CA1047035A - 1-(amino-alkyl)-2-aryl-cyclohexane alcohols and esters - Google Patents

Abstract

Abstract of the Disclosure Analgesics, local anesthetics, and antiarrhythmics which are 1-(amino-alkyl)-2-aryl-cyclohexane alcohols and esters having the structure

Description

~047~35 Ihls lnvention relatcs to analgeslcs, local anesthetlcs, and antiarrhythmlcs whlch are l-(amlno~alkyl)-2-aryl-cyclohexanol compounds havlng the following structure:

R5~)) R Rl "

O(CH-(CH~)n-N~

wherein Rl is hydrogen or alkanoyl (1 to 8 carbon atoms);
R2 and R3 individually are hydrogen, lower alkyl (1 to 8 carbon atoms), nr ic-wer alkenyl !3 to 8 carbon. at^.rn.s~ or R2 and R3 together with the nitrogen to which ~hey are attached form a morpholine radical, a piperazine radical or a ring structure containing 3 to 6 methylene groups; ~ -R4 ls hydrogen or lower alkyl (1 to 8 carbon atoms~;
R5 and R6 lndividually are hydrogen, lower alkyl (1 to 8 carbon atomsj.
- hydroxyl or lower alkoxy (I to 8 carbon atoms);
n is 0 or 1, and the pharmaceutlcally aaceptable acid addition and quaternary salts thereof, as well as stereoisomers and optical isomers thereof. This invention relates also to processes for making and using ~he foregolng compounds.
This lnvention in one of its process aspects (FLOW SHEET A) re-sides in condenslng a 2-aryl cyclohexanone (I) with an alkali metal deriva-tive of a lowcr alkanoyl-(N, N-disubstituted amide), whereln the alkali rnetal ls alpha to the carbonyl group to obtaln an alpha r2-aryl(l-hydroxy-cyclohexyl)~ lower alkanoyl-N, N-disubstituted amide (II). Reductlon of the alkanoyl carbonyl group rcsults ln the 2~aryl-1-(N, N-disubstltutcd amino .

~0~7035 alkyl)-cyclohexanol (III) which may be alkylated with an alkanoyl halide or an alkanoyl anhydride to form the correspondlng ester (IV~.

FLOW SHEET A

R4-~HI~-N~

BN~R

lleducing Agent ~R6 IV R5 R6 HC~2~ 3 ~ [~HCH2N~ 3 whereln M is an alkali metal and Rl is analkanoylcontaining 1 to 8 carbonatoms.
This invention in yet others of its process aspects (FLOW SHEET B) resides in condensing an aryl-cyclohexanone (I) with an organozinc com-pound, derived from an alpha halo aliphatic ester or an alpha halo aliphatic nitrile, to obtain the corresponding alpha-2-(aryl-l~hydroxycyclohexyl)-aliphatic ester (V) or alpha-2-taryl-l-hydroxycyclohexyl) aliphatic nitrile ~I). Reduction of the ester (V) or acid (VI), obtained by hydrolysis oi the ester, to the alcohol (VII) followed by esterification with an sulfonyl halide yields the sulfonic acid ester (VIII) which on reaction with ammonia or an amine, yields the desired l-(amino or N-substituted amino-alkyl)-2-aryl-cyclohexanol (IX). The nitrile (XI) on reduction yields a 1-(aminoalkyl)-2-aryl-cyclohexanol (XII) in which the nitrogen atom is un-substituted and which may be used as such or the nitrogen atom may be alkylated to obtain the N-substituted compound~ (IX or X).

'`~-''' ' '" '' ~ , ' ' ~Lq)47Q3S

o~O~ `~;

~ o ~ ~

lgl~ m ~ ~/

~DO~

Ixl ~ o ~o ~ O O_ e ~

7~35 In yet another of lts process aspects (FLOW SHEET C), this invention resides in reacting the acid (VI) with a halo ester and then with an alkali metal azide to produce the 6-aryl-1-oxa-3-azaspiro [4. 5] decan-

2-one ~III) which can be alkylated to give the corresponding N-alkyl oxa-azaspiro decan-2-one p~IV). The latter may in turn be reduced to the 1-(1-dialkylaminoalkyl)-2~aryl-cyclohexanol ~V). The corresponding ester p~VI) can be forrned by acylating the resulting cyclohexanol p~V) with an alkanoyl halide or with an a lkanoic anhydride. Alternatively, the oxa-aza-spirodecan-2-one (XIII) can be converted to the l(l-aminoalkyl)-2-aryl-cyclohexanol ~VII) by hydrolysis. In yet another alternative, the aryL-oxa-azaspiro-decan-2-one ~III) can be directly reduced to the corresponding alkyl amlno alkyl cyclohexanol p~VIII).

. . ' ' .

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

0~ m ~>~

\ `$\~ ' V

~\ ~

c~v ~ lXI ` ~ .. ,; ~, "i~, _ C`~ , ~ ~

~7~35 Other process aspects of this inventlon are illustrated by Flow Sheets D, E, F, G and H.
Flow Sheet D

~ (CH3)2SO.CH2 O~CH2 1) (R) 3P= CHR4 II l R2 2) [o] (VI)~ R3 R4~ ~ ~ ~ R3 III

An aryl cyclohexanone (I) is condensed either with dimethyl- :
.oxosulfonium methylide or dimethylsulfonium methylide (V), or with the ::
methylene or ethylene Wittig reagent (VI) followed by oxidation, to give the epoxides II and III which are reacted with appropriate amines to give the corresponding l-aminoalkyl-2-arylcyclohexanols (IV).

.

, .. ,, ~ , . .

. ~ .

~0~7~3S

Flow Sheet F
[~1' (~3 }I ~ Li III I 1) R4-CH

~ILi g3 -; ~

CH-VII VIII
L~ 1) NaBH4 ;

': -- ~'.'', ~0~
Rl X I ~ HO IX
or (R ~ ~ R4 1) R2R3NH
2) [H]/Catalyst (~ ' ' ' .

Rl 1) R2R3~l 0 2) [H]/Catalyst X R1 ~ R2 X ~ R
XI
':
T*e epoxide III is condensed with the lithium salt of a 1,3-dithiane or the ketone I is reacted wlth a dihydro-1,3-oxazine to give (VII) and (VLII) respectively wlllch are readily converted to the alde-hydes by procedures known to the art. The resulting hydroxy-aldehydes (IX) ~ ~ 7 ., .

1~47~)3S
can be converted directly to the amines (X) by reductive~zmination pro-cedures or may be first esterified and then converted to ~he amines (XI) .
Flow Sheet F

Ll,C_CH ~ (R)3SiX

-C~ )3 Si / XII ~III

2 ~ ¦
1 L$CHCH=NR

IX ~ ~ * ~ C~3 ~ ~10 1) R~R3NH
XVII 2) ~H]/Catalyst :, ~
. / :
XI .

LiAlH4 ~ ~ XVI
~R R

'' [~3 ' .~

~C~2NHR2 XVIII

.
.,~ ~ ,, ',, ', .. ' "

The ketone I can be condensed with varlous lithium salts to give intermediates (XII) and (XVII) which can then be`converted to ketones ~XIV) or aldehydes (IX) or via the epoxysilanes (XIII) to aldehyde (XV). The carbonyl compounds can subsequently be reductively aminated to the arnino-alcohols (XI) and (XVI). Alternatively, the irnine (XVII) can be reduced directly to the arnino-alcohol (XVIII).

Flow Sheet G

LicHN~R3 - > ~ C -N

I IV ~-.

A further process is the direct alkylation of the 2-arylcyclo-hexanone (I) with the lithium saJt of an arnine to give the amino-alcohols (IV).
Flow Sheet H

HCN or (CH3)3SiC N
~ ~ Si(CH3)3 LiC~ LiCIHN=C(Ph)2 XIX¦ B2H6 2) Hydrolysis LiAlH4 N3C ~ ~H2 ~ I

XX XXI XXII
lhe invention is further illustrated by these processes for pre-paring examples where the amino group is primary. lhe addition of cyanide to I using hydrogen cyanide or trirnethyl silyl cyanide affords the cyano-hydrin (XIX) which can be reduced to the anino alcohol (XXII) by borane or _ g _ .

~0~3S
lithium aluminum hydride, ma lithium salt of an alkyl isocyanide adds to I to give the lsocyanide-alcohol (XX) which can be hydrolyzed to the amino-alcohol (XXI).
The amino-alcohol (XXI) can also be obtained by addition of the lithium salt of the diphenylmethane imines (XXIII) to ketone (I) followed by hydrolysis.
Flow Sheet J

OOH

I XXIII

LiAlH
, 4 1 ~H
or NaAlH2(CH2CH2CH3)2 r ~ CH20H
: . ~ C~3 f~ , .
~ Tosyl Cl ~ H
: ~ ~ CH20 Tos.

.

(CH3) 2NH ~3 ~ 2-N~ 3 .

. CH3COCl 2 ~C~

- ::
::

7~35 EXAMPLE p~
2~ Hydroxy-2-phenylcyc hexyl)-propionic acid A solution of 177 ml (0.89 moles, m.w.=181.31, 161 gm) dicyclo-hexylamine in 1080 ml TEIF was cooled in a MçOH/dry ice bath to <O and a solution of 370 ml n-butyl lithium (2.2 moles solution in hexane, 0.89 moles) was added at ~O. After about 5 minutes, a solution of 33.2 ml (0.~l45 mole, m.w.=74.08) propionic acid in 280 ml THF was added at ~O, then the solution was heated to about 50 over 1~ hours. After cooling the mixture back to -50, a solution of 75.5 gm (78% pure, -56.6 gm pure ketone, 0.325 mole, m.w.=174.24) in 200 ml THF was added as rapidly as possible. Temperature rose to about -25. The reaction mixture was allowed to warm to room temperature, at which point the reaction was com-plete.
The reaction mixture was added to 1100 ml water, then 1400 ml ethyl acetate was added and the mixture extracted with a solution of 560 gm citric acid in 700 ml water, then twice with 500 ml dilute citric acid solution (ca 10%) and once with 500 ml water.
The aqueous extracts were extracted with 2 x 200 ml ethyl acetate9 and this was washed twice with 400 ml water. The organic extracts were combined and extracted with 300 ml 10% K2CO~ solution. The aqueous solu-tion was washed wit~ 2 x 300 ml ethyl aretate. T~e aqueous solution was acidified and extracted with 4 x 300 ml ethyl acetate and dried over MgSO4. Removal of solvent left 95 gm crude product. Yield ~ quantitative.
The crude product was dissolved in 190 ml CC14 and to the solu-tion was added 320 ml hexane. The mixture was allowed to crystallize, the crystalline material was filtered off and washed with hexane. Wgt=29.9 gm "major isomer".
P~emoval of solvent from the filtrate gave 60.5 gm of a resinous mixture of "major" and "minor" isomers.
2-(1 Hy roxy-2-phenylcyclohe~yl)-propanol "minor"_ isomer The mixture of "maj or" and "minor" acid isomers from the pre-ceding preparation (60.5 g, 0.244 mole, m.w.=248.33) was dissolved in 240 ml THF and added dropwise to a solution of 16.5 gm (0.43 mole, m.w.=
38) LAH in 265 ml THF. The reaction mixture was refluxed for 2 hours, then cooled to c~O and the excess LAH decomposed with 120 ml ethyl acetate, after which a solution of 87 ml H2O in 87 ml THF was carefully added.
After stirring a few minutes, the mixture uas filtçred and the cake washed thoroughly with l~IF. The solution was dried over MgSO4 and the solvent removed on a rotovap. Crude wt - 46.7 gm.
The mixture was dissolved 140 ml of a l:l::cyclohexane:hexane ~7~3~

mixture and seeded with a few crystals of pure "mlnor" diol. Crystalliza-tion of the "minor" diol commenced rapidly. After a few hours, the crystals were filtered off and washed with solvent. Wgt = 8.6 gm, m.p. =
94-96, The filtrate was about a 1:1 mixture of "major" and "minor"
diols. Attempted crystallization of more "minor" diol by cooling the fil-trates resulted in crystallization of a mixture (ca 1:1) of the two diols.
The diols could be completely separated by chromatographing on SiO2 (100 gm dry column SiO2/gm mixture, developing with 20% EtAc in cyclohexane).
2-(1-Hydroxy-2-phenylcyclohexyl)-propyl p-toluenesulfonate, "minor'! isomer This was prepared from the "minor" diol and p-toluenesulfonyl chloride in pyridine using exactly the same procedure as for the preparation of the "major" tosylate. (Example II) 1-(2-Dimethylamino-l-methylethyl)-2-phenylcyclohexanol "minor" isomer Dimethylamine (14 ml, 9~3 gm, 0.2 mole, m.wO=45.09, neat liquid) was added to a solution of 13.3 g (0.034 mole, m.w.=388.51) of the "minor"
tosylate in 80 ml DMSO in a pressure bottle. The mixture was heated under head pressure at 80 for 5 hours.
The reaction mixture was cooled to room temperature, added to 900 ml water and extracted 5 times with 200 ml CC14. The CC14 layer was washed with water and then extracted with 100 ml 7% HCl and twice with 75 ml 3.5% HCl. The aqueous layer was washed with CCl49 then basified with NaOH and the product extracted into CC14. The CC14 solution was dried over MgS04 and the solvent removed on the rotovap leaving 6.1 gm product.
1-(2-Dimethylamino-l-methylethyl)-2-phenylcyclohexyl acetate, "minor" isomer Acetyl chloride (2.7 ml, 3 gm, 0.038 mole, m~w.=7~.50) was added to a solution of 6.1 gm (0.023 mole, m.w.=261.42) "minor" aminoalcohol in 70 ml CHC13. Stirred 45 min, then added 60 ml 10% NaOH and stirred vigorously for a few minutes. Allowed to stand for 1 min, then added, with slow stirring, under the CHC13 layer, 3 ml AcCl. Allowed to stand 30 min, then stirred vigorously again for a few minutes, allowed to stand 1 min and added 3 ml more AcCl with gentle stirring. After 1 hour, most of the alcohol had reacted. Separated the CHC13 layer and extracted the aqueous layer with 3 x 25 ml CHC13. Dried, filtered and added 7 ml AcCl.
Relatively little change on standing overnight. Added 15 ml MeOH, allowed to stand for about an hour, extracted with dil NaOH, dried and removed the solvent on the rotovap. Crude wt = 5.9 gm tlc (20% EtAc in cyclohexane on ammonia treated SiO2) showed product, Rf-0.27, small amount of "ma~or"

~9L7~35 isomer, Rf=0,36, and traces of three impurities, Rf2 0,55, 0.68 and 0.96.
Dissolved in 18 ml i-PrOH, filtered, rinsP-washed with 6 ml i-PrOH, acidified with gaseous IICl and diluted with 1000 ml Et2O. Allowed to crystallize, Eiltered and washed with i-PrOH/Et20 and Et2O. Wgt = 3.5 g, m.p.-173-175~C. -:

.~,. - ' . .' .

1~L7(J 35 The compounds of this invention may exhibit geometrical or optical lsomerism and may be obtained as mixtures of the lsomers, The lsomers may be separated from their mixture by well-known techniques, e. g, by chemical, mechanical or biological methods The invention in another of its process aspects resides in using the compounds of this invention as analgesic, local anesthetlc or anti-arrhythmiG agents, The compounds of this invention in the form of their free base or acid addition and quaternary salts thereof, possess the characteristic of exerting analgesic, local anesthetic or antiarrhythmic effects and there-iore as such are therapeutically useful.
The alkanoyl substituents include, for example, acetyl, propionyl, .
butyryl and their branched chaln analogues, e, g., pivalyl and alpha methylpropionyl .
The lower alkyl substituents (R2, R3, R4) include such monovalent radicals as ethyl, propyl, butyl and such other straight and branched chain aliphatic hydrocarbon radicals having 1 to 8 carbon atoms, but pref erably methyl .
VVhen R2 and R3, together with the nitrogen atom to which they are attached, form a cyclic amino structure, the resulting heterocyclic radical lncludes piperidino, pyrrolidino, morpholino, and phenylpiperazinyl, etc.
The lower alkenyl radicals includé allyl, butenyl, etc.
The alkoxy substituents include, for example, methoxy, ethoxy, propoxy, butoxy, and the like.
The acid additlon salts include those prepared from such acids as hydrochloric acid, phosphoric acld, sulfuric acid, maleic acid, ci~ric acid, p-taluenesulfonic acid and other well-known pharmaceutically , ... . . .
, ~7V3~

acceptable acids. The quaternary salts include those prepared from such organic halides as methyl iodide, ethyl iodide, benzyl chloride and the like .
In general, the amlno-cyclohexanols of this invention are pre-S pared by the synthetlc schemes set forth in the examples which are illustrative of the processes employed to prepare the composition aspect of this invention. In the examples, percent concentrations (e. g. 10%
H2SO4) are percent by weight; percent yields are mol percents, and temperatures (e. g. reaction temperatures melting points, etc. ) are in degrees Centrlgrade.

~:, . ..

3L09~7U3S
~A PLE I

Preparation of_l-(2~DLmethylamlno-l-methylethyl?-2-Phenylcyclohexanol._ -Synthetic Scheme~

= H ~P
N(CH3) 2 LiAlH4 ~ ' ' r i ¦ OH

~qHcH2N (CH3) 2 :
T o one mole of phenyl lithium in benzsne-ether solution !ca 2~ r?~ dl!ufed with 1000 ml ether, add a solution of 100 ml dimethylamine in 200 ml ether .
over about 15 minute period, then reflux for 15 minutes. Then add a solutlon of 100 ml N, N-dimethylpropionamide in 200 ml ether over about 15 minutes. Following an additional 15 minute reflux period, add a solution of 175 g of 2-phenylcyclohexanone in 200 ml ether during about 1/2 hour period. Reflux the reaction mixture 2 hours, cool to 0 and treat all at once with 1000 ml 3N-hydrochloric acid. The ether layer is separated from the aqueous layer and the latter is extracted with ether. The combined ether layers are washed with 3N-hydrochloric acid, then water, and last with potasslum bicarbonate solution. After drying over magnesium sulfate, remove the solvent by evaporation under vacuum.
The crude amide which results is dissolved in 200 ml ether and added to 40 grams lithium aluminum hydride in 500 ml ether over about 1/2 hour . -10~7~35 period. After a 2-1/2 hour reflux, the mlxture is cooled to -5 and the excess lithium aluminum hydride is deskoyed with 300 ml ethyl acetate.
Add 200 ml water, filter the resulting slurry and wash the filter cake with ether. Extract the etherwith dilute hydrochloric acid. The acid layer is then made basic to litmus using sodium hydroxide solution and is extracted with chloroform. After evaporation of the chloroform, 42. 5 grams of crude product is obtained as a residue.
This product is a mixture of two geometrical isomers which is separated into two isomers by chromatography on SiO2 giving 31. 0 grams major isomers and 5. 2 grams minor isomer3 both distilling at 97-105 at 0. 005 mm.
EXAMPLE I (a) 1-12-Dimethylamino-l-methylethyl)-2-~henylcyclohexyl propionate maleate! (Ma~or Isomer) The propionate ester of the major isomer is prepared by dissolving 16 grams of 1-(2-dimethylamino-1-methylethyl)-2-phenyl-cyclohexanol (major isomer) in 100 ml of chloroform and adding 16 grams of propionyl chloride. After standing for 2 hours, the solution is concentrated by evaporation under vacuum to a thick paste which is shaken with 200 ml ether. The propionate ester is obtained as the hydrochloride salt.
Conversion of hydrochloride salt to the maleate salt yields 10 grams of ; product melting at 163-165 C.
EXAMPLE I (b) 1- (2-Dimethylamino-l-methylethYl) -2-Phenylcyclohexyl propionate maleate (Minor Isomer) The procedure of Example I(a) is followed using 10 grams of 1-(2-Dimethylamino-l-methylethyl)-2-phenylcyclohexanol (minor isomer) and 6 .. . .

~L~47~35 grams propionyl chloride. The resulting propionate ester, obtained as the hydrochloride salt, is contaminated with alcohol and is purlfied by chroma-tography on silica gel. Conversion to the maleate salt yields 3. 5 grams product, melting at 104-105 C.
EXAMPLE I (c) 1-(2-Dimethylamino-l-methylethyl~-2-phenylcyclohexyi acetate maleate (Major Isomer) The procedure of Example I (a) is rollowed using 12 grams of 1-(2-Dimethylamino-1-methylethyl)-2-phenylcyclohexanol (major isomer) and 4. 2 grams of acetyl chloride. Conversion of the resulting acetate hydro-chloride salt to the maleate salt yields 11 grams of product. After recrystal-lization from isopropanol, the melting point is 170. 5 to 172C.

Preparation of l-(l-Methyl-2-piperidinoethyl)-2-phenylcyclohexanol.
.
Synthetic Scheme:

~) ~OH ~[~OH
~ ~CHC02H ~:HCH2~I
l~ Jl.CH3CHBrCO2Et/Zn ~ J ~ l~ J I
2. H~ CH3 ~' CH3

3. OH- I II
p-toluene-sulfonyl chloride Pyridine IV III

.

a7~3~
Preparation of 2~ Hydroxy-2-phenylcyclohex~1)-propionic acid (1) -2~Phenylcyclohexanone (100 grams) and 111 grams of ethyl 2-bromo-propionate are dissolved in 225 ml benzene plus 225 ml toluene. Freshly activated zinc dust (38.~ grams) is added and the mixture heated to reflux with stirring. The vigorous reaction, which commences soon after refluxing begins, is moderated with an ice bath. After the initial reaction is over (about 5 minutes), the mixture is refluxed for 1-1/2 hours, then cooled and added to 1000 ml ice cold 10~ sulfuric acid. The a~queous layer is extracted with benzene and the combined organic layer is washed with water and potassium bicarbonate solution. The solvent is removed by evaporation ; under vacuum and the crude ester hydrolyzed by refluxing for three hours in a mixture of 360 ml methanol, 1080 ml water, and 225 ml of 50~ sodium hydroxide solution. The hydrolysate is cooled and extracted with chloro-form, to remove unreacted 2-phenylcyclohexanone.
The a¢queous solution is acidified and the product extracted there-from wi~h chloroform. The chloroform layer is washed with water, dried with magnesium sulfate and the solvent is removed by evaporation leaving 116.5 grams of acid (I). Recrystallization oE I from 800 ml cyclohexane yields 110 grams product melting at 128-130 C.
Preparation of 2~ ydroxy-2-phenylcyclohexyl)-propanol (II) A solution of 61 grams of 2-(1-hydroxy-2-phenylcyclohexyl)-propionic acid (I) in 200 ml tetrahydrofuran is added dropwise to 30 grams of lithium aluminum hydride in 700 ml ether. After refluxing for 2-1/2 hours, the mixture is cooled to -5 and treated successively with 1~0 ml ethyl acetate and 150 ml water. The slurry is filtered, the residue on the filter paper is washed well with ether which is combined with the filtrate and the solution dried over magnesium sulfate. Evaporation of the solution left 57 grams of product (II) melting at 89-93 C.

.. . . .

: . ....... . . . ..
~; - ' ' ~ ' ' ' ~7~35 Preparatlon of 2-(1-Hydroxy-2-phenylcyclohexyl)-propyl ~toluenesulfonate (III) A solution of 57 grams of 2~ hydroxy-2-phenylcyclohexyl)-propanol (II) in 350 ml pyridine is treated with 72 grams of p-toluenesulfonyl chloride and the mixture is stirred at room temperature for 40 hours. It is then poured into 1500 ml cold water and the product extracted into chloroform.
The chloroform solution is washed with dilute hydrochloric acid plus ice water, and finally with potasslum bicarbonate solution. After drying over magnesium sulfate and removal of the solvent by evaporation under vacuum, 79 grams of product (III) melting at 100-105C is obtained.
Preparation of l-(l-Methyl-2-piperidinoethyl)-2-phenylcyclohexanol (IV) A solution of 18 grams 2-(1-hydroxy-2-phenylcyclohexyl)-propyl-p-toluenesulfonate (III) and lS ml piperidine in 150 ml dimethylsulfoxide is heated at 75 for 5 hours. The solution is then added to lOUO ml water and lS extracted with n-hexane. The hexane solution is washed with water, dried over magnesium suliate and the solvent removed by evaporation under vacuum leaving 14.1 grams of product. The hydrochloride salt is made by . .
passing dry hydrogen chloride into an ether or hexane solution of the free base. The salt is filtered and washed with ether giving the product (IV) - 20 melting at 239-240C.
EXAMPLE III
Preparation of 1-(1-Methyl-2-pyrrolidinoethyl)-2-phenylcyclohexanol.
The procedure of example II is repeated in all essential details with the exception that 15 ml pyrrolidine is substituted for the 15 ml piperidine.
The yield of pror~uct is 14.1 grams which melts at 253-253. 5C
(hydrochloride salt).
~XAMPLE IV
Pr.~aratl on of 2- (l-HydroxY- 2-phenylcyclohexyl) - 2-methylethylamine.

.
... .
.'; ' : ~

7~)3S
Synthetic Scheme:

Li~lH4 b~
CH3C~ ~I3 ~22 2-Phenylcyclohexanone ~15. 9 grams) and 9. 9 ml 2-bromopropionitrile is dissolved in 25 ml tetrahydrofuran and 7. 3 grams of freshly activated zinc dust is added. The mixture ls cooled to 8 C and 0. 3 grams of HgC12 is added. The temperature rises to 32C with ice bath cooling. When the temperature starts to fall, the ice bath is removed and heating commenced.
The reaction may become mildly exothermic again at about 70 C. After the intial reaction is over, the mixture is refluxed for 15 minutes, cooled and added to 300 ml of 5% hydrochloric acid and ice. This~mixture is extracted ::
with chloroform and after washing the resulting solution and evaporating the solvent, 20 grams of semi-solid brown material is obtained.
The above material is dissolved in 400 ml ether and 100 ml n-hexane, filtered, and added dropwis0 to 6 grams of lithium aluminum hydride in 250 ml ether. After refluxing for 3 hours, the mixture is cooled to -5C
and treated successively with 30 ml ethyl acetate and 30 ml water. The mixture is filtered and the solid washed wlth ether. The ether solution is extracted with dilute hydrochloric acid. The acid solution is made basic and the product was extracted into chloroform. The solution is washed with water, dried over magnesium sulfate and the solvent evaporated under vacuum leaving about 8. 7 grams of crude product which contains two geometrical isomers plus small amounts of impurities. The isomers are separated by chromatographing on silica gel, giving 3. 5 grams of the major isomer and 1 gram of the minor isomer. A cyclohexylsulfamate salt of the - '' ' ' , ` ": ' ' major isomer is macle and found to melt at 9~-lO0 C.
EXA~PLE V
Preparation of [2-(1-Hydroxy-2-phenylcyelohexyl)-prop~l~ -trimethyl-monium iod3de.
A solucion of 3.5 grams of 1-(2-dimethylamino-1-methylethyl)-2-phenyl-cyclohexanol in 250 ml ether and lO ml tetrahydrofuran is treated with 6 ml met:hyl iodide and allowed to s-tand for 7 days. The crystalline product is filtered and washed with ether and recrystallized from water giving 2.1 grams melting at 155-159C.
EXA~PLE VI
Resolution of d, Q-2-(1-Hydroxy-2-p enylcyclohexyl)-propionic aeid.
The optieally aetive aleohols and esters of this invention ean be prepared from the optieally active intermediate 2-(1-hydroxy-2-aryl cyclohexyl)-propionic acids, in turn prepared by the resolution of the corresponding d, R -acid.
A solution of dehydroabietylamine (263 gm) in 810 ml methanol is added to a solution of 230 gm d,~ -2-(1-hydroxy-2-phenylcyclohexyl)-propionie acid in 800 ml methanol and the resulting solution is brought to persistent eloudiness with 365 ml water, then made clear again with 185 ml methanol. The solution is stored at 8 for 24-48 hours, then filtered and the solid washed with aeetone, eollecting the wash separately from the mother licluor.
The acetone insoluble fraction is reerystalliæed three times from methanol-water mixture (40 ml boiling methanol/gm to dissolve salt, fol-lowed by 6 ml water/gm salt added to the eooled methanol solution). After -:, : . - -, .

3L(~4'i~(~3~
each recrystallizatlon, the crystalline salt ls filtered off and washed wlth 5:1::methanol:water mixture. The yield of resolved salt is 82 gm.
[~] 365=~5. 4 (c 1, CH30H), Further recrystallizations of this salt gives no further change in optical rotation.
The salt is decomposed with dilute sodium hydroxide and the free amine is extracted into chloroform. The resolved acid is preclpitated with dilute hydrochloric acid, extracted into chloroform, washed with water, dried over magnesium sulfate and the solvent is removed in vacuo leaving - 37 gm of acid with [a] 365= -196 (~1, CHC13).
The mother liquor from the original crystallization and the first recrystallization are combined and the methanol is removed on a rotary evaporator. The salt is filtered off and washed with acetone, giving 165 gm of salt with [~] 365= ~79 (c 1, CH30H) . This salt is dissolved in 8500 ml methanol, cooled, diluted with 3900 ml water, stirred foriseveral hours and filtered.
Removal of methanol from the mother liquor, followed by filteringand drying the salt gives 81 gm of partially resolved material with [a]32655=+89. 1(~, 1, CH3OH).
The partially resolved (~)- acid is obtained as described on the preceding page for the (-)- acid, yielding 32 gm product with [CL]3565=-~103 (c 1, CHC13) .
EXAMPLE VII
Preparation of (-)-1-(2-Dimethylamino-l-methylethyl)-2-~henylcyclohexanol.
The preparation is identical to the last four steps (I~II~III~IV) in Example II, except that (-)-2-(1-hydroxy-2-phenylcyclohexyl)-propionic acid is u~ed in place of the dJR-acid (I in Example II) and dimethylamine is used in place of piperidlne in going from III~IV of Example II. The free amino alcohol has the following optical rotation:

~L0~3S

[a] 52859=-5.1; (c 13 CHC13).
EXAMPLE VIII
Preparation of (+)-1-(2-Dimethylamino-l-methylethyl)-2-phenylcyclohexanol The procedure is identical to that used in Example VII except that (+)-2-(1-Hydroxy-2-phenylcyclohexyl)-propionic acid is used in place of (-)-2-(1-Hydroxy-2-phenylcyclohexyl)-propionic acid. The free amino alcohol has the following optical rotation-[a] 52859- ~. 3; (c 1, CHC13).
EXAMPLE IX
Preparation of (-)-1-(2-Dimethylamino-l-methylethyl)-2-phenylcyclohexyl acetate.
:
(-)-1-(2-Dimethylamino-l-methylethyl)-2-phenylcyclohexanol (8 gm) In 65 ml chloroform is cooled to 0 and 2. 7 ml acetyl chloride is added at S5- After warming to room temperature, the solution-is extracted with dilute aqueous sodlum hydroxide, washed with water and dried over magnesium sulfate. The dried chloroform solution is then cooled to 0 and treated with another 3. 0 ml acetyl chloride at <5 and again allowed to warm to room temperature, extracted with dilute sodium hydroxide, washed with water and dried over magnesium sulfate. Removal of solvent leaves 9. 3 gm of an oil which crystallizes spontaneously. This is recrystallized from 30 ml n-hexane (at -50) yielding S. 7 gm product melting at 63-66. The -~ optical rotation is as follows: [a] 52859= -76. 7; ~2,1, CHC13).
EXAMPLE X
Pre~aration of (~)-1-(2-Dimethylamino-l-methylethyl)-2-Pheny cyclohexyl acetate.
, The procedure used ls identical to that used in Example IX except (~)-1-(2-Dimethylamino-l-methylethyl)-2-phenylcyclohexanol is used in place of (-)-1-(2-Dimethylamino-l-methylethyl)-2-phenylcyclohexanol, and --2~--70~5 the product is isolated as the hydrochloride salt by precipitation with gaseous hydrogen chloride of an ether solution of the free amine:
m. p. = 150-153. The optical rotation i5 glven below:
[a] 55 9- +29. 1; (c 1, (: HC13) EXAMPLE XI
Preparation of 1-(2-Dimethylamino-l-methylethyl)-2-phenylcvclohexanol-p-toluene sulf onate .
A solution of 3. 6 g 1-(2-Dimethylamino-l-methylethyl)-2-phenyl-cyclohexanol (Example I) in 30 ml acetone is added to a solution of 3. 6 g p-toluenesulfonic acid. The solution is seeded and diluted after a few minutes with 75 ml dry ether to give 5 g crude product which is recrystal-lized from 50 ml acetone to give 4. 2 product, m. 140-2.
EXAMPLE XII
Preparation of l-(l-Methyl-2-~peridinoethyl)-2-phenylcyclohexyl acetate hydrochloride.
A solution of 6. 6 g 1-(1-~ethyl-2-piperidinoethyl)-2-phenylcyclo-hexanol (Example II) in 150 ml benzene is treated with 11. 5 ml methyl lithium (2 molar in ether), stirred 1/2 hr, added another 1. 5 ml methyl lithium solution, then 5 ml acetic anhydride is added and the mixture stirred for 48 hours. The mixture is added to 400 ml water and 50 ml concentrated ; NH40H and extracted with benzene, the benzene extract washed with water, dried and concentrated. The residue ls chromatographed on alumina (dry column) to give 3 g product which is converted to the hydrochloride salt to give 2. 9 g., m. 155-9.
EXAMPLE XIII
Preparation of 1-(2-Allylmethylamino-l-methylethyl)-2-phenylcyclohexyl acetate.

~L~)4~3~ii a) 1-(2-~ lmethylamino-1-methylethyl)-2-phenylcyclohexanol.
The procedure of Example II is followed exeept that plperidine is replaced by allylmethylamine. Starting wlth 12 g allylmethylamine and 30 g of the tosylate (Compound III), 5. 9 g of produet is obtained.
b) 1-(2-Allylmethylamino-l-methylethyl)-2-phenylcyelohexyl aeetate The procedure of Example I(c) is followed using 4. 8 g of 1-(2-Ally]methylamino 3-methylethyl)-2-phenyleyelohexanol and 13 ml acetyl ehloride to give 3. 2 g pure product.
EXAMPLE XIV
, Preparation of 1-(2-Dimethylaminoethyl)-2-phenylcyclohexanol.
The procedure of Example II is followed except that e$hyl-2-bromo-propionate is replaced by ethyl bromoaeetate and piperidine is replaeed by dimethylamine. In this manner, 60 g 2-phenyleyclohexanone and 62 g ethyl bromoaeetate gives 20 g of 2-(1-Hydroxy-2-phenyleyelohexyl) aeetie aeid, m. 122-5; 19 g of the aeid gives 13. 4 g 2-(1-Hydroxy-2-phenyleyelo-hexyl) ethanol, m. 105-8; 13. 2 g of the aleohol gives 15. 4 g of crude 2-(l-Hydroxy-2-phenyleyelohexyl) ethyl tosylate which gives 10. 5 g of 1-(2-Dimethylaminoethyl)-2-phenyleyclohexanol, m. 64-6.
EXAMPLE XV
Preparation of 1-(2-Dimethylaminoethyl)-2-phenylcyclohexyl acetate eyelohexylsulfamate .
The procedure of Example I (c) is followed using 7. 5 g of 1-(2-Dimethylaminoethyl)-2-phenyleyelohexanol (Example XIV) and 8 ml of aeetyl ehloride with 18 ml triethylamine giving 11. 8 g crude aeetate whieh is treated with 12 g cyclohexanesulfamie aeid in tetrahydrofuran to give 6. 7 g pure produet, m. 140-1.

.. ,,~ .

~0~7035 EXAMPLE XVI
Preparation of 1-(2-Dialls~lamino-l-methylethyl)-2-phenylcyclohexyl acetate.
a) 1- (2-Diallylamino- l-methylethyl) -2-phenylcyclohexanol.
The procedure of Example II is followed except that piperidine is replaced by diallylamine. In this manner, 37 g 2-(1-Hydroxy-2-phenyl-cyclohexyl) propyl-p-toluenesulfonate and 30 g diallylamine gives 16. 2 g product.
b) 1-(2-Diallylamino-l-methylethyl)-2-phenylcyclohexyl acetate.
The procedure of Example I(c) is followed using 19. 7 g of 1-(2-Diallylamino-l-methylethyl)-2-phenylcyclohexanol, 50 ml acetyl chloride, and 75 ml N-methylmorpholine to give 12. 8 crude product which gives 3. 9 g pure product after chromatography on alumina.
EXAMPLE XVII
PreT~aration of 1- (2-Dimethylamino~l-meth~lethyl) - 2- [~-methoxyPhenvl) cyclohexanol hydrochloride.
The procedur3 o Example II is followed except that 2-phenylcyclo-hexanone is replaced by 2-(p~Methoxyphenyl)cyclohexanone and piperidine is replaced by dimethylamine. By this method is obtained 196 g crude Ethyl-2-(1-hydroxy-2-[p-methoxyphenyl]cyclohexyl) propionate from 128. 7 g 2-(p-Methoxyphenyl)cyclohexanone (which is prepared by known methods) and 121. 8 g Ethyl-2-bromopropionate; 50 g crude 2-(1-Hydroxy-2-[p-methoxy-phenyl]cyclohexyl) propioriic acid from 196 g Ethyl-2-(1-hydroxy-2-[p-methoxyphenyl]cyclohexyl)propionate; 54. 6 g crude 2-(1-Hydroxy-2-[p-methoxyphenyllcyclohexyl) propanol from 50 g 2-(1-Hydroxy-2-~p-methoxy-phenyl~cyclohexyl) propionic acld. The crude 2-~1-Hydroxy-2-[p-methoxy-phenyl]cyclohexyl) propanol is converted to the tosylate and treated with 125 ml dimethylamine (according to the procedure of Example II) to 0ive ~4 g crude base which is converted to the hydrochloride and recrystallized from .: . ' .. . . . . . .

~47(~
lsopropanol to give 33. 5 g product, m. 245-6.
EXAMPLE XVIII
-Preparation of l-(l-Methyl-2-morpholinoethyl)-2-phenylcyclohexanol hydro-chloride .
The procedure of Example II is followed except that piperidine is replaced by morpholine. In this way, 75 g of 2-(1-Hydroxy-2-phenyl-cyclohexyll propyl tosylate and 120 ml morpholine gives 59. 3 g oi the hydrochloride salt, m. 278.
EXAMPLE XIX
Preparation of l-(l-Methyl-2-morpholinoethyl)-2-phenylcyclohexyl acetate hydrochloride.
l-(l-Methyl-2-morpholinoethyl)-2-phenylcyclohexanol hydro-chloride (Example XVIII) is converted to the free base and treated with acetyl chloride according to the procedure of Example I (c) using 14 ml acetyl chloride and a reaction time of 90 hours. The product is treated with NaOH to give the base which is dissolved in ether and acidified with HC1 gas to give lQ. 7 g., m. 176. 5-7. 5 after recrystallization from isopropanol.
EXAMP~E ~
Preparation of l-(l-Methyl-2-~4-phenyl-1-piperazinyl]ethyl)-2-phen~o-hexanol.
The procedure of Example II is followed except that piperidine is replaced by l-phenylpiperazine. In this way 73 g of 2-(1-Hydroxy-2-phenyl-cyclohexyl)propyl tosylate and 57 g l-phenylpiperazine give 51 g crude product which is recrystallized from hexane to give the product which melts at 219-220 .

1~7~S

_A~IPLE ~XI
Preparation of l~ Methyl 2- ~q-phenyl-l-pipera n ~ ethyl)-2-phenvlcyclo-hex~l acetate hydrochloride l-(l-Methyl-2-~4-phenyl-l-piperaziny ~ ethyl-2-phenylcyclohexanol (Example XX) (10 g) is acylated following the procedure of Example I(c) using 20 ml acetyl chloride and a reaction time of approximately 100 hours to give 7.4 g product, m. 180-1 after recrystallization from 300 ml isopropanol.
EXAMPLE XXII
Preparation of l-(l-Methyl-2-pyrrolidinoethyl)-2-phenylcyclohexyl acetate sulfate.
l-Methyl-2-pyrrolidinoethyl)-2-phenylcyclohexanol hydrochloride (Example III) is converted to the free base with NaOH and extracted into chloroform. The chloroform solution i5 treated with 10 ml acetyl chloride according to the procedure in Example I(c) using a reaction time of 6 hours.
The HCl salt is converted to the free base and 7 g of base is treated with 7 ml sulfuric acid in ether to give the sulfate salt which is recrystallized from 20 ml isopropanol and 50 ml tetrahydrofuran to give 3.1 g crude product.
The sulfate salt (7.5 g) is recrystallized from 40 ml isopropanol and 200 ml tetrahydrofuran to give 7 g., m. 154-4.5 .
EXAMPLE XXIII
Preparation of l-(1-Aminoethyl)-2-phenylcyclohexanol hydrochloride.
a) 4-Methyl-6-phenyl-1-oxa-3-azas~iro C4.5~decan-2-one.
2-(1-Hydxoxy-2-phenylcyclohexyl) propionic acid (Example II, Compound I) (33 g) in 110 ml acetone is treated with 20.5 ml triethylamine.
The solution is cooled to -5 and 14 ml ethyl chloroformate in 35 ml acetone added at a temperature below 0 . The mixture is stirred 10 minutes and 17.2 g of sodium azide in 50 ml water is added at or helow 0 . The mixture is stirred 1-1/2 hours, added to 500 ml ice water and extracted with toluene.
~" ;' ., ... . . , : ' .
- :' .
'.:, , " .. ,. , ,' : ' ":. .

, :

~0470~5 The extract is dried and heated at 100 until the evolution of nitrogen is about over, then refluxed 2 hours, concentrated~ to a slurry on the rotovap and the solid filtered and washed with benzene and cyclohexane to give 28. 8 g of 4-methyl-6-phenyl--1-oxa-3-azaspiro [4. 5] decan-2-one, m. 171-3 b) 1- (l-Aminoethyl) - 2-phenylcyclohexanol hydrochloride .

4-Methyl-6-phenyl-1-oxa-3-azaspiro [4. 5~ decan-2-one (8 g) is refluxed with 30 ml alcohol, 15 ml water, and 15 ml 50% NaOH for 20 hours, cooled, added to 150 ml water and extracted with chloroform. The extract is washed with water, dried and concentrated. The residue is dissolved in 10 ml isopropanol, acidLfied with HCl gas and 5 ml ether added.
When crystallization starts, another 15 ml ether is added to give 4. 3 g product, m. 247-7. 5.
EXAMPLE XXIV
-Pre~d~ OI. ~,r l-~ vIe~liylarninoe-t'nyi~-2-pilen~lcyclohexanol nydrochloride.
4-Methyl-6-phenyl-1-oxa-3-azaspiro [4. S] decan-2-one (Example X~III) (S g) in 60 ml tetrahydrofuran is added to 1. 6 g LiAlH4 in 100 ml tetrahydrofuran. The mixture stirred for 65 hours. The mixture is cooled, 8 ml water added and the solid is filtered off. The filtrate is dried and concentrated. The residue is dissolved in ether and the solution acidified with IICl gas to give the HCl salt which is dissolved in 10 ml isopropanol and 50 ml ethanol, cooled, diluted with 150 ml ether to give 4. 4g. product, m. 235-7~.
XAMPLE X~V
Preparation of 1- (2-Dimethylamino-l-methylethyl) - 2- (p-methoxyphenyl) -cyclohexylacetate hydrochloride.
1- (2-Dim ethylamino-l-m ethylethyl) - 2 (p-methoxyphenyl) cyclo-hexanol (Example XVII) (10 g) is treated with 20 ml acetyl chloride according to the procedure of Example I(c) with a reactlon time of 8 hour~. The crude ~47V35 HCl salt was recrystallized from 25 ml isopropanol and 125 ml ether to give 3. 5 g product, m. 190-2.
EXAMPLE ~XVI
.
Preparation of 1-(2-Methylamin_-l-methylethyl)-2-phenylcyclohexanol hydrochloride.
The procedure of Example II is followed except that piperidine is replaced by methylamine. By this method, 47. 5 g 2-(1-l~Iydroxy-2-phenyl-cyclohexyl)propyl-p-toluenesulfonate and 80 ml methylamine gives 28. 5 g base which is converted to the hydrochloride salt to give 26. 5 g product, m. 225-6.
EXAMPLE ~VII
Preparation of l-(l-Dimethylaminoethyl~-2-phenylcyclohexanol hydrochloride.
a) 3, 4-Dimethyl-6-pher~-1-oxa-3-azaspiro ~4. 51 decan-2-one 4-Melhyl-6-phenyl-1-oxa-3-azaspiro [4. 5] decan-2-one (Example XXIII) (23. 6 g) in hexamethylphosphoric triamide (HMPT) is added dropwise to 5 g sodium amide in 35 ml HMPT. The mixture is stirred until NH3 evolution is essentially finished and 11 ml methyl iodide added at about 40 over a 1/2 hour period. The mixture is stirred 1 hour, added to 700 ml water and extracted with ethyl acetate. The extract is washed with water, dried and concentrated to give 25 g crude product. A sample of the crude product, recrystallized from cyclohexane, gave the crystalline product, m. 85-6.
b)l- (l-Dimethylaminoethyl) -2-phenylcvcl~ he~nol hydrochloride A solution of 25. 5 g crude 3, 4-Dimethyl-6-phenyl-1-oxa-3- ~ ~ ;
azaspiro [4. 5] decan-2-one in 125 ml tetrahydrofuran is added to 8 g LiAlH4 25 in 300 ml tetrahydrofuran and the mixture reiluxed 1-1/4 hours, cooled and treated with 40 ml water. The mixture is filtered and the filtrate washed, dried and concentrated to give 26. 6 crude base. A 5 g sample of this crude , ~ . . .

~47035 product is dissolved in 25 ml isopropanol, acidified with HCl gas and diluted with 150 ml ether to give 4. 4 g product, m. 206-7.
EXAMPLE XXVIII
Preparation of l-(l-Dimethylaminoethyl)-2-phenylcyclohexyl acetate cyclo-

5 hexylsulfamate.
1- (l-Dimethylaminoethyl) - 2 -phenylcyclohexanol (Example XXVII) (20 g) is acylated according to the procedure of Example I (c) using 18 ml acetyl chloride. Conversion of the HCl salt to the cyclohexylsulfamate salt gives 20 g of product, m. 128-9.
10 EXAMPLE XX~
Preparation of 1-(2-Dimethylaminoethyl)-2-m-tolyl-cyclohexyl acetate.
The procedure of Example XIV is followed except that 2-phenylcyclo-hexanone is replaced by 2-m-tolylcyclohexanone. By this method 10. 2 g 2-m-tolylcyclohexanone gives 4. 4 g crude 1-(1-Hydroxy-2-m-tolycyclohexyl) 15 -acetic acid which is reduced '4O give 2. 0 g 2~ Hydroxy-2-m-tolylcyclo-hexyl)ethanol, m. 50-5; 2. S g of 2-(1-Hydroxy-2-m-tolylcyclohexyl~ethanol gives 2. 5 g crude 2-(1-Hydroxy-2-m-tolylcyclohexyl) ethyl tosylate which gives 2 g crude 1-(2-Dimethylaminoethyl)-2-m-tolylcyclohexanol. Acetyl-ation of this compound fo~lowing the procedure of Example I(c) gives 2. 0 g 20 product.
EXAMPLE ~XX
Preparation of 1- (2 -Dlmethylamino-~methylethyl) - 2 - (p-hydroxyphenyl) -cyclo-hexanol.
1- (2-Dimethylamino-l- methylethyl) ~ 2- (p-methoxyphenyl) cyclo-25 hexanol hydrochloride (Example XVII) (7. 2 g) is added to a solution of 8. 5 g50% sodium hydride dispersion in 130 ml dimethylformamide with 12. 4 g ethanethiol. The mixture is kept at 100 for 9 d ~s, cooled,,diluted with 2 "

76);~
volumes of water and 1 volume of saturated NH~Cl colution and extracted 5 times with ether. The ether is washed, dried and concentrated and the residue azeotroped with bénzene and concentrated. The residue is washed with ether, dried, and recrystallized from 45 ml isopropanol to give 3. 4 g product, m. 189-91.
In an alternate procedure for the preparation of 1-(2-Dimethylamino-l-methylethyl)-2-(p-hydroxyphenyl) cyclohexanol, 51 g ethanethiol in 50 ml dimethylformamide is added dropwise to 35. 5 g of 50% sodium hydride in 500 ml dimethylformamide. To this is added 31. 8 g of 1-(2-Dimethylamino-1-methylethyl)-2-(p-methoxyphenyl)cyclohexanol hydrochloride. The mixture is then set up for distillation. Distillation is continued until the internal temperature reaches 140. The mixture is refluxed 5-1/2 hours and then cooled, added to 2 volumes of water and 1 volume of NH4Cl and ex-tracted with 700 ml and 4x300 rnl ethyl acetate. The extract is washed with water, dried, concentrated, a little ether added and the solid filtered and washed with ether to give 24. 7 g product, m. 189-91.
EXAMPLE X~I
Preparation ~f 1- (2-Dimethylamino-l-methylethyl) -2- (p-hydroxyphenyl) -cyclohexyl- acetate hYdrochloride, ~-.
a) 2- (p-Benzyloxyphenyl) -1- (2-dimethylamino-1-methylethyl) -cYclohexanol hydrochloride.
1-(2-Dimethylamino-l-methylethyl) -2- (p-hydroxyphenyl) -cyclo-hexanol (Example XXX) (5. 6 g) in 50 ml dimethylformamide is treated with 3. 8 g benzyl chloride and 6 g potassium carbonate and stirred 3 hours at 90. The mixture is cooled, 200 ml water added and extracted with 7x50 ml ethyl acetate. The extract is washed with water, dried and concentrated.
The residue is dissolved in 65 ml ethyl acetate and acidified with HCl gas to give 5. 7 g product, m. 253-4.

- ,i 7~3S
b) 2- (p- BenzYloxyphenyl)-l- (2-dlmethylamino-l methylethyl) -cyclohexyl acetate.
2- (p-Benzyloxyphenyl) -1- (2-dimethylamino-1-methylethyl) -cyclohexanol hydrochloride (11. 3 g) is stirred with 140 ml chloroform and 26 g potassium carbonate. Acetyl chloride (6. 5 ml) is added and the mixture is stirred overnight, washed with water, and the chloroform dried. The chloroform solution is stirred for 6 hours with 6. 5 ml acetyl chloride and 26 g potassium carbonate, then washed with water, dried and concentrated to give 14 g crude product.
1~ c) 1- (2-Dimethylamino-l-methylethyl) - 2- (p-hydroxyphenyl) cyclo- hexyl acetate hydrochloride.
.
2- (p-Benzyloxyphenyl) -1- (2-dimethylamino-1-methylethyl) -cyclohexyl acetate (14 g) in 200 ml acetic acid is reduced catalytically using 5 g Pd/C at 50 psi. The catalyst is filtered off and the filtrate con-centrated. The residue is dissolved in chloroform, washed with dilute NaOH, dried and concentrated. The residue is dissolved in 75 ml isopropanol and acidified with HCl gas to give 11. 2 g product, m. 218-19~.
EXAMPLE ~II
Preparation of 2-(3, 4-Dimethoxyphenyll-1-(2-dimethylamino-1-methylethyl)-cyclohexanol P-toluenesulfonate.
The procedure of Example II is followed except that 2-phenylcyclo-hexanone is replaced by 2-(3, 4-Dimethoxyphenyl)cyclohexanone and piperidine is replaced by dimethylamine. In this way, 15 g of 2-(3, 4-Dimethoxyphenyl)cyclohexanone gives 14. 4 g crude 2-[2-(3, 4-Dimethoxy-phenyl)-~hydroxycyclohexyl] propionic acid which gives 13 g crude 2-[2-(3, 4-Dimethoxyphenyl)-l-hydroxycyclohexyl]propanol which gives 21 g crude 2-[2-(3, 4-Dimethoxyphenyl)-l-hydroxycyclohexyl]propyl tosylate which is treated with 38 ml dimethylamine to give 12. 2 g 2-(3, 4-Dimethoxy-,, , .

~gL`7~

phenyl)-l-(2-dimethylamino-1-methylethyl)cyclohexanol. The base (4. 9 g) is converted to the p-toluenesulfonate by additlon of p-toluene sulfonic acid in acetone to an acetone solution of the base to give 3. 9 g product, m. 196-7.
EXAMPLE X~III
Preparation of 2- (3, 4-DimethoxyPhenyl)-1- (2-dimethylamino-1-methylethyl)-cyclohexyl acetate hydrochloride.
The procedure of Example I(c) is followed using 6. 5 ml acetyl chloride and 11. 5 g 2-(3, 4-Dimethoxyphenyl) ~ 2-dimethylamino-1-methyl-ethyl)cyclohexanol and a reaction time of 6 hours to give 9. 5 g. crude HCl salt which is dissolved in 50 ml isopropanol and diluted with 440 ml tetrahydrofuran and 60 ml ether to give 7.1 g product, m. 200.
EXAMPLE XXXIV
Preparati on of [ I - (l -~ydroxy- 2-r)henvl ~yclohexyl! ethyl ltrim thyl ammf~nil~m iodide.
1-~l-Dimethylaminoethyl)-2-phenylcyclohexanol hydrochloride (Example ~VII) (5. 6 g) is converted to the base, extracted with chloroform, dried and concentrated to give 4. 9 g base. The base is dissolved in 20 ml ethanol, 8 ml methyl iodide added and the mixture heated in a pressure bottle at 65 for 17 hours, then at 95 for 3 hours. The mixture is cooled, 100 ml ethyl acetate added and concentrated to a slurry. Another 100 ml ethyl acetate is added and about half of the solvent is removed on the rotovap. The solid is filtered and washed with ethyl acetate to give 5. 9 g product, m. 18 8-9 0 .
EXAMPLE XXXV
Preparation of ~2-(1-Hydroxy 2-phenylcyclohexyl)propylltrimethylammonium p-toluenesulf onate .
2-(1-Hydroxy-2-phenylcyclohexyl)propyl p-toluenesulfonate ~ : :

~Lt;)47~)35 (Example II, Compound III) (10 g) ln 75 ml ethanol is stirred at room tempera-ture for S~ hours with 15 ml trimethylamine. The mixture is then heated at 75 for 7 hours in a pressure bottle, concentrated and 125 ml water added.
The solution is seeded and the resultant solid filtered and washed to give

6. 5 g product, m. 85-7.
XAMPLE XXXVI
Preparation of 1-(2-Dimethylamino-l-methylethyl)-2-phenylcyclohexyl acetate maleate.
a) 1-(2-Dimethylamino-l-methylethyl)-2-phenylcyclohexanol hydrochloride 2-(1-Hydroxy-2-phenylcyclohexyl)propyl-p-toluene sulfonate (Example II, Compound III) (160 g) is dissolved in 1200 ml dimethylsulfoxide.
A solution of 160 ml dimethylamine in 240 ml dimethylsulfoxide is added over about 15 minutes and the mixture stirred at room temperature for 3 days, then lS at 65-70 for 24 hours. The mixture is poured into 8 liters of water and ex-tracted 3 times with ether. The combined ether extracts are washed with water, dried, and concentrated on the rotovap. The residue is dissolved in one liter of dry ether and acidified (cooling below 20) with a solution of 18 g HCl gas in 100 ml ether. The solid is filtered, washed with ether and dried to give 119 g product, m. 250-1.
b) 1-(2-Dimethylamino-l-methylethyl)-2-phenYlcyclohexy~cetate maleate 1-(2-Dimethylamino-l-methylethyl)-2-phenylcyclohexanol hydr3s chloride (119 g) is converted to base which is dissolved in 960 ml chloroform.
A solution of 36. 2 ml acetyl chloride in 290 ml chloroform is added over a 15 minute period. The mixture is left overnight at room temperature, con-centrated to dryness on the rotovap and the residue shaken up with 2 liters of ether. The solid is filtered, washed with ether, dried, dissolved in 1. 5 liters of water, made alkaline with 10% NaO~I, and extracted with ether.
The ether extract is washed with water, dried, and treated with a solution of 76.7smalelc acid in 192 ml absolute alcohol and 960 ml ether. The mixture is cooled overnight at 10 and filtered to give 108. 5 g crude product which is recrystallized twice from isopropanol (4 ml solvent/gm salt), cool~
ing the recrystallization mixture to 10 overnight before filtering off the product in each case. This yields 54. 8 gm product melting at 171. 5-172. 5.
The identity with the material obtained in Example I(c) is shown by compari-son of infrared spectra, elemental analyses and melting point.

~37-, ~7035 The compounds of thls invention were-tested for analgesicJ local anesthetic and antiarrhythmic activity in experimental animals. Results of analgesic tests are summarized and compared with the standard anal-gesics morphine and meperidine, etc. in Table I. In addition, general ~;
pharmacologic profiles were evaluated and compared with these standards.
Analgesia was assessed in mice utilizing the hot plate method of Eddy and Leimbach, Journal Pharmacology Expt. Therap., 107, 385, 1953, and/or the phenylbenzoquinone writhing method described by Sigmund et al, Proc. Soc. Exptl. Biol. Med., 95, 729, 1957. The hot plate method is bas~d upon the delay in reaction time, following administration of an active analgesic when animals are placed on a heated metal plate maintained at constant temperature. Thus, t~le numbers of mice showing elevation of response times over control values after administration of various doses of an unknown compound are used to determine the median effective dose (ED50), which is that dose affecting 50% of the animals. The writhing method is based upon inhibition by an analgesic of the response which occurs when the chemical agent phenylbenzoquinone is injected intraperi-- toneally. This response is characterized by a twisting or stretching of the body and is referred to as writhing. Following administration of an analgesic or unknown compound into mice, the numbers of animals not responding to the phenylbenzoquinone challenge by writhing are determined. The ED50 can then be calculated to indicate the level of analgesic activity; the lower the ED50 value, the more active the compound as an analgesic.
A modification of the mathod originally described by Irwin ~Animal and Clinical Pharmacologic Techniques in Drug Evaluation, Ed. J. ~I. Nodine and P. E. Siegler, pp 36-54, Philadelphia: Year Book Med. Pub. 1964) was used to establish pharmacologic profiles through use of a multidimensional , .. . .

~347~3S
general screening procedure ln mice. This method is based upon direct observation of animals for behavioral changes~at intervals after administra-tion of various dose levels of the unknown compound. (;?ualltative and semiquantitative effects are recorded and comparison is made with profiles of standards. Since active compounds of thls invention approach analgesic potency displayed by several narcotic analgesics, morphine and meperidine were used as standards for comparison. Although similar to these standards in several respects, the active compounds of this invention differ in certain qualitative eharacteristies. In miee, the narcotic analgesics cause stimulation eharacterized by an increase in locomotor activity. This inereased response has been used to estimate the relative levels of morphine-like intrinsie activity of analgesics (Stoekhaus, K. E. H. and Villarreal, J. E., 32nd meeting of Committee on Problems of Drug Dependence, - WashingLo-1, D. C., February i970, pg ~ô3G of minu~es3.
Active compounds of this invention not only failed to cause increased locomotion, but acted in the opposite direction to decrease motility over a wide range of dosage. These results suggest that compounds of this invention might represent a significant advance over existing narcotic analgesics through deviation frorn certain characteristic morphine-like actions but without sacrificing analgesic effectiveness.
Local anesthetic activity of the compounds oi this invention was determined by a study of their effects on the mouse sciatie nerve and by their ability to block conduction of the isolated frog sciatic nerve. Results of these tests are listed in Table I. The mostactive eompound, 1-(2-Dimethylamino-l-methylethyl)-2-phenylcyclohexyl acetate maleate (Major isomer) produced sciatie bloeks similar to but more prolonged than those produeed by lidocaine.

' ' '; ' ~ 47~
ol _~
~, ~ ~ ~ + + +
C

o ~ o o ~ ~ o o U~ ~

o ~ o o ~ o ~ o _ o o ~ :

~ X X ~ Cl o D
~1 1 ~ o ,s r x ,1~

r ~ ~ ~ , u X ~ X ~ X

7~)35 ,v . ..
a~ , ~ , .
3~ + + + ~ + +
C~ C~

U~ ~ o, ~ o o o o o o a ~ . ~
CO o O O O C7 0 0 ' O O . .
: ~ ~ ~ _ o .
nU'~

S

~5 s ~ E E E s ~, x s ~ ~ o ~ ~ ~ ~ ~ d ~ v R -- - ~
I
~ ~ ~ O ~ ~
~ ~

:~ a F y y~

~~ ~ Q~ C`l ~ S ~ S
V _ t) _ ~ N ~ C~
~;
E

~703~i ~, ';I
c.~
+ + ,~ + + + + ~ + s:

---- o ~ s .
O O O ~ O O C~
~4 o~
a) ,_ ", ~ U~
a F~ ~, O co a E _ ~ a i '~5,~ x ~' ~ c~

~ i a ~ ~ x I
E ~ a P

-~2-~LC147(;~35 Anti-arrhythmic activity was determined by measuring the effect of the test compound in preventing or reversing the arrhythmia produced in dogs or cats by ouabain. In the test method, the animal was pretreated with 10 mg/kg (i. v, ) of the test compound. The animal was then glven 15 micro-grams/kg of ouabain (i, v. ) followed by doses of 10 micrograms/kg of ouabain at 15-minute intervals (the last dose of ouabain could be less than 10 micrograms/kg) until an arrhythmia was produced which lasted for 10 minutes. The animal was then given 5 mg/kg (i. v, ) of test compound, If the arrhythmia was not reversed after 3 minutes, 1 mg/kg of xylocaine was given (i. v. ) to reverse the arrhythmia. If the arrhythmia was reversed within 3 minutes by the test compoundJthe period of timeduringwhichthetest compound ei'fected reversal was measured (Arrythmia Reversal Time).
Xesults of these tests are given in Table II. With the most-active compound, pretreatment of the animal prevented the appearance of arrhythmia when ouabain was given.

, -43--1~47035 .~ ~
E 0 ~ o ~ ~ o . ~ ~

.~ ~ u7 0 ~
_, o o C~ '~ CO o ~o ,,~ ~ .
~:O

_ j ~ ~ C

,~ ,~ o .`. -- E -- I ~ ~ ~D ~' d ;;

E ~E ~ E 'L, _ U

~ ~ ~ L~ L~
E,~ E o ~ ~ ~ E ,~

-~ d ~
.~ ~ 0 V ~

_ ~ o X I X H ~ d --~L4--

Claims (36)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE PROPERTY OR PRIVILEGE
IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for preparing a compound having the formula X

X

wherein R1 is hydrogen or alkanoyl containing 1 to 4 carbon atoms;
R2 and R3 individually are hydrogen, alkyl containing 1 to 4 carbon atoms, or lower alkenyl containing 3 or 4 carbon atoms or R2 and R3 together with the nitrogen to which they are attached form a morpholino radical, a 4-phenyl-piperazino radical; or a pyrolidino or piperidino radical;
R4 is hydrogen or methyl;
R5 and R6 individually are hydrogen, lower alkyl containing 1 to 4 carbon atoms, hydroxyl, or lower alkoxy containing 1 to 4 carbon atoms;
n is 0 or 1; and the pharmaceutically acceptable acid addition and quaternary salts thereof;
and stereoisomers and optical isomers thereof, which comprises a process selected from the following processes:
A. Condensing a 2-aryl cyclohexanone of the formula (I) I

wherein R5 and R6 are as defined above, with an alkali metal derivative of a lower alkanoyl -(N,N-disubstituted amide) of the formula wherein R2, R3 and R4 are as defined above and M is an alkali metal, to obtain an alpha [2-aryl(1-hydroxy-cyclohexyl)] lower alkanoyl-N,N-disubstituted amide of the formula II

II

wherein R2, R3, R4, R5 and R6 are as defined above; reducing the alkanoyl carbonyl group to obtain the 2-aryl-1-(N,N-disubstituted amino alkyl)-cyclohexanol of the formula III

III

wherein R2, R3, R4, R5 and R6 are as defined above; and alkylating with an alkanoyl halide or an alkanoyl anhydride to form the corresponding ester, of the formula X and when required converting the ester to a pharmaceutically acceptable acid addition or quaternary salt;
B. Condensing an aryl-cyclohexanone of the formula I defined above with an organozinc compound derived from an alpha halo aliphatic ester or an alpha halo aliphatic nitrile of the formula or , respectively wherein X is halogen, R is a hydrocarbon radical and R4 is as defined above to obtain the corresponding alpha-2-(aryl-1-hydroxycyclohexyl)-aliphatic ester of the formula V or an alpha-2-(aryl-1-hydroxycyclohexyl) aliphatic nitrile of the formula XI, respectively V XI

wherein R, R4, R5 and R6 are as defined above; when required hydrolysing the ester of the formula V to an acid of the formula VI

VI

wherein R4, R5 and R6 are as defined above; reducing the ester of the formula V or the acid of the formula VI to the alcohol of the formula VII

VII

where R4, R5 and R6 are as defined above; esterifying the alcohol of the formula VII with a sulfonylhalide of the formula R7SO2C1, wherein R7 is a hydrocarbon radical to obtain the sulphonic acid ester of the formula VIII

VIII

wherein R4, R5, R6 and R7 are as defined above; reacting the ester with ammonia or an amine of the formula R2R3NH to obtain the desired 1-(amino or N-substituted amino-alkyl)-2-aryl-cyclohexanol of the formula X

X

wherein R1, R2, R3, R4, R5 and R6 are as defined above; and when required reducing the nitrile of formula XI to obtain a 1-(aminoalkyl)-2-aryl-cyclohexanol of the formula XII

XII

whereinR4, R5 and R6 are as defined above; and when required alkylating the compound of formula XII to obtain the N-substituted compounds of formula X;
and when required converting the ester to a pharmaceutically acceptable acid addition or quaternary salt; and C. Reacting an acid of the formula VI defined above with a halo ester of the formula , where X is halogen and R is a hydrocarbon radical and then with an alkali metal azide of the formula MN3 where M is an alkali metal to produce a 6-aryl-1-oxa-3-azaspiro[4,5]decan-2-one of the formula XIII

XIII

wherein R4, R5 and R6 are as defined above; when required alkylating a compound of the formula XIII to obtain the corresponding N-alkyl oxa-azaspiro decan-2-one of the formula XIV

XIV

wherein R2, R4, R5 and R6 are as defined above, reducing the compound of the formula XIV to the 1-(1-dialkyl-aminoalkyl)-2-aryl-cyclohexanol of the formula XV

XV

wherein R2, R4, R5 and R6 are as defined above, and forming the corresponding ester of the formula XVI by acylating the resulting cyclohexanol (XV) with an alkanoyl halide or an alkanoic anhydride XVI

wherein R1, R2, R4, R5 and R6 are as defined above; or when required converting the compound of formula XIII to the 1(1-aminoalkyl)-2-aryl-cyclohexanol of formula XVII by hydrolysis XVII
wherein R4, R5 and R6 are as defined above; or when required reducing the compound of formula XIII directly to the corresponding alkylamino-alkyl-cyclohexanol of the formula XVIII

XVIII

wherein R4, R5 and R6 are as defined above; and when required converting the resulting compounds to their pharmaceutically acceptable acid addition or quaternary salts; and when required isolating the stereoisomers and optical isomers of any of the above compounds.

2. A process as claimed in Claim 1 for the preparation of 1-(2-dimethyl-amino-1-methylethyl)-2-phenyl-cyclohexyl acetate hydrochloride which comprises reacting 2-phenylcyclohexanone with ethyl 2-bromo-propionate and freshly activated zinc dust to yield 2-(1-hydroxy-2-phenylcyclohexyl)-propionic acid which on reduction with lithium aluminum hydride yields the corresponding propanol, treatment of the propanol with p-toluenesulfonyl chloride yields the corresponding propyl p-toluenesulfonate which is then reacted with dimethylamine to yield 1-(2-dimethylamino-1-methylethyl)-2-phenylcyclohexanol which on treatment with acetyl chloride and subsequent acidification yields 1-(2-dimethylamino-1-methylethyl)-2-phenylcyclohexyl acetate hydrochloride.

3. A process as claimed in Claim 1 for the preparation of 1-(2-dimethyl-amino-1-methyl-ethyl)-2-phenyl-cyclohexanol-p-toluenesulfonate which comprises condensing 2-phenylcyclohexanone with a lithium metal derivative of the forrnula CH3CH(Li)CON(CH3)2 to obtain an alpha [2-phenyl(1-hydroxy-cyclohexyl)] propanoyl-N,N-dimethylamide which on reduction of the carbonyl group with lithium aluminum hydride yields 1-(2-dimethylamino-1-methyl-ethyl)-2-phenylcyclohexanol which on treatment with p-toluenesulfonic acid yields the p-toluenesulfonate.

4. A process as claimed in Claim 1 for the preparation of (-)-1-(2-dimethylamino-1-methyl-ethyl)-2-phenyl-cyclohexyl acetate which comprises reacting 2-phenylcyclohexanone with ethyl 2-bromo-propionate and freshly activated zinc dust to yield (-)-2-(1-hydroxy-2-phenylcyclohexyl)-propionic acid which is then reduced with lithium aluminum hydride to obtain the corresponding propanol, the alcohol is then treated with pyridine and p-toluenesulfonyl chloride to obtain the corresponding propyl p-toluene-sulfonate which is then reacted with dimethylamine to obtain (-)-1-(2-dimethylamino-1-methylethyl)-2-phenylcyclohexanol which is then treated with acetyl chloride to obtain (-)-1-(2-dimethylamino-1-methylethyl)-2-phenylcyclohexyl acetate.

5. A process as claimed in Claim 1 for the preparation of (+)-1-(2-dimethylamino-1-methyl-ethyl)-2-phenyl-cyclohexyl acetate which comprises reacting 2-phenylcyclohexanone with ethyl-2-bromo-propionate and freshly activated zinc dust to yield (+)-2-(1-hydroxy-2-phenylcyclohexyl)-propionic acid which is then reduced with lithium aluminum hydride to obtain the corresponding propanol, the alcohol is then treated with pyridine and p-toluenesulfonyl chloride to obtain the corresponding propyl p-toluenesulfonate which is then reacted with dimethylamine to obtain (+)-1-(2-dimethylamino-1-methylethyl)-2-phenylcyclohexanol which is then treated with acetyl chloride to obtain (+)-1-(2-dimethylamino-1-methylethyl)-2-phenylcyclohexyl acetate.

6. A process as claimed in Claim 1 for the preparation of 1-(1-methyl-2-morpholino-ethyl)-2-phenyl-cyclohexyl acetate hydrochloride which comprises reacting 2-phenylcyclohexanone with ethyl-2-bromo-propionate and freshly activated zinc dust to yield 2-(1-hydroxy-2-phenylcyclohexyl)-propionic acid which is then reduced with lithium aluminum hydride to obtain the corresponding propanol, the alcohol is then treated with pyridine and p-toluenesulfonyl chloride to obtain the corresponding propyl p-toluenesulfonate which is then reacted with morpholine to obtain 1-(1-methyl-2-morpholino-ethyl)-2-phenyl-cyclohexanol hydrochloride which on conversion to the free base and treatment with acetyl chloride yields 1-(1-methyl-2-morpholinoethyl)-2-phenylcyclohexyl acetate hydrochloride.

7. A process as claimed in Claim 1 for the preparation of 1-(1-methyl-2-[4-phenyl-1-piperazinyl]-ethyl)-2-phenyl-cyclohexyl acetate hydrochloride which comprises reacting 2-phenylcyclohexanone with ethyl 2-bromo-propionate and freshly activated zinc dust to yield 2-(1-hydroxy-2-phenylcyclohexyl)-propionic acid which is then reduced with lithium aluminum hydride to obtain the corresponding propanol, the alcohol is then treated with pyridine and p-toluenesulfonyl chloride to obtain the corresponding propyl p-toluene-sulfonate which is then reacted with 1-phenylpiperazine to obtain 1-(1-methyl-2-[4-phenyl-1-piperazinyl]ethyl)-2-phenylcyclohexanol which on treatment with acetyl chloride yields 1-(1-methyl-2-[4-phenyl-1-piperazinyl]ethyl)-2-phenylcyclohexyl acetate hydrochloride.

8. A process as claimed in Claim 1 for the preparation of 1-(2-dimethylamino-1-methyl-ethyl)-2-(p-methoxy-phenyl)-cyclohexyl acetate hydrochloride which comprises reacting 2-(p-methoxy-phenyl) cyclohexanone with ethyl-2-bromo-propionate and freshly activated zinc dust to yield ethyl-2-(1-hydroxy-2-(p-methoxy-phenyl)cyclohexyl)-propionic acid which is then reduced with lithium aluminum hydride to obtain the corresponding propanol, the alcohol is then treated with pyridine and p-toluenesulfonyl chloride to obtain the corresponding propyl p-toluenesulfonate which is then reacted with dimethylamine to yield 1-(2-dimethylamino-1-methylethyl)-2-(p-methoxy-phenyl)cyclohexanol which on treatment with acetyl chloride yields 1-(2-dimethylamino-1-methylethyl)-2-(p-methoxy-phenyl)-cyclohexyl acetate hydro-chloride.

9. A process as claimed in Claim 8 for the preparation of 1-(2-dimethylamino-1-methyl-ethyl)-2-(p-methoxy-phenyl)-cyclohexanol hydrochloride wherein the 1-(2-dimethylamino-1-methylethyl)-2-(p-methoxy-phenyl)cyclo-hexanol is acidified to obtain the hydrochloride.

10. A process as claimed in Claim 1 for the preparation of 2-(3,4-dimethoxy-phenyl)-1-(2-dimethylamino-1-methyl-ethyl)-cyclohexyl acetate hydrochloride which comprises reacting 2-(3,4-dimethoxy-phenyl)cyclohexanone with ethyl-2-bromo-propionate and freshly activated zinc dust to yield 2-[2-(3,4-dimethoxy-phenyl)-1-hydroxycyclohexyl] propionic acid which on reduction with lithium aluminum hydride gives 2-[2-(3,4-dimethoxy-phenyl)-1-hydroxycyclohexyl]propanol which on treatment with pyridine and p-toluene-sulfonyl chloride gives 2-[2-(3,4-dimethoxy-phenyl)-1-hydroxycyclohexyl]
propyl tosylate which on treatment with dimethylamine yields 2-(3,4-dimethoxy-phenyl)-1-(2-dimethyl-amino-1-methylethyl)cyclohexanol which on treatment with acetyl chloride yields 2-(3,4-dimethoxy-phenyl)-1-(2-dimethylamino-1-methyl-ethyl)-cyclohexyl acetate hydrochloride.

11. A process as claimed in Claim 1 for the preparation of 1-(1-amino-ethyl)-2-phenylcyclohexanol hydrochloride which comprises reacting 2-(1-hydroxy-2-phenylcyclohexyl)propionic acid with ethyl chloroformate and then with sodium azide to yeild 4-methyl-6-phenyl-1-oxa-3-azaspiro[4,5]decan-2-one which on alkylation and acidification yields 1-(1-aminoethyl)-2-phenyl-cyclohexanol hydrochloride.

12. A process as claimed in Claim 11 for the preparation of 1-(1-methyl-amino-ethyl)-2-phenyl-cyclohexanol hydrochloride wherein 4-methyl-6-phenyl-1-oxa-3-azaspiro[4,5]decan-2-one is reduced with lithium aluminum hydride and subsequently acidified to yield 1-(1-methylaminoethyl)2-2phenyl-cyclohexanol hydrochloride.

13. A process as claimed in Claim 1 wherein the reactants are chosen such that R1 is acetyl, R2, R3 and R4 are each methyl, R5 and R6 are each hydrogen, n is 1 and M, X, R and R7 are as defined in Claim 1.

14. A process as claimed in Claim 1 wherein the reactants are chosen such that R1 is hydrogen, R2, R3 and R4 are each methyl, R5 and R6 are each hydrogen, n is 1 and M, X, R and R7 are as defined in Claim 1.

15. A process as claimed in Claim 1 wherein the reactants are chosen such that R1 is acetyl, R2, R3 and R4 are each methyl, R5 and R6 are each hydrogen and n is 1, and M, X, R and R7 are as defined in Claim 1.

16. A process as claimed in Claim 1 wherein the reactants are chosen such that R1 is acetyl, R2, R3 and R4 are each methyl, R5 and R6 are each hydrogen and n is 1, and M, X, R and R7 are as defined in Claim 1.

17. A process as claimed in Claim 1 wherein the reactants are chosen such that R1 is acetyl, R2 and R3 together with the nitrogen atom to which they are attached form a morpholino radical, R4 is methyl, R5 and R6 are each hydrogen and n is 1, and M, X, R and R7 are as defined in Claim 1.

18. A process as claimed in Claim 1 wherein the reactants are chosen such that R1 is acetyl, R2 and R3 together with the nitrogen atom to which they are attached form a 4-phenylpiperazino radical, R5 and R6 are each hydrogen and n is 1, and M, X, R and R7 are as defined in Claim 1.

19. A process as claimed in Claim 1 wherein R1 is acetyl, R2, R3 and R4 are each methyl, R5 and R6 are each hydrogen, and n is 1, and M, X, R and R7 are as defined in Claim 1.

20. A process as claimed in Claim 1 wherein R1 is hydrogen, R2, R3 and R4 are each methyl, R5 is methoxy, R6 is hydrogen, and n is 1, and M, X, R and R7 are as defined in Claim 1.

21. A process as claimed in Claim 1 wherein R1 is acetyl, R2, R3 and R4 are each methyl, R5 and R6 are each methoxy and n is 1, and M, X, R and R7 are as defined in Claim 1.

22. A process as claimed in Claim 1 wherein R1, R2, R3, R4, R5 and R6 are each hydrogen and n is 1, and M, X, R and R7 are as defined in Claim 1.

23. A process as claimed in Claim 1 wherein R1, R2, R3, R5 and R6 are each hydrogen and R4 is methyl and n is 1, and M, X, R and R7 are as defined in Claim 1.

24. A process as claimed in Claim 1 wherein R1, R2, R3, R5 and R6 are each hydrogen, R4 is methyl and n is 1, and M, X, R and R7 are as defined in Claim 1.

25. Compounds of the formula X as defined in Claim 1, pharmaceutically acceptable acid addition or quaternary salts thereof, and stereoisomers and optical isomers thereof whenever prepared by a process of Claim 1, or an obvious chemical equivalent thereof.

26. The compound 1-(2-dimethyl-amino-1-methylethyl)-2-phenyl-cyclohexyl acetate hydrochloride whenever prepared by the process of Claim 2 or 13 or an obvious chemical equivalent thereof.

27. The compound 1-(2-dimethylamino-1-methyl-ethyl)-2-phenyl-cyclohexanol-p-toluenesulfonate whenever prepared by the process of Claim 3 or 14 or an obvious chemical equivalent thereof.

28. The compound (-)-1-(2-dimethylamino-1-methyl-ethyl)-2-phenyl-cyclohexyl acetate whenever prepared by the process of Claim 4 or 15 or an obvious chemical equivalent thereof.

29. The compound (+)-1-(2-dimethylamino-1-methyl-ethyl)-2-phenyl-cyclohexyl acetate whenever prepared by the process of Claim 5 or 16 or an obvious chemical equivalent thereof.

30. The compound 1-(1-methyl-2-morpholino-ethyl)-2-phenyl-cyclohexyl acetate hydrochloride whenever prepared by the process of Claim 6 or 17 or an obvious chemical equivalent thereof.

31. The compound 1-(1-methyl-2-[4-phenyl-1-piperazinyl]-ethyl)-2-phenyl-cyclohexyl acetate hydrochloride whenever prepared by the process of Claim 7 or 18 or an obvious chemical equivalent thereof.

32. The compound 1-(2-dimethylamino-1-methyl-ethyl)-2-(p-methoxy-phenyl)-cyclohexyl acetate hydrochloride whenever prepared by the process of Claim 8 or 19 or an obvious chemical equivalent thereof.

33. The compound 1-(2-dimethylamino-1-methyl-ethyl)-2-(p-methoxy-phenyl)-cyclohexanol hydrochloride whenever prepared by the process of Claim 9 or 20 or an obvious chemical equivalent thereof.

34. The compound 2-(3,4-dimethoxy-phenyl)-1-(2-dimethylamino-1-methyl-ethyl)-cyclohexyl acetate hydrochloride whenever prepared by the process of Claim 10 or 21 or an obvious chemical equivalent thereof.

35. The compound 1-(1-aminoethyl)-2-phenylcyclohexanol hydrochloride whenever prepared by the process of Claim 11 or 22 or an obvious chemical equivalent thereof.

36. The compound 1-(1-methyl-amino-ethyl)-2-phenyl-cyclohexanol hydrochloride whenever prepared by the process of Claim 12 or 23 or an obvious chemical equivalent thereof.