CA1041499A - Process for the preparation of benzodiazepine derivatives - Google Patents
Process for the preparation of benzodiazepine derivativesInfo
- Publication number
- CA1041499A CA1041499A CA109,681A CA109681A CA1041499A CA 1041499 A CA1041499 A CA 1041499A CA 109681 A CA109681 A CA 109681A CA 1041499 A CA1041499 A CA 1041499A
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- Prior art keywords
- compound
- phenyl
- halogen
- group
- chloro
- Prior art date
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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
-
- 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
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
TRICYCLIC BENZODIAZEPINES
Abstract of the Disclosure Tricyclic benzodiazepine derivatives ("A") bearing a hetero-cyclic ring joined between positions 4 and 5 of the benzodiazepine moiety are described. The heterocyclic ring will contain the nitrogen atom appearing at position 4 of the benzodiazepine ring as well as the hetero atom, which may be either oxygen or nitro-gen, attached to the carbon atom at the 5-position of the benzo-diazepine ring. "A" bearing an oxygen atom in the new hetero-cyclic ring may be formed from the corresponding 4,5-unsaturated benzodiazepines by treatment with an epoxide compound in the presence of an acid catalyst. "A" bearing either a nitrogen or an oxygen atom in the new heterocyclic ring may be prepared by cyclization of the corresponding open compound. "A" are useful as sedative, muscle relaxant and anti-convulsant agents.
Abstract of the Disclosure Tricyclic benzodiazepine derivatives ("A") bearing a hetero-cyclic ring joined between positions 4 and 5 of the benzodiazepine moiety are described. The heterocyclic ring will contain the nitrogen atom appearing at position 4 of the benzodiazepine ring as well as the hetero atom, which may be either oxygen or nitro-gen, attached to the carbon atom at the 5-position of the benzo-diazepine ring. "A" bearing an oxygen atom in the new hetero-cyclic ring may be formed from the corresponding 4,5-unsaturated benzodiazepines by treatment with an epoxide compound in the presence of an acid catalyst. "A" bearing either a nitrogen or an oxygen atom in the new heterocyclic ring may be prepared by cyclization of the corresponding open compound. "A" are useful as sedative, muscle relaxant and anti-convulsant agents.
Description
ll~Cross Re~erence to Related Appllcationis _ , , . ~ ._ .
19The ~pplication is a con~lnuation-l:n-part o~ Serial No.
20 7683909, ~i~ed Oc~cober 18, 1968.
21. ~ - .
22Description o~ the Invention .
23The presen~ invention relates to trlcyclic benzodiazepines
19The ~pplication is a con~lnuation-l:n-part o~ Serial No.
20 7683909, ~i~ed Oc~cober 18, 1968.
21. ~ - .
22Description o~ the Invention .
23The presen~ invention relates to trlcyclic benzodiazepines
2~ of the following formula 2~ R2 . . .
26 ~ xN
\ ,~
Rs æ~ \
R /~ ( CH2 )n . .~ .
. ...
.
.
l -: F 915~2 ~ .
. .
'.
~ , .
:~
:
The present invention relates to the preparation of ;~
tricyclic benzodiazepines of the general formula '',. . ~ ' ' Y
erein A represents thegroup -C-; Z is -0-;
Rl is hydrogen, halogen, nitro, tri~luoro-methyl, lower alkyl, lower alkyl mercap~o or lower alkoxy; R2 is hydroxy-lowex alkyl; R3 i5 hydrogen or lower alk~ is a di- or trimethylene group;
and R5 is phenyl or phenyl substituted with halogen.
10As used herein, the term "lower alkyl", either alone or in combination, comprehends straight or branched chain hydrocarbon groups having from 1-7 carbon atoms, preferably 4 carbon atomsj such as methyl, ethyl, propyl, isopropyl :~
~ and the like. The term "acyl'l encompasses an organic radical .. . .
:, , ~ 2 -.
derived by removal of a hydroxyl group from an organic acid, ; such as an alkanoic acid containing from 2-7 carbon atoms, for example propionyl and the like. The term "lower alkoxy"
comprehends a lower alkyl group having an oxygen function substituted therein, such as methoxy, ethoxy~ propoxy, etc.
The term "halogen" represents all four forms thereof, i.e., fluorine, chlorine, bromine and iodine, unless expressly in-dicated otherwise. The term "lower alkanol" connotes primary, secondary, or tertiary saturated aliphatic alcohols such as methanol, ethanol, propanol, isopropanol and the like.
A particularly preerred embodiment of the present invention encompasses the compounds of formula I
and whereln Rl is hydrogeng halogen, nitro, trifluoro-meth~l, or lower alkyl.
A still more preerred embodiment of the present in- ;
vention encompasses the compounds of formula I wherein Rl is hydrogen or halogen~ with chlorine being the preferred halogen, and is joined to the benzodiazepine moie~y at the 7-position thereo ci.e. the p-pOsitioll with respect to the -N-A g~ouping~; R3 ls hyd~ogen; and R5 is phenyl or phenyl substituted at the ortho position with halogen, with 1uorine being the most preferred halogen.
~,, ' ~.
'' :
" . .
~ 3 ~
. ! ; ~:
''. : ' :.' 4~
Most preferred among the compounds of formula I above are those wherein Rl is chlorine and is joined to the benzodiazepine moiety at the 7-position thereof; R2 is ~-hydroxy ethyl; R3 is hydrogen; Y is the dim~thylene group and :~.
R5 is phenyl or phenyl substituted in the ortho position with fluorine.
Examples of compounds which correspond to formula I and which are thus representative of the present invention may be ~ ted as follows:
10-Chloro-7-~2-hydroxyethyl~-2,3,5,11b-tetrahydro-llb-phenyloxazolo~3,2-d]~1,4]benzodiazepin-6-~7H)-one;
10-Chloro-llb-t2-fluorophenyl)-7-~2-hydroxyethyl)-2,3,5,11b-tetrahydrooxazolo[3,2-d]~1,4]benzodia~epin- ::
6-(7H)-one;
llb-~2-Fluorophenyl)-7-~2-hydroxyethyl)-10-iodo-2,3 J 5,1lb-tetrahydrooxazolo~3,2-d~1,4~benzodiazepin-6~7H)-one;
llb-(2-Chlorophenyl)-7-~2-hydroxyethyl)-10-nitro- :~
2,3,5,11b-tetrahydrooxazolo~3,2-d][1,4}benzodiazepin-6~7H)-one.
In accordance with the present inven~ion, compounds of formula I may be prepared by a) splittîng off the protecting group from a compound of the : general formula :; :
'~ :
::
., ~ . . . . . , . ~ ~ , .
3L(1 ~499 2 ; .:
N - A
Rl ~ ~ N
Y
II
: .
" ~ , ., wherein Rl, R~, R5, AJ ~ and Z are as defined s earlier and R12 is a hydroxy-lower alkyl group with the hydroxy group being protected by a . .
protecting group, -.
: : - .
o~
; b~ h~droxy-lowe~ alkylating a compound of the general formula Bl ~
- R Z ~ III
, . ~ .
~-~n Bi, R3~ R5~ A~ Y and Z are as defined 0~ : earlier, to lntroduce the requlred group R2, . :
cl~reducing a:compound o~ the general ~ormuIa ( I H2 )mC~R7 n~ ~ N~ > ~H3 IV
wherein R~ R5, AJ Y and Z are as de~ined earlier, R'l is halogen, ~ is lower alkyl and m is a whole integer ~rom l-6, to the correspondlng carblnol.
Thus, in a rirst process aspect of the present invention, the protecting group is ~}r}~ off from a compound Or the rormula II, above. Suitable protecting groups ~or the purpose of thls rirst process aspect Or the present invention include ;~
the acyl mo~ety o~ a lower alkanoic acid such as acetyl, propionyl and the like or oarbobenzoxy. The splitting Or~ o~
: the protecting group ~an be e~rected by conventlonal techniques9 ror example, by alkaline hydrolysls. The alkaline hydrolysis is expeAiently carrled out in the presence Or an inert solvent.
~ ; 15 Sultable bases include alkall-hydroxldes or alkaline earth metal hydroxldes, such as sodlum hydroxide~ calcium hydroxlde ; ~ and the like.
In a further process aspect Or the present invention, a hydroxy-lower alkyl group can be introduced into a compound of:~ormula III9 above, by reactlng said compound with a ;
suitable hydroxy-lower alkylating agent. Thus, one can prepare a compound of the formula I, above, by first preparing the l-sodio derivative of a compound of the formulcl III, above~
and without isolation reacting said l-sodio derivative wi~h a suitable hydroxy-lower alkylating agent, e.g. with halo-lower alkanols.
Representative of such hydroxy-lower alkylating agents are 2-bromoethanol, 3-bromopropanol and the like.
The l-sodio derivative of a compound of formula III
above can be prepared by treating said compound with a sodium lower alkoxideJ such as sodium methoxide, or with sodium hydride. This reaction is expediently effected in the presence of an inert organic solvent such as dimethylformamide, aromatic hydrocarbons, e.g. benzene~ toluene and the like, with di-methylformamide being the pre~erred solvent. For the purposes o this reaction, temperatures above and below room temperature may be employed. In a preferred embodiment temperatures between about 0 and 10C are utilized.
The hydroxy-lower alkylation of the l-sodio derlvative o a compound o ormu1a III above is expediently effected in the presence oE an inert solvent such as dimethylformamide, aromatic hydrocarbons, e.g. benzene, toluene and the like, ~ith dimethylformamide being the preerred solvent. This re-action may be ef~ected usin~ temperatures above and below room temperature, with temperatures between about 10C and room temperature being preferred.
''' In a further process aspect of the present invention, a compound of for~ula I above wherein Rl is halogen may be prepared by reducing a compound of the formula IV, aboveJ with a suitable reducing agent such as lithium aluminum hydride.
Said compound of formula IV is prepared by reacting the l-sodlo derivative of a compound of the formula III, above, wherein Rl is halogen with a compound of the formula X'-(CH2)mC00-lower alkyl V
wherein X' is chlorine, bromine or iodine and m is as defined earlier.
The compound of formula IV thus obtained is then without isolation, reduced with a suitable reducing agent such as lithium aluminum hydride, to produce the corresponding compound of formula I.
Representative of the compounds of formula V suitable for this process aspect are ethyl bromoacetate, ethyl 3-bromo-propionate~ and the like. The l-sodio derivative of the compound of ~ormula III, wherein Rl is halogen, can be prepared, as described hereinbefore, i.e. by treating said compound with a sodium lower alkoxide, such as sodium methoxide or with sodium hydride. This reaction is expediently effected in the presence of an inert organic solvent swch as dimethylformamide, aromatic hydrocarbons, e.g~ benzene, toluene and the like, with dimethylformamide being the preferred solvent. ~or the .-, .
-, purposes of this reaction, temperatures above and belo~ room temperature may be employed. In a preferred embodiment tempera-tures between about 0 and lO~C are utilized. The esterification reaction is expediently effected in the presence of an inert ~I
.. ..
'. .
~' solvent such as dimethylformamide.
The startlng materials Or ~ormulae II and III may be prepared by reacting a 2-substituted aminophenyl ketone Or the formula . ' ~ N -A -CH --X' Rl ~ ~ VI
~-0 : ., ..
whereln Rl, R3, ~5, A and X are as defined earlier and R"2 represents hydrogen or a hydroxy-lower . alkyl group wlth the hydroxy group being protected by any sultable protecting group ~ ~ ~o ~ /co ~o/
:1 ~ 10 wlth a d~amine or a~ee}~ehe~ Or the general formula ~ , l H2N- Y~ ZH VII
. I . .
I wherein Y and Z are as derined earlier.
., .
The reaction between the ¢ompounds Or ~ormulae YI and ;
,: VII above is conducted in a reacti on medium con~aining a base l 15 and an inert or~anic solvent at a temperature in the range Or ,~ ~ rrom about 25C to the rerlux temperature Or the reactlon medlum, preferably at about the reflux temperature. Suitable :.
bases for the purposes o~ this process are inorgarlic bases, such as sodium acetate, and organic bases such as the . tertlary amlnes, for example, trialkylamines, with triethylamlne and pyridine being prererred. A variety Or or~anic solvents are userul ror the purposes Or this process. Among these sultable solvents are lower alkanols, such as methanol, ethanol, propanol, etc.g with ethanol being pre~erred; aromatic alcohols, such as benzene, toluene, xylene, etc ; hlgh boiling point ethers, such as tetrahydroruran and dioxane; and a~lides, such as dimethylrormamide, dlethyl~ormamide and the like. Examples of compounds o~ formula VII userul in this lnvention include 2-aminoethanol, ethylenediamine, 3-aminopropanol, etc.
.
; The compounds Or rormulae VI and VII above are readily prepared in a manner known in the art. lt should be noted that in preparlng the compounds Or rormula VI above wherein R"2 is a hydroxy-lower alkyl group with the hydroxy group being pro , 15 tected by any sultable protecting group, i.e. compounds of `~ formula ~ N- A- CH - X
; Rl ~ VI-a ~; Rs ~.:
Rl, R 2' R3, R5, A and X are as de~ined earlier, lt ls expedient to first protect the hydroxyl group present ~ in the ketone startlng material before introducing the -A~H-X' :~ substituent9 A, R~ and X being derined as above, into the , , .. . . : . . -molecule, i.e. to first prepare a compound of formula R~
.
I ,''.
NH
R~
VIII
~5 :' ' wherein Rl, R'2 and R5 are as defined earlier.
By so-protecting the hydroxyl group, one can avoid unwanted side reactions and unwanted side products which of necessity render the reaction less eficient. ~ -If, in the compounds of ormula VI, X' is chlorine or ~ bromine~ the reaction mixture may also contain sodium iodide - in order to exchange the X' substituent for the more reactive iodine atom whicll then is removed in the ensuing reaction.
j 10 The reaction path descri~ed above for the cyclization ;'~ ' ' ~' . ~ .. ...
.:
; ~ ' h '' " ' :'~ '' ' '' , .
. ' ' .`
., ', . . ' process ls believed to proceed via an intermediate of the ~ollowing proposed structure t 2 ~3 N- A- H - NH- Y- Z- H
Rl t II IX
~ ~=0 , . .
1' 2' R3, R5, A, Y and Z are as de~ined earlier which need not be isolated from the reaction mixture as it cyclizes to the deslred compounds under the reactlon conditions employed. By uslng less energetic reaction conditions, the compounds o~ the ~ormula IX can be isolated and subsequently cyclized to the deslred product. However3 in a preferred embo-dlment, the lntermediate ls not isolated but is permitted to -l cyclize in the reaction medium in which it is prepared.
Compounds Or rormula .. . .
~ - A
~1 ~ k ~ A
~ ':
R~4 wherein Rl~ R2. R3, R5 and A are as defined earlier .:
- 12 - ~
.
and R'4 represents hydrogen, lower alkyl or CH2X
where X is as de~ined earlier, may also be obtained by reactlng a 4,5-unsaturated 1,4-benzo-diazeplne Or the general rormula ~ A
R1~ XR X
wherein Rl, R2, R3, R5 and A are as defined earlier with an epoxide compound of the general formula C ~ CH R'4 XI
1 .
wherein R'4 is as deflned above in the presence of an acidlc agent such as, for example, an aprotic acid, e.g., alumlnum chloride, ferric chloride, zinc chloride, tltanium tetrachloride, boron trifluoride, etc.;
or p-toluene sulronic acid, benzene sul~onic acid, and the i like. The most prererred acidic a~ent ls alumlnum chloride.
Examples o~ compounds o~ formula XI lnclude ethylene oxide, propylene oxide, l-chloro-2~3-epoxy propane, etc.
The reactlon is conveniently conducted in the presence an anhydrous inert organlc solvent. Suitable inert or-ganlc solvents for thls purpose include, for example, aromatic hydrocarbons such as benzene3 toluene, xylene, etc.l ethers~
.. . .
: .~ - 13 ~
. ~ . . . ~ . , .
such as tetrahydroruran and diethyl ether, or carbon disulride.
This reaction may be carried out at a temperature in the range of` from about -10C to the ref`lux temperature o~ the reaction medium, most preferably from 10C to t;he reflux temperature.
-- 5 The selection of temperature is not critical f`or the purposes of the present reactlon and will, of courseJ depend upon the characteristics of the compounds selected as reagents, the ~- solvent medium employed and the nature of the acidic agent used.
:~
I 10 It would appear that when a compound of formula X is i reacted with a compound o~ ~ormula XI wherein R'l~ is other than hydrogen, the R'4 bearing carbon atom can be attached relative to the benzodiazepine ring in one of two alternate positions, depending upon the point where the epoxide ring l 15 cleaves during the reaction. However, experimentation has i shown that the epoxide ring evidences a propensity to favor cleavage between the oxygen and the unsubstituted carbon atom.
Thus, when cleavage occurs at thls point, the carbon atom bear-ing the R'4 substituent is bonded to the oxygen atom in the heterocyclic ring.
It should be noted that compounds of' ~ormula XI above rnay, in addltion to forming the heterocyclic ring between the 4 and 5 positions of' the benzodiazepine moiety upon reaction with the compound of formula X, also react with the nitrogen atom in the l-position of' the compounds of formula X~ Thus~
the reaction can result in a mixture of compounclsv the first showing no substitution on the l-nitrogen and the second being ' ' correspondingly substituted on the l-ni~rogen. Experimentation has shown that by controlling the reaction conditions, sub-stitution at the l-nitrogen can be avoided.
The compounds of ormula XI, above, are readily prepared ~- in a manner known in the art. -The tricyclic benzodiazepine derivatives of formula I
above are useul as pharmaceuticals and are characterized by activity as sedative, muscle relaxant and anti-convulsant agents.
The pharmacological activity of 10-chloro-llb-(2-fluoro-10 phenyl)-7-(2-hydroxyethyl)-2,395,11b-tetrahydrooxa~olo~3,2-d]
; ~1,4]benzodiazepin-6-(7H)-one was determined in two standard screening tests.
The test results from these tests are summarized below.
Footshock: 100% Blocking Dose Level - 4 mg/kg Inclined Screen: PD50 - 15 mg/kg The compounds of for~ula I can be used in the form of conven~ional pharmaceutical preparations; for example, the aforesaid compounds can he mixed with conventional organic or inorganic, inert pharmaceutical carriers suitable for parenteral 20 or enteral administration such as ~or example, water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oil, gums, , ~ . .
.~
.
~ - 15 - ~ ~
~; ~ ,'~, '' ~'' '~,' .' D
polyalkylene glycols, Vaseline or the like. They can be ad-ministered in conventional pharmaceutical forms, e.g., solid forms, for example, tablets, dragees, capsule~s, suppositories or the like, or in liquld forms, for example, solutions, sus-- pensions or emulsions. Moreover, the pharmaceutical compositions containing compounds of formula I can be subjected to conventional pharmaceutical expedients such as sterilization, and can contain conventional pharmaceutical excipients such as preservatives, stabilizing agents, wetting agents, emulsi-` 10 fying agents, salts for the adjustment of osmotic pressure,or buffers. The compositions can also contain other thera-peutically active materials.
A suitable pharmaceutical dosage unit can conta:in from about 1 to about 500 mg of the aforesaid compounds o formula I with a dosage range of rom about 1 mg to about 100 mg being preferred for oral administration and a dosage range of from about 1 mg to about 50 mg being preferred for parenteral ad- ;
ministration. However, for any particular subject, the specific dosage regimen should be adjusted according to individual need and the professional judgment of the person administering or supervising the administration of the aforesaid compounds. It is to be understood that the dosages set forth herein are exemplary only.
The following examples are illustrative, but not limitative ; of this invention. All temperatures given are in degrees centi-grade~ unless indicated otherwise.
:::
'' - 16 - ~
; ' '-ample 1 A solution of O.S g (0.0012 M) of 7-(2-acetoxyethyl)-10-chloro-llb-(2-fluorophenyl)-2,3,5, llb-tetrahydrooxazolo-~3,2-d]~1,4~benzodiazepin-6~7~1)-one in 5 ml of methanol was tr~ated with 2 ml of 3N sodium hydroxide. A-fter 3 hours, 50 ml of water was added and the solution was extracted with 40 ml of h-~- dichloromethane, which was then dried over anhydrous sodium sulfate and evaporated to dryness. The residue was crystallized from a mixture o methanol and water to give 10-chloro-llb-10 (2-fluorophenyl)-7-~2-hydroxyethyl)-2~3,5,11b-tetrahydrooxazolo-L3,2-d]~1,4]benzodiazepin-6~7~ one as whita prisms, m.p~
141-1~6.
The starting material can be prepared as follows:
A solution of 10 g ~0.04 M) of 2-amino-5-chloro-2'-fluoro-benzophenone in 100 ml of dry benzene was treated with 10.6 g ~0.08 M) of aluminum chloride under nitrogen. The reaction ~ixture was next treated with 7 g Co.l6 M~ of ethylene oxide ~5 minute period)~ k~eping the temperature below 35 with an , ice bath. After-65 hours at room t~mperature, the procedure 20 was repeated using the same amounts of aluminum chloride and ethylene oxide as before. After 5 hours at room temperature, the benzene was removed by distillation, and tha residue was ; .
made basic with ammonium hydroxide, stirred with 100 ml of ;;~
dichloromethane and filtered. The organic layer was separated~
, . , :.
", ,~ ,: "
~' ' ~ 17 -: . .
~ ~ ' washed with saturated brine, dried over anhydrous sodium sulfate and evaporated ~o dryness. The product was recrystallized three times from a mixture of ether and petroleum e~her to -~ give 5-chloro-2'-fluoro-2-~2-hydrQxyethyl)aminobenzophenone as yellow needles~ m.p. 96-101.
A solution of 15 g ~0.0516 M) of 5-chloro-2'-fluoro-2 (2-hydroxyethyl)aminobenzophenone in 75 ml of ace~ic anhydrlde was heated on the steam bath for 1 hour. The solvent was re-moved under reduced pressure and the residue was dissolved in 10 75 ml of benzene. This solution was ~iltered through a column of 100 g of silica gel. The column was eluted with 500 ~1 of benzene which was discarded, and 1 liter of dichloromethane.
Removal of the dichloromethane gave a residuewhich was crystallized from a mixture of ether and petroleum ether to , give 2-(2-acetoxyethylamino~-5-chloro-2'-fluorobenzophenone as ; yollow rods, m.p. 48-55.
A mixture of 2.5 g (0.0074 M) of 2-(2-acetoxyethylamino)-5-chloro-2'-fluorobenzophenone and 5 g (0.0362 M) of potassium carbonate in 25 ml of dry chloroorm was treated with 2.0 g 20 (0.0096 M) of bromoacetyl bromide over a 20 minute period with s~irring. The mixture was stirred for 1 hour at room tempera-ture when 25 ml of water was added, and the chloroform layer was separated. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and evaporated to dryness. The residual oil ~as dissolved in 10 ml of benzene, and chromatographed over 100 g o Florisil*. Elution with 1 liter of benzene gave 0.2 g of an oil and elution with 1.5 liter of '.' '' ' ' .:
*Trade mark for a highly selectiYe absorbent o~ extremely white, hard granular or powdered magnesia-silica gel ~magnesium silicate).
: . . .
ether and I liter of ethyl acetate ~ave 1.~ g and 1.0 g,respectively o~ a colorless oil which were combined and re-crystallized from a mixture of dichloromethane and petroleum ether to give 2-[N-(2-acetoxyethyl)-N (2-bromoacetyl)aminoJ-5~
chloro-2'-fluorobenzophenone as white prisms, m.p. ~4-~.
': ' A solution containing 1.5 g (0.0033 M) of 2-LN-(2-acetoxy-ethyl)-N-(2 bromoacetyl)aminoJ-5-chloro-21-rluorobenzophenone, 0.5 ml of triethylamine and 0.23 g (0.0036 M) of ~thanolamine in 15 ml of benzene was kept at room temperature for 65 hours and then was partitioned between 25 ml Or ethyl acetate and 25 ml Or water. The organic layer wa~ separated, washed with sa-turated brine, dried over anhydrous sodlum sul~ate and eva-porated to dryness. The residue was partioned between 20 ml o~
ether and 20 ml o~ lN hydrochloric acid. The acid layer was se-parated and extracted wlth 25 ml of ethyl acetate. The organic ., layer was then washed with 20 ml o~ dilute ammonium hydroxide, i dried over anhydrous sodium sulfate and evaporated to dryness.
The re~idual oll was crystalllzed from ether and recrystallized rrom a mlxture of methanol and water to give 7-(2-acetoxyethyl~-10-chloro-llb-(2-rluorophenyl)-2,3,5,11b-tetrahydrooxazolo-L3J2-d~Ll34lbenzodlazepin-6(7H)-one as white prisms, m.p.
120-12~.
;~1 ' ~ , . .
.. . .
A solutlon o~ 5 g (0~015 M) of 10-chloro-llb-(2-fluoro-~ 25 phenyl)-2,3,5~11b-tetrahydrooxazolo~3,2-d~194~benzodiazepin-- 6(7H)-one ln 50 ml Or dry N7N-dlmethyl~ormamlde under nitrogen :, . ~ .,. ... .- - , was treated with 1.~ g (0~0~0 M) of a 57~ dispersion Or sodium hydride in mineral oil and after 30 minutes, 4.0 g (0.0~0 M) Or 2-bromocthanol was added. The mixture was kept at 600 for 1~ hours, when 450 ml Or water was added, followed by enough 3N hydrochloric acid to lower pH to less than 5. The mixture was extracted with dichloromethane (3 x 125 ml)~ The organic layers were comblned, washed with saturated brlne, dried over anhydrous sodium sulf`ate and evaporated to dryness. The resldue was dissolved in ether (50 ml) and ~iltered through 75 g Or neutral alumina. Elution with ethyl acetate and methanol gave ; 10-chloro-llb-(2-f`luorophenyl)-7-(2-hydroxyethyl)-2,~,5~11b-~t ra h~!r~o~q æo/~7 h~e*~ oL3,2-d]L1,4Jbenzodiazepin-6(7H)-one, which was crystallized from ether to give the product as white prisms, m.p. 142-147.
The starting material may be prepared as follows:
To 15 g (51.9 mmole) of` 7-chloro-5-(2-~luorophenyl)-1~3-dihydro-2H-1,4-benzodiazepin-2-one in 150 ml of` dry benzeneJ
g (67.7 mmole) of' aluminum chloride was added and stirring was continued 15 minutes. The reaction mixture was cooled in an ice bath and 2.~ g (0.2 mole) Or ethylene oxide was added dropwise. After 1~ hours Or stirrlng at room temperatureJ the reaction mixture was heated to 40 ~or 1 hour and then cooled to room te~perature and treated with 5 g (~7.6 mmole) of aluminum chloride, f`ollowed by 4.4 g (0.1 mole) of ethylene oxide. The reaction mixture wa~ heated 4 hours at 45-50 and then evaporated to dryness. Methylene chloride, ice and ammonium hydroxide were added and the solid removed by fil-tration. The f`iltrate was separated and the organic phase re-~ 20 ~
49~
duced to dryness in vacuo. The residue was dissolved in dilute hydrochloric acld and the pH of` the solution ad~usted to 5 with ammonium hydroxide. The acidic solution was washed with ether, made basic and extracted with rnethylene chloride. The organic phase was washed with brine, dried and evaporated to dryness. Recrystallization from methylene chloride-hexane gave 10-chloro-llb-(2-fluorophenyl~-2J3~5~11b-tetrahydroxazolo-~2-d~LlJ4]benzodiazepin-6(7H)-one as colorless rods, m.p.
~ 1~3-1~4.
.,, ~ .
Exam~le ~
A solutlon of o.8 g (0.00187 M) of llb-(2-~luorophenyl)-2,3J5,11b-tetrahydro-10-iodooxazolo[3,2-d~Ll,41benzodlazepin-~, 6(7H)-one in 25 ml Or dry N,N-dimethylformamide under nitrogen was treated with 0.11 g ~0.00262 M) Or a 57~ dlspersion Or sodium hydrlde in mlneral oil. Af`ter stirring ror 30 minutes ~, in an ice bath, 0.37 g (0.00374 M) Or 2-bromoethanol was added, and the reaction was heated to 115-120 for 3 hours and at i 125-130 ~or 1 hour. The solvent was removed under vacuum, and the residue was dissolved in 25 ml of dichloromethane and washed with saturated brine, dried over anhydrous sodium i sulf`ate and evaporated to dryness. The residue was heated under '~
re~lux ror 15 minutes ln a solution of 10 ml o~ triethylamine, ~ containing 0.5 g (0.005 M) Or succinic anhydride. The solvent g was removed under reduced pressure and the residue was dis-solved in 25 ml of dichloromethane. The hal~ ester was ex-tracted lnto 20 ml of dilute ammonium hydroxide which was then tre~ted ~:rlth 5 ml o~ ~N sodlum hydroxide for 1 hour. The ,ij;
... ~ . . . , . . ,, . , .. , .. :. .. . . : . . . .
solution was extracted wi~h 25 ml of dichloromethane/ which was dried with anhydrous sodium sul~at;e, and evaporated. The resulting oil was crystallized f'rom et;her to glve llb-(2-fluoro-phenyl)-7-(2-hydroxyethyl)-10-iodo-2,3,5~11b-tetrahydrooxazolo-[~,2-d~1,43benzodiazepin-6(7H)-one as whlte plates, m.p.
160-165.
The starting material may be prepared as ~ollows:
.
- To a stirred solution of 43 g (0.2 mole) Or 2-amino-2'-f~luorobenzophenone in 1 liter Or chloro~orm was added 65 g (0.4 mole) of iodine monochloride in 50 ml of chloroform at roorn temperature. This mixture was stirred 1 hour at room temperature and the excess iodine monochloride was destroyed by the addltion Or 1 liter Or saturated sodlum bisulrite sol~
ution. It was then neutralized with concentrated ammonium hydroxide. The chloroform layer was separated~ dried over sodium sulfate and concentrated in vacuo. The residue crystalllzed with hexane to give 2-amino-2'-rluoro-5-iodobenzophenone~ m.p.
~3-~6. Recrystallization ~rom ethanol/water gave orange needles ` m.p. 102-105.
A mixture of 32.1 g (~4.3 mmole) of 2~amino-2'-~luoro-5-iodobenzophenone, 40.2 g (0.2 mole) of bromoacetyl bromlde and 500 ml o~ benzene was heated under re~lux for 2 hours, cooled, and neutralized with dllute ammonium hydroxide. Methylene chloride was added and the organic phase separated. It was washed with water, dried over sodium sulfate and concentrated in vacuo to 200 300 ml. Addition of petroleum ether gave 2-bromo ~ -fluorobenzoyl)-4' iodoace~anilida, m~p. 14~-151o Recrystallization -from ethanol gave oFf-white needles, m.p.
150-151.
A mixture of 27 g (58.5 mmole~ of 2-bromo-2' (2 fluoro-benzoyl)-4'-iodoacetanilide and 750 ml of liquid ammonia was stirred under a dry ice condenser for 5 hours, and the ammonia was allowed to evaporate overnight. The residue was heated under reflux with 1.2 liter of pyridine wit~ stirring for 2 hours. Fhe pyridine was distilled out in vacuo and the residue partitioned between methylene chloridç and water. The residue from the ~, 10 dried (sodium sulfate) organic phase was crystallized from ` ether to give 5-~2-fluorophenyl)-1,3-dihydro-7-iodo-2H-1,4-benzodiazepin-2-one, m.p. 221-223. Recrystallization from ethanol gave colorless needles, m.p. 222-224. During this re-action 2-amino-2'-~2-fluorobenzoyl)-4'-iodoacetanilide is formed as an intermediate without being isolated.
To a mixture of 5.34 g ~40 mmole) of aluminum chloride and 250 ml of benzene was added 7.6 g ~20 mmole) of 5-(2-1uoro- ~
phenyl)-1,3-dihydro-7-iodo-2H-1,4-benzodiazepin-2-one. This ~ ;
mixture was then cooled in an ice bath, 10 ml (0.2 mole) of ethylene oxide was added to it and then it was stirred for 2 days at room temperature. The mixture was concentrated in vacuo and the residue shaken with methylene chloride and saturated sodium bicarbonate solution. The insoluble material was filtered off and discarded The methylene chloride layer was separated, dried over sodium sulfate and concentrated in vacuo.
The residue was erystallized with ether ko give llb-~2-fluoro-phenyl)-2,3,5,11b-tetrahydro-10-iodooxazolo~3,2-d3~1,4]benzo--:
~ - 23 ~
~,, ., -diazepin-6(7H)-one, mOp. 1~0-1~4. Recrystalllzation rrom 70 aqueous ethanol gave colorless needles, m.p. 193-1~6.
Example 4 A solutlon o~ 1.5 g ~0.0041 M) of llb-(2-chlorophenyl)-10-nitro-2~3,5,11b-tetrahydrooxazolo[3,2-dlLlJ41benzodiazepin-6(7H)-one in 30 ml o~ dry N,N-dimethylformamide was treated with 0.34 g (o.oo8 M) of a 57~ dispersion o~ sodium hydride in mineral oll with stlrring under nitrogen. After 30 ~inutes, 1.5 g (0.012 M) Or 2-bromoethanol was added and the reaction was heated to ~0 for 3 hours. The solvent was removed under vacuum, and the residue was dissolved in 50 ml of dichloro-methane which was then washed wlth 50 ml of water, 25 ml of a saturated solution o~ brineJ dried over anhydrous sodium sulrate and evaporated to dryness. The residue was crystallized , ........................................................................ .
from ether, and recrystallized from a mixture Or dichloro-methane and methanol to glve llb-(2-chlorophenyl)-7-(2-hydroxy-ethyl)-10-nitro-2,3,5,~11b-tetrahydrooxazoloL3,2-d~L1,4]benzo-diazepln-6(7H)-one as pale yellow prisms, m.p. 185-190 (dec.).
;, The starting material can be prepared as follows:
A solution of` 5.2 g (0.02 M) o~ stannic chloride in 60 ml of dry ethylene dichloride under nitro~en was treated " .
wlth 2.~ g (0.0091 M) of 5-(2-chlorophenyl)-1,3-fllhydro-7-nitro-2H-1~4-benzodlazepin-2-one. The reaction was cooled in ~ -an ice bath, and 2.6 g (o.o6 M) of ethylene oxide in 10 ml o~ ethylene dichloride was added with stirrlng over an j minute perlod. Aft-r 1 8hours at room temperature~ the _ 21~ _ .. . . .
solution was made basic with concentrated ammonium hydroxide and filtered. The iltrates were washed with a saturated solution of brine, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was crystallized from a mixture of dichloromethane~ methanol and petroleum ether to give llb-~2~chlorophenyl)-10-nitro-2,3,5,11b-tetrahydrooxazolo-L3,2-d]~1,4]benzodiazepin-6(7H)-one as white rods, melting at 201-Z03.
ample 5 A solution o 33.3 g ~0.1 M) of 10-chloro-llb-(2-fluoro-phenyl)-2,3,5,11b-tetrahydrooxazolo~3,2-d]~1~4]benzodiazepin-6~71-1)-one in 100 ml of dry N,N-dimethylformamide was treated with 6.6 g (0.138 M) of a 50 per cent dispersion of sodium hydride in mineral oil. The mixture was stirred for 0.5 hour `
at room temperature, was then cooled to 5-10 and treated with a solution of 31 g ~0.186 M) of ethyl bromoacetate in 25 ml of dry N,N-dimethylfo~mamide. The resulting mixture was allowed ~ to stir at room temperature for 18 hours when 3 ml of water was ; carefully added. The solution was next e~aporated to dry-ness under reduced pressure. The residue was next treated with 50 ml of toluene and evaporated to dryness. This procedure was repeated twice in order to remove any rema ming water or N,N-dimethylformamide. The crude ester thus obtained was dis-solved in 250 ml of dry tetrahydrofuran, cooled to 0 and was treated by the portionwise addition o~ 1.9 g ~0.05 M~ of lithium aluminum hydride. The cooling bath was removed and the mixture was allowed to stir for 3 hours. Enough saturated sodium bicarbonate solutlon was added to coagulate the sol.lds and the mixture was riltered. The filtrates were concentrated to dryness and dlssolved in dichloromethane. The solution was washed with lN hydrochlorlc acid, water, saturated brine, dried over anhydrous sodium sulrate and evaporated. The residue was crystallized rrOm toluene to give 10-chloro-llb-(2-fluoro-phenyl)-7-~2-hydroxyethyl)-2,3,5Jllb-tetrahydrooxazolo[~,2-d~-[1,4¦benzodiazepin-6(7H)-one as white prlsms, m.p. 142-147.
' - .
`: :
..
`',' ' .
,, ~
: ':'
26 ~ xN
\ ,~
Rs æ~ \
R /~ ( CH2 )n . .~ .
. ...
.
.
l -: F 915~2 ~ .
. .
'.
~ , .
:~
:
The present invention relates to the preparation of ;~
tricyclic benzodiazepines of the general formula '',. . ~ ' ' Y
erein A represents thegroup -C-; Z is -0-;
Rl is hydrogen, halogen, nitro, tri~luoro-methyl, lower alkyl, lower alkyl mercap~o or lower alkoxy; R2 is hydroxy-lowex alkyl; R3 i5 hydrogen or lower alk~ is a di- or trimethylene group;
and R5 is phenyl or phenyl substituted with halogen.
10As used herein, the term "lower alkyl", either alone or in combination, comprehends straight or branched chain hydrocarbon groups having from 1-7 carbon atoms, preferably 4 carbon atomsj such as methyl, ethyl, propyl, isopropyl :~
~ and the like. The term "acyl'l encompasses an organic radical .. . .
:, , ~ 2 -.
derived by removal of a hydroxyl group from an organic acid, ; such as an alkanoic acid containing from 2-7 carbon atoms, for example propionyl and the like. The term "lower alkoxy"
comprehends a lower alkyl group having an oxygen function substituted therein, such as methoxy, ethoxy~ propoxy, etc.
The term "halogen" represents all four forms thereof, i.e., fluorine, chlorine, bromine and iodine, unless expressly in-dicated otherwise. The term "lower alkanol" connotes primary, secondary, or tertiary saturated aliphatic alcohols such as methanol, ethanol, propanol, isopropanol and the like.
A particularly preerred embodiment of the present invention encompasses the compounds of formula I
and whereln Rl is hydrogeng halogen, nitro, trifluoro-meth~l, or lower alkyl.
A still more preerred embodiment of the present in- ;
vention encompasses the compounds of formula I wherein Rl is hydrogen or halogen~ with chlorine being the preferred halogen, and is joined to the benzodiazepine moie~y at the 7-position thereo ci.e. the p-pOsitioll with respect to the -N-A g~ouping~; R3 ls hyd~ogen; and R5 is phenyl or phenyl substituted at the ortho position with halogen, with 1uorine being the most preferred halogen.
~,, ' ~.
'' :
" . .
~ 3 ~
. ! ; ~:
''. : ' :.' 4~
Most preferred among the compounds of formula I above are those wherein Rl is chlorine and is joined to the benzodiazepine moiety at the 7-position thereof; R2 is ~-hydroxy ethyl; R3 is hydrogen; Y is the dim~thylene group and :~.
R5 is phenyl or phenyl substituted in the ortho position with fluorine.
Examples of compounds which correspond to formula I and which are thus representative of the present invention may be ~ ted as follows:
10-Chloro-7-~2-hydroxyethyl~-2,3,5,11b-tetrahydro-llb-phenyloxazolo~3,2-d]~1,4]benzodiazepin-6-~7H)-one;
10-Chloro-llb-t2-fluorophenyl)-7-~2-hydroxyethyl)-2,3,5,11b-tetrahydrooxazolo[3,2-d]~1,4]benzodia~epin- ::
6-(7H)-one;
llb-~2-Fluorophenyl)-7-~2-hydroxyethyl)-10-iodo-2,3 J 5,1lb-tetrahydrooxazolo~3,2-d~1,4~benzodiazepin-6~7H)-one;
llb-(2-Chlorophenyl)-7-~2-hydroxyethyl)-10-nitro- :~
2,3,5,11b-tetrahydrooxazolo~3,2-d][1,4}benzodiazepin-6~7H)-one.
In accordance with the present inven~ion, compounds of formula I may be prepared by a) splittîng off the protecting group from a compound of the : general formula :; :
'~ :
::
., ~ . . . . . , . ~ ~ , .
3L(1 ~499 2 ; .:
N - A
Rl ~ ~ N
Y
II
: .
" ~ , ., wherein Rl, R~, R5, AJ ~ and Z are as defined s earlier and R12 is a hydroxy-lower alkyl group with the hydroxy group being protected by a . .
protecting group, -.
: : - .
o~
; b~ h~droxy-lowe~ alkylating a compound of the general formula Bl ~
- R Z ~ III
, . ~ .
~-~n Bi, R3~ R5~ A~ Y and Z are as defined 0~ : earlier, to lntroduce the requlred group R2, . :
cl~reducing a:compound o~ the general ~ormuIa ( I H2 )mC~R7 n~ ~ N~ > ~H3 IV
wherein R~ R5, AJ Y and Z are as de~ined earlier, R'l is halogen, ~ is lower alkyl and m is a whole integer ~rom l-6, to the correspondlng carblnol.
Thus, in a rirst process aspect of the present invention, the protecting group is ~}r}~ off from a compound Or the rormula II, above. Suitable protecting groups ~or the purpose of thls rirst process aspect Or the present invention include ;~
the acyl mo~ety o~ a lower alkanoic acid such as acetyl, propionyl and the like or oarbobenzoxy. The splitting Or~ o~
: the protecting group ~an be e~rected by conventlonal techniques9 ror example, by alkaline hydrolysls. The alkaline hydrolysis is expeAiently carrled out in the presence Or an inert solvent.
~ ; 15 Sultable bases include alkall-hydroxldes or alkaline earth metal hydroxldes, such as sodlum hydroxide~ calcium hydroxlde ; ~ and the like.
In a further process aspect Or the present invention, a hydroxy-lower alkyl group can be introduced into a compound of:~ormula III9 above, by reactlng said compound with a ;
suitable hydroxy-lower alkylating agent. Thus, one can prepare a compound of the formula I, above, by first preparing the l-sodio derivative of a compound of the formulcl III, above~
and without isolation reacting said l-sodio derivative wi~h a suitable hydroxy-lower alkylating agent, e.g. with halo-lower alkanols.
Representative of such hydroxy-lower alkylating agents are 2-bromoethanol, 3-bromopropanol and the like.
The l-sodio derivative of a compound of formula III
above can be prepared by treating said compound with a sodium lower alkoxideJ such as sodium methoxide, or with sodium hydride. This reaction is expediently effected in the presence of an inert organic solvent such as dimethylformamide, aromatic hydrocarbons, e.g. benzene~ toluene and the like, with di-methylformamide being the pre~erred solvent. For the purposes o this reaction, temperatures above and below room temperature may be employed. In a preferred embodiment temperatures between about 0 and 10C are utilized.
The hydroxy-lower alkylation of the l-sodio derlvative o a compound o ormu1a III above is expediently effected in the presence oE an inert solvent such as dimethylformamide, aromatic hydrocarbons, e.g. benzene, toluene and the like, ~ith dimethylformamide being the preerred solvent. This re-action may be ef~ected usin~ temperatures above and below room temperature, with temperatures between about 10C and room temperature being preferred.
''' In a further process aspect of the present invention, a compound of for~ula I above wherein Rl is halogen may be prepared by reducing a compound of the formula IV, aboveJ with a suitable reducing agent such as lithium aluminum hydride.
Said compound of formula IV is prepared by reacting the l-sodlo derivative of a compound of the formula III, above, wherein Rl is halogen with a compound of the formula X'-(CH2)mC00-lower alkyl V
wherein X' is chlorine, bromine or iodine and m is as defined earlier.
The compound of formula IV thus obtained is then without isolation, reduced with a suitable reducing agent such as lithium aluminum hydride, to produce the corresponding compound of formula I.
Representative of the compounds of formula V suitable for this process aspect are ethyl bromoacetate, ethyl 3-bromo-propionate~ and the like. The l-sodio derivative of the compound of ~ormula III, wherein Rl is halogen, can be prepared, as described hereinbefore, i.e. by treating said compound with a sodium lower alkoxide, such as sodium methoxide or with sodium hydride. This reaction is expediently effected in the presence of an inert organic solvent swch as dimethylformamide, aromatic hydrocarbons, e.g~ benzene, toluene and the like, with dimethylformamide being the preferred solvent. ~or the .-, .
-, purposes of this reaction, temperatures above and belo~ room temperature may be employed. In a preferred embodiment tempera-tures between about 0 and lO~C are utilized. The esterification reaction is expediently effected in the presence of an inert ~I
.. ..
'. .
~' solvent such as dimethylformamide.
The startlng materials Or ~ormulae II and III may be prepared by reacting a 2-substituted aminophenyl ketone Or the formula . ' ~ N -A -CH --X' Rl ~ ~ VI
~-0 : ., ..
whereln Rl, R3, ~5, A and X are as defined earlier and R"2 represents hydrogen or a hydroxy-lower . alkyl group wlth the hydroxy group being protected by any sultable protecting group ~ ~ ~o ~ /co ~o/
:1 ~ 10 wlth a d~amine or a~ee}~ehe~ Or the general formula ~ , l H2N- Y~ ZH VII
. I . .
I wherein Y and Z are as derined earlier.
., .
The reaction between the ¢ompounds Or ~ormulae YI and ;
,: VII above is conducted in a reacti on medium con~aining a base l 15 and an inert or~anic solvent at a temperature in the range Or ,~ ~ rrom about 25C to the rerlux temperature Or the reactlon medlum, preferably at about the reflux temperature. Suitable :.
bases for the purposes o~ this process are inorgarlic bases, such as sodium acetate, and organic bases such as the . tertlary amlnes, for example, trialkylamines, with triethylamlne and pyridine being prererred. A variety Or or~anic solvents are userul ror the purposes Or this process. Among these sultable solvents are lower alkanols, such as methanol, ethanol, propanol, etc.g with ethanol being pre~erred; aromatic alcohols, such as benzene, toluene, xylene, etc ; hlgh boiling point ethers, such as tetrahydroruran and dioxane; and a~lides, such as dimethylrormamide, dlethyl~ormamide and the like. Examples of compounds o~ formula VII userul in this lnvention include 2-aminoethanol, ethylenediamine, 3-aminopropanol, etc.
.
; The compounds Or rormulae VI and VII above are readily prepared in a manner known in the art. lt should be noted that in preparlng the compounds Or rormula VI above wherein R"2 is a hydroxy-lower alkyl group with the hydroxy group being pro , 15 tected by any sultable protecting group, i.e. compounds of `~ formula ~ N- A- CH - X
; Rl ~ VI-a ~; Rs ~.:
Rl, R 2' R3, R5, A and X are as de~ined earlier, lt ls expedient to first protect the hydroxyl group present ~ in the ketone startlng material before introducing the -A~H-X' :~ substituent9 A, R~ and X being derined as above, into the , , .. . . : . . -molecule, i.e. to first prepare a compound of formula R~
.
I ,''.
NH
R~
VIII
~5 :' ' wherein Rl, R'2 and R5 are as defined earlier.
By so-protecting the hydroxyl group, one can avoid unwanted side reactions and unwanted side products which of necessity render the reaction less eficient. ~ -If, in the compounds of ormula VI, X' is chlorine or ~ bromine~ the reaction mixture may also contain sodium iodide - in order to exchange the X' substituent for the more reactive iodine atom whicll then is removed in the ensuing reaction.
j 10 The reaction path descri~ed above for the cyclization ;'~ ' ' ~' . ~ .. ...
.:
; ~ ' h '' " ' :'~ '' ' '' , .
. ' ' .`
., ', . . ' process ls believed to proceed via an intermediate of the ~ollowing proposed structure t 2 ~3 N- A- H - NH- Y- Z- H
Rl t II IX
~ ~=0 , . .
1' 2' R3, R5, A, Y and Z are as de~ined earlier which need not be isolated from the reaction mixture as it cyclizes to the deslred compounds under the reactlon conditions employed. By uslng less energetic reaction conditions, the compounds o~ the ~ormula IX can be isolated and subsequently cyclized to the deslred product. However3 in a preferred embo-dlment, the lntermediate ls not isolated but is permitted to -l cyclize in the reaction medium in which it is prepared.
Compounds Or rormula .. . .
~ - A
~1 ~ k ~ A
~ ':
R~4 wherein Rl~ R2. R3, R5 and A are as defined earlier .:
- 12 - ~
.
and R'4 represents hydrogen, lower alkyl or CH2X
where X is as de~ined earlier, may also be obtained by reactlng a 4,5-unsaturated 1,4-benzo-diazeplne Or the general rormula ~ A
R1~ XR X
wherein Rl, R2, R3, R5 and A are as defined earlier with an epoxide compound of the general formula C ~ CH R'4 XI
1 .
wherein R'4 is as deflned above in the presence of an acidlc agent such as, for example, an aprotic acid, e.g., alumlnum chloride, ferric chloride, zinc chloride, tltanium tetrachloride, boron trifluoride, etc.;
or p-toluene sulronic acid, benzene sul~onic acid, and the i like. The most prererred acidic a~ent ls alumlnum chloride.
Examples o~ compounds o~ formula XI lnclude ethylene oxide, propylene oxide, l-chloro-2~3-epoxy propane, etc.
The reactlon is conveniently conducted in the presence an anhydrous inert organlc solvent. Suitable inert or-ganlc solvents for thls purpose include, for example, aromatic hydrocarbons such as benzene3 toluene, xylene, etc.l ethers~
.. . .
: .~ - 13 ~
. ~ . . . ~ . , .
such as tetrahydroruran and diethyl ether, or carbon disulride.
This reaction may be carried out at a temperature in the range of` from about -10C to the ref`lux temperature o~ the reaction medium, most preferably from 10C to t;he reflux temperature.
-- 5 The selection of temperature is not critical f`or the purposes of the present reactlon and will, of courseJ depend upon the characteristics of the compounds selected as reagents, the ~- solvent medium employed and the nature of the acidic agent used.
:~
I 10 It would appear that when a compound of formula X is i reacted with a compound o~ ~ormula XI wherein R'l~ is other than hydrogen, the R'4 bearing carbon atom can be attached relative to the benzodiazepine ring in one of two alternate positions, depending upon the point where the epoxide ring l 15 cleaves during the reaction. However, experimentation has i shown that the epoxide ring evidences a propensity to favor cleavage between the oxygen and the unsubstituted carbon atom.
Thus, when cleavage occurs at thls point, the carbon atom bear-ing the R'4 substituent is bonded to the oxygen atom in the heterocyclic ring.
It should be noted that compounds of' ~ormula XI above rnay, in addltion to forming the heterocyclic ring between the 4 and 5 positions of' the benzodiazepine moiety upon reaction with the compound of formula X, also react with the nitrogen atom in the l-position of' the compounds of formula X~ Thus~
the reaction can result in a mixture of compounclsv the first showing no substitution on the l-nitrogen and the second being ' ' correspondingly substituted on the l-ni~rogen. Experimentation has shown that by controlling the reaction conditions, sub-stitution at the l-nitrogen can be avoided.
The compounds of ormula XI, above, are readily prepared ~- in a manner known in the art. -The tricyclic benzodiazepine derivatives of formula I
above are useul as pharmaceuticals and are characterized by activity as sedative, muscle relaxant and anti-convulsant agents.
The pharmacological activity of 10-chloro-llb-(2-fluoro-10 phenyl)-7-(2-hydroxyethyl)-2,395,11b-tetrahydrooxa~olo~3,2-d]
; ~1,4]benzodiazepin-6-(7H)-one was determined in two standard screening tests.
The test results from these tests are summarized below.
Footshock: 100% Blocking Dose Level - 4 mg/kg Inclined Screen: PD50 - 15 mg/kg The compounds of for~ula I can be used in the form of conven~ional pharmaceutical preparations; for example, the aforesaid compounds can he mixed with conventional organic or inorganic, inert pharmaceutical carriers suitable for parenteral 20 or enteral administration such as ~or example, water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oil, gums, , ~ . .
.~
.
~ - 15 - ~ ~
~; ~ ,'~, '' ~'' '~,' .' D
polyalkylene glycols, Vaseline or the like. They can be ad-ministered in conventional pharmaceutical forms, e.g., solid forms, for example, tablets, dragees, capsule~s, suppositories or the like, or in liquld forms, for example, solutions, sus-- pensions or emulsions. Moreover, the pharmaceutical compositions containing compounds of formula I can be subjected to conventional pharmaceutical expedients such as sterilization, and can contain conventional pharmaceutical excipients such as preservatives, stabilizing agents, wetting agents, emulsi-` 10 fying agents, salts for the adjustment of osmotic pressure,or buffers. The compositions can also contain other thera-peutically active materials.
A suitable pharmaceutical dosage unit can conta:in from about 1 to about 500 mg of the aforesaid compounds o formula I with a dosage range of rom about 1 mg to about 100 mg being preferred for oral administration and a dosage range of from about 1 mg to about 50 mg being preferred for parenteral ad- ;
ministration. However, for any particular subject, the specific dosage regimen should be adjusted according to individual need and the professional judgment of the person administering or supervising the administration of the aforesaid compounds. It is to be understood that the dosages set forth herein are exemplary only.
The following examples are illustrative, but not limitative ; of this invention. All temperatures given are in degrees centi-grade~ unless indicated otherwise.
:::
'' - 16 - ~
; ' '-ample 1 A solution of O.S g (0.0012 M) of 7-(2-acetoxyethyl)-10-chloro-llb-(2-fluorophenyl)-2,3,5, llb-tetrahydrooxazolo-~3,2-d]~1,4~benzodiazepin-6~7~1)-one in 5 ml of methanol was tr~ated with 2 ml of 3N sodium hydroxide. A-fter 3 hours, 50 ml of water was added and the solution was extracted with 40 ml of h-~- dichloromethane, which was then dried over anhydrous sodium sulfate and evaporated to dryness. The residue was crystallized from a mixture o methanol and water to give 10-chloro-llb-10 (2-fluorophenyl)-7-~2-hydroxyethyl)-2~3,5,11b-tetrahydrooxazolo-L3,2-d]~1,4]benzodiazepin-6~7~ one as whita prisms, m.p~
141-1~6.
The starting material can be prepared as follows:
A solution of 10 g ~0.04 M) of 2-amino-5-chloro-2'-fluoro-benzophenone in 100 ml of dry benzene was treated with 10.6 g ~0.08 M) of aluminum chloride under nitrogen. The reaction ~ixture was next treated with 7 g Co.l6 M~ of ethylene oxide ~5 minute period)~ k~eping the temperature below 35 with an , ice bath. After-65 hours at room t~mperature, the procedure 20 was repeated using the same amounts of aluminum chloride and ethylene oxide as before. After 5 hours at room temperature, the benzene was removed by distillation, and tha residue was ; .
made basic with ammonium hydroxide, stirred with 100 ml of ;;~
dichloromethane and filtered. The organic layer was separated~
, . , :.
", ,~ ,: "
~' ' ~ 17 -: . .
~ ~ ' washed with saturated brine, dried over anhydrous sodium sulfate and evaporated ~o dryness. The product was recrystallized three times from a mixture of ether and petroleum e~her to -~ give 5-chloro-2'-fluoro-2-~2-hydrQxyethyl)aminobenzophenone as yellow needles~ m.p. 96-101.
A solution of 15 g ~0.0516 M) of 5-chloro-2'-fluoro-2 (2-hydroxyethyl)aminobenzophenone in 75 ml of ace~ic anhydrlde was heated on the steam bath for 1 hour. The solvent was re-moved under reduced pressure and the residue was dissolved in 10 75 ml of benzene. This solution was ~iltered through a column of 100 g of silica gel. The column was eluted with 500 ~1 of benzene which was discarded, and 1 liter of dichloromethane.
Removal of the dichloromethane gave a residuewhich was crystallized from a mixture of ether and petroleum ether to , give 2-(2-acetoxyethylamino~-5-chloro-2'-fluorobenzophenone as ; yollow rods, m.p. 48-55.
A mixture of 2.5 g (0.0074 M) of 2-(2-acetoxyethylamino)-5-chloro-2'-fluorobenzophenone and 5 g (0.0362 M) of potassium carbonate in 25 ml of dry chloroorm was treated with 2.0 g 20 (0.0096 M) of bromoacetyl bromide over a 20 minute period with s~irring. The mixture was stirred for 1 hour at room tempera-ture when 25 ml of water was added, and the chloroform layer was separated. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and evaporated to dryness. The residual oil ~as dissolved in 10 ml of benzene, and chromatographed over 100 g o Florisil*. Elution with 1 liter of benzene gave 0.2 g of an oil and elution with 1.5 liter of '.' '' ' ' .:
*Trade mark for a highly selectiYe absorbent o~ extremely white, hard granular or powdered magnesia-silica gel ~magnesium silicate).
: . . .
ether and I liter of ethyl acetate ~ave 1.~ g and 1.0 g,respectively o~ a colorless oil which were combined and re-crystallized from a mixture of dichloromethane and petroleum ether to give 2-[N-(2-acetoxyethyl)-N (2-bromoacetyl)aminoJ-5~
chloro-2'-fluorobenzophenone as white prisms, m.p. ~4-~.
': ' A solution containing 1.5 g (0.0033 M) of 2-LN-(2-acetoxy-ethyl)-N-(2 bromoacetyl)aminoJ-5-chloro-21-rluorobenzophenone, 0.5 ml of triethylamine and 0.23 g (0.0036 M) of ~thanolamine in 15 ml of benzene was kept at room temperature for 65 hours and then was partitioned between 25 ml Or ethyl acetate and 25 ml Or water. The organic layer wa~ separated, washed with sa-turated brine, dried over anhydrous sodlum sul~ate and eva-porated to dryness. The residue was partioned between 20 ml o~
ether and 20 ml o~ lN hydrochloric acid. The acid layer was se-parated and extracted wlth 25 ml of ethyl acetate. The organic ., layer was then washed with 20 ml o~ dilute ammonium hydroxide, i dried over anhydrous sodium sulfate and evaporated to dryness.
The re~idual oll was crystalllzed from ether and recrystallized rrom a mlxture of methanol and water to give 7-(2-acetoxyethyl~-10-chloro-llb-(2-rluorophenyl)-2,3,5,11b-tetrahydrooxazolo-L3J2-d~Ll34lbenzodlazepin-6(7H)-one as white prisms, m.p.
120-12~.
;~1 ' ~ , . .
.. . .
A solutlon o~ 5 g (0~015 M) of 10-chloro-llb-(2-fluoro-~ 25 phenyl)-2,3,5~11b-tetrahydrooxazolo~3,2-d~194~benzodiazepin-- 6(7H)-one ln 50 ml Or dry N7N-dlmethyl~ormamlde under nitrogen :, . ~ .,. ... .- - , was treated with 1.~ g (0~0~0 M) of a 57~ dispersion Or sodium hydride in mineral oil and after 30 minutes, 4.0 g (0.0~0 M) Or 2-bromocthanol was added. The mixture was kept at 600 for 1~ hours, when 450 ml Or water was added, followed by enough 3N hydrochloric acid to lower pH to less than 5. The mixture was extracted with dichloromethane (3 x 125 ml)~ The organic layers were comblned, washed with saturated brlne, dried over anhydrous sodium sulf`ate and evaporated to dryness. The resldue was dissolved in ether (50 ml) and ~iltered through 75 g Or neutral alumina. Elution with ethyl acetate and methanol gave ; 10-chloro-llb-(2-f`luorophenyl)-7-(2-hydroxyethyl)-2,~,5~11b-~t ra h~!r~o~q æo/~7 h~e*~ oL3,2-d]L1,4Jbenzodiazepin-6(7H)-one, which was crystallized from ether to give the product as white prisms, m.p. 142-147.
The starting material may be prepared as follows:
To 15 g (51.9 mmole) of` 7-chloro-5-(2-~luorophenyl)-1~3-dihydro-2H-1,4-benzodiazepin-2-one in 150 ml of` dry benzeneJ
g (67.7 mmole) of' aluminum chloride was added and stirring was continued 15 minutes. The reaction mixture was cooled in an ice bath and 2.~ g (0.2 mole) Or ethylene oxide was added dropwise. After 1~ hours Or stirrlng at room temperatureJ the reaction mixture was heated to 40 ~or 1 hour and then cooled to room te~perature and treated with 5 g (~7.6 mmole) of aluminum chloride, f`ollowed by 4.4 g (0.1 mole) of ethylene oxide. The reaction mixture wa~ heated 4 hours at 45-50 and then evaporated to dryness. Methylene chloride, ice and ammonium hydroxide were added and the solid removed by fil-tration. The f`iltrate was separated and the organic phase re-~ 20 ~
49~
duced to dryness in vacuo. The residue was dissolved in dilute hydrochloric acld and the pH of` the solution ad~usted to 5 with ammonium hydroxide. The acidic solution was washed with ether, made basic and extracted with rnethylene chloride. The organic phase was washed with brine, dried and evaporated to dryness. Recrystallization from methylene chloride-hexane gave 10-chloro-llb-(2-fluorophenyl~-2J3~5~11b-tetrahydroxazolo-~2-d~LlJ4]benzodiazepin-6(7H)-one as colorless rods, m.p.
~ 1~3-1~4.
.,, ~ .
Exam~le ~
A solutlon of o.8 g (0.00187 M) of llb-(2-~luorophenyl)-2,3J5,11b-tetrahydro-10-iodooxazolo[3,2-d~Ll,41benzodlazepin-~, 6(7H)-one in 25 ml Or dry N,N-dimethylformamide under nitrogen was treated with 0.11 g ~0.00262 M) Or a 57~ dlspersion Or sodium hydrlde in mlneral oil. Af`ter stirring ror 30 minutes ~, in an ice bath, 0.37 g (0.00374 M) Or 2-bromoethanol was added, and the reaction was heated to 115-120 for 3 hours and at i 125-130 ~or 1 hour. The solvent was removed under vacuum, and the residue was dissolved in 25 ml of dichloromethane and washed with saturated brine, dried over anhydrous sodium i sulf`ate and evaporated to dryness. The residue was heated under '~
re~lux ror 15 minutes ln a solution of 10 ml o~ triethylamine, ~ containing 0.5 g (0.005 M) Or succinic anhydride. The solvent g was removed under reduced pressure and the residue was dis-solved in 25 ml of dichloromethane. The hal~ ester was ex-tracted lnto 20 ml of dilute ammonium hydroxide which was then tre~ted ~:rlth 5 ml o~ ~N sodlum hydroxide for 1 hour. The ,ij;
... ~ . . . , . . ,, . , .. , .. :. .. . . : . . . .
solution was extracted wi~h 25 ml of dichloromethane/ which was dried with anhydrous sodium sul~at;e, and evaporated. The resulting oil was crystallized f'rom et;her to glve llb-(2-fluoro-phenyl)-7-(2-hydroxyethyl)-10-iodo-2,3,5~11b-tetrahydrooxazolo-[~,2-d~1,43benzodiazepin-6(7H)-one as whlte plates, m.p.
160-165.
The starting material may be prepared as ~ollows:
.
- To a stirred solution of 43 g (0.2 mole) Or 2-amino-2'-f~luorobenzophenone in 1 liter Or chloro~orm was added 65 g (0.4 mole) of iodine monochloride in 50 ml of chloroform at roorn temperature. This mixture was stirred 1 hour at room temperature and the excess iodine monochloride was destroyed by the addltion Or 1 liter Or saturated sodlum bisulrite sol~
ution. It was then neutralized with concentrated ammonium hydroxide. The chloroform layer was separated~ dried over sodium sulfate and concentrated in vacuo. The residue crystalllzed with hexane to give 2-amino-2'-rluoro-5-iodobenzophenone~ m.p.
~3-~6. Recrystallization ~rom ethanol/water gave orange needles ` m.p. 102-105.
A mixture of 32.1 g (~4.3 mmole) of 2~amino-2'-~luoro-5-iodobenzophenone, 40.2 g (0.2 mole) of bromoacetyl bromlde and 500 ml o~ benzene was heated under re~lux for 2 hours, cooled, and neutralized with dllute ammonium hydroxide. Methylene chloride was added and the organic phase separated. It was washed with water, dried over sodium sulfate and concentrated in vacuo to 200 300 ml. Addition of petroleum ether gave 2-bromo ~ -fluorobenzoyl)-4' iodoace~anilida, m~p. 14~-151o Recrystallization -from ethanol gave oFf-white needles, m.p.
150-151.
A mixture of 27 g (58.5 mmole~ of 2-bromo-2' (2 fluoro-benzoyl)-4'-iodoacetanilide and 750 ml of liquid ammonia was stirred under a dry ice condenser for 5 hours, and the ammonia was allowed to evaporate overnight. The residue was heated under reflux with 1.2 liter of pyridine wit~ stirring for 2 hours. Fhe pyridine was distilled out in vacuo and the residue partitioned between methylene chloridç and water. The residue from the ~, 10 dried (sodium sulfate) organic phase was crystallized from ` ether to give 5-~2-fluorophenyl)-1,3-dihydro-7-iodo-2H-1,4-benzodiazepin-2-one, m.p. 221-223. Recrystallization from ethanol gave colorless needles, m.p. 222-224. During this re-action 2-amino-2'-~2-fluorobenzoyl)-4'-iodoacetanilide is formed as an intermediate without being isolated.
To a mixture of 5.34 g ~40 mmole) of aluminum chloride and 250 ml of benzene was added 7.6 g ~20 mmole) of 5-(2-1uoro- ~
phenyl)-1,3-dihydro-7-iodo-2H-1,4-benzodiazepin-2-one. This ~ ;
mixture was then cooled in an ice bath, 10 ml (0.2 mole) of ethylene oxide was added to it and then it was stirred for 2 days at room temperature. The mixture was concentrated in vacuo and the residue shaken with methylene chloride and saturated sodium bicarbonate solution. The insoluble material was filtered off and discarded The methylene chloride layer was separated, dried over sodium sulfate and concentrated in vacuo.
The residue was erystallized with ether ko give llb-~2-fluoro-phenyl)-2,3,5,11b-tetrahydro-10-iodooxazolo~3,2-d3~1,4]benzo--:
~ - 23 ~
~,, ., -diazepin-6(7H)-one, mOp. 1~0-1~4. Recrystalllzation rrom 70 aqueous ethanol gave colorless needles, m.p. 193-1~6.
Example 4 A solutlon o~ 1.5 g ~0.0041 M) of llb-(2-chlorophenyl)-10-nitro-2~3,5,11b-tetrahydrooxazolo[3,2-dlLlJ41benzodiazepin-6(7H)-one in 30 ml o~ dry N,N-dimethylformamide was treated with 0.34 g (o.oo8 M) of a 57~ dispersion o~ sodium hydride in mineral oll with stlrring under nitrogen. After 30 ~inutes, 1.5 g (0.012 M) Or 2-bromoethanol was added and the reaction was heated to ~0 for 3 hours. The solvent was removed under vacuum, and the residue was dissolved in 50 ml of dichloro-methane which was then washed wlth 50 ml of water, 25 ml of a saturated solution o~ brineJ dried over anhydrous sodium sulrate and evaporated to dryness. The residue was crystallized , ........................................................................ .
from ether, and recrystallized from a mixture Or dichloro-methane and methanol to glve llb-(2-chlorophenyl)-7-(2-hydroxy-ethyl)-10-nitro-2,3,5,~11b-tetrahydrooxazoloL3,2-d~L1,4]benzo-diazepln-6(7H)-one as pale yellow prisms, m.p. 185-190 (dec.).
;, The starting material can be prepared as follows:
A solution of` 5.2 g (0.02 M) o~ stannic chloride in 60 ml of dry ethylene dichloride under nitro~en was treated " .
wlth 2.~ g (0.0091 M) of 5-(2-chlorophenyl)-1,3-fllhydro-7-nitro-2H-1~4-benzodlazepin-2-one. The reaction was cooled in ~ -an ice bath, and 2.6 g (o.o6 M) of ethylene oxide in 10 ml o~ ethylene dichloride was added with stirrlng over an j minute perlod. Aft-r 1 8hours at room temperature~ the _ 21~ _ .. . . .
solution was made basic with concentrated ammonium hydroxide and filtered. The iltrates were washed with a saturated solution of brine, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was crystallized from a mixture of dichloromethane~ methanol and petroleum ether to give llb-~2~chlorophenyl)-10-nitro-2,3,5,11b-tetrahydrooxazolo-L3,2-d]~1,4]benzodiazepin-6(7H)-one as white rods, melting at 201-Z03.
ample 5 A solution o 33.3 g ~0.1 M) of 10-chloro-llb-(2-fluoro-phenyl)-2,3,5,11b-tetrahydrooxazolo~3,2-d]~1~4]benzodiazepin-6~71-1)-one in 100 ml of dry N,N-dimethylformamide was treated with 6.6 g (0.138 M) of a 50 per cent dispersion of sodium hydride in mineral oil. The mixture was stirred for 0.5 hour `
at room temperature, was then cooled to 5-10 and treated with a solution of 31 g ~0.186 M) of ethyl bromoacetate in 25 ml of dry N,N-dimethylfo~mamide. The resulting mixture was allowed ~ to stir at room temperature for 18 hours when 3 ml of water was ; carefully added. The solution was next e~aporated to dry-ness under reduced pressure. The residue was next treated with 50 ml of toluene and evaporated to dryness. This procedure was repeated twice in order to remove any rema ming water or N,N-dimethylformamide. The crude ester thus obtained was dis-solved in 250 ml of dry tetrahydrofuran, cooled to 0 and was treated by the portionwise addition o~ 1.9 g ~0.05 M~ of lithium aluminum hydride. The cooling bath was removed and the mixture was allowed to stir for 3 hours. Enough saturated sodium bicarbonate solutlon was added to coagulate the sol.lds and the mixture was riltered. The filtrates were concentrated to dryness and dlssolved in dichloromethane. The solution was washed with lN hydrochlorlc acid, water, saturated brine, dried over anhydrous sodium sulrate and evaporated. The residue was crystallized rrOm toluene to give 10-chloro-llb-(2-fluoro-phenyl)-7-~2-hydroxyethyl)-2,3,5Jllb-tetrahydrooxazolo[~,2-d~-[1,4¦benzodiazepin-6(7H)-one as white prlsms, m.p. 142-147.
' - .
`: :
..
`',' ' .
,, ~
: ':'
Claims (21)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of tricyclic benzodiazepines of the general formula I
wherein A represents the group -C-;
Z is -O-;
R1 is hydrogen, halogen, nitro, trifluoromethyl, lower alkyl, lower alkyl mercapto or lower alkoxy;
R2 is hydroxy-lower alkyl;
R3 is hydrogen or lower alkyl;
Y is a di- or trimethylene group; and R5 is phenyl or phenyl substituted with halogen, which comprises (a) splitting off the protecting group from a compound of the general formula II
wherein R1, R3, R5, A, Y and Z are as above defined and R2 is a hydroxy-lower alkyl group with the hydroxy group being protected by a protecting group, or (b) hydroxy-lower alkylating a compound of the general formula III
wherein R1, R3, R5, A, Z and Y are as above defined, to introduce the required group R2, or (c) reducing a compound of the general formula IV
wherein R3, R5, A, Y and Z are as above defined, R? is halogen, R7 is lower alkyl and m is a whole integer from 1-6, to the corresponding carbinol.
wherein A represents the group -C-;
Z is -O-;
R1 is hydrogen, halogen, nitro, trifluoromethyl, lower alkyl, lower alkyl mercapto or lower alkoxy;
R2 is hydroxy-lower alkyl;
R3 is hydrogen or lower alkyl;
Y is a di- or trimethylene group; and R5 is phenyl or phenyl substituted with halogen, which comprises (a) splitting off the protecting group from a compound of the general formula II
wherein R1, R3, R5, A, Y and Z are as above defined and R2 is a hydroxy-lower alkyl group with the hydroxy group being protected by a protecting group, or (b) hydroxy-lower alkylating a compound of the general formula III
wherein R1, R3, R5, A, Z and Y are as above defined, to introduce the required group R2, or (c) reducing a compound of the general formula IV
wherein R3, R5, A, Y and Z are as above defined, R? is halogen, R7 is lower alkyl and m is a whole integer from 1-6, to the corresponding carbinol.
2. A process as claimed in claim 1 wherein the protecting group present in the compound of formula II is the acyl moiety of a lower alkanoic acid or carbobenzoxy.
3. A process as claimed in claim 1 wherein the protecting group is acetyl or propionyl.
4. A process as claimed in any one of claims 1 to 3 wherein the protecting group is split off by alkaline hydrolysis.
5. A process as claimed in claim 1, 2 or 3 wherein the protecting group is split off by alkaline hydrolysis effected by means of an alkali hydroxide or an alkaline earth metal hydroxide in the presence of an inert solvent.
6. A process as claimed in claim 1 wherein the compound of formula III
is converted into the 1-sodio derivative which is then reacted with a hydroxy-lower alkylating agent.
is converted into the 1-sodio derivative which is then reacted with a hydroxy-lower alkylating agent.
7. A process as claimed in claim 6 wherein the compound of formula III
is converted into the 1-sodio derivative by treating said compound with a sodium lower alkoxide or with sodium hydride in the presence of an inert organic solvent.
is converted into the 1-sodio derivative by treating said compound with a sodium lower alkoxide or with sodium hydride in the presence of an inert organic solvent.
8. A process as claimed in claim 6 or 7 wherein a halo-lower alkanol is used as the hydroxy-lower alkylating agent.
9. A process as claimed in claim 1 wherein the compound of formula IV
is reduced with lithium aluminum hydride.
is reduced with lithium aluminum hydride.
10. A process as claimed in claim 1 wherein R1 is hydrogen, halogen, nitro, trifluoromethyl or lower alkyl.
11. A process as claimed in claim 10 wherein R1 is hydrogen or halogen which is joined to the fused benzene nucleus in the para-position to the -?-A- grouping, R3 is hydrogen, Y is a di- or trimethylene group and R5 is phenyl or phenyl substituted at the ortho position with halogen.
12. A process as claimed in claim 11, wherein R1 is chlorine, R2 is .beta.-hydroxyethyl, Y is a dimethylene group and R5 is phenyl or o-fluorophenyl.
13. A process as claimed in claim 12 wherein Y is -CH2?CH2-, R5 is o-fluorophenyl and A is -CO-.
14. A process as claimed in claim 13 wherein 10-chloro-11b-(2-fluoro-phenyl)-7-(2-hydroxyethyl)-2,3,5,11b-tetrahydrooxazolo[3,2-d][1,4]benzodiazepin-6(7H)-one is prepared by treating 7-(2-acetoxyethyl)-10-chloro-11b-(2-fluoro-phenyl)-2,3,5,11b-tetrahydrooxazolo[3,2-d][1,4]benzodiazepin-6(7H)-one with sodium hydroxide.
15. A process as claimed in claim 13 wherein 10-chloro-11b-(2-fluoro-phenyl)-7-(2-hydroxyethyl)-2,3,5,11b-tetrahydrooxazolo[3,2-d][1,4]benzodiazepin-6(7H)-one is prepared by treating 10-chloro-11b-(2-fluorophenyl)-2,3,5,11b-tetrahydrooxazolo[3,2-d][1,4]benzodiazepin-6(7H)-one with sodium hydride followed by addition of 2-bromoethanol.
16. A process as claimed in claim 13 wherein 10-chloro-11b-(2-fluoro-phenyl)-7-(2-hydroxyethyl)-2,3,5,11b-tetrahydrooxazolo[3,2-d][1,4]benzodiazepin-6(7H)-one is prepared by treating 7-carbethoxymethyl-10-chloro-11b-(2-fluoro-phenyl)-2,3,5,11b-tetrahydrooxazolo[3,2-d][1,4]benzodiazepin-6(7H)-one with lithium aluminium hydride.
17. A tricyclic benzodiazepine of the general formula I defined in claim 1 whenever prepared by the process claimed in claim 1 or by an obvious chemical equivalent thereof.
18. A compound as claimed in claim 17 wherein R1 is hydrogen, halogen, nitro, trifluoromethyl or lower alkyl, whenever prepared according to the process claimed in claim 10 or by an obvious chemical equivalent thereof.
19. A compound as claimed in claim 17 wherein R1 is hydrogen, or halogen which is joined to the fused benzene nucleus in the para-position to the -N-A-grouping, R3 is hydrogen, Y is a di- or trimethylene group and R5 is phenyl or phenyl substituted at the ortho position with halogen, whenever prepared according to the process claimed in claim 11 or by an obvious chemical equivalent thereof.
20. A compound as claimed in claim 17 wherein R1 is chlorine joined to the fused benzene nucleus in the para-position to the -N-A-grouping, R2 is .beta.-hydroxyethyl, Y is a dimethylene group and R5 is phenyl or o-fluorophenyl, whenever prepared according to the process claimed in claim 12 or by an obvious chemical equivalent thereof.
21. 10-Chloro-11b-(2-fluorophenyl)-7-(2-hydroxyethyl)-2,3,5-11b-tetrahydrooxazolo[3,2-d][1,4]benzodiazepin-(7H)-one, whenever prepared according to the process claimed in claim 14, 15 or 16 or by an obvious chemical equivalent thereof.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA152,329A CA982563A (en) | 1970-04-06 | 1972-09-22 | Process for the preparation of benzodiazepine derivatives |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US026068A US3905956A (en) | 1969-10-02 | 1970-04-06 | Tricyclic benzodiazepines |
Publications (1)
Publication Number | Publication Date |
---|---|
CA1041499A true CA1041499A (en) | 1978-10-31 |
Family
ID=21829705
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA109,681A Expired CA1041499A (en) | 1970-04-06 | 1971-04-06 | Process for the preparation of benzodiazepine derivatives |
CA109,679A Expired CA1042886A (en) | 1970-04-06 | 1971-04-06 | Benzodiazepine derivatives |
CA109,680A Expired CA946385A (en) | 1970-04-06 | 1971-04-06 | Benzodiazepine derivatives |
Family Applications After (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA109,679A Expired CA1042886A (en) | 1970-04-06 | 1971-04-06 | Benzodiazepine derivatives |
CA109,680A Expired CA946385A (en) | 1970-04-06 | 1971-04-06 | Benzodiazepine derivatives |
Country Status (15)
Country | Link |
---|---|
JP (1) | JPS5320520B1 (en) |
AR (3) | AR192875A1 (en) |
AT (2) | AT307427B (en) |
BE (2) | BE765252A (en) |
CA (3) | CA1041499A (en) |
CH (7) | CH579088A5 (en) |
DE (2) | DE2116499A1 (en) |
ES (1) | ES389911A1 (en) |
FR (2) | FR2092007B1 (en) |
GB (1) | GB1281499A (en) |
HU (1) | HU163551B (en) |
IL (2) | IL36551A (en) |
NL (3) | NL165169C (en) |
YU (3) | YU35026B (en) |
ZA (2) | ZA712179B (en) |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
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US3914215A (en) * | 1967-11-27 | 1975-10-21 | Sankyo Co | Benzodiazepine derivatives and process for preparing the same |
-
1971
- 1971-03-24 CH CH103774A patent/CH579088A5/xx not_active IP Right Cessation
- 1971-03-24 CH CH81774A patent/CH574960A5/xx not_active IP Right Cessation
- 1971-03-24 CH CH433471A patent/CH558807A/en not_active IP Right Cessation
- 1971-03-24 CH CH81674A patent/CH574443A5/xx not_active IP Right Cessation
- 1971-03-24 CH CH103674A patent/CH579569A5/xx not_active IP Right Cessation
- 1971-03-24 CH CH425671A patent/CH569015A5/xx not_active IP Right Cessation
- 1971-03-24 CH CH425771A patent/CH547810A/en not_active IP Right Cessation
- 1971-04-01 NL NL7104373.A patent/NL165169C/en not_active IP Right Cessation
- 1971-04-05 ES ES389911A patent/ES389911A1/en not_active Expired
- 1971-04-05 IL IL36551A patent/IL36551A/en unknown
- 1971-04-05 BE BE765252A patent/BE765252A/en unknown
- 1971-04-05 AT AT392172A patent/AT307427B/en not_active IP Right Cessation
- 1971-04-05 ZA ZA712179A patent/ZA712179B/en unknown
- 1971-04-05 BE BE765253A patent/BE765253A/en unknown
- 1971-04-05 IL IL36550A patent/IL36550A0/en unknown
- 1971-04-05 FR FR7111884A patent/FR2092007B1/fr not_active Expired
- 1971-04-05 FR FR7111882A patent/FR2092006B1/fr not_active Expired
- 1971-04-05 ZA ZA712178A patent/ZA712178B/en unknown
- 1971-04-05 DE DE19712116499 patent/DE2116499A1/en active Pending
- 1971-04-05 DE DE19712116532 patent/DE2116532A1/en active Pending
- 1971-04-05 AT AT288071A patent/AT308119B/en not_active IP Right Cessation
- 1971-04-06 JP JP2132371A patent/JPS5320520B1/ja active Pending
- 1971-04-06 YU YU852/71A patent/YU35026B/en unknown
- 1971-04-06 CA CA109,681A patent/CA1041499A/en not_active Expired
- 1971-04-06 HU HUHO1368A patent/HU163551B/hu unknown
- 1971-04-06 AR AR234883A patent/AR192875A1/en active
- 1971-04-06 NL NL7104585A patent/NL7104585A/xx unknown
- 1971-04-06 CA CA109,679A patent/CA1042886A/en not_active Expired
- 1971-04-06 CA CA109,680A patent/CA946385A/en not_active Expired
- 1971-04-06 NL NL7104592A patent/NL7104592A/xx unknown
- 1971-04-19 GB GB26331/71A patent/GB1281499A/en not_active Expired
-
1972
- 1972-04-12 AR AR241431A patent/AR200636A1/en active
- 1972-04-12 AR AR241430A patent/AR200635A1/en active
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1978
- 1978-09-21 YU YU2238/78A patent/YU35005B/en unknown
- 1978-09-21 YU YU2239/78A patent/YU35006B/en unknown
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