CA1063120A - Cyclic polymethylene phenoxy aminopropanols and related compounds - Google Patents

Abstract

Abstract This invention relates to new cyclic polymethylene phenoxy-aminopropanols and related compounds, which are useful in coronary diseases, lowering blood pressure, as central nervous system depressants, water softening and corrosion inhibition, having the formula wherein the aminopropoxy chain is in the 1- or 2- position, wherein R3, R4, R5, R6 and R7 are the same or different and are hydrogen or lower alkyl, R8, R9 and R10 are the same or different and are hydrogen, lower alkyl, aralkyl, lower alkoxy, carboxy, monocyclic cycloalkyl, lower alkenyl, nitro, halogen, acyl, amino, acylamino, R14O(CH2)n'- where R14 is hydrogen, lower alkyl or aralkyl and n' is 0,1 or 2; the radical is a basic nitrogen containing radical of up to about 18 carbons, Z and Z1 are the same or different and are hydrogen, formyl, cyano, azido, R15-X or R16-Y-, wherein X and Y are ?, -(CH2)n2 where n2 is 1 to 8, -0-, -S-, where R17 is hydrogen or acyl and R15 and R15 are the same or different and are hydrogen, lower alkyl, lower alkoxy, hydroxy aryl, acyl, lower alkenyl or , R11 is hydrogen, lower alkyl or aralkyl, n is 0, 1 or 2; the dashed lines indicate that Z2 is or is not present, where Z2 is present, Z2 is

Description

~63~ZO
This lnventlon relate~ to new chem1cal compound~ of the rormula (I) R6 R7 R3 j ~ / R ~ :

R~l / R OH R , \ R2 ;

~R~

and salts thereof, wherein R3, R4, R5, R6 and R7 are the same or different and can be hydrogen or lower alkyl, R8, R9 and R10 are the same or different and can be hydrogen, lower alXyl, aralkyl, lower alkoxy, carboxy, monocyclic cycloalkyl, . ~.
lower alkenyl, nitro, halogen, acyl, amino, acylamino, R140(CH2)n,- where R14 is hydrogen, lower alkyl or aralkyl and n' is 0 or 1; the radical ~Rl is a basic nitrogen ~R2 : ' containing radical of up to about 18 carbons, Z and zl can be the same or different and can be hydrogen, formyl, cyano, azido, R15-X or R16-Y-, wherein X and Y can be -C-, -(CH2)n2 : ' where n2 is 1 to 8, -0-, -S- "~-R17 where R17 is hydrogen or acyl and R15 and R16 can be the same or different and can be hydrogen, lower alkyl, lower alkoxy, hydroxy, aryl, acyl, lower alkenyl or /Rl ; Rll is hydrogen, lower alkyl or aralkyl, N~ R2 n is 0, 1 or 2 and, in addition, z and zl can be taken together to form _0, ~ or NR .
Where n is 1 and Z and zl are in the 6- and 7-positions, either or both of Z and zl are other than hydrogen or acyl.

. -2- ~ - .

~6312(} HAlll Where in Formula I the o~ Z2-----N group is present, then, in such case, R and the hydrogen attached to the oxygen will be deleted. Thus, the present invention includes compounds of the structures (II) R6 R7 R3 1 :.-O - C C - C N

Rll / 15 I R4 \ R2 zl ~ R

and (III) R6 R R3 /
o c _ T--C--N ;~

zl ~R ~ _Z

In Formulae I and III, z2 repre~ents CH2 ~ R12-CH , ~ C , O=C , S=C \, and ~ C=C

wherein R12 and R13 can be the same or different and can be hydrogen, lower alkyl, aryl, hydroxy, alkoxy, aryloxy or amino.

1C3 63~2(~ HAlll ~

Th~ term "lower alXyl" as employed herein includes both straight and branched chain radical~ of up to and including eight carbon atoms, for instance, methyl, ethyl, pxopyl, isopropyl, butyl, s butyl) t-bu-tyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl and the like.
The aryl-lower alkyl groups include benzyl, phenethyl and the like.
The term "lower alkoxy" includes straight and branched ~ chain radicals of the structure R0- wherein R includes any of the above lower alkyl groups.
The term "halogen" includes each of the four haloyens, but Cl and Br are preferred.
The l'amino" groups include un~ubstituted amino or mono- or di-lower alkyl-amino groups, wherein lower alkyl is as defined above, such as amino, methyl amino, ethyl amino, isopropyl amino, heptylamino, dimethyl amino, diethyl amino, me~nyl ethyl amino, methyl butyl aminoJ ethyl i-propyl amino an~ the like.
The acyl radicals represented by R" include lo~er atty acl~ radicals such as acetyl, propionyl, butyryl, isobutyryl an~ the like, as well as long chain Patty acid radical~ such as hexanoyl, heptanoyl, decanoyl, dodecanoyl and the like, monocyclic aryl and aralkanoic acid radicals such as benzoyl, phenacetyl and the like.
The term "lower alkenyl~ refers to C3 to C8 aliphatic groups which include one double bond such as allyl and all isomers of pro-penyl, butenyl, pentenyl, hexenyl, heptenyl and octenyl.
The term "monocyclic aryl" as employed herein contemplates monocyclic carbocyclic aryl radicals, for instance, phenyl and substituted phenyl radicals, such . ~

~0631Z0 HAlll as lower alXyl phenyl (e.g.) o-, m- or ~-tolyl, ethylphenyl, butylphenyl and the like, di(lowar alkyl)phenyl (e.g., 2,4-dimethylphenyl, 3,5-diethylphenyl and the like) halophenyl (e.g., chlorophenyl, bromophenyl, iodophenyl, fl~orophenyl), o-, m- or p-nitrophenyl, dinitrophenyl, (e.g., 3,5-dinitro-phenyl, 2,6-dinitrophenyl and the like) J and trinitrophenyl (e.g., picryl).
The terms "monocyclic cycloalkyl" includes cyclic radicals containing from 3 to 6 ring members ~e g., cyclopropyl, cyclo-butyl, cyclopentyl and cyclohexyl~
In the basic nitrogen containing radical / R

in formula I, R and R each represents hydrogen, lower alkyl, lower alkenyl, hydroxy-lower alkyl and phenyl-lower alkyl forming such basic gr~ups as amino, lower alkylamino, e.g., methylamino, ethylamino, isopropylamino, di(lower alkyl)amino, e.g., dimethylamino, diethylamino, dipropylamino, lower alkenylamino, e.g., allylamino, di(lower alkenyl)amino, e.g., diallylamino, (hydroxy-lower alkyl)amino, e.g., hydroxyethyl-amino, di(hydroxy-lower alkyl)amino, Q.g., di(hydroxyethyl)amino, phenyl(lower alkyl~amino, e~g., be~zylamino, phenethylamino, ~-N-(lower alkyl)phenyl(lower alkyl~amino, e.g., N-me~hylbenzyl-amino, and the like.
The -N R2 radical may ~orm a heterocyclic radical.
The symbols Rl and R2 may together repre~ent the carbon (and hydrogen) and the oxygenJ sulfur or nitrog~ atoms which, with the nitrogen or carbon atom in the above group, form a 5- or 6-'' .' :. ~ ,, ' ~C9631ZO H~

membered nitrogen heterocyclic containing not more than one hetero atom in addition to the nitrogen already ~hown in the group and less than 21 atoms in the radical (excluding hydrogen).
The heterocyclic radicals may include one to three substituents including lower alkoxy or lower alkyl as deined hereinbefore;
trifluoromethoxy; trifluoromethylmercapto; N,N-dialkylsulfamoyl groups, such as N,N-dimethylsulfamoyl; lower alkanoyl groups (R-C- where R is lower alkyl) as defined hereinbefore, such as acetyl, propionyl, and the like; hydroxy-lower alkyl, such as hydroxymethyl,2-hydroxyethyl or the like; hydroxy-lower alkoxy-lGwer alkyl, such as 2-(2-hydroxy-ethoxy)ethyl, or the like;
lower alkanoyl-lower alkyl, such as 2-heptanoyloxyethyl; carbo-lower alkoxy, such as carbomethoxy, carboethoxy, carbopropoxy, or the like; or 2-(lower alkanoyloxy-lower alkoxy)lower alkyl such as 2-(decanoyloxyethoxy)ethyl, or the like.
1 Illustrative of the heterocyclic radicals represented by 2~N- are the following: piperidino; (lower alkyl)piperidino ~e.g., 2-, 3-, or 4-(lower alkyl)piperidino or 4-(N-lower alkyl)- -~
piperidino, such as 2~(ethyl)piperidino or 4-(N-isopropyl)-piperidino]; di(lower alkyl)piperidino Ce.g., 2J4-~ 2,5- or 3,5-di(lower alkyl)piperidino, ~uch as 2,4-dimethyl piperidino or 2,5-di-t-butyl piperidino]; (lower alkoxy)piperidino [c.g., 2-methoxypiperidino or 3-methoxypiperidino]; hydroxy-piperidino ~e.g., 3-hydroxy- or 4-hydroxypip~ridino]; amino- ;
methylpiperidino re.g., 4-aminomethylpiperidino]; pyrrolidino;
(lower alkyl)pyrrolidino [e.g., 3 methylpyrrolidino]; di(lower alkyl)pyrrolidino [e.g., 3,4-dimethylpyrrolidino~; ~lower alkoxy)pyrrolidino ~e.g., 2-methoxypyrrolidino~; morpholino;
(lower alXyl)morpholino [e.g., 3-methylmorpholino]; di(lower ~ , -6- ;

. . . . .

~0~3~2~ HAlll alkyl)morpholino, ~e.g., 3,5-dimethylmorpholino]; (l~wer alkoxy)-morpholino~ [e.g., 2-methoxymorpholino~; thiamorpholino;
(lower alkyl)thiamorpholino [e.g., 3-methylthiamorpholino];
di(lower alkyl)thiamorpholino, [e.g., 3,5-dimethylthiamorpholino], (lower alkoxy~thiamorpholino, [e.g., 3-methoxythiamorpholino];
piperazino; (lower alkyl)piperazino, re.g., N4-methylpiperazino~;
di(lower alkyl)piperazino, [e.g., 2,5-dimethy:Lpiperazino or

2,6-dimethylpiperazino]; (lower alkoxy)piperazino, ~e.g., 2-methoxypiperazino]; (hydroxy-lower alkyl)piperazino, [e.g., N -(2-hydroxyethyl)piperazino]; (lower alkanoyloxy-lower alkyl)-plperazino, ~e.g., N4-(2-heptanoyloxyethyl)piperazino or N -t2-ProPionyloxyethyl)piperazino~; (hydroxy-lower alkoxy-lower alkyl)piperazino, ~e.g., (hydroxymethoxymethyl)piperazino];
(carbo-lower alkoxy)piperazino, ~e.g., N4-(carbomethoxy-, carboethoxy-, or carbopropoxy)piperazino]; piperidyl;
(lower alkyl)piperidyl [e.g., l-, 2-, 3- or 4-(lower alkyl)-piperidyl, such as l-N-methylpiperidyl or 3-ethylpiperidyl];
di(lower alkyl)piperidyl, ~e.g., 2,4-, 2,5-, or 3,5-di(lower alkyl)-piperidyl wherein lower alkyl is methyl, ethyl, n-propyl, isopropyl, etc.]; lower alkoxy piperidyl, [e.g., 3-methoxy-piperidyl or 2-ethoxypiperidyl]; hydroxypiperidyl [e.g.,

3-hydroxy- or 4-hydroxypiperidyl~; aminomethylpiperidyl, ~e.g., 4-aminoethylpiperidyl]; pyrrolidyl; lower alkyl pyrrolidyl, ~e.g., l-N-methylpyrrolidyl]; di(lower alkyl)pyrrolidyl, -~

~e.g., 2,3-dimethylpyrrolidyl]: lower alkoxy p~rrolidyl, ~e.g., 4-N-methoxypyrrolidyl~; morpholinyl; (lower alkyl)-morpholinyl, ~e.g., 3-methylmorpholinyl]; di~lower alkyl)-morpholinyl, ~e.g., 3-methyl-4-N-ethylmorpholinyl]; ~lower alkoxy)morpholinyl, [e.g., 2-ethoxymorpholinyl]; thiamorpholinyl;

.. . .

3LOti3~ZO HAlll ~lower al~yl)thiamorpholino, [e.g., 3-ethylthiamorpholinylJ;
di(lower alkyl)thiamorpholinyl, [e.g.l 3-methyl-4-N-ethylthia~ , morpholinyl]; lower alkoxy thiamorpholino, [e.g., 3-methoxy-thiamorpholinyl]; piperazinyl; alkyl, dialkyl, alkoxy or hydroxy-lower alkyl substituted piperazinyl.
The compounds of ~ormula I orm acid addition salts ` with i-norganic and organic acids. I'hese acid addition salts frequently provide useful means for isolating the products ; fr3m reaction mixtures by forming the salt in a medium in which it i5 insoluble. The free base may then be obtained by neutralization~ e.g., with a base such as sodium hydroxide.
Then any other salt may again be formed from the free base and the appropriate inorganic or organic acid. Illustrative are the hydrohalides, especially the hydrochloride and hydrobromide which are preferred, sul~ate, nitrate, phosphate, borate, acetate, oxalate, tartrate, maleate, citrate, succinate, benzoate, ascorbate, salicylate, methanesulfonate, benzenesul~onate, toluenesulfonate and the like. Quaternary ammonium salts are also formed, e.g., by reacting the free base with an alkylating agent, e.g., lower alkyl halide such as methyl chloride, ethyl bromide or the like, lower alkyl sulfate such as methyl sul~ate, aralkyl halides such as benzyl chloride, aralkyl sulfates such as benzyl sul~ate and the like.
Preferred a~e those compounds wherein R3, R , R5, R , R7, R8, R9, R10 and Rll are all hydrogen, Rl is hydrogen or lower alkyl, especially hydrogen, R2 is lower alkyl, especially isopropyl, and Z is OH and Z' is OH or N~ . ;`
The new compounds of this invention are useful as water softeners and for inhibiting the corrosivity of engine lubricants.

:: . . .: ~ , - :
. .

~63120 HAlll They are also useful as central nervous system depres~ants and antifibrillatory agents, for example, in arresting cardiac arrhythmia in mammals, e.g., by inhibition of beta adrenergic receptors in the myocardium. For these purposes a compound of formula ~ or a physiologically acceptable acid addition salt may be incorporated in a conventional dosage form such as tablet, capsule, elixir, injectable or the like along with the n~cessary carrier material, excipient, lubricant, buffer or the like. Single or divided doses of about 5 to 25 mg/kg/day, preferably about 4 to 10 mg/kg, two to four times daily may be administered in dosage forms as described abo~eO
Compounds of formula I can be prepared by reacting a phenol of the structure Rll ~OR)nl (I~) Z ~ R8 '.
with an alkali metal alkoxide such a3 NaOCH3 in an alcohol solvent boiling below about 100, ~uch as methanol, and removing the solvent in vacuo to give the dry salt which is reacted with an epoxide of formula V, (V ) R6 ~0~
Y ( : - C ~ C-R3 I

(Y is chlorine or bromine), _g_ ~ , ' .
. .
-.
... . :.

~111 ~ ` ' ~631~0 such as epichlorohydrin in a solvent quch as dimethyl~ulfoxide (as described herein) to form 1,2,3,4-tet:rahydro-5-~2,3-epoxy propoxy]-naphthalenes of the structur~ :
R6 ::

/ \ / ` :
VI O - C ~ C - - C
17 \R4 ll Z~ 8 zl ~ ~R9 ~

R :

The above epoxy-propoxy-naphtholene can be converted to the formula I compounds of the invention by heating with an amine : R -~
j VII H~

in an inert organic solvent, such as n-propanol, benzene or ~
toluene, e.g., for about 16 to 24 hours; the reactants may ~;
also be heated in a Parr pressure reactor at a temperature within the range of from about 70 to about 110 for 6 - 12 ... . .~
hours. :¦ :
Compounds of formulae I and III wherein z2 is present, that is , , '--- --10--.. . . . . .

~ i312~

O C C - C--~ ~

Rll / 15 L ~ ¦
z _~R8 z;
zl ~ ~ R

R

where Z is R -CH or 13~ C can be prepared by reacting . :~
a compound of formula II, that i9 II ~6 R7~3 l l I / R
Q - C --C -C N ~.

. Rll / RS OH R4 \ R2 zl ~ R9 ~; . .
with a ketone or an aldehyde of the structure ~ C=0 or R12-cHo VIII IX
wherein R and R13 are the same or different and can be lower alkyl, monocyclic aryl or lower alkyl-monocyclic aryl in the presence of a solvent boiling below about 100C., such as benzene or chloroform to form an oxazolidine compound . ~: :

of the structure ~ . - - : ' .
~ . "

~L~6312~

: , O C --~ - C ~ '~

X j R ~ ~ N--R
Zl ~R8j~/ \R12 10Where it is desired to form esters of these compounds, that i~ where one or both of Z and zl are OCR12, the above oxazolidine is reacted with an acid ;~
anhydride or an acid halide exemplified by the acids mentioned hereinbefore, ln the pre~ence of a suitable base such as pyridine to give the ester o~ the oxazolidine of the structure X.
Compounds of formula III wherein Z is 0=C~ or S= C ~ ~
can be prepared by reacting compounds of formula II with : :
phosgene (COC12) or thiophosgene (CSC12) to form compound~
of the structure '~ .

XI ~ 4 Zl ~$R9 RlO : ', where Z3 is o or S.

: ~ ..... . .. : . , .. .. .. . :... .:, Compounds wherein z2 is 13/ C=C can be prepared by reacting compounds of formula II with an equiv~lent of an acid halide or anhydride to produce : O ~ C C - C ~ R
XII I Is l I l I R OH N - -R
: Rll ¦ O=C~

Zl ~R9 Cll~

which are then treated with suitable dehydrating agents such as thionyl chloride or phosphorous oxychloride, or simply heated at temperatures rangin~ from a~out 80 to about 180C.
Where Z and zl are two adjacent functional groups having a free proton on each group, on the cyclo polymethylene ring, for example where in the compounds of formula II one of Z
and zl is hydroxyl and the other amino or mercapto, reaction ; of the formula II compound with a ketone or aldehyde R13/ or Rl2-CHO

VIII IX

will produce compounds of the structure .

XIII Rll / R O R /

Rl,Y `~ R12/ ~R13 : , : :.

~0~i3 11 20 : ~

where Y i~ N or S depending on whether one of Z and zl i9 amino or mercapto. 1~eaction of formula II compoun~ wher~
Z and zl are adjacent functional groups with phosgene or thiophosgene will produce compoundsof the structure :~

R6 R7 :R3 XIV
O ~ C C--C
Rll / R o ~4 /

Z3=C~ ~R9 33 where Z3 i~ 0 or S and Y is NH or S.
However, where Z and zl do not contain a free proton, they will not form a third ring when formula II compounds are reacted with the ketone, aldehyde, phosgene or thiophos~
gene mentioned hereinbefore, but only the ~ ~ 2 ~ ring .~.

will form.
Alternatively, compound~ of structure I can ba prepared by reacting a starting ~aterial of ~tructure IV with a compound of the structure XV

XV C 1 C C_C
\ R4 ~ :~

R :
to form ethers of the structure XVI

,~:

:, -: , , , -f~
1~63120 HA~
, ;~

XVI Rll OC--C_C

z ~/ R R
which are epoxidized by reaction with a suitable oxidizing agent such as m-chloroperbenzoic acid or other peracid in : a solvent such as chloroform to form compounds of structure VI.
This method is particularly applicable where R , R4 and/or .
~7 are other than hydrogen and R5 and R6 are hydrog~n~
The cyclic polymethylene phenols of ~tructure IV
employed as starting materials herein are disclosed in copending application Serial No..174,840, filed June 25, 1973 ~ entitled SUBSTITU~ED CYCLIC POL~METHYLENE PHENOLS.
.~ Preferred compounds of the invention include those .
having the structures O~I ; i O_cH2cH_cH2_NH_c(cH3)2 ,~

OH ~--~~~-~~~`~~~
o-CH2lH~CH2-NHCtCH3)2 .

~ " Ç~
~ : HO OH ~`
'` ~, .~~

--14a-- ~
'' , 10631ZC~ HAlll 1,2-trans-1,2,3,4-Tetrahydro-5-~2-hydroxy-3-(isopropylamino)-.-- -- . . : .
propoxy]-l-methoxy-2-naphthol,oxalate salt A. 5,6-and 7,8-dihydro-1-naphthol A mixture of 105.8 g of crude 5,8-dihydro-1-naphthol and 480 g of 50~k sodium hydroxide was refluxed under nitrogen for 2 hr, poured onto 2 kg of ice and acidified with conc.
hydrochloric acid. The solid was taken up in ether, the ether dried and evaporated and the residue distilled to ` :~
10 give 88 g, bp 91-95oat 0.05 mm. Four recrystallizations from 400 ml of hexane gave 59 g, mp 70.5-76 which contained ca.
10-15% of 5,6,7,8-tetrahydro-1-naphthol in addition to the two olefins. VPC and NMR showed the abc~ence of 5,8-dihydro-l-naphthol and l-naphthol.

B. Epoxidation of 5,6- and 7~8-dihydro-l-naphthyl acetate. ~-A solution of 18.4 g (0.10 mole) of the acetate of the above mixture (prepared with pyridine and acetic anhydride) in 400 ml of methylene chloride was cooled to 0 and 20.0 g 20 (ca. 0.1 mole) of commercial m-chloroperbenzoic acid added.
A:Eter 2 hr at 0 100 ml of cold 6% sodium hydroxide was added with good stirring. ~fter 5 min the ~ayer~ were ~eparated and the organic layer dried and evaporated to give 19.8 g of oil.
The above 19.8 g of epoxide was dissolved in 400 ml of methanol and stirred overnight with 200 mg of TsO~. The solution was cooled to 0 and 100 ml of 9/c sodium hydroxide added. After 2 hr at 0 the bulk of the methanol was removed in vacuo and 75 ml of 10/c hydrochloric acid added :' ~ . . . :, .

1~63~20 H~lll at 0. Extraction with chloroform (5x200 ml) gave 19.2 g of oil which showed five major spots on TLC (CHC13, alumina, I2) coded A-E in order of decreasing Rf. This material was absorbed onto 150 ml neutral Alumina II, placed on a 550 g column of dry packed Alumina II and eluted with:
1400 ml of 1:1 hexane/CHC13, 700 ml 2:1 CHC13/hexane, 700 ml of 3:1 CHC13/hexane, 600 ml of CHC13, and 1500 ml of 5/O
methanol in CHC13 (100 ml fractions).
Fractions 1-6 contained 2.38 g of TLC pure A, identical by mp and TLC to 5,6,7,8-tetrahydro-1-naphthol.
Fractions 9-12 contained 0.63 g of Tl.C pure B, iclentical by TLC and IR to the starting olefin mixture.
Fractions 15-21 contained 1.68 g of C that i9 cis-8-methoxy-5,6,7,8-tetrahydro-1,7-naphthalenediol contaminated with the by-product D. Recrystallization from ethyl acetate gave 812 mg of rrLC pure C, mp 131-135.5.
Fractions 22-28 contained 2.13 g of D
contaminated with E, that i~ trans-5-methoxy-5,6,7,~-tetrahydro-1,6-naphthalenediol. Recrystallization from ethyl acetate gave 1.36 g of TLC pure D, mp 110.5-113.
Fractions 2g-51 contained 8.33 g of E with small amounts of contaminants which were removed by recrystallization from ethyl acetate to give 4.79 g of TLC pure E, mp 137.5-139.

C. 1,2-trans-1,2,3,4-Tetrahydro-5-[2-hydroxy-3-(isopropyl-amino)propoxyl-l-methoxy-2-naphthol, oxalate salt (1:1).
A solution of 3.84 g ~0.02 mole) of trans-5-methoxy-5,6,7,8-tetrahydro-1,6-naphthalenediol,(E) and 1.11 g of sodium methoxide in methanol was prepared and evaporatecl ., . ; ~ , .
- . .,. ~.. :-. . .: . .

~ ~63120 HA~

in vacuo. The residue was dissolved in 60 ml of DMS0 and stirred overnight under N2 with 5 ml of epichlorohydrin.
The DMS0 was largely removed at 50 at 0.05 mm and the residue dissolved in chloroform and washed twice with water.
Drying and solvent removal gave 4.95 g of oil which was homogeneous on TLC. This material was heated at 80 + 5 for 15 hr with 35 ml of isopropyl amine in the small Parr boTr~. Solvent removal gave an oil which gave only an oily solid upon crystallization. The oxalate salt was prepared from this oil and 1.82 g of oxalic acid in 70 ml of absolute ethanol. Two recrystallizations Erom the same solvent gave 2.75 g, mp 168-169.5.
Anal. Calcd for ClgH29N08: C, 57.13; H, 7.32; N, 3.51.
Found: C, 57.36; H, 7.40; N, 3.31.

1,2-cis-1,2,3,4-Tetrahydro-8-[2-hydroxy-3-(isopropylamino)-....
propoxy]-l-methoxy-2-naphthol,oxalate salt (1 A solution of 1.146 g (0.0059 mole) of cls-8-~nethoxy-5,6-20 7,8-tetrahydro-1,7-naphthalenediol(Compound C described above in Example 1) and 324 mg of sodium methoxide in 50 ml of methanol was prepared and the solvents removed ln vacuo.
The residue was stirred overnight with 2 ml of epichlorohydrin in 40 ml of DMSO under nitrogen. The DMS0 was removed in vacuo and the residue dissolved in 200 ml of chloroform, washed with water, dried and evaporated. The resulting oil (1.39 g) was heated at 80~ 5 overnight with 25 ml of isopropylamine. The excess isopropylamine was removed in vacuo and the residue converted to its oxalate salt in . . . ~ . . .
~ . ... .

ethanol. Two recrystallizations from the same solvent gave 780 mg, mp 142-149.
Anal. Calcd for Cl9H29N08: C, 57.13; H, 7.32; N, 3.51.
Found: C, 56.93; H, 7.04; N, 3.41.

EXhMPLE 3 . . .
trans-5-~3-(tert-Butylamino)-2-hydroxypropoxy]-1,2,3,4- ;

tetrahydro-1,2-naphthalenediol.
.: .
A. trans-1,2,3,4-Tetrahydro-5-acetoxy-1,2-naphthalenediol.
_.
A solution of 41.3 g of the epoxy acetate (prepared in overall 73% yield from 5,8-dihydro-l-naphthol as described in Example 1 in 420 ml of THF and 105 ml of water was cooled to 0 and 2.4 ml of 70~O HC10~, added. After 150 min at 0 the solution was partitioned between 600 ml of ether and a mixture of 600 ml of sat'd salt and 100 ml of sat'd sodium bicarbonate solution. The organic layer was separated, dried and evaporated to give 46.2 g of oily solid. Trituration with 200 ml of boiling ether gave 13.4 g, mp 153-158.
Recrystallization from 250 ml of ethyl acetate gave 10.2 g, mp 161-162.5, homogeneous on TLC.
. .
B. trans-1,2,3,4-Tetrahydro-1,2,5-naphthalenetriol.
. _ . . : . .
A solution of 13.3 g of the above acetate in 500 ml of THF was cooled to 0 and 140 ml of l~ sodium hydroxide solution added under nitrogen. After 2 hr at 0, carbon dioxide was bubbled through to pH = 8, the slurry diluted with 1 liter of sat'd salt and the mixture extracted with CHC13 (3 x 500 ml) to give 9.1 g of solid. Recrystallization -from lO0 ml of ethyl acetate gave 5.7 g, mp 147.5-149.5.
C. trans-5-(2,3-Epoxypropoxy)-1,2,3,4-tetrahydro-1,2-naphthalenediol.

.
-18- ~
..

... ~ , .
j . .

1~631;Z~
~ `
A solution of 5.4 g (0.03 mole) of the above phenol and 1.75 g tO.032 mole) of sodium methoxide was prepared in methanol and the solvent removed ln vacuo~ The residue ~;
was dissolved in 80 ml of DMSO, ca. 10 ml distilled out at 0.2 mm, and the resulting solution stirred overnight under nitrogen with 3 ml of epichlorohydrin. The bulk of the DNSO
was removed ln vacuo and the residue partitioned between 400 ml each of water and chloroform. The aqueous layer was ,~
washed with 2 x 300 ml of chloroform and the combined organic layer washed with 3 x 250 ml of water, dried and evaporated to give 5.12 g of solid (73%). Recrystallization from 150 ml of benzene gave 3.7 g, mp 123-127.
D. trans-5-[3-tert-ButYlamino)-2-hydroxypropoxy~-1,2,3,4-tetrahydro-1,2 naphthalenediol.
A solution of 3.5 g of the above epoxide and 40 ml of t-butyl amine was heated at 80 + 5 for 15 hr in the small Parr bomb. The so]vent was removed in vacuo to give 4.7 g ~ ~
of solid. Two recrystal1izations from 150 ml of acetonitrile ~ ~;
gave 3.0 g, mp 168-169.
Anal. Calcd for C17H27~O4: C, 65.99; H, 8.80; N, 4.53.
Found: C, 66.02; H, 8.89; ~, 4.78.

trans-5-[3-(tert-Butylamino)-2-hYdroxy-2-methylpropoxy~-1,2,3,4-tetrahydro-2-(isoPro~vlamino)-3-hydrox~-na~hthalene A. 6,7-Epoxy-5,6 ! 7,8-tetrahydro-1-na~hthol acetate.
A solution of 101 g (0.542 M) of 5,8-dihydro-l~naphthol acetate in 1.5 liters of CH2C12 was cooled to 0 and 89 g (0.516 M) of m-chloroperbenzoic acid was added over a period of 5 min. and the mixture was stirred --19-- , :

.

~L~lll 3~

overnight at room temperature.
The suspension was poured into a mixture of 500 ml of ~ /c NaOH and 1000 y of ice. The aqueous layer wa~: extracted with C~2C12 (2 x 500 ml), and the combined organic layers were washed with water and satd. NaCl soln, dried and evaporated in vacuo to give the title compound, 105g (95% yield) of pink solid~
B. 6,7-trans-5,6,7,8-Tetrahydro-7(and 6)-(isopropylamino)-.
1,6(and 7)-naphthalenediol~ hydrochlorlde.
A mixture of epoxy acetate (10.2 g; 0.05 M) and 10 isopropylamine was charged to the small bomb and heated overnight in an oil bath maintained at 100. After cooling, the excess amine was removed in vacuo leaving a dark brown viscous material which was chromatographed on activity 3 neutral alumina. E'ractions elu-ted with 10-20% MeOH in CHC13 yielded crystalline material on standing under hexane.
Two recrystallizations from ether gave a sample melting 112-117. This was dissolved in IPA-ether and converted to the hydrochloride by adding a solution of HCl in IPA. The white hydrochloride was recrystallized from IPA-MeOH-ether togive isomers of the above name, 2.2 g (17%), mp 207-210C.
Anal. Calcd for C13H20O2NCl: C, 60.57; H, 7.82;
N, 5.43; Cl, 13.75 Found: C, 60.81; H, 7.72;
N, 5.24, Cl, 13.61 C. 2-Methyl-3~-(trans-7(or 6)-(isopropylamino)-6(or 7)-hydroxy-5,6,7 ! 8-tetrahydro-1-naphthox~)-1-propene.
A solution of 9.O g ~0.05 mole) of 6,7-trans-5,6,7,8-tetrahydro-7(or 6)-(isopropylamino)-1,6(or 7)~naphthalenediol and 2.7 g (0.05 mole) of sodium methoxide is prepared in ~063~ HAlll ;

200 ml of methanol and the solvent removed ln vàcuo. The residue is dissolved in 120 ml of DMS0, 20 ml distilled out at 40at 0.2 mm, and the resulting solution stirred for

4 hr under nitrogen with 6.3 g (0.07 mole) of ~-methallyl chloride. The bulk of the DMS0 is removed ln vacuo and the residue triturated with 200 ml of ice water. The resulting solid is filtered, dissolved in chloroform, dried and the solvent removed to give the title compound~
D. 2-Methyl-3-(trans-7(or 6)-(isopropylamino)-1,6(or 7)-.
dihydrox~y-5,6,7,8-tetrahydro-l-naphthoxy)-1,2-epoxypropane.
A solution of 7.5 g (0.033 mole) of the above olefin in 220 ml of dichloromethane is allowed to stand at room tempera-ture with 7.0 g of _-chloroperbenzoic acid. The resulting slurry i9 extracted with cold sodium hydroxide solutlon, dried and evaporated to give the title compound.
E. trans-5-[3-tert-Butylamino)-2-hydroxy-2-methylpropoxy]-1,2,3,4-tetrahydro-2-(isopropylamino)-3-hydr~ L~ L~=
A mixture of 5.2 g of the compound of part D and 50 ml of ;
t-butyl amine is heated at 80 + 5 for 17 hr in the small Parr bomb. Solvent removal gives 6.91 g of oil. A solution of 4.61 g of this oil in 15 ml of acetonitrile crystallizes after 2 weeks at -20. Two recrystalliæations from ether gives the title compound.

trans-5-~3-(tert-Butylamino)-2-hydroxy-2-methyl-propoxy~-1,2 ! 3,4,-tetrahydro-2-hydroxy-3-(benzylmethylamino)-naphthalene ~ "

~6312() HAlll A. trans-6(and 7)-(benzylmethylamino)-5,6,7,8-tetrahydro-. _ . . .
1,7(and 6)-naphthalenediol.
A mixture of 6,7-epoxy-5,6,7,8-tetrahydro-1-naphthol acetate (10.2 g, 0.05 M)~ prepared in Example 4A, methyl-benzylamine (50 g) and xylene (50 ml) is heated under reflux overnight. After cooling the solution is taken to dryness in vacuo and the dark brown viscous material remaining is chromatographed on silica gel (Davison Grade 923, 100-200 mesh).
Fractions eluted with 1-5% MeOH in CHC13, containing 11.0 g (~76%), show a single spot on TLC (silica gel, developed 2% MeOH in CHC13). Ether is added to these fractions and after standing a small amount of cryqtalline material is deposited. This i9 harvested (1.6 g) and recrystallized from ether to give the title compound 1.15 g (8%), mp 152-154C.
Anal- Calcd for C18H21O2N: C, 76.29; H, 7.47: N, 4.94.
Found: C, 76.24; H, 7.69; N, 4.75.
B. 2-Methyl-3-(trans-6(or 7)-(benzylmethylamino)-6(or 7~--hydroxy-5,6,7,8-tetrahydro-1-naphthoxy)-1-propene A solution of 9.0 g (0.05 mole) of trans-6(or 7)-(benzylmethylamino)-5,6,7,8-tetrahydro-1,7(or 6)-naphthalene-diol and 2.7 g (0.05 mole) of sodium methoxide is prepared in 200 ml of methanol and the solvent removed in vacuo. The residue is dissolved in 120 ml of DMSO, 20 ml distilled out at 40 at 0.2 mm, and the resulting solution stirred for 4 hr under nitrogen with 6.3 g (0.07 mole) of ~-methallyl chloride. The bulk of the DMSO is removed ln vacuo and the residue triturated with 200 ml of ice water. The resulting solid is filtered, dissolved in chloroform, dried and the i:.

10~31ZO HAlll solvent removed to give the title compound.

C. 2-Methyl-3-(trans-6(or 7~(benzylmethylamino)-1,7(or 6)-.
dihydroxy-5,6,7,8-tetrahydro-1-naphthoxy)-1,2-epoxypropane.
A solution of 7.5 g (0.033 mole) of the above olefin in 220 ml of dichloromethane is allowed to stand at room tempera-ture overnight with 7.0 g of m-chloroperbenzoic acid. The resulting slurry is extracted with cold sodium hydroxide solution, dried and evaporated to give the title compound.
D. trans-5-~3-~ert-Butylamino)-2-hydroxy-2-methylpropoxy]-1,2,3,4-tetrahydro-2-hydroxy-3-(benzylmethylamino)-_ naphthalene.
.

A mixture of 5.2 g of the above compound of part C and S0 ml of t-butyl amine is heated at 80 ~ 5 for 17 hr in the small Parr bomb. Solvent removal gives 6.91 g of oil. A solution of 4.61 g of this oil in 15 ml of acetonitrile crystallizes after 2 weeks at -20. Two recrystallizations from ether gives the title compound.

. .:

trans-5-~3-(tert-Butylamino)-2-hydroxy-2-methylpropoxy~-1,2,3,4-.
tetrahydro-2-hydroxy-3-amino-na-ph-halene , .
A. trans-6(and 7)-Amino-5,6,7,8-tetrahydro~l, 7(and 6)-naphthalenediol.
A solution of 6,7-epoxy~5,6,7,8-tetrahydro-1-naphthol acetate (20.4 g, 0.1 M),prepared as in Example 4A,in 200 ml dioxane is heated to 40 and a solution of sodium azide (6.8 g, 0.11 M) in water (20 ml) is added dropwise. The ~ 63~LZ~

mixture is heated under reflux overnight, cooled, filtered and the solvent is removed in vacuo.
The crude azide is dissolved in ethanol, platinum oxide ~; (~J 1 g) is added and the mixture is hydrogenated at up to 45 psi for 20 hrs n During this time the hottle is vented and - refilled with hydrogen six times. The catalyst is removed by filtration and washed with ethanol. The filtrate is taken to dryness in vacuo, hexane is added and crystalline product is removed by filtration (13.1 g, 73%). A 3.0 g sample o~i this is recrystallized twice from ethyl acetate methanol to give the title compound, 1.5 g (37%), mp 172-193dec.
Anal- Calcd for CloH13NO2 C, 67-02; H~ 7-31; N, 7.82.
Found: C, 67.24; N, 7.33; N, 7.84.
B. 2-Methyl-3 (e-~n--6(~r 7)-amino-7~or 6)-hydroxy-5,6,7,8- `~
tetrah dro-l-naPhthoxy)-l-~rorene.
A solution of 9.0 g (0.05 mole) of trans-6tor 7)-amino-

5,6,7,8-tetrahydro-1,7(or 6)-naphthalenediol and 2.7 g (0.05 mole) of sodium methoxide is prepared in 200 ml of methanol and the solvent removed in vac~uo. The residue is dissolved in 120 ml of DMSO, 20 ml distilled out at 40 at 0.2 mm, and the resulting solution stirred for 4 hr under nitrogen with 6.3 g (0.07 mole) of ~-methallyl chlorideO
The bulk of the DMS0 is removed in vacuo and the residue ~, triturated with 200 ml of ice water. The resulting solid is filtered~ dissolved in chloroform, dried and the solvent removed to give the title compound.
C. 2-Methyl-3-(tr~ns-6(or 7)-amino-1,6(or 7)-dihydroxy-5,6,7,8-tetrahydro-1-naphthoxy)-1,2-epoxypro ane.
~ solution of 7.5 g (0.033 mole) of the above olefin in ~ ;~
220 ml of dichloromethane is allowed to stand at room temperature :i: - , : ., .
:. . . .
. . .

631ZO H~

overnight with 7.0 g of m-chloroperbenzoic acid. The re~ulting slurry is extracted with cold sodium hydroxide solution, dried and evaporated to give the title compound.
D. trans-5-[3-tert-Butylamino)-2-hydroxy-2-methylpropoxy]-~ .
1,2,3,4-tetrahydro-2-hydroxy-3-amino-naLphthalene.
A mixture of 5.2 g of the compound of part C and 50 ml of t-butyl amine is heated at 80 + 5 for 17 hr in the small Parr bomb. Solvent removal gives 6.91 g of oil. A solution of 4.61 g of this oil in 15 ml of acetonitrile crystallizes after 2 weeks at -20. Two recrystallizations from ether gives the title compound.
:~' _.
CiS-5- ~ 3-tert-Butylamino)-2-hydroxy-2-methylpropoxy~-1,2,3,4-~ . . ~
tetrah~dro-2,3-na~hthalenediol A. 2-Methyl-3-~cis-6,7-dihYdroxY-5,6,7,8-tetrahydro-1-naphthoxy)-l-propene A solution of 9.0 g (0.05 mole) of cls-5,6,7,8-tetrahydro-1,6,7-naphthalenetriol and 2.7 g (0.05 mole) of sodium methoxide was prepared in 200 ml of methanol and the solvent removed ln vacuo. The residue was dissolved in 120 ml of DMS0, 20 ml distilled out at 40 at 0,2 mm, and the resulting solution stirred for 4 hr under nitrogen with 6.3 g (0.07 mole) of ~-methallyl chloride. The bulk of the DMS0 was removed ln vacuo and the residue triturated with 200 ml of ice-water.
The resulting solid was filtered, dissolved in chloroform, dried and the solvent removed to give 9.6 g of white solid, mp 117-119.5. Recrystallization of a small sample gave material of mp 119.5-120.5.

HAlll ~ 06312(;~
B. 2-Methyl-3-( ClS -6,7-dihydroxy-5,6,7,8-tetrahydro-1-naphthoxy)-1,2-epoxypropane A solution of 7.5 g (0.033 mole) of the above olefin in 220 ml of dichloromethane was allowed to ~;tand at 5 for 20 hr with 7.0 g of m-chloroperbenzoic acid. The resulting slurry was extracted with cold sodium hydroxide solution, dried and evaporated to give 6.96 g of foam which contained ca 20/c (NMR analysis) of the starting material. Chromatography over silica gel gave 4.98 g of TLC pure epoxide which crystallized from hot ether to give 4.62 g of solid, mp ` -~
112-20.
It was later determined that reaction at RT overnight gave the pure epoxide with no trace of starting material.
C . CiS-5- ~ 3-tert-Butylamino)-2-hydroxy-2-methylpropoxy]-1,2,3,4-tetrahydro-2,3-naphthalenediol A mixture of 5.2 g of the above compound and 50 ml of t-butyl amine was heated at 80 ~ 5 for 17 hr in the small Parr bomb. Solvent removal gave 6.91 g of oil. A solution , of 4.61 g of this oil in 15 ml of acetonitrile crystallized ~

after 2 weeks at -20. Two recrystallizations from ether ~ ;
gave 1.8 g, mp 91-100.
Anal. Calcd for C18H2gN04 C, 66.84; H, 9.04; N, 4.33 Found: C, 66.89: H, 8.89; N, 4.30 EXAMPLE 8~
l-(Isopropylamino)-3-(2-piperidino-5-indanyloxy)-2-propanol.

A. 2-Piperidino-5-indanol A 2.8 g (0.013 moles) sample of 5-amino-2-piperidinoindan ' . .. , . . . - - . .

:: ~ : . :, . : . , .

~ ~~
HAlll ~63~Z~
was taken up in 100 ml of 5% sulfuric acid and clarified by filtering through a Hy-~lo pad. The clear yellow solution was cooled in ice and treated over 5 minutes with a solution of 0.9 g (0.013 moles) sodium nitrite in 20 ml of water.
The cold mixture was stirred at 0-5C for 1/2 hr, then added over 40 minutes to 400 ml of vigorouqly boi]ing 5% sulfuric acid. After refluxing another 1/2 hr the mixture was cooled to room temperature and treated with solid potassium carbonate until C02 evolution ceased. Methylene chloride was added and the brown solid which collected at the interface was retrieved by filtratlon and washed with water. (This material was soluble in dilute sodium hydroxide). The solid was suspended in hot absolute ethanol and evaporated to dryness.
Cry~tallization from ethyl acetate gave 1.8 g (64%) brown crystals, mp 246-247C. ~orit treatment and crystallization afforded the 1.3 g analytical sample of 2-piperidino-5-indanol, a bright yellow solid, mp 243-246C.
Anal. Calcd for C14HlgN0 : C, 77.38; H, 8.81; ~, 6.45 ; Found: C, 77.46; H, 9.08; N, 6.79 B. l-~Isopropylamino)-3-(2-p peridino-5-indanYloxv)-2- propanol A 4.4 g (0.02 mole) sample of 2-piperidino-5-indanol is added to a slurry of 0.85 g (0.02 mole) of 57% sodium hydride oil dispersion in 300 ml of dry dimethyl sulfoxide under nitrogen. The mixture is stirred at room temperature until the bubbling ceases and a clear, very dark ~olution results (5 hours?. Then a solution of 1.90 g (0.02 mole) of distilled epichlorohydrin in 60 ml of dimethyl sulfoxide is added dropwise over two hours. The mixture is stirred another 16 hrs at room temperature, then evaporated at 45-50C

i312( i HA~ ?

~0.2 mm Hg) to a ~emi-solid. Ether and water ar~ added and the mixture clarified by filtration. The phaseY are separated and the aqueous extracted with more ether. The organics are dried briefly tpotassium carbonate) and evaporated to 5 g of crude thick oily epoxide. ~;
The oil i~ taken up in 20 ml of isopropylamine and heated at 80C overnight in a Parr bomb. The mixture is cooled, washed out with methylene chloride and evaporated to a foam which is soluble in ether and benzene. A solution in 50 ml hexane deposits 0.2 g of solid epoxide on standing at room temperature for 2 hrs. The filtrate is cooled at 5C and in several days deposits 3.1 g of a solidO Recry-stallization from hexane with Norit treatment gives 2.0 g purer material. Reworking all the mother liquors afords another 1.5 g (52%). The 3.5 g of compound is taken up in ether, treated with ~orit, filtered, and treated with filtered hexane. The ether is boiled off and the solution concentrated to 75 ml of hexane. Cooling 3 days at 5C
affords the 11.2 g analytical sample, mp 76-83C.
Anal. calcd for C20H32N2O2:
Found: C, 71.99; H, 9.85; N, 8.21.
~, .

EXAMPLE 9:
cis-6-~3-(tert-Butylamino)-2-hydroxypropoxy]-1,2,3,4-tetra-hydro-2,3-naphthalenediol.
A. 5,8- i~ydro-2-naphthol The procedure of Marshall, et al, Can. J. Chem., 47, 3127 (1969)is followed exactly. From 25.0 g of ~-naphthol is obtained 18.9 g of crude product. NMR analysis indicates . , .
;' -. :: ' , . : : ~
. ~- . .. ..

~631~0 ~111 it to contain ca. 40~ of the desired 5,8-dihydro-2-naphthol and 60 /c of 5,6,7,8-tetrahydro-2-naphthol.
B. cis-5,6,7,8-Tetrahydro-2,6,7-naphthalene triol.

. ~ . _ ., . . _ The 18.9 g of crude product of part A is converted to the acetate by reaction with acetic anhydride in the presence of pyridine and the resulting oil (23.8 g) is heated at 90 for 3 hr with 300 ml of acetic acid, 20 ml of water, 23.5 g of silver acetate and 18.0 g of iodine. The slurry is cooled and filtered.
~he filtrate is evaporated and the residue stirred overniyht under nitrogen with 100 ml each of water and methanol and 20 g of sodium hydroxide. The methanol is removed ln vacuo and the residue acidified at 0~ with 155 ml of 12% hydrochloric acid. The oil which separates crystallizes when shaken in a separatory funnel with chloroform. Filtration gives 7.9 g of tan solid. Recrystallization from ethanol/ethyl acetate gives in several crops 4.03 g, mp 193-195.5.
C. l-(cis-5,6,7,~-Tetrahydro-6,7-dihydroxy-2-naphtholoxy)-2,3-epoxy propane.
A solution is prepared from 3.76 g of the above phenol, 1.10 g of sodium methoxide and 100 ml of methanol and the solvent removed in vacuo. The residue is dissolved in 120 ml of dry dimethylsulfoxide and ca, 20 ml distilled out. To the resulting solution is added 4 ml of epichlorohydrin and the solution stirred under nitrogen overnight. The bulk of the DMS0 is removed in vacuo and the residue dissolved in 400 ml of chloroform. This solution is washed with 3 x 150 ml of water, dried and evaporat~d to give 4.01 g of oily solid.
Recrystallization from 60 ml of benzene gives 2.62 g, mp 99 - 107.

3L~63~Z[l HAlll D. ClS -6-[3-(tert~Butylamino)-2-hydroxypropoXy~-1,2,3,4-tetrahydro-2,3-naphthalenediol. ~;
A mixture of 2.5 g of the above epoxy~diol and 25 ml of ;
t-butyl amine is heated at 80 + 5 for 15 hr and the solvent removed ln vacuo. The residue i5 triturated with ether and allowed to stand overnight to give 2.16 g of solid. Two recrystallization3 from acetonitrile give 1.15 g, mp 106-129. -~
Anal- Calcd for C17H27NO4 C~ 65-99; H~ 8.80; ~ 4-53 Found: C, 66.16; H, 9.07; N, 4.47 ~ ;
~ . .

. .
l-(Isopropvlamino?-3-~2- ~ eridino-5-indanyloxy~~2- g panol ,,~
A 4.4 g (0.02 mole) Qample o~ 2-piperidino-5-indanol (Example 8A) was added to a ~lurry o~ 0.85 g (0.02 mole) of 57% sodium hydride oil dispersion in 300 ml of dry dimethyl ~; `
1 . . , sulfoxide under nitrogen. The mixture was stirred at room ~ ~ -temperature until the bubbling ceased and a clear, very dark ~`
solution resulted (5 hours~. Then a solution of 1.90 g (0.02 mole) of distilled epichlorohydrin in 60 ml of dimethyl 20 sulfoxide was added dropwiYe over two hours. The mixture was stirred another 16 hrs at room temperature then evaporated at 45-50C (0.2 mm Hg) to a semi-solid. Ether and water were added and the mixture clarified by fil~ration. The phases were separated and the aqueous extracted with more ether. ~-The organics were dried briefly (potassium carbonate) and -~
evaporated to S g of crude thick oily epoxide.
The oil was taken up in 20 ml of isopropylamine and heated at 80C overnight in a Parr bomb. The mixture was cooled, washed out with methylene chloride and evaporated to 11~631%~

a foam which was soluble in ether and benzene. A solution in 50 ml hexane deposited 0~2 g of solid epoxide on standing at room temperature for 2 hrs. The filtrate was cooled at 5C
and in several days deposited 3.1 g o a solid. Recrystallization from hexane with Norit treatment gave 2.0 g purer material.
Reworking all the mother liquors afforded another 1.5 g (52%). The 3.5 g of compound was taken up in ether, treated with ~orit, filtered, and treated with filtered hexane.
The ether was boiled off and the solution concentrated to 75 ml of hexane. Cooling 3 days at 5C afforded the 11.2 g analytical sample, mp 76-83C.
Anal. Calcd for C20H32N2O2: , Found: C, 71.99; H, 9.85; N, 8.21 .
5-[3-(tert-Butylamino)-2-hydroxypropoxy]-2-indanol - --A. 2-Indanol -A 60 g sample of 2-indanone (0.45 moles) in 1.5 liters of 4~/~ aqueous methanol was treated with 18 g (0.46 moles) of sodium borohydride in portions with cooling to maintain T < 40C. After the addition was complete (15 min), the mixture was stirred for 2 hrs then allowed to stand overnight at room temp. Ether extraction, drying over potassium carbonate and evaporation gave 58.3 g crystalline 2-indanol (96%).
B. 4- and 5-Nitro-2-acetoxyindan A slurry of 6.7 g (0.05 moles) of 2-indanol in 75 ml acetic anhydride was cooled to -15C (ice-acetone bath) and treated with 0.2 ml of 98% sulfuric acid. In about 10 ,' ' :' ~63iZC~ HAlll minutes the solid had completely dissolved. The stirred and cooled mixture was then treated over 15 min with a cold solution of 3.6 ml ~5.0 g~ of 7~/D nitric acid in 125 ml of acetic anhydride. The mixture was qtored at -20C overnight, then poured into 1 kg of crushed ice. The mixture was stirred until the ice had completely melted and most of the anhydride had reacted. The mixture was extracted with 500 ml of hexane.
The organics were washed with saturated bicarbonate and -evaporated to 3.0 g of an oil which solidified on standing. ;
Trituration with hexane and recrystallization from the same solvent gave 1.1 g of 2-acetoxy-5-nitroindan, mp 84-85 QC. The .. .. .
aqueous from the hexane extraction yielded 5.3 g of an oil on extraction with benzene. All but 0.9 g of this oil went into hot hexane. Cooling to room temperature gave ~ome oil. The mother liquor was decanted and cooled to 5C
overnight to give 2.0 g (35% total) of the 5-nitro compound, mp 82-84C. The filtrate was concentrated to 100 ml cooled again and filtered to give another 0.4 g crude 5-nitro, mp 60-74C. The mother liquors were concentrated but gave no 2~ solid on cooling. Evaporation afforded 2.0 g (22%) of oily 2-acetoxy-4-nitroindan, contaminated with some 4-nitroindene.
C. 5-Amino-2-acetoxyindan A slurry of 8.0 g (0.045 moles) of 2-acetoxy-5-nitroindan in 25 ml of absoIute ethanol and 32 ml of concentrated hydrochloric acid was treated over 1 hr with a solution of 24 g (0.11 moles) of stannous chloride in 32 ml of absolute ~-ethanol, with water bath cooling to maintain T=20C. The mixture was stirred for 1 day at room temperature, diluted with 100 ml of water and extracted twice with ether. The ~ ~..

HAlll ~63~L20 : ;:
: ,.
aqueous was basified with l~/c sodium hydroxide until the hydroxides redissolved, then extracted with chloroform, dried (sodium sulfate) and evaporated to an oil which crystal-lized to 3.9 g (82%) 5-amino-2-hydroxyindan, the hydrochloride of which had mp 237-239 after one crystallization from ether-methanol isopropanol.
D. 2,5-DihYdroxyindan 3.9 g (0.026 moles) amine were dissolved in 130 ml 5% H2SO4 and filtered thxough Hy-Flo. The solution was cooled in an ice bath and a solution of 1.99 g (0.0288 moles) NaNO2 in 20 ml H2O added over 5 min with stirring (T c 5C).
After stirring for 1/2 hr at 0C, urea (0.2 g) was added and solution stirred for another 10 min at 0C. with stlrring.
This cold solution was added to 400 ml vigorously boiling 5%
H2S04 over 2 hrs. Thi~ was refluxea for an additional 1/2 hr and cooled to room temperature. A small amount of brown solid was filtered off, and the filtrate extracted with CHC13. Organics were dried (MgSO4) and evaporated (0.4 g). The aqueous was extracted with n-BuOH. Organic were dried (MgSO4) ` 20 and evaporated (15 g).
The brown ~olid, CHC13 and n-BuOH extracts were combined and chromatographed on 300 g basic alumina (Act III) in CHC13. Elution with 5% MeOH in CHC13 yielded 2.5 g cryskalline phenol, mp 112-115C.
A portion recrystallized twice from ethylacetate-hexane had mp 116-118C.

~' ~ 30 '' _33_ , . . . .

HAlll .
113 ~;3~
:
E. 5-~2,3-(Epoxv)propoxyl-2-indanol To a solution of 7.5 g (0.05 moles) of the phenol in ~`
100 ml dry dimethylsulfoxide was added sodium methoxide (2.7 g, 0.05 moles) with stirring. The resulting methanol and 25 ml of dimethylsulfoxide were distilled off at 43C ;~
and 0.1 mm Hg. After the solution had cooled to room tempera~
ture, epichlorohydrin (5.55 g, 0.06 mole) was added and the solution was stirred under nitrogen at room temperature for ;~
23 hrs. The dimethylsulfoxide was distilled off at 45C and 0.1 mm Hg and the residue dissolved in water and ether. The ;~
layers were separated and the a~ueous extracted with ether.
The combined organics were dried (magnesium sulfate) and evaporated to yield 7.5 g (75%) 5-[2,3-(epoxy)pxopoxy}-2-indanol.
F. 5-~3-(tert-Butylamino)-2-hydroxypropoxy]-2-indanol To a solution of the epoxide (7.5 g, 0.036 moles) in 100 ml tert-butylamine was added 50 ml methanol. This solution was refluxed under nitrogen for 18 hrs. The solu-tion was evaporated and the residue dissolved in benzene-20 ether. After prolonged standing in the cold room, 2.5 g(25%) crystalline 5-[3-(tert-butylamino)-2-hydroxy-propoxy~-2-indanol was obtained. This sample was dried for 16 hrs at 40C over P205 and paraffin to yield the analytical sample 2.1 g, mp 95-98C.
Anal. Calad forCl6H25No3: C, 68.78 ~, 9.02; N, 5.01 Found: C, 68.72; H, 9.11; ~, 4.74 .. . . .. . . .. . . . .. . . ..

E~All].
1~i312~

2,3-trans-Sr3-~ert-Butylamino)-2-hydroxy-propoxyl l. 2 ~ 3 r 4~
, ~
tetrahydro-2-hydroxy-3-metllyla ino-naphthalene and the 8-isomer A, 5,8-Dihydro-l _aphthol, benzyl ether A solution of 5,8-dihydro-1-naphthol ~3 g, 005 M) in 400 ml DMSO was treated with 0.5 M of sodium methoxide.
The mixture was cooled in an ice bath while benzyl bromide (85.5 g, 0.5 M) was added dropwise. The mixture had to be shaken periodically since there was difficulty in stirring.
Toward the end of the addition the mixture was allowed to warm to ~45, and stirring was continued for 2-3 hrs after addition was complete. The mixture was then poured into 1 liter H20 and the product was extracted into ether. The ether extracts were washed with l~/o NaOH, dried and the solvent was removed ln vacuo to give a ~uantitative yield of crude crystalline product.
A small sample (4 g) of this was recrystallized twice from methanol to give the benzyl ether, 1.3 g, mp 70-74.

~0 Found: C, 86.58; H, 6.60 B. 6,7-EpoxY-5,6,7,8-tetrahydro-1-naphthol, benzyl ether The dihydro benzyl ether (47 g, 0.2 M) was dissolved in 200 ml chloroform and treated with a chloroform solution of 50 g m-chloroperbenzoic acid whi~h was added dropwise over a period of 1 hour. The mixture was stirred overnight at room temperature. A small amount of insoluble material was then removed by filtration and the filtrate was poured into dil. K2C03 solution. After stirring a few minutes the layers were separated and the chloroform solution was dried over K2C03, filtered, and the solvent was removed _ vacuo . .
.

HAlll leaving a quantitative yield of crude epoxide.

C. trans-3-tsenzylmethylamino)-5~(and 8) benzyloxy-1,2,3,4-- , tetrahydro-2-naphthol.
A mixture of the crude epoxide (lO g, 0.042 M) and methylbenzyl amine ~35 g) in 125 ml toluene was heated under reflux overni~ht. After cooling the reaction mixture was taken to dryness in vacuo leaving 15.2 g of dark brown oil. This was chromatographed on activity 2 neutral alumina. Fractions eluted with benzene-chloroform and chloro-form crystallized on standing. These contained 6.0 g (38% yield). Part of this material was recrystallized twice from ether to give the title compound, 400 mg, mp 126-136.
Anal. Calcd for C25H27O2N: C, 80.39, N, 7.29, ~, 3,75 Found: C, 80.64; N, 7.11; N, 3.78 D. trans-3-(Methylamino)-5-(and 8)-hydroxy-1,2,3,4-tetrahydro-2-naphthol The compound of part C is catalytically debenzylated over 5% Pd on C in acetic acid to yield the title compound.
E. 2,3-trans-5r3-(tert-Butylamino)-2-hydroxypropoxy~-1,2,3,4-. . .
2~ tetrahydro-2-hydroxy-3-methYlamino-naphthalene and the 8-isomer;

The procedure of Example 3 C and D are then followed employing the diol o part D to form the title compound.

5~ t 3-(tert-butylamino)-2-hydroxypropoxy]-1,2,3,4-tetrahydro-2,3-epithio-naphthalene and the 8-isomer ;

A. 6,7-E~ mino-5,6,7,8-tetrahydro-1-naphthyl benzyl ether . , , ~0631~

To an ether solution of iodine isocyanate ~ormed by ~;
reaction of 25.4 g (0.1 m) I2 and 20 g (0.13 m) ~ilver cyanate) i8 added 0.1 m of 5,8-dihydro-l-naphthyl benzyl ether over 1/~ hour. After stirring several hour~, the mixture i9 filtered and treated with anhyclrous methanol plu8 a little likhium methoxide. After standirlg in the dark overnight it i9 refluxed briefly then take!n to near dryne~s in vacuum. The residual liquid i8 poured into ice-water containing a little sodium sulfide and extracted with ether.
After washing with saturated salt solution, the ether solution of khe iodo isocyanat~ i8 treated with 40~ aqueous sodium bi~ulfite and stirred. The crude b~ulfite addition product i8 di~olved ~n 2N NaO~in methanol and heated under re~lux for 3 hour~ poured into ~alt ~olution and extracted with ether.
Evaporation of the dxied ether leave~ the des~red epimino compound. . -~
Refs Ha~ner et al. JOC 32 540 (1967~.
B. 6,7-Epithio-5,6,7,8-tetrahvdronaphthyl benzyl ether To 0.125 mole of pota3si~m thiocyanate i~ 20 ml of 50% ethanol ls added 0.10 mole of 6,7-epoxy-5,6,7,8 tetrahydro-l-naphthyl ben2yl ether and the mixture etirred vigorou~ly for 48 houre. The product i~ extracted into eth~r, wa~hed ' .
with ~alt solution, dried and freed of solvent.
Ref~ O.~. IV 232. ~-C. 5-[3-(tert-butylamino)-2-hydroxypropoxy]-1,2,3,4-~.:
tetrahydro~2,3-epithio-naphthalene ~:
The procedure of Example 3 C and D is then followed employing the epithio compound of part B to form the tikle compound.

1~;3~ 0 HAlll 5-[3-~ert-butylamino~-2-hydroxyprepoxy]-1,2,3,4-tetrahydro-- ~ .
: 2~(or 3)-mercapto-naphthalerle A. 6-Mercapto(or 7-mercapto)-5,6,7,8-tetrahyd:ro-1-naphthol To an ether solution of 0.25 m lithium aluminum hydrido in 200 ml Et20 i8 added dropwise a solution of 5.36 g ~0.02 m) of the episulfide of Example 13B in 50 ml of dioxane. ~fter :.
refluxing overnight the mixture i~ decomposed wi~h K2CO3 solution and the ino;rganics removed by i~iltration. Evaporation of the filtrates leaves crude mercaptan. This i~ taken up :
in ether, added to liquid ammonia and treated with 0,05 mole of lithium in small pieces. After removal of ammonia ~he re8idue is takan up ~n water and ~cid~ied. P~oduct i8 ' .
extraated into CHC13, dried, And ~ro~d of ~olv~nt. The mlxture of mercaptans i~ then.~hromatographed on ~ a gel to effect separation of 6- and 7~mercapto-5,6,7,8-tetrahydro-l-naphthol.
B. 5-[3~tert-Butylamino)-2-hydroxypropoxy]-1,2,3,4-tetrahydro- :
.
2-(or 3)-merc~to-naphthalene The procedure of Example 3 C and D is followed employing the mercapto compound of part A to form the title compound.
, 5-~3-(isopropy ~ ,4-tetrahydro-2-(or 3?-merca~to-3-(or 2)-methoxy-naphthalene A. 6~and 7)mexcapto-7~and 6)methoxy-5,6!7,8-tetrahydro-1-naphthol . .

, .

1~6312~ HAlll A ~olution of 5.36 g (0.02 m~ of the epi~ulfide of Ex~mple 13~
in 100 ml of methanol i8 treated with a few drop~ of perchloric acid ~ .
and heated to reflux for several hour~. The mixture i9 diluted with ~ :
water and the products extracted into chloroform. Solvent removal leaveq a mixture of the isomeric~ product~ w~ch 1~ separated on ~ilica. The ~ep~rated i~omeric products a~e then debenzylated - .
to give the title compounds.
B. 5- r 3-(Isopropylamino)-2-hydroxy-p-opoxy~ 2~3~4-tetrahydr 2-(or 3)-mercapto-3-(or 2~-methoxY-naphthalene Following the procedure of Example 2, employing the l-naphthol compound of part A, the title compound is obtained.

2~3-trans-5-r3-(i~opropylamino~-2-hydroxy-propoxy~-1,2,3,4- `' tetrahydro-3-~or_2)-methylthio-2-(or 3)-hYdroxY-naphthalene A. 6,7-trans-5,6,7,8-Tetrahydro-7(or 6)-(methylthio)-1,6- :
(or 7)-naphthalenediol To a 801ution of 5 g (0.2 m) ~a in 150 ml EtOH i3 added 20.4 g (0.1 m) of the epoxy acetate of Example 4A
followed by 15 g ~~~.3 m) CH3SH with ice-acetone cooling. The ::

mixture i8 atirred, allowed to warm up and finally refluxed overnight. ~he mixture i9 cooled, acidified with HOAc and taken to near dryne~s in vacuum. The re~idue i~ dissolved ~ ~
in water and the produ~t extracted into CHC13. Drying and~ :
solvent removal leaves 22 g of cr.ude products. These are chrom~to- :
graphed on 500 g neutral Alumina II. Early fractio~ (1 2% MeOH in CHC13) elute i~omer A(6,7-tran~-5,6,7,8-tetrahydro-7-(methylthio)-1,6-naphthalenedio~ mp. 116-122 rom ather.
~ater fractions (5-10~ MeOH in C~C13) elute iso~er B

~63~Z~

~,7-trans-5,6,7,8-tetrahydro-~-(methylthio)-1,7-nap~t:lalenedlol) mp. 132 134 from etherO
B 2,3-trans~5-~3-(isopropylamino)-2-hyclroxy-propoxy~-1,2,3,4- .
___ _ tetrahydro-3-(or 2)-methylthio-2-(or 3)-hydroxy-naphthalene Following the procedure of Example 2, employing the above diol, the title compound is obtained.

2~3-trans-5-r3-(Isopropylamino)-2-hydroxy-propoxy~ 2~3~4 .
tetrahydro~3-(or 2)-methoxY-2-(or 3)-hydroxy~e~ r A. 6,7-trans-5,6,7,8-tetrahydro-7(or 6)-methoxy-1,6(or 7)-na~hthalenediol A ~olu~lon of 22 g (0.11 m) o the epoxy acetate of Example 4A in 500 ml MeOH is treated wi~h 0.5 g p-toluene ~ulfonic acid hydrate and stirred overnight. After remo~al of moat of the solvent, the re~idual liquid is poured into water and the product extracted into CHC13. Drying and solvent removal leaves 13.3 g of crude produ~t. Thiæ is chromatographed on 300 g neutral.alumina II . Barly fraction, 5% MeOH in CHC13 yield~ isomer A 6,7-tran~-5,6,7,8- .
tetrahydro-7-methoxy-1,6-naphthalenediol, mp. 153-155 from ether~ethyl acetate~ later fractio~ yield isomer ~ 6,7-trans-5~6,7,8-tetrahydro-6-methoxy-1,7-naphthalenediol mp. 106-108 from ether.

B. 2,3-trans-5-r3-(Isopropylamino)-2-hydroxy-propoxy~-1,2,3,4_ .
tet.rahydro-3-(or 2)-methoxy-2-(or 3)-hydroxy-naphthalene Following the procedure of Example 2, employing the above diol, the title compound is obtained.

.. --~0--~ '~
~l~63120 HAlll . EXAMPLE 18 ; 2~3-trans-s-~3-(Isopropylamino)-2-hydroxypropoxy]-l~2~3~4 - . _ tetrahydro-2-(or 3)-amino-3-(or 2)-hydroxy naphthalene A. trans-6(and 7)-Amino-5,6,7,8-tetrahydro-1,7(and 6)-- .. .
naphthalenediol To ~ ~olution of 20.4 g ~0.1 m) of ~he ~poxy acetate of Example 4A ~n 200 ml dioxane heated to 40 is added a ~olu-tion of 6.8 g (0.11 m) of Na~3 in 20 ml H20 dropwise. The mixture i8 heated under reflux overnight, cooled, filtered and take~ to arynes~. Strong azide absorption in I~ R. i8 noted. The residue i9 dissolved in EtOH and hydrogenated over PtO2 a~ 1-3 atm. H2 in a Paar ~haker with repeated flushes : with H2 to ensure sufficient exposure to H2. Catalyst is filtered off and wa~hed with warm alcohol. Solvent i8 removed and the re~idue i~ triturated with hexane to induce crystalli-zat~on mp. 172-193 (d) ~rom ~tR~c-MeOH. ; ~ .
B. trans-5 [3~ opropylamino)-2-hydroxypropoxy]-l~2~3~4 tetrahydro-2-(or 3)amino-3-(or 2~hYdroxynaphthalene .~
~ollowing the procedure o~ Example 2, employing the : ~.
20 above diol, the title compound i~ obtained. ; ~ :

EXAMPLE lg 2~3-trans-s-r3-(Iqopropylamino)-2-hydroxypropoxy~ 2~3~4 tetrahydro-3-(or 2~-(isopropylamino)-2-(or 3)hydrox~-naphthalene A. 6,7-trans-5,6,7,8-T~trahydro-7(and 6)-(isopropylamlno)-1,6(and 7)-naphthalenediol A mix*ure of ~0.7 g ~0~ 05 m) of the epoxy acetate of Exampl~ 4A and 50 ml o~ _-propylamine i~ heated in a bomb ~t 100 oYernight. Removal of exce~s amine leaves a vi~cou~q '.

~0f~i31Z~ H~lll . materlal that i8 chromatograph~d on 500 g of neutral ~lumina : III. 10-20~ MeOH in CHC13 elut~s the de~ired product~
The product (a mixture of the above i~omers) i~ cry~tallized from ether and found to have a mp of 112-117. ~e hydrochloride salt ha~ a mp 207-210.
B. 2,3-trans-5-~3-(Isopropylamino)-2-hydroxypropoxy]-1,2,3,4-tetrahy__o-3-~or ? ) -(isopropylami-no~-2-(or 3~hydrox~-naphthalene Following the procedure of Example 2, employing the above diol, the title compound is obtained.

.,.
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Claims (6)

The embodiments of the invention in which an ex-clusive property or privilege is claimed are defined as follows:

1. A process for the preparation of a compound of the formula;

wherein the aminopropoxy chain is in the 1- or 2- position, wherein n is 0 or 1; wherein Z and Z1 are the same or different and are hydrogen, hydroxy, alkoxy containing 1 to 4 carbon atoms, mercapto, alkylmercapto wherein the alkyl group con-tains 1 to 4 carbon atoms, amino, monoalkylamino wherein the alkyl group contains 1 to 4 carbon atoms or piperidino, with the proviso that when one of Z and Z1 is piperidino, the other is hydrogen, or wherein Z and Z1 together form ; wherein R7 is hydrogen or methyl, with the proviso that when R7 is hydrogen and n is 1 only one of Z and Z1 can be hydroxy; and wherein R1 and R2 are hydrogen or alkyl containing 1 to 4 carbon atoms and wherein at least one of R1 and R2 is hydrogen, or a pharmaceutically acceptable acid addition salt thereof, which comprises heating an epoxide of the formula:

with an amine of the formula:

wherein n, Z, Z1, R7, R1 and R2 have the meaning stated above, to produce a compound of the formula first stated above.

2. The process of claim 1 wherein Z is hydroxy, Z1 is hydroxy or monoalkylamino, and R7 is hydrogen.

3. The process of claim 1 wherein Z is hydroxy, Z1 is hydroxy or isopropylamino, and R7 is hydrogen.

4. A compound of the formula wherein the aminopropoxy chain is in the 1- or 2- position, wherein n is 0 or 1; wherein Z and Z1 are the same or different and are hydrogen, hydroxy, alkoxy containing 1 to 4 carbon atoms, mercapto, alkylmercapto wherein the alkyl group contains 1 to 4 carbon atoms, amino, monoalkylamino wherein the alkyl group contains 1 to 4 carbon atoms or piperidino, or wherein Z and Z1 together form ; wherein R7 is hydrogen or methyl, with the proviso that when R7 is hydrogen and n is 1 only one of Z and Z1 can be hydroxy; and wherein R1 and R2 are hydrogen or alkyl containing 1 to 4 carbon atoms and wherein at least one of R1 and R2 is hydrogen, or a pharmaceutically acceptable acid addition salt thereof, whenever prepared according to the process of claim 1.

5. A compound or a salt thereof, as defined in claim 4 wherein Z is hydroxy, Z1 is hydroxy or monoalkylamino, and R7 is hydrogen, whenever prepared by the process of claim 2.

6. A compound, or a salt thereof, as defined in claim 4 wherein Z is hydroxy, Z1 is hydroxy or isopropylamino, and R7 is hydrogen, whenever prepared by the process of claim 3.