfate and concen- trated under reduced pressure to give a gum as residue. The gum crystallized when saturated with peteroleum ether. The solid was collected by filtration, washed with petroleum ether and recrystallized from 2-propanol to yield 39.4 g (50%) of the title compound as an off-white solid, m.p. 158-160°C.
x . -117- :
Analysis: Calculated for Co4H2;FoNO9 : C, 73.27; H,5.38:N, 3.56
Found : C,73.09; H,5.38; N, 3.53 :
Preparation 182 a,a-Bis(4-fluorophenyl)-1-(phenylmethyl)-3-pyrrolidinemethanol.
To a stirred slurry of 7.6 g (0.02 mole) of lithium aluminum hydride in 150 ml of freshly distilled tetrahydrofuran was added dropwise, over a 45 min period, a solution of 38.5 g (0.098 mole) of 4-[bis(4-fluorophenyDhydroxy- methyl-1-(phenylmethyl)-2-pyrrolidinone in 150 ml of tetrahydrofuran.
After the addition was complete, the mixture was heated at reflux for 2 hr and then let stir at ambient temperature overnight. The excess lithium aluminum hydride was decomposed by the successive addition of 8 ml of water, 8 ml of a 15% sodium hydroxide solution, and 24 ml of water. The mix- ture was stirred for 30 min and filtered. The filtrate was concentrated under reduced pressure and the residue crystallized when triturated with petro- leum ether (30°-60°C). The solid was collected by filtration and recrystallized from 2-propanol to yield 30.3 g (81%) of the title compound as a white solid, mp 99-100°C.
Analysis: Calculated for Co4H93FoNO : C,75.97:H,6.11:N, 3.69
Found : C, 76.07; H,6.06;N, 3.70
Preparation 183 a.a-Bis(4-fluorophenyl)-3-pyrrolidinemethanol.
A solution of 26.6 g (0.07 mole) of a,a-bis(4-fluorophenyl)-1-(phenyl- ~ methyl)-3-pyrrolidinemethanol in 500 ml of ethanol was hydrogenated at 60 psi and and 70°C over 5% palladium on carbon catalyst for 2 days. The mix- ture was cooled and filtered through Celite®. The filtrate was concentrated under reduced pressure to give a solid as residue. The solid was triturated with petroleum ether (30°-60°C), collected by filtration and dried to yield 18.5 g (91%) of the title compund as a white solid, m.p. 152-153°C with 2-propanol given off.
Analysis: Calculated for Cy7H17F9NO : C,70.57; H, 5.92; N, 4.84
Found : C,70.90; H,6.02; N, 4.83
Preparation 184
“ : -118- 1-[4-(3-Chloropropoxy)-2-methoxyphenyljethanone.
A solution of 4-hydroxy-2-methoxyacetophenone, 1-bromo-3-chloropro- pane and potassium carbonate in acetone is heated at reflux for about 12 hr to give the title compound.
Preparation 185 a-Cyclohexyl-a-(4-fluorophenyl)-4-piperidinemethanol.
A solution of (4-fluorophenyl)(4-pyridinyl)methanone (23.44 g, 0.117 mole) was prepared in 400 ml of tetrahydrofuran. The solution was chilled in an ice bath and stirred under nitrogen atmosphere for 0.5 hr. A solution of cyclohexylmagnesium chloride (70 ml of ~2 molar solution) was added via syringe and a dark brown solution resulted immediately. This soution was stirred 0.5 hr at room temperature and then heated at reflux for 4 hr. The solution was cooled to room temperature and solvents were removed. The residue was treated with aqueous ammonium chloride and extracted with chloroform. The chloroform layer was dried over sodium sulfate, filtered, and solvent removed to give a dark brown residue. This residue was triturated with diethyl ether and then chilled at about 0°C and solvent removed to give an oil. This oil was dried in vacuo overnight at 80°C. The oil crystallized to give 2.95 g (33.8% yield) of white crystalline solid, m.p. 78-81°C.
Analysis: Calculated for C1gHooNF : C, 80.26; H, 7.48; N, 5.20
Found : C,79.96:H, 7.45; N, 5.23 <5 Preparation 186 a.a-Bis(3,4-difluorophenyl)-1-(phenylsulfonyl)-4-piperidinemethanol.
To a mechanically stirred mixture of 2.70 g (0.11 mole) of magnesium turnings and a crystal of iodine in 100 ml of dry tetrahydrofuran was slowly added a solution of 19.6 g (0.102 mole) of 1,2-difluro-4-bromobenzene in 50 ml of tetrahydrofuran. The three-necked reaction flash was fitted with a reflux condenser, and the reaction mixture was stirred under an atmosphere of nitrogen. The mixture was stirred for 1 hour, and 11.88 g (0.040 mole) of ethyl N-benzenesulfonylnipecotate was added as a solid. The solution was stirred at 23°C for 12 hours and was poured into an icy solution of ammonium chloride. The aqueous mixture was extracted with methylene chloride, and the methylene chloride solution was dried over magnesium sulfate. The solvent was removed in vacuo, and the residue was recrystallized from - methylene chloride-hexane to give 17.43 g (90%) of the title compound as a white solid, m.p. 152-154°C.
Analysis: Calculated for Co4HoiNO3SF, © (,60.12: H,4.41:N, 2.92
Found : C,60.18, H,4 40; N, 2.95
Preparation 187 4-[Bis(3,4-difluorophenyl)methylene]piperidine oxalate [1:1].
A mixture of 15.0 g (0.0313 mole) of a,a-bis(3,4-difluorophenyl)-1- (phenylsulfonyl)-4-piperidinemethanol, 21 g (0.22 mole) of phenol, and 200 ml] of 48% hydrobromic acid was refluxed for 5 hours and stirred at ambient temperature for 6 hours. The reaction mixture was poured over ice, and the mixture as made basic with 50% sodiun hydroxide soution. The basic mixture was extracted with methylene chloride, and the methylene chloride solution was dried over magnesium sulfate. The solvent was removed in vacuo. The residue was dissolved in 300 ml of methanol, 2.90 g (0.032 mole) of oxalic acid was added, and the voume of the solution was reduced to 200 ml.
Ether was added until the soution became cloudy, and the solution was placed in the freezer. A white solid was collected to give 8.91 g (69.3%) of the title compound as a crystalline solid, m.p. 202-203°C.
Analysis: Calculated for CogH7NF4O4 : C, 58.40; H, 4.17; N, 3.41
Found : (C,58.28;H,4.11; N, 3.38 5 Preparation 188 : : 4-[a,a-Bis(3-fluorophenyhhydroxvmethyl]-1-phenvlmethvlpiperidine fumarate [1:1].
A Grignard solution was prepared from 100 g (0.57 mole) of 1-bromo-3- fluorobenzene and 12.2 g (0.5 mole) of magnesium chips in 750 ml of dry tetrahydrofuran. This solution was treated with a solution of 45.8 g (0.185 mole) of ethyl-N-benzylisonipecotate in 2560 ml of dry tetrahydrofuran and the mixture was stirred at ambient temperature overnight. The solution was poured into 2.5 liters of a saturated ammonium chloride solution and the layers were separated. The aqueous layer was extracted once with 500 miof methylene chloride and twice with 250 ml of water, 250 ml of a 4% sodium hydroxide solution, 250 ml of water and 250 ml of brine, dried over sodium sulfate and concentrated to give a glass as residue. The glass was dissolved in 2-propanol and converted to the fumaric acid salt. The solid was collected by filtration and dried to yield 85 g (90%) of the title compound as a white solid. An analytical sample was recrystallized from acetonitrile - water, m.p. 212-214°C with decomposition.
Analysis: Calculated for CogHogF2NOs : C, 68.36; H,5.74, N, 2.75
Found : C,68.46; H,5.74; N, 2.83
Preparation 189 4-[a,a-Bis(3-fluorophenylhhydroxymethyllpiperidine.
A solution of 39.3 g (0.1 mole) of the free base of 4-[a,a-bis(3-fluoro- phenyl)hydroxymethyl]-1-phenylmethylpiperidine (free base obtained in
Preparation 188) in 750 ml of absolute ethanol was hydrogenated over 5% palladium on carbon in a Parr apparatus at 50 psi and 60°C for 3.5 days. The mixture was cooled and filtered through Celite®. The filtrate was concen- trated, and the residue was dissolved in diethyl ether and filtered through cotton to remove some insoluble material. The filtrate was concentrated to give a gum which crystallized when triturated with petroleum ether (30° 60°C). The solid was collected by filtration and dried to yield 27.9 g (92%) of the title compound as a white solid. An analytical sample, m.p. 117-118°C, was recrystallized from 2-propyl ether- 2-propanol.
Analysis: Calculated for CygH19FoNO : C, 71.27; H,6.31; N, 4.62
Found : C,71.24,H,6.27; N, 4.66 ¢5
Preparation 190 1-Phenylsulfonyl-4-piperidinecarboxvlic acid.
In the preparation of a,a-Bis(3,4-difluorophenyl)-1-(phenylsulfonyl)-4- piperidinemethanol, the title compound was obtained as a side product. To a mixture of 6.56 g (0.27 mole) of magnesium trimmings and a few crystals of iodine in 500 ml of anhydrous ether under an atmosphere of nitrogen was slowly added a solution of 49.0 g (0.25 mole) of 4-bromo-1,2-difluorobenzene in 100 ml of diethyl ether. The mixture was then stirred for 45 min. Ethyl N- benzenesulfonylisonipecotate (32.77 i, 0.11 mole) was added as a solid, and a gum formed in the bottom of the reaction flask after 20 min. Dry tetrahydro-
\ -121- furan (200 ml) was added, and the reaction mixture was stirred for an addi- tional hour. The reaction mixture was poured into an icy aqueous solution of ammonium chloride. The organic and aqueous phases were separated and the aqueous phase was extracted with several portions of ether. The organic phases were combined and dried over magnesium sulfate, and the solvent was removed in vacuo to give an oil. A NMR of this oil showed it to be a mixture of 4-(phenylthio)butanamide and ethyl N-benzenesulfonylisoni- pecotate. A solution of the reaction mixture oil in 800 m1 of 95% ethanol and 200 ml of 10% was heated at refluxed for 16 hr. The solvent was removed in vacuo, and the residue was partitioned between methylene chloride and dilute sodium hydroxide solution. The methylene chloride solution was con- centrated on to give 32.89 g (62.4%) of a,a-bis(3,4-difluorophenyl)-1-(phenyl- : sulfonyl)-4-piperidinemethanol. The aqueous solution was made acidic with dilute sulfuric acid solution, and the acidic solution was extracted with methylene chloride. The methylene chloride solution was dried over magnesium sulfate. The solvent was removed in vacuo, and the residue was i recrystallized from methylene chloride-hexane to give 5.36 g (18.1%) of the title compound as a crystalline solid, m.p. 156-157.5°C.
Analysis: Calculated for C12H5NO4S : C, 53.52: H, 5.61; N, 5.20
Found : C,53.19;H,5.54; N,5.16
Preparation 191 : 4] a,a-Bis(3.4-difluorophenyl)methyllpyridine.
A mechanically stirred mixture of 49.0 g (0.43 mole) of 1.2-difluoro- benzene, 20.6 g (0.19 mole) of 4-pyridylcarboxaldehyde and 80 ml of concen- : "trated sulfuric acid was heated at 70°C for 21 hr. The reaction mixture was poured over ice, and the icy mixture was made basic with 50% sodium : hydroxide solution. The resulting mixture was extracted with methylene : chloride and the methylene chloride solution was dried over sodium sulfate. + The solvent was removed in vacuo to give 54.95 g (89.8%) of a solid. This was } recrystallized from a mixture of methylene chloride and hexane to give 44.82 g (74.3%) of the title compound as a crystalline solid, m.p. 79-82°C. Proton
NMR showed that this sample contained ~5% of the 2,3-difluoro isomer.
Analysis: Calculated for C1gH 1 NFy: C,68.14; H,3.50; N, 4.14
Found + C,68.14; H, 3.36: N. 4.46 .
Preparation 192 4-(3,4-Difluorobenzoyl)pyridine hydrochloride [1:1].
To a mechanically stirred mixture of 3.36 g (0.14 mole) of magnesium turnings and a few crystals of iodine in 300 ml of tetrahydrofuran under a nitrogen atmosphere was added dropwise a solution 25.48 g (0.13 mole) of 1,2- difluoro-4-bromobenzene in 50 ml of tetrahydrofuran. The mixture was stirred at ambient temperature for 1 hr, and 14.0 g (0.14 mole) of 4-cyano- pyridine was added as a solid. The mixture was stirred for 7 hr at room tem- perature and then was poured over ice. The icy mixture was made acidic with dilute sulfuric acid solution, and the aqueous acidic solution was allowed to stand for 40 hr. The aqueous solution was made basic with ammonium hydroxide, and was extracted with methylene chloride. The methylene chlor- ide layer was dried over magnesium sulfate, and the solvent was removed in vacuo. The residue was subjected to flash column chromatography (silica gel, gradiently elution with methylene chloride/methanol) to give 1.80 g of the \ nonsalt form of the title compound which was converted to the hydrochloride salt, and recrystallized from methanol-ether to give 1.40 g (4.2%) of the title compound as a white, crystalline solid, m.p. 146-148°C with decomposition.
Analysis: Calculated for Cj2HgNOF5Cl © C,56.38; H,3.15;N, 5.48
Found : C,56.41;H,3.07;N,5.49 = Example 1 : 4-(Diphenvlmethylene)-1-(3-phenoxvpropyl)piperidine oxalate [1:1].
A mixture of 3.3 g (0.013 mole) of 4-diphenylmethylenepiperidine, 3.3 g (0.015 mole) of (3-bromopropoxy)benzene and 5.3 g (0.05 mole) of anhydrous sodium carbonate in 100 ml of 1-butanol was heated at reflux for 20 hr. The mixture was concentrated under reduced pressure and the residue was parti- tioned between water and benzene. The benzene layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give an oil as residue, the free base of the title com- pound. The free base was converted to the oxalic acid salt and the solid was recrystallized from absolute ethanol to yield 4.3 g(70%) of the title product as a white powder, m.p. 175-178°C.
Analysis: Calculated for C2gH3iNOs: C, 73.55; H, 6.60; N, 2.96
Found + C,73.59;H,6.64;N,2.83
Example 2 : a,a-Bis-(4-fluorophenyl)-1-(3-phenoxypropyl)-4-piperidinemethanol oxalate hydrate [1:1:0.5].
A mixture of 3.37 g (0.011 mole) of a,a-bis(p-fluorophenyl)-4-piperi- dinemethanol, 2.52 g (0.011 mole) of (3-bromopropoxy)benzene and sodium bicarbonate (0.92 g, 0.011 mole) in 200 ml of 1-butanol was heated overnight to reflux. The butanol was removed by the rotary evaporator, and the residue : partitioned between chloroform and water. Removal of the chloroform in vacuo gave a dark brown oil, the free base of the title compound. The base was converted to the oxalate salt and recrystallized from methanol-diethyl \ ether to give 1.41 g (23.9%) of white solid, m.p. 163°C.
Analysis: Calculated for CogH3oNOgsFg : C,64.92;H,6.01;N, 2.61
Found + C,65.27;H,5.87;N, 2.61
Example 3
Co 4-[Bis(4-fluorophenyDmethylene]-1-(3-phenoxypropyl)piperidine
J oxalate [1:1].
A solution of 7.37 g (0.0168 mole) a,a-bis(4-fluorophenyl)-1-(3-phenoxy- " propyl)-4-piperidinemethanol in 100 ml of methanol containing 100 ml of 6N hydrochloric acid was gently refluxed for 4 hr. The reaction mixture was cooled, made alkaline with ice/50% sodium hydroxide, and diluted to 1 liter with water. The aqueous phase was extracted with chloroform, and removal ; ; of chloroform gave an oil. The oil was converted to the oxalate salt and recrystallized from methanol-dieth y! ether to give 3.45 g (40.3%) of white solid, m.p. 190-192°C.
Analysis: Calculated for CogHogNQ5Fg : C, 68.36; H,5.74; N, 2.75 3s Found : C,68.43;H,5.75; N, 2.69
Example 4 a,a-Bis(4-fluorophenyl)-1-(3-phenoxypropyl)-4-piperidinemethanol oxalate [1:1].
To a mixture of 5.10 g (0.21 mole) of magnesium turnings and a crystal of iodine in 800 ml of dry tetrahydrofuran (distilled from lithium aluminum hydride) was added a solution of 36.75 g (0.21 mole) of p-bromofluorobenzene in 100 ml of tetrahydrofuran. The reaction flask was cooled in an ice bath during this addition, and the reaction mixture was under an atmosphere of nitrogen. The mixture was stirred at ambient temperature for 1 hr. A solution of 20.17 g (0.0693 mole) of ethyl N-(3-phenoxypropyl)isonipecotate in 100 ml of tetrahydrofuran was added and the solution was stirred at room temperature for 16 hr. The mixture was poured into an icy solution of ammonium chloride, and the aqueous mixture was extracted with methylene chloride. The methylene chloride solution was extracted with dilute sodium hydroxide and was dried over magnesium sulfate. The solvent was removed in vacuo to give a gummy residue. The residue was treated with a solution of oxalic acid in methanol, and the salt was recrystallized from methanol-ether to give 24.17 g (66.2%) of white crystalline solid, m.p. 153-155°C.
Analysis: Calculated for CogH31NOgFg : C, 66.02; H, 5.92: N, 2.66
Found : C,65.78; H,5.93; N, 2.63
Example 5 4-(Diphenylmethvl)-1-(4-phenoxvbutyl piperidine fumarate [1:1].
A solution of 6.99 g (0.0278 mole) of 4-diphenylmethylpiperidine, 6.64 g (0.029 mole) of (4-bromobutoxy)benzene and 5 g (0.060 mole) of sodium bicarbonate in 400 ml of 1-butanol was refluxed for 11 hr. The solvent was removed in vacuo, and the residue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene chloride solution was dried over magnesium sulfate, and the solvent was removed in vacuo to give an oil, the free base of the title compound. The base was dissolved in 500 ml of ether, and a small amount of solid was filtered from the solution. To the filtrate was added a solution of 3.2 g (0.0276 mole) of fumaric acid in 60 ml of methanol. A white precipitate was collected to give 7.97 g (55.7%) of white crystalline solid, m.p. 146-147°C.
Analysis: Calculated for C32H37NO5: C, 74.54; H, 7.23; N,2.72
Found : C,74.68;H.7.24; N, 2.68
Example 6 4-(Diphenylmethyl)-1-(3-phenoxypropyl)piperidine fumarate [1:1].
Following the procedure of Example 5, 4-(diphenylmethyl)piperidine and (3-bromopropoxy)benzene were reacted to give the free base of the title compound which was reacted with fumaric acid in methanol to give the white fumarate salt in 71% yield, m.p. 171-172°C.
Analysis: Calculated for C31H35NO5: C, 74.23; H, 7.03: N, 2.79
Found : C,74.62;H,7.03;N,2.73
Example 7 4:[Bis(4-fluorophenyl)methyl |-1-(3-phenoxypropyl)piperidine oxalate [1:1].
Following the procedure of Example 2, 4-[bis(4-fluorophenyl)methyl]- piperidine and (3-bromopropoxy)benzene were reacted to give the free base of . the title compound which was reacted with oxalic acid, and recrystallizing from methanol-diethyl ether to give the white oxalate salt in 60% yield, m.p. 178-181°C. oo Analysis: Calculated for CogH3;NOsF2 : C, 68.09; H, 6.11; N, 2.74
Found : C,68.37;H,6.13;N, 2.76 0 Example 8 - 2 " 4-(Dipheny Imethyl)-1-(2-phenoxyethyl)piperidine fumarate [1:1]. ~~ Following the procedure of Example 5, 4-(diphenylmethyl)piperidine - and (2-bromoethoxy)benzene were reacted to give the free base of the title compund which was reacted with fumaric acid in ether-methanol mixture to give the white fumarate salt in 85% yield, m.p. 189-190°C.
Analysis: Calculated for C30H33NOs: C,73.90; H, 6.82: N, 2.87
Found : C,74.07;H,6.91; N, 2.85
M
-126-
Example 9 4-[Bis(4-fluorophenyl)methyl}-1-(2-phenoxyethyl)piperidine oxalate
A mixture, 5.83 g (0.02 mole) of 4-[bis(4-fluorophenyl)methyl]piperi- dine, 4.02 g (0.02 mole) of (2-bromoethoxy)benzene and sodium carbonate (3.18 g, 0.03 mole) as heated overnight at gentle reflux in 300 ml of 1-butanol.
The reaction was filtered and solvent removed in vacuo. The residue was dissolved in chloroform and extracted with water and 5% sodium hydroxide.
Removal of chloroform gave an oil which was converted to the oxalate salt.
The salt was recrystallized from ethanol-diethyl ether to give 6.0 g (60.3%) of white crystalline product, m.p. 180-182°C.
Analysis: Calculated for CogHogNO5F2 : C, 67.60; H, 5.88; N, 2.82
Found : C,67.68,H,5.87; N, 2.81
Example 10 4-[Bis(4-fluorophenyl)methyl]-1-(4-phenoxybutyl)piperidine oxalate
Following the procedure of Example 2, 4-[bis(4-fluorophenyl)methyl]- piperidine and (4-bromopropoxy)benzene were reacted to give the free base of the title compound which was reacted with oxalic acid to give the white oxalate salt (recrystallizing from ethanol-diethyl ether), in 48% yield, m.p. 206°C.
Analysis: Calculated for C30H33NO3sF9 : C,68.56; H, 6.33; N, 2.67 ; Found : C,68.79; H,6.35; N, 2.67 : Example 11 4-[(4-Fluorophenyl)-phenylmethyl]-1-(3-phenoxypropyl)piperidine fumarate [1:1].
A mixture of 5.4 g (0.02 mole) of 4-[a-(p-fluorophenyl)-a-phenylmethyl]: piperidine, 4.5 g (0.021 mole) of (3-bromopropoxy)benzene and 8.0 g (0.075 mole) of anhydrous sodium carbonate in 150 ml of acetonitrile was refluxed for about 20 hr and concentrated under reduced pressure to give a gummy residue. The residue was purified by column chromatography on 160 g of
Florisil®, and the product was eluted with 2% acetone in benzene to give an oil, the free base of the title compound. The free base was reacted with fum-
aric acid, and the salt was recrystallized from isopropyl alcohol to give 4.0 g (38%) of white solid, m.p. 169-171°C (with decomposition). .
Analysis: Calculated for C31 H34FNOs : C, 71.66; H, 6.60; N, 2.70
Found : C,71.37;H, 6.55; N, 2.66
Example 12 4-[Bis(4-fluorophenyl)methyl]-1-[2-(2-6-dichlorophenoxy)ethyllpiperi- dine.
A mixture of 6.13 g (0.021 mole) of 4-[bis(4-Nuorophenyl)methyl]piperi- dine, 5.38 g (0.03 mole) of 2-(2-bromoethoxy)-1,3-dichlorobenzene was heated overnight at gentle reflux in 200 ml of 1-butanol. The reaction mixture was filtered and stripped to dryness. The residue was dissolved in chloroform and extracted with water and 5% sodium hydroxide solution. The oil which was obtained was chromatographed on 300 g of silica gel using hexane-ethyl acetate (50/50 v/v) as eluant. The fractions containing product were combined and solvent removed to furnish an oil. The oil was dried overnight in vacuo at 80°C. This furnished 5.99 g (59%) of product oil.
Analysis: Calculated for CogH25NOF2Clg : C, 65.55; H, 5.29; N, 2.94
Found : C,65.43;H,5.34; N, 2.77
The 'H NMR spectrum of the subject compound was obtained in CDCls, containing tetramethylsilane and is consistent with the structure indicated by the title, : 2.2-238 aliphatic protons (cyclic) 7H 2.8 8 or triplet CHz nextto N 2H 2.8-3.18 Hydrogen next to N 2H 3.5 8 doublet methine proton 1H 4.18 triplet CHj3 next to oxygen 2H 6.8-746 aromatic protons 11H
Example 13 1-[3-(4-Chlorophenoxy)propyll-a,a-bis(4-fluorophenyl)-4-piperidine- methanol.
A mixture of 3.0 g (0.01 mole) of a,a-bis(p-fluorophenyl)4-piperidine- methanol, 2.0 g (0.01 mole) of 1-chloro-4-(3-chloropropoxy)benzene, 5.3 g (0.05 mole) of anhydrous sodium carbonate and 0.3 g of potassium iodide in
100 ml of 1-butanol was refluxed for 20 hr to give, after working up asin
Example 1 (recrystallizing the free base from isopropyl alcohol), 1.7 g (36%) of white solid, m.p. 92-93°C.
Anaysis: Calculated for Co7HgClF2oNO2 : C, 68.71: H, 5.98; N, 2.97
Found : C,68.66; H,5.99; N, 2.92
Example 14 4-[Bis(4-fluorophenyl)methyl]-1-[3-(2-fluorophenoxy)propyllpiperidine oxalate [1:1].
A mixture of 5.85 g (0.02 mole) of 4-[bis(4-fluorophenyl)methyl]}- piperidine, 3.76 g (0.02 mole) of 2-(3-chloropropoxy)-1-fluorobenzene, and sodium carbonate (4.80 g, 0.045 mole) in 300 m] of 1-butanol containing 0.3 g of potassium iodide was heated overnight at gentle reflux. The reaction mixture was stripped to dryness and the resulting oil partitioned between chloroform-5% sodium hydroxide and then between chloroform-water.
Removal of chloroform gave an oil which was converted to the oxalate salt.
The salt was recrystallized from ethanol-diethyl ether. The salt was subse- quently triturated with isopropanol, and was dried overnight at 80°C to give 5.82 g (55%) of product, m.p. 182-183°C.
Analysis: Calculated for CogH3oNOsF3 : C, 65.78; H,5.71; N, 2.65
Found : C,66.05;H,5.79; N, 2.59
Example 15 4-[Bis(4-fluorophenvl)methvl}-1-[3-(3-fluorophenoxy)propvllpiperidine mandelate [1:1].
Following the procedure of Example 14, 4-[bis(4-fluorophenyl)methyl]- piperidine and 3-(3-chloropropoxy)-1-fluorobenzene were reacted to give the free base of the title compound which was reacted with mandelic acid to give the white mandelate salt (recrystallizing from isopropyl alcohol) in 62% yield, m.p. 145-147.5°C.
Analysis: Calculated for C3sH3gNO4F3 : C, 71.05; H, 6.13; N, 2.37
Found : C,71.10; H,6.20; N. 2.36
Example 16 4-[Bis(4-fluorophenyl)methyl]}-1-[3-(4-chlorophenoxy)propyl]piperidine fumarate [1:1].
Following the procedure of Example 14, 4-[bis(4-fluorophenyl)methyl]- piperidine and 1-[4-(3-chloropropoxy)]chlorobenzene were reacted to give the free base of the title compound. The free base was chromatographed on silica gel eluting with hexane-ethyl acetate and reacted with fumaric acid (recrystallizing from methanol-diethyl ether) in 9% yield, m.p. 169-170°C.
Analysis: Calculated for C3 H3oaNOsF2Cl : C, 65.10; H,5.64; N, 2.45
Found : C,64.85;H,5.63; N, 2.46 : Example 17 4-[Bis(4-fluorophenyl)methyl]-1-[3-(4-fluorophenoxy)propyljpiperidine.
Following the combined procedures of Examples 14 and 16, 4-[bis(4- fluorophenyl)methyllpiperidine and 4-(3-chloropropoxy)-1-fluorobenzene were reacted and worked up by chromatography as in Example 16, to give the free base in 53% yield as a yellow oil after drying in vacuo at 80°C overnight.
Analysis: Calculated for Cg7HogNOF; : C, 73.78; H, 6.42; N, 3.19
CT Found : C,73.64;H,6.39;N, 3.14 : 20 : Example 18 4-[Bis(4-fluorophenyl)methyl]-1-[3-(4-methoxyphenoxy)propyl]piperi- dine fumarate [1:1].
Following the procedure of Example 14, 4-[bis(4-fluorophenyl)methyl]- . 25 piperidine and 1-(3-chloropropoxy)-4-methoxybenzene were reacted to give : "the free base of the title compound which was reacted with fumaric acid to give the white fumarate salt (recrystallizing from methanol-diethyl ether) in : 64% yield, m.p. 172-173°C. :
Analysis: Calculated for C3o0H3sNOgF2 : C, 67.71; H, 6.22; N, 2.47
Found : C,67.89;H, 6.25; N, 2.39
Example 19 4-[Bis(4-fluorophenyl)methyl}-1-[2-methoxyphenoxy)propyllpiperidine.
A mixture of 5.99 g (0.021 mole) of 4-[bis(4-fluorophenyl)methyl]piperi- dine, 4.35 g (0.022 mole) of 2-(3-chloropropoxy)-1-methoxybenzene, and
. ~ -130- sodium carbonate (3.18 g, 0.03 mole) in 1-butanol was heated overnight at gentle reflux. The reaction mixture was filtered and stripped to dryness.. The residue was dissolved in chloroform and extracted with water and 5% sodium hydroxide. Removal of chloroform gave a dark brown oil. The oil was chromatographed on silica gel using acetone-ethyl acetate for elution. After combining fractions and removing solvent, an oil was obtained. The oil was dried in vacuo at 80°C overnight, This gave 3.18 g (33.5%) of title product.
Analysis: Calculated for CogH33NOoF2 : C, 74.48, H,6.92; N, 3.12
Found . C,74.42;H,6.95;N,3.00
The 'H NMR spectrum of the subject compound was obtained in CDCl3, containing tetramethylsilane and is consistent with the structure indicated by the title, 6.88 singlet; or protons on ring 4H containing methoxy group. 6.8-7.38 aromatic protons on fluoro- 8H . phenyl rings. 4.08 triplet CH-O. oH : 3.88 singlet O-CH3. 3H 3.46 doublet; methine proton. 5: 0.8-3.18 multiplet. 13H
Example 20 : a.a-Bis(4-fluorophenvl)-1-[3-(2-methoxvphenoxv)voropvl]-4-piperidine- methanol.
Following the procedure of Example 1 a,a-bis(p-fluorophenyl)-4-piperi- . dinemethanol and 1-chloro-3-(2-methoxyphenoxy)propane were reacted using in addition potassium iodide catalyst to give the title compound in 66% yield, (recrystallizing from isopropyl alcohol), m.p. 127-218°C.
Analysis: Calculated for C2gN31F2NO3 : C,71.93;H,6.68;N, 3.00 ‘Found . C,71.88;H,6.67;N,2.98
Example 21 4-[Bis(4-fluorophenyl)methylene]-1-[3-( 2-methoxyphenoxy)propyl)- piperidine oxalate [1:1].
Following the procedure of Example 14, 4-[bis(4-fluorophenyl)methyl- enelpiperidine and 2-(3-chloropropoxy)-1-methoxybenzene were reacted using in addition potassium iodide catalyst to give the free base of the title compound which was reacted with oxalic acid to give the white oxalate salt (recrystallizing from methanol-diethyl ether) in 73% yield, m.p. 184-186°C.
Analysis: Calculated for C30H31NOgF2 : C, 66.78; H,5.79; N, 2.60
Found . C,66.74;H,5.79:N, 2.61
Example 22 4-[Bis(4-fluorophenyl)methyl]-1-[3-(3.4-dimethoxyphenoxy)propyl)- piperidine oxalate [1:1].
A mixture of 6.02 g (0.021 mole) of 4-[bis(4-fluorophenyl)methyllpiperi- dine, 4.83 g (0.021 mole) of 4-(3-chloropropoxy)-1,2-dimethoxybenzene, and potassium carbonate (5.52 g, 0.04 mole) was refluxed overnight in 300 ml of 1-butanol containing potassium iodide (0.3 g). The reaction mixture was stripped to dryness and partitioned between chloroform and water several times. The chloroform layer was dried over anhydrous sodium sulfate and then filtered. The chloroform was removed by rotary evaporator. The oil obtained was converted to the oxalate salt and then recrystallized from methanol-diethyl ether and methanol isopropanol ether. This furnished 7.77 : g (64.7%) of white solid, m.p. 188°C. 26 Analysis: Calculated for C3;H3sNO7F2 : C, 65.14; H,6.17; N, 2.43 - Found . C, 64.78; H, 6.14; N, 2.44
Example 23 ’ oo 4-[Bis(4-methylphenyl)methyl]-1-[ 3-(2,6-dimethoxyphenoxy)propyl}- piperidine fumarate [1:1].
Following the procedure of Example 22, 4-[bis(4-methylphenyl)methyl]- piperidine and 2-(3-chloropropoxy)-1,3-dimethoxybenzene were reacted to give the free base of the title compound which was reacted with fumaric acid to give the white fumarate salt (recrystallizing from methanol-diethyl ether) 3% in66%yield, m.p.206-207°C.
) -132-
Analysis: Calculated for C3sH43NO7: C,71.29; H, 7.35; N, 2.38
Found . C,71.24;H,7.38;N,2.36
Example 24 4.[Bis(4-fluorophenyl)methylene]-1-[3-(3,4-dimethoxyphenoxy)propyl] piperidine oxalate [1:1].
Following the procedure of Example 22, 4-[bis(4-fluorophenyl)methyl- enelpiperidine and 4-(3-chloropropoxy)-1,2-dimethoxybenzene were reacted to give the free base of the title compound which was reacted with oxalic acid to give the cream colored oxalate salt (recrystallizing from methanol-diethyl ether) in 51% yield. m.p. 173-176°C.
Analysis: Calculated for C31H33NO7F2 : C, 65.37; H, 584: N,2.46
Found . C,65.02; H,5.83; N, 2.50 1s Example 25 4-[Bisf 4-fluorophenyl)methyl]-1- 3-(2,6-dimethoxyphenoxy)pro pyll- piperidine oxalate hydrate [1:1 l.
Following the procedure of Example 22, but substituting dimethoxy ethane for butanol, 4-[bis(4-fluorophenyl)methyl]piperidine and 2-(3- chloropropoxy)-1,3-dimethoxybenzene were reacted to give the free base of the title compound which was reacted with oxalic acid to give the white oxalate salt (recrystallizing from methanol-diethyl ether) in 9% yield, m.p.
C 132-134°C.
Analysis: Calculated for C31H37NOgFg : C, 63.15; H,6.32; N, 2.38
Found : C,62.89;H,5.98;N, 2.41
Example 26 4-[Bis(4-fluorophenyl)methyl -1-[3-(3,5-dimethoxyphenoxy)propyll: piperidine.
A mixture of 5.51 g (0.019 mole) of 4-[bis(4-fluorophenyl)methyllpiperi- dine, 4.42 g (0.019 mole) of 1-(3-chloropropoxy)-3,5-dimethoxybenzene and potassium carbonate (5.53 g, 0.04 mole) was heated overnight at reflux in 350 ml of 1-butanol containing potassium iodide (0.3 g). The reaction mixture was stripped to dryness and the residue partitioned between chloroform-5% 3 sodium hydroxide and chloroform-water. Removal of chloroform gave a
% : R -133- brown oil. The oil was subjected to chromatography on a silica gel column using a gradient elution series of hexane-ethyl acetate and ethyl acetate-. dimethoxyethane. After combining proper fractions eluted from the column and removing solvent, the residue oil was dried in vacuo overnight at 80°C.
This produced 2.61 g (28.5%) of brown oil.
Analysis: Calculated for C2gH33NO3F2 : C,72.33;H,6.91;N, 2.91
Found + C,71.62;H,6.80; N, 2.98
The 'H NMR spectrum of the subject compound was obtained in CDCl3 containing tetramethylsilane and is consistent with the structure indicated by the title: 7.0 8 (multiplet, aromatic protons on fluorophenyl ring), 6.0 (singlet, aromatic protons on methoxyphenyl ring, 3H), 2.8 (triplet, methyl- ene next to ether oxygen, 2H), 3.75 (singlet, OCHj, 6H), 3.4 (doublet, methine attached to two aromatic rings, 1H), 0.75 - 2.6 (multiplet, remaining ~ aliphatics, 13H).
Example 27 4-[Bis(4-methoxyphenyl)methyl]-1-{ 3-(3,4-dimethoxyphenoxy)propyl]- piperidine. : = A mixture of 5.58 g (0.02 mole) of 4-[bis(4-methoxyphenyl)imethyl]- piperidine, 4.83 g (0.021 mole) of 4-(3-chloropropoxy)-1,2-dimethoxybenzene, and potassium carbonate, 5.52 g (0.04 mole) was heated overnight at reflux in 350 ml of 1-butanol containing potassium iodide (0.3 g). The reaction mix- "ture was stripped to dryness, and the residue partitioned between chloro- form-5% sodium hydroxide and chloroform-water. Removal of chloroform gave a dark brown oil. The oil was subjected to column chromatography on a <5 silica gel column with elution via ethyl acetate-dimethoxy ethane. This © produced 4.72 g (46.7%) of dark brown oil.
Analysis: Calculated for C3;H3gNOs : C, 73.64; H,7.77; N, 2.77
Found : C,72.38;H,7.70; N, 2.72
The 'H NMR spectrum of the subject compound was obtained in CDCl3 containing tetramethylsilane and is consistent with the structure indicated by the title: 87.1 (multiplet, aromatic protons ortho to methine of
C-(4-OCH;CeHala. 4H), 6.75 (multiplet, aromatic protons adjacent to methoxy groups, 5H), 6.4 (multiplet, aromatic protons adjacent to ether , 3 linkage, 2H), 3.9 (triplet, methylene protons next to ether linkage, 2H), 3.7
(OCHaj, 6H), 3.6 (OCH3, 6H), 3.3 (doublet, methine attached to aromatic rings, 1H), 0.75-3.0 (multiplet, aliphatic protons, 13H). .
Example 28 4-[Bis(4-methoxyphenyl)methyl]-1-[3-(4-methoxyphenoxy )propyl}- piperidine fumarate hydrate [1:1:0.5].
Following the procedure of Example 22, 4-[bis(4-methoxyphenyl)- methyl}piperidine and 4-(3-chloropropoxy)-1-methoxybenzene were reacted to give the free base of the title compound which was separated by extracting with sodium hydroxide-chloroform and reacted with fumaric acid to give the title salt (recrystallizing from methanol-diethyl ether several times as well as isopropyl alcohol) in 15% yield, m.p. 163-165°C.
Analysis: Calculated for C34H42NOg 5 : C, 67.98; H,7.05; N, 2.33
Found : C,68.16; H,6.97; N, 2.34 10
Example 29 1-[4-[3-[4-Bis(4-fluorophenyl)methylene ]-1-piperidinyl]propoxy]- phenyllethanone oxalate [1:1].
Following the procedure of Example 2, 4-[bis(4-fluorophenyl)methyl- enelpiperidine and 1-[4-(3-chloropropoxy)phenyllethanone, substituting sodium carbonate for sodium bicarbonate, were reacted to give the free base of the title compound which was reacted with oxalic acid to give the oxalate salt (recrystallizing from ethanol-diethyl ether) in 59% yield, m.p. 196-198°C.
Analysis: Calculated for C31H31F2NOg : C, 67.50; H, 5.66; N. 2.54
Found . C,67.18;H,5.68;N,2.43
Example 30 1- 4-[3-[4-Bis(4-fluorophenyl)methyl]-1-piperidinyl]propoxylphenyl)- ethanone oxalate [1:1].
Following the procedure of Example 2, 4-[bis(4-fluorophenyl)methyl]- piperidine and 1-[4-(3-chloropropoxy)phenyl)ethanone and substituting sodium carbonate for sodium bicarbonate were reacted to give the free base of the title compound which was reacted with oxalic acid to give the oxalate salt (recrystallizing from methanol-diethyl ether) in 75% yield, m.p. 141-143°C.
Analysis: Calculated for C31H33NOgF2 : C,67.26;H,6.01; N, 2.53
Found : C,66.94;H,6.01;N, 2.40 . _ Example 31 ’ 1-[4-[3-[4-Bis(4-fluoropheny)hydroxymethyl]-1-piperidinyllpropoxy}- phenyljethanone compound with 2-propanol [1:1].
Following the procedure of Example 1, a,a-bis(p-fluorophenyl)-4-piperi- dinemethanol and 1-[4-(3-chloropropoxy)phenyljethanone were reacted using nN potassium iodide catalyst to give the free base of the title compound which
Hv when recrystallized from isopropyl alcohol gave the white title compund in 71% yield, m.p. 72-84°C.
Analysis: Calculated for CogH13FoNO3 C3HgO : C, 71.22; H, 7.28; N, 2.60
Found : C,71.26;H,7.34;N, 2.56
Exaraple 32 1-{4-[3-] 4-[Bis(4-fluorophenyDhydroxymethyl]-1-piperidinyl propoxyl- 3-methylphenyliethanone.
Following the procedure of Example 1, a,a-bis(p-fluorophenyl)-4-piperi- . dinemethanol and 1-[4-(3-chloropropoxy)-3-methylphenyllethanone were reacted using potassium iodide catalyst to give the white title compound (recrytallizing from isopropyl alcohol) in 76% yield, m.p. 116-117°C.
Analysis: Calculated for C3oH33F2NO3 : C, 73.00; H,6.74;N, 2.84 - Found : | : C,72.90;H,6.80; N, 2.78
B Example 33 4-13-[4-[Bis(4-fluorophenyhhvdroxymethyl]-1-piperidinylipropoxy] benzonitrile.
Following the procedure of Example 1, a,a-bis(p-fluorophenyl)-4-piperi- “0 dinemethanol and 4-(3-chloropropoxy) benzonitrile were reacted using potas- sium iodide as catalyst to give the white title compound (recrystallizing from . isopropyl alcohol-isopropyl ether) in 30% yield, m.p. 107-108°.
Analysis: Calculated for CogHggF2N20g : C,72.71; H,6.10; N, 6.06
Found . C,72.82;H,6.11;N, 6.05
Example 34 4-[3-[4-[Bis(4-fluorophenyl)methyl]-1-piperidinyllpropoxy jucucusises sax fumarate [1:1].
Following the procedure of Example 22, 4-[bis(4-fluorophenyl)methyl]- piperidine and 4-(3-chloropropoxy)cyanobenzene were reacted using potas- sium iodide catalyst to give the free base of the title compund which was reacted with fumaric acid to give the fumarate salt which was (recrystallized from ethanol-diethyl ether) in 53% yield, m.p. 167°C.
Analysis: Calculated for C32H32N205F2 : C, 68.32; H,5.73; N, 4.98
Found : C,68.10;H,5.70; N, 4.94
Example 35 4-[3-[4-[Bis(4-fluorophenyl)methyl]-1-piperidinyl}propoxy lbenzoic acid ethyl ester hydrochloride [1:1].
A mixture of 6.0 g (0.02 mole) of a,a-bis(p-fluorophenyl-4-piperidine- methanol, 5.0 g (0.02 mole) of 4-(3-chloropropoxy))benzoic acid methyl ester, 7.4 g (0.07 mole) of anhydrous sodium carbonate, 0.3 g of potassium iodide and 150 ml of dimethylformamide was heated on a steam bath for 20 hrand then poured into 1.5 liter of ice-water. A gum precipitated, and the aqueous solution was decanted. The gum was dissolved in benzene, and the solution was washed with water and dilute sodium hydroxide solution, dried over "anhydrous sodium sulfate and concentrated under reduced pressure to give 9.2 g of gum as residue. The gum was purified by column chromatography on 200 g of Florisil®, and the desired product was eluted with 20% acetone in benzene. The fractions containing the free base of the title compound were combined and concentrated under reduced pressure to give a gum, the free base, as residue. The free base was converted to the hydrochloric acid salt which was recrystallized from 2-propanol to give 5.3 g (49%) of white powder, m.p. 193.5-194.5°.
Analysis: Calculated for C30H34C1F2NOy4 : C,65.99; H, 6.28; N, 2.57
Found : C, 66.16; H,6.32; N, 2.56
Example 36 4-[3-[4- Bis(4-fluorophenyl)hydroxymethyl-1-piperidi benzoic acid hydrochloride hydrate [1:1:0.5).
A solution of 2.7 g (0.005 mole) of 4-[3-[4-[bis(4-fluorophenyl)hydroxy- methyl]-1-piperidinyl]propoxy]benzoic acid ethyl esterand 1.2 g (0.022 mole) of potassium hydroxide in 50 ml of ethanol and 20 ml of water was heated on a steam bath for 2 hr. Acetic acid, 10 m}, was added the solution was poured into 500 ml of ice water, and the mixture was allowed to stand at ambient temperature overnight. Sodium chloride was added to the mixture to give a coagulated solid. The solid was collected by filtration and air dried. The solid was dissolved in 20 ml of isopropyl alcohol, and the solution was poured into 30 ml of ethereal hydrogen chloride. The salt which gradually crystallized was collected by filtration, washed with ethyl ether and dried to give 0.2 g (8%) of white powder, m.p. 148-158°C with decomposition.
Analysis: Calculated for C19H31CIFeNOy 5: C, 63.82; H, 5.93; N, 2.66
Found : C,53.97;H,6.25; N, 2.51 : Example 37 : 4-[3-[4-] Bis(4-fluorophenyl)methylene-1-piperidinyl |propoxylbenzoic acid ethyl ester hydrobromide [1:1].
A mixture of 6.09 g (0.021 mole) of 4-[bis(4-fluorophenyl)methylene]- © piperidine, 5.20 g (0.02 mole) of 1-[4-(3-chloropropoxy)-phenyllcarbethoxy- benzene and sodium carbonate 4.30 g (0.04 mole) in 230 ml of 1-butanol containing potassium iodide (0.3 g) was heated overnight at gentle reflux.
The reaction mixture was stripped to dryness and partitioned between chloroform water and chloroform - 5% sodium hydroxide. Removal of chloro- form gave an oil. The oil was converted to the hydrobromide salt using hydrogen bromide in glacial acetic acid. The acetic acid and excess hydrogen bromide were removed in vacuo. The salt was recrystallized from ethanol- . 30 diethyl ether. The salt was washed with water to remove acetamide present as an impurity. The salt washed with diethyl ether and dried in vacuo overnight at 80°C. A yield of 6.81 g (59.5%) of white solid, m.p. 192-194°C, was obtained. : Analysis: Calculated for C30H32NO3F2Br : C,62.94; H, 5.63: N, 2.45
Found : C,62.83;H,5.58;N, 2.45
Example 38 4-[3-[4-[Bis( 4-fluorophenyl)methyl]-1-piperidinyl lpropoxylbenzoic acid ethyl ester hydrobromide [1:1].
Following the procedure of Example 14, 4-[bis(4-fluorophenyl)methyl]- piperidine and 4-(3-chloropropoxy)benzoic acid ethyl ester were reacted using potassium iodide as catalyst to give the free base which was reacted with hydrogen bromide in glacial acetic acid. The oil was stripped to dryness and the solid obtained was recrytallized from isopropyl alcohol-diethyl ether to give the white salt in 20% yield, m.p. 142-144°C. i0 Analysis: Calculated for C30H34NO3F2Br : C, 62.72; H, 5.97: N, 2.44
Found : C,62.66;H,5.95; N, 2.45
Example 39 4-[3-[4-[Bis(4-methoxyphenyl )methyl]-1-piperidinyl]propoxy [benzoic acid butyl ester.
A mixture of 6.22 g (0.02 mole) of 4-[bis(4-methoxyphenyl)methyl}- piperidine, 4.84 g (0.02 mole) of 4-(3-chloropropoxy)benzoic acid ethyl ester, and potassium carbonate, 5.60 g (0.04 mole) in 350 ml of 1-butanol was refluxed overnight with potassium iodide. The reaction mixture was stripped 0 todryness and the residue patitioned between chloroform-5% sodium "hydroxide then chloroform-water. Removal of chloroform gave an oil. This oil was chromatographed on a 200 g silica gel column packed in 50/50 v/v hexane-ethyl acetate. The material was eluted with hexane-ethyl acetate mixtures and finally 1% methanol-ethyl acetate.
From the chromatography was obtained 5.09 g (46.6%) of an oil.
Analysis: Calculated for C34H43NOs : C, 74.83; H, 7.94; N, 2.57
Found : C,74.19;H,7.91;N, 2.53
The 'H NMR spectrum was obtained in CDC]; and is consistent with the structure indicated by the title, 5 8.0 (H’s ortho to COg2, 2H), 6.8 (m, aromatic, 10H), 4.2 (m, CHz alpha to O, 4H), 3.7 (S, OCH3, 6H), 0.9-3.5 (m, aliphatics, 21H).
Example 40 4-[3-[4-[Bis( 4-methoxyphenyl)methyl -1-piperidinylipropoxy jueusuiy acid butyl ester fumarate hydrate {1:1:0.5}.
Following the procedure of Example 22, but substituting dimethyl- formamide at 73°C for butanol, 4-[bis(4-methoxyphenyl)methyl]piperidine and 4-(3-chloropropoxy)benzoic acid ethyl ester were reacted to give the free base of the title compound which was reacted with fumaric acid, to give the white fumarate salt (recrystallizing from methanol-diethyl ether) in 27% yield, m.p. 147.5-148.5°C.
Analysis: Calculated for C36H44NOg 5 : C,67.27; H,6.90; N, 2.18
Found : C,67.26;H,6.78;N, 2.19
Example 41 4-[3-[4- Bis(4-fluorophenyl )hydroxymethyl ]-1-piperidinyllethoxy)- benzoic acid ethyl ester hydrochloride.
Following the procedure of Example 35, a,a-bis(p-fluorophenyl)-4- piperidine methanol and 4-(2-chloroethoxy)benzoic acid ethyl ester are reacted and the hydrochloride salt is prepared.
Example 42 oo 4-[3-[4-[Bis( 4-fluorophenylhydroxymethyl )-1-piperidinyljpropoxy}-3- methoxybenzeneacetic acid ethyl ester hydrochloride.
Co Following the procedure of Example 35, a,a-bis(p-fluorophenyl)-4- : piperidinemethanol and 4-(3-chloropropoxy)-3-methoxybenzeneacetic acid ethyl ester are reacted and the hydrochloride salt is prepared. = Example 43 4- Bis(4-fluorophenyl)methylene ]-1-[3-[4-( 1,1-dimethylethyl)phenoxy]- propyl]piperidine fumarate [1:1].. . | 30 Following the procedure of Example 9, 4-[bis(4-fluorophenyl)- methylene)piperidine and 4-(3-chloropropoxy)-(1,1-dimethylethyl)benzene were reacted using potassium iodide catalyst to give an oil which was dis- solved in ethyl acetate and filtered through silica gel to give the free base of 45 the title compound. The free base was reacted with fumaric acid to give the white fumarate salt (recrystallizing from isopropyl alcohol 40% yield, m.p. 208.5-209.5°C. .
Analysis: Calculated for C35H3gNOsFa2: C, 71.05; H, 6.64; N, 2.37
Found : C,7091;H,6.57; N, 2.38
Example 44 4-[Bis(4-fluorophenyl)methyl]-1-[3-] 4-(1,1-dimethylethyl)phenoxy]- propyl]piperidine fumarate hydrate [1:1:0.5].
Following the procedure of Example 9, 4-[bis(4-fluorophenyl)- methylene}piperidine and 4-(3-chloropropoxy)-(1,1-dimethylethyl)benzene were reacted using potassium iodide catalyst to give the free base title compound which was reacted with fumaric acid to give the white fumarate salt (recrystallizing from methanol-diethyl ether and isopropyl alcohol- diethyl ether) in 55% yield, m.p. 194-196°C with decomposition.
Analysis: Calculated for C35H42NOs 5F2: C,69.75;H, 7.02; N, 2.32
Found : C,70.01;H,6.89;N, 2.44
Example 45 : 4-[Bis(4-methoxyphenyl)methyl]-1-[3-[4-( 1,1-dimethylethyl)pheoxy]- propyl]piperidine oxalate [1:1].
Following the procedure of Example 22, 4-[bis(4-methoxyphenyl)- methyl]piperidine and 4-(3-chloropropoxy)-(1,1-dimethylethyl)benzene were reacted using potassium iodide catalyst to give the free base which was reacted with oxalic acid to give the white oxalate salt (recrystallizing from methanol-diethyl ether) in 35% yield, m.p. 212°C. : Analysis: Calculated for C3sH4sNO7: C,71.04;H,7.67;N, 2.37 " Found . C,70.91;H,7.70;N, 2.35
Example 46 1-[3-[4-(1,1-Dimethylethyl)phenoxy]propyl ]-a,a-bis(4-fluorophenyl)-4- piperidinemethanol.
Following the procedure of Example 1, a,a-bis(p-fluorophenyl)-4- piperidinemethanol and 4-(3-chloropropoxy)-(1,1-dimethylethyl)benzene were reacted using potassium iodide catalyst to give white powder (recrystallizing from isopropyl alcohol) in 41% yield, m.p. 126-127°C.
Analysis: Calculated for C3;H37FoNOg: CC, 75.43; H,7
Found : C,75.21;H,7
Example 47 4-[Bis(4-fluorophenyl)methyl]-1-[3-[3-(trifluoromethyl)phenoxy]- propylipiperidine oxalate [1:1].
Following the procedure of Example 9, 4-[bis-(4-fluorophenyl)methyl]- piperidine and 1-[3,chloropropoxy]-3-trifluoromethylbenzene were reacted using potassium iodide catalyst to give the free base of the title compound which was reacted with oxalic acid to give the white oxalate salt (recrystal- lizing from methanol-diethyl ether) in 39% yield, m.p. 185-186°C. :
Analysis: Calculated for C30H3oNOsFs: C, 62.17; H, 5.22; N, 2.42
Found : C,62.54; H,5.27; N, 2.52
Example 48
N-[4-[3-[4-[Bis(4-methylphenyl)methyl]-1-piperidinyl]propoxy]phenyl] acetamide fumarate hydrate {1:1:0.5].
Following the procedure of Example 22 but substituting dimethyl- formamide at 73°C for refluxing butanol, 4-[bis-(4-methylphenyl)methyl]- piperidine and N-[4-(3-chloropropoxy)phenyl]acetamide were reacted using : potassium iodide catalyst to give the free base of the title compound which was reacted with fumaric acid to give the white fumarate hydrate (recrystallizing from methanol-diethyl ether), m.p. 149-152°C. : Analysis: Calculated for C33H43N20g5: C, 70.57; H, 7.28: N. 4.70
Found : C,170.80; H, 7.28; N, 4.65 : Example 49
N-{4.[3-[4-[Bis(4-fluorophenyl)methyl]-1-piperidinyl]propoxylphenyl}- ~*~ acetamide hydrobromide [1:1]. : A mixture of 25.68 g (0.089 mole) 4-(bis(4-fluorophenyl)methylene)- - piperidine, 20.3 g (0.089 mole) of N-[4-(3-chloropropoxy)phenyljacetamide, and potassium carbonate, 21.4 g, (0.155 mole) was stirred overnight at 70- 80°C in 350 ml of dimethylformamide. The reaction mixture was stripped to dryness and the residue was partitioned between chloroform and water; removal of chloroform gave a dark red oil. The oil was dissolved in glacial acetic acid, and the hydrobromide salt was formed with hy glacial acetic acid. Solvent was removed in vacuo, and the residue was recrystallized from methanol-diethyl ether. A yield of 21.68 g (43.5%) of pale- white solid, m.p. 223-225°C, was obtained.
Analysis: Calculated for CogH33N2OoF2Br: C, 62.26; H, 5.95; N., 5.01
Found : C,61.99;H,5.94;N, 5.01
Example 50 4-[3-[4-[Bis(4-fluorophenyl)methyl |-1-piperidiny!]propoxy]benzene- amine fumarate hydrate [1:1:0.5].
A solution of 11.8 g (0.02709 mole) of N-[4-[3-[bis(4-fluorophenyl)- methyl]-1-piperidinyl]propoxylacetamide was heated at gentle reflux for four hours in 500 ml of methanol containing 500 ml of 6N hydrochloric acid. The reaction stopped and allowed to cool overnight. The reaction mixture was evaporated to a small volume on the rotary evaporator, diluted with water and made alkaline with 5% sodium hydroxide. The reaction mixture was then partitioned between the alkaline phase and chloroform. The chloroform layer was dried, filtered, and solvent removed to give an oil. The oil was converted to the fumarate salt and the salt was recrystallized from methanol- diethyl ether. The white solid obtained was dried overnight in vacuo at 80°C : to give 8.49 g (71%) of white crystalline product, m.p. 121.5-124.0°C. . Analysis: Calculated for C31H35N205 5F2: C, 66.30; H, 6.28; N, 4.99
Found : C,66.49;H,6.13; N, 4.92
Example 51
N-[4-[3-[4-[Bis(4-flucrophenyl)hydroxymethyl ]-1-piperidinyl]propoxy]- ~ phenyl]acetamide hydrochloride hydrate [1:1:1].
A mixture of 3.0 g (0.01 mole) of a,a-bis(p-fluorophenyl)-4-piperidine- methanol, 2.3 g (0.01 mole) of N-[4-(3-chloropropoxy)phenylacetamide, 53¢g (0.05 mole) of anhydrous sodium carbonate and 0.3 g of potassium iodide in 100 ml of 1-butanol gave a gum as residue. The gum was purified by column chromatography on 80 g of Florisil® and the product was eluted with 20% acetone in benzene. The combined fractions containing product were concentrated under reduced pressure to give a glass as residue. The glass was dissolved in ethyl ether, filtered through cotton, and the filtrate treated with ethereal hydrogen chloride. The resulting solid was co filtration, washed with ethyl ether and dried to yield 2.1 g (38%) of white’ solid, m.p. 135-170°C (with decompositon).
Analysis: Calculated for C29H33CIF2N203eH20: C, 63.44; H,6.43; N, 5.10 ,
Found : C,63.32;H,6.56; N, 4.92
Example 52 a,a-Bis(4-fluorophenyl)-1-| 3-(4-nitrophenoxy)propyl ]-4-piperidine- methanol.
Following the procedure of Example 1 and using potassium iodide catalyst, a mixture of 9.1 g (0.03 mole) of a,a-bis(p-fluorophenyl)-4-piperi- dinemethanol and 6.7 g (0.03 mole) of 1-(3-chloropropoxy)-4-nitrobenzene were reacted to give 10.5 g of the title compound which was recrystallized from isopropyl ether, m.p. 93.5-94.5°C.
Analysis: Calculated for C27H28FaN204: C, 67.21; H, 5.85; N, 5.81
Found : C,67.05;H,5.83; N, 5.74
Example 53 4-[3-[4-] Bis(4-fluorophtnyDhydroxymethyl |-1-piperidinyl]propoxy]- benzamide. oo
Following the procedure of Example 1 and using potassium iodide catalyst, a mixture of 3.0 g (0.01 mole) of a,a-bis(p-fluorophenyl)-4-piperi- dineméthanol, 1 g (0.01 mole) of 4-(3-chloropropoxy)benzamide and 69g ~ (0.05 mole) of anhydrous potassium carbonate in 100 ml of 1-butanol were
C25 reacted to give 3.0 g (63%) of white powder, m.p., 200-204°C. The recrystal- lizing solvent used was absolute ethanol. oo Analysis: Calculated for CegH30F2N203: C, 69.98; H, 6.29; N, 5.83 oo Found : C,69.61;H,6.49; N, 5.70 3 Example 54 4-[Bis(4-fluorophenyl)methyl |-1-[2-(1-naph thalenyloxy)ethyl]- piperidine hydrochloride [1:1 ].
A mixture of 2.84 g (0.0099 mole) of 4-[a,a-bis(p-fluorophenyl)methyl)- piperidine, 3.01 g (0.012 mole) of 1-(2-bromoethoxy)naphthalene and 5.0 g (0.060 mole) of sodium bicarbonate in 400 m] of 1-butanol was refluxed for 16 hr. The solvent was removed in vacuo, and the residue was between methylene chloride and dilute sodium hydroxide. ...c ocean, conan chloride solution was dried over magnesium sulfate, and the solvent was removed in vacuo to give an oil. This was dissolved in a mixture of ether and methanol, an excess of ethereal hydrochloride was added, and a white precipitate was collected to give 3.13 g (64%) of white crystalline solid, m.p. 155-158°C.
Analysis: Calculated for C30H3oNOF2Cl: C, 72.94; H, 6.12; N, 2.84
Found : C,73.20;H,6.10; N, 2.78
Example 55 : 4-(Bis(4-fluorophenyl)methyl]-1-| 2-(2-naphthalenyloxy)ethyl]- piperidine oxalate [1:1].
Following the procedure of Example 54 and substituting 2-(2-bromo- ethoxy)naphthalene and oxalic acid for hydrogen chloride, the title compound was obtained in 61.9% yield as white crystalline solid, m.p. 168-171°C.
Analysis: Calculated for C39H31NOsF: C,70.19; H,5.71; N, 2.56
Found ~~: C,70.26;H,5.75;N, 2.63
Example 56 1-[4-[3-[4-[Bis(4-fluorophenyl)methyl -1-piperidinyl |propoxyl-3- . methoxyphenyllethanone oxalate [1:1].
The title compound was prepared by the method described in U.S.
Patent 3,956,296 (see Example 13 of that patent) as follows: A mixture of 4.75 g (0.0165 mole) of 4-[a,a-bis(p-fluorophenyl)methyllpiperidine, 4.0 g (0.0165 mole) of 3-(p-acetyl-o-methoxyphenoxy)propyl chloride and 1.4 g (0.0165 mole) of sodium bicarbonate in 60 ml of dimethylformamide was heated at 80°C for about 2 hours. TLC showed no product at this point. The temperature was raised to 100°C for 1 hr, at which time TLC showed the reaction to be complete. After cooling, the reaction mixture was filtered and the dimethylformamide was removed under reduced pressure. The crude product was dissolved in chloroform and filtered and the filtrate was concentrated under reduced pressure to give 7.7 g (94%) of crude product.
The solid was dissolved in benzene and placed on a Florisil® column. Upon eluting with an acetone-benzene gradient, 5.5 g of product was obtained. The oxalate salt was prepared and upon recrystallization from i methanol gave 3.8 g of salt was obtained, m.p. 164.5-166°C.
Analysis: Calculated for C32H35F2NO7: C, 65.86; H, 6.05; N, 2.40
Found : C,66.11;H,6.13; N, 2.39
Example 57 : 1-[4-[3-[4-[Bis(4-fluorophenyl)methyl }-1-piperidinyl]propoxy]-3- methoxyphenyljethanone fumarate [5:6].
A mixture of 58.26 g (0.203 mole) of 4-[bis(4-fluorophenyl)methyl)- piperidine, 54.5 g (0.225 mole) of 1-chloro-3-(4-acetyl-2-methoxyphenoxy)- propane, 18.7 g (0.223 mole) of sodium bicarbonate and 1.2 g (0.0072 mole) of potassium iodide in 800 ml of 1-butanol was refluxed for 16 hr. The hot reaction mixture was filtered, and the solvent was removed in vacuo from the filtrate. The residue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene chloride solution was dried over magne- sium sulfate, and the solvent was removed in vacuo to give an oil. The oil was dissolved in 600 ml of anhydrous ether, and 4.91 g of a solid was collected at room temperature. The ether solution was then treated with a solution of 30.2 g (0.26 mole) of fumaric acid in methanol. Anhydrous ether was added and 99.88 g (77.7%), m.p. 160-163°C, of title compound was isolated. This was recrystallized from isopropanol-diethyl ether, (2.5 g, 0.0216 mole of addi- oo "tional fumaric acid was added) to give 2 crops of title compound. {CropI- 44.15 g, m.p. 163-164.5°C; Crop II - 38.75 g, m.p. 161-163°C] An additional 10.00 g (8.786%), m.p. 159-162°C of title compound collected from the original ether-methanol filtrate. NMR showed that the salt contained 1.2 equivalents : of fumaric acid.
Anaysis: Calculated for C34 8H37.8NO7.8F2: C,66.05;H,6.02; N, 2.21
Found + C,65.96;H,6.18;N, 2.16
Example 58 1-[4-[3-[4-[Bis(4-fluorophenyl)methylene }-1-piperidinyllpropoxy]-3- methoxyphenyllethanone oxalate [1:1].
The title compound was prepared by the method described in U.S. :
Patent 3,922,276 (see Example 12 of that patent) as follows: A mixture of : 4.7 g (0.0165 mole) of 4-[a,a-bis(p-fluorophenyl)methylene)piperidine, 4.0 g
(0.0165 mole) of 3-(p-acetyl-o-methoxyphenoxy)propyl chlo sodium bicarbonate in 60 ml of dimethylformamide was heaweu —. overnight. After cooling, the reaction mixture was filtered and the dimethyl- formamide was removed at reduced pressure. The residual oil was dissolved in benzene and placed on a Florisil® column. Elution with a gradient of acetone-benzene gave 5.7 g (70%) of a viscous brown oil. The free base was reacted with oxalic acid to give the oxalate salt, m.p. 169-170°C after : recrystallization from isopropyl alcohol and drying under nitrogen.
Analysis: Calculated for C32H33FgNO7: C, 66.08, H,5.72; N, 2.41
Found . C,66.01;H,5.67;N,2.40
Example 59 1-[4-[3-14-[(4-Fluorophenyl)( phenyl)methylene]-1-piperidinyl |propoxyl- 3-methoxyphenyllethanone oxalate [1:1 l.
The title compound was prepared by the method described in U.S. 3,922,276 (see Example 12 of that patent) as follows: A mixtureof7.1g (0.027 mole) of 4-[a-(p-fluorophenyl)-a-phenylmethylene]piperidine, 6.5¢g (0.027 mole) of 3-(p-acetyl-o-methoxyphenoxy)propyl chlorideand 2.3 g (0.027 mole) of sodium bicarbonate in 100 ml of dimethylformamide was stirred and heated at 100°C for approximately 8 hours. The mixture was filtered, and the dimethylformamide was removed under reduced pressure. "The residual oil was dissolved in chloroform, and the mixture was filtered.
The filtrate was concentrated under vacuum to give 11.5 ¢g of crude free base (925). The free base was reacted with oxalic acid to give the oxalate salt, 26 m.p. 143-145°C, after recrystallization from methyl isobutyl ketone.
Analysis: Calcualted for C32H34FNO7: C, 68.19; H, 6.08; N, 2.49
Found : C,68.14;H,6.12;N, 2.54
Example 60 1-[3-Methoxy-4-[3-[4-[phenyl[3-( trifluoromethyl)phenyllmethylene]-1- piperidinyllpropoxylphenyllethanone oxalate [1:1].
The title compound was prepared by the method described in U.S.
Patent 3,922,276 (see Example 10 of that patient) as follows; A mixture of 5.0 g (0.0157 mole) of 4-{a-phenyl-a-(m-trifluoromethylphenyl)methylene]- piperidine, 3.82 g (0.0157 mole) of 3-(p-acetyl-o-methoxyphenoxy)propyl chloride and 2.52 g (0.03 mole) of sodium bicarbonate in 75 was stirred and heated at reflux for 17.5 hrs. The mixture was cootea una filtered, and the filtrate was concentrated under reduced pressure. The glassy residue obtained weighed 4.25 g (52%) and was dissolved in benzene and placed on a Florisil® column. Using an acetone-benzene gradient elution, product was obtained as a glassy residue. This residue was dissolved in ether and the oxalate salt was obtained. The salt has a glassy appearance, m.p. 120-125°C.
Analysis: Calculated for C33H34F3NO7: C, 64.59; H, 5.58; N, 2.28
Found : C, 64.34; H,5.72;N, 2.04
Example 61 1-[4-[3-[4-(Cyclohexylphenylmethylene)-1-piperidinyl]lpropoxy]-3- methoxyphenyllethanone oxalate [1:1].
The free base of the title compound was obtained asin Example 1 of
U.S. Patent 3,922,276 by reacting 4-[(a-cyclohexyl-a-phenyl)methylene]- . piperidine with 3-(p-acetyl-o-methoxyphenoxy)propyl chloride in a mixture with sodium bicarbonate in dimethylformamide and converted to the oxalate salt, m.p. 184-185°C.
Analysis: Calculated for C3oH41NO7: C,69.67;H, 7.49; N, 2.54
Found : C,69.83;H,7.58;N, 2.56 or Example 62 co " 1.[4-[3-[4-(Cyclohexylphenvimethvl)-1-piperidinyljpronoxy]-3- methoxyphenyljethanone oxalate hydrate {1:1:0.5].
Co oo A mixture of 5.2 g (0.02 mole) of 4-[(a-cyclohexyl-a-phenyl)methyl)- piperidine, 4.9 g (0.02 mole) of 3-(p-acetyl-o-methoxyphenoxy)propyl chloride and 1.7 g (0.02 mole) of sodium bicarbonate in 100 ml of dimethylformamide was stirred and heated at 100°C for 4 hrs. The reaction mixture was cooled, : 30 filtered, and the dimethylformamide was removed under reduced pressure.
The residual material was dissolved in benzene and placed on a Florisil® column. Elution using an acetone-benzene gradient gave 7.0 g (74.5%) of free base of the title compound. The oxalate salt was prepared and recrystallized from isopropanol, m.p. 155-160°C.
Analysis: Calculated for CgsHgsN2015: C, 68.31; H, 7.88
Found : C,68.60;H,7.78,
The free base of the title compound was obtained by reacting 4-((a- cyclohexyl-a-phenyl)methyl]piperidine and 3-(p-acetyl-o-methoxyphenoxy)- propyl chloride in a mixture with sodium bicarbonate, isolated and reacted with oxalic acid. The oxalate salt was recrystallized from 2-propanol, m.p. 155-160°C.
Example 63 4-[3-[4-[Bis( 4-fluorophenyl)methylene -1-piperidinyl]propoxy}-a- methylbenzenemethanol oxalate [1:1).
A solution of 1-[4-[3-[4-[bis(4-fluorophenyl)methylene]-1-piperidinyl]- propoxyJphenyllethanone, 3.56 g (0.0077 mole), and sodium borohydride, 1.51 g (0.04 mole), was stirred 6 hrs at room temperature. The reaction mixture was stripped to dryness and partitioned between chloroform-water and chloroform-5% sodium hydroxide. Removal of chloroform gave an oil which was converted to the oxalate salt. Recrystallization from methanol- diethyl ether gave 2.67 g (62.1%) of white crystalline product, m.p. 142- 145°C.
Analysis: Calculated for C31H33NOgF2: C, 67.26; H, 6.01; N, 2.53
Found . C,67.17;H,5.92; N, 2.47
Example 64 4-[3-[4-[Bis( 4-fluorophenylmethyl)-1-piperidinvl]propoxy ]-3-methoxy- a-methylbenzenemethanol.
Sodium borohydride (3.0 g, 0.079 mole) was added to 250 ml of 95% ethanol. To the mixture was added 4.40 g (0.00885 mole) of 1-[3-(p-acetyl-o- methoxyphenoxy)propyll-4-[a,a-bis(p-fluorophenyl)methyllpiperidine in 100 ml of 95% ethanol over 15 minutes. The resulting solution was stirred 2.5 hr at room temperature. The reaction mixture was stripped to dryness and partitioned between chloroform and 5% sodium hydroxide. The organic layer was back extracted with 5% sodium hydroxide and water; removal of chloroform gave an oil. The oil formed a white solid in diethyl ether. The white solid was filtered off and recrystallized from methylene chloride- diethyl ether. This furnished 2.16 g (49.2%) of white solid, m.p. 132-135°C.
Analysis: Calculated for C30H35NO3Fe: C, 72.72; H, 7.12
Found : C,72.28;H,7.21;N, 2.52 .
Example 65 1-[4-[3-[4-(Diphenylmethyl)-1-piperidinyl]propoxy]-3-methoxyphenyl]- : ethanone oxalate [1:1]. : : A mixture of 5.0 g (0.02 mole) of 4-(a-phenylbenzyl)piperidine, 4.85 g (0.02 mole) of 3-(p-acetyl-o-methoxyphenoxy)propyl chloride, and 3.4 g (0.04 mole) of sodium bicarbonate in 100 ml of dimethylformamide was heated at 100°C for about 3 hrs. The reaction mixture was cooled, filtered and the filtrate was concentrated under reduced pressure. The residual oil was . dissolved in chloroform, and the chloroform was filtered to remove insolubles. . The filtrate was concentrated under reduced pressure to give 8.6 g of a red oil (94.5%). The oil was dissolved in a mixture of 4:1 ether-isopropancl and treated with 2.3 g of oxalic acid dihydrate. The oxalate salt crystallized upon standing and trituration in ether gave 8.4 g of salt melting at 149-155°C.
Recrystallization from isobutyl methyl ketone gave 7.0 g of the salt, m.p. 153- 155°C. (See Example 11, U.S. 3,956,296).
Analysis: Calculated for C32H37NO7: C,70.18; H, 6.81; N, 2.56
Found . C,70.00;H,6.76;N,2.56 oo Example 66 oo 1-[4-[3-[4-[Bis(4-fluorophenvl)hydroxvmethvl]-1-piperidinvl]propoxy]- : 3-methoxyphenyllethanone. | © A mixture of 5.0 g (0.0165 mole) of a,a-bis(p-fluorophenyl)-4-piperidine- . methanol, 4.0 g (0.0165 mole) of 3-(p-acetyl-o-methoxyphenoxy)propyl chloride and 1.4 g (0.0165 mole) of sodium bicarbonate in 60 ml of dimethyl- ) formamide was stirred and heated at 80°C for two hours. The temperature was raised to 100°C for one hour. After cooling, the reaction mixture was ’ 30 filtered and the dimethylformamide was removed at reduced pressure. The residual oil which crystallized on standing in ether was dissolved in benzene and placed on a Florisil® column. Using a gradient elution of acetone- benzene, 1.8 g (21.4%) of product was obtained from the column, m.p. 141.5- 143°C. (See Example 12, U.S. 3,956,296).
\ -150-
Analysis: Calculated for C3oH33F2NO4: C, 70.71; H, 6.5!
Found + C,70.49; H, 6.56; 1v, «uo
Example 67 1-[4-[3-[4-{ (4-Fluorophenyl)hydroxyphenylmethyl -1-piperidinyl]- propoxyl-3-methoxyphenyl]ethanone.
A mixture of 6.5 g (0.023 mole) of a-(p-flucrophenyl)-a-phenyl-4- piperidinemethanol, 5.5 g (0.023 mole) of 3-(p-acetyl-o-methoxyphenoxy)- propyl chloride and 1.92 g (0.023 mole) of sodium bicarbonate in 80 ml of dimethylformamide was heated at 100-1 10°C for 2 hrs. The reaction mixture was cooled and filtered, and the dimethylformamide was removed at reduced pressure. The residual oil was dissolved in chloroform and filtered. The chloroform was removed at reduced pressure. The solid residue which remained weighed 8.6 g (77%) and was recrystallized from ethanol to give 3.1 g of material melting at 147-148°C. A sample was dried over refluxing toluene and submitted for analysis. (See Example 14, U.S. 3,956,296).
Analysis: Calculated for C3oH34NO4F: C, 73.30; H, 6.97; N, 2.85
Found . C,73.15;H,7.05;N, 2.77 vo
Example 68 1-[4- 3-[4-(Diphenylhydroxymethyl)-1-piperidinyllpropoxy |-3-methoxy- ' phenyljethanone oxalate [1:1].
A mixture of 5.2 g (0.0194 mole) of a,a-diphenyl-4-piperidinemethanol, 4.7 g (0.0194 mole) of 3-(p-acetyl-o-methoxyphenoxy)propyl chloride and 1.6¢g (0.0194 mole) of sodium bicarbonate in 60 ml of dimethylformamide was stirred at 100°C for 3 hrs. After cooling, the reaction mixture was filtered and the dimethylformamide was removed under reduced pressure. The residual oil weighed 8.3 g (90%). Some of the product crystallized upon trituration in anhydrous ether and was collected by filtration. The filtrate was evaporated to dryness and the residue was dissolved in hot benzene- isooctane. Upon cooling, the crystalline product was obtained. A total yield of 6.3 g of solid product was obtained. The solid free base was converted to the oxalate salt. Recrystallization from isobutyl methyl ketone gave the off- white solid melting at 174-176°C. (See Example 15, U.S. 3,956,296).
Analysis: Calculated for C3oH37NOs: C, 68.19; H,6.62 : Found : C,68.34;H,6.75; N, 2.42 .
Example 69 1-[4-[3-[4-[Hydroxyphenyl{3-(trifluoromethyl)phenyl jmethyl]-1- piperidinyl}propoxy)-3-methoxyphenyljethanone hydrochloride hydrate [1:1:0.5]).
A mixture of 7.0 g (0.021 mole) of a-phenyl-a-(m-trifluoromethylphenyl- 4-piperidinemethanol, 5.1 g (0.021 mole) of 3-(p-acetyl-o-methoxyphenoxy)- propyl chloride and 3.0 g (0.036 mole) of sodium bicarbonate in 125 ml of dry dimethylformamide was stirred and heated at 90-95°C for 5 hours. The mixture was cooled and filtered. An excess of water was added to the reaction mixture. The mixture was extracted several times with benzene, and the collected extracts were dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude solid which was obtained was dissolved in benzene and placed on a } " Florisil® column. Elution using an acetone-benzene gradient gave a gummy solid. The gum was dissolved in ether, and the hydrochloride salt was . prepared. The hydrochloride salt weighed 3.1 g (25%) arid became a clear meltat 95°C. (See Example 16, U.S. 3,956,296).
Analysis: Calculated for CgoH72CloFgN20g: C,63.42;H, 6.18; N, 2.39 p Found : C,63.68;H,6.03;N,2.33
Example 70 1-[4-[3-[4-(Cyelohexylhydroxyphenylmethyl)-1-piperidinyllpropoxy]-3- " methoxyphenyllethanone hydrochloride [1:1].
A mixture of 3.9 g (0.143 mole) of a-cyclohexyl-a-phenyl-4-piperidine- methanol, 3.5 g (0.143 mole) of 3-(p-acetyl-o-methoxyphenoxy)propyl chloride _ and 2.35 g (0.28 mole) of sodium bicarbonate in 100 ml of dimethylformamide was heated at 100°C for 4 hrs. After cooling, the reaction mixture was diluted with about 600 ml of water and extracted with benzene. The collected benzene extracts were washed with water and dried over anhydrous magne- sium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. A crude solid weighing 5.1 g (74.5%) was obtained.
The solid was dissolved in ether, and the ether solution was treated with an we “oe -152- excess of ethereal hydrogen chloride. The hydrochloride sal recrystallized from isobutyl methyl ketone to give 4.0 g of the salt, m.p. 152- 155°C. (See Example 17, U.S. 3,956,296).
Analysis: Calculated for C30H42CINO4: C, 69.82; H, 8.20; N, 2.71
Found : C,69.50;H,8.31;N, 2.62
Example 71 1-[4-[2-[4-[Bis(4-luorophenyl)hydroxymethyl]-1-piperidinyljethoxy]-3- methoxyphenyllethanone.
Following the procedure of Example 1 and utilizing potassium iodide catalyst, a mixture of 3.0 g (0.01 mole) of a,a-bis(p-fluorophenyl)-4-piperi- dinemethanol, 2.3 g (0.01 mole) of 1-[4-(2-chloroethoxy)-3-methoxyphenyl]- ethanone and sodium carbonate in butanol, the title compound was prepared in 22% yield, m.p. 131-135°C after the recrystallization from isopropyl alcohol.
Analysis: Calculated for CogH31F2NO4: C, 70.29; H, 6.31; N, 2.83
Found : C,70.00; H,6.39; N, 2.60
Example 72 1-[4-[4-[4-[Bis(4-fluorophenyDhydroxymethyl]-1-piperidinyl]butoxy)-3- . methoxyphenyllethanone.
This compound was prepared according to the procedure used to synthesize the compound of Example 35. A mixture of 3.0 g (0.01 mole) of a,a-bis(p-fluorophenyl)-4-piperidinemethanol, 3.0 g (0.01 mole) of 1-(4-(4- bromobutoxy)-3-methoxyphenyljethanone, 5.3 g (0.05 mole of anhydrous . sodium carbonate and 0.3 g of potassium iodide in 100 ml of dimethyl- formamide gave, after purification by column chromatography on Florisil® (acetone-benzene), 0.8g (15%) of off-white powder, m.p. 104-105°C, after recrystallization from 2-propanol-isopropyl ether.
Analysis: Calculated for C3;H3sFoNO: C, 71.11; H,6.74;N, 2.68
Found + C,70.84;H,6.71; N, 2.65
-153- 1
Example 73 1-[4-[5-[4-Bis(4-Nuorophenyl)hydroxymethyl]-1-piperidinyljpentoxyJ-o- methoxyphenyllethanone.
Following the procedure of Example 1 and utilizing potassium iodide catalyst, a mixture of 3.0 g (0.01 mole) of a,a-bis(p-fluorophenyl)-4-piperi- dinemethanol, 2.7 g (0.01 mole) of 1-(4-(5-chloropentoxy)-3-methoxyphenyl] ethanone and sodium carbonate in butanol, the title compound was prepared in 65% yield as white solid after recrystallization from isopropyl alcohol, m.p. 117.5-118.5°C.
Analysis: Calculated for C3gH37FeNO4: C,71.49;H, 6.94; N, 2.61
Found : C,71.51;H,7.06;N, 2.50
Example 74 1-[4-[2-[4-[Bis(4-fluorophenyl)methyl]-1-piperidinyljethoxy]-3- methoxyphenyllethanone.
A mixture of 4-[bis(4-fluorophenyl)methyl]piperidine, 4.88 g (0.017 mole), 1-[4-(2-chloroethoxy)-3-methoxyphenyllethanone, 3.86 g (0.017 mole), and potassium carbonate, 5.53 g (0.04 mole), was heated overnight at gentle reflux in 350 ml of 1-butanol containing potassium iodide (0.3 g). The reaction mixture was filtered and stripped to dryness. The dark brown oil obtained was dissolved in chloroform and extracted with 1N sulfuric acid and 5% sodium hydroxide. The chloroform layer was dried, filtered, and solvent removed. This furnished a brown oil which was subjected to flash chromato- graphy on silica gel using hexane-ethyl acetate for elution. A white solid was : obtained by evaporating the fractions containing the product. The solid was .. extracted with diethyl ether, and the mixture was placed in the freezer over- night. A white solid was obtained which was dried at 80°C in vacuo over- night. A yield of 2.2 g (27%) of white crystalline solid, m.p. 129-131°C was . obtained.
Analysis: Calculated for CogH3)NO3Fge: CC, 72.63; H, 6.52; N, 2.92
Found : C,72.52;H,6.45; N, 2.87 - : )
Example 75 1-[4-[3-[4-[Bis(4-chlorophenyl)methylene]-1-piperidinyl]propoxy]-3- methoxyphenyllethanone.
A mixture of 3.96 g (0.01305 mole) of 4-[bis-(4-chlorophenyl)- methylenejethanone in 300 ml of 1-butanol containing 0.3 g of potassium iodide was heated overnight at gentle reflux. The reaction mixture was stripped to dryness and partitioned between chloroform-water and chloroform-5% sodium hydroxide. Removal of chloroform gave an oil which crystallized from isopropyl alcohol. The solid was again crystallized from isopropyl alcohol to give 4.16 g (61%) of light yellow solid, m.p. 143-144°C.
Analysis: Calculated for C30H31NO3Clg: CC, 68.70; H, 5.96; N, 2.67
Found : C,69.11;H,6.02; N, 2.55
Example 76 1-[4-[3-[4-[(4-Fluorophenyl)phenylmethyl)-1-piperidinyl]propoxy}-3- methoxyphenyllethanone oxalate [1:1].
A solution of 4.42 g (0.0164 mole) of 4-[(4-fluorophenyl)phenylmethyl]- piperidine and 4.11 g (0.0170 mole) of 1-[4-(3-chloropropoxy)-3-methoxy- phenyllethanone, 0.01 g of potassium iodide and 1-butanol was refluxed for 18 hr. The solvent was removed in vacuo, and the residue was partitioned between methylene chloride and dilute sodium hydroxide. The solvent was removed in vacuo to give an oil. A solution of the oil in methanol was treated with an equivalent of oxalic acid, ethyl ether was added, and 6.39 g (68.9%) of white crystalline solid, m.p. 161-163°C was obtained.
Analysis: Calculated for C3gH3gNO7F: C, 67.95; H, 6.42; N, 2.48 : Found + C,67.92;H,6.42;N, 2.44
Example 77 1-[4-[3-[4-[Bis(4-methoxyphenyl)methy}]-1-piperidinyllpropoxy -3- methoxyphenyllethanone oxalate [1:1].
A mixture of 7.78 g (0.025 mole) of 4-[bis(4-methoxyphenyl)methyl]- piperidine, 6.05 g (0.025 mole) of 1-[4-(3-chloropropoxy)-3-methoxyphenyl}- ethanone, and potassium carbonate (5.53 g, 0.04 mole) in 300 ml of 1-butanol containing potassium iodide (0.3 g) was refluxed overnight. The reaction mixture was stripped to dryness, and the residue was partitioned between
7 0 1 -155- chloroform and water; removal of chloroform in vacuo gave ¢
The oil was subjected to column chromatography on silica get using a gradient elution composed of methanol and ethyl acetate. The corresponding fractions from the column were combined and reacted with oxalic acid.
Recrystallization of the salt from methanol-diethyl ether gave 4.16 g (27.4%) of white solid, m.p. 163.5-165°C. :
Analysis: Calculated for C34H41NOg: C,67.20; H,6.80; N, 2.31
Found : C,66.76;H,6.84; N, 2.26
Example 78 1-[4-[3-[4-[Bis(4-methylphenyl)methyl]-1-piperidinyllpropoxy)-3- methoxyphenyljethanone.
A mixture of 5.10 g (0.018 mole) of 4-[bis(4-methylphenyl)methyl]- piperidine and 4.42 g (0.018 mole) of 1-[4-(3-chloropropoxy)-3-methylphenyl]- ethanone in 350 ml of 1-butanol was heated overnight at gentle reflux with potassium carbonate (5.53 g, 0.04 mole) and potassium iodide (0.3 g). The reaction mixture was stripped to dryness, and the resulting residue was - : partitioned between chloroform-5% sodium hydroxide and chloroform-water.
Removal of chloroform gave a dark brown oil. The oil was subjected to : column chromatography on a silica gel column with a gradient elution series of hexane-ethyl acetate and ethyl acetate-dimethoxyethane. The proper : . fractions from the column were combined. This resulted in 2.60 g (29.7%) of oil (after drying in vacuo at 80°C overnight).
Analysis: Calculated for C33H3gNO3: C, 79.14; H, 8.09; N, 2.88
Found ; C, 78.70; H, 8.08; N, 2.80 1H NMR (CDCl3): 7.5 8 (multiplet, protons on ring next to ketone, 2H), 6.7-7.6 (multiplet, aromatic proton, 9H), 4.0 (triplet, methylene adjacent to ether oxygen, 2H), . 3.8 singlet, OCHj3, 3H), 3.3 (doublet, methine next to rings, 1H), 2.5 (singlet, methyl of ketone, 3H), 2.2 (singlet, methyl groups attached to aromatic rings, 6H), 1.0-3.0 (multiplet, remaining aliphatic protons, 13H).
Example 79 1-[4-[4-[4-[Bis(4-fluorophenyl)methyl]-1-piperidinyl]butoxy]-3- methoxyphenyllethanone.
A mixture of 6.15 g (0.021 mole) of 4-[bis(4-fluorophenyl)methyl]- piperidine and 6.45 g (0.02 mole) of 1-[4-(4-bromobutoxy)-3-methoxyphenyl]- ethanone in 350 ml of acetonitrile was stirred overnight at room temperature with potassium carbonate, 5.53 g (0.04 mole) and potassium iodide (0.3 g).
The mixture was then heated five hours at reflux. The reaction mixture was stripped to dryness on a rotary evaporator, and the residue was partitioned between chloroform-5% sodium hydroxide and chloroform-water. Removal of chloroform gave a dark brown oil. The oil was subjected to chromatography on a silica gel column and eluted with a hexane-ethyl acetate-dimethoxy- ethane series. Fractions from the column were combined and solvent removed by pumping in vacuo overnight at 80°C. This provided 3.34 g (31.3%) of brown oil.
Analysis: Calculated for C31 HasNO3Fy: C, 73.35; H, 6.95; N, 2.76
Found : C,72.34;H,6.92;N, 2.70
NMR analysis was obtained as follows: 1H NMR (CDCl3): 6.8-7.6 & (multiplet, aromatics, 11H), 4.1 (triplet methylene next to ether linkage, 2H), 3.4-3.6 (doublet, methine attached to two fluorophenyl rings, 1H), 3.8 (singlet, OCH3, 3H), 2.5 (singlet, COCH3, 3H), 1.1-3.0 (multiplet, remaining aliphatics, 15H). : Example 80 4-[3-[4-[Bis(4-fluorophenyl)hydroxymethyl}-1-piperidinyllpropoxy]3- methoxybenzoic acid methyl ester.
Following the procedure of Example 1 and utilizing potassium iodide catalyst and substituting dimethylformamide for butanol, a mixture of54¢g (0.021 mole) of 4-(3-chloropropoxy)-3-methoxybenzoic acid methyl ester, 6.0 g (0.02 mole) of [a,a-bis(p-fluorophenyl)}-4-piperidinemethanol, 7.4 g (0.07 mole) of anhydrous sodium carbonate and 0.3 g of potassium iodide in 150 ml of dimethylformamide was reacted to give 5.7 g (53%) of white solid, m.p. 131- 132°C after recrystallization from isopropyl alcohol.
Analysis: Calculated for C3oH33F2NOs: C, 68.56; H, 6.33
Found : C,68.23;H, 6.35; N, z.0u .
Example 81 a,0-[Bis(4-fluorophenyl)]-1-[3-[4-(methylthio)phenoxylpropyl]-4- piperidinemethanol. :
Following the procedure of Example 1, a mixture of 3.0 g (0.01 mole) of [a,a-bis(p-fluorophenyl)]-4-piperidinemethanol, 2.2 g (0.01 mole) of 1-chloro- 3-(4-methylthiophenoxy)propane, 5.3 g (0.05 mole) of anhydrous sodium carbonate and 0.3 g of potassium iodide in 100 ml of 1-butanol was reacted to give 2.3 g (48%) of white powder, m.p. 113-115°C after recrystallization from isopropyl ether.
Analysis: Calculated for C2gH31F2NO3S: C, 69.54; H, 6.46; N, 2.90
Found : C,69.57;H,6.51;N,2.85
Example 82 a,a-[Bis(4-fluorophenyl)}-1-[3-[4-(methylsulfonyl)phenoxy]propyl]-4- piperidinemethanol fumarate [1:1]. \
Following the procedure of Example 1, a mixture of 3.0 g (0.01 mole) of [a,a-bis(p-fluorophenyl)}-4-piperidinemethanol, 2.5 g (0.01 mole) of 1-(3- chloropropoxy)-4-(methylsulfonyl)benzene, 5.3 g (0.05 mole) of anhydrous "sodium carbonate and 0.3 g of potassium iodide in 100 ml of 1-butanol was reacted to give a brown gum as residue. The gummy residue was reacted with fumaric acid, and the fumarate salt obtained was recrystallized from acetonitrile to give 3.0 g (48%) of white solid, m.p. 176-178°C.
Analysis: Calculated for C32H3s5F2NOgS: C, 60.85; H, 5.59; N, 2.22 . Found : : C,60.72; H,5.54; N, 2.20
Example 83 - 30 4-[3-[4-[Bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]lpropoxy}-3- methoxybenzeneacetic acid ethyl ester hydrochloride.
Following the procedure of Example 45, a,a-bis(p-fluorophenyl)-4- piperidinemethanol and 4-(3-chloropropoxy)-3-methoxybenzeneacetic acid, ethyl ester are reacted, and the hydrochloride salt is prepared. . 35 He
Co Le, Lo Ce aq
Example 84 4-[3-[4-[Bis(4-fluorophenyl)hydroxymethyl]-1-piperidin benzoic acid ethyl ester hydrochloride.
Following the procedure of Example 45, a,a-bis(p-fluorophenyl)-4- piperidinemethanol and 4-(2-chloroethoxy)benzoic acid ethyl ester are reacted and the hydrochloride salt is prepared.
Example 85 4-[3-[4-[Bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]propoxy]-3- methoxybenzeneacetic acid sodium salt hydrate [1:1:0.5].
This compound was prepared according to the procedure of Example 1.
A mixture of 3.0 g (0.01 mole) of a,a-bis(p-fluorophenyl)-4-piperidine- methanol, 2.9 g (0.01 mole) of 4-(3-chloropropoxy)-3-methoxybenzeneacetic acid ethyl ester, 5.3 g (0.05 mole) of anhydrous sodium carbonate and 0.3 g of 5 potassium iodide in 150 ml of acetonitrile gave the ester as a gum. The gum was converted to the hydrochloride with ethereal hydrogen chloride to give a white solid. The solid could not be recrystallized so it was partitioned between methylene chloride and a 5% sodium hydroxide solution. An emulsion resulted which was let stand until the layers separated. During this time a solid precipitated. The mixture was filtered. The filter cake was recrystallized from ethyl acetate to yield 0.7 g (13%) of fluffy, white solid, m.p. 102-112°C.
Analysis: Calculated for C3gH33F2NNa0O5 5: C,64.74; H,5.98; N,2.52
Found : (C,64.50; H,5.97; N,2.39
Example 86 7-[3-[4-[Bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]propoxy]-2H- 1-benzopyran-2-one.
This compound was prepared according to the procedure of Example 1.
A mixture of 3.0 g (0.01 mole) of a,a-bis(p-fluorophenyl)-4-piperidine- methanol, 2.4 g (0.01 mole of 7-(3-chloropropoxy)-2H-1-benzopyran-2-one, 5.3 g (0.05 mole) of anhydrous sodium carbonate and 0.3 g of potassium iodide in 100 ml of 1-butanol gave 3.6 g (71%) of pale yellow crystals, m.p. 99-120°C with decomposition.
Analysis: Calculated for C30H29F2NO4: C,71.27;H,5.7
Found : C,71.02;H,5.85,iv, coun
Example 87 2-[3-[4-[Bisf 4-fluorophenyDhydroxymethyl}- 1:piperidineyl]propoxy}- benzoic acid ethyl ester fumarate [4:3].
This compound is prepared according to the procedure of Example 1. A "mixture of 3.0 g (0.01 mole) of [a,a-bis(p-fluorophenyl)}-4-piperidine- methanol, 2.4 g (0.01 mole) of 2:(3-chloropropoxy)benzoic acid ethyl ester, 5.3 g (0.05 mole) of anhydrous sodium carbonate and 0.3 g of potassium iodide in 100 ml of dimethylformamide gave 5.7 g of gum as residue. The gum was purified by column chromatography on 100 g of silica gel. Fractions eluted with 35% acetone in benzene were combined and concentrated to give 3.0 g of pale yellow gum as residue. The gum was converted to the fumaric acid salt “and the solid was recrystallized twice from 92-propanol to yield 2.0 g (32%) of white solid, m.p. 138-141°C.
Analysis: Calculated for C33H3gF2NO7: C, 66.43; H, 6.08; N, 2.35
Found : C,66.25;H, 6.08; N, 2.27 :
Example 88
Co 2 3-[4-[Bis(4-fluorophenylimethyl -1-piperidinyl |propoxylbenzoic acid © ethyl ester. oo
A mixture of 32.79 g (0.116 mole) of 4-[bis(4-fluorophenyl)methyll- ~ piperidine, 27.04 g (0.114 mole) of 2-(3-chloropropoxy)benzoic acid ethyl ester, and potassium carbonate, 19.40 g (0.140 mole) was heated overnight at
Co reflux in 500 ml of diethoxyethane containing potassium iodide (0.4 g). The reaction was filtered and stripped to dryness. The residue obtained was dissolved in chloroform and extracted with 5% sodium hydroxide, sodium sulfite, and water. The chloroform layer was dried (anhydrous sodium . 30 sulfate), filtered, and solvent removed to furnish a dark brown oil (56.20 g).
The oil was subjected to flash chromatography onan 83.5¢g silica gel column : (with ethyl acetate). Fractions were combined with similar purity. One sample of 6.49 g (56.5%) was dried in vacuo at 80°C overnight and analyzed.
CL
1H NMR (CDCl3): 7.8 8 (m, 1, aromatic proton ortho to este aromatic), 4.38 (q, 2, C-O-CHjy),4.15(t,2,-OCH2), 3.58 (d, (t,3,CHj), 1.7-3.0 § (m, 13, aliphatic).
Analysis: Calculated for C30H33NO3F2: C, 73.00; H,6.74; N, 2.84
Found : C,72.98;H,6.70; N, 2.93
Example 89 1-[4-[5-[4-[Bis(4-fluorophenyl)methyl}-1-piperidinyl]pentoxy]-3- methoxyphenyljethanone hydrate [1:0.5].
A mixture of 6.03 g (0.021 mole) of 4-[bis(4-fluorophenyl)methyl]- piperidine, 5.69 g (0.021 mole) of 1-[4-(5-chloropentoxy)-3-methoxyphenyl]- ethanone, and potassium carbonate (5.53 g, 0.04 mole) was heated overnight at gentle reflux in 350 ml of 1-butanol containing potassium iodide (0.2 g).
The reaction mixture was cooled at room temperature, filtered, and stripped to dryness. The residue obtained was dissolved in chloroform and extracted several times with water. The chloroform layer was dried (sodium sulfate), filtered, and solvent removed to give a brown oil. This oil was subjected to : flash chromatography on silica gel using ethyl acetate and 2% methanol- ethyl acetate for elution. Fractions of similar purity were combined and solvent removed. The sample was dried in vacuo at 70°C overnight after being exposed to the atmosphere for 24 hours. A yield of 2.7 g (24.6%) of ~ brown oil was obtained. 1H NMR (CDCl3): 6.8-7.6 8 (m, 11, aromatic), 4.18 (t, 2,-OCHj3),3.96(s, 3,
OCHj3),3.4-3.6 8 (d, 1, methine of difluorophenyl group), 2.5 8 (s, 3, -C-CH3), 1-3.0 8 (m, 18, aliphatics and 0.5 Hy0) > . Analysis: Calculated for C39H3sNO3 s5F2: C, 72.43; H, 7.22; N, 2.64
Found : C,72.75;H,7.23; N, 2.57
Example 90 4-[3-[4-[Bis(4-fluorophenyl)methyl]-1-piperidinyl]propoxylbenzamide fumarate [2:3].
A mixture of 6.10 g (0.02125 mole) of 4-[bis(4-fluorophenyl)methyl]- piperidine and 4.53 g (0.02125 mole) of 4-(3-chloropropoxy)benzamide in 350 ml of 1-butanol containing potassium carbonate (5.53 g, 0.02125 mole) and potassium iodide (0.2 g ) was heated ovrnight at gentle reflux. The reaction was filtered and stripped to dryness. The residue: dissolved in chloroform and extracted with water. The chic dried, filtered, and solvent removed to give an oil. This material was converted to the fumarate salt and recrystallized from methanol-diethyl ether. The white crystalline solid obtained was dried in vacuo overnight at 65°C. A yield of 5.47 g (40.3%) of white crystalline product was obtained, m.p. 193-194°C.
Analysis: Calculated for C34H3gN20gF2: C, 63.94; H, 5.68; N, 4.39
Found : C,64.03;H,5.73; N, 4.37
Example 91 4-[Bis(4-fluorophenyl)methyl}-1-[3-[4-(methylsulfonyl)phenoxy]- propyllpiperidine oxalate [1:1].
A mixture of 6.02 g (0.021 mole) of 4-[bis(4-fluorophenyl)methyl]- piperidine and 5.22 g (0.021 mole) of 1-(3-chloropropoxy)-4-(methylsulfonyl)- benzene in 350 ml of 1-butanocl containing potassium carbonate (5.53 g, 0.04 mole) and potassium chloride (0.2 g) was heated overnight at gentle reflux.
The reaction was filtered and stripped to dryness. The residue obtained was dissolved in chloroform and extracted with water. The chloroform layer was dried, filtered, and solvent removed to give an oil. The dark brown oil was converted to the oxalate salt and recrystallized from methanol-diethyl ether ~ to give a white solid. This material was dried in vacuo overnight at 65°C. A yield of 6.21 g (50.1%) of white crystalline solid, m.p. 202-204°C, was obtained. :
Analysis: Calculated for C3gH33NSO7Fg : C, 61.11; H, 5.64; N, 2.38
Found : C,60.99; H, 5.64; N, 2.36
Example 92 1-[4-[6-[4-[Bis(4-fluorophenyl)hydroxymethyl]-1-piperidinylJhexyloxy]- 3-methoxyphenyliethanone.
Following the procedure of Example 1 and utilizing potassium iodide catalyst, a mixture of [a,a-bis(p-fluorophenyl)]-4-piperidinemethanol and 1- [4-(6-chlorohexoxy)-3-methoxyphenyllethanone and sodium carbonate in w butanol, the title compound is prepared. to
Example 93 1-[4-[3-[4-[Bis(4-fluorophenyl)hydroxymethyl]-1-pipei 2-methoxyphenyljethanone.
Following the procedure of Examples 1 and 686, [a,a-bis(p-fluoro- phenyl)]-4-piperidinemethanol and 3-(p-acetyl-m-methoxyphenoxy)propyl chloride are reacted to give the title compound.
Example 94 a,a-Bis(4-fluorophenyl)-1-[3-(2-hydroxyphenoxy)propyl]-4-piperidine- methanol.
Following the procedure of Example 2 and using potassium iodide catalyst, a,a-bis(p-fluorophenyl)-4-piperidinemethanol and 2-(3-chloro- propoxy)-1-benzyloxybenzene are reacted to give 1-[3-(2-benzyloxphenoxy)- propyl]-a,a-bis(4-fluorophenyl)-4-piperidinemethanol which is reacted with hydrogen over palladium on carbon catalyst to give the title compound.
Example 95 . a,a-[{Bis(4-fluorophenyl))-1-[3-[4-(methylsulfinyl)phenoxylpropyl]-4- oo piperidine methanol fumarate.
Following the procedure of Examples 1 and 82, [a,a-bis(p-fluoro- phenyl)]-4-piperidenemethanol and 1-(3-chloropropoxy)-4-(methylsulfinyl)- benzene are reacted to give the free base of the title compound which is then reacted with fumaric acid to give the title compound.
Example 96 4-[3-[4-[Bis(4-fluorophenyl)hydroxvmethyll-1-piperidinyl]propoxy]- - benzenesulfonamide hydrochloride [1:1].
This compound was prepared according to the procedure of Example 1.
A mixture of 3.0 g (0.01 mole) of [a,a-bis(p-fluorophenyl)}-4-piperidine- methanol, 2.5 g (0.01 mole) of 4-(3-chloropropoxy)benzenesulfonamide, 5.3 g (0.05 mole) of anhydrous sodium carbonate and 0.3 g of potassium iodide in 100 ml of 1-butanol gave a gum as residue. The gum was converted to the hydrochloride with ethereal hydrogen chloride and the solid was recrytal- lized from absolute ethanol to yield 3.5 g (64%) of white solid, m.p. 152-175°C.
Analysis: Calculated for Co7H3;CIFaN204S : C, 58.64; F :
Found : C,5843;H
Example 97
N-[4-[3-[4-[Bis(4-fluorophenyl)hydroxym ethyl]-1-piperidinyl]propoxy]- phenyllmethanesulfonamide.
Following the procedure of Example 1, (a,a-bis(p-fluorophenyl))-4- piperidinemethanol and N-[4-(3-bromopropoxy)phenyljmethanesulfonamide 0 are reacted to give the title compound. : Example 98 oe N-[4-[3-[4-[Bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]propoxy]- phenyl]-N'-methylurea.
Following the procedure of Example 1, [a,a-bis(p-fluorophenyl)]-4- piperidinemethanol and N-[4-(3-bromopropoxy)phenyl]-N'-methylurea are reacted to give the title compound. .
Example 99 [4-[3-[4-[Bis(4-fluorophenyDhydroxymethyl)-1-piperidinyl]propoxy]- : phenyl]carbamic acid ethyl ester. a
Following the procedure of Example 1, [a,a-bis(p-fluorophenyl)]-4- piperidinemethanol and [4-(3-bromopropoxy)phenyl]carbamic acid ethyl ester are reacted to give the title compound. , | Example 100
N-{3-[3-[4-[Bis(4-fluorophenyl)hydroxymethyl)-1-piperidinyl]propoxy]- : ~ phenyllurea. Co
Following the procedure of Example 1, [a,a-bis(fluorophenyl))-4-piperi- dinemethanol and N-[3-(3-bromopropoxy)phenyl]urea are reacted to give the title compound. | N SE
Example 101 4-[3-{4-[Bis(4-fluorophenyDhydroxymethyl]-1-piperiumsy sp vpoey, « methoxybenzoic acid sodium salt.
Following the procedures of Examples 1 and 85 but substituting 4-(3- chloropropoxy)-2-methoxybenzoic acid for the corresponding 3-methoxy compound, the title compound is prepared.
Example 102 1-[4-[3-[4-[Bis(4-fluorophenyl)hydroxymethyl |piperidinyl]propoxy]-2- hydroxyphenyllethanone.
Following the procedure of Example 1, a,a-bis(p-fluorophenyl)-4-piperi- dinemethanol and 1-[4-(3-bromopropoxy)-2-hydroxyphenyllethanone are reacted to give the title compound.
Example 103 7-[3-[4-[Bis(4-fluoropheny)hydroxymethyl]-1-piperidinyl]propoxy]-4- oxo-4H-1-benzopyran-2-carboxylic acid ethyl ester hydrochloride [1:1].
A mixture of 3.0 g (0.01 miole) of [a,a-bis(p-fluoropheny)]-4-piperidine- methanol, 3.1 g (0.01 mole) of 7-(3-chloropropoxy)-4-oxo-4H-1-benzopyran-2- carboxylic acid ethyl ester, 5.3 g (0.05 mole) of anhydrous sodium carbonate and 0.3 g of potassium iodide in 150 ml of acetonitrile heated at reflux for 48 - hr gave a gum as residue. The gum was purified by column chromatography on 120 g of Florisil®. The desired fractions eluted with 10% acetone in ben- zene were combined and concentrated under reduced pressure to give a glass as residue. The glass was dissolved in ether-2-propanol, and treated with ethereal hydrogen chloride. The solid which precipitated was collected by filtration and recrystallized from absolute ethanol to give 1.9 g (31%) of white solid, m.p. 191°C with decomposition.
Analysis: Calculated for C33H34CIF3NQg : C, 64.55; H, 5.58; N, 2.28
Found : C,64.41;H,5.51;N, 2.26
Example 104 7-[3-{4-[Bis(4-fluoropheny)hydroxymethyl}-1-piperidinyijpivpuay j-o,0- dihydro-4H-1-benzopyran-4-one hydrochloride.
Following the procedure of Example 103, [a,a-bis(p-fluoropheny!)]-4- piperidinemethanol and 7-(3-bromopropoxy)-2,3-dihydro-4H-1-benzopyran- 4-one are reacted to give the title compound.
Example 105 1-[4-[3-[4-(Diphenylmethylene)-1-piperidinyl]propoxy)]-3-methoxy- phenyllethanone oxalate hydrate [1:1:0.5].
A mixture of 7.5 g (0.030 mole) of 4-diphenylmethylenepiperidine, 6.3 g (0.032 mole) of 3-(p-acetyl-o-methoxyphenoxy)propyl bromide 25 g of potas- sium carbonate and 150 ml of toluene was heated at reflux for 16 hr, cooled, filtered and the solvent evaporated at reduced pressure. The residual oil was taken up in benzene, washed with water, dried over magnesium sulfate and then the solvent was evaporated. The free base was dissolved in 2-propanol and treated with 3.8 g (0.03 mole) of oxalic acid dihydrate in dry ether. The white salt which separated was recrystallized from an 2-propanol-methanol mixture. The product weighed 8.5 g (54%), m.p. 186-188°C.
Analysis: Calculated for C32H3gNO75 : C, 69.29; H, 6.54; N, 2.53
Found : C,69.20;H,6.49; N, 2.71
Example 106 1-[4-[3-[4-(Cyclohexylphenylmethyl)-1,2,3.6-tetrahydropyridin-1-yl]- propoxyl-3-methoxyphenyllethanone oxalate hydrate [1:1:0.5]. :
The free base of the title compound was obtained by reacting 4-(a-cyclo- hexylphenylmethyl)-1,2,3,6-tetrahydropyridine with 3-(p-acetyl-o-methoxy- phenoxy)propyl chloride in a mixture with sodium bicarbonate in dimethyl- formamide and isolated on a Florisil® column eluting with benzene. The title i 30 salt was prepared, m.p. 110°C.
Analysis: Calculated for Cg4HgyN20y5: C, 68.55; H, 7.55; N, 2.50
Found : C,68.79; H,7.64; N, 2.47
Example 107 1-[4-[3-[4-[Bis(4-fluorophenyl)hydroxymethyl]-1-pipe _ 2-methoxyphenyllethanone hydrochloride [1:1].
This compound was prepared according to the procedure used to syn- thesize the compound of Example 1. A mixture of 3.0 g (0.01 mole) of [a,a- bis(p-fluorophenyl)]-4-piperidinemethanol, 2.4 g (0.01 mole) of 1-[4-(3-chloro- propoxy)-2-methoxyphenyllethanone, 5.3 g (0.05 mole) of anhydrous sodium carbonate and 0.3 g of potassium iodide in 100 ml of 1-butanol gave a gum as residue. The gum was purified by column chromatography on 80 g of
Florisil® and the fractions eluted with 20% acetone in benzene were com- bined and concentrated under reduced pressure to give a solid as residue.
The solid was converted to the hydrochloride and this solid was recrystallized from 2-propanol-isopropyl ether to yield 2.2 g (40%) of white powder, m.p. 196-197°C.
Analysis: Calculated for C30H34CIFgNO4 : C, 65.99; H, 6.28; N, 2.57
Found : C,65.87;H,6.31; N, 2.54
Example 108 | { 4-[Bis(4-fluorophenyl)methyl]-1-[3-( 2,6-dichlorophenoxy)propyllpiperi- dine.
A mixture of 4-[bis(4-fluorophenyl)methyl]piperidine (free base 6.90 g, 0.024 mole), 1,3-dichloro-2-(3-chloropropoxy)benzene (5.72 g, 0.024 mole), and potassium carbonate (5.54 g, 0.04 mole) was heated overnight at gentle reflux in 350 ml of 1-butanol containing potassium iodide (0.2 g). The reaction was stripped to dryness. The residue was partitioned several times between chloroform and water. The chloroform layer was dried, filtered, and ~ solvent removed to give an oil. The oil was placed in the refrigerator overnight in 50 ml of methanol. A white solid was obtained and dried in vacuo overnight at 80°C. A yield of 3.26 g (27.7%) of white crystalline solid, m.p. 101.5-103°C was obtained.
Analysis: Calculated for Co7H27NOCIgF3 : C, 66.13; H, 5.55; N, 2.85
Found : C,66.12; H, 5.56; N, 2.88
Example 109 4-[Bis(4-fluorophenyl)methyl]-1-| 3-(2,6-dichlorophenc.., ,.._, .... dine oxalate [1:1].
Free base of the compound of Example 108 was converted to the oxalate salt and recrystallized from methanol-diethyl ether and dried in vacuo at 80°C overnight, m.p. 158-161°C.
Analysis: Calculated for C29H29NOs5ClgF2 : C, 60.01; H, 5.04; N, 2.44
Found : C,60.02;H,5.07; N, 2.46
Example 110 2-(3-[4-[Bis(4-fluorophenyl)methyl -1-piperidinyl]propoxy]benzonitrile.
A mixture of 7.41 g (0.025 mole) of [4-[bis(4-fluorophenyl)methyl]- piperidine, 4.90 g (0.025 mole) of 2-(3-chloropropoxy)benzonitrile, and potassium carbonate, 5.54 g (0.04 mole) was heated overnight at reflux in 350 ml of 1-butanol containing potassium iodide (0.2 g). The mixture was stripped to dryness, and the resulting residue was partitioned several times between water and chloroform. The chloroform layer was dried (anhydrous sodium sulfate), filtered, and solvent removed to give a brown oil. The oil was triturated with diethyl ether and placed in a freezer overnight. White crystals were obtained and dried in vacuo overnight at room temperature. A yield of 5.15 g (46.1%) of analytically pure material, m.p. 88.5-90°C was obtained.
Analysis: Calculated for CogHggN3OF9 : C,75.31;H,6.32; N, 6.27
Found : C,75.16;H,6.34; N, 6.26
Example 111 a,0-Bis(4-fluorophenyl)-1-[2-(phenylthio)ethyl ]-4-piperidinemethanol maleate [1:1].
A Grignard solution was prepared in tetrahydrofuran (ice bath) from magnesium, 5.81 g (0.242 mole) and p-fluorobromobenzene, 42.4 g (0.242 mole). This Grignard reagent in about 350 ml of tetrahydrofuran was stirred about 3 hr at room temperature. The reaction mixture was then transferred to a 500 ml addition funnel (under nitrogen). This solution was added drop- wise to a tetrahydrofuran solution of 1-[2-( phenylthio)ethyl]-4-piperidine- carboxylic acid ethyl ester, 29.10 g (0.1 mole) in about 200 m1 of tetrahydro-
} i -168- furan. The solution was stirred overnight at room temperatur onto ice containing 35 g of ammonium chloride. The solution * with chloroform and the chloroform back extracted with 5% sodium hydroxide. Removal of chloroform gave a dark brown oil. The oil was converted to the maleate salt and recrystallized from methanol-diethyl ether to give 5.0 g (56.5% yield based on aliquot taken) of white crystalline product, m.p. 171-173°C.
Analysis: Calculated for C30H3;NO5SFy: C,64.85;H,5.62; N, 2.52
Found : C,64.80; H,5.62; N, 2.45
Example 112 4-[Bis(4-fluorophenymethylene]-1-[2-( phenylthio)ethyl]piperidine. a,a-Bis(4-fluorophenyl)-1-[2-(phenylthio)ethyl-4-piperidinemethanol maleate, 26.13 g (0.047 mole) was converted to the free base of partitioning 5 with methylene chloride and weak alkaline solution and evaporating the organic layer to give an oil. The oil was dissolved in 150 ml of methanol con- taining 100 ml of 6 N hydrochloric acid, and the solution was heated 4-1/2 hr at gentle reflux. The reaction mixture was cooled to room temperature, niade :
Co alkaline with an ice-50% sodium hydroxide mixture and extracted with chloroform. The chloroform layer was evaporated to leave an oil which crystallized. Trituration of the solid in methanol followed by refrigeration and filtering gave the title compound, m.p. 101.5-103.5°C, in 60% yield.
Analysis: Calculated for CogHgsNSFy: C, 74.08; H, 5.98; N, 3.32
Found : C,74.12;H,5.96; N, 3.25 2h
Example 113 : a,a-Bis(4-fluorophenyl)-1-[2-[(4-chlorophenyl)sulfonyl]ethyl]-4- piperidinemethanol.
A mixture of 5.85 g (0.0193 mole) of a,a-bis(4-fluorophenyl)-4- piperidinemethanol, 4.76 g (0.020 mole) of 2-chloroethyl-p-chlorophenyl- sulfone and 4.90 g (0.0462 mole) of sodium carbonate in 600 ml of acetonitrile was heated at 65°C for 18 hr. The solvent was removed in vacuo, and the residue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene chloride solution was dried over sodium sulfate, and the solvent was removed in vacuo to give a solid. This was recrystallized from a mixture of methylene chloride (400 ml), methanol (50 (200 ml) to give 6.99 g (71.7%) of white crystalline solid, m.p.
Analysis: Calculated for CogHggNO3SF2Cl: C, 61.72; H, 5.18; N, 2.77
Found : C,61.51;H,5.16; N, 2.81
Example 114 1-{2-[(4-Chlorophenyl)sulfonyljethyl]-4-[bis(4-fluorophenyl)- methylene]piperidine.
A mixture of 2.74 g (0.0054 mole) of a,a-bis(4-fluorophenyl)-1-[2-[(4- chlorophenyl)sulfonyljethyl]-4-piperidinemethanol in 100 ml of glacial acetic acid and 40 ml of 2 M sulfuric acid was refluxed for 6 hr. The solvent was removed in vacuo, and the resulting solid was recrystallized from methylene _ chloride-hexane to give 1.95 g (74%) of white crystalline solid, m.p. 152- 153°C.
Analysis: Calculated for CogH4NO9SCIFy: C, 63.99; H, 4.96; N, 2.87
Found : C,64.24;H,4.95;N, 2.84 .
Example 115 4-[Bis(4-fluorophenyl)methyl]-1-[3-(phenylsulfonyl)propyl]piperidine fumarate [1:1.5]. :
A mixture of 5.74 g (0.02 mole) of 4-[bis(4-fluorophenyl)methyl}- piperidine, 4.36 g (0.02 mole) of 3-chloropropyl phenyl sulfone, 3.18 g (0.03 mole) of sodium carbonate, and potassium iodide (0.3 g) in 300 m! of n- butanol ws refluxed overnight. The reaction mixture was stripped to dry- - ness, and the residue partitioned between chloroform-5% sodium hydroxide and then between chloroform-water. Removal of chloroform gave an oil + which was converted to the fumarate salt. Recrystallization from isopropyl alcohol-diethyl ether gave 3.31 g (25.7%) of white solid, m.p. 172-173°C.
Analysis: Calculated for CooH35NOgF9S: C, 61.58; H, 5.48; N, 2.18
Found : C,61.69;H,5.54;N, 2.14
-170- A
Example 116 4-[Bis(4-fluorophenyl)methyll-1-[2-[(4-chlorophenyl)sulfi piperidine maleate [1:1].
A mixture of 4.22 g (0.0147 mole) of 4-[bis(4-fluorophenyl)methyl]- piperidine, 3.63 g (0.0152 mole) of 2-chloroethyl-p-chlorophenyl sulfone, and 4.1 g (0.039 mole) of sodium carbonate in 400 ml of acetonitrile was refluxed for 22 hr. The solvent was removed in vacuo, and the residue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene chloride solution was dried (magnesium sulfate), and the solvent was removed in vacuo to give an oil. This was converted to the maleate salt, and the salt was recrystallized from methanol-diethyl ether to give 6.84 g (76.9%) of white crystalline solid, m.p. 185-186°C.
Analysis: Calculated for C30H3oNOgSF2Cl: C, 59.45; H, 4.99; N, 2.31 : Found : C,59.57;H,4.99; N, 2.32
Example 117 4-[Bis(4-fluorophenyl)methyll-1-[2-(phenylsulfonylethyl]piperidine maleate [1:1]. - A mixture of 5.20 g (0.016 mole) of 4-[bis(4-fluorophenyhmethylj- piperidine, 3.32 g (0.0162 mole) of 2-chloroethyl phenyl sulfone, and 500 g (0.0362 mole) of potassium carbonate in 500 ml of acetonitrile was refluxed for 19 hr. The solvent was removed in vacuo, and the residue was partitioned between methylene chloride and dilute sodium hydroxide. The organic solution was dried (magnesium sulfate), and the solvent was removed in vacuo to give an oil, This was converted to the maleate salt, and the salt was recrystallized from methanol-ether to give 4.82 g (52.4%) of white crystalline solid, m.p. 183-5-184.5°C.
Analysis: Calculated for C30H31NOgF2S: C, 63.04; H,5.47; N, 2.45 ” Found : C,62.88;H,5.40;N, 2.45
Example 118 1-(2,3-Dihydro-1,4-benzodioxan-2-ylmethyl)-a,a-diphenyl-4-piperidine- acetonitrile.
A mixture of 6.24 g (0.027 mole) of 2-(bromomethyl)-1,4-benzodioxan, (7.45 g, 0.027 mole) of a,a-diphenyl-4-piperidineacetonitrile and potassium carbonate (6.91 g, 0.05 mole) was stirred overnight at room reaction mixture was refluxed for 5 hours and then stirred ¢ vc.oepyeee temperature. The reaction mixture was stripped to dryness. The residue was dissolved in chloroform and the solution was extracted with water and 5% sodium hydroxide. Removal of chloroform gave an oil. NMR showed a 2/1 ~ ratio of product to starting material. The reaction was then refluxed overnight in 350 ml of 1-butanol containing potassium iodide (0.3 g) and potassium carbonate (6.91 g, 0.05 mole). The reaction mixture was stripped to dryness, and the resulting residue was partitioned between chloroform- water and chloroform-5% sodium hydroxide. Removal of chloroform gave an oil which was crystallized from methanol and dried in vacuo at 80°C overnight. A yield of 7.18 g (62.6%) of white crystalline product, m.p. 130- 131.5°C was obtained.
Analysis: Calculated for CogHogN9Og: C, 79.22: H, 6.65; N, 6.60
Found : C, 78.88; H,6.62;N, 6.56
Example 119 1-[3-(4-Acetyl-2-methoxyphenoxy)propyll-a,a-diphenyl-4-piperidine- acetonitrile oxalate [1:1].
A mixture of 6.78 g (0.05 mole) of 1-[4-(3-chloropropoxy)-3-methoxy- phenyljethanone, 7.72 g (0.028 mole) of a,a-diphenyl-4-piperidineacetonitrile ~ was heated overnight at reflux in 350 ml of 1-butanol containing potassium iodide (0.4 g). The reaction mixture was stripped to dryness, and the residue was dissolved in chloroform. The chloroform layer was extracted with 1N sulfuric acid and then with 5% sodium hydroxide. The chloroform was removed in vacuo to give a brown oil. The oil was converted to the oxalate salt, and the salt crystallized from methanol. The salt was dried in vacuo at 80°C overnight. A yield of 8.36 g (52.2%) of white solid was obtained, m.p. 226-227°C (with decomposition).
Analysis: Calculated for C33H3gN207: C, 69.21; H, 6.34; N, 4.89
Found : C,68.78;H,6.32; N, 4.84
Example 120 1[3-(4-Acetyl-2.-methoxyphenoxy)propyl]-a,a-dipheny. “ pepessmesas propanenitrile.
A mixture of 5.80 g (0.02 mole) of a,a-diphenyl-3-piperidinepropane- nitrile, 4.84 g (0.02 mole) of 1-{4-(3-chloropropoxy)-3-methoxyphenyl]- ethanone, and potassium carbonate, 5.60 g (0.04 mole) was heated overnight at 68°C in 400 ml of dimethylformamide containing potassium iodide (0.3 g).
The reaction mixture was stripped to dryness and partitioned between chloroform-water and chloroform-5% sodium hydroxide. The chloroform layer was dried, filtered, and solvent removed to give an oil. The oil was subjected to column chromatography on a silica gel column with elution via ethyl acetate. Fractions containing the product were combined and trans- ferred to brown glass bottles with acetone. The oil was triturated with diethyl ether and pumped to dryness in vacuo at 80°C overnight. A yield of 2.37 g (23.9%) of oil was obtained.
Analysis: Calculated for C3gH3gN203: C, 77.39; H, 7.31; N, 5.64
Found : C,77.00;H,7.35;N, 5.63 } Example 121 1-[4-(4-Acetyl-2-methoxyphenoxy)butyl ]-a,a-diphenyl-3-piperidine- propanenitrile.
A mixture of 5.80 g (0.02 mole) of a,a-diphenyl-3-piperidinepropane- nitrile, 6.02 g (0.02 mole) of 1-[4-(4-bromobutoxy)-3-methoxyphenyl]- ethanone, and 5.60 g, (0.04 mole) of potassium carbonate was stirred overnight at room temperature in 400 ml of acetonitrile containing potassium iodide (0.3 g). The mixture was then stirred overnight at reflux, * then strippéd to dryness, and the resulting residue was partitioned between chloroform-water and chloroform-5% sodium hydroxide. The chloroform layer was dried, filtered, and solvent removed to give a dark yellow oil. The oil was subjected to column chromatography on silica gel with elution via ethyl acetate. Pure fractions were combined, and the oil was triturated with diethyl ether. The oil was dried in vacuo at 80°C overnight. A yield of 5.96 g (58.4%) of light yellow oil was obtained. 1H NMR (CDCl3) 6 7.2-7.8 (m, 12, aromatic), 6.9 (d, 1, aromatic), 4.1 (t, 2, CH20),3.9¢(s, 3,-OCH3),2.5(s, 3, C-
CHj), 1.1-2.4 (m, 17, aliphatic).
Analysis: Calculated for C33H3gN203: C, 77.61; H, 7.50;
Found : C,76.96; H, 7.55
Example 122 1-[3-(4-Acetyl-2-methoxypenoxy)propyl)-a,a-diphenyl-3- pyrrolidine- acetamide.
A mixture of 5.00 g (.018 mole) of a,a-diphenyl-3-pyrrolidineacetamide, 4.14 g (.018 mole) of 3-chloro-1-[(4-acetyl-2-methoxy)phenoxylpropane and 1.91 g (.018 mole) of sodium carbonate in 100 ml of 1-butanol was refluxed 18 hrs. The solution was cooled and concentrated in vacuo. The residue was taken up in 300 ml of methylene chloride, washed with 100 ml dilute sodium hydroxide, 100 ml dilute hydrochloric acid, and 100 ml dilute sodium } hydroxide, dried over magnesium sulfate and concentrated to yield 7.70 g (88%) of yellow glass. The glass was crystallized from methylene chloride- diethyl ether to yield 5.70 g (67%) of a fine tan powder which contained ether.
The powder was recrystallized from ethyl acetate and acetonitrile to give an off-white powder, m.p., 143.5-148.5°C.
Analysis: Calculated for C30H34N204: C, 74.05; H, 7.04; N, 5.76
Found : C,73.80;H,7.01;N, 5.80
Example 123 : 1-[3-(4-Acetyl-2-methoxyphenoxy)propyl]-a.a-diphen vl-4-piperidine- acetamide fumarate hydrate [1:0.5:1].
A mixture of 5.88 g (0.02 mole) of a,a-diphenyl-4-piperidineacetamide, 4.84 g (0.02 mole) of 1-{4-(3-chloropropoxy)-3-methoxyphenyllethanone, and 6.91 g (0.05 mole) potassium carbonate was heated at reflux overnight in 350 * mlof 1-butanol containing potassium iodide (0.3 g). The reaction mixture was stripped to dryness. The residue obtained was partitioned between chloroform-water and chloroform-5% sodium hydroxide layer. The chloro- form layer was dried, filtered, and solvent removed by rotary evaporator.
The residue obtained was converted to the fumarate salt. The salt was recrystallized from methanol-diethyl ether. The white solid obtained was dried in vacuo overnight at 80°C. A yield of 3.71 g (32.2%) of white solid, m.p. 211-213°C was obtained.
Analysis: Calculated for C33H4oN207: C, 68.73; H, 6.99;
Found + (C,68.56;H,6.72;
Example 124 1-[4-(4-Acetyl-2-methoxyphenoxy)butyl]-a,a-diphenyl-4-piperidine- acetamide fumarate hydrate [1:0.5:1].
A mixture of 6.0 g (0.02 mole) of a,a-diphenyl-4-piperidineacetamide, 6.02 g (0.02 mole) of 1-[4-(4-bromobutoxy)-3-methoxyphenyl]ethanone and potassium carbonate (5.60 g, 0.04 mole) was stirred overnight at room temperature in 300 ml of acetonitrile containing potassium iodide (0.2 g).
The mixture was then heated overnight at gentle reflux. The mixture was stripped to dryness, and the residue obtained was partitioned between chloroform and water. The chloroform layer was dried, filtered, and solvent removed to give a gummy residue. This material was converted to the fumarate salt. The salt was recrystallized from methanol-diethyl ether and was dried in vacuo overnight at 80°C to give 5.91 g (50.0%) of white solid, m.p. 169-171°C.
Co _ Analysis: Calculated for C34H42N207: C,69.13; H,7.17; N, 4.74. Co
Found : C,69.22; H,6.89; N, 4.44
Example 125 1-[3-(4-Acetyl-2-methoxyphenoxy)propyl]-a.a-diphenyl-3-piperidine- propanamide hydrate [1:0.5].
A mixture of 7.00 g (0.0227 mole) of a,a-diphenyl-3-piperidine- propanamide, 5.50 g (0.0227 mole) of 1-[4-(3-chloropropoxy)-3-methoxy- phenyljethanone and potassium carbonate (11.2 g, 0.08 mole) was heated "overnight at reflux in 350 ml of 1-butanol containing potassium iodide (0.3 g).
The reaction mixture was stripped to dryness, and the resulting residue was partitioned between chloroform-water and chloroform-5% sodium hydroxide.
The chloroform layer was dried, filtered, and solvent removed to give an oil.
The oil was subjected to column chromatography on silica gel and eluted with dimethoxyethane-ethyl acetate. Fractions of pure material were combined and dried in vacuo at 80°C overnight. A yield of 3.75 g (31.5%) of a light yellow amorphous solid was obtained, 1H NMR (CDCl3): 87.7 (m, 12,
aromatic, 6.9 (d, 1, aromatic), 5.8 - 6.4 (brs, 2, NHo), 5.1 (br (t,2,CH20),3.9(s,3,0CH3)2.5(s,3,C-CH3),1.1-2.4(m, ]
Analysis: Calculated for C39H3gN90O4 5: C, 73.40; H, 7.51; N, 5.35 . Found : C,73.42;H,747;N,5.22 .
Example 126 4-[Bis(4-fluorophenyl)methyl]-1-[(2,3-dihydro-1.4-benzodioxan-2- yl)methyl]piperidine oxalate [1:1].
A mixture of 5.53 g (0.019 mole) of 4-[bis(4-fluorophenyl)methyl]- piperidine (4.39 g, 0.019 mole) of 2-(bromomethyl)-2,3-dihydro-1,4- benzodioxane, and potassium carbonate (7.80 g, 0.056 mole) was stirred overnight at room temperature in 250 ml of acetonitrile. The reaction mixture was stripped to dryness and partitioned between chloroform and water. Removal of chloroform gave a yellowish brown oil which was 18 converted to the oxalate salt. The salt was recrystallized from methanol- diethyl ether. A yield of 3.63 g (36.3%) of white solid, m.p. 142-145°C was } obtained.
Analysis: Caluclated for CogHagNOgF2: C, 66.28; H, 5.56; N, 2.61 \
Found : C,66.06; H,5.50;N, 2.61
Example 127 : 1-[2-(2,6-Dichlorophenoxy)ethyl]-a,a-diphenyl-3-piperidine- propanenitrile.
A mixture of 6.09 g (0.021 mole) of a,a-diphenyl-3-piperidine- propanenitrile and 5.63 g (0.021 mole) of 2-(2-bromoethoxy)-1,3-dichloro- benzene in 350 ml of acetonitrile was stirred overnight at room temperature "with potassium carbonate (5.53 g, 0.04 mole) and 0.2 g of potassium iodide.
The mixture was then heated overnight at gentle reflux. The mixture was then stripped to dryness, and the resulting residue was dissolved in chloro- form. The chloroform was extracted with 5% sodium hydroxide and water.
The chloroform layer was then dried, filtered, and solvent removed to give 12.2 g of oil. The oil was subjected to flash chromatography on silica gel using 20% ethyl acetate-hexane and 50% ethyl acetate-hexane for elution.
Fractions of pure material were combined and solvent removed in vacuo. The brown oil was dried overnight in vacuo at 80°C. A yield of 5. brown oil was obtained. 1H NMR (CDCl3) 5 6.8-7.4 (m, 13, aromatic), 4.1 (t, 2, -OCHzgj, v.1-a.v vues «oy remaining aliphatic)
Analysis: Calculated for CogH2gN20Clg: C, 70.14; H, 5.89; N, 5.84
Found : C,70.08;H,5.88; N,5.76
Example 128 1-[5-(4-Acetyl-2-methoxyphenoxy)pentyl]-a,a-diphenyl-3-piperidine- propanenitrile hydrate [1:0.5].
A mixture of 5.80 g (0.02 mole) of a,a-diphenyl-3-piperidinepropane- nitrile, 5.42 g (0.02 mole) of 1-{4-(5-chloropentoxy)-3-methoxyphenyl]- ethanone, and potassium carbonate (5.53 g, 0.04 mole) was heated overnight at gentle reflux in 350 ml of 1-butanol containing potassium iodide (0.3 g).
The reaction mixture was stripped to dryness, and the residue dissolved in chloroform. The chloroform layer was extracted with water and then dried with anhydrous sodium sulfate. The chloroform was removed by rotary evaporation following filtration. The oil obtained upon removal of chloroform : was subjected to column chromatography (flash chromatography) on silica -. ~ gel with methanol-ethyl acetate (4:96 v/v) for elution. Similar fractions were combined and removal of solvent gave a clear brown oil. The oil was dried in ~ vacuo overnight at 80°C. The oil was triturated with diethyl ether and dried "in vacuo again, at 80°C overnight. A yield of 6.37 g (59.6%) of clear brown oil was obtained, 1H NMR (CDCl3) § 7.2-7.8 (m, 12, aromatic), 6.9 (d, 1, 9 aromatic), 4.1 (t, 2 CH20), 3.9 (s, 3, OCH3), 2.5 (s, 3, C-CHa3), 1.2-2.4(m, 19, . aliphatic).
Analysis: Calculated for C34H41N2035: C, 76.52; H, 7.74; N, 5.25
Found : C,76.37;H,7.65;N,5.19
Example 129 1-[3-(4-Acetyl-2-methoxyphenoxy)propyll-a,a-bisf 4-fluorophenyl)-4- piperidineacetonitrile maleate 1:1}.
A mixture of a,a-bis(4-fluorophenyl)-4-piperidineacetonitrile (6.45 g, ) 0.021 mole), 1[4-(3-chloropropoxy)-3-methoxyphenyilethanone (5.00 g, 0.021 at. “ a -177- mole), and potassium carbonate (5.53 g, 0.04 mole) was heat gentle reflux in 350 ml of 1-butanol containing potassium io reaction mixture was stripped to dryness and then partitioned several times between chloroform and water. The chloroform layer was dried, filtered, and solvent removed to give a dark brown oil. The oil was converted to the maleate salt. The salt was recrystallized from methanol-diethyl ether and dried in vacuo at 80°C overnight. A yield of 6.80 g (51.8%) of white crystals, m.p. 158-160°C was obtained.
Analysis: Calculated for C3sH3gN207F2: C, 66.24; H, 5.72; N,4.14
Found : C,66.13;H,5.69; N, 4.41
Example 130 1-[3-(2,6-Dichlorophenoxy)propyll-a,a-bis(4-fluorophenyl )-4-piperidine- ’ acetonitrile oxalate [1:1].
A mixture of a,a-bis(4-fluorophenyl)-4-piperidineacetonitrile (5.99 g, 0.0192 mole) and 1,3-dichloro-2-(3-chloropropoxy)benzene (4.76 g, 0.02 mole) was heated at reflux overnight in 350 ml of 1-butanol containing potassium carbonate, 5.53 g (0.04 mole), and potassium iodide, 0.2 g. The reaction mixture was stripped to dryness and the resulting residue was partitioned - several times between water and chloroform. The chloroform layer was dried (anhydrous sodium sulfate), filtered, and solvent removed to give a light . brown oil. The entire oil was converted to the maleate salt. The salt was recrystallized from methanol-diethyl ether, and dried in vacuo overnight at 80°C. A yield of 4.55 g (37.5%) of white crystals, m.p. 162-163°C was obtained. :
Analysis: Calculated for C3gH39N205F2Clg: C, 60.83; H,4.79; N, 4.14
Found : C,60.89;H,4.82; N, 4.44
Example 131 1-[3-(2,6-Dichlorophenoxy)propyl]-a,a-diphenyl-3-piperidine- propanenitrile oxalate [1:1].
A mixture of 5.80 g (0.02 mole) of a,a-diphenyl-3-piperidinepropane- nitrile and 1,3-dichloro-2-(3-chloropropoxy)benzene (4.76 g, 0.02 mole) in 350 ml of 1-butanol was heated overnight at reflux with potassium carbonate (5.54 g, 0.04 mole) and potassium iodide (0.2 g). The reaction mixture was stripped to dryness, and the residue partitioned several tim: and chloroform. The chloroform layer was dried (anhydrout filtered, and solvent removed to give an oil. The entire oil was converted to the oxalate salt. The salt was recrystallized from methanol-diethyl ether, and was dried in vacuo overnight at 80°C. A yield of 7.23 g (62%) of white crystals, m.p. 159-161°C was obtained.
Analysis: Calculated for C31H32N205Cl2: C, 63.81; H, 5.53; N, 4.80
Found : C,64.02;H,5.61;N, 4.86
Example 132 1-[4-(4-Acetyl-2-methoxyphenoxy)butyl]-a.a-bisf 4-fluorophenyl)-4- piperidineacetonitrile fumarate [1:1].
A mixture of 5.38 g (0.0172 mole) of a,a-bis(4-fluorophenyl)-4- piperidineacetonitrile and 5.20 g (0.0172 mole) of 1-[4-(4-bromobutoxy)-3- methoxyphenyllethanone was heated overnight at reflux in 350 ml of acetonitrile containing potassium carbonate (5.54 g, 0.04 mole) and potassium iodide, 0.2 g. The reaction mixture was stripped to dryness and the residue obtained was partitioned several times between chloroform and water. The chloroform layer was dried (anhydrous sodium sulfate), filtered, and solvent removed to give an oil. The oil was converted to the fumarate _ salt. The salt was recrystallized from methanol-diethyl ether, and was dried in vacuo overnight at 80°C. A yield of 5.78 g (51.7%) of white crystals, m.p. 181.5-182°C was obtained.
Analysis: Calculated for C36H3gN207F2: C, 66.66; H,5.90; N, 4.32
Found : C, 66.56; H,5.92; N, 4.28
Example 133 1-{2-(2,6-Dichlorophenoxy)ethyl ]-a,a-diphenyl-3-piperidine- propanamide.
A mixture of 7.65 g (0.025 mole) of a,a-diphenyl-3-piperidinepropane- nitrile, 2-(2-bromoethoxy)-1,3-dichlorobenzene (6.70 g, 0.025 mole), and potassium carbonate (5.54 g, 0.04 mole) was stirred overnight at reflux in 350 ml of acetonitrile containing potassium iodide, (0.2 g). The reaction mixture was stripped to dryness, and the residue was partitioned between chloroform and water several times. The chloroform layer was dried (anhydrous sodium
: \ -179- sulfate), filtered, and solvent removed to give 12.91 g of bro oil was subjected to flash chromatography on silica gel usin acetate-hexane and 100% ethyl acetate for elution. Similar fractions were combined and solvent was removed. The resulting oil was dried in vacuo overnight at 65°C. A yield of 6.98 g (56.1%) of clear oil was obtained. 1H NMR (CDCl3): §6.9-7.5 (m, 13, aromatic), 6.0 (br 2, NH3), 4.0 (t, 2, O-
CHy2), 2.7 (t,2,N-CH9), 1.0-2.3 (m, 11, aliphatics).
Analysis: Calculated for CogH30N202Cla: C, 67.61; H, 6.08; N, 5.63
Found : C,67.52:H,6.08;N, 5.63
Example 134 a-[1-[3-(4-Acetyl-2-methoxyphenoxy)propyl}-4-piperidinyl]-a-(4- fluorophenyl)-2-pyridineacetonitrile fumarate [1:1]. 0
A mixture of a-(4-fluorophenyl)-a-(4-piperidinyl)-2-pyridineacetonitrile (7.18 g, 0.024339 mole), 1-[4-(3-chloropropoxy)-3-methoxyphenyllethanone (5.89 g, 0.024339 mole), and potassium carbonate (5.54 g, 0.04 mole) was heated overnight in 350 ml of 1-butanol containing potassium iodide (0.15 g).
The reaction mixture was stripped to dryness, and the residue obtained was partitioned between chloroform and water. The chloroform layer was extracted in 1N sulfuric acid, 5% sodium hydroxide and water. The chloro- form layer was dried over sodium sulfate, filtered, and the solvent removed to . give an oil. The oil was converted to the fumarate salt and recrystallized from methanol-diethyl ether. A white solid was obtained and dried in vacuo overnight at 80°C to give 9.43 g (62.7%) of white crystals, m.p. 166-167°C.
NMR indicated 0.25 HO was present.
Analysis: Calculated for C34H3¢N307F : C, 66.11; H, 5.87; N, 6.80
Found : C, 65.57; H,5.89; N, 6.70
Example 135 . 30 a-[1-[3-(4-Acetyl-2-methoxyphenoxy)propyl ]-4-piperidinyl}-a-(4- fluorophenyl)-2-pyridineacetonitrile fumarate hydrate [1:1:1].
A portion of the compound prepared in Example 111 was exposed to the air for 3 days, m.p. 166-167°C.
Anaysis: Calculated for C34H3gN30gF : C, 64.24; H, 6.02; N, 6.61 oo 35 Found : C,64.07;H,5.82; N, 6.58
Example 136 a,a-Diphenyl- 1-[3-(8-quinolinyloxy)propyl]-3-piperidir hydrate [1:0.5].
A mixture of a,a-diphenyl-3-piperidinepropanenitrile (8.12 g,0.028 mole), 8-(3-chloropropoxy)quinoline (6.18 g, 0.028 mole), and potassium carbonate (5.53 g, 0.04 mole) was heated at reflux overnight in 350 ml of 1- butanol containing potassium iodide (0.3 g). The reaction mixture was filtered and stripped to dryness on a rotary evaporator. The residue obtained was dissolved in chloroform and extracted with 5% sodium hydroxide and water. The chloroform layer was dried over anhydrous sodium sulfate, filtered, and solvent removed to give a dark red mass. This material was subjected to flash chromatography on a silica gel column using 10% methanol-ethyl acetate, 20% methanol-ethyl acetate, and 50% methanol- ethyl acetate for elution. Fractions of similar purity were combined, and solvent was removed by rotary evaporator. The red black residue obtained was dried in vacuo at 80°C overnight. This furnished 5.29 g (39%) of a dark black residue.
Co IH NMR (CDCl3): 5 8.9 (m, 1, proton ortho to Nin ring), 7.9-8.1 (m, 1, proton para to N in ring), 6.9-7.6 (m, 14, aromatics), 4.2 lt, 2, methylenes adjacent to oxygen atom), 1.1-2.7 (m, 16, aliphatic portions and 1H from 0.5 H20).
Analysis: Calculated for C32H33N3015 : C, 79.31; H,7.07; N, 8.67
Found : C,79.47;H,7.19; N, 8.69
Example 137 8-[3-[4-[Bis(4-fluorophenylimethyl -1-piperidinyl]propoxylguinoline hvdrate {1:0.5].
A mixture of 4-[a-(p-fluorophenyl)-p-fluorobenzyl}-piperidine (8.03 g, 0.28 mole), 8-(3-chloropropoxy) quinoline (6.18 g, 0.28 mole), and potassium carbonate (5.53 g, 0.04 mole) was heated overnight at gentle reflux in 350 ml of 1-butanol containing potassium iodide (0.3 g). The reaction mixture was filtered through activated charcoal, and solvent was removed by rotary evaporator. The dark red residue was dissolved in chloroform and then extracted with 5% sodium hydroxide and water. The chloroform layer was dried over anhydrous sodium, filtered, and solvent removed to provide a dark red mass. This material was subjected to flash chromatography on silica gel using 10, 20 and 50% methanol in ethyl acetate for elution. 1 similar purity were combined and solvent removed to give da wich was dried at 80°C in vacuo overnight. This furnished 3.74 g (28%) of a dark red mass. "TH NMR (CDCl3): 8 8.9 (m, 1, proton ortho to N in ring), 7.9-8.1 (mm, 1, proton para to N in ring), 6.8-7.4 (m, 12, aromatics), 4.2 (t, 2, CH3 attached to -0), 3.5 (d, 1, methine attached to to aromatic rings), 1.0-3.2 (m, 14, aliphatic protons and 1H for 0.5 H20).
Analysis: Calculated for C30H32N2015F2 : C, 75.53; H, 6.44; N, 5.87
Found : C, 75.66: H, 6.56; N, 5.86
Example 138 2-[3-[4-[Bis(4-fluorophenyl)methyl]-1-piperidinyllpropoxylbenzoic acid hydrate [1:0.5]. 5 A solution of 2-[3-[4-[bis(4-fluorophenyl)methyl}-1-piperidinyl]- propoxylbenzoic acid ethyl ester (25.3 g, 0.051 mole) in 400 ml of 200 ethanol containing potassium hydroxide (16.8 g, 0.30 mole) was heated at reflux for 4 * hours. The reaction mixture was concentrated to a volume of approximately 200 ml. The reaction mixture was made acidic with 1N sulfuric acid. The acidic layer was extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate, filtered, and solvent removed to give a - gummy residue. The material was subjected to flash chromatography using 20% methanol-80% ethyl acetate and 50% methanol-50% ethyl acetate for elution. Fractions of similar purity were combined. Solvent was removed in vacuo, and the residue was dried in vacuo overnight at 80°C to give 5.72 g (23.6%) of material. " 1H NMR (CDCl3): §9.2 (br 2, COOH and 0.5 H20), 7.8 (m, 1, H next to
COOH), 6.7-7.3 (m, 11, aromatic), 4.1 (m, 2, CH3z next to 0), 1.5-3.66 (m, 14, aliphatics).
Analysis: Calculated for CogH3gNO3 5F9: C, 70.87; H, 6.37; N, 2.95
Found : C,71.42;H,6.31;N,3.01
Example 139 4-[Bis(4-fluorophenyl)methyl}-N-phenyl-1-piperidiner maleate [1:2].
A solution of 4-[bis(4-fluorophenyl)methyl]-1-(3-chloropropyl)piperi- dine (35.27 g, 0.097 mole) in 200 ml of aniline (204.4, 2.2 mole) was stirred overnight at 100°C. The solution was cooled at room temperature and then extracted several times with 1N sulfuric acid. The chloroform layer was extracted with 5% sodium hydroxide and then dried over anhydrous sodium sulfate. The solution was filtered, and then solvent removed in vacuo to give a dark brown oil. The oil was converted to the maleate salt which was recrystallized from methanol-diethyl ether. The solid obtained was dried in vacuo overnight at 80°C to give 29.84 g (47.1%) of light brown solid, m.p. 153- 154°C.
Analysis: Calculated for C27H30N20F2: C,64.41;H,5.87; N, 4.29
Found : C,64.36;H,5.87; N, 4.39
Example 140
N-[3-[4-[Bis(4-fluorophenyl)methyl]- 1-piperidinyl]propylj-N- methylbenzeneamine. voor
A solution of 4-[bis(4-fluorophenyl)methyl}-1-(3-chloropropyl)piperi- dine (8.43 g, 0.023 mole) in 100 ml of N-methylaniline was stirred 30 hours at 100°C. The reaction mixture was cooled to room temperature and diluted with 300 ml of chloroform. The chloroform layer was extracted with three 100 ml portions of 1N sulfuric acid (each neutral to litmus paper). The fourth 100 ml portion of 1N sulfuric acid used for extraction was strongly acidic to litmus paper. This fourth fraction was made alkaline with ice and 50% "sodium hydroxide and then extracted with chloroform. The chloroform layer was back extracted with 5% sodium hydroxide and dried over anhydrous sodium sulfate. Chloroform was removed by rotary evaporation to give a reddish brown oil. This oil was subjected to flash chromatography on silica gel using ethyl acetate for elution. Fractions of similar purity were combined and solvent removed. The residue was obtained and dried in vacuo overnight at 80°C to give 4.41 g (44.1%) of brown oil.
1H NMR (CDCl3): §6.6-7.2 (m, 13, aromatic), 3.5 (d, 1, metk aromatic nuclei), 3.3 (t, 2, methylene attached to aromatic N
CHj), 1.1-2.7 (m, 13, aliphatics).
Analysis: Calculated for CogH3gNoFa: C, 77.39; H, 7.42; N, 6.45
Found : C,77.44;H,7.44;N, 6.42
Example 141 1-[3-(4-Acetyl-2-methoxyphenoxy)propyl ]-a,a-bis(4-fluorophenyl)-3- piperidineacetonitrile oxalate hydrate [1:1:1).
A mixture of a,a-bis(4-fluorophenyl)piperidineacetonitrile (6.55 g, 0.02 mole), 1-[4-(3-chloropropoxy)-3-methoxyphenyllethanone (5.08 g, 0.04 mole) was heated overnight at gentle reflux in 350 ml of 1-butanol containing potassium iodide (0.2 g). The reaction mixture was stripped to dryness and the residue obtained was dissolved in chloroform. The chloroform was extracted with water and 5% sodium hydroxide. The chloroform layer was dried over anhydrous sodium sulfate, filtered, and solvent removed to give a dark brown oil. This oil was converted to the oxalate salt which was
Lo : - recrystallized twice from methanol-diethyl ether. The salt was dried in vacuo overnight at 80°C to give 2.28 g (17.4%) of white crystalline solid, m.p. 108- 109°C.
Analysis: Calculated for C33H3gN20gF2: C, 63.25; H, 5.79; N, 4.47
Found : C,63.08;H,5.48;N, 4.39
Example 142 1-[3-(4-Cyanophenoxy)propyll-a.o-bis(4-fluorophenyl)-3-piperidine- acetonitrile.
Co A mixture of 4-(3-chloropropoxy)benzonitrile (6.39 g, 0.0327 mole), a,a- bis(4-fluorophenyl)piperidineacetonitrile (10.22 g, 0.0327 mole), and potas- sium carbonate (5.54 g, 0.04 mole) was heated overnight at reflux in 350 ml of . 30 1-butanol containing potassium iodide (0.2 g). The reaction mixture was stripped to dryness, and the residue obtained was partitioned between chloro- form and water. The chloroform layer was back extracted with water. The chloroform layer was dried over anhydrous sodium sulfate, filtered, and solvent removed to give an oil. The oil was flash chromatographed on 300 g of silica gel using 50% hexane-50% ethyl acetate and 75% ethyl acetate-25%
hexane for elution. Fractions of similar purity were combi ing oil was dried in vacuo overnight at 80°C. The material drying overnight. The solid obtained was recrystallized from equal volumes of isopropanol and low boiling petroleum ether. The solid obtained was dried in vacuo overnight at 80°C to give 5.84 g (37.9%) of white crystalline product, m.p. 132-133°C.
Analysis: Calculated for CogH27N3OFg: C, 73.87; H,5.77; N, 8.91
Found : C,73.56;H,5.75; N, 8.85
Example 143 4-[3-[4-[Bis(4-fluorophenyl)methyl]-1-piperidinyl]propoxy]-3- methoxybenzonitrile.
The sodium salt of 4-hydroxy-3-methoxybenzonitrile was prepared by reacting sodium hydride (60%, 0.8 g, 0.02 mole), 4-hydroxy-3-methoxybenzo- nitrile (3.00 g, 0.02 mole), and 250 ml of dry dimethylsulfoxide. Initially, the solution had a cloudy white color, but shortly (about 10 minutes) after stirring, the solution had a clear brown color. The reaction mixture was stirred for 30 minutes at room temperature. A dimethylsulfoxide solutionof . 4-[bis(4-fluorophenyl)methyl]-1-(3-chloropropyl)piperidine (7.26 g, 0.02 mole) was added, and the resulting solution was stirred overnight at 50°C.
The dimethylsulfoxide was removed in vacuo, and the residue obtained was dissolved in chloroform. The organic layer was extracted with 5% sodium hydroxide and also water. The chloroform layer was dried over sodium sulfate, filtered, and solvent removed to give a dark brown oil. The oil was flash chromatographed on silica gel using ethyl acetate and 2% methanol- ethyl acetate for elution. Fractions of similar purity were combined and © solvent removed in vacuo. The residue was dried in vacuo overnight at 80°C to give 4.40 g (46.2%) of brown oil. 1H NMR (CDCl3): §6.8-7.3 (m, 11, aromatics), 4.1 (t, 2,-CH20 ~O) methylenes), 3.8 (s, 3, -OCH3), 3.4-3.6 (d, 1, methine attached to carbon containing two fluorophenyl groups), 1.2-3.0 (m, 13, aliphatics). NMR also indicated 0.25 H20 and a trace of ethyl acetate.
Analysis: Calculated for CogH3gN2O2F2: C, 73.09; H, 6.34; N, 5.88
Found : C,72.38;H,6.34;N,5.78
Example 144 4-[Bis(4-fluorophenyl)methyl}-1-{3-(1-naphthalenylox: piperidine hydrobromide hydrate [1:1:0.5].
The sodium salt of a-naphthol was formed in 300 ml of dimethyl sul- foxide from a-naphthol (2.59 g, 0.018 mole) and sodium hydride (60%, 0.72 g, 0.018 mole). The sodium salt was stirred 2-1/2 hours at room temperature. 4- [bis(4-Mluorophenyl)methyl)-1-(3-chloropropyl)piperidine (6.52 g, 0.018 mole of free base) in 100 ml of dimethyl sulfoxide was added, and the resulting solution was stirred overnight at 65°C. The solvent was removed in vacuo, and the residue obtained was partitioned between chloroform-water, chloro- form-1N sulfuric acid, and chloroform-5% sodium hydroxide. The chloroform layer was dried over sodium sulfate, filtered and solvent removed to give a green oil. The oil was converted to the hydrobromide salt which was recrystallized from methanol-diethyl ether. The white salt obtained was dried in vacuo at 80°C overnight. The crystalline solid was left exposed to the air overnight to give 1.88 g (18.6%) of white crystalline solid, m.p. 220-223°C.
Analysis: Calculated for C31H33NO; sF2Br: C, 66.31; H, 5.92; N, 2.49 : Found : C,66.46; H,5.84; N, 2.49
Example 145 2-[3-[4-[Bis(4-fluorophenyl)methyl]-1-piperidinyl]propoxylquinoline - hydrate [1:0.5].
The sodium salt of 4-[bis(4-fluorophenyl)methyl-1-piperidinepropanol was formed in 300 ml of dimethyl sulfoxide from its free base (6.90 g, 0.02 mole) and sodium hydride (60%, 0.8 g, 0.02 mole). 2-Chloroquinoline (3.26 g, 0.02 mole) was added and the reaction mixture was heated at 60°C for "approximately 72 hr. The reaction mixture was stripped to dryness, and the residue obtained was dissolved in chloroform. This chloroform layer was extracted with water and 5% sodium hydroxide. The chloroform layer was dried over sodium sulfate, filtered, and solvent removed to give an oil. The oil was subjected to flash chromatography on silica gel using ethyl acetate for elution. Fractions of similar purity were combined and solvent removed. The residue was dried in vacuo overnight at 80°C to give 5.16 g (53.6%) of clear brown oil.
'H NMR (CDCl3): 6 6.8-7.9 (m, 14, aromatics), 4.5 (t, 2, -OC] (d, 1, methine attached to two aromatic rings), 1.2-3.1 (m, 13, _ remaining).
Analysis: Calculated for C3gH31N2oO75F2 : C, 74.82; H, 6.49; N, 5.82
Found : C,74.56; H,6.36; N, 5.69
Example 146 ~ 4-[Bis(4-fluorophenyl)methyl}-1-[3-(2-naphthalenyloxy)propyl)- piperidine hydrate [1:0.5].
The sodium salt of 2-naphthol was prepared in 300 ml of dimethyl sulfoxide from 2-naphthol (3.00 g, 0.0208 mole) and sodium hydride (60% 0.83 g, 0.0208 mole). The solution was stirred 1 hr at room temperature and had a clear brown color. Then, 4-[bis(4-fluorophenyl)methyl}-1-(3-chloro- propyl)piperidine (free base 7.55 g, 0.0208 mole) in 100 ml of dimethyl- sulfoxide was added. The resulting solution was stirred overnight at 60°C.
The solvent was removed in vacuo, and the residue obtained was partitioned between chloroform-water and chloroform-5% sodium hydroxide. The chloro- form layer was dried over sodium sulfate, filtered, and solvent removed to give a brown oil. An oxalate salt could not be obtained in pure form so the oil (free base) was subjected to flash chromatography on silica gel using 50-50 ethylacetate-hexanes and 75-25 ethylacetate-hexanes for elution. Fractions . of similar purity were combined and solvent removed to give an oil. The oil was dried in vacuo at 80°C overnight to give 2.97 g (32.3% yield) of a dark brown glass after being dried overnight at room temperature. 1H NMR (CDCl3): §6.8-7.8 (m, 15, aromatics), 4-4.3 (t, 2, -OCHy), og 3.4-3.6 (d, ], methine attached to two fluorophenyl groups), 1.1-3.0 (m, 13, " aliphatics).
Analysis: Calculated for C3oH31 NO 5F9: C, 77.48; H,6.71; N, 2.91
Found : C,77.86;H,6.65;N, 2.94
Example 147 _ 3-[3-[3-[Bis(4-fluorophenyl)methyl}-1-piperidinyl]propoxylbenzonitrile hydrate [1:0.5].
A mixture of 4-[bis(4-fluorophenyl)methyl]piperidine, the free base of
Parparation 10 (7.85 g, 0.027 mole), 3-(3-chloropropoxy)-1-benzonitrile
(5.33 g, 0.027 mole), and potassium carbonate (5.84 g, 0.027 overnight at reflux in 350 ml of 1-butanol containing potassi
The reaction mixture was filtered and stripped to dryness. The residue obtained was dissolved in chloroform and extracted with water and 5% sodium hydroxide. The chloroform layer was dried over sodium sulfate, filtered, and solvent removed to give a brown oil. The oil was subjected to flash chromatography on silica gel using ethyl acetate-hexanes for elution.
Fractions of similar purity were combined and solvent removed. The dark brown oil obtained was dried in vacuo overnight at 80°C to give 5.65 g (45.9% yield) of dark brown oil.
H! NMR (CDCl3): §6.7-7.3 (m, 12, aromatics), 3.8-4.1 (t, 2, methylenes adjacent to oxygen atom), 3.4-3.6 (d, |, methine attached to two phenyl rings), 1.1-3.0 (m, 13, remaining aliphatic protons).
Analysis: Calculated for CogHogN20; sFo: C, 73.83; H, 6.42; N, 6.15
Found : (C,74.05;H,6.27; N, 6.09
Example 148 a.a-Bis(4-fluorophenyl)-1-[3-(4-methoxyphenoxy)propyl]-4-piperidine- a , methanol.
This compound was prepared according to the procedure used to synthesize the compound of Example 1. A mixture of 3.0 g (0.01 mole) of a,a- ~ bis(p-fluorophenyl)-4-piperidinemethanol, 2.0 g (0.01 mole) of 1-chloro-3-(4- methoxyphenoxy)propane, 5.3 g (0.035 mole) of anhydrous sodium carbonate and 0.3 g of potassium iodide in 100 ml of 1-butanol gave 2.3 g (49% yield) of title compound as a white solid, mp 107-108°C.
Analysis: Calculated for CogH3;FoNO3: C, 71.93; H, 6.68; N, 3.00 : Found : C,71.90;H, 6.70; N, 2.99
Example 149 a,a-Bis(4-fluorophenyl)-1-[3-(4-methylphenoxy)propyll-4-piperidine- methanol fumarate {1:1].
This compound was prepared according to the procedure used to synthesize the compound of Example 1. A mixture of3.0g (0.01 mole) of a,a- bis(p-fluorophenyl)-4-piperidinemethanol, 1.8 g (0.01 mole) of 1-chloro-3-(4- methylphenoxy)propane, 5.3 g (0.035 mole) of anhydrous sodium carbonate and 0.3 g of potassium iodide in 100 m] of 1-butanol gave a g
The gum was purified by column chromatography on 100 g ¢
Fractions eluted with 10% acetone in benzene were combined and concen- trated to give a gum. This gum was converted to the fumaric acid salt, and the solid was recrystallized from absolute ethanol to yield 3.2 g (66%) of title compound as a white solid, mp 193-194°C with decomposition.
Analysis: Calculated for C32H3s5FoNQOg: C, 67.71; H, 6.22; N, 2.47
Found : C,67.93;H,6.25;N, 2.53
Example 150 1-[3-(4-Fluorophenoxy)propyll-a,a-bis(4-fluorophenyl)-4-piperidine- methanol fumarate hydrate [1:1:1].
This compound was prepared according to the procedure used to synthesize the compound of Example 1. A mixture of 3.0 g (0.01 mole) of a,a- bis(p-fluorophenyl)-4-piperidinemethanol, 1.9 g (0.01 mole) of 1-chloro-3-(4- fluorophenoxy)propane, 5.3 g (0.035 mole) of anhydrous sodium carbonate and 0.3 g of potassium iodide in 100 ml of 1-butanol gave a solid as residue.
The solid was further purified by column chromatography on 60 g of Florisil®.
Fractions eluted with 2-10% acetone in benzene were combined and concen- trated to give a solid residue. The solid was converted to the furmaric acid salt and this solid was recrystallized from isopropanol to yield 2.2 g (39%) of title compound as a white solid, mp 155-157°C.
Analysis: Calculated for C3;H34F3NO7: C, 63.14; H, 5.81; N, 2.38
Found : C,62.99;H,5.64;N, 2.28
Example 151 : 1-[4-[3-[4-[(4-Fluorophenyl)(2-pyridinyl)methyl]-1-piperidinyl}- propoxy]-3-methoxyphenyllethanone.
A mixture of 2-[(4-fluorophenyl)(4-piperidinyl)methyl]pyridine (6.28 g, 0.0232 mole), 1-[4-(3-chloropropoxy)-3-methoxyphenyllethanone (5.62 g, 0.0232 mole), and potassium carbonate (5.53 g, 0.04 mole) was heating overnight at reflux in 350 ml of 1-butanol containing potassium iodide (0.2 g).
The reaction mixture was stripped to dryness and the residue obtained was dissolved in chloroform. The chloroform layer was extracted with 5% sodium hydroxide and water. The chloroform layer was dried over sodium sulfate,
filtered, and solvent removed to give a borwn oil. This oil wa flash chromatography on silica gel using 10% methanol-ethy methanol-ethylacetate, and 30% methanol-ethylacetate for elution.
Fractions of similar purity were combined and solvent removed to give a brown oil. This material was dried in vacuo overnight at 80°C to give 6.89 g (62.3% yield) of dark brown oil.
H! NMR (CDCl3): 6 6.8-7.8 (m, 15, aromatics), 4-4.3 (t, 2, -OCHyg), 3.9 (s, 3,-OCHjy), 3.6-3.8 (d, 1, C-H attached to pyridine ring), 2.6 (s, 3, C-CHj), 1.2- 3.6 (m, 9, remaining aliphaties).
Analysis: Calculated for CogH33N203F: C, 73.09; H, 6.98; N, 5.88
Found : C,72.51;H,7.10; N, 5.81
Example 152 {4-[3-[4-[Bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]propoxy]- phenyljcarbamic acid ethyl ester oxalate hydrate [1:1:1.5].
This compound was prepared according to the procedure used to synthe- size the compound of Example 1. A mixture of 3.0 g (0.01 mole) of a,a-bis(4- fluorophenyl)-4-piperidinemethanol, 2.6 (0.01 mole) of N-{4-(3-chloropro- poxy)phenyljcarbamic acid ethyl ester, 5.3 g (0.05 mole) of anhydrous sodium carbonate and 0.3 g of potassium iodide in 100 ml of dimethylformamide heated in a steambath for 24 hr gave a gum as residue. The gum was con- + verted to the oxalic acid salt in ethyl acetate and the solid was recrystallized from 2-propanol to yield 32 g (50%) of title compound as a white solid, mp 70- 90°C. :
Analysis: Calculated for C3gH43F2N20Og 5 : C,59.90;H,6.13; N, 4.37
Found : C,59.69; H,5.80; N,4.21
Example 153 1-[3-( 4-Acetyl-2-methoxyphenoxy)propyl |-a,a-bis(4-fluorophenyl-3- pyrrolidinepropanenitrile.
A mixture of a,a,-bis (4-fluorophenyl)-3-pyrrolidinepropanenitrile (5.00 g, 0.016 mole), 1-[4-(3-chloropropoxy)-3-methoxyphenyllethanone (3.88 g, 0.016 mole), and potassium carbonate (5.53 g, 0.04 mole) was heated overnight at reflux in 350 ml of 1-butanol containing potassium iodide (0.2 g). ~ The reaction mixture was cooled to room temperature and filtered. The
\ -190- butanol was removed by rotary evaporator to produce a dar oil was dissolved in chloroform, and the organic phase was times with water. The chloroform layer was dried over sodium sulfate, filtered, and solvent removed to provide a dark brown oil. The entire oil was subjected to flash chromatography on silica gel using ethyl acetate, 5% : methanol-ethyl acetate, and 10% methanol-ethyl acetate for elution. Frac- tions of similar purity were combined and solvent removed in vacuo. A dark brown oil was obtained and dried in vacuo overnight at 80°C to give 4.33 g (52.2% yield) of a glassy brown residue.
H! NMR (CDCl3): 8 6.8-7.7 (m, 11, aromatics), 4.0-4.25 (t, 2, -CH2-0), 3.9(s, 3,-OCHg3), 1.5-2.7 (mm, 16, aliphatics).
Analysis: Calculated for C3 H32N203F2: C, 71.80; H, 6.22; N, 5.40
Found : C,71.66;H,6.29; N, 5.53
Example 154 2-[3-[4-[Bis(4-fluorophenyl)methylene}-1-piperidinyl]propoxylphenol.
A mixture of 6.0 g (0.02 mole) of a,a-bis(p-fluorophenyl)-4-piperidine- methanol, 5.5 g (0.02 mole) of 3-(2-benzyloxyphenoxy)propyl chloride, 7.4 g (0.07 mole) of anhydrous sodium carbonate and 0.3 g of potassium iodide in 100 ml of 1-butanol was heated at reflux for 24 hr. The mixture was con- centrated, and the residue was partitioned between benzene and water. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated to give a gum as residue. The gum was converted to a crystalline hydrochloride. The salt changed to an oil upon standing over- night. The oil was partitioned between methylene chloride and a saturated - sodium bicarbonate solution. The organic layer was dried over sodium sul- fate and concentrated to give a gum as residue.
The gum was dissolved in 500 ml of absolute ethanol and hydrogenated in a Parr apparatus over 5% palladium on carbon catalyst at 70°C overnight.
The mixture was filtered through Celite®, and the filtrate was concentrated to give a gummy solid as residue. The solid was triturated with ethyl ether, and the mixture was filtered. The filtrate was slowly evaporated, and a solid precipitated. The solid was collected by filtration and recrystallized from isopropyl ether to yield 1.6 g (18% yield) of title compound a mp 125-127°C.
Analysis: Calculated for Co97H97F3NOg: C, 74.46; H, 6.25; N, 3.22
Found : C,7447;H,6.29;N, 3.12 : Example 155 1-[3-(4-Ethyl-2-methoxyphenoxy)propyl]-a,a-bis (4-fluorophenyl)-4- piperidinemethanol.
This compound was prepared according to the procedure used to synthesize the compound of Example 1. A mixture of 3.0 g (0.01 mole) of a,a- bis(p-fluorophenyl)-4-piperidinemethanol, 2.3 g (0.01 mole) of 3-(4-ethyl-2- methoxyphenoxy) propyl chloride, 5.3 g (0.05 mole) of anhydrous sodium carbonate and 0.3 g of potassium iodide in 100 ml of 1-butanol gave 3.7 g (74%) of title compound as a white solid, mp 118-120°C.
Analysis: Calculated for C3gH35F2NOs3: C,72.70; H, 7.12; N, 2.83
Found : C,72.72;H,7.43; N, 2.81
B Example 156 \
LL . 1-(3-Phenoxypropyl)-a,a-diphenyl-4-piperidinemethanol. i» This compound was prepared according to the procedure used to synthe- 020 size the compound of Example 1. A mixture of 4.0 g (0.015 mole) of a,a- . diphenyl-4-piperidinemethanol, 3.2 g (0.015 mole) of 1-bromo-3-phenoxy- ~ propane, 5.3 g (0.05 mole) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 ml of 1-butanol gave 3.2 g (53%) of title compound as a white solid, mp 87-88°C.
Analysis: Calculated for C97H31NO9: CC, 80.76; H, 7.78; N, 3.49
Found : C,80.82;H,7.79; N, 3.52
Example 157 a,a-Bis(4-fluorophenyl)-1-[3-[4-(methylsulfinyl)phenoxylpropyl]-4- piperidinemethanol oxalate hydrate [1:1:1.5] compound with 2-propanol {1:0.5].
This compound was prepared according to the procedure used to synthesize the compound of Example 1. A mixture of 3.0 g (0.01 mole) of a,a- bis(p-fluorophenyl)-4-piperidinemethanol, 2.3 g (0.01 mole) of 1-(3-
. chloropropyl)-4-methylsulfinyl)benzene, 5.3 g (0.05 mole) « sodium carbonate and 0.3 g of potassium iodide in 100 ml o; gum as residue. The gum was purified by column chromatography on 120 g of Florisil®. Fractions eluted with 15-25% acetone in benzene were combined and concentrated to give the purified base as an oil. The oil was converted to the oxalic acid salt, and the solid was recrystallized from 2-propanol to yield 2.6 g (40% yield) of title compound as a white solid, mp 75-105°C.
Analysis: Calc'd for C30H36F2NOg 58¢0.5(C3HgO): C, 58.50;
H,6.23;N, 2.17
Found : C, 58.32;
H, 5.99; N, 2.05
Example 158 a,a-Bis(4-fluorophenyl)-1-[3-[4-(1-methylethyl)phenoxy]propyl]-4- piperidinemethanol oxalate [1:1].
This compound was prepared according to the procedure used to synthesize the compound of Example 1. A mixture of 4.6 g (0.015 mole) of a,a- bis(p-fluorophenyl)-4-piperidinemethanol, 3.2 (0.015 mole) of 1-chloro-3-(4- .. . ... .. isopropylphenoxy) propane, 6.3 g (0.05 mole) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 ml of 1-butanol gave a solid as residue.
The solid was converted to the oxalic acid salt, and this solid was recrystal- lized from ethyl acetate to yield 4.6 g (54% yield) of title compound as a white : solid, mp 105-109°C with decomposition.
Analysis: Calculated for C3oH37FoNOg: CC, 67.47; H, 6.55: N, 2.46
Found : C,66.92; H,6.61; N.2.52
Example 159 3-[3-[4-[Bis(4-fluorophenyl)hydroxymethyl}-1-piperidinyljpropoxy]- benzoic acid ethyl ester fumarate [1:1]. ‘This compound was prepared according to the procedure used to synthesize the compound of Example 1. A mixture of 3.0 g (0.01 mole) of a,a- bis(p-fluorophenyl)-4-piperidinemethanol, 2.4 g (0.01 mole) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 ml of dimethyl- formamide gave a gum as residue. The gum was converted to the fumaric acid salt, and the solid was recrystallized from acetonitrile t (67%) of title compound as a fluffy, white solid, mp 123-131°
Analysis: Calculated for C34H37F2NOg: C, 65.27; H, 5.96; N, 2.24
Found : C,65.09;H,5.95; N, 2.25
Example 160 1-[4-[3-[4-[Bis(4-methylphenyl)methylene)-1-piperidinyl]propoxy]-3- methoxyphenyllethanone.
This compound was prepared according to the procedure used to synthe- size the compound of Example 1. A mixture of 4.6 g (0.015 mole) of a,a-bis(4- methylphenyl)-4-piperidinemethanol, 3.6 g (0.015 mole) of 1-[4-(3-chloro- propoxy)-3-methoxyphenyllethanone, 5.3 g (0.05 mole) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 ml of 1-butanol gave a brown gum as residue. The gum was dissolved in ethyl ether and filtered to remove insolubles. The filtrate was treated with ethereal hydrogen chloride and a solid gradually crystallized. Attempted recrystallization of the solid from } isopropanol failed. the solid was partitioned between methylene chloride and a sodium bicarbonate solution. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give a brown gum. The gum was converted to the fumaric acid salt. The solid was recrystallized twice from 2-propanol but a satisfactory combustion analysis could not be ~ obtained. This salt was partitioned between methylene chloride and a sodium bicarbonate solution as above to give a gum as residue. The gum crystallized after standing for several days. The solid was triturated with petroleum ether, collected by filtration, and recrystallized from 2-propanol to yield 2.2 g (46%) of title compound as an off-white solid, mp 92-95°C with - decompositon.
Analysis: Calculated for C3gH37NO3: C, 79.47; H, 7.71; N, 2.90
Found : C,79.18; H, 7.88; N, 2.88
Example 161 1-[4-[3-[4-[Bis(4-methylphenyl)hydroxymethyl]-1-piperidinyl]propoxy]- 3-methoxyphenyllethanone oxalate hydrate [1:1:1].
This compound was prepared according to the procedure used to | synthesize the compound of Example 1. A mixture of 4.6 g (0.015 mole) of a,a-
bis(4-methylphenyl)-4-piperidinemethanol, 3.6 g (0.015 mol chloropropoxy)-3-methoxyphenyllethanone, 5.3 g (0.05 mole : sodium carbonate and 0.4 g of potassium iodide in 100 ml of 1-butanol gave a brown gum as residue. The gum was converted to the oxalic acid salt and the solid was recrystallized from absolute ethanol to yield 5.3 g (58%) of title compound as an off-white solid, mp 92-95°C with decomposition.
Analysis: Calculated for C34H43NOg : C,66.97:H, 7.11; N, 2.30
Found : (C,66.61;H,6.79; N, 2.29
Example 162 : 4-[3-[4-[Bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]propoxy]- benzoic acid methyl ester fumarate [1:1].
A mixture of 9.1 g (0.03 mole) of a,a-bis(p-fluorophenyl)-4-piperidine- methanol, 6.7 g (0.03 mole) of 4-(3-chloropropoxy)benzoic acid methyl ester, 10.6 g (0.1 mole) of anhydrous sodium carbonate and 0.6 g of potasium iodide in 125 ml of dimethylformamide was heated in a steambath for 25 hr. The reaction mixture was poured into 1.5 liters of ice-water. The resulting solid was collected by filtration, washed with water and dried. The solid was converted to the fumaric acid salt to yield 12.5 g (68%) of title compound as a white solid, mp 140-174°C with decomposition.
Analysis: Calculated for C33H3sF2NOg: C, 64.80; H,5.77; N, 2.29
Found : C,64.67;H,5.80; N, 2.34
Example 163 1-[3-(4-Aminophenoxy)propyl}-a.a-bis(4-fluorophenyl)-4-piperidine- methanol oxalate [1:2].
A solution of 2.6 g (0.0054 mole) of a,a-bis(4-fluorophenyl)-1-{3-(4- nitrophenoxy)propyl}-4-piperidinemethanol in 50 ml of tetraydrofuran was hydrogenated at ambient temperature over 5% palladium on carbon catalyst at 40 psi. The mixture was filtered, and the filtrate was concentrated to give a gum as residue. The gum was converted to the dioxalate salt, and the solid was recrystallized from 95% ethanol to yield 2.1 g (62%) of title compound as : an off-white solid, mp 136-139°C with decompositon.
Analysis: Calculated for C3)H34F2N2019: C, 58.86; H,5.42; N, 4.43
Found : C,58.73; H,5.48; N, 4.43
Example 164 1-[4-[3-[4-[Bis(4-fluorophenyl)methyl]-1-piperidinyllpropoxy]-2- methoxyphenyljethanone oxalate [1:1].
A mixture of 4-[bis(4-fluorophenyl)methyl]piperidine (5.74 g, 0.02 mole), 1-[4-(3-chloropropoxy)-2-methoxyphenyl]ethanone (4.85 g, 0.02 mole), and potassium carbonate (5.54 g, 0.04 mole) was heated at reflux overnight in 350 ml of 1-butanol containing potassium iodide (0.2 g). The reaction mixture was stripped to dryness, and the residue obtained was partitioned between chloroform and water. The chloroform layer was extracted with water, dried over sodium sulfate, filtered, and solvent removed to give a brown oil. The oil was converted to the oxalate salt. The oxalate salt was recrystallized from methanol-diethyl ether. A white solid was obtained and dried in vacuo overnight at 80°C to give 7.04 g (60.3% yield) of white crystalline product, mp 190.5-191°C.
Analysis: Calculated for C3aH3sNO7F9: C, 65.86; H, 6.05; N, 2.40 1B Found : C,65.73;H, 6.05; N, 2.45
Example 165 4-[Bis(4-fluorophenyl)methyl}-1-[3-(4-ethyl-2-methoxyphenoxy)- propvllpiperidine oxalate [1:1].
A mixture of 4-[bis(4-fluorophenyl)methyllpiperidine (5.74 g, 0.024
Co mole), 1-{4-(3-chloropropoxy)-2-methoxyphenyllethanone (5.57 g, 0.024 mole), and potassium carbonate (5.54 g, 0.04 mole) was heated overnight at gentle reflux in 350 ml of 1-butanol containing potassium iodide (0.2 g). The reaction mixture was stripped to dryness. The residue was partitioned "several times between chloroform and water. The chloroform layer was back extracted with water and 5% sodium hydroxide. The chloroform layer was dried over sodium sulfate, filtered, and solvent removed to give an oil. The oil was converted to the oxalate salt and recrystallized from methanol-diethyl ether. A white solid was obtained and dried overnight in vacuo at 80°C to give 10.04 g (73.4% yield) of white crystalline product, mp 185-186°C.
Analysis: Calculated for C3oH37NOgFq2: C, 67,47; H, 6.55; N, 2.46
Found : C,67.41;H,6.53; N, 2.50
Example 166 1-[3-(J1,1'-Biphenyl]-4-yloxy)propyl]-a,a-bis(4-fluoro) i} piperidinemethanol.
This compound was prepared according to the procedure used to synthe- size the compound of Example 1. A mixture of 3.0 g (0.01 mole) of a,a-bis(p- fluorophenyl)-4-piperidinemethanol, 2.5 g (0.01 mole) of 4-(3-chloropropoxy)- 1,1'-biphenyl, 3.7 g (0.035 mole) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 ml of 1-butanol gave 3.5 g (69%) of title compound as a white solid, mp 108-109°C.
Analysis: Calculated for C33H33FoNO2: CC, 77.17; H, 6.48; N, 2.73
Found : C, 76.80; H, 6.83; N, 2.72
Example 167
N-[4-[3-[4-[Bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]propoxy]- phenyl]-N'-methylurea. :
To a solution of 4.5 g (0.01 mole) of 1-[3-(4-aminophenoxy)propyl]-a,a- bis(4-fluorophenyl)-4-piperidinemethanol in 50 ml of benzene was added dropwise a solution of 0.6 g (0.01 mole) of methylisocyanate in 10 ml of : benzene. The mixture was stirred for 1 hr during which time a solid precipi- tated. The mixture was diluted with 25 ml of cyclohexane, the solid was collected by filtration and recrystallized from 2-propanol to yield 1.6 g (31%) of title compound as a white solid, mp 177-178°C.
Analysis: Calculated for CogH33F9N303: C, 68.35; H, 6.53; N, 8.25 : Found : C,68.69;H,6.65; N, 8.29
Example 168
N-[4-[3-[4-[Bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyllpropoxy]- phenyllmethanesulfonamide fumarate [1:0.5] compound with 2-methoxy- ethanol [1:1].
To a solution of 4.5 g (0.01 mole) of the base of 1-[3-(4-aminophenoxy)- propyl}-a,a-bis(4-fluorophenyl)-4-piperidinemethanol and 1.5 g (0.015 mole) of triethylamine in 50 ml of benzene and 100 ml of ethyl acetate was added dropwise a solution of 1.2 g (0.01 mole) of methanesulfonyl chloride in 10 ml of benzene. A gum immediately precipitated. The mixture was stirred at ambient temperature for 2 hr and then treated with a saturated sodium bicarbonate solution. The mixture was stirred for 0.5 hr dus all solids dissolved. The layers were separated, and the org: washed with brine, dried over sodium sulfate and concentrated under reduced pressure to give a gum as residue. The gum was converted to the fumaric acid salt, and the solid was recrystallized from 2-methoxyethanol to yield 4.0 g (61%) of title compound as a tan solid, mp 153-156°C with decomposition.
Analysis: Calc'd for C3gH34F2N206SeC3HgOo: C, 59.62; H, 6.37; N, 4.21
Found : C,59.84; H,6.59; N, 4.17
Example 169 1-[4-[3-[4-[Bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyllpropoxy]- phenyl]-1-propanone compound with 2-propanol [1:1].
This compound was prepared according to the procedure used to synthe- size the compound of Example 1. A mixture of 3.0 g (0.01 mole) of a,a-bis(p- fluorophenyl)-4-piperidinemethanol, 2.3 g (0.01 mole) of 1-[4-(3-chloro- ~ propoxy)phenyl]-1-propanone, 3.7 g (0.035 mole) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 ml of 1-butanol gave 3.7 g : (76%) of title compound as a white solid, mp 57-62°C.
Analysis: Calculated for C3gH33F2NO3¢C3HgO: C, 71.59; H, 7.46; N, 2.53
Found : C,71.42;H,7.29; N, 2.63
Example 170 1-[4-[3-[4-[Bis(4-methoxyphenyl)hydroxymethyl]-1-piperidinvl]- * propoxy]-3-methoxyphenyllethanone oxalate [1:1].
This compound was prepared according to the procedure used to synthe- "size the compound of Example 1. A mixture of 3.2 g (0.01 mole) of a,a-bis(4- methoxyphenyl)-4-piperidinemethanol, 2.4 g (0.01 mole) of 1-[4-(3-chloro- propoxy)-3-methoxyphenyllethanone, 3.7 g (0.035 mole) of anhydrous sodium ~ carbonate and 0.4 g of potassium iodide in 100 ml of 1-butanol gave a gum as residue. The gum was purified by column chromatography on 100 g of
Florisil®. Fractions eluted with 5-40% acetone in benzene were combined and concentrated under reduced pressure to give a brown glass as residue.
The glass was converted to the oxalic acid salt. The solid was recrystallized oo -198- from absolute ethanol to yield 3.3 g (53%) of the title comps solid, mp 139-142°C with decomposition.
Analysis: Calculated for C34H41NO1o: C, 65.48; H, 6.63; N, 2.25
Found : C,65.38,H,6.70; N, 2.38 5 .
Example 171 1-[4-[6-[4-[Bis(4-fluorophenyl hydroxymethyl l-1-piperidinyl]hexyloxy]- 3-methoxyphenyljethanone hydrochloride (1:1].
This compound was prepared according to the procedure used to synthesize the compound of Example 1. A mixture of 3.0 g (0.01 mole) of a,a- bis(p-fluorophenyl)-4-piperidinemethanol, 2.8 g (0.01 mole) of 1-[4-(4- chlorohexyloxy)-3-methoxyphenyllethanone, 5.3 g (0.05 mole) of anhydrous sodium carbonate and 0.3 g of potassium iodide in 100 ml of 1-butanol gave a gum as residue. The gum was purified by column chromatography on 80 g of
Florisil®. Fractions eluted with 2-5% acetone in benzene were combined and concentrated to give a glass as residue. The glass was dissolved in anhydrous ethyl ether, filtered, and the filtrate treated with ethereal hydrogen chloride. :
A gummy solid precipitated. This solid was triturated with fresh ethyl ether until a fine, white solid resulted. The solid was collected by filtration and dried to yield 1.0 g (17%) of title compound as a white solid, mp 182-186°C with decomposition.
Analysis: Calculated for C33H40Cl1F2NO4: C,67.37;H,6.86; N, 2.38
Found : C,67.17;H,6.94; N, 2.37
Example 172 a.a-Bis(4-fluorophenyl)-1-[3-[4-(1-hvdroxvethyl )-2-methoxyphenoxyj-4- piperidinemethanol oxalate hydrate {1:1:1.5].
To a stirred slurry of 0.6 g (0.015 mole) of lithium aluminum hydride in 50 ml of dry tetrahydrofuran was added a solution of 5.6 g (0.015 mole) of 1- [4-[3-[4-[bis(4-fluorophenyl)hydroxymethyl)-1-piperidinyl]propoxy}-3- methoxyphenyllethanone in 100 mi of dry tetrahydrofuran. The mixture was stirred at ambient temperature for 2 hr and then cautiously treated succes- sively with 1 ml of water, 1 ml of a 20% sodium hydroxide solution and 3 ml of water. The mixture was stirred for 0.5 hr, filtered and the filtrate concen- trated to give a gummy solid as residue. The gum was converted to the oxalic acid salt. The gum was recrystallized from 2-propanol and absolute ethanol-ethyl ether to yield 3.5 g (39%) of title con solid, mp 81-87°C with decomposition.
Analysis: Calculated for C32H40F2NOg 5 : C,61.14;H,6.41;N, 2.23
Found : C,61.13;H,597;N, 2.17
Example 173 4-14-[4-[Bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]butoxy]- benzoic acid methyl ester fumarate [1:1].
This compound was prepared according to the procedure used to synthe- size the compound of Example 1. A mixture of 9.1 g (0.03 mole) of a,a-bis(p- fluorophenyl)-4-piperidinemethanol, 7.3 g (0.03 mole) of 4-(4-chlorobutoxy)- benzoic acid methyl ester, 10.6 g (0.1 mole) of anhydrous sodium carbonate and 0.5 g of potassium iodide in 125 ml of dimethylformamide gave a gum as residue. The gum was converted to the fumaric acid salt, and the solid was recrystallized from acetonitrile-dimethylformamide to yield 12.2 g (65%) of title compound as a white solid, mp 186-188°C. oo Analysis: Calculated for C34H37F2NOg: C, 65.27; H, 5.96; N, 2.24
Found . C,65.23; H,6.00; N, 2.32 a Example 174 1-[4-[3-[4-[2,2-Bis(4-fluorophenyl)-2-hydroxyethyl]-1-piperidinyl]- propoxy)-3-methoxyphenyllethanone fumarate hydrate {1:1:1].
A mixture of 4.52 g (0.0143 mole) of a,a-bis(4-fluorophenyl)-4-piperi- dineethanol, 3.75 g (0.0155 mole) of 3-(4-acetyl-2-methoxyphenoxy)-1- chloropropane, 4.1 g (0.049 mole) of sodium bicarbonate, and 0.20 g (0.0012 . mole) of potassium iodide in 300 ml of 1-butanol was refluxed for 8 hr. The : solvent was removed in vacuo, and the residue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene chloride solution was treated with a small portion of activated charcoal and was dried over magnesium sulfate. The solvent was removed in vacuo to give the non- salt form of the title compound. This was converted to the fumarate salt, and the salt was recrystallized from methanol ether to give 5.94 g (64.9%) of the title compound as a white crystalline solid: mp 135-136°C. : no . Lo te Th a
LD I
-200-
Analysis: Calculated for C35sH41NOgF9: C, 63.92; H, 6.28
Found : C,64.03;H,6.07,.., ~..
Example 175 1-[4-[3-[4-[2,2-Bis(4-fluorophenyl)ethyl]-1-piperidinyl]propoxy]-3- methoxyphenyllethanone fumarate [1:1].
A mixture of 5.15 g (0.0148 mole) of 4-[2,2-bis(4-fluorophenyl)ethyl]- piperidine hydrochloride hydrate [(1:1:1], 3.71 g (0.0153 mole) of 3-(4-acetyl-2- methoxyphenoxy)-1-chloropropane, 1.59 g (0.015 mole) of sodium carbonate, 2.30 g (0.0274 mole) of sodium bicarbonate and a 0.2 g (0.0012 mole) of potassium iodide in 400 ml of 1-butanol was heated at reflux for 12 hr. The solvent was removed in vacuo, and the residue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene chloride solution was dried over magnesium sulfate, and the solvent was removed in vacuo to give the free base of the title compound as an oil. This was converted to the fumarate salt, and the salt was recrystallized from methanol-ether to give 5.87 g (63.6 g) of title compound as a white crystalline solid; mp 156- . 157°C. : : :
Analysis: Calculated for C3sH3gNO7F2: C, 67.40; H, 6.30; N, 2.25
Found : C,67.51;H,6.34;N,2.29 :
Example 176 1-14-[3-14-[2.2-Bis(4-fluorophenyl)ethylenel-1-piperidinyllpropoxy]-3- methoxvphenvllethanone fumarate [1:1].
A solution of 3.89 g (0.013 mole) of 4-[2,2-bis(4-fluorophenyl)ethylene}- piperidine, 3.20 g (0.013 mole) of 3-(4-acetyl-2-methoxyphenoxy)-1-chloro- propane and 2.02 g (0.024 mole) of sodium bicarbonate in 400 ml of 1-butanol was heated at reflux for 14 hr. The solvent was removed in vacuo, and the residue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene chloride solution was dried over magnesium sulfate, and the solvent was removed in vacuo to give an oil. This was sub- jected to flash column chromatography (silica gel; eluted with 99/1 mixture of methylene chloride and methanol) to give the free base of the title compound.
This was converted to the fumarate salt, and the salt was recrystallized from methanol ether to give 5.19 g (64.2%) of title compound as a solid; mp 179-179.5°C.
Analysis: Calculated for C3sH37NO7Fg: C, 67.62; H, 6.00; N, 2.25
Found : C,67.59; H,6.00; N, 2.23
Example 177 a-(4-Fluorophenyl)-a-[1-(3-phenoxypropy!)-4-piperidinyl}-2-pyridine- acetonitrile oxalate [1:1.5].
A mixture of a-(4-fluorophenyl)-a-(4-piperidinyl)-2-pyridine aceto- nitrile (11.30 g, 0.0383 mole), 3-phenoxypropyl bromide (8.20 g, 0.0383 mole), and potassium bicarbonate (4.0 g, 0.04 mole) was heated overnight at reflux in 350 ml of acetonitrile (dried over 4A molecular sieves). The reaction mixture was cooled to room temperature and filtered, and solvent removed by rotary evaporator. A dark brown oil was obtained and dissolved in chloro- form. The chloroform layer was extracted with 5% sodium hydroxide and water, dried over sodium sulfate and filtered, and the solvent was removed to . give abrown oil. A 0.55 g sample of the oil was converted to the oxalate salt in methanol-diethyl ether. A white crystalline solid was isolated and dried in vacuo overnight at 80°C, to give 0.35 g of product; mp 121-125°C.
Analysis: Calculated for C30H31N307F: C, 63.82: H, 5.53; N, 7.44
Found . C,63.78;H,5.56;N, 7.67 : Example 178 1-[4-[3-[4-[Bis(4-chlorophenyl)methyl]-1-piperidinyl}propoxy]-3- - methoxvphenyllethanone oxalate hydrate [1:1:0.5].
A mixture of 4-[bis(4-chlorophenyl)methyl]piperidine (11.39 g, 0.0357 mole), 1-[4-(3-chloropropoxy)-3-methoxyphenyllethanone (8.64 g, 0.0357 mole), and potassium carbonate (5.54 g, 0.04 mole) was heated overnight at : reflux in 300 ml of 1-butanol containing potassium iodide (0.2 g). The reac- tion mixture was stripped to dryness, and the residue obtained was parti- tioned several times between chloroform and water. The chloroform layer oo was dried over sodium sulfate and filtered, and the solvent was removed to give a dark brown oil. This oil was converted to the oxalate salt and the salt was recrystallized from methanol-diethyl ether. A yellow solid was isolated ~~ anddried in vacuo overnight at 80°C. The yellow solid was next exposed to the atmosphere for 24 hours and submitted for analysis. This procedure produced 6.65 g (30% yield) of light yellow solid; mp 169-171°C. ’
Analysis: Calculated for C33H36NO7.5Cl2: C, 61.44; H, 5.80; N, 2.24 :
Found : C,61.40;H,5.71;N, 2.24
Example 179 1-[4-[3-[4-[Bis(4-chloropheny)hydroxymethyl]-1-piperidinyl]propoxy l- 3-methoxyphenyljethanone oxalate [1:1.5].
This compound was prepared according to the procedure used to synthesize the compound of Example 1. A mixture of 2.5 g (0.0075 mole) of a,a-bis(4-chlorophenyl)-4-piperidinemethanol, 1.8 g (0.0075 mole) of 1-{4-(3- chloropropoxy)-3-methoxyphenyl]ethanone, 3.7 g (0.035 mole) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 ml of 1-butanol gave a gummy solid as residue. This solid was converted to the oxalic acid salt, and the solid was recrystallized from absolute ethanol to yield 1.4 g (30%) of title : compound as a pale-yellow solid, mp 89-113°C with decomposition. EE
Analysis: Calculated for C33H36C12NO10: C, 58.50; H, 5.36; N, 2.07
Found + C,58.22;H,5.32; N, 2.07
Example 180 4-[3-[4-[Bis(4-fluorophenyl)methyl]-1-piperidinyl]propoxy }-3-methoxy- benzoic acid methyl ester.
The sodium salt of methyl vanillate was formed from methyl vanillate (11.26 g, 0.062 mole) and sodium hydride (2.47 g, 60%, 0.062 mole) in 300 ml - of dimethyl! sulfoxide (dried over 4A molecular sieves). During the formation of this sodium salt, the dimethyl sulfoxide solution turned light green. The salt was stirred 0.5 hr at room temperature under nitrogen atmosphere.
Next, 4-[bis(4-fluorophenyl)methyl)-1-(3-chloropropyl)piperidine (21.32 g, 0.062 mole) in 100 ml of dimethyl sulfoxide was added dropwise. The result- ing solution was stirred overnight at 60°C. The warm reaction mixture was stripped to dryness on a rotary evaporator. The residue was dissolved in chloroform and extracted several times with water. The chloroform layer was dried over sodium sulfate, filtered, and solvent removed to give a dark brown oil (31.35 g). The oil was dissolved in ethyl acetate and placed on an 800 g silica gel column. This column was eluted with ethyl acetate.
\ -203-
Fractions of similar purity were combined and dried in vacuo at BU"U overnight to give 22.70 g (71.9% yield) of brown oil. .
IH NMR (CDCl3): 86.7-7.7 (m, 11, aromatics), 4.0-4.3 (t, 2, -OCHy), 3.9 (s, 6, OCHj3 of ether and ester), 3.5 (d, 2, methine group attached to two fluorophenyl groups), 1.3-3.0 (m, 12, remaining aliphatics).
Analysis: Calculated for C3gH33NO4F2: C, 70.71; H, 6.53; N, 2.75
Found : C,70.48;H,6.60; N, 2.71
Example 181 1-[4-[3-[4-[Bis(3-fluorophenyl)methyl]-1-piperidinyl]propoxy]-3- methoxyphenyllethanone fumarate [1:1].
A mixture of 5.32 g (0.019 mole) of 4-[bis(3-fluorophenyl)methyl}- piperidine, 4.80 g (0.020 mole) of 3-(4-acetyl-2-methoxyphenoxy)-1-chloro- propane, 2.4 g (0.029 mole) of sodium bicarbonate and 0.20 g (0.0012 mole) of potassium iodide in 400 ml of 1-butanol was heated at reflux for 23 hr. The solvent was removed in vacuo, and the residue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene chloride solution was dried over magnesium sulfate, and the sovlent was removed in vacuo to give an oil. This was dissolved in methanol and the solution was treated with an excess of fumaric acid. Ether was added and a gum formed. "the gum was triturated with acetonitrile to give 1.75 g (15.1%) of the title compound as a white crystalline solid, mp 180-181°C.
Analysis: Calculated for C34H37NO7F2: C,66.98;H,6.12; N, 2.30
Found : C,66.70;H,6.11;N, 2.32 i
The solvent was removed in vacuo from the filtrate and the residue was recrystallized from a mixture of methanol-ether-acetonitrile to give 2.83 g (24.4%) of title compound, mp 181-182°C.
Analysis: Calculated for C34H37NO7Fe: C, 66.98; H,6.12; N, 2.30
Found : C,66.95;H,6.09;N, 2.28
Example 182 4-[3-[4-[Hydroxy(diphenyl)methyl]-1-piperidinyl]propoxy]lbenzoic acid methyl] ester.
This compound was prepared according to the procedure used to synthesize the compound of Example 1. A mixture of 5.3 g (0.02 mole) of a,a- diphenyl-4-piperidinemethanol, 4.6 g (0.02 mole) of 4-(3-chloropropoxy)- benzoic acid methyl ester, 7.4 g (0.07 mole) of anhydrous sodium carbonate and 0.5 g of potassium iodide in 100 ml of dimethylformamide give 6.8 g (74%) of title compound as a fluffy, white solid, mp 146-147°C.
Analysis: Calculated for CogH33NO4: C, 75.79; H, 7.24; N, 3.05
Found : C,75.68;H,7.22;N, 3.11
Example183 1-[4-[6-[4-[Bis(4-fluorophenyl)methyl)-1-piperidinyl]hexyloxy]-3- methoxyphenyllethanone.
A mixture of 4-[bis(4-fluorophenyl)methyl]piperidine (7.90 g, 0.0275 mole), 1-(4-(6-chlorohexyloxy)-3-methoxyphenyllethanone (7.82 g,0.025 mole), and potassium carbonate (5.54 g, 0.04 mole) was heated overnight at reflux in 400 ml of 1-butanol containing potassium iodide (0.2 g). The mixture was cooled to room temperature and filtered. Butanol was removed by rotary evaporation. The brown oil obtained was dissolved in chloroform and the solution was extracted several times with water. The chloroform layer was dried over sodium sulfate, filtered, and solvent removed to give a brown oil. This oil was dissolved in ethyl acetate and subjected to flask : chromatography on silica gel using ethyl acetate and 5% methanol-ethyl acetate for elution. Fractions of similar purity were combined and solvent removed to give an oil. The oil was dried at 80°C overnight in vacuo to give 7.28 g (54.4% yield) of title compound as a light brown oil. 1H NMR (CDCls3): §6.7-7.5 (m, 11, aromatics), 4-4.2 (m, 2,-OCH32), 3.9 (s,3,-OCHj3), 3.4-3.6 (d, 1, methine on carbon attached to two fluorophenyl groups), 2.6 (s, 3, C-CH3), 1.5-3.0 (m, 13, remaining aliphatics). 0
Analysis: Calculated for C33H3gNO3Fa: C,73.99; H,7.34; N, 2.61
Found + C,73.92;H,7.54;N, 2.62 | -
Example 184 4-[3-[4-[Bis(4-fluorophenyl)methyl}-1-piperidinyllpropoxy]-3- . methoxybenzoic acid hydrate [1:0.5].
A solution of 4-[3-[4-[bis(4-fluorophenyl)methyl]-1-piperidinyl}- propoxy]-3-methoxybenzoic acid methyl ester (18.58 g, 0.0365 mole) in 400 ml of ethanol was heated for 6 hr at reflux with potassium hydroxide (16.8 g) in 50 ml of water. The ethanol was removed by rotary evaporation. Next, IN sulfuric acid (~200 ml) was added. The aqueous phase was made neutral to litmus paper by the addition of 5% sodium hydroxide. The neutral aqueous layer was extracted several times with chloroform. The chloroform layer was dried over sodium sulfate, filtered, and solvent removed to give a white solid.
The white solid was triturated with diethyl ether and cooled to about 0°C.
The white solid was then filtered out of solution and then dried in vacuo overnight at 80°C to give 11.38 g (61.8% yield) of white crystalline product, the title compound, mp 123-126°C.
Analysis: Calculated for CogH3aNO45F2: C, 69.03; H, 6.39; N, 2.78
Found : C,69.18;H,6.32; N, 2.78
Example 185 4-[Bis(4-fluorophenyl)methyl)-1-[3-(3-methoxyphenoxy)propyljpiperi- + dine hydrate [1:0.5].
Co The sodium salt of m-methoxyphenol was prepared in dimethyl sul- oo foxide from sodium hydride (60%, 1.10 g, 0.027 mole) and m-methoxyphenol : . (3.36 g, 0.027 mole). The salt was stirred for 0.75 hr at room temperature, .- 25 and a clear brown solution was obtained. Next, 4-[bis(4-fluorophenyl) methyl]-1-(3-chloropropyl)piperidine (9.34 g, 0.027 mole) in 100 ml of dimethyl sulfoxide was added. The resulting solution was stirred overnight at 55°C. The solvent was removed in vacuo, and the oil obtained was sub- jected to flash chromatography on silica gel using 50% hexanes-ethyl acetate for elution. Fractions of similar purity were combined and solvent removed.
A brown oil was obtained and dried at 80°C overnight in vacuo to give 3.96 g (31.8%) of brown oil. 'H NMR (CDCl3): §6.3-7.3 (m, 12, aromatics), 3.8-4.1 (m, 2, -OCH2), 3.7 (s, 3, -OCHj3), 3.4-3.6 (d, 1, methine attached to two fluorophenyl rings), 1.2-3.0 (m, 13, remaining aliphatic protons).
~ -206-
Analysis: Calculated for CogH32NO2 sF2: C, 73.02; H, 7.00; N, 3.04
Found : C,72.66;H,6.89;N,3.06 -
Example 186 1-[4-[3-[4-[Cyclohexyl(4-fluorophenyl)methyl]-1-piperidinyl}propoxy]- 3-methoxyphenyllethanone.
A mixture of 4-[cyclohexyl(4-fluorophenyl)methyl]piperidine (5.71 g, 0.0207 mole), 1-[4-(3-chloropropoxy)-3-methoxyphenyljethanone (5.03 g, 0.0207 mole), and potassium carbonate (5.53 g, 0.04 mole) was heated overnight at reflux in 350 ml of 1-butanol containing potassium iodide (0.2 g).
The reaction mixture was cooled to room temperature and filtered. The 1- butanol was removed by rotary evaporation to give a brown oil. This oil was dissolved in chloroform, and the chloroform layer was extracted with 5% sodium hydroxide and water. The chloroform layer was dried over sodium sulfate, filtered, and solvent removed to give a brown oil. This oil was . 15 subjected to flash chromatography on silica gel. Elution was performed using ethyl acetate, 5% methanol-ethyl acetate, and 10% methanoi-ethyl acetate.
Separate fractions of similar purity were combined, and solvent was removed to give a yellow oil. This oil was dried in vacuo overnight at 80°C to give 7.36 - g(73.8%) of title compound. 'H NMR (CDCl3): § 839.5 (m, 7, aromatics), 4.0 (m, 2, -O-CHp), 3.9 (s, 3,-0-CHj3), 2.5 (s.3,-C-CHa), 1.0-3.0 (m, 25, remaining aliphatics).
Analysis: Calculated for C30H4oNO3F : C, 74.81; H,8.37;N, 2.91 26 Found : C,74.39; H,8.36; N, 2.81
J
Example 187 4-[Bis( 4-fluorophenyl)methyl -1-[3-(phenylthio)propyllpiperidine citrate [1:1].
A mixture of 19.23 g (0.067 mole) of 4-[bis(4-fluorophenyl)methyl]- piperidine, 16.0 g (0.069 mole) of 3-thiophenoxy-1-bromopropane, and 6.72 g (0.080 mole) sodium bicarbonate in 400 mi of 1-butanol was heated at reflux for 25 hours. The solvent was removed in vacuo, and the residue was parti- tioned between methylene chloride and dilute sodium hydorxide solution.
The methylene chloride solution was dried over magnesium sulfate, and the
: solvent was removed in vacuo to give the non-salt formoft... ..... = as an oil. This was converted to the citrate salt, and the salt was recrystal- lized from methanol-ether to give 33.05 g (78.3%) of title compound as a white crystalline solid: mp 149.5-151°C.
Analysis: Calculated for C33H37NO7SFa: C, 62.94; H, 5.92; N, 2.22
Found : C,63.08;H,5.94; N, 2.23 ~~ Example 188 4-[Bis(4-fluorophenyl)methyl]-1-[3-(phenylsulfinyl)propyllpiperidine oxalate [1:1].
A solution of 4.33 g (0.0099 mole) of 4-[bis(4-fluorophenyl)methyl]}-1-[3- (phenylthio)propyllpiperidine and 7.70 g (0.050 mole) of sodium perborate ~ tetrahydrate in a mixture of 150 ml of methanol and 100 ml of 30% sulfuric acid solution was stirred at room temperature for 2 hr. The reaction mixture was poured over ice, and the mixture was made basic with 50% sodium hydroxide solution. The mixture was extracted with methylene chloride.
The extract was dried over magnesium sulfate, and the solvent was removed in vacuo to give the non-salt form of the title compound as an oil. This was converted to the oxalate salt, and the salt was recrystallized from methanol- ether to give 4.38 g (81.4%) of the title compound as a white crystalline solid; © mp 173.5-174°C (with decomposition).
Analysis: Calculated for CogH31NOsSFa: C, 64.07; H,5.75; N, 2.58
Found : C,63.91;H,5.74;N, 2.57 : In a similar procedure 3.46 g of the title compound was obtained; mp 169-170.5°C.
Analysis: Calculated for CogH31NO5sSF2: C, 64.07; H, 5.75; N, 2.58 " Found : C,63.80;H,5.75;N, 2.61
Example 189 2-[(4-Fluorophenyl)[1-(3-phenoxypropyl)-4-piperidinyl Jmethyllpyridine hydrate [1:0.5].
A solution of a-(4-fluorophenyl)-a-[1-(3-phenoxypropyl)-4-piperidinyl]- 2-pyridineacetonitrile oxalate [1:1.5] (2.34 g, 0.00545 mole) in 75 ml of glacial acetic containing 10 drops of concentrated hydrochloric acid was prepared.
To this solution was added 2 grams of platinum on carbon catalyst (1%).
After reacting with hydrogen for 5 days at 80°C and 1000 psi, the reaction mixture was allowed to cool to room temperature. The mixture was filtered through Celite®, and the filtrate washed with glacial acetic acid. The acetic acid was removed by rotary evaporation. The residue obtained was dissolved in chloroform, and the solution was extracted with 5% sodium hydroxide.
The chloroform was dried over sodium sulfate and filtered, and the solvent removed to give a brown oil. This oil was subjected to flash chromatography on silica gel using 5% methanol - ethyl acetate for elution. Fractions of similar purity were combined, and solvent removed to give a brown oil. The oil was dried in vacuo overnight at 80°C, to give 0.35 g (15.5% yield) of brown oil. 1H NMR (CDCl3): 88.5 (m, 1, proton adjacent to nitrogen atom in pyridine ring), 6.8-7.5 (m, 12, aromatics), 4.0 (t, 2, -OCH32-),3.6(d, 1, methine proton attached to carbon bonded to fluorophenyl ring and also pyridine ring), 1.0-3.0 (m, 13, remaining aliphatic protons).
Analysis: Calculated for C26H39N201 sF : C,75.52;H,7.31;N,6.77
Calculated for CogHag 5N20O1 25F : C, 76.35: H, 7.27: N, 6.85
Found : C,76.28;H,7.14; N, 6.85
Example 190 1-(4-[3-[4-[(3.4-Difluorophenyl)(4-fluorophenyl)methvl |-1-piperidinyl]- propoxyl-3-methoxyphenyllethanone oxalate [1:1].
A mixture of 2.68 g (0.036 mole) of 4-[(3,4-difluorophenyl)methyvl}- piperidine, 2.50 g (0.110 mole) of 1-chloro-3-(4-acetyl-2-methoxyphenoxy)- propane, 3.0 g (0.036 mole) of sodium bicarbonate, and 0.20 g (0.0012 mole) of potassium iodide in 300 ml of 1-butanol was heated at reflux for 30 hours.
The solvent was removed in vacuo, and the residue was partitioned between methylene chloride and dilute sodium hydroxide. Methylene chloride solu- tion was dried over sodium sulfate, and the solvent was removed in vacuo to 0 give an oil. The oil was flash chromatographed (silica gel, elution with 95/5 methylene chloride - methanol) to give the nonsalt form of the title com- pound. This was converted to the oxalate salt, and the salt was recrytallized from methanol-ether to give 3.85 g (72.7%) of the title compound as a white crystalline solid, m.p. 170-171°C.
Analysis: Calculated for C3oH34NO7F3 : C,63.89; H,5.70; N, 2.50
Found : C,63.87;1,5.71;N,2.34
Example 191 1-[3-(4-Acetyl-2-methoxyphenoxy)propyl]-a,a-bis (4-fluorophenyl)-3- pyrrolidineacetonitrile.
A mixture of a,a-bis(4-fluorophenyl)-3-pyrrolidineacetonitrile (5.13 g, 0.0172 mole), 1-[4-(3-chloropropoxy)-3-methoxyphenyllethanone (4.17 g, 0.0172 mole), and potassium carbonate (5.53 g, 0.04 mole) was heated over- night at reflux in 350 ml of 1-butanol containing potassium iodide (0.2 g).
The butanol was removed by rotary evaporator. The residue obtained was dissolved in chloroform and extracted several times with water. The chloro- form layer was dried over sodium sulfate, filtered, and solvent removed in vacuo to give a dark brown oil. The oil was subjected to flash chromatog- raphy on silica gel using ethyl acetate and 25% methanol-75% ethyl acetate for elution. Fractions of similar purity were combined, and solvents removed.
A dark brown oil was obtained and dried in vacuo 2 days at 80°C to give 5.85 g (57.5% yield) of the title compound as a dark brown gum. ~ 'HNMR(CDCl3): §6.8-7.6 (m, 11, aromatics), 4.3 (t, 2, -OCH3-), 3.9, 3, - ~ OCH3y),2.6(s, 3,-COCH3-), 1.3-3.8 (m, 11, aliphatic). ol | Analysis: Calculated for C30H30N203Fg : C,71.41;H,5.99;N, 5.55
Found : C,70.94; H,5.99; N, 5.51 : Example 192 1-[3-(4-Acetyl-2-methoxvphenoxy)propyl]-a.a-bis(4-fluorophenvl)-3- piperidinepropanenitrile hydrate [1:0.5].
A mixture of 1-[4-(3-chloropropoxy)-3-methoxyphenyllethanone (4.45 g, 0.0184 mole), a,a-bis(4-fluorophenyl)-3-piperidinepropanenitrile (6.00 g, .. 30 0.0184 mole), and potassium carbonate (5.54 g, 0.04 mole) was heated over- night at reflux. The mixture was cooled to room temperature and stripped to dryness on a rotary evaporator. The residue was partitioned between chloro- form and water. The chloroform layer was back-extracted with water and 5% sodium hydroxide solution. The chloroform layer was dried over sodium sul- fate, filtered, and solvent removed to give a dark brown oil. The oil was
MN
-210- subjected to flash chromatography on silica gel using 75% ethyl acetate - 25% hexanes and 100% ethyl acetate for elution. Fraction of similar purity were combined and solvent removed. A dark brown oil was obtained and dried in vacuo at 80°C to give 590 g (59.2% yield) of title compound as a yellowish- brown gum.
H! NMR (CDCl3): 8 6.8-7.8 (m, 11, aromatics), 4.2 (s, 3, -OCH3), 4.2 (m, 2,-OCHy), 2.6 (s, 3,-0-CH3), 1.1-2.8 (m, 15, aliphatics).
Analysis: Calculated for C32H35N203 5F2: C, 70.96; H,6.51;N,5.17
Found + C,71.58;H,6.49;N,5.12
Example 193 1-[3-(4-Acetyl-2-methoxyphenoxy)propyl]-a,a-bis( 4-fluorophenyl)-4- 18 piperidineacetamide fumarate hydrate [1:0.5:0.5].
A mixture of a,a-bis(4-fluorophenyl)-4-piperidineacetamide, (6.94 g, : 0.021 mole), 1-[4-(3-chloropropoxy-3-methoxyphenyllethanone (5.09 g, 0.021 : mole), and potassium carbonate (5.53 g, 0.04 mole) was heated overnight at reflux in 350 ml of 1-butanol containing potassium iodide (0.2 g). The mixture was stripped to dryness. The residue obtained was partitioned between chloroform and water. The chloroform layer was dried over sodium sulfate and filtered, and solvent removed to give a yellowish-brown residue.
This material was converted to the fumarate salt and recrystallized from methanol-diethyl ether. A white solid was obtained and dried in vacuo 26 overnight at 80°C to give 8.47 g (66.8%) of title compound as a white crystalline solid, mp 258-260°C (with decomposition).
Analysis: Calculated for C33H37N206 sF2: C,65.66;H,6.18; N, 4.64
Found . (C,65.88:H,6.13; N, 4.65
Example 194 ) 1-[4-[3-[4-[Bis(3,4-difluorophenylmethyl -1-piperidinyl]propoxy]-3- methoxyphenyljethanone.
A mixture of the free base of 4-[bis(4-fluorophenyl)methyl]piperidine hydrochloride [1:1] (6.46 g, 0.02 mole), 1-[4-(3-chloropropoxy)-3-methoxy- phenyllethanone (4.84 g, 0.02 mole), and potassium carbonate (5.54 g, 0.04 mole) was heated overnight at reflux in 1-butanol (350 ml) containing
-\ -211- potassium iodide (0.2 g). The mixture was cooled to room temperatuic anu then stripped to dryness. The residue obtained was partitioned between. chloroform and 5% sodium hydroxide solution. The chloroform layer was dried over sodium sulfate, filtered, and solvent removed in vacuo to give a yellow residue (11.17 g). The oil was subjected to flash chromatography on silica gel using ethyl acetate, 5% methanol-ethyl acetate and 10% methanol- ethyl acetate for elution. Fractions of similar purity were combined and solvent removed. A thick viscous oil was obtained and dried in vacuo overnight at 80°C. This procedure furnished 6.74 g (63.4%) of the title compound as a viscous oil. 1H NMR CDCl3: 6 6.8-7.6 (m, 9, aromatics), 4.1-4.3 (t, 2,-O-CH2),3.9(s, 3, - : OCHz3), 2.5 (s, 3, -C-CHy), 1.2-3.6 (m, 14, remaining aliphatics).
Oo
Analysis: Calculated for C30H31NO3F4: C,68.04;H, 5.90; N, 2.64
Found : C, 67.49; H,6.06;N, 2.56
Example 195
When in the procedure of Example 66 and substituting the following for a,a-bis(p-fluorophenyl)-4-piperidinemethanol: 20. a) a,a-bis(3,4-difluorophenyl)-4-piperidinemethanol, b) a,a-bis(2,5-difluorophenyl)-4-piperidinemethanol, ¢) a,a-bis(2,4-difluorophenyl)-4-piperidinemethanol, d) a,a-bis[3-(trifluoromethyl)phenyl])-4-piperidinemethanol, and e) a,a-bis[4-(trifluoromethyl)phenyl}-4-piperidinemethanol there are obtained: a) 1-[4-[3-[4-[bis(3,4-difluorophenyl)hydroxymethyl]-1-piperidinyl]- ’ propoxyl-3-methoxyphenyllethanone, b) 1-[4-[3-[4-[bis(2,5-difluorophenyl)hydroxymethyl]-1-piperidinyl]- propoxyl-3-methoxyphenyl]ethanone, ¢) 1-[4-[3-[4-[bis(2,4-difluorophenyl)hydroxymethyl)-1-piperidinyl]- propoxy]-3-methoxyphenyl)ethanone, d) 1-[4-[3-14-[bis[3-(trifluoromethyl)phenyl]hydroxymethyl]-1- piperidinyllpropoxyl-3-methoxyphenyllethanone, and gh -212- e) 1-[4-[3-[4-[bis[4-(trifluoromethyl)phenyllhydroxymeuny;-a- piperidinyl]propoxy]-3-methoxyphenyllethanone. .
Example 196
When in the procedure of Example 56 and substituting the following for 4-[a,a-bis(p-fluorophenyl)methyl]piperidine: a) 4-[a,a-bis(3,4-difluorophenyl)methyl]piperidine, b) 4-[a,a-bis(2,5-difluorophenyl)methyl]piperidine, ¢) 4-[a,a-bis[3-(trifluoromethyl)phenyllmethylipiperidine, and 0 d) 4-[a,a-bis[4-(trifluoromethyl)phenylimethyl]piperidine. there are obtained the following: a) 1-[4-[3-[4-[bis(3,4-difluorophenyl)methyl]-1-piperidinyllpropoxy]- 3-methoxyphenyljethanone oxalate salt, b) 1-[4-[3-[4-[bis(2,5-difluorophenyl)methyl]-1-piperidinyl}propoxy]- 3-methoxyphenyljethanone oxalate salt, c) 1-(4-(3-(4-(bis(3-(trifluoromethyl)phenyllmethyl}-1-piperidinyl}- propoxy}-3-methoxyphenyllethanone oxalate salt, and d) 1-[4-[3-[4-[bis[4-(trifluoromethyl)phenyllmethyl]-1-piperidinyl}- propoxyJ-3-methoxyphenyllethanone oxalate salt.
Example 197
When in the procedure of Example 58 and substituting the following for oc : 4-[a,a-bis(p-fMluorophenyl)methylenelpiperidine: a) 4-[a,a-bis(3,4-difluorophenyl)methylene]piperidine, b) 4-[a,a-bis(2,5-difluorophenyl)methylene]piperidine, ¢) 4-[a,a-bis(2,4-difluorophenyl)methylene]piperidine, d) 4-[a,a-bis[3-(trifluoromethyl)phenyllmethylene]piperidine, and e) 4-[a,a-bis[4-(trifluoromethyl)phenyllmethylene]piperidine there are obtained: ’ a) 1-[4-[3-[4-[bis(3,4-difluorophenyl)methylene]}-1-piperidinyl]- propoxy)-3-methoxyphenyllethanone oxalate salt,
b) 1-[4-[3-[4-[bis(2,5-difluorophenyl)methylene)-1-piperidinyl)- propoxy]-3-methoxyphenyllethanone oxalate salt, . c) 1-[4-{3-14-[bis(2,4-difluorophenyl)methylene]-1-piperidinyl]- propoxy]-3-methoxyphenyllethanone oxalate salt, d) 1-[4-[3-[4-[bis[3-(trifluoromethyl)phenyllmethylene]-1-piperi- dinyl}propoxy]-3-methoxyphenyllethanone oxalate salt, and e) 1-[4-[3-[4-[bis{4-(trifluoromethyl)phenyllmethylene]-1-piperi- dinyllpropoxy]-3-methoxyphenyllethanone oxalate salt.
Example 198 1-4-[3-[4- (a-3.4-Difluorophenyl-a-4-fluorophenyl hydroxymethyl }-1- piperidinyl]propoxy)-3-methoxyphenyljethanone.
When in the procedure of Example 66 and substituting a-(3,4- difluorophenyl)-a-(4-fluorophenyl)-4-piperidinemethanol for a,a-bis(p- fluorophenyl)piperidinemethanol, the title compound is obtained.
Example 199 yo 1.[4-[3-[4-[a-(3,4-Difluorophenyl)-a-(4-fluorophenyl)methylene}-1- piperidinyl}propoxy -3-methoxyphenyljethanone oxalate.
Ve 20 : When in the procedure of Example 58 and substituting 4-{a-(3,4- oo oo difluorophenyl-a-(4-fluorophenylmethylene]piperidine for 4-[a,a-bis(p- ; fluorophenyl)methylenelpiperidine the title compound is obtained. oo Example 200 . 1-[4-[3-[4-] Bis(2.4-difluorophenyl)methyl -1-piperidinyl]propoxy]-3- methoxyphenyljethanone oxalate [1:1].
A mixture of 4-[bis(2,4-difluorophenymethylipiperidine (7.30 g, 0.023 mole), 3-(4-acetyl-3-methoxyphenoxy)propyl chloride (5.57 g, 0.023 mole), and potassium carbonate (5.54 g, 0.04 mole) was heated overnight at reflux in 350 ml of 1-butanol containing potassium iodide (0.2 g). The reaction mixture was filtered and then stripped to dryness. The residue was dissolved in chloroform, and the solution was extracted with 5% sodium hydroxide. : The chloroform layer was dried over sodium sulfate and filtered. The re- moval of chloroform provided a dark brown oil. This material was converted to the oxalate salt in methanol-diethyl ether. A white solid was isolated and dried in vacuo overnight at 80°C. This procedure furnished 8.23 g (57.7%) of : white crystalline product, mp 151-153°C. :
Analysis: Calculated for C32H33NO7F4: C, 62.03; H,5.37;N, 2.26
Found : C,62.10;H,5.37; N, 2.33
Example 201
Utilizing Method F, supra, and reacting the following compounds: a) 1-[4-[3-[4-(bis(3,4-difluorophenyl)hydroxymethyl]-1-piperidinyl)- propoxy)}-3-methoxyphenyllethanone, b) 1-[4-[3-[4-[bis(2,5-difluorophenyl)hydroxymethyl]-1-piperidinyl}- propoxyl-3-methoxyphenyllethanone, ¢) 1-[4-[3-[4-[bis(2,4-difluorophenyl)hydroxymethyl]-1-piperidinyl]- propoxy}-3-methoxyphenyllethanone, d) 1-[4-[3-[4-[bis[3-(trifluoromethyl)phenyl]hydroxymethyl]-1- piperidinyllpropoxy]-3-methoxyphenyljethanone, and e) 1-[4-[3-[4-[bis[4-(trifluoromethyl)phenyl]hydroxymethyl}-1- piperidinyllpropoxy)-3-methoxyphenyljethanone with (1) potassium hydride and (2) iodoethane; there are obtained: : a) 1-[4-[3-[4-[bis(3,4-difluorophenyl)ethoxymethylimethyl]-1- piperidinyllpropyl]-2-methoxyphenoxyjethanone, b) 1-[4-[3-[4-[bis(2,5-difluorophenyl)ethoxymethylimethyl]-1- piperidinyl]propyl}-2-methoxyphenoxylethanone, ok : ¢) 1-[4-[3-[4-[bis(2,4-difluorophenyl)ethoxymethyllmethyl]-1- piperidinyl)propyll-2-methoxyphenoxylethanone, d) 1-[4-[3-[4-[bis[3-(trifluoromethyl)phenyljethoxymethyllmethyl)-1- piperidinyllpropyl}-2-methoxyphenoxylethanone, and e) 1-[4-[3-[4-[bis[4-(trifluoromethyl)phenyllethoxymethylimethyl]-1- piperidinyl)propyl]-2-methoxyphenoxylethanone.
Example 202 -
Utilizing the procedure of Example 129 and substituting the following for a,a-bis(4-fluorophenyl)-4-piperidineacetonitrile: a) a,a-bis(3,4-difluorophenyl)-4-piperidineacetonitrile,
} \ =~ -215- b) a,a-bis(2,5-difluorophenyl)-4-piperidineacetonitrile, ¢) a,a-bis(2,4-difluorophenyl)-4-piperidineacetonitrile, d) a,a-bis(3-(trifluoromethyl)phenyl)-4-piperidineacetonitrile, and e) a,a-bis[4-(trifluoromethyl)phenyl])-4-piperidineacetonitrile : there are obtained: ; a) 1-[3-(4-acetyl-2-methoxyphenoxy)propyl]-a,a-bis(3,4-difluoro- phenyl)-4-piperidineacetonitrile maleate, b) 1-[3-(4-acetyl-2-methoxyphenoxy)propyl}-a,a-bis(2,5-difluoro- phenyl)-4-piperidineacetonitrile maleate, ¢) 1-[3-(4-acetyl-2-methoxyphenoxy)propyl}-a,a-bis(2,4-difluoro- phenyl)-4-piperidineacetonitrile maleate, d) 1-[3-(4-acetyl-2-methoxyphenoxy)propyll-a,a-bis[3-(trifluoro- methyl)phenyl]-4-piperidineacetonitrile maleate, and ~~ e) 1-[3-(4-acetyl-2-methoxyphenoxy)propyl]-a,a-bis[4-(trifluoro- methyl)phenyl]-4-piperidineacetonitrile maleate. .
Example 203
Utilizing Method G, supra, and reacting the following compounds with lithium aluminum hydride: : a) 1-[3-(2-methoxyphenoxy)propyll-a,a-bis(3,4-difluorophenyl)-4- piperidineacetonitrile, b) 1-[3-(2-methoxyphenoxy)propyl}-a,a-bis(2,5-difluorophenyl)-4- piperidineacetonitrile, ¢) 1-[3-(2-methoxyphenoxy)propyl)-a,a-bis(2,4-difluorophenyl)-4- piperidineacetonitrile, d) 1-[3-(2-methoxyphenoxy)propyl]-a,a-bis[3-(trifluoromethyl)- phenyl]-4-piperidineacetonitrile, and e) 1-[3-(2-methoxyphenoxy)propyll-a,a-bis{4-(trifluoromethyl)- phenyl)-4-piperidineacetonitrile there are obtained: a) 1-[3-(2-methoxyphenoxy)propyl]-4-[bis(3,4-difluorophenyl)- (aminomethyl)methyl)piperidine,
“\ - : -216- b) 1-[3-(2-methoxyphenoxy)propyl}-4-[bis(2,5-difluorophenyl)- (aminomethyl)methyl]piperidine, . ¢) 1-[3-(2-methoxyphenoxy)propyl}-4-[bis(2,4-difluorophenyl)- (aminomethyl)methyl]piperidine, d) 1-(3-(2-methoxyphenoxy)propyl]-4-[bis(3-(trifluoromethyl)- phenyll(aminomethyl)methyl)piperidine, and e) 1-[3-(2-methoxyphenoxy)propyl]-4-[bis[4-(trifluoromethyl)- phenyl}(aminomethyl)methyl]piperidine.
Example 204
Utilizing Method H, supra, and reacting the following compounds: a) 1-[3-(4-acetyl-2-methoxyphenoxy)propyll-a,a-bis(3,4-difluoro- phenyl)-4-piperidineacetonitrile, b) 1-[3-(4-acetyl-2-methoxyphenoxy)propyl}-a,a-bis(2,5-difluoro- phenyl)-4-piperidineacetonitrile, ¢) 1-[3-(4-acetyl-2-methoxyphenoxy)propyl}-a,a-bis(2,4-difluoro- phenyl)-4-piperidineacetonitrile, d) 1-[3-(4-acetyl-2-methoxyphenoxy)propyl]-a,a-bis[3-(trifluoro- \ methyl)phenyl]-4-piperidineacetonitrile, and : e) 1-[3-(4-acetyl-2-methoxyphenoxy)propyll-a,a-bis[4-(trifluoro- methyl)phenyl]-4-piperidineacetonitrile stepwise with (1) potassium hydroxide, water and heating and (2) acid; there are obtained: a) a,a-bis(3,4-difluorophenyl)-1-[3-(4-acetyl-2-methoxyphenoxy)- : propyl)-4-piperidineacetic acid, b) a,a-bis(2,5-difluorophenyl)-1-[3-(4-acetyl-2-methoxyphenoxy)- propyl)-4-piperidineacetic acid, c) a,a-bis(2,4-difluorophenyl)-1-(3-(4-acetyl-2-methoxyphenoxy)- propyl]-4-piperidineacetic acid, d) a,a-bis[3-(trifluoromethyl)phenyl]}-1-[3-(4-acetyl-2-methoxy- phenoxy)propyl]-4-piperidineacetic acid, and e) a,a-bis[4-(trifluoromethyl)phenyl}-1-[3-(4-acetyl-2-methoxy- phenoxy)propyl)-4-piperidineacetic acid.
Example 205 .
Utilizing Method I, supra, and reacting the following compounds: a) 1-[4-[3-[4-[bis(3,4-difluorophenyl)hydroxymethyl]-1-piperidinyl}- propoxyl-3-methoxyphenyljethanone, b) 1-[4-[3-[4-[bis(2,5-difluorophenyl)hydroxymethyl]-1-piperidinyl]- propoxy]-3-methoxyphenyllethanone, ¢) 1-[4-[3-[4-[bis(2,4-difluorophenyl)hydroxymethyl]-1-piperidinyl]- . propoxy]-3-methoxyphenyllethanone, d) 1-[4-[3-[4-[bis[3-(trifluoromethyl)hydroxymethyl]-1-piperidinyl)- propoxyl-3-methoxyphenyllethanone, and e) 1-[4-[3-[4-[bis[4-(trifluoromethyDhydroxymethyl]-1-piperidinyl]}- propoxy]-3-methoxyphenyllethanone ‘with acetic anhydride there are obtained: oo a) a,a-bis(3,4-difluorophenyl)-1-[3-(4-acetyl-2-methoxyphenoxy)- propyll-4-piperidinemethanol ethanoate (ester), ~~ b) a,a-bis(2,5-difluorophenyl)-1-[3-(4-acetyl-2-methoxyphenoxy)-
C20 ~ propyll-4-piperidinemethanol ethanoate (ester), = ¢) a,a-bis(2,4-difluorophenyl)-1-[3-(4-acetyl-2-methoxyphenoxy)- :
SE ~ propyll-4-piperidinemethanol ethanoate (ester), oo d) a,a-bis(3-(trifluoromethyl)phenyl])-1-[3-(4-acetyl-2-methoxy- . phenoxy)propyl]-4-piperidinemethanol ethanoate (ester), and e) a,a-bis[4-(trifluoromethyl)phenyl)-1-[3-(4-acetyl-2-methoxy- phenoxy)propyl]-4-piperidinemethanol ethanoate (ester).
Example 206
Utilizing the procedure of Example 66 and substituting the following compounds for a,a-bis(p-flucrophenyl)-4-piperidinemethanol: a) a,a-bis(3,4-difluorophenyl)-4-piperidineacetic acid ethyl ester, b) a,a-bis(2,5-difluorophenyl)-4-piperidineacetic acid ethyl ester, ¢) a,a-bis(2,4-difluorophenyl)-4-piperidineacetic acid ethyl ester, :
ND iw -218- d) a,a-bis[3-(trifluoromethyl)phenyl}-4-piperidineacetic acid ethyl ester, e) a,0-bis[4-(trifluoromethyl)phenyl]-4-piperidineacetic acid ethyl ester, fH 1,1-bis(3,4-difluorophenyl)-1-(4-piperidinyl)-2-butanone, g) 1,1-bis(2,5-difluorophenyl)-1-(4-piperidinyl)-2-butanone, h) 1,1-bis(2,4-difluorophenyl)-1-(4-piperidinyl)-2-butanone, i) 1.1-bis[3-(trifluoromethyl)phenyl}-1-(4-piperidinyl)-2-butanone, and 1 1,1-bis[4-(trifluoromethyl)phenyl]-1-(4-piperidinyl)-2-butanone there are obtained: : a) a,0-bis(3,4-difluorophenyl)-1-(3-(4-acetyl-2-methoxyphenoxy)- propyl}-4-piperidineacetic acid ethyl ester, b) @,0-bis(2,5-difluoropheny)-1-[3:(4-acetyl-2:methoxyphenoxy)- : propyll-4-piperidineacetic acid ethyl ester, c) a,0-bis(2,4-difluorophenyl)-1-(3-(4-acety]-2-methoxyphenoxy)- propyl)-4-piperidineacetic acid ethyl ester, d) a,a-bis[3-(trifluoromethyl)phenyl]-1-[3-(4-acetyl-2-methoxy- phenoxy)propyl]-4-piperidineacetic acid ethyl ester, e) a.0-bis[4-(trifluoromethyl)phenyl)-1-(3-(4-acetyl-2-methoxy- phenoxy)propyl]-4-piperidineacetic acid ethyl ester, f) 1.1-bis(3,4-difluorophenyl)-1-{1-[3-(4-acetyl-2-methoxyphenoxy)- 25 . propyl}-4-piperidinyl}-2-butanone, g) L,1-bis(2,5-difluorophenyl)-1-{1-[3-(4-acetyl-2-methoxyphenoxy)- propyl}-4-piperidinyl]-2-butanone, h) 1.1-bis(2,4-difluorophenyl)-1-[1-[3-(4-acetyl-2-methoxyphenoxy)- propyl]-4-piperidinyl]-2-butanone, i) 1,1-bis[3-(trifluoromethyl)phenyl)-1-[1-[3-(4-acetyl-2-methoxy- phenoxy)propyl]-4-piperidinyl]-2-butanone, and
J) 1,1-bis[4- (trifluoromethyl phenyl)-1-[1-[3-(4-acetyl-2-methoxy- phenoxy)propyl]-4-piperidinyl}-2-butanone.
Example 207 1] 3-(4-Acetyl-2-methoxyphenoxy)propyl l-a,a-bis(3-fluorophenyl)-4- piperidinemethanol.
This compound was prepared according to the procedure used to syn- thesize the compound of Example 1. A mixture of 3.0 g (0.01 mole) of 4- [a,a,bis(4-fluorophenyl)hydroxymethyllpiperidine, 2.4 g (0.01 mole) of 1-[4- (3-chloropropoxy)-3-methoxyphenyljethanone, 3.7 g (0.035 mole) of anhy- drous sodium carbonate and 0.4 g of potassium iodide in 100 mL of 1-butanol gave 3.6 g (71%) of the title compound as an off-white solid, m.p. 149-151°C (absolute ethanol).
Analysis: Calculated for CaoH35F2NOy4: C, 70.71; H, 6.53; N, 2.75
Found : C,70.66;H,6.53;N, 2.79
Example 208 [[4-[3-[4-] Bis(4-fluorophenyl )hydroxymethyl)-1-piperidinyl Ipropoxy)- phenyljaminojoxoacetic acid ethyl ester fumarate [1:0.5].
To a solution of 2.4 g (0.0054 mole) of the free base of 1-[3-(4-amino- phenoxy)propyl)-a,a-bis(4-fluorophenyl)-4-piperidinemethanol oxalate [1:2] and 1.5 g (0.015 mole) of triethylamine in 50 mL of benzene was added ~~ dropwise a solution of 1.0 g (0.008 mole) of ethyl oxalyl chloride in 10 mL of benzene, and the mixture was stirred at ambient temperature overnight.
The mixture was treated with 20 mL of water and vigorously stirred. The layers were separated, and the organic layer was washed with a saturated sodium bicarbonate solution, dried over sodium sulfate and concentrated to . give a gum as residue. The gum was dissolved in ethyl ether and filtered to remove insolubles. The filtrate was concentrated, and the gummy residue was converted to the fumaric acid salt. The salt was recrystallized from ~ absolute ethanol-water to yield 1.1 g (33%) of the title compound as a white solid, mp 215-216°C (dec.) :
Analysis: Calculated for CazHagFgN207 : C, 64.91; H, 5.94; N, 4.59
Found : C,64.62;H,5.90; N, 4.59
Example 209 } a,a-Bis( d-fluorophenyl)-1.[3-(2-methoxy-4-methylphenoxy)propyl ]-4- piperidinemethanol.
This compound was prepared according to the procedure used to synthesize the compound of Example 1. A mixture of 4.5 g (0.015 mole) of [a,a-bis (4-fluorophenyl)]-4-piperidinemethanol, 3.2 (0.015 mole) of 1- chloro-3-(2-methoxy-4-methylphenoxy)propane, 9.3 g (0.05 mole) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 mL of 1- butanol gave 5.4 g (75%) of the title compound as a white solid, mp 121-122°C (2-propanol).
Analysis: Calculated for C29H33FoNO3 C,72.33; H, 6.91; N, 2.91
Found : C,72.34; H, 6.95; N, 2.90 :
Example 210 1-(2-[3-] 4-Bis(4-fluorophenyhydroxymethyl -1-piperidinyl |propoxyl- phenyllethanone. - This compound was prepared according to the procedure used to synthesize the compound of Example 1. A mixture of 3.0 g (0.01 mole) of [a,a- bis(4-fluorophenyl)[-4-piperidinemethanol, 2.1 g (0.01 mole) of 2'-(3-chloro- pPropoxy)acetophenone, 3.7 g (0.035 mole) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 mL of 1-butanol gave 3.4 g (71%) of the title compound as a white solid, mp 113-114°C. .
Analysis: Calculated for CogH3FoNO; C,72.63; H, 6.52; N, 2.92
Found : C,72.54; H, 6.56; N, 2.94 ? Example 211 1-[3-[3-[4-] Bis(4-fluorophenyl Jhydroxymethyl]- 1-piperidinyl |propoxy]- phenyllethanone oxalate hydrate [1:1:1].
This compound was prepared according to the procedure used to synthesize the compound of Example 1. A mixture of 3.0 g (0.01 mole) of [q,a- bis(4-fluorophenyl))-4-piperidinemethanol, 2.1 (0.01 mole) of 3'-(3-chloro- propoxy) acetophenone, 13.7 g (0.035 mole) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 mL of 1-butanol gave a gum as residue.
The gum was converted to the oxalic acid salt, and the solid was recrystal- :
lized from 2-propanol to yield 4.4 g (75%) of the title compound as a tan solid, mp 95-100°C.
Analysis: Calculated for C31H35FaNOg C, 63.36; H, 6.00; N, 2.38
Found + C,62.94; H, 6.02; N, 2.20
Example 212 a,a-Bis(4-fluorophenyl)-1.| 3-(3-methoxyphenoxy)propyl ]-4-piperidine- methanol.
This compound was prepared according to the procedure used to synthesize the compound of Example 1. A mixture of 3.0 g (0.01 mole) of [a,a- bis(4-fluorophenyl)}-4-piperidinemethanol. 2.0 g (0.01 mole) of 1-chloro-3-(3- methoxyphenoxy)propane, 3.7 g (0.035 mole) of anhydrous sodium carbonate - and 0.4 g of potassium iodide in 100 mL of 1-butano] gave 3.1 g (66%) of the title compound as a white solid, mp 107-108°C (2-propanol).
Analysis: Calculated for CogH31F2NO3 : C, 71.93; H, 6.68; N, 3.00 i} Found : C,71.90;H, 6.70; N, 3.01 : BE Example 213 1] 3-(4-Ethylphenoxy)propyl)-a.a-bis( 4-fluorophenyl)-4-piperidine- 200 ‘methanol oxalate [1:1].
This compound was prepared according to the procedure used to synthesize the compound of Example 1. A mixture of 3.0 g (0.01 mole) of [a,a- bis(4:fluorophenyl)lpiperidinemethanol, 2.0 g (0.01 mole) of 1-chloro-3-(4- ethylphenoxy)propane, 3.7 g (0.035 mole) of anhydrous sodium carbonate and 05 * 0.4 g of potassium iodide in 100 mL of 1-butanol gave a solid as residue. This solid was converted to the oxalic acid salt, and the salt was recrystallized from 2-propanol to yield 3.0 8 (54%) of the title compound as a white solid, mp 132-135°C.
Analysis: Calculated for C31H35F3NOg C,67.01; H, 6.35; N, 2.52
Found : GC, 66.60; H, 6.32; N, 2.31
Example 214 1:(3-(2-Ethoxyphenoxy)propyl |-a.0-bis(4-fluorophenyl)-4-piperidine.- methanol.
This compound was prepared according to the procedure used to synthesize the compound of Example 1. A mixture of 3.0 g (0.01 mole) of [a,a- bis(4-fluorophenyl)}-4-piperidinemethanol, 2.1 g(0.01 mole) of 1-chloro-3-(2- ethoxyphenoxy)propane, 3.7 g (0.035 mole) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 mL of 1-butanol gave 3.6 g (75%) of the title compound as an off-white solid, mp 89-91°C (petroleum ether, 60-110°C).
Analysis: Calculated for Co9H33F3NO; C, 72.33; H, 6.91; N, 2.91
Found : C,72.39;H,6.90; N, 2.96
Example 215 a.a-Bis( 4-fluorophenyl)-1-| 3-(2-methylphenoxy)propyl l-4-piperidine- methanol.
This compound was prepared according to the procedure used to synthe- size the compound of Example 1. A mixture of 3.0 g (0.01 mole) of [a,a-bis(4- fluorophenyl)]-4-piperidinemethanol, 1.8 g (0.01 mole) of 1-chloro-3-(2- methylphenoxy)propane, 3.7 g (0.035 mole) of anhydrous sodium carbonate and 0.4 g of potassium jodide in 100 mL of 1-butanol gave 2.5 g (56%) of the title compound as a white solid, mp 108.5-109°C (petroleum ether, 60-110°C).
Analysis: Calculated for C2sH31FaNOg C,74.48;H, 6.92; N,3.10
Found : C,74.57;H, 6.92; N, 3.11 } Example 216 9.0-Bis(4-fluorophenyl)-1.(3-(3-methylphenoxy)propyl]-4- piperidine. methanol.
This compound was prepared according to the procedure used to syntheisze the compound of Example 1. A mixture of 3.0 g (0.01 mole) of a,a- bis(4-fluorophenyl))-4-piperidinemethanol, 1.8 g (0.01 mole) of 1-chloro-3-(3- methylphenoxy)propane, 3.7 (0.035 mole) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 mL of 1-butanol gave 2.8 g (62%) of the title compound as a white solid, mp 112.5-114°C (2-propanol).
Analysis: Calculated for CogH3 1 FoNO, C,74.48,H,6.92: N, 3.10
Found : C,74.44;H, 6.95; N,3.15
~ -223. a,a-Bis( 4-fluorophenyl)- 1-[3-(2-phenylmethoxy)phenoxylpropyl.4. piperidinemethanol fumarate [1:1].
This compound was prepared according to the procedure used to synthe- size the compound of Example 1. A mixture of 7.6 g (0.025 mole) of a,a-bis(4- fluorophenyl)]-4-piperidinemethanol, 6.9 g (0.025 mole) of 1-chloro-3-(2- benzyloxyphenoxy)propane, 8.5 g (0.08 mole) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 150 mL of 1-butanol gave a gum as residue.
The gum was converted to the fumaric acid salt, and the solid was recrystal- lized from acetonitrile to yield 10.5 g (64%) of the title compound as an off- ~ white solid, mp 172-174°C.
Analysis: Calculated for C3gH39FsNO; C,69.18;H,5.96;N, 2.12
Found : C,69.15; H, 5.92; N, 2.19
Example 218 a.a-Bis(4-fluorophenyl)- 1-[ 3-(2-hydroxyphenoxy )propyl]-4-piperidine- methanol fumarate [1:1] with ethyl acetate [1:1]. '
A solution of 6.1 g (0.011 mole) of a,a-bis(4-fluorophenyl)-1-[3-[2- : (phenylmethoxy)phenoxylpropyl)-4-piperidinemethanol dissolved in 200 mL of absolute ethanol was hydrogenated in a Parr apparatus over 5% palladi um . on carbon catalyst at 60°C overnight. The cooled mixture was filtered through Celite®, and the filtrate was concentrated to give a gum as residue.
The dark gum was dissolved in ethyl ether and filtered to remove insolubles. * The filtrate was concentrated to give 2.8 g of tan gum as residue. The gum was dissolved in ethyl acetate and mixed with an equivalent amount of fumaric acid dissolved in ethyl acetate. The solution was filtered, and a solid crystallized from the filtrate. The solid was collected by filtration and dried to yield 2.3 g (32%) of the title compound as a white solid, mp 106-116°C (dec).
The presence of 1 mole of ethyl acetate was confirmed by !H NMR.
Analysis: Calculated for C31H33F2NO7C4HgO5 : C,63.92;H,6.28;N, 2.13
Found : C,63.62; H, 6.08; N, 2.24
Example 219 a,a-Bis(4-Fluorophenyl)-1-[3-[2-( 1-methylethoxy)phenoxylpropyl]-4- piperidinemethanol.
This compound was prepared according to the procedure used to synthesize the compound of Example 1. A mixture of 3.0 € (0.01 mole) of [a,a- bis(4-fluorophenyl)]-4-piperidinemethanol, 2.3 g (0.01 mole) of 1-chloro-3-[2- (1-methylethoxy)phenoxy]propane, 3.7 g (0.035 mole) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 mL of 1-butanol gave 2.9 g (58%) of the title compound as a fluffy, white solid, mp 75-79°C (2-propyl ether).
Analysis: Calculated for C30H35F2NO3 : C,72.70;H, 7.12; N, 2.83
Found : C,72.65;H,7.47;:N, 2.69 :
Example 220
Co .., 43:(4-[Bis(4-fluorophenyDhydroxymethyl]-1-piperidinyl]propoxy]- Co
Fors benzeneacetic acid ethyl ester oxalate [1:1] with ethyl acetate [1:0.5].
This compound was prepared according to the procedure used to syn- thesize the compound of Example 1. A mixture of 7.6 g (0.025 mole) of [a,a- bis(4-fluorophenyl)}-4-piperidinemethanol, 6.1 g (0.025 mole) of 4-(3-chloro- propoxy)benzeneacetic acid methyl ester, 9.5 g (0.09 mole) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 150 mL of dimethyl- formamide gave a gum as residue. The gum was purified by column chroma- tography on 250 g of Florisil®. Fractions eluted with 5-25% acetone in ben- zene were combined and concentrated to give a gum as residue. The gum was - converted to the oxalic acid salt, and the solid was recrystallized from ethyl acetate to yield 7.0 g (43%) of the title compound as a white solid, mp 93-98°C (dec).
Analysis: Calculated for C32H35F2NOg0.5C4HgO03: C, 63.44; H, 6.10; N, 2.18
Found :C, 63.00; H,5.99; N, 2.23
Example 221 4-[3-[4-[Bis(4-fluorophenyl)hydroxymethyl ]-1-piperidinyl]propoxy]-
N.N-dimethylbenzamide fumarate [1:1].
This compound was prepared according to the procedure used to syn- thesize the compound of Example 1. A mixture of 3.0 g (0.01 mole) of [a,a-
bis(4-fluorophenyl)]-4-piperidinemethanol, 2.4 g (0.01 mole) of 4-(3-chloro- propoxy)-N, N-dimethylbenzamide, 3.7 g (0.035 mole) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 mL of 1-butanol gave a gum as residue. The gum was converted to the fumaric acid salt, and the solid was recrystallized from acetonitrile-water to yield 4.0 g (65%) of the title com- pound as a white solid, mp 166-168°C.
Analysis: Calculated for C34H3gF9eN2O7 : C, 65.37: H, 6.13; N, 4.48
Found : C,65.21;H,6.12; N, 4.45
Example 222 1-[3-(2,6-Dimethoxyphenoxy)propyl l-a,a-bis(4-fluorophenyl)-4- piperidinemethanol. :
This compound was prepared according to the procedure used to syn- thesize the compound of Example 1. A mixture of 3.0 g (0.01 mole) of [a,a- bis(4-fluorophenyl)]-4-piperidinemethanol, 2.3 g (0.01 mole) of 1-(3-chloro- propoxy)-2,6-dimethoxybenzene, 3.7 g (0.035 mole) of anhydrous sodium Co carbonate and 0.4 g of potassium iodide in 100 mL of 1-butanol gave2.0g (40%) of the title compound as a white solid, mp 136-137°C (2-propyl ether/2- propanol). © Analysis: Calculated for C29H33F2NO4: C, 70.00; H, 6.68; N, 2.81 © Found : C,70.15;H,6.78: N, 2.85
Example 223 [4-[3-4-] Bis(4-fluorophenylhydroxymethyl ]-1-piperidinyl]propoxy]- ~ phenyl]phenylmethanone fumarate [1:1].
This compound was prepared according to the procedure used to synthe- size the compound of Example 1. A mixture of 3.0 g (0.01 mole) of [a,a-bis(4- fluorophenyl)}-4-piperidinemethanol, 2.7 g (0.01 mole) of [4-(3-chloropro- poxy)phenyllphenylmethanone, 3.7 g (0.035 mole) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 mL of 1-butanol gave a gum as residue. The gum was converted to the fumaric acid salt, and the solid was recrystallized from absolute ethanol to yield 4.3 g (65%) of the title compound as a tan solid, mp 200-201°C (dec). oo - oo co
Analysis: Calculated for C3gH37FeNO7: C, 69.39; H, 5.67; N, 2.13
Found : C,69.36;H,5.63;N, 2.17
Example 224 1 4-[3-[4-[Bis(3,4-difluorophenyl) hydroxymethyl ]-1-piperidinyl]- propoxy]-3-methoxyphenyljethanone.
The compound was prepared according to the procedure used to synthe- size the compound of Example 1. A mixture of 1.4 g (0.004 mole) of a,a- bis(3,4-difluorophenyl)-4-piperidinemethanol, 1.0 g (0.004 mole) of 1-[4-(3- chloropropoxy)-3-methoxyphenyllethanone, 1.6 g (0.015 mole) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 mL of 1-butanol gave 1.1g (48%) of the title compound as an off-white solid, mp 143-146°C (2- propanol).
Analysis: Calculated for C30H31F4NOy4: CC, 66.05; H, 5.73; N, 2.57 :
Found : C,66.03;H,5.89; N, 2.50
Example 225 4-[3-[4-[Bis(4-fluorophenyDhydroxymethyl):1-piperidinyl]propoxy ]- benzeneacetic acid hydrate [1:0.5].
A mixture of 3.7 g (0.0073 mole) of the free base of 4-[3-[4-[bis(4-Nuoro- phenyl)hydroxymethyl)-1-piperidinyllpropoxyJbenzeneacetic acid ethyl ester oxalate [1:1], 0.8 g (0.0145 mole) of potassium hydroxide, 10 mL of water and 50 mL of 95% ethanol was heated at reflux under a nitrogen atmosphere for 1.5 hr. The solution was poured into a mixture of 1.3 g (0.022 mole) of glacial acetic acid in 500 mL of ice-water and let stand at ambient temperature over : night. The solid which had precipitated was collected by filtration, washed © with water, air dried, and recrystallized from 2-propanol to yield 2.9 g (78%) of the title compound as a white solid, mp 113-121°C (dec).
Analysis: Calculated for CogH32F3NOy45: C, 69.03; H,6.39;: N, 2.78
Found : C,69.35;H,6.43:N, 2.74 : Example 226 1-[4-[3-(3-[Bis(4-fluorophenyl)hydroxymethyl |-1-piperidinyl]propoxy]- 3-methoxyphenyllethanone.
The compound was prepared according to the procedure used to synthe- size the compound of Example 1. A mixture of 3.0 g (0.01 mole) of a,a-bis(4- fluorophenyl)-3-piperidinemethanol, 2.4 g (0.01 mole) of 1-(4-(3-chloropro-
» wo -227- poxy)-3-methoxyphenyllethanone, 3.7 g (0.035 mole) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 mL of 1-butanol gave 4.0 g (78%) of the title compound as an off-white solid, mp 100-105°C (2-propanol).
Analysis: Calculated for CaoH33F2NO4: C, 70.71; H,6.53; N, 2.75
Found : C,70.62;H,6.61;N, 2.77
Example 227 1-[4-{3-[3-] 2,2-Bis(4-fluorophenyl)-2-hydroxyethyl ]-1-piperidinyl]- propoxy)-3-methoxyphenyllethanone fumarate [1:1].
This compound was prepared according to the procedure used to syn- thesize the compound in Example 1. A mixture of 3.7 g (0.012 mole) of the free base of [a,a-bis(4-fluoropheny))]-3-piperidineethanol hydrochloride [1:1], 2.8 g (0.012 mole) of 1-(4-(3-chloropropoxy)-3-methoxyphenyllethanone, 4.3 g (0.04 mole) of anhydrous sodium carbonate and 0.5 g of potassium iodide in 100 mL of 1-butanol gave a gum as residue. The gum was purified by column chromatography on 120 g of Florisil®. Fractions eluted with 20-60% acetone in benzene were combined and concentrated to give a gum. This gum was converted to the fumaric acid salt, and the solid was recrystallized from ethyl acetate - acetonitrile to yield 2.6 g (35%) of the title compound as white solid, mp 133-136°C. :
Analysis: Calculated for C35H3gFaNOg: C, 65.72; H, 6.15; N. 2.19
Found : C,65.41:H,6.15:N, 2.18
Example 228 1-(4-[3-[3-[Bist 4-tluorophenylhhydroxymethyl |-1-pvrrolidinvlipropoxv]- 3-methoxvphenyllethanone.
A mixture of 2.9 g (0.01 mole) of a,a-bis(4-fluoropheny!)-3-pyrrolidine- methanol, 2.4 g (0.01 mole) of 1-(4-(3-chloropropoxy)-3-methoxyphenyl- ethanone, 5.3 g (0.05 mole) of anhydrous sodium carbonate and 0.3 g (0.002 mole) of potassium iodide in 100 mL of 1-butanol was heated at reflux for 24 hr. The mixture was concentrated under reduced pressure, and the residue partitioned between 100 mL of benzene and 100 mL of water. The benzene layer was washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure to give a brown gum. The gum was 3 purified by column chromatography on 80 g of Florisil® using a gradient
. -228- elution system of 0-10% acetone in benzene. The fractions containing the desired product were combined and concentrated under reduced pressure to give 3.2 g of a brown gum. This gum was further purified by high-pressure : liquid chromatography (Waters Associates Prep LC/System 500A; Preppac 500 silica; 1% methanol in methylene chloride; flow rate 150 mL/min). The fractions containing the desired product were combined and concentrated under reduced pressure to yield 1.7 g (34% yield) of the title compound as a light-yellow, glassy solid, mp 44-46°C.
Analysis: Calculated for Co9H3;FgNO4: C, 70.29: H, 6.31; N, 2.83
Found : C,69.60;H,6.26; N, 2.86
Example 229 : [[4-[3-[4-[Bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]propoxy]- phenyl]aminoloxoacetic acid ethyl ester. :
To a solution of 4.5 g (0.01 mole) of the base of 1-[3-(4-aminophenoxy)- propyl}-a,a-bis(4-flucrophenyl)-4-piperidinemethanol (free base obtained in
Preparation 133), and 1.5 g (0.015 mole) of triethylamine in 50 mL of benzene is added dropwise a solution of 1.4 g (0.01 mole) of ethyloxolyl chloride in 10 mL of benzene. The mixture is stirred at ambient temperature for 3 hr and then treated with 50 mL of water. The layers are separated and the organic ‘layer is washed with brine, dried over sodium sulfate, and concentrated to : give the title compound.
Example 230 : 1[4-(3-(4-{Bis(4-fluorophenyllhvdroxymethyll-1-piperidinyl]propoxy]- phenvlaminol-oxoacetic acid.
A solution of [[4-[3-(4-[Bis(4-fluorophenyl)hydroxymethyl)-1-piperi- dinyl]propoxyjphenylJamino]oxoacetic acid ethyl ester in 50 m) of ethanol is treated with 20 ml of a 2N sodium bicarbonate solution and the mixture is heated at reflux overnight. The mixture is cooled and poured into 500 ml of water containing 10 ml of acetic acid. The resulting solution is collected by filtration and dried to give the title compound.
Example 231 a,a-Bis(4-fluorophenyl)-1-[3-[4-(dimethylamino)phenoxylpropyl]-4-’ piperidinemethanol.
A solution of 4.8 g (0.01 mole) of a,a-bis(4-fluorophenyl)-1-[3-(4-nitro- phenoxy)propyl-4-piperidinemethanol (obtained in Example 52) and 2.0 g (0.025 mole) of 37% formalin in 100 ml of absolute ethyl alcohol is hydro- genated at ambient temperature over 5% palladium on carbon catalyst overnight. The mixture is filtered through Celite® and the filtrate is concentrated to give the title compound.
Example 232 1-[4-[3-[4-[Bis(4-fluoropheny)hydroxymethyl)-1-piperidinyl]propoxy)- . phenyl}-2,2-dimethyl-1-propanone.
A mixture of 3.0 g (0.01 mole) of a,a-bis(p-fluorophenyl)-4-piperidine- methanol, 2.5 g (0.01 mole) of [4-(3-chloropropoxy)phenyl][t-butyl]ketone, 3.7 g (0.035 mole) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 ml of 1-butanol is heated to reflux overnight. The mixture is concen- trated and the residue is partitioned between benzene and water. The organic layer is dried over sodium sulfate and concentrated to give the ~ desired title compound.
Example 233 1-[4-[3-[4-[Aminobis(4-fluorophenvl)methyl]-1-piperidinyl]-3-methoxy- plicnyliethanene fumarate hydrate [1:21].
A mixture of 7.65 g (0.023 mole) of a,a-bis(4-fluorophenyl)-4-piperidine- acetamide, 2.17 g (0.023 mole) of methyl chloroformate in 400 ml of methylene chloride at room temperature was stirred overnight. The mixture was extracted with dilute sodium hydroxide and was dried over sodium sulfate. The solvent was removed in vacuo to give 5.95 g (66.6%) of 4-[2- amino-1,1-bis(4-fluorophenyl)-2-oxoethyl}-1-piperidinecarboxylic acid methyl ester as a white solid, mp 126-129°C.
Analysis: Calculated for C2) H2oN203F3 : C,64.94;H,5.71; N, 7.21
Found : C,64.83;H,5.97; N, 6.92
-230- Fasee poms
To a magnetically stirred solution of 3.88 g (0.01 mole) of 4-[2-amino-1,1- bis(4-fluorophenyl)-2-oxoethyl]-1-piperidinecarboxylic acid methyl ester and . 4.0 g (0.05 mole) of 50% sodium hydroxide solution in 40 ml of methanol at room temperature was added dropwise a solution of 4.04 g (0.025 mole) of bromine in 25 ml of methanol. The mixture was heated at reflux for 16 h.
The solvent was removed in vacuo, and the residue was partitioned between chloroform and water. The organic layer was dried (sodium sulfate), and the solvent was removed in vacuo to give 3.60 g (86.1%) of 4-[bis(4-fluorophenyl)- (methoxycarbonyl) aminomethyl]-1-piperidinecarboxylic acid methyl ester.
A pure sample was prepared by subjecting 0.26 g of this material to flash chromatography (silica gel, elution with a 50/50 mixture of ethylacetate- hexanes) to give 0.13 g of a white solid, mp 213°C.
Analysis: Calculated for CoogHo4N2O4F2 : C,63.15;H,5.78; N, 6.70 ~ Found : C,62.64;H,5.81;N, 6.53 . A mixture of 2.98 g (7.1 mmole) of 4-[bis(4-fluorophenyl) (methoxycarbonyl) i ‘ aminomethyl)-1-piperidinecarboxylic acid methyl ester and 20.0 g(0.25 mole) of 50% sodium hydroxide solution (w/w) in 40 ml,of methanol was heated at reflux overnight. Water (100 ml) was added, and the mixture was extracted with chloroform. The organic phase was dried (sodium sulfate), and the solvent was removed in vacuo to give an 1.92 g (89.5%) of a,a-bis(4- fluorophenyl)-4-piperidinemethanamine as a yellow oil: 1H NMR (CDCl3) 51.0-1.9 (m, 7H, CHg at 3 and 5 position of piperidine ring, NH and NH), 2.2- 1.2 (m, 5H, CHoNCHj3 and CH), 6.8-7.6 (m, 8H, aromatic); CIMS, m + 1/e 303, 25 . 286. A small sample was converted to the oxalate salt, and the salt was recrystallized from methanol/ether to give a,a-bis(4-fluorophenyl)-4-piperi- dinemethanamine ethanedioate hemihydrate [1:2:0.5] as a white crystalline solid, mp 151-154°C.
Analysis: Calculated for CogHo4NgF20g°0.5H20 : C,53.77; H, 5.13; N, 5.70
Found : C,53.39;H,5.20; N, 6.04
A mixture of 7.34 g (0.0243 mole) of a,a-bis(4-fluorophenyl)-4-piperidine- methanamine, 5.88 g (0.0243 mole) of 1-{4-(3-chloropropoxy)-3-methoxy- phenyllethanone and 5.53 g (0.04 mole) of potassium carbonate in 500 ml of 1-butanol containing 0.2 g of potassium iodide was heated at reflux over-
D
-231- Ann-4v0on-wis night. The solvent was removed in vacuo, and the residue was partitioned between chloroform and dilute sodium hydroxide. The organic layer was" dried (sodium sulfate) and the solvent was removed in vacuo to give 12.94 g of the nonsalt form of the title compound. This was converted to the fumarate salt, and the salt was recrystallized from methanol/ether to give 11.25 g (61.0%) of the title compound as a pale yellow solid, mp 124-128°C.
Analysis: Calculated for C3sH44N2012F2 : C, 60.15; H, 5.84; N, 3.69
Found : C,59.84;H,5.56;N, 3.56
Example 234
N-[[1-[3-(4-Acetyl-2-methoxyphenoxy)propyl]-4-piperidinyl]bis(4- fluorophenyl)methyl]acetamide.
A mixture of 3.53 g (6.95 mmole) of 1-[4-[3-[4-[aminobis(4-fluoro- phenyl)methyl]-1-piperidinyl]-3-methoxyphenyllethanone, 1.10 g (14.0 mmole) of acetyl chloride and 0.96 g (6.95 mmole) of potassium carbonate in 100 m1! of acetonitrile was stirred at room temperature overnight. The ] reacton was then stripped to dryness, and chloroform was added. Water was slowly added. The chloroform layer was extracted with water and also 5% sodium hydroxide. The chloroform layer was dried (sodium sulfate) filtered, and the solvent removed to give a fluffy brown residue (3.68 g, 96.3%). This material was subjected to flash chromatography on silica gel using 20% methanol-80% ethyl acetate for elution. Fractions of similar purity were combined and solvent was removed to give a fluffy white residue. This material was dried in vacuo overnight at 80°C to give 1.63 g (42.6% yield) of "fluffy white amorphous material (mp 98°C — glass 128°C — oil).
Analysis: Calculated for C32H3gN204F2 : C, 69.80; H, 6.59; N, 5.09
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BAD ORIGINAL seni emaidliiimatl abd
Screening Method for Calcium Channel Blocking Activity in Isolated
Rabbit Aorta.
A non-fasted rabbit is killed by cervical dislocation. Spiral arterial strips are prepared from the thoracic aorta by the method of Furchgott, R. F., and
Bhadrakom, S. (1953), J. PHARMACOL. EXP. THER. 108:129-43. The strips suspended in water-jacketed, 10 ml, organ baths that are kept at 37°C and aerated with a mixture of 95% oxygen and 5% carbon dioxide. An iso- metric recording of tissue response is made with a Grass force-displacement transducer (Model FT03C) and a Grass polygraph.
The loading tension on the strips is about 1 g. About 90 min is allowed for maximum relaxation to occur, and during this time the bath is changed at 15 to 20 min intervals. The bath contains a physiological solution, hereafter - referred to as normal bath solution, prepared in glass-distilled water and adjusted to pH 7.4. The composition of the solution in millimoles per liter ‘will be sodium chloride 120.0 potassium chloride 5.6 calcium chloride 2.6 magnesium chloride 6 hydrate 1.2 sodium dihydrogen phosphate hydrate 1.5 sodium bicarbonate 25.0 glucose 9.1 : Strips are first checked for viability based on their response to norepi- nephrine at a final bath concentration of 10-5 M; then they are washed with the normal bath solution until resting tension has returned to baseline.
Following this, the normal bath solution is replaced with a physiological solution, hereafter referred to as a calcium-free bath solution, having the same pH and compositon as the normal bath solution except that the calcium is omitted. Strips are then incubated in this calcium-free solution for 10 min.
During this time the solution is exchanged by fresh physiological (calcium- free) solution three times.
Strips are then tested for completeness of calcium depletion by incubation for 15 min in potassium depolarizing solution. The composition of the - depolarizing solution in millimoles per liter is sodium chloride 32.2 potassium chloride 100.0 magnesium chloride 6-hydrate 1.2 trihydroxymethyl hydro- chloride 12.0 glucose 9.1
The solution is prepared in glass-distilled water and adjusted to pH 7.4. If the strips contract, they will be washed with physiological solution and then ‘reincubated in the depolarizing solution. The process is repeated if necessary until the strips are unresponsive and thus calcium depleated. Alternatively, the strips may be rewashed with depolarizing solution until they are calcium depleted.
Cumulative concentration response curves (controls) are made with calcium chloride as the agonist by the method of Van Rossum, J. M. (19630,
ARCH. INT. PHARMACODYN. 143:299-330. Final bath concentrations of calcium chloride will be 0.1 millimolar, 0.3 millimolar, and 1.0 millimolar (See Godfraind, T. & Kaba, A (1969) BRIT. J. PHARMACOL. 36:549-60).
Responses are allowed to reach a plateau before adding the next increment of calcium chloride. oo : After control responses are obtained, the strips are washed with normal oo bath solution containing test drug (Formula I) at 10-7 molar concentration for 25 . aboutone hour at 15-20 min intervals (see Broekaert, A. and Godraind, T. (1979). During this time the tissues have returned to resting tension.
The strips are then incubated in the physiological solution (calcium-free) - for 10 min and finally in the depolarizing solution for 15 min, both of which + solutions at this point contain Formula I test drug. If the strips contract in the depolarizing solution, they will be washed as mentioned above until unresponsive. The cumulative concentration response to calcium chloride is then made over the range of concentrations used for the control determina- tion.
As a final test to determine selectivity and whether a-blocking activity is present, the strips are washed with the normal bath solution containing the
CD ol -252- Prasvcav pon - “research compound until the resting tension is again at baseline. The strips are then retested for their response to norepinephrine at a final bath ~~ concentration of 105 molar.
In the foregoing primary screen, a minimum of 2 strips are used to test each drug at 10-7molar. Those compounds which consistently produce at least 20% inhibition of the calcium induced contractions will be tested further. For those test drugs giving interesting positive results, a PAg value may be obtained, see Van Rossum (1963) ibid. Reference articles which may be used for comparison are lidoflazine, diltiazem, verapamil, nifedipine or other appropriate drugs. In this test, the more active compounds such as those of Examples 56, 57 and 60 showed 100% change (reduction) in contraction at 10-7 molar concentration of these agents caused by 1 millimolar concentration of calcium. Compared to the reference calcium 5 channel blocking drugs, these compounds were found to be superior.
Le - Test Method for Antihypertensive Effect of Orally Administered Drugsto
Unanesthetized Spontaneously Hypertensive Rats.
Surgical Preparation of Rats
Charles River, spontaneously hypertensive rats are anesthetized with sodium pentobarbital (50 mg/kg, IP). The abdomen and the top of head are shaved and cleaned. A midline incision, approximately 5 mm long, is made in the skin of the dorsal surface of the animal's neck. Brass tubing, 22 ecm long with a slight bend in the end, is passed through the incision, under the skin diagonally down the animal's back and around to the right side of the : lower abdomen of the rat.
The animal is then taped to the table in a supine position. A midline incision approximately 4 cm long is made with scissors in the skin and another through the abdominal muscle wall. With small blunt hemostats, the skin is separated from the abdominal muscle at the midline to expose the tip of the brass tube. A small opening is made through the abdominal muscle at the appropriate angle with the blunt tips of the hemostats.
The distal end of a modified Week's cannula is inserted in the abdominal cavity and the other end is threaded through the brass tube until it exits at the base of the animal's neck. The brass tubing is removed and the 7mm cured polyethylene tip of the cannula is aligned and positioned for insertion :
into the abdominal aorta. The positioned cannula is filled with isotonic saline. ’
The abdominal viscera is gently moved to the side, exposing the aorta in the region of bifurcation. The aorta is isolated and 2 silk ligatures, 1to 1.5 cm apart, are placed around it. The ligatures are used to briefly and gently occlude blood flow. The abdominal aorta is punctured craniad to the bifurcation with the tip of a 23-gauge hypodermic needle. The needle is removed, and the tip of the cannula inserted through this opening toward the heart. Caution is taken to keep the tip vertically aligned in the aorta. Blood is allowed to flow back through the cannula to check correct insertion. The cannula is cleared of blood with a 0.4 cc flush of isotonic saline. The stability of the cannula in the artery is ensured by suturing the ligature tied around the cannula to the dorsal muscle layers lying directly beside the aorta. The cannula is also satured to the abdominal wall at the point of exit. The abdominal viscera is repositioned, and the abdominal wall and skin sutured in separate layers with blanket stitch. The animal is given 0.2 ml i
Combiotic® (procaine penicillin G and dihydrostreptomycin sulfate).
The end of the cannula exteriorized at the base of the neck is tied offand ~~ passed through an L-shaped piece of aluminum tubing fastened to the skull by screws and dental cement (Purdy and Ashbrook, 1978), J. PHARM.
PHARMACOLOGY 30:436-41.
For protection and attachment of the cannula to the cage, the cannula is inserted through a length of flexible metal spring, which is attached to the aluminum tubing and to a part of a swivel device that permits the animal to move with relative freedom around the cage. During recovery, each rat is given a bottle of 5% dextrose containing terramycin (1 tsp. Pfizer Terramycin soluble powder/L 5% dextrose) to drink. :
Blood Pressure Recordings
On the day following surgery, the tied-off cannula is reopened and attached to the swivel device. One end of a saline filled length of poly- ethylene 50 tubing is attached to the swivel and the other to a Statham pressure transducer (Model P23ID) creating a continuous saline-arterial connection. Continuous tracings from the direct aortic blood pressure are recorded on a Grass polygraph (Model 7). Heart rate is determined from the blood pressure pulse.
I -254-
The electrical output of the blood pressure signal from the polygraph is fed into a Buxco Channel Cardiovascular analyzer (Model 12). The blood pressure signals are averaged for a 1-min period and measurements of blood pressure and heart rate is printed on a Texas Instruments data terminal (Model 700 ASR).
Maintenance of Rats
To maintain patency of cannula and to permit the animal to be used for maximum time, animals are continuously infused with heparin in sterile saline (2 mg/ml) at a rate of .05 to .06 ml/hr. Purina Mouse Chow and water are available ad libitum. A solution containing 5% dextrose and terramycin is given once weekly. Surgically prepared rats may be used more than once during a study. A minimum of 3 days must lapse before rats are used again,
A rat is used only once in a dosage group.
Experimental Procedure
Each surgically prepared rat is individually housed in a separate cage.
Each cage is labeled with the lot number and sequiéntial rat number. Single = + doses of 10, 20, and 30 mg/kg of the test drug calculated on free base content is administered orally by using a syringe and size 16 gavage tube. Control : article is PEG-300: saline at ratio of 1:1. Reference articles are verapamil ~ and nifedipine. The carrier for compounds of Formula I and verapamil is
PEG-300: saline, 1:1, and for nifedipine, it is ethanol. The dosage volume for test and control articles is 1 mUkg body weight. Arterial blood pressure and heart rate are measured in each rat prior to and at 30, 60, 90, 120, 180, 240, -5 300, 360 minutes and 24 hours after drug administration.
The more active compounds such as compounds of Examples 56 and 57 are slightly less active in lowering blood pressure in hypertensive rats than nifedipine, but duration of action is longer.
Procedure for Determinating Effect of Compounds on Coronary Blood
Flow.
The procedure used to determine the effect of the aforementioned compounds on coronary arterial blood flow is described as follows.
Mongrel dogs of either sex were anesthetized with phenobarbital sodium (100 mg/kg) and pentobarbital sodium (100 mg total dose). The trachea was surgically exposed, a tracheal tube was inserted and the dog was artifically respired with room air using a Harvard Model 613 Respirator. The heart was exposed by a left thoracotomy at the fourth intercostal space. An approxim- ately 1.5 crn segment of the left anterior descending coronary artery was exposed and a Statham electromagnetic blood flow probe was implanted * around the vessel. The flow probe was implanted around the vessel. The flow probe cable was connected to a Statham Model 2201 Blood Flow Meter.
Continuous recordings of carotid arterial blood pressure, and of coronary arterial blood flows, were obtained using a Grass Model 5 Polygraph.
The compounds were administered via a femoral vein. Changes in both " magnitude and duration of change in coronary blood flow from pre-drug levels were determined. Generally, multiple doses of the compounds tested . were administered to a single dog. Appropriate intervals between doses were allowed to permit the blood flow to return to control levels.
Illustratively, the compounds of Examples 56, 57, 61, 62, 69, 74, 76, 89, 105, 106, and 128 showed an increase in coronary arterial blood flow at 0.5 mg/kg of the compounds of about 75-120 ml/min. : Screening Procedure for Antihistamine Activity
The compounds of the present invention exhibit antihistaminic activity in guinea pigs. The method of testing is a modification of the procedure of Tozzi et al (Agents and Actions, Vol. 4/4, 264-270, 1974) as follows: Guinea pigs are fasted 18-24 hrs in individual cages. Water is available ad libitum. On the test day, animals in groups of 3 are injected intraperitoneally with 30 mg/kg of the test compound prepared in an appropriate vehicle. Thirty minutes later histamine at a dosage level of 1.2 mg/kg (=2 x the LDgg) is injected into " amarginal ear vein. Survival of the guinea pigs for 24 hrs is positive . evidence of antihistaminic activity. If the vehicle used for the test compound . _ isother than water, its effect is established by testing an equal amount as a control. The dose protecting 50% of the animals (PDs) from death may be established from dose-response curves. Compounds such as in Examples 58 and 105 were found to be active at dosages at least as low as 3 mg/kg.
Screening Procedure for Gastric Antisecretory Activity In Pyloric-Ligated
Rats.
Female Sprague-Dawley rats weighing 130-180 g were starved 24 hours in individual screen-bottom cages with water ad libitum. Animals were
Ce -256- arranged into groups of 9 rats each for treated animals and 8 rats for controls.
Each group was injected intraduodenally at the time of pyloric-ligation with test drug in doses of 25.0 mg/kg (0.2 ml/100 g body weight). Rats dosed with deionized water (2 ml/kg) served as controls. Four hours following ligation, rats were killed, the stomachs removed, gastric juice collected and the volume determined. Total hydrochloric acid output was determined by potentiometic titration to pH 7.0 endpoint using a Radiometer TTA-61 autopipetting titration system. Statistical analysis was performed by using the "Student's t-test” significance. Illustratively, at a dose of 25 mg/kg, significant reduction of secretion occurred of about 85% in volume and 98% in acid was obtained for the compound of Example 58. Similarly, reduction in volume obtained for the compound of Example 105 was about 65% for both volume and acid.
Pharmaceutical Compositions and Administration
Compositions for administration to living animals are comprised of at least one of the compounds of Formula I according to the methods of treatment of the invention in association with a pharmaceutical carrier or excipient. Effective quantities of the compounds may be administered in any * one of various ways, for example, orally as in elixirs, capsules, tablets or coated tablets, parenterally in the form of sterile solutions, suspensions and in some cases intravenously in the form of sterile solutions, intranasally and "to the throat or bronchial region in the form of drops, gargles, syrups, powders, etc. or subcutaneously. Suitable tableting excipients include lactose, potato and maize starches, talc, gelatin, stearic and silicic acids, magnesium stearate and polyvinyl pyrrolidone.
For the parenteral administration, the carrier or excipient can be comprised of a sterile parenterally acceptable liquid, e.g., water or arachis oil contained in ampoules.
Advantageously, the compositions are formulated as dosage units, each unit being adapted to supply a fixed dose of active ingredients. Tablets, coated tablets, capsules, ampoules, sprays and suppositories are examples of preferred dosage forms. It is only necessary that the active ingredient constitute an effective amount such that a suitable effective dosage will be consistent with the dosage form employed, in multiples if necessary. The exact individual dosages, as well as daily dosages, will of course be determined according to standard medical principles under the direction of a physician or veterinarian. Generally, the following guide to projected human : oral dosages is derived by knowledge of the activity obtained in animal screening tests for the various indications in the methods of the invention compared to activity of known agents in the field in the same animal screening tests. However, the amount of the active compounds administered need not be limited by these comparisons due to uncertainty in transposing comparative animal data to human treatments.
Oral dosages projected for hypertension for an adult human are of the order of 40-300 mg/day divided into 2 or 3 doses. Thus, for example, two capsules each containing 10-50 mg active agent of Formula I could be administered 2-3 times daily for blood pressure lowering.
Oral dosages projected for use in the tretment of angina for an adult human are of the order of 60-400 mg/day divided into 2 or 3 doses. Thus, for +5 example, two capsules each containing 10-30 mg active agent of Formula I could be administered 2-5 daily to increase coronary blood flow.
Oral dosages projected for use as antihistamines for an adult human are of the order 10-120 mg/day divided into 2 or 3 doses. Thus, for example, one or two capsules each containing 10-40 mg active agent of Formula could be administered 2-3 times daily for temporary relief of cough due to minor throat and bronchial irritation which may occur with the common cold or “with inhaled irritants. ; -
Oral dosages projected for use as antisecretory agents for an adult human are of the order of 4 to 150 mg/day divided into 2 or 3 doses. Thus, for 5 example, one or two doses each containing 0.5 to 50 mg active agent of ~ Formula I could be administered 2-3 times daily for temporary relief due to excessive acid release in the stomach.
Other routes of administration such as subcutaneous, intraperitoneal, intravenous, etc. are possible with dosage forms being adapted to the situation as will be obvious to one skilled in the art of medicine.
Various modifications and equivalents will be apparent to one skilled in the art and may be made in the compounds, methods of treatment and compositons of the present invention without departing from the spirit or scope thereof, and it is therefore to be understood that the invention is to be limited only by the scope of the appended claims. bo -
INCIPS IRI RET:

Claims (1)

  1. WHAT 18 CLAIMED 15:
    1. A componnd selected from the group having the formila A (A) SN JT C= QE NACH), D (Cll) ) Ze (P) R wherein: p is zero, one or two; o RrR' DO 0 0 , ns n [1 Hl : Ais hydrogen, -O-R',-C=N,-C-N_ _C-R!, -C-O-R!, -O-C-R!, R2 R! R! J / ~CII20R!, -CH2-N Nor -NHC(O)CH3; . R? R2 m is one to six inclusive; OH Q is -CH, --CHax-or -t-; H d, e and n are nero or one and the dotted lines represent double bods which may form consistent with the valence of carbon: X een rh O D is ) or - ; i 30 Y . X Jet Ar is O) : } 3s y A R is selected from the group consisting of cycloalkyl, ! BAD ORIGINAL
    X Y ~~ and Or
    7 . N and D may have additionally the values: 0 0 i fl 0 Or ory J OL J N : ~~ , 0 0 ~~ 0 0 oO - I N ) - or Ar (CHz)i-a—: X, Y and 7 are selected from Lhe group consisting ol hydrogen, loweralkyl, halogen, ir! 1! + 1 1 o . T 4 < t ~ ~ 1 4 NO, OY, -C-RR ,-CFy,-C=N, -C(O)-N_ ON ,-croon ,-Clla-CHOIOR , SORT, " 0 Rr? Rr? : SR -S(OIR?, lowerhydroxyalkanyl, ACRYL, -CH,C(0)0M, N-CIOICL0)-O-loweralkyl, 1 R'O H Rr! 0 Rp? 0 on ] s . ns " -St0NN NS(01Cla HCY ANCOR or -CH-loweralkyl: = y 2 3 R® pt pt Bg! B is selected from the group consisting of 0 0 i I"
    0, .-5-. =~ and N= . ’ 30 0 n - is one or zero with the proviso that z cannot be zero at the same Lime n is zero when one of the following occurs al the same time that D is phenyl or i 35 substituted phenyl: (Ala is hydrogen, (A)a is cyano, (Ma is aminacarbonyl. or a double hond forms between the of carben atom and a carbon of the central heterocyclic amine ring: R*, RZ and R?, same or aif ferent, are ATE [I TA . BAD ORIGINAL hydrogen or loweralkyl; Ra ja 1oweralkyl; M is a pharmacentically acceptable melal tun: and Lhe pharmacentically acceplable salls thereof, including acid addition salls, quaternary salls, and hydrates and alcoholntes thereof, with Lhe (urther : proviso thal (I) = cannot represenl oxygen at the same Lime A is phenyl substituted phenyl when n is zero and (Ma is hydrogen or hydroxyl or when d is mero and a double bond forms between the od carbon and a carbon of a saturated central heterocyclic amine ring.
    2. The compound of claim 1 which is 1-{3-(4- acelyl—-2-melhoxyphenoxy) propyl] oo bisA-fiuoro- pheny1)-3-pyrrolidinepropanenitrile or a pharmaceutic- ally acceptable sall. thereof.
    3. The compound of claim 1 which is 1-1{3-(t1,1'- biphenyl]-4-yloxy)propyl] o .o ~bis(4-fluorophenyl)- 4-piperidinemethanol or a pharmaceutically acceptable salt thereof.
    4. The compound of claim 1 which is 4-[4-[4-bis~— (4-fluorophenyl hydroxymethyl] ~1-piperidinyl]butoxy ]- benzoic acid methyl ester or a pharmaceutically acceptable salt thereof.
    5. The compound of claim 1 which ia 1-14-13--14~
    (2.2-bis (4-f luorophenyl)—-2-hydroxyethyl j—1l-piperidinyl}- propoxy]—3-melhoxyphenyl]lethanone or a pharmaceutically acceptable sall thereof.
    6. The componnd of claim 1 which is 1-t4-13-14-
    (2.2-bis (4-f luorophenyl)ethyll-1-piperidiny l]propoxy|=9= - 35 methoxyphenyl}ethanone or a pharmaceutically acceptable salt thereof .
    7. The compound of claim 1 which is 1-14-1314
    (2.7-bis (4-f luorophenyl) ethylene] -1-piperidinylipropoxyl : BAD ORIGINAL
    Dts. assent ;
    ~3-methoxyphenylielhanone or a pharmaceul ically acceptable salt thereof.
    8. ‘fhe compound of claim 1 which is -(4-f1lnoro- pheny 1) - —[1-(3-phenoxypropy 1) —4-piperidiny l1=2= pyridine-acetonitrile or a pharmaceutically acceptable salt Lhereof.
    9. The compound of claim 1 which is A-{bis(I1- f luorapheny 1)methy 1] -1-[3= (pheny 1 thio)propyllpiperidine or a pharmaceutically acceplable salls thereof.
    10. The compound of claim 1 which is A-[bis(4- f luorophenyl)methyl | ~1--{3~(phenylsulf inyl) propyl lpiperi- dine or a pharmaceutically acceptable salls thereof .
    11. the compound of claim | which is 1-13-04 acetyl—2-me Lhoxy phenoxy) propyll ~f co ~bis(i-{luoro- phenyl) -3-pyrrolidincacetonitrile or a pharmaceutically acceptable salts thereof.
    12. The compound of claim 1 which is 1-[3-(4- acetyl-2-methoxy-phenoxy)propy 11-o A ~bis(A-flucro- pheny 1)-3~-piperidinepropanenitrile or a pharmaceuti- cal ly’ acceptable salls thereof. }
    13. The compound of claim 1 which is 1-{3-(4= acety]—2-methoxy—-phenoxy) propyl ) of A -bis(4-fluoro— “phenyl )-3-piperidineacetamide or a pharmaceutical ly acceptable salts thereof.
    14. NM method of treating hypertension which comprises administering an effective amount of a compound having calcium antagonist property selected : 35 from the group of compounds having the formula: (A) Ar | ; ~ ’ . LQ NACHIB)D (Clg)e (Pp)
    Rr . SRO Da - BAD ORIGINAL Cal, _. i *
    wherein: p is zero, one or two: oO r!'O 0 0 Ws i i . i . - A is hydrogen, -0-R!, -C=aN,-C-N, -C-R',-C-O-R ,-0-C-R', > h - R! R! Rr? W/ / _CH,OR',-ClIpN , -N _ or -NHC(O)CH3: Spd Sp? Re R m is one Lo six inclusive; OH Q is -CH, -CHa-or + , e and n are zero or one and the dotted lines represent double bonds which may form consistent with the valence of carbon; X p is Oy or i : O X Y Ar is O) : Y or T
    R is selected from the group consisting of cycloalkyl. . X YJ and ‘ N Z and D may have additionally the valnes: i ] AN X ~ 0 of _ \ ’ » o 0 0 ~~ 0 0 . O50) OO) - LL SOD ) N : BAD ORIGINAL ~ ee eammaasssma eed or Ar(Cliz)i_a—; X, Y and Z are selected from Lhe group consisting of hydrogen, loweralkyl, halogen. bh a a -NO,, -O-R', -C-R', -CFy, CwmN,-CO-N oN _C(OI0R, -CIT,CLOIOR!, -SO%RY, SRY, : rR? OR? Mu aw i SOM, NCI, -CILCOIOM. SOL NSOKCH NCR NCO no Roo I Rr i on .CHl-loweralkyl, lowerhydroxyalkanyl or N-CLOICLONO-lowernliyl : t PB is selected from the group consisting of Q 0 oO, 5. Hh and ~N-; b he Zz is one or zero with the proviso that =z cannot be zero at the same time n is zero when one of the following occurs at the same time that D is phenyl or substituted phenyl : (A)a is hydrogen, (Aa is cyano, (Na is aminocarbonyl, or a double bond forms between the o carbon atom and a carbon of the central heterocyclic amine ring; Rt, R= and R?, same or different, ave hydrogen ovr Jowerallyl: } RY is loweralkyl; ’ M is o pharmacentically acceplable melal ion: and the pharmaceutically acceplable salts thereof including acid addilion salts, qualernary salts, and hydrates and alcoholates thereof. © 15. The method of claim 11 wherein Lhe compound used is o, o -bis(4- f luoropheny1)—1-[3-(4-methoxy- - 35 phenoxy) propy 1 -4-piperidinemethanol or a pharmaceuli- cally acceptaple salt thereof.
    16. The method of claim 14 wherein the compound used is of, _bis (4-fluoropheny 1) —1-[3~=(4-methyl- Ardong a oo { BAD ORIGINAL phenoxy) propy | —A-piperidinemethanci or a pharmaceukbi- cally acceptable salt thereof.
    17. The method of claim 14 wherein Lhe compound used is |= {3- (4-f luorophenoxy) propy 1) =. «( ~bis(4- f luorophenyl}—4-piperidinemethancl or a pharmaceutically acceptable sall thereof.
    18. The method of claim 14 wherein the compound used is 1— [4-13-14 (4~f luorophenoxy) = (2-pyridiny 1) = methyl) —1-piperidinyl } propoxy—3-methoxypheny i jet hanone ’ or a pharmaceutically acceptable salt thereof.
    19. The method of claim 14 wherein the compound used is [(4-13-14-[bis (4-f luorophenyl yhydroxymethyl 1- 1-piperidinyl]propoxylphenyllcarbamic acid ethyl ester or a pharmaceutically acceptable salt thereof. Co
    20. The method of claim 14 wherein the compound ’ used is |- [9 (4-acelyl=2-methoxyphenoxy)propy I=. of -bis- (4—f luorophenyl) -3-pyrrol jidine—propaneni trile or a pharmaceutically acceptable salt thereof. , 21. The method of claim 14 wherein the compound used is 7-13-[4-bisa (4-fluoropheny 1)methy lene] -1- piperidiny L]-1-propoxylphenol or a pharmaceut ically acceptable salt Lhereof ’
    22. The method of claim 14 wherein the compound used i8 | — (3= (=e ly 1=2-methoxy phenoxy) propy L=e( o ~bis(4-fluorophenyl y—4-pi peridinemethanol or a pharmaceutically acceptable sall thereof.
    23. The method of claim 14 wherein Lhe compound used is 1- (3-phenoxypropy 1) -d , o —diphenyl-4-piperi- dine-methanpl or a pharmaceutically acceptable salt thereof .
    24. ‘The melhod of claim 14 wherein the compound Co BAD ORIGINAL . ] a et *
    used is oo ~bis(A-fluoropheny 1) =1-[3=(4=(methyl- sul finy1) phenoxy] propyll-4-piperidinemethanol or a pharmaceutically acceptable salt thereof .
    25. The method of claim 14 wherein the compound used is o o ~Din (4-fluoropheny 1) -1-{3= {A= (1-methy l= ethyl) -phenosy propyl }-4-piperid inemethanol or a pharmaceutically acceptable sall thereof.
    26. The mel hod of claim 14 wherein the compound uged jis 3--[3-{bis (4—fluorophenyl yhydrosxymethy bl—1- piperidinyl]propoxylbenzoic acid elhyl esler or a pharmaceutically acceptable small thereof.
    27. ‘The melhod of claim 14 wherein the compound uaed is 1-[4-13-{4-Ibisg(4-meLhy phenyl ymethylenel--1-- . biperidinyl]propoxy)-3-methoxyphenyllethanone or a " pharmaceutically acceptable salt Lhereof. ¥
    28. The method of claim 14 wherein the compound : used is 1- [4-[3-[1- [bis (4-methy phenyl) hydroxymethyl]= B J-piperidinyl]propoxy}-3-methoxyphenyljethancne or a so pharmaceutically acceptable salt thereof .
    29. The method of claim 14 wherein the compound nged is A-13-14-1his(4-1) vorophenyl yhydvoxymethyl]— 1-piperidinyl)propoxylbenzoic acid methyl esler or a pharmaceutically acceptable sall thereof.
    30. ‘The method of claim 14 wherein Lhe compound uged is 1— [3— { 4—aminophenoxy) propy 1) =¢(, «(bis (4-fluoro= ) phenyl) ~4-piperidinemethancl or a pharmaceutically acceptable salt thereof .
    31. The method of claim 14 wherein the compound used is 1-[4-[3~(1~ [bis (4-f luorophenyl)-methyl-1- piperidinyl]-propoxy—2-methoxyphenyl]-ethanone or a pharmaceutically acceptable sall thereof . Ee ge, . Co BAD ORIGINAL
    32. The method of claim 14 wherein the compound used is L—(3-(11,1 -biphenyl]-4-yloxylpropyt-c( .« —-bis(4— f luoropheny 1) —4-piper idinemethanol or a pharmaceutically acceptable salt thereof .
    33. The method of claim 14, wherein the compound used is N-[4-1[3-14- (bis (4-fluorophenyl)hydroxy= methyl] —l-piperidinyl]lpropoxylphenyl]-N'-methylurea or a pharmaceutically acceptable salt thereof.
    34. The method of claim 14, wherein Lhe compound used is N-{[4-[3-(4-(bis(4-fluorophenyl)hydroxy- methyl]—1-piperidinyl]propoxylphenylimethanesulfon= amide or a pharmaceutically acceptable salt thereof .
    35. The method of claim 14 wherein the compound used is 1-[4-[3-14~ (bis (4-f luorophenyl)hydroxy=- methyl ]-1-piperidinyllpropoxylphenyl]-l-propanohe or a pharmaceutically acceptable salt thereof .
    36. The method of claim 14 wherein Lhe compound used is 1- (4-3 [4- (bis (4-methylphenyl yhydroxymethyl } 1-piperidiny] J propoxy 1 -3-methoxyphenyl Jethanone or a pharmacentically acceptable sall thereof.
    37. The melhod of claim 14 wherein Lhe compound ’ nged is 1-(4-16-14 (big (Af Ine opheny 1) hydroxymethy bl = 1-piperidinyl [hexy Laxy=3-mel hoxypheny 1 elhanone or a pharmaceukically acceptable salt thereof. 30)
    38. The method of claim i1 wherein the compound used is o . Ee bis (A-fluoropheny]l y—L=[3= (4 (L-hydroxy~= ethyl ) —2-me Lhoxy phenoxy 1 —4-pi peridineme thanol oxalate hydrate or a pharmaceutically acceptable salt thereof. : 35
    39. The method of claim 14 wherein the compound used is 4-(9- {4-(bis (4-f lnorophenyl yhydroxymethyl J — J-piperidiny) Ibutozylbenzeic acid methyl esler or a ao, pharmaceutically acceptable salt thereof. : BAD ORIGINAL
    40. The method of claim 14 wherein the compound used is |= {A-[3-14-12,2=bis (4=f lnoropheny 1) -2-hydroxy- ethyl}-1-piperidiny]l | propoxy] -3-methoxyphenyl leLhanone or a pharmaceul ically acceptable salt thereof
    41. The melhod of claim 14 wherein the compound used is 1—-(4-13-14-12,2-bis (4-fluorophenyl)ethyl]-1- piperidinyl]propoxyl -3-methoxyphenyllethanone or a pharmaceutically acceptable salt thereof .
    42. The melhod of claim 14 wherein the compound used is (o( -(4-Cluorophenyl)—c(-[1=(3-phenoxypropy 1) =4- piperadinyl]-2-pyridineacetonitrile or a pharmaceubtic- ally acceptable salt thereof.
    43. The method of claim 14 wherein the compound used is 1-{4-(3-(4-(bis(4-chlorophenyl}-methyl-1~ piperdinyl]propoxy | -3-methoxyphenyljethanone or a : pharmaceutically acceptable salt thereof.
    44. The method of claim 14 wherein the compound used is 1-14-(3-[4- [bis (4—chlorophenyl)hydroxymethyl-1- piperidinyl]propoxy | -3-methoxyphenyljethanone or a pharmaceutically acceptable salt thereof.
    45. The method of claim 14 wherein the compound used is A—13-14-Dbis(A-fluorophenyl)methy t-1-piperidin- y1]-propoxy-3-methoxybenzoic acid methyl ecler or a pharmaceutically acceptable salt thereof.
    46. The method of claim 114 wherein the compound used is 1~[4-[3-14-(bis(3-fluorophenyl)methyl]-1- biperidinyl]propoxy |-3-methoxyphenyl]ethanone or a pharmaceutically acceptable salt thereof.
    47. The method of claim 14 wherein the compound used is 4 [3 [4-hydroxy (dipheny 1) methyl} -1-piperidin- yl]propoxylbenzoic acid methyl ester or a pharmaceutically acceptable salt Lhereof . i Cai BAD ORIGINAL g
    48. The method of claim 14 wherein the compound used is 1-14-16-{4- (bis (4~(luoropheny )methy lb] -1- piperidinyl}hexyloxy|-3-methoxyphenyllelhanone ora pharmaceutically acceptable sall lLhereof.
    5 .
    49. The method of claim 14 wherein Lhe compound used is 1-(4-13-14-{cyclohexy (4-fluorophenyl)methyl]-1- piperidinyl]propoxyl-3-methoxyphenyliethanone or a pharmaceutically acceptable salt Lhereof.
    50. The melhod of claim 14 wherein the compound used is 4-{bis (4-fluorophenyl)methyl|—-i-{3-(phenyl- thio)propyli-piperidine or a pharmaceutically acceptable salt thereof. }
    51. The method of claim 14 wherein the compound used is 4-(bis (4—f Inoropheny methyl] -1-[3-(phenyl- sulfinyl)propy!lpiperidine or a pharmaceutically “ acceptable salt thereof.
    52. The method of claim 14 wherein the compound used is 2—[(4=fluoropheny 1) [1-(3-phenoxypropyl)-4- : piperidinyllmethyl]pyridine or a pharmaceutically acceptable galt thereof.
    53. The method of claim 14 wherein the compound : used is 1-{4-13-(4~[(3,4-difluorophenyl)-(4-fluoro- pheny 1) -methy1]1-1-piperidinyl}propoxy)-3-methoxyphenyl]= ethanone or a pharmaceutically acceptable salt thereof. :
    54. The method of claim 14 wherein the compound . used is 1-(3-(4-acelyl-2-methoxyphenoxy)propy 11 ,< - bis (4-fluorophenyl)-3-pyrrolidine acetonitrile or a pharmaceutically acceptable salt thereof. . 35
    55. The method of claim 14 wherein the compound uged is 1-{3-(4-acetyl-2-methoxyphenoxy)propyll-o oo = bis (4—f luorophenyl)-3-piperidineacetonitrile or a pharmaceutically acceptable salt thereof.
    269 9 G rr 8 5 AOEN:
    56. The method of claim 14 wherein the compound used is 1-{4-{3~14-lbhis(3,4-difluorophenyl)methyl]-1- piperidinyl|propoxy]-3-methoxyphenyl]ethanone or a pharmaceutically acceptable salt Lhereof.
    57. The method of claim 14 wherein Lhe compound used is 1-[4-(3-14—(bis(2,4-difluorophenyl)methyl]-1- piperidinyl] propoxy-3-methoxyphenyl lethanone or a pharmaceutically acceptable salt thereof.
    58. ‘The method of claim 14 wherein Lhe compound used is 1-[4-(3~(4—-bis(2,4-difluorophenyl)methyl]-1- piperidinyl]propoxy-3-methoxyphenyllethanone or a pharmaceutically acceptable sall thereof.
    59. ‘The method of claim 14 wherein Lhe compound used is 1-[4—{3-4-1bis(3,4-dif lnorophenyl)hydroxy- methyl]-1-piperidiny!]propoxy-3-methoxyphenyliethanone or a pharmaceutically acceptable salt thereof.
    60. The method of claim 14 wherein the compound used is 1-[4-[3-[3~ (bis (4-fluorophenyl)hydroxymethyl]- 1-pyrrolidinyl] propoxy] —3-methoxyphenyl } ethancone or a pharmaceutically acceptable salt thereof . :
    61. NA method for treating angina by increasing coronary blood [low which comprises administering an anti—anginal effective amount of a compound selected from the group baving the formula: = (A ’ : Ard ) TN C= Qin === N-(C Hd yn-110,-D : (Clg), =) ot * iP) R - 35 wherein: p is zero, one or two: i Cn BAD ORIGINAL amnion remota pg f 3? ’ i : A is hydrogen, ~O-R!, -C = N, -C(O)N_ __C-R!,-C-O-R},-0-C-R', : 2 q _R! _R! R -CH0R}, -CH2-N CN or -NHC(O)CHy; “R2 R2 m is one Lo six inclusive; OH Q is -CH, -CHax-or —
    H d. e and n are zero or one and the deotled lines represent double bonds which may form consistent with the valence of carbon; " + (O) D is O) or : (O) YH Ar is O : Y R is selected from the group consisting of cycloalkyl, xX Y and Or 7 N and Dh may have additionally Lhe values: - i i
    : . 0 QOL RL) LJ Q 0 0 0 0 ' - 35 : : 1h, ) wt : r . \ : ; BAD ORIGINAL . \ inet - . .
    47) 2, 65 8 5 or AY (CHa) g-n—: X, XY and Z are aelected row the arou) consisting of hiydrogetr. fowerallyl., hatogen, Jr NO, -O-R!,-C-R", CFy,-C=N,-ClO-N_ clon, Cig Ccoor! 51021, ‘ 0 nt oR? .SR*..SIOR*, lowerhydroxyalkanyl, N-C-RY, .CH,C(OYOM, A-CLOICIO-O-loweralkyl, R'O i! / n I fH fu SI00N SOC LCR . ,-N-C-OR or Cll-loweralhat R? mi Rt R Rr! ois sclecled from the aromp consiat ina of 0 a, gh and -H 1S 4 Ny =~ ig one or zeio With the proviso that = cannol be zero at the same Lime n ig zero when one of the following occurs at the same time that I is phenyl or substituted phenyl: (Ala is hydrogen, (Na 18 2U cyano, (Ala is aminccarbonyl, or a double bond forms between the of carbon atom and a carbon of the central heterocyclic amine ring: Rr, R2 and R®, same OY different. are hydrogen or lowerallyl: Re is loweralkyl: M is a pharmaccutically acceptable metal ion: and the pharmaceut ically acceptable salts thereof, incinding acid addil ion galta, quaternary salls and hydrates and atvoholates bthereol.
    62. ‘The method of claim 61 wherein he compound used is Abi (A=f Inoropheny Dmethy 1-1-3 thethy ds 5-melhoxy ) phenoxy J pr opyllpiperidine or a pharmaceutics ally acceptable sall thereof. : - 63. ‘The method of claim 6) wherein the compound used is |—1d4—(3-14-(2,2-bis(4-fluorcphenyl)ethylenel-1= piper idiny1]ppopoxy- 3-methoxyphenyl]ethanone ol a pharmaceutically acceptable salt thereof. Co | BAD —
    oo oS . 272
    G4. ‘The method of claim 61 wherein the compound used is 4-[3-{4- bis (4-fluoropheny tymethy Ll -i-piperidin- y1|-propoxy—3-methoxybenzolc acid or a pharmaceutically acceptable salt thereof.
    65. The method of claim 61 wherein the compound used is A- [bis (4-1 Inorophenyl)methy1]-1-13-(3-methoxy= phenoxy) -propy Lipiperidine or a pharmaceutically acceptable sall thereof.
    66. ‘The method of claim 61 wherein the compound used is | (3 A-acetyl-2 met hexyphenoxy) propy 11 =c bis (d-f1uorophenyl)-4-piperidine acetamide or a pharmaceutically neceptable salt thereof. : 15 JAMES ROBERY SUHANKLIN, JR. ANTHONY GEONUE IROAKIS ' (Invenltore) y L500, wo s Choo Lo BAD ORIGINAL ER
PH38517A 1988-02-10 1989-04-27 N-substituted-arylalkyl and arylalkylene aminoheterocyclics as cardiovascular antihistamic and antisecretory agents PH26585A (en)

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AU629534B2 (en) * 1988-02-24 1992-10-08 A.H. Robins Company, Incorporated New methods and related compounds
IL96150A0 (en) * 1989-10-30 1991-07-18 Syntex Inc Benzylpyrrolidine derivatives,their preparation and pharmaceutical compositions containing them
WO1991018602A1 (en) * 1990-06-01 1991-12-12 Merrell Dow Pharmaceuticals Inc. (+)-α-(2,3-DIMETHOXYPHENYL)-1-[2-(4-FLUOROPHENYL)ETHYL]-4-PIPERIDINEMETHANOL
US6004980A (en) * 1990-06-01 1999-12-21 Merrell Pharmaceuticals, Inc. (+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol
DK0553191T3 (en) * 1990-10-10 1995-08-07 Schering Corp Pyridine and pyridine N-oxide derivatives of diarylmethylpiperidines or piperazines, preparations and uses thereof
DE4111861A1 (en) * 1991-04-11 1992-10-15 Schwabe Willmar Gmbh & Co BENZOPYRANONE, PROCESS FOR THEIR PREPARATION AND USE
US6028083A (en) * 1997-07-25 2000-02-22 Hoechst Marion Roussel, Inc. Esters of (+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl) ethyl]-4-piperidinemethanol

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US4810713A (en) * 1985-12-20 1989-03-07 A. H. Robins Company, Incorporated Arylalkyl-heterocyclic amines, n-substituted by aryloxyalkyl groups used in a method for allergy treatment
DE3600390A1 (en) * 1986-01-09 1987-07-16 Hoechst Ag DIARYLALKYL-SUBSTITUTED ALKYLAMINE, METHOD FOR THE PRODUCTION THEREOF, THEIR USE AND MEDICINAL PRODUCTS CONTAINING THE SAME
IL78939A (en) * 1986-01-17 1990-04-29 Robins Co Inc A H Pharmaceutical compositions containing n-substituted arylalkyl-and arylalkylene-piperidines and tetrahydropyridines and certain such novel compounds

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