CA1105938A

CA1105938A - 4-amino-4-arylcyclohexanone ketals

Info

Publication number: CA1105938A
Application number: CA359,623A
Authority: CA
Inventors: Daniel Lednicer
Original assignee: Upjohn Co
Current assignee: Pharmacia and Upjohn Co
Priority date: 1976-06-03
Filing date: 1980-09-05
Publication date: 1981-07-28

Abstract

ABSTRACT OF THE DISCLOSURE

A class of new 4-amino-4-arylcyclohexanones, their ketals, and acid addition salts have been synthesized and found to be useful for relieving pain in animals. Their analgesic activity appears to be of high order, and in addition some exhibit narcotic antagonist activity that is useful in modifying the cardiovascular, respiratory, and behavioral depression caused by other analgesics. Several show mixed analgesic and narcotic antagonist activity.
Preferred compounds of the class are 4-(m-hydroxyphenyl)-4-dimethylaminocyclohexanone ethylene ketal, and 4-(m-hydroxy-phenyl)-4-(n-butylmethylamino)cyclohexanone ethylene ketal as free bases and as their hydrochloride salts. Processes for synthesis and intermediates are described. Unit dosage forms and therapeutic treatments are disclosed. The compounds of the invention have the formula:

Formula 1 wherein X is oxo, and

Description

3~3~3 This application is a division of copending Canadian application Serial No. 278,494, filed May 16, 1977 .

SUMMARY OF THE INVENTION
This invention pertains to some new organic chemical compounds that are active as analgesics (Formula I), and also to novel compounds useful as intermediates in the preparation of the compounds of Formula I, such as Formulae II, III, IV, and V, and acid addition salts when the amino functionality is present, Ar Ar X~X )C~l OCN II /N\ III
.

~0= NC~

. . - - . IV . Y
H2N . Rl~ ~ R2 . 20 wherein Ar, Rl, R2, and X are as de,ined below.
The invention is more particularly directed to some new 4-amino-4-arylcyclohexanones, their ketals, and acid addition salts thereof, two processes for preparing the same; and a me,thod and formulations for treating pain in animals and humans.
The new 4-amino-4-arylcyclohexanones and ketals are represented by the general schematic formula:

R~

,,~
R, R2 Formula I

where;n X is oxo, and ~ ~ I ~ R4 ; 10 ~ 0 1 ~ R 5 ~ ' .
wherein n is zero or one and R4 is hydrogen or methyl; Rs is hydrogen, phenyl, -CH2-alkenyl wherein alkenyl is of 2 to 4 carbon atoms, inclusive, or methyl; aryl is thiophene, or ~ wherein m is zero, one or two, and Y is halogen, CF3, alkyl of 1 to 4 carbon atoms, inclusive, alkoxy of 1 to 4 carbon atoms, inclusive, hydroxy, cyclo-alkyloxy of 3 tG 6 carbon atoms, inclusive, alkanoyloxy of 2 to 4 carbon atoms, inclusive, alkylthio of 1 to 4 carbon atoms, inclusive, or -0-(CH2), ~ where Y' is halogen, CF3, alkyl of 1 to 4 carbon atomsm, inclusive, or alkoxy of 1 to 4 carbon atoms, inclusive; Rl is hydrogen, or lower alkyl of 1 to 8 carbon atoms, inclusive, R2 is hydrogen, lower alkyl of 1 to 8 carbon atoms, inclusive, -CH2-alkenyl wherein alkenyl is of 2 to 8 carbon atoms, in-clusive, acetyl, cycloalkylalkyl wherein cycloalkyl is oF 3 to 6 carbon atoms, inclusive, and alkyl is of 1 to 3 carbon atoms, inclusive,~~hydroxyethyl, carbethoxymethyl,cycloalkyl of 3 to 6 carbon atoms, inclusive, -(CH2) ~ , or Y m ~ 38 -(CH2 )2 ~ ; R3 is hydrogen, lower alkyl of 1 to 5 carbon atoms, lnclusive; and N \ can be a saturated cycloalkylamino group N ~ C)n~ wherein n' is 3, 4, 5, or 6; or mono- or di-alkyl substituted cycloalkylamino wherein each alkyl is of 1 to 3 carbon atoms, inclusive; and the acid addition salts thereof.
R, and R2 taken together with the nitrogen atom to which they are attached form a saturated cycloalkylamino group N ~ C)nl wherein n' is 3, 4, 5, or 6, and mono- or di-alkyl substituted cycloalkylamino wherein each alkyl is from 1 to 3 carbon atoms, inclusive.
The wavy line (~ ) denotes the possibility of cis-trans stereoisomerism with respect to substitution at the 4-position.
When R3 is lower alkyl, the carbon atom to which R3 is attached (# 2) becomes asymmetric (possesses chirality and the 2-substituted cyclohexanone can exist as two - enantiGmers which can be resolved by known methods.
In compounds of the formula:

Ym~

~ /3--~

~ s ___6j /N\ VI
Rl R2 wherein Ym~ Rl, R~, R3, and X are as defined above, since the Y variable can be hydroxy, the compounds of the invention include 4-(meta-hydroxyphenyl)-4-aminocyclohex-_ _ 32~6 ~5~

anones, their ketals, and acid addition salts that areparticularly interesting and especially preferred. They exhibit excellent narcotic antagonist activity in addition to their own analgesic effect. They are therefore pros-pectively useful for antagonizing the tox;c effects ofmorphine, meperidine, and codeine by inhibition of the cardiovascu1ar, respiratory, and behavioral depression caused by these and other potent analgesics. These also possess the additional useful property of low physical dependence liability as measured by methods described by E. L. Way, et al., J. Pharmacol. Exp. Ther., 167, 1 (1969), J. K. Sealens, et al., Arch. Int. Pharma-codyn., 190, 213 (1971), and S. E. Smits, Res. Commun. in Chem. Path. and Pharmac., 10, 651 (1975).
A preferred class of compounds for analgetic activity are compounds of the formula:

~ R3 Formula VII
/N\
Rl R2 wherein X is oxo or ___--~ --CH2 R3 is hydrogen or lower alkyl of from 1 to 5 carbon atoms, inclusive, Y is halogen, CF3, alkyl of 1 to 4 carbon atoms, inclusive, alkoxy of 1 to 4 carbon atoms, inclusive, hydroxy `5~

or alkanoyloxy of 2 to 4 carbon atoms, inclusive, and Rl is hydrogen, or lower alkyl of 1 to 8 carbon atoms, inclu-sive, R2 is hydrogen, lower alkyl of 1 to 8 carbon atoms, inclusive, -CH2-alkenyl wherein alkenyl is of 2 to 8 carbon atoms, inclusive, acetyl, cycloalkylalkyl wherein cycloalkyl of 3 to 6 carbon atoms, inclusive, and alkyl is of 1 to 3 carbon atoms, inclusive, ~-hydroxyethyl, carb-ethoxymethyl, cycloalkyl of 3 to 6 carbon atoms, inclusive, -(CH2)l0r2 ~ , or -(CH2)2 ~ , and R3 is hydrogen, lower alkyl of 1 to 5 carbon atmoms, inclusive, and N/ can be a saturated cycloalkylamino group N (C) wherein n' is 3, 4, 5, or 6; or mono- or di-alkyl substi-tuted cycloalkylamino wherein each alkyl is of 1 to 3 carbon atoms, inclusive; and the acid addition salts thereof.
. An especially preferred class of compounds for anal-getic activity coupled with lower to moderate physical dependence liability are compounds of the formula..

V 1 ~ ,~ " _~

N VIII
Rl R2 wherein X is oxo or R3 is hydrogen or lower alkyl of from 1 to 5 carbon atoms, r~
--lnclusive~ Rl is lower alkyl of from 1 to 8 carbon atoms~ inclusive~
R2 is lower alkyl of from 1 to 8 carbon atoms~ inclusive, ~-hydroxyethyl~
cycloalkylalkyl wherein cycloalkyl is from 3 to 6 carbon atoms~ inclusive, and alkyl is from 1 to 3 carbon atoms, lnclusive, acetyl or carbethoxy-methyl; and Y is hydroxy, alkanoyloxy of 2 to 4 carbon atoms, inclusive, alkoxy of 1 to 4 carbon atoms, inclusive, or -0-(CH2) ~ Y'm wherein m is 0, 1, or 2 and Y' is alkyl of 1 to 4 carbon atoms, inclusive, or alkoxy of 1 to 4 carbon atoms, inclusive.
It is accordingly a general object of this invention to provide novel and useful analgesic agents, new and appropriate formulations of the new compounds designed for administration to humans and animals, e.g., cats, dogs, cows, horses, suffering from pain, and a novel method for treating and relieving pre-treatment pain in animals. Other more limited objects of this invention, such as the new synthesis of the desired new active compounds and intermediates, will be apparent to those skilled in the art as this description of the invention becomes more detailed.
This divisional application is particularly directed to a process for preparinq a compound of the formula:

A ~ I / R4 /

wherein Ar' is ~0~

n is zero or one~ Rl is alkyl of 1 to 8 carbon atoms, inclusive; R2 is alkyl of 1 to 8 carbon atoms~ inclusive~ cycloalkylalkyl wherein cyclo-alkyl is of 3 to 6 carbon atoms, inclusive, and alkyl is of 1 to 3 carbon atoms, ln-lusive, cycloalkyl of 3 to 6 carbon atoms, inclusive, ~~C~ ~ - ~ or -(CH2 ~ 0 ~ wherein Y' is halogen, CF3, alkyl Of 1 to 4 carbon ato~s, inclusive, or alkoi~y of 1 to 4 carbon atoms, , . . ... . .

.

5~3~3 lncluslve, and m ls O, 1 or 2;

The process is exempllfied in the examples, of Examples 42 and 43, and comprises (a) reacting a compound of the formula H ~ O with a diol of the formula:
HO-CH2~--CH2--OH
wherein n is ~ero or one and R4 is hydrogen or methyl; R5 is hydrogen, phenyl, -CH2-alkenyl wherein alkenyl is of 2 to 4 carbon atoms, inclusive, or methyl; in the presence of acid in an inert solvent to obtain a compound of the formula:

R~ i~X ~ R5 (b) oxidation of the above compound to obtain a compound of the formula:

20' ~R

(c) reacting the above compound with HCN and an amine of the formula HN ~ 1 to obtain a compound of the formula:

R2 N' ` '~`~R5 (d) reacting the above compound with a Grignard Reagent of the formula Ar'MgX wherein Ar' is ~ O
' \~/ -ln anhydrous organic solvent to obtain a compound of the formula:

- 7~ -.1...

~5~

wherein Ar', R , R2, R4 and R5 are defined hereinbefore.

DETAILED DESCRIPTION OF T~E INVENTION
In the foregoing schematic representation (see Formula 1, above) of the new 4-amino-4-arylcyclohexanones and ketals of this invention, the variable X is defined as oxo(=0) when a cyclohexanone itself is intended.
Otherwise the X variable represents an alkylene ketal which is preferably an ethylene ketal, i.e., a spiro-l-3-dioxolane group, but is also tri-methylene ketal. For purposes of consistency and perhaps simplicity the ethylene ketals are named as 1- or 2-substituted ethylene.

; .'- e~ - 7b ~ ~'~!5~f~ 3286 When the alkylene ketal has a trimethylene chain, the chain carbons can be similarly hydrocarbon, optionally substituted by lower-alkyl, lower alkenyl, phenyl, benzyl, phenethyl, or other non-critical, non-interfering hydrocar-bon groups. This group with two oxygens and the cyclohex-anone carbon form a spiro-1,3-dioxane group. These are conveniently designated as 2-substituted trimethylene.
As stated, the new 4-amino-4-arylcyclohexanones, ketals, and acid addition salts of this invention, repre-sented by schematic Formula I, above, as limited bydefined variables, are active as analgesics. The compounds have been discovered to in some way interfere with nerve transmission or cortical awareness of normally painful insults to the animal body. By and large this interfering action has been observed to be physiologic, and no major interference with other physiological activities of the , body has been observed. The new compounds can therefore be used to treat and relieve pain regardless of origin in animals and humans.
Certain compounds of this invention are extremely potent and desirable analgesics. Many of them are compar-able to or exceed in potency the well-known analgesic meperidine (N-methyl-4-phenyl-4-carbethoxypiperidine) and are therefore preferred as pure analgetics. Among these many preferred, newly prepared, and tested compounds are 4-(p-c'nlorophenyl)-4-dimethylaminocyclohexan-1-one, ethylene ketal;
4-(p-fluorophenyl)-4-dimethylaminocyclohexàn-1-one, ethylene ketal;
4-(p-bromophenyl)-4-dimethylaminocyclohexan-1-one, ~ S~3~ 3286 ethylene ketali 4-dimethylamino-4-(p-tolyl)cyclohexan-l-one, ethylene ketal;
4-(p-anisyl)-4-dimethylaminocyclohexan-l-one, ethylene ketal;
4-(p-tolyl)-4-dimethylaminocyclohexanone;
4-(p-bromophenyl)-4-dimethylaminocyclohexanone; and 4-(p-chlorophenyl)-4-dimethylaminocyclohexanone.
- Other preferred compo~nds of this invention for low physical dependence liability activity and analgetic activity are 4-(m-hydroxyphenyl)-4-dimethylaminocyclohexan-l-one, ethylene ketali 4-(m-hydroxyphenyl)-4-(methyl-n-butylamino)cyclohexan-l-one, ethylene ketal hydrochloride, 4-(m-hydroxyphenyl)-2-methyl-4-dimethylaminocyclohexan-l-one and its ketals.
The (Y) variable substituent on the 4-phenyl ring can be any of a wide variety of non-interfering elemental atoms and organic groups. Illustratively, Y can be halogen, CF3, alkyl of from l to 4 carbon atoms, inclusive; alkoxy of from l to 4 carbon atoms, inclusive; alkylthio of from l to 4 carbon atoms, inclusive; hydroxy; alkanoyloxy of 2 to 4 carbon atoms; -(CH2)1 ~ as defined above.
Specific examples of the foregoing general classes of elemental atoms and organic groups include: chlorine, bromine, iodine, fluorine, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, methoxy, ethoxy, propoxy, trifluoromethyl, methyl-thio, ethylthio, tert-butylthio, benzyloxy, and acetoxy.
Representative CH2-alkenyl wherein alkenyl is of 2 to 8 carbon atoms include such groups as 3-methyl-2-butenyl, 4-ethyl-2-hexenyl, 3-methyl-2-hexenyl, allyl, methallyl, and the like. Cycloalkylalkyl may be cyclohexylmethyl, cyclopropylmethyl, cyclopentylethyl and the like. The foregoing are just samples of such acceptable groups.
/ Rl The characteristic -N \ group has been broadly defined above, and it will be recognized by those skilled in the art that any of a great variety of "amino" groups can be employed. For purposes of exemplification only, some representative basic nitrogen groups are specified.
The methylamino embodiment was obtained in many of the intermediates. Likewise, a 4-allylmethylamino group, a butylmethylamino group, a (carbethoxymethyl)methylamino group, a (2-hydroxyethyl)methylamino group, and a methyl acetamido group are embodiments actually prepared in final compounds.
Other representative "amino" embodiments consistent with the general description include: lower-alkylamino, dilower-alkylamino, lower-alkenylamino, cycloaliphaticamino of from 3 to 6 carbon atoms, inclusive, (cycloaliphatic-alkyl)amino of from 4 to 9 carbon atoms, inclusive, lower-alkyl alkanamido of from 3 to 6 carbon atoms, inclusive, l-pyrrolidinyl, l-piperidinyl, 4-alkylpiperidinyl, 3-alkyl-pyrrolidinyl, and 3,4-dialkylhexamethyleneimino.
The basic amino nitrogen endows the new compounds of this invention with the facility for preparation of acid addition salts. In order to accomplish this transformation, the free bases are merely reacted with a selected acid, preferably in the presence of an organic solvent substan-tially inert to the basic compound, the acid, and the acid 32~fi ~L~! 5$ 38 addition salt that is formed. Anhydrous conditions are preferred. The salt usually precipitates from an appro-priate organic solvent or it can be recovered by evaporation of solvent until crystallization occurs, followed by filtration.
Acid addition salts suitable for physiological anal-gesia are necessarily non-toxic to the animal to be benefited. Hence, the anion of the acid add;tion salt will be by definition relatively innocuous to the treated animal at the therapeutic dosage administered. The beneficial action of the analgesic will not be vitiated by side-effects ascribable to an inherently toxic anion.
Appropriate acid addition salts include those prepared from suitable mineral acids, e.g., hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, and phosphoric acids; and those prepared from organic acids, e.g., acetic, propionic, butyric, citric, lactic, benzoic, palmitic, succinic, gluconic, mucic, tartaric, pamoic, salicylic, cyclohexyl-sulfamic, and p-toluenesulfonic acid. On occasion the compounds or their acid addition salts in their crystalline state are isolated as solvates, e.g., with a discreet quantity of solvent, e.g., water, ethyl acetate, and the like, associated physically, and thus removable without effective alteration of the chemical entity per se.
Reference to Example 1 of this description of the invention reveals a relatively involved multi-step procedure for making the new 4-amino-4-arylcyclohexanones and ketals of Formula I. This original procedure consists of eight separate chemical conversions. Each step will be generally described hereinbelow and the details are available in the ~ ~5 !~J

various Examples.
The synthesis begins with preparation of a dialkyl 4-cyano-4-arylpimelate via a Michael-type condensation involving an arylacetonitrile and methyl acrylate. A sol-vent medium, e.g., tert-butyl alcohol, is employed and a basic catalyst, for example, 40% methanolic tetramethyl-ammonium hydroxide (Triton B~). The reaction mixture is heated at the reflux temperature for several hours, and the desired dialkyl 4-cyano-4-arylpimelate first intermedi-ate thus formed is recovered by conventional techniquessuch as solvent extraction and distillation.
The second intermediate, an alkyl 5-cyano-2-oxo-5-aryl-cyclohexanecarboxylate, is prepared by heating a dialkyl 4-cyano-4-arylpimelate from Step 1 in the presence of a strong base, e.g., an alkali metal, sod;um hydride or potassium tert-butoxide. An organic solvent medium such as toluene or tetrahydrofuran is suitable and the desired intermediate is recovered by conventional techniques of solvent extraction and distillation. These intermediates can be named as 2-carbalkoxy-4-cyano-4-arylcyclohexanones as related in the Examples.
The third intermediate, a 4-cyano-4-arylcyclohexanone is prepared by a conventional hydrolysis and deca~rboxylation of the second intermediate alkyl 5-cyano-2-oxo-5-arylcyclo-hexanecarboxylate. The desired degradation is accomplishedwith a strong mineral acid such as sulfuric acid. Aqueous acetic acid is an appropriate and convenient solvent medium for heating at the reflux temperature. The desired inter-mediate is recovered by solvent extraction followed by removal of the solvent, and purificat-ion, for example by recrystallization.
In the next step of the synthesis, the carbonyl func-tion of the 4-cyano-4-arylcyclohexanone is protected by conversion to a ketal. Any alkylene ketal is suitable, but an ethylene ketal readily obtainable with an ethylene glycol in the presence of an acid catalyst such as p-tolu-enesulfonic acid and an organic solvent medium is preferred in the process embodiment. The ketalization reaction is promoted by heating, conveniently at the reflux temperature and by azeotropic removal of the water formed. Ketals other than ethylene ketal are obtained using, e.g., l,3-di-hydroxypropane. The alkylene chains constituting the ketal function can be substituted with non-interfering hydrocarbon groups such as lower-alkyl, phenyl, lower

2-alkenyl. These ketal intermediates are recovered with appropriate organic solvents such as benzene and purified by conventional techniques.
Having protected the carbonyl function of the cyclo-hexanone, the 4-cyano-group is converted to a carboxylic group (saponification). This is readily accomplished by heating the fourth intermediate, above, a 4-cyano-4-aryl-cyclohexanone, alkylene ketal, with an alkali metal hydroxide (preferably potassium hydroxide) in the presence of a relatively high boiling solvent such as ethylene glycol, followed by neutralization of the reaction mixture in with a mineral acid, e.g., hydrochloric acid. The thus produced 4-carboxyl-substituted fifth intermediate is readily recovered and purified by solvent extraction, physical removal of the solvent, and recrystallization. It is preferable that prior to saponification of the 4-cyano-4-arylcyclohexanone ethylene ketal wherein the aryl is substituted by hydroxy, the hydroxy group is protected by a readily removable group, e.g., benzyl. Introduction of the protective group can be accomplished by standard methods, using benzyl halide, e.g., benzyl chloride, and base, e.g., sodium hydride.
The sixth intermediate, which is a 4-isocyanato-4-arylcyclohexanone, alkylene ketal, is prepared by a modified Curtius rearrangement utilizing an azide, (e.g., diphenyl phosphonic azide (C6HsO)2PON3) in a modification - oF the procedure described by T. Shioiri, K. Ninemiya and S. Yamada, J. Amer. Chem. Soc., 94, 6203, (1972). Use of an aprotic solvent medium, e.g., anisole, is preferred.
The reaction mixture is heated at about 100 C. but reaction can start to occur at lower temperatures with the evolution of nitrogen. The desired isocyanate is recovered by removing volatile components, and then chromatographic procedures followed by, if necessary, recrystallization.
The next step in the synthesis provides a 4-methylamino embodiment of the invention according to Formula I wherein X is an alkylene ketal. This step involves reduction of tne isocyanate group; chemical reducing agents, e.g., lithium aluminum hydride, can be used. The reaction is conventional and is promoted by heating. The desired pro-duct is obtained treating the reaction mixture with analkali metal hydroxide so as to obtain the inorganic aluminum salts as gelatinous precipitate which is removed by filtration. Evaporation of the filtrate gives the amine which is purified by conventional methods. Alternatively the isocyanate may be reduced by catalytic hydrogenation.

Another embodiment of the invention, the disubstituted amino subject matter according to Formula I, are obtained by adding an R2 group as defined onto the already described methylamino group. Alkylations, acylations, and reduction of acyl functions and the like are accomplished by usual methods.
Alkylations with allyl halide, e.g., allyl bromide, or ~~haloester, e.g., ethyl bromoacetate in polar aprotic solvent, e.g., dimethylformamide, in the presence of inorganic base, e.g., potassium carbonate proceed as des~
cribed in the literature. When converting the secondary ; amine to the tertiary amine form, it is necessary to first protect the hydroxy moiety (if it is present) by an easily removable protecting group such as benzyl.
Preferred acylating agents are acyl chlorides (e.g., cyclopropanecarbonyl chloride, butyryl chloride) and anhydrides of monobasic carboxylic acids (e.g., acetic anhydride and the like).
Addition of R3 to the 2-position of 4~aryl~4-amino-cyclohexanone is effected by reaction of equivalent amountsof the subject cyclohexanone and a strong base, e.g., lithium diisopropylamide, at low temperature, e.g., -10 to -40 C. in an inert solvent, e.g., tetrahydrofuran, followed by reaction with the desired alkyl (R3) halide, e.g., methyl iodide, n~propyl bromide and the like.
Isolation of the product is made using conventional pro~
cedures such as washing, chromatography, and recrystalliza~
tion.
Stereochemistry cf the R3 substituent in reference to the 4-amino functionality is not exclusive; both the cis (Z) or trans (E) isomers are formed; the cis isomer has been observed to form predominantly. Preferential conformation with the phenyl group in an axial position of the cyclohexane ring was found in an x-ray study of geminally-substituted cyclohexanes (e.g., l-acetoxy-4-phenyl-4-acetoxymethylcyclohexane) as described in D.
Lednicer and D. J. DuChamp, J. Org. Chem., 39, 2311 (1974).
Reduction of the amide group resulting from acylation can be accomplished by usual literature methods, e.g., using diborane or lithium aluminum hydride in appropriate solvents.
Removal of the protecting group from a benzyloxy substituted phenyl ring is effected by hydrogenolysis under mild conditions over noble metal catalyst, e.g., palladium on carbon, in solvent which may contain mineral acid, e.g., hydrochloric acid. The method is standard in the art.
When a 4-amino-4-arylcyclohexanone, according to Formula I and the invention, is desired, the ketal is removed by prolonged action of an aqueous mineral acid such as hydrochloric acid in the presence of methanol as a solvent. "Prolonged action" means as much as 48 hours' time.
If an unsubstituted amino nitrogen is desired, the best way to accomplish such objective is to heat the 4-isocyanato intermediate with an alkali metal hydroxide particularly sodium hydroxide in the presence of ethylene glycol at the reflux temperature followed by brief treat-ment with acid. When a lower boiling solvent such as methanol was used as the solvent medium, a dimeric urea instead of the primary amine was obtained.
During the course of developing this invention an improved process of synthesis was discovered. It has been found that many of the compounds of this invention can be readily prepared by a Grignard reaction between a-phenyl Grignard reagent of the kind ~ MgX and a 4-dialkylamino-4-cyanocyclohexanone, ketal. In the fore-going Formula the Y and m variables are as heretofore defined, except that Y cannot be the ùnprotected hydroxy nor the alkanoyloxy functionalities.
This process can also be used to prepare the 4-dialkyl-amino-4-hydroxy-substitutedphenylcyclohexanone ketals if the hydroxy function is protected by a protect;ng group, e.g., tetrahydropyranyl, which can be removed under mild hydrolytic conditions using aqueous acid, e.g., hydrochloric, acetic, and the like.
The basis for the new synthesis was provided by the teachings of Hauser, C. R. and D. Lednicer, J. Org. Chem.
24, p. 46 (1959) and Lednicer, D., and J. C. Babcock, J.
Org. Chem. 27, p. 2541 (1962). These authors showed that the nitrile group of an ~-amino nitrile is displaced by the organometallic reagent so that a different result obtains than that taught by Whitmore, Frank C., Organic Chemistry, at pp. 852-854 and p. 416 (publ;shed by D. VanNostrand Co., Inc., New York, 1951) where a Grignard reagent adds to nitriles to produce imines. In this new and improved process of this invention, the phenyl ring attaches directly to the 4-carbon of the cyclohexanone ring to which same carbon the amino group is attached.
The indicated reaction takes place when the selected Grignard reagent is heated at the reflux temperature in an organic solvent medium in the presence of a 4-amino-4-cyano-cyclohexanone, ketal. A suitable organic solvent medium is tetrahydrofuran, and it is preferable that it be anhy-drous. Prolonged heating might be necessary; thosenitrile displacements already successfully completed have required from 18 hours to three days. In most cases, 15 to 24 hours would appear to be adequate reaction time.
The desired 4-dialkylamino-4-phenylcyclohexanone, ketals are recovered in the usual way by decomposition of the reaction mixture with aqueous ammonium chloride. The organic layer is recovered and further purification tech-niques are a~pplied such as solvent evaporation, washing, drying, chromatography, and recrystallization.
The 4-dialkylamino-4-cyanocyclohexanone, ketal ante-cedent compounds are obtained from 4-oxocyclohexanone, monoketals by reaction with an alkali metal cyanide, e.g., potassium cyanide, and an amine acid addition salt as described. This reaction proceeds readily and no heating is required. Room temperatures with stirring are suitable.
Recovery-purification methods are conventional.
The 4-oxocyclohexanone, monoketals are prepared by methods known in the art, e.g., as described by M.
Haslanger and R. G. Lawton, Synthetic Commun., 4, 155 (1974)-The foregoing improved method of synthesis provides shorter synthesis to some compounds of the invention. Illus-tratively the 4-(meta-hydroxyphenyl)-4~dimethylaminocyclo-hexanone, and 4-(m-hydroxy)-4-(n-butylmethylamino)cyclo-hexanone ketal compounds of the invention have been prepared and found to possess unexpected narcotic antagonistactivity and, advantageously, low to moderate physical dependence liability as well dS the analgesic activity observed with other compounds of the invention. It provides access to many compounds that would otherwise require the complicated and time-consuming multiple reac-tion steps of the original synthesis.
Preparation A p-tert-Butylphenylacetonitrile A solution consisting of 4 ml. thionyl chloride and 10 ml. benzene is added to a solution consisting of 10.0 gm.
(0.061 mole) p-_ert-butylbenzyl alcohol and 85 ml. benzene.
The reaction mixture is stirred at 25 C. for 30 min. and then heated at the reflux temperature for 4 hours.- After cooling, the benzene is removed by evaporation under reduced pressure. The residue thus obtained is distilled at 0.05 mm Hg. pressure, and 10.14 gm. (92% yield) of benzyl chloride having a boiling range of 62 to 65 C.
is obtained.
Some 9.64 gm. (0.053 mole) of this benzyl chloride is mixed with 10.13 gm. potassium cyanide, 0.10 gm.
potassium iodide in 75 ml. water, and 150 ml. methanol and heated at the reflux temperature for one (1) hour. After removing the bulk of the methanol by evaporation under reduced pressure, the residue thus obtained is extracted with diethyl ether and the resulting ether solution is washed first with water and then with brine. The washed, ether solution is then concentrated by evaporation of the ether, and the oil thus obtained is distilled at 0.03 mm pressure. There is thus obtained 6.38 gm. (70% yield) of p-tert-but~lphenylacetonitrile having a boiling range between 79 and 84 C.
Analysis:
Calc'd. for Cl2HlsN:
C, 83.19; H, 8.73; N, 8.09.
Found: C, 82.56; H, 8.68; N, 7.34.
Example 1 Preparation of 4-(p-chlorophenyl)-4-dimethyl-aminocyclohexanone, ethylene ketal free base and the hydrochloride thereof.
Part A Preparation of precursor, the Dimethyl diester of 4-(p-chlorophenyl)-4-cyanopimelic acid A mixture consisting of 25.0 gm. (0.165 mole) p-chloro-phenylacetonitrile, 77 ml. methyl acrylate, and 80 ml.
tert-butyl alcohol is heated to the reflux temperature. The source of heat is removed, and a mixture consisting of 25 ml. of 40 percent methanolic tetramethylammonium hydroxide (Triton B~) and 37 ml. tert-butyl alcohol is quickly added.
Heating at the reflux temperature is resumed and continued for four (4) hours. The reaction mixture is allowed to cool, and is then diluted with 300 ml. water and 100 ml. ~-benzene. The organic solvent and aqueous phases that form are separated and the aqueous phase is discarded. The organic phase is washed successively with 2.5 N hydrochloric acid, water, and finally with brine. (The washed solution is ~hen dried over Na2S04). The organic solvent is removed -by evaporation under reduced pressure, and the residue thus obtained is distilled under reduced pressure. The initial pressure is 40 mm mercury at which pressure any remaining methyl acrylate or other volatile components are eliminated.
The final pressure is 0.35 mm mercury, and 38.06 gm. (71.4 yield) of the dimethyl ester of 4-(p-chlorophenyl)-4-cyano-~ 3286 pimelic acid is obtained as an oil. The compoun~ has a boiling point at 186 to 191 C.
Part B Preparation of first intermediate, 2-Carbo-methoxy-4-(p-chlorophenyl)-4-cyanocyclohex-anone A reaction mixture consisting of 34.97 gm. (0.108 mole) dimethyl ester of 4-(p-chlorophenyl)-4-cyanopimelic acid, (prepared in Part A, above), dissolved in 700 ml. tetra-hydrofuran with 24.4 gm. (0.218 mole) potassium tert-butoxide added is heated at the reflux temperat~re for 4~2 hours. After cooling, the reaction mixture is chilled in an ice-bath and 175 ml. 2.5 N acetic acid is added. The organic and aqueous phases separate and the organic phase is recovered. It is d;luted with 600 ml. benzene before being washed successively with aqueous sodium bicarbonate, water, and brine. The organic solvents are then removed by distillation under reduced pressure. There is thus obtained 30.2 gm. (96% yield) of 2-carbomethoxy-4-(p-chloro-phenyl)-4-cyanocyclohexanone having a melting point at 139 to 143 C.
Analysis:
Calc'd. for Cl5H, 4Cl N03:
C, 61.75; H, 4.84; N, 4.80.
Found: C, 61.65; H, 5.02; N, 4.85.
Part C Preparation of second intermediate 4-(p-Chloro-phenyl)-4-cyanocyclohexanone A reaction mixture consisting of 29.8 gm. (0.102 mole) of 2-carbomethoxy-4-(p-chlorophenyl)-4-cyanocyclohexanone (prepared in Part B, abo~e), 660 ml. glacial acetic acid, and 330 ml. 10~ aqueous sulfuric acid is heated on a steam ~ 3 ~

bath at about ,00 C. for 24 hours. The mixture is stirred continuously. After cooling, the mixture is diluted with 1300 ml. water, and extracted with benzene. The benzene phase is recovered and washed successively with water, with aqueous sodium bicarbonate, and with br;ne. The benzene is then removed by evaporation under reduced pressure to give a solid residue. The solid residue is recrystallized from diethyl ether to give 12.13 gm. (82% yield) of 4-(p-chlorophenyl)-4-cyanocyclohexanone having a melting point at 94.5 to 97 C.
Analysis:
Calc'd. for Cl3H,2ClN0:
C, 66.81; H, 5.18; N, 5.99.
Found: C, 67.03; H, 5.16; N, 5.95.
Part D Preparation of third intermediate, 4-(p-chloro-phenyl)-4-cyanocyclohexanone, ethylene ketal A reaction mixture consisting of 19.49 gm. (0.084 mole) of 4-(p-chlorophenyl)-4-cyanocyclohexanone (prepared in Part C, above), 4.8 ml. (5.33 gm.) (0.086 mole) ethylene glycol, 0.21 gm. (1.1 mmole) p-toluenesulfonic ac;d, and 150 ml. benzene is heated at the reflux temperature in a reaction vessel equipped with a Dean and Stark trap for six (6) hours. The reaction solution is then allowed to cool before washing it successively with aqueous sodium bicarbonate, with water, and with brine. The washed solu-tion is then taken to dryness by evaporation of the benzene.
The solid residue thus obtained is crystallized from cyclohexane to give 21.87 gm. (79% yield) of 4-(p-chloro-phenyl)-4-cyanocyclohe~anone, ethylene ketal having a melt-ing point at 124 to 126.5 C.

~.

Analysis:
Calc'd. for Cl sHI 6Cl N02:
C, 64.86; H, 5.81; N, 5.04.
Found: C, 64.77; H, 5.81; N, 4.92.
Part E Preparation of fourth intermediate, 4-Carboxy-4-(p-chlorophenyl)cyclohexanone, ethylene ketal A reaction mixture consisting of 21.87 gm. (0.079 mole) 4-(p-chlorophenyl)-4-cyanocyclohexanone, ethylene ketal (prepared in Part D, above), 22.0 gm. (0.39 mole) potassium hydroxide and 220 ml. ethylene glycol is heated at the reflux temperature for 16 hours. After cooling and diluting with water, the solutin is chilled in an ice-bath, layered with diethyl ether and cautiously acidified with concentrated hydrochloric acid. The ether layer is recov-ered and the acidified aqueous solution is extracted two more times with ether. The ether fractions are combined and washed with brine before removing the ether by evapor-ation. The residue thus obtained is recrystallized from a mixture of methylene chloride and technical hexane to give 19.26 gm. (82% yield) of 4-carboxy-4-(p-chlorophenyl)-cyclohexanone, ethylene ketal having a melting point at ~62.5 to 164.5 C.
Analysis:
Calc'd. for ClsHl 7Cl 04 C, 60.71; H, 5.78; Cl, 11.95.
- Found: C, 61.01; H, 5.77; Cl, 12.12.
Part_F Preparation of fifth intermediate 4-(p-Chloro-phenyl)-4-isocyanatocyclohexanone, ethylene ketal ~ ~ 3286 To a mixture consisting of 15.79 gm. (0.0532 mole) 4-carboxy-4-(p-chlorophenyl)cyclohexanone, ethylene ketal (prepared in Part E, above) 7.4 ml. (5.36 gm., 0.0532 mole) triethylamine, and 135 ml. anisole is added 14.7 gm.
(0.053 mole¦ diphenylphosphoric azide. This reaction mixture is then heated at 90 to 100 C. in an oil bath for two (2) hours. The volatile components are then removed by evaporation under reduced pressure, and the gummy residue thus obtained is chromatographed on a 1500 ml. column of silica gel. The column is eluted with a mixture of ethyl-acetate and technical hexanes (in pro-portion of 1:9) and 400-ml. fractions are collected. After combining fractions 14 through 29 and removing the solvents by evaporation under reduced pressure, there is obtained 7.75 gm. of crude product. Recrystallization from petroleum ether g;ves 6.72 gm. (43% yield) of 4-(p-chlorophenylj-4-isocyanatocyclohexanone, ethylene ketal having a melting point at 76.5 to 80 C.
Analysis:
Calc'd. for Cl sHl 6Cl N03:
C, 61.33; H, 5.49; N, 4.77.
Found: C, 61.44; H, 5.50; N, 4.59.
Part G Preparation of sixth-intermediate, 4-(p-Chloro-phenyl)~4-methylaminocyclohexanone, ethylene ketal A solution consisting of 6.62 gm. (0.0226 mole) 4-(p-chlorophenyl)-4-isocyanatocyclohexanone, ethylene ketal (prepared in Part F, above) in 50 ml. tetrahydrofuran is mixed ~Jith a suspension of 1.29 gm. (0.045 mole) lithium aluminum hydride in 20 ml. tetrahydrofuran and the `

resulting reaction mixture is heated at the reflux temper-ature for four (4) hours. After cooling, followed by chilling in an ice bath, 1.3 ml. water, 1.3 ml. 15% sodium hydroxide, and finally another 3.9 ml. water are added successively. A gelatinous precipitate forms which is collected on a filter. The filtrate is saved, and the volatile components are removed by evaporation under reduced pressure. The residue thus obtained is recrystallized from petroleum ether to give 5.78 gm. (91~ yield) of 4-(p-chlorophenyl)-4-methylaminocyclohexanone, ethylene ketal that has a melting pOl nt at 63.5 to 66.5 C.
Analysis:
Calc'd. for Ci5H20ClN02:
C, 63.93; H, 7.15; N, 4.97.
Found: C, 64.14; H, 7.32; N, 5.15.
Part H Preparation of object compound, 4-(p-Chloro-phenyl)-4-dimethylaminocyclohexanone, ethylene ketal free base and the Hydrochloride thereof A reactlon solution consisting of 5.68 gm. (0.0201 mole) 4-(p-chlorophenyl)-4-methylaminocyclohexanone, ethylene ` ketal (prepared in Part G, above), 22 ml. 37 percent formalin (aqueous formaldehyde), and 75 ml. methanol is heated at the reflux temperature for four (4) hours, after which heating the solution is allowed to cool and then chilled in an ice-bath. Small portions of sodium borohy-dride are cautiously added with stirring to a total of 2.89 gm. (0.076 mole). Stirring is continued for two (2) hours at 25 C. when the solution is concentrated by removing most of the solvent under reduced pressure. The concentrate is diluted with a mixture of 100 ml. methylene ~5~;~8 chloride and 20 ml. water. The aqueous phase that separates is discarded, and the organic phase is washed successively with water and then with brine. The methylene chloride solvent is then removed by evaporation under reduced pressure. The residue thus obtained is dissolved in the formalin and methanol as initially, heated at the reflux temperature, cooled in an ice bath, and treated again with the sodium borohydride as previously. Following the same work-up as described, the crude 4-(p-chlorophenyl)-4-dimethylaminocyclohexanone, ethylene ketal free base obtained following the removal of the methylene chloride is dissolved ;n a small amount of diethyi ether, and the ether solution is treated with 3 N hydrogen chloride in ether. A precipitate forms which is recrystallized from ;~
methylene chloride and ethyl acetatè to give 3.96 gm.
~59% yield) of object compound 4-(p-chlorophenyl)-4-di- r methylaminocyclohexanone, ethylene ketal hydrochloride having a melting point at 261 to 262 C. (with decompo-sition).
Analysis:
Calc'd. for Cl6H2 3Cl 2N02:
C, 57.83; H, 6.98, N, 4.27.
Found: C, 58.10i H, 7.01; N, 4.41.
Example 2 Preparation of an object compound 4-(p-Chloro-phenyl)-4-dimethylaminocyclohexanone A reaction solution consisting of 4.52 gm. (0.0136 mole) of 4-(p-chlorophenyl)-4-dimethylaminocyclohexanone, ethylene '~etal hydrochloride (prepared in Example 1, Part H, above), 22.5 ml. 2.5 N hydrochloric acid, and 45 ml.
methanol is set aside at 25 C. for 48 hours. The methanol 5~

medium is substantially removed by evaporation under reduced pressure to give a concentrate that is made strongly basic by additions of 50% aqueous sodium hydroxide.
A precipitate forms which is collected on a filter and dissolved in diethyl ether. This ether solution is washed with brine to remove the residual water and the ether is then removed by evaporation under reduced pressure. The residue thus obtained is recrystallized from diethyl ether to give 2.30 gm. (70% yield) of 4-(p-chlorophenyl)-4-dimethylaminocyclohexanone having a melting point at 108 to ~11 C.
Analysis:
Calc'd. for Cl4Hl8ClN0:
C, 66.79; H, 7.21; N~ 5.57.
Found: C, 67.10; H, 7.36; N, 5.42.
Example 3 Preparation of 4-(p-Fluorophenyl)-4-dimethyl-aminocyclohexanone, ethylene ketal free base Part A Preparation of precursor, the Dimethyl diester of 4-cyano-4-(p-fluorophenyl)p;melic acid A reaction mixture consisting of 25.0 gm. (0.185 mole) of p-fluorophenyl acetonitrile, 86 ~1. methyl acrylate, and 90 ml. tert-butyl alcohol is heated to the reflux temperature. The source of heat is then removed and a mixture consisting of 28.1 ml. of 40% methanolic tetra-methylammonium hydroxide (Tribon B ) and 43 ml. tert-butyl alcohol is quickly added. Heating at the reflux temperature is resumed and continued for four (4) hours. The reaction mixture is allowed to cool and is then diluted with a mix-ture of 300 ml. water and 100 ml. benzene. When the organic -aqueous phases forms, the aqueous phase is discarded and the organic (benzene) phase is saved. It is washed successively with 2.5 N hydrochloric acid, water, and finally with brine. The benzene is then removed by evapor-5 ation under reduced pressure, and the residue thus obtained is distilled under reduced pressure in order to removed any low-boiling by-products. The initial pressure is at 40 mm mercury, and the final pressure is at 0.25 mm mercury. There is thus obtained 50.99 gm. (72% yield) of 10 the dimethyl ester of 4-cyano-4-(p-fluorophenyl)pimelic - acid as an oil. Its boiling point is 179 to 181 C. ;
Part B Preparation of first intermediate, 2-carbo-methoxy-4-cyano-4-(p-fluorophenyl)cyclohex-anone 15To a solution consisting of 42.71 gm. (0.139 mole) of the dimethyl ester of 4-(p-fluorophenyl)-4-cyanopimelic acid (prepared in Part A, above) and 900 ml. tetrahydrofuran is added 31.3 gm. (0.28 mole) potassium tert-butoxide. This reaction mixture is heated at the reflux temperature for 20 four and one half (4~) hours. It is allowed to cool. It is then ch;lled in ice and 225 ml. of 2.5 N aqueous acetic acid is added. The organic layer that forms is recovered and diluted with 750 ml. benzene. The benzene:tetrahydro-furan solution is washed successively with sodium bicarbonate, 25 with water, and finally with brine. The solvents are then removed by evaporation under reduced pressure to give 35.6 gm. (93% yield) of 2-carbomethoxy-4-cyano-4-(p-fluorophenyl)-cyclohexanone as a gum.
Part C Preparation of second intermediate, 4-Cyano-304 (p-fluorophenyl)cyclohexanone -~8-A reaction mixture consisting of 33.9 gm. (0.123 mole) of 2-carbomethoxy-4-cyano-4-(p-fluorophenyl)cyclohexanone (prepared in Part B, above), 900 ml. glacial acetic acid, and 450 ml. 10% aqueous sulfuric acid is heated with stirring on a steam bath for twenty-four (24) hours. After allowing the reaction mixture to cool, it is diluted with 2000 ml. water and extracted thoroughly with benzene.
The benzene extracts are combined and washed successively with water, with aqueous sodium bicarbonate, and finally with brine. The benzene is then removed by evaporation under reduced pressure, and the solid residue thus obtained is recrystallized from diethyl ether to afford 16.23 gm.
(67% yield) of 4-cyano-4-(p-fluorophenyl)cyclohexanone having a melting point at 84 to 88 C.
Analysis:
~ Calc'd. for Cl3HI2FNO:
: C, 71.87; H, 5.57i N, 6.45.
Found: C, 71.64, H, 5.65; N, 6.30.
Part D Preparation of third intermediate, 4-Cyano-4-(p-fluorophenyl)cyclohexanone, ethylene ketal A reaction mixture consisting of 16.23 gm. (0.075 mole) of 4-cyano-4-(p-fluorophenyl)cyclohexanone (prepared in Part C, above), 6 ml. ethylene glycol, 0.6 gm. p-toluene-sulfonic acid, and 250 ml. benzene is heated at the reflux temperature in a reaction vessel fitted with a Dean and Stark trap for six (6) hours. The reaction solution is allowed to cool and then is washed successively with aqueous sodium bicarbonate, with water, and finally with brine. The benzene and volatile components are then re ~ 5~

mo~led by evaporation under reduced pressure and the solid residue thus obtained is recrystallized from technical hexanes to give 18.17 gm. (94% yield) of 4-cyano-4-(p-fluoro-phenyl)cyclohexanone, ethylene ketal having a melting point at glv to 93.5~ C.
Analysis:
Calc'd. for C15Hl6FN02:
C, 6g.95; H, 6.17; N, 5.36.
Found: C, 68.41, H, 6.05; N, 5.35.
Part E Preparation of fourth intermediate, 4-Carboxy-4-(p-fluorophenyl)cyclohexanone, ethylene ketal A reaction mixture consisting of 18.17 gm. (0.070 mole) of 4-cyano-4-(p-fluorophenyl)cyclohexanone, ethylene ketal (prepared in Part D, above), 15.0 gm. (0.38 mole) sodium hydroxide, and 150 ml. ethylene glycol is heated at the reflux temperature for about sixteen (16) hours before it is allowed to cool, and is then diluted with water. The aqueous solution is then chilled in an ice-bath and layered with diethyl ether. The aqueous phase is cautiously acidified with concentrated hydrochloric acid. The ether layer is separated, and the aqueous layer is extracted two times with diethyl ether. The original ether layer and ether extracts are comb~ned, washed once with brine, and the ether is removed by evaporation under reduced pressure. There is thus obtained 18.2 gm. (93% yield) of 4-carboxy-4~(p fluorophenyl)-cyclohexanone, ethylene ketal as a solid that cannot be recrystallized satisfactorily (melting range 117 to 122 C.).
Part F Preparation of fifth intermediate, 4-(p-fluoro-phenyl)-4 isocyanatocyclohexanone, ethylene ketal To a suspension consisting of 24.5 gm. (0.0875 mole) of 4 carboxy-4-(p-fluorophenyl)cyclohexanone, ethylene ketal (prepared in Part E, above), 12.1 ml. (8.8 gm., 0.087 mole) of triethylamine, and 220 ml. anisole there is added 24.1 gm. diphenylphosphonic azide. This reaction mixture is then heated at 90 to 100 C. with stirring in an oil bath for two (2) hours. The reaction medium and other volatile components are removed by evaporation under reduced pressure. The gummy residue thus obtained is chromatographed on a 1000 ml. column of silica gel. Elu-tion was effected with a solvent system consisting of 1 percent ekhyl acetate in methylene chloride.
The appropriate fractions are combined, and the solvents are removed by evaporation under reduced pressure to give 8.49 gm. of 4-(p-fluorophenyl)-4-isocyanatocyclo-hexanone, ethylene ketal that has the qualities of a gum.
Part G Preparation of sixth intermediate, 4-(p-fluoro-phenyl)-4-methylaminocyclohexanone, ethylene ketal free base and hydrochloride thereof A solution consisting of 10.11 gm. (0.0365 mole) of 4-(p-fluorophenyl)-4-isocyanatocyclohexanone, ethylene ketal (prepared in Part F, above~ and 80 ml. tetrahydro-furan is added to a suspension consisting of 2.08 gm.
(0.055 mole? lithium aluminum hydride and 30 ml. tetra-hydrofuran, and this reaction mixture is heated at the reflux temperature with stirring for four (4) hours. The mixture is allowed to cool, and is then chilled in an ice bath. To the chilled mixture is added in sequence: 2.1 ml.

water, 2.1 ml. 15% aqueous sodium hydroxide, and another 6.3 ml. water. A gelatinous material is obtained that is removed by filtration. The filtrate is recovered and evaporated to dryness. The residue thus obtained is dissolved in a small amount of diethyl ether and enough

3 N hydrogen chloride in diethyl ether is added to precipi-tate all of the amine free base as the hydrochloride acid addition salt. The precipitate is collected on a filter and recrystallized from a mixture of methylene chloride and ethyl acetate to give 9.34 gm. (56% yield) of 4-(p-fluorophenyl)-4-methylaminocyclohexanone, ethylene ketal hydrochloride having a melting point at 262.5 to 263.5 C.
(with decomposition).
Analysis:
Calc'd. for Cl5H2lClFN02:
C, 59.69, H, 7.01; N, 4.64.
Found: C, 59.27; H, 7.21; N, 4.60.
Part H Preparation of object compound, 4~p-Fluoro-phenyl)-4-dimethylaminocyclohexanone, ethylene ketal free base A solution consisting of the free base from 9.24 gm.
(0.0307 mole) of 4-(p-fluorophenyl)-4-methylaminocyclo-hexanone, ethylene ketal hydrochloride (prepared in Part G, above), 33 ml. of 37% formalin, and 110 ml. methanol is heated at the reflux temperature for four (4) hours. The mixture is allowed to cool before chilling in an ice-bath and slowly adding small portions of sodium borohydride until a total of 4.4 gm. (0.115 mole) has been added. Stirring is continued for two (2) hours at about 25 C. A substan-tial part of the volatile liquid components, i.e., solvents 33~
is removed by evaporation under reduced pressure, and the concentrate thus obtained is diluted with 200 ml.
methylene chloride and 50 ml. water. When the organic and aqueous phases have stabilized, the organic phase is recovered, washed with water and washed with brine. After - removing the methylene chloride solvent, the residue thus obtained is again reacted with sodium borohydride and worked up as described immediately above. This time the residue from removal of the methylene chlor;de solvent ;s recrystallized from petroleum ether to give 7.29 gm. (89%
yield) of 4-(p-fluorophenyl)-4-dimethylaminocyclohexanone, ~ ethylene ketal having a melting point at 79.5 to 82 C.
; Analysis:
~- Calc'd. for Cl6H22FN02:
C, 68.79; H, 7.94, N, 5.02.
Found: C, 69.16; H, 7.70; N, 4.91.
Example 4 Preparation of an object compound of 4-(p-Fluoro-phenyl)-4-dimethylaminocyclohexanone A solution consiting of 6.29 gm. (0.0226 mole) of

4-(p-fluorophenyl)-4-dimethylaminocyclohexanone, ethylene ketal (prepared in Example 3, Part H), 32 ml. of 2.5 N
hydrochloric acid, and 64 ml. met-hanol is set aside at 25 C. for 48 hours. A substantial part of the methanol is then removed by evaporation under reduced pressure, and the concentrate is made strongly basic with 50% sodium hydroxide. A precipitate forms which is collected on a filter and dissolved in diethyl ether. The ether solution is washed with water and finally with brine before removing the ether by evaporation under reduced pressure. The residue thus obtained is recrystallized from diethyl ether 1~5~3B

to give 3.97 gm. (75% yield) of 4-(p-fluorophenyl)-4-dimethylaminocyclohexanone having a melting point at 126 to 128 C.
Analysis:
Calc'd. for C,4H,8FN0:
C, 71.46, H, 7.71; N, 5.95.
Found: C, 71.45; H, 7.86; N, 5.83~
_xample 5 Preparation of 4-(3,4-dimethoxyphenyl)-4-di-methylaminocyclohexanone, ethylene ketal free base Part A Preparation of precursor, the dimethyl ester of 4-cyano-4-(3,4-dimethoxyphenyl)pimelic acid Following the procedure of Example 1, Part A, but substituting 25.0 gm. (0.141 mole) 3,4-dimethoxyphenyl acetonitrile, 66 ml. methyl acrylate, and 70 ml. tert-butyl alcohol for the 25.0 gm. p-chlorophenyl acetonitrile, the 77 ml. methyl acrylate, and the 80 ml. tert-butyl alcohol, using 21.5 ml. of the 40% methanolic tetramethyl-ammonium hydroxide, and 32 ml. of the tert-butyl alcohol, and final distillation at 0.20 mm pressure, there is prepared 32.22 gm. (65% yield) of the dimethyl ester of 4-cyano-4-(3,4-dimethoxyphenyl)pimelic acid as an oil having a boiling range of 210 to 214 C.
Part B Preparation of first intermediate, 2-Carbo-methoxy-4-cyano-4-(3,4-dimethoxyphenyl)-cyclohexanone Following the procedure of Example 1, Part B, but substituting 34.25 gm. (0.098 mole) of the dimethyl ester of 4-cyano-4-(3,4-dimethoxyphenyl)pimelic acid (pre-~5~

pared in Part A, above) for the dimethyl ester of 4-(p-chlorophenyl)-4-cyanopimelic acid and using 640 ml. of the tetrahydrofuran, 22.0 gm. (0.196 mole) of the potassium tert-butoxide and 155 ml. of the 2.5 N of the aqueous acetic acid instead of the 700 ml. the 24.4 gm. (0.218 mole), and the 175 ml. respectively, there is prepared 29.2 gm. (94% yield) of 2-carbomethoxy-4-cyano-4-(3,4-di-methoxyphenyl)cyclohexanone as crystals having a melting range of 110 to 113 C. An analytical sample recrystal-lized from a mixture of ethyl acetate and cyclohexane melts in the range of 112.5 to 114.5 C.
Analysis:
Calc'd. for C,5Hl7N03:
C, 69.48; H, 6.61, N, 5.40.
Found: C, 69.73; H, 6.64; N, 5.16.
Part C Preparation of second intermediate, 4-Cyano-4-(3,4-dimethoxyphenyl)cyclohexanone Following the same procedure described in Example 1, Part C, but substituting 29.0 gm. (0.0915 mole) of 2-carbo-methoxy-4-(3,~-dimethoxyphenyl)-4-cyanocyclohexanone (prepared in Part B, above) for the 29.8 gm. of 2-carbo-methoxy-4-(p-chlorophenyl)-4-cyanocyclohexanone, using 600 ml. acetic acid and 300 ml. 10 percent aqueous sulfuric acid instead of the 660 ml. and 330 ml., respectively, heating on the steam bath for 48 hours instead of 24 hours, and recrystallizing from a mixture of ethyl acetate and hexane instead of diethyl ether, there is obtained 16.83 gm. (67% yield) of the desired 4-cyano-4-(3,4-di-methoxyphenyl)cyclohexanone which has a melting point at 112.5 t~ 114.5 C.

Analysis:
Calc'd. for ClsH,7N03:
C, 69.48, H, 6.61; N, 5.40.
Found: C, 69.73; H, 6.64i N, 5~16.
Part D Preparation of third intermediate, 4-Cyano-(3,4-dimethoxyphenyl)cyclohexanone, ethylene ketal Following the procedure of Example 1, Part D, but substituting 15.96 gm. (0.0616 mole) of 4-cyano-4-(3,4-di-methoxyphenyl)cyclohexanone (prepared in Part C, above)for the 19.49 gm. of 4-(p-chlorophenyl)-4-cyanocyclohexa-none; using 3.6 ml. ethylene glycol, 0.16 gm. p-toluene-sulfonic acid, and 110 ml. benzene instead of the 4.8 ml., 0.21 gm., and 150 ml., respectively; and recrystallizing from diethyl ether instead of the cyclohexane there is obtained 16.85 gm. (90% yield) of 4-cyano-4-(3,4-dimethoxy-phenyl)cyclohexanone, ethylene ketal having a melting range at 93.5 to 96.5 C.
- Analysis:
Calc'd. for Cl7H2lN04:
C, 67.31; H, 6.98; N, 4.62.
Found: C, 67.29; H, 7.01; N, 4.44.
Part E Preparat;on of fourth intermediate, 4-Carboxy-4-(3,4-dimethoxyphenyl)cyclohexanone, ethylene ketal Following the procedure of Example 1, Part E, but substituting 17.54 gm. (0.058 mole) of 4-cyano-4-(3,4-di-methoxyphenyl)cyclohexanone, ethylene ketal (prepared in Part D, above) for the 21.87 gm. of 4-(p-chlorophenyl)-4-cyanocyclohexanone, ethylene ketal, and using 17.5 gm.

(0.31 mole) potassium hydroxide and 175 ml. ethylene glycol instead of the 22.0 gm. and 220 ml., respectively;
there is obtained, after removal of the ether, 19.0 gm.
(99% yield) of 4-carboxy-4-(3,4-dimethoxyphenyl)cyclohex-anone, ethylene ketal as a gum that gives a reasonably expected infrared spectrum.
Part F Preparat;on of fifth intermediate, 4-Iso-cyanato-4-(3,4-dimethoxyphenyl)cyciohexanone, ethylene ketal Following the procedure of Example 1, Part F, but substituting 22.9 gm. (0.0710 mole) of 4-carboxy-4-(3,4-di-methoxyphenyl)cyclohexanone, ethylene ketal (prepared in Part E, above) for the 15.79 gm. of 4-carboxy-4-(p-chloro-phenyl)cyclohexanone, ethylene ketal, and using 10.0 ml.
(7.26 gm., 0.073 mole) triethylamine, 215 ml. anisole, and 19.7 gm. diphenylphosphonic azide instead of the 7.4 ml., the 135 ml., and the 14.7 gm., respectively, there is obtained after chromatographing on a 2000 ml. column of silica gel and elution with 30 percent ethyl acetate in technical hexane 6.44 gm. (28% yield) of 4-isocyanato-4-(3,4-dimethoxyphenyl)cyclohexanone, ethylene ketal as a waxy solid.
Part G Preparation of sixth intermediate, 4-(3,4-Di-methoxyphenyl)-4-methylaminocyclohexanone, ethylene ketal hydroiodide Following the procedure of Example 1, Part G, but substituting 6.44 gm. (0.020 mole) of 4-isocyanato-4-(3,4-dimethoxyphenyl)cyclohexanone, ethylene ketal (prepared in Part F, above) for the 6.62 gm. of 4-(p-chloro-phenyl)-4~isocyanatocyclohexanone, using 95 ml. tetrahydro-~ i5~ ~

furan and a suspension of 1.16 gm. (0.031 mole) lithium aluminum hydride in 11 ml. tetrahydrofuran instead of the 50 ml., the 1~29 gm., and 20 ml., respectively, and adding 1.2 ml. water, 1.2 ml. of 15 percent sodium hydroxide, and 3.6 ml. water instead of the 1.3 ml., 1.3 ml., and 3.9 ml., respectively, there is obtained a residue from the filtrate that is chromatographed on a 600 ml. column of silica gel using ammonium hydroxide (NH40H)-saturated methylene chlo-ride as solvent. After collecting and combining the appropriate fractions and removing the solvent by evapor-ation under reduced pressure, the residue is dissolved in methylene chloride. This solution is acidified with 10% aqueous hydriodic acid and thè solvents are removed by evaporation under reduced pressure. There is thus obtained after recrystallization from a mixture of methylene chloride and diethyl ether S.0 gm. (57~ yield) of 4-(3,4-dimethoxyphenyl)-4-methylaminocyclohexanone, ethylene ketal hydroiodide having a melting point at 200.5 to 201.5 C.
Analysis:
Calc'd. for C,7H26IN04:
C, 46.90; H, 6.02; N, 3.22.
Found: C, 46.82; H, 6.06; N, 3.27.
Part H Preparation of object compound, 4-(3,4-di-methoxyphenyl)-4-dimethylaminocyclohexanone, ethylene ketal Following the procedure of Example 1, Part H, but substituting the free base from 5.0 gm. (0.0155 mole) of 4-(3,4-dimethoxyphenyl)-4-methylaminocyclohexanone, ethylene ketal hydrciodide (prepared in Part G, above) for the

5.68 gm. of 4-(p-chlorophenyl~-4-methylaminocyclohexanone, ethylene ketal, using 12.5 ml. 37 percent formalin and 43 ml. methanol instead of the 22 ml. and 75 ml., respectively, and using 1.65 gm. (0.043 mole) sodium oronydride instea~ of the 2.89 gm. there was obtained the desired free base which is recrystallized as such from technical hexane to give 3.40 gm. (92% yield) of 4-(3,4-dimethoxyphenyl)-4-dimethylaminocyclohexanone, ethylene ketal which has a melting range at 95 to 98.5 C.
10Analysis:
Calc'd. for C,8H27N04:
C, 67.26; H, 8.47; N, 4.36.
Found: C, 67.42; H, 8.65; N, 4.34.
Example 6 Preparation of an object compound, 4-(3,4-Di-15methoxyphenyl)-4-dimethylaminocyclohexanone ! . . free base Following the procedure of Example 2, but substituting 2.4 gm. (0.0075 mole) of 4-(3,4-dimethoxyphenyl)-4-dimethyl-aminocyclohexanone, ethylene ketal free base (prepared in Example 5, Part H, above) for the 4-(p-chlorophenyl)-4-dimethylaminocyclohexanone, ethylene ketal hydrochloride, 12 ml. of 2.5 N hydrochloric acid for the 22.5 ml., and 24 ml. methanol for the 45 ml., there is prepared 1.48 gm.
(71% yield) of 4-(3,4-dimethoxyphenyl)-4-dimethylamino-cyclohexanone as the free base, having a melting point at 97 to 98.5 C.
_nalysis:
Calc'd. for CI~H 2 3 N0 3 :
C, 69.28; H, 8.36; N, 5.05.
30Found: C, 69.14; H, 8.44; N, 5.07.

Example 7 Preparation of 4-(p-Anisyl)-4-dimethylamino-cyclohexanone, ethylene ketal free base and hydrochloride thereof Part A Preparation of precursor, the dimethyl ester of 4-cyano-4-(p-anisyl)pimelic acid Following the procedure of Example 1, Part A, but substituting 36.75 gm. (0.25 mole) p-anisyl acetonitrile, 116 ml. methyl acrylate, and 120 ml. tert-butyl alcohol for the 25.0 gm. p-chlorophenyl acetonitrile, the 77 ml.
methyl acrylate, and the 80 ml. tert-butyl alcohol, and using 38 ml. of the 40% methanolic tetramethylammonium hydroxide and 56 ml. tert-butyl alcohol, followed by final distillation at 0.6 mm pressure, there is prepared 55.90 gm.
(70% yield) of the dimethyl ester of 4-cyano-4-(p-anisyl)-pimelic acid as an oil having a boiling range of 205 ! to 210 C.
Part B Preparation of first intermediate, 2-Carbo-methoxy-4-cyano-4-(p-anisyl)cyclohexanone Following the procedure of Example 1, Part B, but 20 substituting 53.94 gm. (0.169 mole) of the dimethyl ester of 4-cyano-4-(p-anisyl)pimelic acid (prepared in Part A, above) for the dimethyl ester of 4-(p-chlorophenyl)-4-cyano-pimelic acid and using 1100 ml. of the tetrahydrofuran, 38.0 ml. (0.34 mole) of the potassium tert-butoxide, and 25 270 ml. of the 2.5 N hydrochloric acid instead of the 700 ml., the 24.4 gm. (0.218 mole), and the 175 ml., respect-ively, there is prepared 46.2 gm. (95% yield) of 2-carbo-methoxy-4-cyano-4-(p-anisyl)cyclohexanone as a gum.
Part C Preparation of second intermediate, 4-Cyano-4-(p-anisyl)cyclohexanone ~5$~2~

Following the procedure oF Example 1, Part C, but substituting 41.5 gm. (0.145 mole) of 2-carbomethoxy-4-cyano-4-(p-methoxyphenyl)cyclohexanone [same as 2-carbo-methoxy-4-cyano-4-(p-anisyl)cyclohexanone] (prepared in Part B, aboYe) for the 29.8 gm. of 2-carbomethoxy-4-(p-chlorophenyl)-4-cyanocyclohexanone, using 940 ml. glacial acetic acid and 470 ml. 10 percent aqueous sulfuric acid instead of the 660 ml. and 330 ml. respectively, and heat-;ng for 48 hours instead of 24 hours there is obtained 23.6 gm. (71% yield) of the expected 4-cyano-4-(p-anisyl)-cyclohexanone which compound has a melting range at 84 to 86.5 C. An analytical sample recrystallized from diethyl ether has a melting range at 77.5 to 79.5 C.
Analysis:
Calc'd. for Cl4Hl5N02:
C? 73-34i H, 6.59; N, 6.11.
Found: C, 73.21; H, 6.65; N, 6.00.
Part D Preparation of third intermediate, 4-Cyano-4-(p-anisyl)cyclohexanone, ethylene ketal Following the procedure of Example 1, Part D, but substituting ?2.43 gm. (0.098 mole) of 4-cyano-4-(p-anisyl)-cyclohexanone (prepared in Part C, above) for the 19.49 gm.
of the 4-(p-chlorophenyl)-4-cyanocyclohexanone, and using 5.6 ml. (6.15 gm., 0.099 mole) ethylene glycol, 0.24 gm.
p-toluenesulfonic acid, and 175 ml. benzene instead of the 4.8 ml., the 0.21 gm., and the 150 ml., respectively, there is obtained a residual solid that upon recrystalliza-tion from a mixture oF methylene chloride and technical hexane instead of from cyclohexane gives 24.66 gm. (93%
yield) oF the expected intermediate 4-cyano-4-(p-anisyl)-~ 3~

cyclohexanone, ethylene ketal that has a melting range at 101 to 103.5 C.
Analysis:
Calc`d. for C16HlgN03:
C, 70.31; H, 7.01; N, 5.13 Found: C, 70.20; H, 7.01; N, 5.02.
Part E Preparation of fourth intermediate, 4-Carboxy-4-(p-anisyl)cyclohexanone, ethylene ketal Following the procedure of Example 1, Part E, but substituting 27.98 gm. (0.103 mole) of 4-cyano-4-(p-anisyl)-cyclohexanone, ethylene ketal (prepared in Part D, above) for the 21.87 gm. of 4-(p-chlorophenyl)-4-cyanocyclohex-anone, ethylene ketal, and using 28.0 gm. (0.50 mole) potassium hydroxide and 280 ml. ethylene glycol instead of the 22 gm. and 220 ml., respectively, there is obtained - 22.35 gm. (83% yield) of 4-carboxy-4-(p-anisyl)cyclohex-anone, ethylene ketal that has a melting point at 154 to 155.5 C.
Analysis:
Calc'd. for Cl 6 H200~:
C, 65.74; H, 6.90.
Found: C, 65.42; H, 6.93.
Part F Preparation of fifth intermediate, 4-Iso-cyanato-4-(p-anisyl)cyclohexanone, ethylene ,ketal Following the procedure of Example 1, Part F, but substituting 10.0 gm. (0.034 mole) of 4-carboxy-4-(p-anisyl)-cyclohexanone, ethylene ketal (prepared in Part E, above) for the 15.79 gm. of 4-carboxy-4-(p-chlorophenyl)-4-cyano-cyclohexanone, ethylene ketal, and using 4.75 ml. (3.46 gm., ~ S~ ~ 3286 0.034 rnole) triethylamine, 100 ml. anisole, and 9.42 gm.
diphenylphosphonic azide instead of the 7.4 ml., the 135 ml., and the 14.7 gm., respectively, there is obtained a residual gum that is chromatographed on a 1000 ml.
5 column of silica gel instead of 1500 ml., and elution is effected with a solvent system consisting of 2.5 percent ethyl acetate in methylene chloride instead of the mixture of ethyl acetate and technical hexane. There is thus obtained, after removal of the solvents by evaporation,

6.42 gm. of crude product that upon recrystallization from technical hexane affords 6.11 gm. (62% yield) of 4-isocyanato-4-(p-anisyl)cyclohexanone, ethylene ketal melting at 70.5 to 72 C.
Analysis:
Calc'd. for Cl6HIgNO4:
C, 66.41; H, 6.62; N, 4.89.
Found: C, 66.47; H, 6.61; N, 4.77.
Part G Preparation of sixth intermediate 4-(p-anisyl)-4-methylaminocyclohexanone, ethylene ketal p-toluenesulfonate Following the procedure of Example 1, Part G, but substituting 6.11 gm. of 4-isocyanato-4-(p-anisyl)cyclo-hexanone, ethylene ketal (prepared in Part F, above) for the 6.62 gm. of 4-(p-chlorophenyl)-4-isocyanatocyclohex-anone, ethylene ketal; using 80 ml. tetrahydrofuran and 1.22 gm. (0.032 mole) lithium aluminum hydride instead of the 50 ml. and the 1.29 gm., respectively; and then adding 1.22 ml. water, 1.22 ml~ 15 percent aqueous sodium hydroxide, and 3.66 ml. water instead of the 1.3 ml., the 1.3 ml., and the 3.9 ml. respectively, there is obtained B

a residue from the filtrate that is dissolved in a small amount of ether. To the ether solution is added 4.0 gm.
p-toluenesulfonic acid dissolved in ether. The acid addition salt that precipitates is collected on a filter and recrystallized from a solvent mixture of ethyl acetate and methylene chloride. There is thus obtained 8.30 gm.
(88% yield) of the desired intermediate 4-(p-anisyl)-4-methylaminocyclohexanone, ethylene ketal p-toluenesulfon-ate that has a melting point at 206 to 208 C.
Analysis:
Calc'd. for C23H31NO~S:
C, 61.44, H, 6.95; N, 3.12.
Found: C, 61.27j H, 6.95i N, 3.06.
Part H Preparation of object compound, 4-(p-anisyl)-4-dimethylaminocyclohexanone, ethylene ketal hydrochloride Following the procedure of Example 1, Part H, but substituting the free base obtained from 8.30 gm. (0.018 mole) of 4-(p-anisyl)-4-methylaminocyclohexanone, ethylene ketal p-toluenesulfonate (prepared in Part G, above) for the 5.68 gm. of the 4-(p-chlorophenyl)-4-methylaminocyclo-hexanone, ethylene ketal, and using 20 ml. 37 percent formalin, 60 ml. methanol, and 2.44 gm. sodium borohydride instead of the 22 ml., 75 ml., and 2.89 gm., respectively, there is finally obtained a precipitate of the hydrochloride acid addition salt that is recrystallized from a mixture of methylene chloride and ethyl acetate thus affording 4.61 gm. (78% yield) of the object compound 4-(p-anisyl)-4-dimethylaminocyclohexanone, ethylene ketal hydrochloride that has a melting point at 203 to 204 C.

Analysis:
Calc'd. for Cl7H26ClN03:
C, 62.28; H, 7.99; N, 4.27.
Found: C, 62.41; H, 8.20; N, 4.14.
Example 8 Preparation of an object compound, 4-(p-anisyl)-4-dimethylaminocyclohexanone free base Following the procedure of Example 2, but substituting 4.61 gm. (0.014 mole) of 4-(p-anisyl)-4-dimethylaminocyclo-hexanone, ethylene ketal hydrochloride (prepared in Example 7, Part H, above) for the 4-(p-chlorophenyl)-4-dimethylaminocyclohexanone, ethylene ketal hydrochloride, 18.0 ml. of 2.5 N hydrochloric acid for the 22.5 ml., and -, 36 ml. methanol for the 45 ml., there is prepared (after recrystallization from technical hexane instead of diethyl ether) 2.29 gm. (66% yield) of 4-(p-anisyl)-4-dimethyl-aminocyclohexanone as the free base having a melting point at 89 to 91 C.
Analysis:
Calc'd. for Cl5H2lN02:
C, 72.84; H, 8.56; N, 5.66.
Found: C, 73.18; H, 8.63; N, 5.55.
Example 9 Preparation of 4-(o-chlorophenyl)-4-dimethyl-aminocyclohexanone, ethylene ketal hydroiodide Part A Preparation of precursor, the Dimethyl ester of 4-(o-chlorophenyl)-4-cyanopimelic acid Following the procedure of Example 1, Part A, but substituti~g o-chlorophenyl acetonitrile for p-chlorophenyl acetonitrile and decreasing the final distillation pressure to 0.08 mm Hg, there is prepared 39.11 gm. (73% yield) of the dimethyl ester of 4-(o-chlorophenyl)-4-cyanopimelic ~ 8 acid as an oil having a boiling range of 170 to 183 C.
Part B Preparation of first intermediate, 2-Carbo-methoxy-4-cyano-4-(o-chlorophenyl)cyclohex-anone Following the procedure of Example 1, Part B, but substituting 39.11 gm. (0.121 mole) dimethyl-4-(o-chloro-phenyl)-4-cyanopimelate (prepared in Part A, above) for the dimethyl ester of 4-(p-chlorophenyl)-4-cyanopimelic acid, and using 780 ml. of the tetrahydrofuran, 27.4 gm.
(0.24 mole) of the potassium tert-butoxide, and 195 ml.
of the 2.5 N acetic acid instead of the 700 ml., the 24.4 gm. (0.218 mole), and the 175 ml., respectively, there is prepared 33.4 gm. (95% yield) of 2-carbomethoxy-4-cyano-4-(o-chlorophenyl)cyciohexanone as a crystalline solid having a melting range of 113 to 118 C.
Part C Preparation of second intermediate, 4-(o-chlorophenyl)-4-cyanocyclohexanone Following the procedure of Example 1, Part C, but substituting 33.4 gm. (0.115 mole) of 2-carbomethoxy-4-(o-chlorophenyl)-4-cyanocyclohexanone (prepared in Part B, above) for the 29.8 gm. of the 2-carbomethoxy-4-(p-chlorophenyl)-4-cyanocyclohexanone, using 730 ml. glacial acetic acid and 365 ml. 10 percent aqueous sulfuric acid instead oF the 660 ml. and 330 ml., respectively, and heating for 48 hours instead of 24 hours there is obtained a residual solid that is recrystallized from a mixture of methylene chloride and technical hexane thus affording 20.54 gm. (80% yield) of 4-(o-chlorophenyl)-4-cyanocyclo-hexanone having a melting point at 106 to 108 C.
Analysis:

5~ 3~ 3286 Calc~d. for Cl3HI2ClNO:
C, 66.81; H, 5.18; N, 5.99.
Found: C, 66.45; H, 5.13; N, 5.86.
Part D Preparation of third intermediate, 4-(o-chlorophenyl)-4-cyanocyclohexanone, ethylene ketal Following the procedure of Example 1, Part D, but substituting 20.54 gm. (0.092 mole) of 4-(o-chlorophenyl)-4-cyanocyclohexanone (prepared in Part C, above) for the 19.49 gm. of the 4-(p-chlorophenyl)-4-cyanocyclohexanone, and using 5.1 ml. (5.66 gm., 0.92 mole) ethylene glycol, 0.25 gm. p-toluenesulfonic acid, and 160 ml. benzene instead of the 4.8 ml., the 0.21 gm., and the 150 ml., respectively, there is obtained 22.64 gm. (89% yield) of the expected compound 4-(o-chlorophenyl)-4-cyanocyclohex-anone, ethylene ketal having a melting range at 98.5 to 101 C.
Analysis:
~` Calc'd. for Cl5HI~ClNO2:
C, 64.86; H, 5.81; N, 5~04.
Found: C, 64.60; H, 5.79; N, 5.20.
Part E Preparation of fourth intermediate, 4-carboxy-4-(o-chlorophenyl)cyclohexanone, ethylene ketal Following the procedure of ~xample 1, Part E, but substituting 22.54 gm. (0.081 mole) of 4-(o~chlorophenyl)-4-cyanoc~clohexanone, ethylene ketal (prepared in Part D, above) for the 21.87 gm. of 4-(p-chlorophenyl)-4-cyano-cyclohexanone, ethylene ketal and using 23.0 gm. (0.41 mole) potassium hydroxide and 230 ml. ethylene glycol instead of the 22.0 gm. and the 220 ml., respectively, there is obtained 18.49 gm. (77% yield) of 4-carboxy-4-(o-chloro-phenyl)cyclohexanone, ethylene ketal having a melting point at 195 to 197 C.
5Analysis:
Calc'd. for Cl5Hl7Cl 04 C, 60.71; H, 5.78.
Found: C, 61.11; H, 5.96.
Part F Preparation of fifth intermediate, 4-(o-Chloro-phenyl)-4-isocyanatocyclohexanone, ethylene ketal Following the procedure of Example 1, Part F, but substituting 18.49 gm. (0.0625 mole) of 4-carboxy-4-(o-chlorophenyl)cyclohexanone, ethylene ketal (prepared in Part E, above) for the 15.79 gm. of 4-carboxy-4-(p-chloro-phenyl)cyclohexanone, ethylene ketal and using 8.7 ml.
(6.3 gm., 0.063 mole) triethylamine, 160 ml. anisole, and 17.4 gm. diphenylphosphonic azide instead of the

7.4 ml., the 135 ml., and the 14.7 gm., respectively, there is obtained 15.49 gm. (85~ yield) of 4-(o-chlorophenyl)-4-isocyanatocyclohexanone, ethylene ketal as an oil.
Part G Preparation of sixth intermediate, 4-(o-chloro-phenyl)-4-methylaminocyclohexanone, ethylene ketal Following the procedure of Example 1, Part G, but substituting 15.49 gm. (0.053 mole) of 4-(o-chlorophenyl)-4-isocyanatocyclohexanone, ethylene ketal (prepared in Part F, above) for the 6.62 gm. of the 4-(p-chlorophenyl)-4-isocyanatocyclohexanone, ethylene ketal; using 120 ml.
tetrahydrofuran, 3.04 gm. (0.08 mole) lithium aluminum ~ ~r~

hydride, and 50 ml. tetrahydrofuran, respectively; and adding 3.0 ml. water, 3.0 ml. of the 15 percent aqueous sodium hydroxide, and 9.0 ml. water instead of the 1.3 ml., the 1.3 ml., and the 3.9 ml., respectively, there is obtained 14.27 gm. (96% yield) of 4-(o-chlorophenyl)-4-methylaminocyclohexanone, ethylene ketal as a noncrystal- !
line gum.
Part H Preparation of object compound, 4-(o-chloro-phenyl)-4-dimethylaminocyclohexanone, ethylene ketal hydroiodide Following the procedure of Example 1, Part H, but substituting 14.27 gm. (0.051 mole) of the 4-(o-chloro-phenyl)-4-methylaminocyclohexanone, ethylene ketal prepared in Part G, above, for the 5.68 gm. of the 4-(p-chloro-phenyl)-4-methylaminocyclohexanone, ethylene ketal and using 55 ml. of the 37 percent formalin, 190 ml. methanol, and 7.25 gm. (0.191 mole) of the sodium borohydride instead of the 22 ml., the 75 ml., and the 2.89 gm., respectively, there is obtained the free base product from the final removal of methylene chloride, after recycling.
This is then dissolved in a small amount of methylene chloride and washed with 10 percent hydriodic acid.
After removing the methylene chloride by evaporation under reduced pressure, the residue is recrystallized from a mixture of methanol and diethyl ether to afford 2.7 gm.
of the object compound 4-(o-chlorophenyl)-4-dimethylamino-cyclohexanone, ethylene ketal hydroiodide having a melting ranse of 208 to 213 C.
_alysis:
Calc'd. For C,6H2 3Cl IN02:

S~

C, 45.35; H, 5.47; N, 3.31.
Found: C, 45.58; H, 5.65; N, 3.18.
Example 10 Preparation of an object compound, 4-(o-Chloro-phenyl)-4-dimethylaminocyclohexanone Following the procedure of Example 2, but substituting 10.0 gm. (0.034 mole) of 4-(o-chlorophenyl)-4-dimethylamino-cyclohexanone, ethylene ketal (prepared in Example 9, Part H, above) for the 4.52 gm. of the 4-(P-chlorophenyl)-4-dimethylaminocyclohexanone, ethylene ketal hydrochloride, and using 50 ml. 2.5 N hydrochloric acid and 100 ml.
methanol ;nstead of the 22.5 ml. and the 45 ml., respect-ively, there i5 prepared 2.25 gm. (26.3% yield) of 4-(o-chlorophenyl)-4-dimethylaminocyclohexanone having a melting point at 81 to 84 C.
Analysis:
Calc'd. for Cl4H,7ClN0:
C, 66.79; H, 7.21; N, 5.57.
Found: C, 66.98; H, 7.54; N, 5.81.
Example 11 Preparation of 4-(m-anisyl)-4-dimethylamino-cyclohexanone, ethylene ketal hydrochloride Part A Preparation of precursor, the Dimethyl ester of 4-(m-anisyl)-4-cyanopimelic acid Following the procedure of Example 1, Part A, but substituting 25.0 gm. ~0.17 mole) m-anisyl acetonitrile for the 25.0 gm. of the p-chlorophenyl acetonitrile and using 79 ml. methyl acrylate, 27 ml. of the 40% methanolic ~etramPthylammonium hydroxide with 38 ml. tert-butyl alcoho1, instead of the 77 ml., the 24 ml., and the 37 ml., respectively, and decreasing the final distillation presCure to 0.07 mm Hg, there is prepared 30.34 gm. (56%

~3~ 3286 yield) of the dimethyl ester of 4-(m-anisyl)-4-cyanopimelic acid as an oil having a boiling range from 180 to 187 C.
Part B Preparation of first intermediate, 4-(m-anisyl)-2-carbomethoxy-4-cyanocyclohexanone Following the procedure of Example 1, Part B, but substituting 30.34 gm. (0.0951 mole) of the dimethyl ester of 4-(m-anisyl)-4-cyanopimelic acid (prepared in Part A, above) for the 34.97 gm. of the dimethyl ester of 4-(p-chlorophenyl)-4-cyanopimelic acid and using 620 ml. of the tetrahydrofuran, 21.3 gm. (0.19 mole) of the potassium tert-butoxide, and 150 ml. of the 2.5 N glacial acetic acid instead of the 700 ml., the 24.4 gm. (0.218 mole), and the 175 ml., respectively, there is prepared 29.1 gm.
(99~ yield) of 4-(m-anisyl)-2-carbomethoxy-4-cyanocyclo-hexanone as a gum.
Part C Preparation of second intermediate, 4-(m-anisyl)-4-cyanocyclohexanone Following the same procedure as described in Example 1, Part C, but substituting 29.1 gm. (0.101 mole) of 4-(m-anisyl)-2-carbomethoxy-4-cyanocyclohexanone (prepared in Part B, above) for the 29.8 gm. of 2-carbomethoxy-4-(p-chlorophenyl)-4-cyanocyclohexanone, there is obtained 14.93 gm. (64% yield) of 4-(m-anisyl)-4-cyanocyclohexanone having a melting range at 72 to 76 C.
Analysis:
Calc'd. for Cl4HIsNO2:
C, 73.34, H, 6.59, N, 6.11.
Found: C, 73.68; H, 6.76; N, 6.21.
Part D Preparation of third intermediate, 4-(m-anisyl)-4-cyanocyclohexanone, ethylene ketal ~ ~ 3286 Following the procedure of Example 1, Part D, but substituting 14.93 gm. (0.065 mole) of 4-(m-anisyl)-4-cyanocyclohexanone (prepared in Part C, abvoe) for the 19.49 gm. of the 4-(p-chlorophenyl)-4-cyanocyclohexanone, using 4.0 ml. ethylene glycol, 0.16 gm. p-toluenesulfonic acid, and 110 ml. benzene instead of the 4.8 ml., the 0.21 gm., and the 150 ml., respectively, and recrystalliz-ing from technical hexane instead of cyclohexane, there is obtained 16.24 gm. (92% yield) of 4-(m-anisyl)-4-cyano-cyclohexanone, ethylene ketal melting at 70 to 72 C.
Analysis: -Calc'd. for Cl6HlgN03:
C, 70.31; H, 7.01; N, 5.13.
Found: C, 70.09; H, 7.07; N, 4.96.
Part E Preparation of fourth intermediate 4-(0-anisyl)-- 4-carboxycyclohexanone, ethylene ketal Following the procedure of Example 1, Part E, but substituting 16.24 gm. (0.059 mole) of 4-(m-anisyl)-4-cyanocyclohexanone, ethylene ketal (prepared in Part D, above) for the 21.87 gm. of the 4-carboxy-4-(p-chloro-phenyl)cyclohexanone, ethylène ketal and using 7.83 gm.
(0.19 mole) sodium hydroxide and 110 ml. ethylene glycol instead of the 22.0 gm. (0.39 mole) potassium hydroxide and 220 ml., respectively, there is obtained, without recrystallization, 17.31 gm. (99% yield) of 4-(m-anisyl)-4-carboxycyclohexanone, ethylene ketal having a melting range at 102 to 107 C.
Part F Preparation of fifth intermediate, 4-(m-anisyl)-4-isocyanatocyclohexanone, ethylene ketal Following the procedure of Example 1, Part F, but ~ 5~ 3286 substituting the 17.31 gm. (0.059 mole) of 4-(m-anisyl)-4-carboxycyclohexanone, ethylene ketal (prepared in Part E, aboYe) for the 15.79 gm. of the 4-carboxy-4-(p-chloro-phenyl)cyclohexanone, ethylene ketal and using 6.0 ml.
(8.23 gm., 0.059 mole) triethylamine, 160 ml. anisole, and 16.31 gm. diphenylphosphonic azide instead of the 7.4 ml., the 135 ml., and the 14.7 gm., respectively, there is obtained after elution of the silica gel column with a 1.5 percent mixture of ethyl acetate in methylene chloride, 4.07 gm. of 4-(m-anisyl)-4-isocyanatocyclohex-anone ethylene ketal.
Part G Preparation of sixth intermediate, 4-(m-anisyl)-4-methylaminocyclohexanone, ethylene ketal hydrochloride Following the procedure of Example 1, Part G, but substituting 4.07 gm. (0.014 mole) of 4-(m-anisyl)-4-isocyanatocyclohexanone, ethylene ketal (prepared in Part F, above) for the 6.62 gm. 4-(p-chlorophenyl)-4-isocyanato-cyclohexanone, ethylene ketal and using 80 ml. tetrahydro-furan, 0.76 gm. (0.02 mole) lithium aluminum hydride, and 10 ml. tetrahydrofuran instead of the 50 ml., the 1.29 gm., and the 20 ml., adding 0.76 ml. water, 0.76 ml. of 15 per-cent aqueous sodium hydroxide, and 2.28 ml. water instead of the 1.3 ml., the l.3 ml., and the 3.9 ml., respectively, there is obtained a corresponding residue from the filtrate that is dissolved in a small amount of diethyl ether. The ether solution is acidified with an equivalent amount of 3 N hydrogen chloride in ether. The hydrochloride acid addition salt that precipitated is collected on a filter 3n and recrystallized from a mixture of methylene chloride -~3-~ 3286 and ethyl acetate to afford 3.10 gm. (71% yield) of 4-(m-anisyl)-4-methylaminocyclohexanone, ethylene ketal hydrochloride having a melting point at 238 to 239 C.
Analysis:
Calc'd. for Cl6H24ClN03:
C, 61.23; H, 7.71; N, 4.46.
Found: C, 60.07; H, 7.52; N, 4.29.
Part H Preparation of object compound, 4-(m-anisyl)-4~(dimethylamino)cyclohexanone, ethylene ; 10 ketal hydrochloride Following the procedure of Example 1, Part H, but substituting the free base from 3.10 gm. (0.0099 mole) of 4-(m-anisyl)-4-methylaminocyclohexanone ethylene ketal hydrochloride (prepared in Part G, above) for the 5.68 gm.
of the 4-(p-chlorophenyl)-4-methylaminocyclohexanone, ethylene ketal and using 7.5 ml. of 37 percent formalin, 22.5 ml. methanol, and adding 0.91 gm. sodium borohydride instead of the 22 ml., the 75 ml., and the 2.89 gm.
respectively, there is obtained a hydrochloride precipitate that upon recrystallization from a mixture of methylene chlcride and ethyl acetate gives 2.21 gm. (68% yield) of 4-(m-anisyl)-4-(dimethylamino)cyclohexanone, ethylene ketal hydrochloride having a melting point at 184 to 185.5 C.
Analysis:
Calc'd. for Cl7H26ClN03:
C, 62.28; H, 7.99; N, 4.27.
Found: C, 62.11; H, 8.24; N, 4.21.
Example 12 Preparation of an object compound, 4-(m-anisyl)-4-dimethylaminocyclohexanone -5~-~r~e~ 3286 Following the procedure of Example 2, but substituting 1.71 gm. (0.0052 mole) of 4-(m-anisyl)-4-dimethylamino-cyclohexanone, ethylene ketal hydrochloride (prepared in Example 11, Part H, above) for the 4-(p-chlorophenyl)-4-dimethylaminocyclohexanone, ethylene ketal hydrochloride, 7.5 ml. of 2.5 N hydrochloride acid for the 22.5 ml., and 15 ml. methanol for the 45 ml., there is prepared (after recrystallization from petroluem ether instead of diethyl ether) 0.54 gm. (45% yield) of 4-(m-anisyl)-4-dimethyl-aminocyclohexanone as the free base having a melting point at 57 to 59 C.
Analysis:
Calc'd. for ClsH2lN02: -C, 72.84; H, 8.56; N, 5.66.
Found: C, 72.88; H, 8.47; N, 5.72.
Example 13 Preparation of 4-Dimethylamino-4-(p-tolyl)-cyclohexanone, ethylene ketal hydrochloride Part A Preparation of precursor, the Dimethyl ester of 4-cyano-4-(p-tolyl)pimelic acid Following the procedure of Example 1, Part A, but substituting 25.0 gm. (0.191 mole) p-tolyl acetonitrile for the 25.0 gm. of the p-chlorophenyl acetonitrile and using 89 ml. methyl acrylate, 90 ml. tert-butyl alcohol, 29 ml.
of 40 percent methanolic tetramethylammonium hydroxide, and 43 ml. tert-butyl alcohol instead of the 77 ml., the 80 ml., the 25 ml., and the 37 ml., respectively, and decreasing the final distillation pressure to 0.07 mm mercury, there is prepared 42.44 gm. (73% yield) of the dimethyl ester of 4-cyano-4-(p-tolyl)pimelic acid as an oil having a boiling range of 170 to 180 C.

Part B Preparation of first intermediate, 2-carbo-methoxy-4-cyano-4-(p-tolyl)cyclohexanone Following the procedure of Example 1, Part B, but substituting 42.44 gm. (0.14 mole) of the dimethyl ester of 4-cyano-4-(p-tolyl)pimelic acid (prepared in Part A, above) for the dimethyl ester of 4-(p-chlorophenyl)-4-cyano-pimelic acid and using 900 ml. of the tetrahydrofuran, 31.5 gm. (0.28 mole) of the potassium tert-butoxide, and 225 ml. of the 2.5 N aqueous acetic acid instead of the 700 ml., the 24.4 gm. (0.218 mole), and the 175 ml., respectively, there is prepared 39.3 gm. (99% yield) of 2-carbomethoxy-4-cyano-4-(p-tolyl)cyclohexanone as a gum.
Part C Preparation of second intermediate, 4-Cyano-4-(p-tolyl)cyclohexanone Following the procedure of Example 1, Part C, but substituting 39.3 gm. (0.145 mole) of 2-carbomethoxy-4-cyano-4-(p-tolyl)cyclohexanone (prepared in Part B, above) for the 29.8 gm. of the 2-carbomethoxy-4-(p-chlorophenyl)-4-cyanocyclohexanone and using 960 ml. glacial acet;c acid and 480 ml. of 10 percent aqueous sulfuric acid instead of the 660 ml. and 330 ml., respectively, there is obtained after recrystallization from a mixture of di-ethyl ether and petroleum ether 22.84 gm. (74% yield) of 4-cyano-4-(p-tolyl)cyclohexanone having a melting range at 79 to 82 C.
Analysis:
Calc'd. for CI~H~sNO:
C, 78.84; H, 7.09; N, 6.57.
Found: C, 78.96, H, 7.07; N, 6.53.
Part D Preparation of third intermediate, 4-Cyano-4-(p-tolyl)cyclohexanone, ethylene ketal Follo~ing the procedure of Example 1, Part D, but substituting 22.74 gm. (0.107 mole) of 4-cyano-4-(p-tolyl)-cyclohexanone (prepared in Part C, above) for the 19.49 gm.
of the 4-(p-chlorophenyl)-4-cyanocyclohexanone and using 6.3 ml. (7.0 gm., 0.113 mole) ethylene glycol, 0.28 gm.
p-toluenesulfonic acid, and 190 ml. benzene instead of the 4.8 ml., the 0.21 gm., and the 150 ml., respectively, there is thus obtained 25.29 gm. (92% yield) of 4-cyano-4-(p~tolyl)cyclohexanone, ethylene ketal having a melting range at 107.5 to 110 C.
Analysis:
Calc'd. for Cl6HIgNO2:
C, 74.68; H, 7.44; N, 5.44.
Found: C, 75.04; H, 7.40; N, 5.48.
Part E Preparation of fourth intermediate, 4-Carboxy-4-(p-tolyl)cyclohexanone, ethylene ketal Following the procedure of Example 1, Part E, but substituting 25.29 gm. (0.0985 mole) of 4-cyano-4-(p-tolyl)-cyclohexanone, ethylene ketal (prepared in Part D, above) for the 21.87 gm. of the 4-(p-chlorophenyl)-4-cyanocyclo-hexanone, ethylene ketal and using 25.0 gm. (0.45 mole) potassium hydroxide and 250 ml. ethylene glycol instead O~e the 22.0 gm. and the 220 ml., respectively, there is obtained 23.04 gm. (85% yield) of the expected compound 4-carboxy-4-(p-tolyl)cyclohexanone, ethylene ketal having a melting range of 72 to 74 C.
Analysis:
Calc'd. for C! 6 H 2 0 4 C, 69.54; H, 7.30.

Found: C, 69.79; H, 7.31.
Part F Preparation of fifth intermediate, 4-Isocyana-to-4-(p-tolyl)cyclohexanone, ethylene ketal Following the procedure of Example 1, Part F, but substituting 22.94 gm. (0.083 mole) of 4-carboxy-4-(p-tolyl)cyclohexanone, ethylene ketal (prepared in Part E, above) for the 15.79 gm. of the 4-carboxy-4-(p-chloro-phenyl)cyclohexanone, ethylene ketal using 12.6 ml. (9.15 gm., 0.092 mole) triethylamine, 270 ml. anisole, and 24.5 gm. diphenylphosphonic azide for the 7.4 ml., the 135 ml., and the 14.7 gm., respectively, and chromatograph-ing over a 2000 ml. column instead of a 1500 ml. column, there is obtained 19.0 gm. (84% yield) of 4-isocyanato-4-(p-tolyl)cyclohexanone, ethylene ketal as an oil.
Part G Preparation of sixth intermediate, 4-Methyl-! . amino-4-(p-tolyl)cyclohexanone, ethylene ketal Following the procedure of Example 1, Part G, but substituting 19.07 gm. (0.0675 mole) of 4-isocyanato-4-(p-tolyl)cyclohexanone, ethylene ketal (prepared in Part F, above) for the 6.62 gm. of the 4-(p-chlorophenyl)-4-isocyanatocyclohexanone, ethylene ketal, using 325 ml.
tetrahydrofuran, 4.0 gm. (0.105 mole) lithium aluminum hydride, and 40 ml. tetrahydrofuran; and adding 4.0 ml.
water, 4.0 ml. of 15 percent sodium hydroxide, and 12 ml.
water instead of the 1.3 ml., 1.3 ml., and 3.9 ml., res-pectively, there is obtained 14.75 gm. (57% yield) of 4-methylamino-4-(p-tolyl)cyclohexanone, ethylene ketal having a melting range at 56 to 60 C.
~nalysis:

~ 3286 Calc'd. for C,6H23N02:
C, 73.53; H, 8.87; N, 5.36.
Found: C, 73~19; H, 9.01; N, 5.46.
Part H Preparation of object compound, 4-Dimethyl-amino-4-(p-tolyl)cyclohexanone, ethylene ketal hydrochloride Following the procedure of Example 1, Part H, but sub-stituting 7.0 gm. (0.027 mole) of 4-methylamino-4-(p-tolyl)-cyclohexanone, ethylene ketal (prepared in Part G, above) for the 5.68 gm. of the 4-(p-chlorophenyl)-4-methylaminocy-clohexanone, ethylene ketal and initially using 29.2 ml. of 37 percent formalin, 100 ml. methanol, and 3.96 gm. (0.104 ;
mole) sodium borohydride instead of the 22 ml., the 75 ml., and the 2.89 gm., respectively, there is obtained the free base; this on further treatment as in Example 1, Part H gives a hydrochloride acid addition salt precipitate that is re-crystallized from a solvent mixture consisting of methylene chloride and ethyl acetate thus affording 6.27 gm. (76% -`
yield) of the desired, object compound 4-dimethylamino-4-(p-tolyl)cyclohexanone, ethylene ketal hydrochloride salt which melts at 228 to 229 C.
Analysis: Calc'd. for C17H26ClN02:
C, 65.47; H, 8.40; N, 4.49.
Found: C, 65.57; H, 8.30; N, 4.60.
Example 14 Preparation of an object compound, 4-dimethyl-__ amino-4-(p-tolyl)cyclohexanone Following the procedure of Example 2, but substituting 6.27 gm. (0.02 mole) of 4~dimethylamino-4-(p~tolyl)cyclo-hexanone, ethylene ketal hydrochloride (prepared in Example 13, Part H, above) for the 4-(p-chlorophenyl)-4-dimethyl-5~

aminocyclohexanone, ethylene ketal hydrochloride, 31 ml.
2.5 N hydrochloric acid for the 22.5 ml., and 62 ml.
methanol for the 45 ml., there is prepared (after recrystal-lization from petroleum ether instead of diethyl ether) 2.54 gm. (55% yield) of 4-dimethylamino-4-(p-tolyl)-cyclohexanone having a melting poi-nt at 65 to 67.5 C.
Analysis:
Calc'd. for ClsH21N0:
C, 77.88; H, 9.15; N, 6.06.
Found: C, 77.72, H, 9.14, N, 6.24.
Example 15 Preparation of 4-Dimethylamino-4-(o-tolyl)-cyclohexanone, ethylene ketal hydroiodide Part A Preparation of precursor, the Dimethyl ester of 4-cyano-4-(o-tolyl)pimelic acid Following the procedure of Example 1, Part A, but substituting 25.0 gm. (0.191 mole) o-tolyl- acetonitrile for the 25.0 gm. of the p-chlorophenyl acetonitrile and using 89 ml. methyl acrylate, 90 ml. tert-butyl alcohol, 29 ml. of 40 percent methanolic tetramethylammonium hydroxide, and 43 ml. tert-butyl alcohol instead of the 77 ml., the 80 ml., the 24 ml., and the 37 ml., respect-ively, and decreasing the final distillation pressure to 0.03 mm mercury, there is prepared 21.76 gm. (37% yield) of the dimethyl ester of 4-cyano-4-(o-tolyl)pimelic acid as an oil having a boiling range between 168 to 175 C.
Part B Preparation of first intermediate, 2-Carbo-methoxy-4-cyano-4-(o-tolyl)cyclohexanone Following the procedure of Example 1, Part B, but substituting 21.76 gm. (0.0715 mole) of the dimethyl ester of 4-cyano-4-(o-tolyl)pimelic acid (prepared in Part A, ~ 3~

above) for the 34.97 gm. of the dimethyl ester of 4-(p-chlorophenyl)-4-cyanopimelic acid and using 460 ml. of the tetrahydrofuran, 16.3 gm. (0.145 mole) of the potassium tert-butoxide, and 115 ml. of the 2~5 N aqueous acetic acid instead of the 700 ml., the 24.4 gm. and the 175 ml., respectively, there is prepared 18.0 gm. (93% yield) of 2-carbomethoxy-4-cyano-4-(o-tolyl)cyclohexanone as a crystalline solid having a melting-range at 107 to 113 C.
Part C Preparation of second intermediate, 4-Cyano-4-(o-tolyl)cyclohexanone Following the procedure of Example 1, Part C, but substltuting 18.0 gm. (0.0663 mole) of the 2-carbomethoxy-4-cyano-4-(o-tolyl)cyclohexanone (prepared in Part B, above), for the 29.8 gm. of the 2-carbomethoxy-4-(p-chloro-phenyl)-4-cyanocyclohexanone, using 440 ml. of the acetic acid and 220 ml. of the 10 percent aqueous sulfuric acid instead of the 660 ml., and the 330 ml., respectively, and heating for 48 hours instead of 24 hours there is prepared 4-cyano-4-(o-tolyl)cyclohexanone which upon recrystalliza-tion from a mixture of diethyl ether and technical hexane affords 11.05 gm. of the compound having a melting range at 86.5 to 89 C.
- Analysis:
Calc'd. for Cl4HlsN0:
C, 78.84; H, 7.09; N, 6.57.
Found: C, 78.85; H, 7.29; N, 6.55.
Part D Preparation of third intermediate, 4-Cyano-~-(o-tolyl)cyclohexanone, ethylene ketal Following the procedure of Example 1, Part D, but substituting 10.95 gm. (0.0513 mole) of 4-cyano-4-(o-tolyl)-5~a`~3 cyclohexanone (prepared in Part C, above) for the 19.49 gm.
(0.084 mole) of the 4-(p-chlorophenyl)-4-cyanocyclohexanone and using 3.1 ml. (3.44 gm., 0.044 mole) ethylene glycol, 0.14 gm. p-toluenesulfonic acid, and 90 ml. benzene instead of the 4.7 ml., the 0.21 gm., and the 150 ml., respectively, there is thus obtained a residual solid that is recrystallized from a mixture of diethyl ether and petroleum ether thus affording 11.22 gm. (85% yield) of 4-cyano-4-(o-tolyl)cyclohexanone, ethylene ketal having a melting range at 65.5 to 68.5 C.
Analysis:
Calc'd. for Cl6HlgN02:
C, 74.68; H, 7.44; N, 5.44.
Found: C, 74.56; H, 7.50; N, 5.29.
Part E Preparation of fourth intermediate, 4-Carboxy-4-(o-tolyl)cyclohexanone, ethylene ketal Following the procedure of Example 1, Part E, bùt ; substituting 11.22 gm. (0.044 mole) of 4-cyano-4-(o-tolyl)-cyclohexanone, ethylene ketal (prepared in Part D, above) for the 21.87 gm. of the 4-(p-chlorophenyl)-4-cyanocyclo-hexanone, ethylene ketal and using 11.0 gm. (0.20 mole) potassium hydroxide and 110 ml. ethylene glycol instead of the 2..0 gm. and 220 ml., respectively, there is obtained 7.70 gm. (63.3% yield) of 4-carboxy-4-(o-tolyl)cyclohexa-none, ethylene ketal having a melting range at 174 to 177 C.
Analysis:
Calc'd. for Cl6H2 004 C, 69.54; H, 7.30.
3Q Found: C, 69.43; H, 7.62.

<

Part F Preparation of fifth intermediate, 4-lso-cyanato-4-(o-tolyl)cyclohexanone, ethylene ketal Following the procedure of Example 1, Part F, but substituting 7.70 gm. (0.028 mole) of 4~carboxy-4-(o-tolyl)-cyclohexanone, ethylene ketal (prepared in Part E, above) for the 15.79 gm. of the 4-carboxy-4-(p-chlorophenyl)-cyclohexanone, ethylene ketal and using 4.3 ml. (3.12 gm., 0.031 mole) triethylamine, 90.0 ml. anisole, and 8.4 gm.
diphenylphosphonic azide instead ~f the 7.4 ml., the 135 ml., and the 14.7 gm., respectively, followed by chromatographic separation on a 400 ml. column of silica gel instead of the 1500 ml. column and elution with 2 percent ethyl acetate in methylene chloride instead of ethyl acetate and technical hexane, there is obtained 6.09 gm. (79.6% yield) of 4-isocyanato-4-(o-tolyl)cyclohexanone, ethylene ketal as a gum.
Part G Preparation of sixth intermediate, 4-Methyl-amino-4-(o-tolyl)cyclohexanone, ethylene ketal hydrochloride Following the procedure of Example 1, Part G, but substituting 6.09 sm. (0.022 mole) of 4-isocyanato-4-(o-tolyl)cyclohexanone, ethylene ketal (prepared in Part F, above) for the 6.62 gm. of the 4-(p-chlorophenyl)-4-iso-cyanatocyclohexanone ethylene ketal, using 105 ml. tetra-hydrofuran, 1.28 gm. (0.034 mole) lithium aluminum hydride, and 10 ml. tetrahydrofuran instead of the 50 ml., the 1.29 gm., and the 20 ml., respectively, there is obtained a corresponding residue from the filtrate that is dissolved in a small amount of diethyl ether and the solution is ~ Q ~

acidified with just enough 3 N hydrogen chloride in ether to precipitate the hydrochloride salt which is collected on a f;lter and recrystallized from a mixture of methylene chloride and ethyl acetate to afford 4.03 gm. (59.7g yield) of the desired 4-methylamino-4-(o-tolyl)cyclohexanone, ethylene ketal hydrochloride having a melting point at 231 to 233 C.
Analysis:
Calc'd. for Cl6H24ClN0z ~H20:
C, 62.62; H, 8.21; N, 4.57.
Found: C, 62.78; H, 8.01; N, 4.72.
Part H Preparation of object compaund, 4-Dimethyl-amino-4-(o-tolyl)cyclohexanone, ethylene ketal hydroiodide A solution of the free base from 3.93 gm. (0.013 mole) of 4-methylamino-4-(o-tolyl)cyclohexanone, ethylene ketal hydrochloride (prepared in Part G, above) with 14.4 ml. of 37 percent formalin in 50 ml. methanol is heated at the refiux temperature for four (4) hours. The refluxed solu-tion is allowed to cool, and it is then chilled in an ice-bath. Small portions of sodium borohydride are added cautiously with stirring to a total of 1095 gm. (0.051 mole).
Stirring is continued for two (2) hours at 25 C., after which the bulk of the solvent is removed under reduced pressure. The concentrate thus obtained is dispersed in a mixture of 200 ml. methylene chloride and 25 ml. water.
A methylene chloride phase separates upon discontinuance of agitation. It is recovered and washed with water and brine before the methylene chloride is removed by evaporation under reduced pressure. The residue thus obtained is ~ $ ~ ~

recycled through the same reaction and work up. A portion (1.68 9.) of this second residue is dissolved in methylene chloride and washed with 10 percent hydriodic acid. The methylene chloride phase is separated, the solvent removed by evaporation under reduced pressure and the residue thus obta;ned is recrystallized from a mixture of methylene chloride and ether to afford 2.03 gm. (37.1% yie1d) of the desired object compound, 4-dimethylamino-4-(o-tolyl)cyclo-hexanone, ethylene ketal hydroiodide having a melting point ; 10 at 182 to 183.5 C.
Analysis:
Calc'd. for Cl7H26lN02 H20:
C, 48.45; H, 6.70; N, 3.33.
Found: C,;48.77; H, 6.54; N, 3.41.
Example 16 Preparation of an object compound, 4-Dimethyl-!

amino-4-(o-tolyl)cyclohexanone free base and the hydroiodide thereof Following the procedure of Example 2, but substituting 2.0 gm. (0.0073 mole) of 4-dimethylamino-4-(o-tolyl)cyclo-hexanone, ethylene ketal hydroiodide (prepared in Example15, Part H, above) for the 4-(p-chlorophenyl)-4-dimethyl-aminocyclohexanone, ethylene ketal hydrochloride and using 10 ml. of the 2.5 N hydrochloric acid and 20 ml. of the methanol instead of 22.5 ml. and 45 ml., respectively, there is obtained 4-dimethylamino-4-(o-tolyl)cyclohexanone free base as the residue. This residue is dissolved in 50 ml. methylene chloride and shaken with 10 ml. 10 percent aqueous hydriodic acid. The methylene chloride layer is separated and the solvent removed by evaporation under reduced pressure. The residue thus obtained is recrystal-~1~35~

lized from a mixture of methanol and diethyl ether. There is thus obtained 0.94 gm. (35.8% yie1d) of 4-dimethylamino-4-(o-tolyl)cyclohexanone hydroiodide having a melting range of 162 to 165 C.
Analysis:
Calc'd. for Cl sH22 INO:
C, 50.15; H, 6.17; N, 3.90.
Found: C, 49.86; H, 6.37; N, 4.00.
Example 17 Preparation of 4-Dimethylamino-4-phenylcyclo-hexanone, ethylene ketal hydrochloride Part A Preparation of precursor, the Dimethyl ester of 4-cyano-4-phenylpimelic acid Following the procedure of Example 1, Part A, but substituting 20.26 gm. (0.25 mole) of phenyl acetonitrile for the 25.0 gm. of p-chlorophenyl acetonitr;le and using 116 ml~ methyl acrylate, 120 ml. tert-butyl alcohol, 38 ml.
of the 40 percent methanolic tetramethylammonium hydroxide, and 56 ml. tert-butyl alcohol instead of the 77 ml., the 80 ml., the 24 ml., and the 37 ml. quantities stated, respectively, and increasing the final distillation pres-sure to 0.45 mm of mercury, there is prepared 55.15 gm.
(70% yield) of the dimethyl ester of 4-cyano-4-phenylpimelic acid as an oil having a boiling range from 183 to 186 C.
Part B Preparation of first intermediate, 2-Carbo-methoxy-4-cyano-4-phenylcyclohexanone Following the procedure of Example 1, Part B, but substituting 2.0 gm. (0.0069 mole) of the dimethyl ester o~ 4-cyano-4-phenylpimelic acid (prepared in Part A, above) for the 34.97 gm. of the dimethyl ester of 4-(p-chlorophenyl)-4-cyanopimelic acid and using 45 ml. of the ~ 3~

tetrahydrofuran, 1.57 gm. (0.014 mole) of the potassium tert-butoxide, and 10 ml. of the 2.5 N acetic acid instead of the 700 ml., the 24.4 gm., and the 175 ml., respectively, there is thus obtained a residue which upon recrystalliza- .
tion from technical hexane gives 1.07 gm. (60% yield) of the desired 2-carbomethoxy-4-cyano-4-phenylcyclohexanone r having a melting point at 79.5 to 81.5 C.
Analysis:
Calc'd. for Cl sHl sNO3:
? c, 70.02; H, 5.88; N, 5.44.
Found: C, 6~.77; H, 5.88; N, 5.54.
Part C Preparation of second intermediate, 4-Cyano-4-phenylcyclohexanone Following the procedure of Example 1, Part C, but - 15 substituting 44.7 gm. (0.174 mole) of 2-carbomethoxy-4-cyano-4-phenylcyclohexanone (prepared as in Part B, above) for the 29.8 gm. of the 2-carbomethoxy-4-(p-chloro-phenyl)-4-cyanocyclohexanone and using 1200 ml. of the glacial acetic acid, and 600 ml. of the 10% aqueous sul-furic acid instead of the 660 ml. and the 330 ml., respectively, and finally recrystallizing the residual solid from a mixture of ethyl acetate and hexane, there is obtained 25.75 gm. (75% yield) of the desired 4-cyano-4-phenylcyclohexanone having a melting range from il2 to 115.5 C.
Part D Preparation of third intermediate, 4-Cyano-4-phenylcyclohexanone, ethylene ketal Following the procedure of Example 1, Part D, but substituting 10.0 gm. (0.05 mole) of 4-cyano-4-phenyl-cyclohexanone (prepared in Part C, above) for the 4-(p-$~ 3~

chlorophenyl)-4-cyanocyclohexanone and using 2.85 ml.
(3.17 gm., 0.051 mole) of the ethylene glycol, 0.12 gm.
of the p-toluenesulfonic acid, and 90 ml. of the benzene solvent instead of the 4.8 ml., the 0.21 gm., and the 150 ml., respectively, there is obtained 11.27 gm. (92%
yield) of the desired 4-cyano-4-phenylcyclohexanone, ethylene ketal as crystals having a melting range of 120 to 122.5 C.
Analysis:
Calc'd. for ClsHl7No2 C, 74.05; H, 7.04; N, 5.76.
Found: C, 74.10; H, 6.98; N, 5.77.
Part E Preparation of fourth intermediate, 4-Carboxy-4-phenylcyclohexanone, ethylene ketal Following the procedure of Example 1, Part E, but ~- substituting 11.27 gm. (0.0464 mole) of 4-cyano-4-phenyl-cyclohexanone, ethylene ketal (prepared in Part D, above) for the 21.87 gm. of the 4-(p-chlorophenyl)-4-cyanocyclo-hexanone, ethylene ketal, and using 11.3 gm. ~0.2 mole) of the potassium hydroxide, and 90 ml. of the ethylene glycol instead of the 22.0 gm. and 220 ml., respectively, there is obtained 10.51 gm. (86% yield) of the desired 4-carboxy-4-phenylcyclohexanone, ethylene ketal as crystals having a melting range from 136 to 140.5 C.
Analysis:
Calc'd. for Cl sHl 84 C, 68.68; H, 6.92.
Found: C, 68.27; H, 6.90.
Part F Preparation of fifth intermediate, 4-Iso-.
cyanato-4-phenylcyclohexanone, ethylene ketal Following the procedure of Example 1, Part F, but substituting 2.62 gm. (0.01 mole) of 4-carboxy~4-phenyl-cyclohexanone ethylene ketal (prepared in Part E, above) for the 15.79 gm. of the 4-carboxy-4-(p-chlorophenyl)-cyclohexanone, ethylene ketal and using 1.38 ml. (1.01 gm., 0.01 mole) of the triethylamine, 25 ml. of the anisole, ?.75 gm. of the diphenylphosphonic azide, and a 400 ml.
silica gel column instead of the 7.4 ml. (5.36 gm., 0.532 mole), the 135 ml., the 14.7 gm., and the 1500 ml. column, respectively, there is obtained 1.94 gm. (15% yield~ of the desired 4-isocyanato-4-phenylcyclohexanone, ethylene ketal which has a melting range from 47 to 50 C.
Analysis:
Calc'd. for C,5H~7N03:
C, 69.48; H, 6.61; N, 5.40.
Found: C, 69.56; H, 7.01; N, 5.39.
Part G Preparation of sixth intermed;ate, 4-Methyl-amino-4-phenylcyclohexanone, ethylene ketal hydrochloride A solution consisting of 0.96 gm. (0.0037 mole) of 4-isocyanato-4-phenylcyclohexanone, ethylene ketal (pre-pared in Part F, above) and 15 ml. tetrahydrofuran is added to a well-stirred suspension prepared by dispersing 0.20 gm. (0.0053 mole) lithium aluminum hydride in 5 ml.
tetrahydrofuran. The resulting reaction mixture is heated at the reflux temperature with stirring for four (4~
hours. The mixture is then allowed to cool before chilling it in an ice-bath. To the chilled mixture is added 0.2 ml.
water, 0.2 ml. 15% aqueous sodium hydroxide, and a further 0.6 ml. water. A gelatinous precipitate forms and the whole preparation is poured onto a filter. The filtrate is collected and the volatile components are removed by evaporation under reduced pressure. The residue thus obtained is dissolved in a small amount of diethyl ether and 3 N hydrogen chloride in ether is added to the solution to give the desired, insoluble acid addition salt. After collecting the crude salt on a filter and recrystallizing it from a mixture of methylene chloride and ethyl acetate, there is obtained 0.82 gm. (78% yield) of 4-methylamino-4-phenylcyclohexanone, ethylene ketal hydrochloride having a melting point at 243 to 245 C.
Analysis:
Calc'd. for Cl5H22ClN02:
C, 63.48; H, 7.82; N, 4.94.
Found: C, 63.51; H, 7.89; N, 5.00.
Part H Preparation of object compound, 4-Dimethyl-amino-4-phenylcyclohexanone, ethylene ketal hydrochloride A reaction solution consisting of the free base from 2~ 1.0 gm. (0.00354 mole) 4-methylamino-4-phenylcyclohexa-none, ethylene ketal hydrochloride (prepared as in Part G, above), 3.6 ml. 37% formalin, and 12 ml. methanol is heated at the reflux temperature for four (4)-hours. This reaction mixture is allowed to cool to room temperature before chilling it in an ice-bath. Small portions of -sodium borohydride are cautiously added with stirring, to a total amount of 0.48 gm. (0.125 mole). Stirring is continued at 25 C. for two (2) hours, and then the volatile solvents are removed by evaporation under reduced pressure. The residue thus obtained is dispersed in a mixture of 50 ml. methylene chloride and 10 ml. water and the liqu;ds are allowed to separate. The methylene chloride phase is recovered and washed with water and then with brine. After removing the methylene chloride solvent by evaporation under reduced pressure, the residue is dissolved in a small amount of ether. A solution of hydrogen chloride in ether (3 N) is added so as to produce the hydrochloride acld addition salt which precipitates out. The precipitate is collected on a filter and recrystallized from a mixture of methylene chloride and ethyl acetate to give 0.72 gm. (68% yield) of the desired final product, 4-dimethylamino-4-phenylcyclohexanone, ethylene ketal hydrochloride having a melting range from 226 to 229 C. An analytical sample is obtained by recrystallization from methylene chloride and ethyl a-cetate having a melting range from 236 to 238 C.
Analysis:
Calc'd. for C,6H24ClN02:
C, 64.52; H, 8.12; N, 4.70.
Found: C, 64.47; H, 7.85; N, 4.92.
Example 18 Preparation of 4-Dimethylamino-4-phenylcyclo-hexanone Following the procedure of Example 2, but substituting 13.66 gm. (0.052 mole) 4-dimethylamino-4-phenylcyclohex-anone, ethylene ketal (prepared in Example 17, Part H, above) for the 4.52 gm. of the 4-(p-chlorophenyl)-4-dimethyl-aminocyclohexanone, ethylene ketal hydrochloride and using 70 ml. 2.5 N hydrochloric acid and 14 ml. methanol instead of the 22.5 ml. and 45 ml., respectively, there is prepared 7.76 gm. (69% yield) of 4-dimethylamino-4-phenylcyclo-5~ ~

hexanone having a melting point at 98 to 99.5 C. An analytical sample has a melting range at 100 to 103 C.
Analysis:
Calc'd. for Cl4HIgNO:
C, 77.38; H, 8.81; N, 6.45 Found: C, 77.39; H, 8.86; N, 6.41.
Examp1e l9 Part A
Following the procedure of Example lj Part A, but substitut;ng the primary reactant p-bromophenyl acetoni-trile for the p-chlorophenyl acetonitrile and modifying other factors of the procedure as noted in Table A, there is prepared the corresponding precursor dimethyl ester of 4-(p-bromophenyl)-4-cyanopimelic acid as an oil.
Example 20 Part A
Following the procedure of Example l, Part A, but substituting the primary reactant m-chlorophenyl aceto-nitrile for the p-chlorophenyl acetonitriie and modifying other factors of the procedure as noted in Table A, there is prepared the corresponding precursor dimethyl ester of 4-(m-chlorophenyl)-4-cyanopimelic acid as an oil.
Example 21 Part A
Following the procedure of Example l, Part A, but substituting the primary reactant 3,4-dichlorophenyl acetonitrile for the p-chlorophenyl acetonitrile and modifying other factors of the procedure as noted in Table A, there is prepared the corresponding precursor dimethyl ester of 4-(3,4-dichlorophenyl)-4-cyanopimelic acid as an oil .
Example 22 Part A
Following the procedure of Example l, Part A, but ~ !5~3~

substituting the primary reactant 2,4-dichlorophenyl acetonitrile for the p-chlorophenyl acetonitrile and modifying other factors of the procedure as noted in Table A, there is prepared the corresponding precursor, dimethyl ester of 4-(2,4-dichlorophenyl)-4-cyanopimelic acid as an oil.

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~ 5 Example 19 Part B
Following the procedure of Example 1, Part B, but substituting the precursor, dimethylester of 4-(p-bromo-phenyl)-4-cyanopimelic acid (prepared in Part A, above) for the 34.97 gm. of the dimethyl ester of 4-(p-chloro-phenyl)-4-cyanopimelic acid and modifying other factors of the procedure as noted in Table B, there is prepared the corresponding first intermediate 4-(p-bromophenyl)-2-carbo-methoxy-4-cyanocyclohexanone as crystals having a melting range at 164 to 166 C.
Analysis:
Calc'd. for ClsHl4BrNo3:
C, 53.59; H, 4.20; N, 4~51.
Found: C, 53.49; H, 4.46; N, 4.29. - -Example 20 Part B
Following the procedure of Example 1, Part B, but substituting the precursor, dimethyl ester of 4-(m-chloro-phenyl)-4-cyanopimelic acid (prepared in Part A, above) for the 34.97 gm. of the dimethyl ester of 4-(p-chlorophenyl)-4-cyanopimelic acid and modifylng other factors of'the pro-cedure as noted in Table B, there is prepared the corres-ponding first intermediate, 2-carbomethoxy~4-(m-chloro-phenyl)-4-cyanocyclohexanone as crystals having a melting point at 123.5 to 125.0 C.
Analysis:
Calc'd. for Cl5Hl4ClN03:
C, 61.75; H, 4.84; N, 4.80.
Found; C, 61.52; H, 4.96; N, 4.86.
Example 21 Part B
Following the procedure of Example 1, Part B, but ~S'~

substituting the precursor, dimethyl ester of 4-(3,4-di-chlorophenyl)-4-cyanopimelic acid (prepared in Part A, above) for the 34~97 gm. of the dimethyl ester of 4-(p-chlorophenyl)-4-cyanopimelic acid and modifying other factors of the procedure as noted in Table B, there is prepared the corresponding first intermiedate 2-carbo-methoxy-4-(3,4-dichlorophenyl)-4-cyanocyclohexanone as crystals having a melting range at 82 to 87 C. An analytical sample recrystallized from diethyl ether has a melting point at 112 to 113 C.
Analysis:
Calc'd. for Cl5H,3Cl2N03:
C, 55.23; H, 4.12; N, 4.30.
Found: C, 55.47; H, 4.07; N, 4.48.
Example 22 Part B
Following the procedure of Example 1, Part B, but substituting the precursor, dimethyl ester of 4-(2,4-di-chlorophenyl)-4-cyanopimelic acid (prepared in Part A, - above) for the 34.97 gm. of the dimethyl ester of 4-(p- !
chlorophenyl)-4-cyanopimelic acid and modifying other factors of the procedure as noted in Table B, there is prepared the corresponding first intermediate 2-carbo-methoxy-4-(2,4-dichlorophenyl)-4-cyanocyclohexanone as a gum.

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~ '5 Example 19 Part C
Following the procedure of Example 1, Part C, but substituting the first intermediate 4-(p-bromophenyl)-2-carbomethoxy~4-cyanocyclohexanone, (prepared in Part B, above) for the 29.8 gm. of the 2-carbomethoxy-4-(p-chloro-phenyl)-4-cyanocyclohexanone and modifying other factors of the procedure as noted in Tab1e C, there is prepared the corresponding second intermediate 4-(p-bromophenyl)-4-cyanocyclohexanone as crystals having a melting range at 110 to 113 C.
Analysis: -Calc'd. for C,3Hl2BrN0:
C, 56.13; H, 4.35; N, 5.04.
Found: C, 56.35i H, 4.34i N, 5.06.
Example 20 Part C
Following the procedure of Example 1, Part C, but substituting the first intermediate, 2-carbomethoxy-4-(m-chlorophenyl)-4-cyanocyclohexanone (prepared ;n Part B, above) for the 29.8 gm. of the 2-carbomethoxy-4-(p-chlorophenyl,)-4,cyanocyclohexanone and modifying other factors of the procedure as noted in Table C, there is prepared the corresponding second intermediate, 4-(m-chloro-' phenyl)-4-cyanocyclohexanone as crystals having a melting range at 71 to 73.5 C.
Analysis:
Calc'd. for Cl3H,2ClN0:
C, 66.81; H, 5.18; N, 5.99.
Found: C, 66.91; H, 5.11; N, 5~95.
Example 21 Part C
Fo'llowing the procedure of Example 1, Part C, but ~ 3286 substituting the first intermediate, 2-carbomethoxy^
4-(3,4-dichlorophenyl)-4-cyanocyclohexanone, (prepared in Part B, above) for the 29.8 gm. of the 2-carbomethoxy-4-(p-chlorophenyl)-4-cyanocyclohexanone and modifying other factors of the procedure as noted in Table C, there is prepared the corresponding second intermediate, 4-(3,4-dichlorophenyl)-4-cyanocyclohexanone as crystals having a melting point at 156 to 157.5 C.
Analysis;
Calc'd. for Cl3HllCl2N0:
C, 58.22; H, 4.14; N, 5.22.
Found: C, 58.61; H, 4.37; N, 5.50.
Example 22 Part C
Following the procedure of Example 1, Part C, but - 15 substituting the first intermediate 2-carbomethoxy-4-(2,4-dichlorophenyl)-4-cyanocyclohexanone (prepared in Part B, above) for the 29.8 gm. of the 2-carbomethoxy-4-(p-chloro-phenyl)-4-cyanocyclohexanone and modifying other factors of the procedure as noted in Table C, there is prepared the corresponding second intermediate 4,(2,4-dichlorophenyl)-4-cyanocyclohexanone as crystals having a melting range at 119 to 122.5 C.
Analysis:
Calc`d. for Cl3HllCl2N0:
C, 58.22; H, 4.14; N, 5.22.
Found: C, 58.21; H, 3.95; N, 5.41.

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Following the procedure of Example 1, Part D, but substituting the second intermediate, 4-(p-bromophenyl)-4-cyanocyclohexanone (prepared in Part C, above) for the 19.49 gm. of the 4-(p-chlorophenyl)-4-cyanocyclohexanone and modifying other factors of the procedure as noted in Table D, there is prepared the corresponding third intermediate, 4-(p-bromophenyl)-4-cyanocyclohexanone, ethylene ketal as crystals having a melting range at 127 lo to 131 C.
Analysis:
Calc'd. for Cl5H~6BrN02:
C, 55.91; H, 5.00; N, 4.35.
Found: C, 55.78; H, 5.13; N, 4.39.
Example 20 Part D
Following the procedure of Example 1, Part D, but substituting the second intermediate, 4-(m-chlorophenyl)-4-cyanocyclohexanone (prepared in Part C, above) for the 19.49 gm. of the 4-(p-chlorophenyl)-4-cyanocyclohexanone and modifying other factors of the procedure as noted in Table D, there is prepared the corresponding third intermediate, 4-(m-chlorophenyl)-4-cyanocyclohexanone, ethylene ketal as crystals having a melting range at 68 to 71 C.
Analysis:
Calc'd. for Cl5H, 6Cl N02:
C, 64~86, H, 5.81; N, 5.04.
Found: C, 64.94; H, 5.91; N, 4.81 Example 21 Part D
Following the procedure of Example 1, Part D, but 5~ 3286 substituting the second intermediate, 4-(3,4-dichloro-phenyl)-4-cyanocyclohexanone, (prepared in Part C, above) for the 19.49 gm~ of the 4-(p-chlorophenyl)-4-cyanocyclo-hexanone and modifying other factors of the procedure 5 as noted in Table D, there is prepared the corresponding third intermediate, 4-(3,4-dichlorophenyl)-4-cyanocyclo-hexanone, ethylene ketal as crystals having a melting range at 120.5 to 123 C.
Analysis:
10Calc'd. for Cl5Hl5C12N02:
C, 57.51; H, 4.84; N, 4.49.
Found: C, 57.44; H, 5.05; N, 4.50.
Example 22 Part D
Following the procedure of Example 1, Part Di but 15 substituting the second intermediate, 4-(2,4-dichloro-phenyl)-4-cyanocyclohexanone (prepared in Part C, above) for the 19.49 gm. of the 4-(p chlorophenyl)-4-cyanocyclo-hexanone and modifying other factors of the prDcedure as noted in Table D, there is prepared the corresponding 20 third intermediate, 4-(2,4-dichlorophenyl)-4-cyanocyclo-hexanone, ethylene ketal as crystals having a melting range at 109.5 to 112.0 C.
Analysis:
Calc'd. for ClsHlsCl2N02 25C, 57.71; H, 4.84; N, 4.49 Found: C, 57.70, H, 4.81; N, 4.71.

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Follo~ing the procedure of Example l, Part E, but substituting the third intermediate, 4-(p-bromophenyl)-4-cyanocyclohexanone, ethylene ketal, (prepared in Part D, above) for the 21.87 gm. of the 4-(p-chlorophenyl)-4- ~ yclohexanone, ethylene ketal and modifying other factors of the procedure as noted in Table E, there is prepared the corresponding fourth intermediate, 4-(p-bromo-phenyl)-4-carboxycyclohexanone, ethylene ketal as crystals having a melting range at 176 to 178 C.
Analysis:
Calc'd. for C,5H,7BrO4:
C, 52.80; H, 5.02.
Found: C, 53.40; H, 4.92.
Example 20 Part E
Following the procedure of Example l, Part E, but substituting the third intermediate, 4-(m-chlorophenyl)-4-cyanocyclohexanone, ethylene ketal, (prepared in Part D, above) for the 21.87 gm. of the 4-(p-chlorophenyl)-4-cyanocyciohexanone, ethylene ketal and modifying other ,actors of the procedure as noted in Table E, there is prepared thé corresponding fourth intermediate, 4-carboxy-4-(m-chlorophenyl)cyclohexanone, ethylene ketal as crystals having a melting point at 140 to 141.5 C.
Analysis:
Calc'd. for Cl 5 H,7Cl04:
C, 60.71; H, 5.78.
Found: C, 60.51; H, 5.78.
_ample 21 Part E
Following the procedure of Example 1, Part E, but

-8~-~ 3286 substituting the third intermediate, 4-(3,4-dichloro-phenyl)-4-cyanocyclohexanone, ethylene ketal (prepared in Part D, aboYe) for the 21.87 gm. of the 4-tP-chloro-phenyl)-4-cyanocyclohexanone, ethylene ketal and modifying 5 other factors of the procedure as noted in Table E, there is prepared the corresponding fourth intermediate, 4-car-boxy-4-(3,4-dichlorophenyl)cyclohexanone, ethylene ketal as crystals having a melting range at 119 to 121.5 C.
Analysis:
Calc'd. for C~sH~ 6Cl 24 C, 54.39; H, 4.87.
Found: C, 54.69; H, 5.11.
Example 22 Part D
Following the procedure of Example 1, Part E, but substituting the third intermediate, 4-(2,4-dichloro-phenyl)-4-cyanocyclohexanone, ethylene ketal (prepared in Part D, above) for the 21.87 gm. of the 4-(p-chloro-phenyl)-4-cyanocyclohexanone, ethylene ketal and modifying other factors of the procedure as noted in Table E, there is prepared the corresponding fourth intermediate, 4-car-boxy-4-(2,4-dichlorophenyl)cyclohexanone, ethylene ketal as crystals having a melting range at 192 to 195.5 C.
Analysis:
Calc'd. for Cl sHl 6Cl 24 C, 54.39; H, 4.87.
Found: C, 54.63; H, 5.03.

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--~ 6 Example 19 Part F
Following the procedure of Example 1, Part F, but substituting the fourth intermediate, 4-(p-bromophenyl)-4-carboxycyclohexanone, ethylene ketal, (prepared in Part E, above) for the 15.79 gm. of the 4-carboxy-4-(p-chlorophenyl)cyclohexanone, ethylene ketal and modifying other factors of the procedure as noted in Table F, there is prepared the corresponding fifth intermed;ate, 4-(p-bromophenyl)-4-isocyanatocyclohexanone, ethylene ketal as crystals having a melting range at 87 to 89 C.
Analysis:
Calc'd. for Cl5H,6BrN0 3 C, 53.27; H, 4.77; N, 4.14.
Found: C, 53.43; H, 4.89, N, 4.02.
15 Example 20 Part F
- Following the procedure of Example 1, Part F, but substituting the foruth intermediate, 4-carboxy-4-(m-chlorophenyl)cyclohexanone, ethylene ketal (prepared in Part E, above) for the 15.79 gm. of the 4-carboxy-4-(p-20 chlorophenyl)cyclohexanone, ethylene ketal and modifying other factors of the procedure as noted ;n Table F, there is prepared the corresponding fifth intermediate, 4-(m-chlorophenyl)-4-isocyanatocyclohexanone, ethylene ketal as a gum having an I.R-. maximum at about 2290 cm.~'.
25 Example 21 Part F
Following the procedure of Example 1, Part F, but substituting the fourth intermediate, 4-carboxy-4-(3,4-dichlorophenyl)cyclohexanone, ethylene ketal (prepared in Part E, above) for the 15,79 gm. of the 4-carboxy-30 4-(p-chlorophenyl)cyclohexanone, ethylene ketal and modify-3~3 !

ing other factors of the procedure as noted in Table F,there is prepared the corresponding fifth intermediate, 4-(3,4-dichlorophenyl)-4-isocyanatocyclohexanone, ethylene ketal as an oil having an I.R. maximum at about 2250 cm.-'.
5 Example 22 Part F
Following the procedure of Example 1, Part F, but substituting the fourth ;ntermediate, 4-carboxy-4-(2,4-dichlorophenyl)cyclohexanone, ethylene ketal ~prepared in Part E, above) for the 15.79 gm. of the 4-carboxy-10 4-(p-chlorophenyl)cyclohexanone, ethylene ketal and modi-fying other factors of the procedure as noted in Table F, there is prepared the corresponding fifth intermediate, 4-(2,4-dichlorophenyl)-4-isocyanatocyclohexanone, ethylene ketal as crystals having a melting range at 85 to 89.5 C.
Analysis:
Calc'd. for ClsHl5Cl2N03:
C, 54.89; H, 4.61; N, 4.27.
Found: C, 55.02; H, 4.61; N~ 4.36.

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Example 19 Part G
Following the procedure of Example 1, Part G, hut substituting the fifth intermecliate, 4-(p-bromophenyl)-4-isocyanatocyclohexanone, ethylene ketal (prepared in Part F, above) for the 6~62 gm. of the 4-(p-chlorophenyl)-4-iso-cyanatocyclohexanone, ethylene ketal, modifying other factors of the procedure as noted in Table G, and includ-ing the additional step of dissolving the resid~e from the filtrate into a small amount of diethyl ether and treating this solution with sufficient 3 N hydrogen chloride in ether to form the hydrochloride acid addition salt, there is prepared the corresponding sixth inter-mediate, 4-(p-bromophenyl)-4-methylaminocyclohexanone, ethylene ketal hydrochloride as crystals having a melting point at 266 to 267 C.
- Analysis:
Calc'd. for Cl sH2 1 BrCl NO2:
C, 48.99; H, 5.76; N, 3.81.
Found: C, 48.59; H, 5.46; N, 3.63.
Example 20 Part G
Following the procedure of Example 1, Part G, but substituting the fifth intermediate, 4-(2,4-dichloro-phenyl)-4-isocyanatocyclohexanone, ethylene ketal (pre-pared in Part F, above) for the 6.62 gm. of the 4-(p- ;-chlorophenyl)-4-isocyanatocyclohexanone, ethylene ketal, modifying other factors of the procedure as noted in Table G, and including the additional step of dissolving the residue from the filtrate into a small amount of diethyl ether and treating this solution with sufficient 3 N
hydrogen chloride in ether to form the hydrochloride acid ~..;.'S~

addition salt, there is preparecl the corresponding sixth intermediate, 4-(m~chlorophenyl)-4-methylaminocyclohexa-none, ethylene ketal hydrochloride as crystals having a melting range at 252 to 254 C.
Analysis;
Calc'd~ for C,5H21C12N02:
C, 56.61; H, 6.65, N, 4,40~
Found: C, 56~74; H, 6~68; N, 4.64.
Example 21 - Part G
Following the procedure of Example 1, Part G, but substituting the fifth intermediate, 4-(3,4-dichloro-phenyl)-4-isocyanatocyclohexanone, ethylene ketal (prepared in Part G, above) for the 6.62 gm. of the 4-(p-chloro-phenyl)-4-isocyanatocyclohexanone, ethylene ketal, modify-ing other factors of the procedure as noted in Table G, and including the additional step of dissolving the residue from the filtrate into a small amount of diethyl ether and treating this solution with sufficient 3 N hydrogen chloride in ether to form the hydrochloride acid addition salt, there is prepared the corresponding sixth inter-mediate, 4-(3,4-dichlorophenyl)-4-methylaminocyclohexanone, ethylene ketal hydrochloride as crystals having a melting range at 225 to 227 C.
Analysis:
Calc`d. for ClsH2ocl3No2 C, 51.08; H, 5.72; N, 3.97.
Found: C, 51.49; H, 5.91; N, 4.20.
Example 22 Part G
Follo~ing the procedure of Example 1, Part G, but substituting the fifth intermediate, 4-(2,4-dichlorophenyl)-5~

4-isocyanatocyclohexanone, ethylene ketal (prepared in Part F, above) for the 6.62 gm. of the 4-(p-chlorophenyl)-4-isocyanatocyclohexanone, ethylene ketal, modifying other factors of the procedure as noted in Table G, and including the additional step of dissolving the residue from the filtrate into a small amount of diethyl ether and treating this solution with sufficient 3 N hydrogen chloride in ether to form the hydrochloride acid addition salt, there is prepared the corresponding sixth inter-mediate, 4-(2,4-dichlorophenyl)-4-methylaminocyclohexanone, ethylene ketal hydrochloride as crystals having a melting range at 201 to 2.305 C.
- Analysis: -Calc'd. for Cl5H2ocl3No2-lt3H2o ! 15 C, 50.22; H, 5.62; N, 3.91.
Found: C, 50.42; H, 5.92; N, 3.80.

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Following the procedure of Example 1, Part H, but substituting the free base from the sixth intermediate, 4-(p-bromophenyl)~4-methylaminocyclohexanone, ethylene ketal hydrochloride, (prepared in Part G, above) for the 4.68 gm. of the 4-(p-chlorophenyl)-4-methylaminocyclohex-anone, ethylene ketal free base, and modifying other factors of the procedure as noted in Table H, there is prepared the corresponsing object compaund, 4-(p-bromo-phenyl)-4-dimethylaminocyclohexanone, ethylene ketal hydrochloride as crystals having a melting point at 254 to 255.5 C.
Analysis:
Calc'd.for C, 6 H2 3 BrClN02:
C, 51.01; H, 6.14; N, 3.72.
Found: C, 51.29; H, 6.30; N, 3.85.
Example 20 Part H ;
Foliowing the procedure of Example 1, Part H, but substituting the free base from the sixth intermediate, 4-(m-chlorophenyl)-4-methylaminocyclohexanone, ethylene ketal hydrochloride, (prepared in Part G, above) for the 5.68 gm. of the 4-(p-ch1Orophenyl)-4-methylaminocyclohex-anone, ethylene ketal free base and modifying other factors of the procedure as noted in table H, there is prepared the corresponding object compound, 4-(m-chloro-phenyl)-4-dimethylaminocyclohexanone, ethylene ketal hydrochloride as crystals having a melting range at 224 to 227 C.
Analysis:
Calc'd. for Cl~H2 3Cl 2N02:

~,r ~

C, 57.83; H, 6.98; N, 4.22.
Found: C~ 57.71; H, 7.03i N, 4.31.
Example ?l Part H
Following the procedure of Example 1, Part H, but substituting the free base from the sixth intermediate, 4-(3,4-dichlorophenyl)-4-methylaminocyclohexanone, ethylene ketal hydrochloirde (prepared in Part G, above) for the 5.68 gm. of the 4-(p-chlorophenyl)-4-methylamino-cyclohexanone, ethylene ketal free base and modifying other factors of the procedure as noted in Table H, there is prepared the corresponding object compound, 4-(3,4-di-chlorophenyl)-4-dimethylaminocyclohexanone, ethylene ketal as crystals having a melting range at 77 to 81 C.
Analysis:
Calc`d. for C~6H2~C12N02:
C, 58.19; H, 6.41; N, 4.24.
; Found: C, 58.30; H, 6.38; Ni 4.48.
Example 22 Part H
Following the procedure of Example 1, Part H, but substituting the free base from the sixth intermediate, : 4-(2,4-dichlorophenyl)-4-methylaminocyclohexaone, ethylene ketal hydrochloride, (prepared in Part G, above) for the 5.68 gm. of the 4-(p-chlorophenyl)-4-methylamlnocyclohex-anone, ethylene ketal free base and modifying other factors of the procedure as noted in Table H, there is prepared the corresponding object compound, 4-(2,4-dichlorophenyl)-4-dimethylaminocyclohexanone, ethylene ketal hydrochloride as crystals haYing a melting range at 229.5 to 232 C.
Analysis:
Calc'd. for Cl6H22C13N02 ~H20:

5~3~

C, 5l.l4; H, 6.l7; N, 3.73.
Found: C, 5l.47; H, 6.28; N, 3.99.

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sa~ oo oa) a.) aJ a .3 ~~ 3 ~ 8 Example 23 Following the procedure as described in Example 2, but separately substituting the object compaund, 4-(p-bromo-phenyl)-4-dimethylaminocyclohexanone, ethylene ketal hydro-chloride (prepared in Example 19, Part H, above) for the 4.S2 gm. of the 4-tp-chlorophenyl)-4-dimethylaminocyclo-hexanone, ethylene ketal hydroch1Oride and modifying other factors of the procedure as noted in Table J, there is prepared the corresponding further object compound, lo 4-(p-bromophenyl)-4-dimethylaminocyclohexanone as crystals having a melting range at 115 to 118 C.
Analysis:
Calc'd. for C, 4 Hl 8 BrN0:
C, 56.76; H, 6.12; N, 4.73.
Found: C, 56.79; H, 6.14; N, 4.91.
E-xample 24 Following the procedure as described in Example 2, but substituting the object compound, 4-(m-chlorophenyl)-4-di-methylaminocyclohexanone, ethylene ketal hydrochloride (prepared in Example 20, Part H, above) for the 4.52 gm.
o; the 4-(p-chlorophenyl)-4-dimethylaminocyclohexanone, ethylene ketal hydrochloride and modifying other factors of the procedure as noted in Table J, there is prepared the corresponding further object compound, 4-(m-chloro-phenyl)-4-dimethylaminocyclohexanone, as crystals having a melting range at 93 to 95 C.
Analysis:
Calc'd. for Cl4Hl~ClN0:
C, 66.79; H, 7.21; N, 5.59.
Found: C, 67.35, H, 7.33; N, 5.87.

Example 25 Following the procedure as described in Example 2, but substituting the ob~ect compound, 4-(3,4-dichloro-phenyl)-4-dimethylaminocyclohexanone, ethylene ketal hydro-chloride (prepared in Example 21, Part H, above) for the 4.52 gm. of the 4-(p-chlorophenyl)-4-dimethylaminocyclo-hexanone, ethylene ketal hydrochloride and modifying other factors of the procedure as noted in Table J, there is prepared the corresponding further object compound, 4-(3,4-dichlorophenyl)-4-dimethylaminocyclohexanone as crystals having a melting range at 88.5 to 91 C.
Analysis:
Calc'd. for C,4H~7Cl2N0:
C, 5B.75; H, 5.99; N, 4.99.
15Found: C, 59.02; H, 6.14; N, 5.22.
Example 26 Following the procedure as described in Example 2, but substituting the object compound, 4-(2,4-dichloro-phenyl)-4-dimethylaminocyclohexanone, ethylene ketal hydro-chloride (prepared in Example 22, Part H, above) for the4.52 gm. of the 4-(p-chlorophenyl)-4-dlmethylaminocyclo-hexanone, ethylene ketal hydrochloride and modifying other factors of the procedure as noted in Table J, there is prepared the corresponding further object compound, 4-(2,4-dichlorophenyl)-4-dimethylaminocyclohexanone, as crystals having a melting range at 116.5 to 120 C.
Analysis:
Calc`d. for C,4HI7Cl2NO:
C, 58.75; H, 5.99; N, 4.90.
30Found: C, 58.84; H, 6.25; N, 4.87.

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Example 27 Preparation of 4-dimethylamino-4 (2-thienyl)-cyclohexanone, ethylene ketal Part A Preparation of Dimethyl 4-(2-thienyl)-4-cyanopimelate A mixture of 5.0 9. (0.406 mole) of 2-thiophene acetonitrile and 19 ml. of methyl acrylate in 20 ml. t-butyl alcohol is brought to reflux. The heat is removed and there is added quickly 6.5 ml. of 40% methanolic Triton B~ in 9 ml. t-butyl alcohol. Following 4 hours heating at reflux the mixture is allowed to cool and diluted with water and benzene~ The organic layer is separated, washed in turn with 2.5 N hydrochloric acid, water and brine and taken to dryness. The residue is distilled first at 40 mm Hg to remove low-boiling by-products, then at 0.05 mm Hg to afford the product as an oil. There is obtained 7.70 9. (73%) of pimelate, boiling point 162-180 C.
Part B Preparation of 4-(2-thienyl)-4-cyano-2-carbo-methoxycyclohexanone To a solution of 8.80 9. (0.0298 mole) of dimethyl-4-(2-thienyl)-4-cyanopimelate (prepared in Part A, above) in 200 ml. THF there is added 6.70 9. (0.06 mole) of potassium tert-butoxide. Following 4.5 hours' heating at reflux the mixture is cooled in ice and treated with 47 ml.
2.5 N acetic acid. The organic layer is separated and diluted with benzene. That solution is washed in turn with aqueous sodium bicarbonate (NaHC03), water and brine and taken to dryness. There is obtained 8.0 9. (99%) of 4-(2-thienyl)~4-cyano-2-carbomethoxycyclohexanone as a crystalline material, m.p. 76-78 C.
Analysis:

32~6 5~B

Calc'd. for C,3H,3N03S:
C, 59.30; H, 4.98; N9 5.32.
Found: C, 59.16; H, 5.13; N, 5.19.
Part C Preparation of 4-(2-thienyl)-4-cyanocyclo-hexanone A mixture of 8.0 9. (0.0304 mole) of 4-(2-thienyl)-4-cyano-2-carbomethoxycyclohexanone in 200 ml. acetic acid and 100 ml. 10% aqueous sulfuric acid is heated on the steam bath with mechanical stirring for 24 hours. The mix-ture is then allowed to cool, diluted ~ith water and extracted thoroughly with benzene. The organ;c layer is washed in turn with water, aqueous sodium bicarbonate and brine and taken to dryness. The residual so~id is recrys-tallized from methylene chloride:Skellysolve B to afford 4.10 9. (66% yield) of 4-(2-thienyl)-4-cyanocyclohexanone, m.p. 117.5-119 C.
Analysis:
- Calc'd. for CllH1lNOS:
C, 64.36; H, 5.40; N~ 6.82.
Found: C, 64.75; H, 5.49; N, 6.85.
Part D Preparation of 4-(2-thienyl)-4-cyanocyclohex-anone, ethylene ketal A mixture of 4.0 9. (0.0195 mole) of 4-(2-thienyl)-4-cyanocyclohexanone, 1.2 ml. (1.32 9. 9 0.02 mole) ethylene glycol and 0.05 9. p-toluenesulfonic acid in 35 ml. benzene - is heated at reflux under a Dean-Stark trap for 6 hours.
The solution is then allowed to cool 9 washed in turn with aqueous sodium bicarbonate~ water and brine and taken to dryness. The residual solid is recrystallized from benzene to give 4.38 9. (90% y1eld) of 4-(2-thienyl)-4-cyanocyclo-~ . .

,. , , ... ~ ... . .

~1~3~ 3286 hexar,one, ethylene ketal, m.p. 90.5-92 C.
Analysis:
Calc'd. for Cl3HIsNO2S:
C, 62.62; H, 6.06i N, 5.62.
5Found: C, 62.47; H, 5.99; N, 5.71.
Part E Preparation of 4-carboxy-4-(2-thienyl)cyclo-hexanone, ethylene ketal A mixture of 4.98 9. (0.02 mole) of 4-cyano-4-(2-thi-enyl)cyclohexanone ethylene ketal and 0.70 9. (0.02 mole) of sodium hydroxide in 40 ml. ethylene glycol ;s heated overnight at reflux. The mixture is allowed to cool and ~ diluted with water. The solution is then cooled'in ice, ;~ covered with ether and cautiously acidified. The organic layer is separated and the aqueous layer is washed twice more with ether. The extracts are combined, washed once with brine and taken to dryness. The residual solid is recrystallized from methylene chloride:Skellysolve B to afford 4.64 9. (82% yield) of 4-carboxy-4-(2-thienyl)cyclo-hexanone, ethylene ketal, m.p. 125-127 C.
- 20 Analysis:
Calc'd. for Cl3Hl604S:
C, 58.19; H, 6.01.
~ound: C, 58.38; H, 5.93.
Part F Preparation of 4-isocyanato-4~(2-thienyl)cyclo-hexanone, ethylene ketal To a mixture of 4.64 g. (0.017 mole) of 4-carboxy-4-(2-th-ienyl)cyclohexanone ethylene ketal and 2.4 ml. (1.75 9., 0.017 mole) triethylamine in 60 ml. anisole there is added 4.68 9. diphenylphosphonic azide. The mixture is then stirred in an oil bath at 90-100 C. for 2 hours; the solvent ~ 3~ 3286 is removed under oil pump vacuum. The residual gum is chromatographed on 400 ml. silica gel (elution with 5%
ethyl acetate:Skellysolve B). The appropriate fractions are combined to give 1.28 9. (28%) of crude isocyanate as a mobile oil; (rnfrared absorption: vmax 2280 cm ~
Part G Preparation of 4-methylamino-4-(2-thienyl)-cyclohexanone, ethylene ketal hydrochloride A solution of 2.21 9. (8.3 mmole) of 4-isocyanato-4-(2-thienyl)cyclohexanone ethylene ketal in 40 ml. tetra-hydrofuran (THF) is added to a suspension of 0.32 g.
(8.4 mmole) of lithium aluminum hydride (LAH) in 5 ml. THF.
Following 4 hours' stirring under reflux the mixture is cooled in ice. There is then added in turn 0.32 ml. water, 0.32 ml. 15~0 NaOH and 0.96 ml. water. The inorganic gel is collected on a filter and the filtrate taken to dryness.
A solution of the residue in a small amount of ether is treated with a just-sufficient amount of 3 N hydrogen chloride in ether. The precipitated salt is recrystallized from methylene chloride:ethyl acetate to afford 0.84 9.
(35% yield) of 4-methylamino-4-(2-thienyl)cyclohexanone, ethylene ketal hydrochloride, m.p. 211-214 C.
Analysis:
Calc'd. for C,3H20ClNO2S:
C, 53.87; H, 6.96; N, 4.83.
Found: C, 53.47; H, 6.81; N, 5.04.
Part H Preparation of object compound, 4-dimethyl-amino-4-(2-thienyl)cyclohexanone, ethylene ketal A solution of the free base from 0.84 9. (2.9 mmole) of 4-methylamino-4-(2 thienyl)cyclohexanone ethylene ketal hydrochloride and 2.2 ml. 37% formalin in 6.6 ml. methanol is heated at reflux for 4 hours. ~he mixture is cooled in ice and treated cautiously in sma11 portion with 0.27 9.
(7.1 mmole) sodium borohydride. Following 2 hours' stirr-ing at room temperature the bulk of the solvent is removedin vacuum. The residue is taken up in methylene chloride and water. The organic layer is washed with water and brine and taken to dryness. The residue is recycled twice through the same reaction conditions and workup. The solid ~ 10 which is finally obtained is recrystallized twice from ;~ ether (cooling in Dry-Ice:acetone) to afford 0.14 9.
~` (18% yield) of 4-dimethylamino-4-(2-thienyl)cyclohexanone, ethylene ketal, m.p. 99-103 C.
Analysis:
Calc'd. for C,4H21NO2S:
- C, 62.88; H, 7.92; N, 5.24.
Found: C, 62.75; H, 8.21; N, 5.49.
Example 28 Preparation of 4-dimethylamino-4-(2-thienyl)-cyclohexanone Following the procedure of Example 2, but substituting the appropriate quantity of 4-dimethylamino-4-(2-thienyl)-cyclohexanone ethylene ketal (prepared above in Example 27H) for the 4-(p-chlorophenyl)-4-dimethylaminocyclohex-anone, ethylene ketal hydrochloride there is prepared (after recrystallization from methanol-water) the title compound in 64~ yield, m.p. 102-103 C.
Analysis:
Calc'd. for Cl2H,7NOS:
C, 64.53; H, 7.67; N, 6.27.
Found: C, 64.41; H, 7.76; N, 5.94.

~'5~38 Example 29 Alternate preparation of 4-methylamino-4-(2-thienyl)cyclohexanone ethylene ketal hydro-chloride Part A Preparation of precursor, 4-(2-thienyl)-4-ethoxycarbonylaminocyclohexanone ethylene ketal To a solution of 2.68 9. (0.010 mole) of 4-carboxy-4-(2-thienyl)cyclohexanone ethylene ketal and 1.39 ml.
~ triethylamine in 40 ml. ethanol there is added 2.75 9.
;; 10 diphenylphosphonic azide. Following 5 hours' heating at reflux the bulk of the solvent is removed in vacuum. The residue is dissolved in water and ether:benzene. The organic layer is washed in turn with water, ice cold 2.5 N
hydrochloric acid, water, saturated sodium bicarbonate and brine and taken to dryness. The residual solid is recrys-tallized from cyclohexane to give 1.58 g. (51% yield) of 4-(2-thienyl)-4-ethoxycarbonylaminocyclohexanone ethylene ketal, m.p. 113-117 C.
Analysis:
Calc'd. for ClsH2lN04S:
C, 57.85; H, 6.80; N, 4.50.
Found: C, 57.50; H, 6.79, N, 4.55.
Part B Preparation of 4-methylamino-4-(2-thienyl)-cyclohexanone ethylene ketal hydrochloride To a suspension of 2.0 9. of lithium aluminum hydride in 50 ml. of THF (tetrahydrofuran) is added a solution of 11.58 9. (.037 mole) of 4-(2-thienyl)-4-ethoxycarbonylamino-cyclohexanone ethylene ketal (prepared in Part A, above) in 150 ml. of THF. The reaction mixture is heated at reflux temperature for 5 hours, and then is cooled. To 5~3~ 3 86 this cooled reaction mixture are added, in order, 2 ml.
H20, 2 ml. 15% NaOH, and 6 ml. H20. The inorganic gel which accumulates is filtered off and the filtrate is taken to dryness. The residue is dissolved in ether and a just-sufficient volume of 2.5 N HCl in ether is added to givethe title compound. Recrystallization is effected from methylene chloride-ethyl acetate to give 7.25 9. of the 4-methylamino-4-(2-thienyl)cyclohexanone ethylene ketal hydrochloride, m.p. 212-214 C. 0 Example 30 Preparation of 4-(p-t-butylphenyl)-4-dimethyl-aminocyclohexanone Part A 4-p-t-butylphenyl-4-isocyanatocyclohexanone ethylene ketal Following the procedure of Example 1, Parts A-F, but initially substituting p-t-butylphenylacetonitrile (pre-pared as in the "Preparation" above) for p-chlorophenyl-acetonitrile, and substituting appropriate guantities of each appropriate corresponding intermediate subsequently in each step, there is obtained a 71% yield of 4-p-t-butylphenyl-4-isocyanatocyclohexanone ethylene ketal, on elution from a silica gel column with a 2:1 mixture of ethyl acetate in methylene chloride, and recrystallization from Skellysolve B, m.p. 103-105.5 C.
Analysis:
Calc'd. for ClgH25NO3:
C, 72.35; H, 7.99; N, 4.44.
Found: C, 72.66; H, 8.03; N, 4.50.
Part B Preparation of 4-(p-_-butylphenyl)-4-methyl-aminocyclohexanone ethylene ketal Follo~ing the procedure of Example 1, Part G, but substituting an appropriate quantity of 4-(p-t-butyl-phenyl)-4-isocyanatocyclohexanone ethylene ketal for 4-p-chlorophenyl-4-isocyanatocyclohexanone there is obtained 4-tp-t-butylphenyl)-4-methylaminocyclohexanone ethylene ketal which as a m.p. 118.5-121 C. (94% yield).
Analysis:
Calc'd. for ClgH2gN02:
C? 75.20i H, 9.63; N, 4.62.
Found: C, 75.32; H, 9.92; N, 4.15.
Part C Preparation of 4-(p-t-butylphenyl)-4-dimethyl-aminocyclohexanone ethylene ketal Following the procedure of Example 1, Part H, but substituting 4-methylamino-4-(p-t-butylphenyl)cyclohexa-none ethylene ketal (Part B, above) for 4-(p-chlorophenyl)-4-methylaminocyclohexanone ethylene ketal there is obtained 4-(p-t-butylphenyl)-4-dimethylaminocyclohexanone ethylene ketal in 90% yield, m.p. 103.5-107 C.
Analysis:
Calc'd. for C20H3,N02:
C, 75.66; H, 9.84; N, 4.41.
Found: C, 75.49; H, 9.73; N, 4.68.
Part D Preparation of 4-(p-t-butylphenyl)-4-dimethyl-aminocyclohexanone Following the procedure of Example 2, but substitut-ing 4-(p-t-butylphenyl)-4-dimethylaminocyclohexanone ethylene ketal (Part C, above) for 4-(p-chlorophenyl)-4-dimethylaminocyclohexanone ethylene ketal hydrochloride there is obtained a 60% yield of the 4-(p-t-butylphenyl)-4-dimethylaminocyclohexanone after recrystallization from petroleum ether, m.p. 82.5-87 C.

~ 35~'`3~

Analysis:
Calc'd. for Cl8H27N0:
C, 79.07; H, 9.96; N, 5.12.
Found: C, 78.85i H, 10.05, N, 4.85.
Example 31 Preparation of 4-(m-tolyl)-4-dimethylamino-cyclohexanone Part A Preparation of 4-(m-tolyl)-4-isocyanatocyclo-hexanone ethylene ketal Following the procedure of Example 15, parts A-F, but initially substituting m-tolylacetonitrile for o-tolyl-acetonitrile and subsequently substituting each inter-mediate appropriately and in appropriate quantities, there is obtained a 90% yield of 4-(m-tolyl)-4-isocyanatocyclo-hexanone ethylene ketal as an oil. ~Infrared absorption v at 225~-2270 cm~l) eluted from a silica gel column with methylene chloride instead nf 2% ethyl acetate in methylene chloride.
Part B Preparation of 4-(m-tolyl)-4-methylamino-cyclohexanone ethylene ketal hydrochloride Following the procedure of Example 15, Part G, but substituting 4-isocyanato-4-(m-tolyl)cyclohexanone ethylene ketal for 4-isocyanato-4-(o-tolyl)cyclohexanone ethylene ketal there is obtained a 58% yield of 4-(m-tolyl)-4-methyl-aminocyclohexanone ethylene ketal hydrochloride, m.p.
219-221 C.
Analysis:
Calc'd. for Cl6H2 4Cl N02:
C, 64.52; H, 8.12; N, 4.70.
Found: C, 64.35; H, 8.18; N, 4.93.
P_~t C Preparation of 4-(m-tolyl)-4-dimethylamino-cyclohexanone ethylene ketal hydroiodide Following the procedure of Example 15, Part H, but substituting 4-(m-tolyl)-4-methylaminocyclohexanone ethylene ketal hydrochloride for 4-(o-tolyl)-4-methylamino-5 cyclohexanone ethylene ketal hydrochloride there is ob-tained an 85% yield of 4-(m-tolyl)-4-dimethylaminocyclo-hexanone ethylene ketal hydro;odide, m.p. 214-215.5 C.
Analysis:
Calc'd. for Cl7H26IN02:
C, 50.62; H, 6.50; N, 3.47.
Found: C, 50.60; H, 6.58; N, 3.59.
Part D Preparation of the object compound 4-(m-tolyl)-4-dimethylaminocyclohexanone hydro-iodide salt Following the procedure of Example 16, but substitut-ing 4-(m-tolyl)-4-dimethylaminocyclohexanone ethylene ketal hydroiodide for the 4-(o-tolyl)-4-dimethylamino-cyclohexanone ethylene ketal hydroiodide there is obtained the 4-(m-tolyl)-4-dimethylaminocyclohexanone hydroiodide salt in 75% yield after recrystallization from methylene chloride:ethyl acetate; m.p. 172-174.5 C.
Analysis:
Calc'd. for ClsH22IN0:
C, 50.15; H, 6.17; N, 3.90.
Found: C, 49.91; H, 6.22; N, 4.14.
Example 32 Preparation of 4-amino-4-phenylcyclohexanone, ethylene ketal hydrochloride A reaction mixture consisting of 21.9 gm. ~0.085 mole) 4-isocyanato-4-phenylcyclohexanone ethylene ketal (pre-pared as in Example 17, Part G), 10.9 gm. sodium hydroxide, ' 5~;33B

and 210 ml. ethylene glycol is heated at the ref1ux temperature for sixty-six (66) hours. A solution results which is cooled in an ice-water bath. A small amount of ice is added to the solution followed by 23 ml. of concen-trated hydrochloric acid which is added dropwise withstirring. After five minutes, the acidified solution is made strongly basic by adding 50% aqueous sodium hydroxide.
The basic solution is diluted with 800 ml. water. The strongly basic, dilute aqueous solution is then extracted four times with 200 ml. portions of diethyl ether. The extracts are combined and washed with water and with brine, before removing the ether by evaporation under reduced pressure. The residue thus obtained is dissolved in 50 ml.
of diethyl ether and the oily solution is treated with an equivalent of 3 N hydrogen chloride in diethyl ether. A
precipitate forms which is collected on a filter and re-crystallized from a mixture of methylene chloride and ethyl acetate. There is thus obtained 15.2 gm. (52% yield) of 4-amino-4-phenylcyclohexanone, ethylene ketal hydro-Z0 chloride which has a melting point at 226 to 228 C.
(with decomposition). A second crop of crystals weighs 1.60 gm. and has a ~elting range from 222 to 226 C. An analytical sample has a melting point at 248 to 249 C.
Analysis:
Calc'd. for C14H20ClN02:
C, 62.33; H, 7.47; N, 5.19.
Found: C, 61.93; H, 7.58; N, 5.53.
Example 33 Preparation of 4-(N-allyl-N-methylamino)-4-phenylcyclohexanone, ethylene ketal hydro-chloride ~5~3i~
A reaction mixture consisting of the free base from 2.46 gm. (0.0087 mole) of 4-methylamino-4-phenylcyclo-hexanone ethylene ketal hydrochloride (prepared in Example 17, Part G9 above), 1.05 gm. (0.75 ml.) allyl bromide, 1.28 gm. potassium carbonate, 10.0 ml. dimethylformamide, and 40.0 ml. benzene is heated at the reflux temperature, with stirring, for eighteen (18) hours. After cooling, this mixture is washed with water and then with brine before the volatile solvents are removed by evaporation under reduced pressure. The residue thus obtained is dissolved in diethyl ether and 0.6 N hydrogen chloride in diethyl ether is added in order to form the hydrochlo-ride salt. The hydrochloride thus formed, precipitates and is collected on a filter. The filter cake is recrys-tallized from a mixture of methylene chloride and ethyl acetate and there is thus obtained 1.82 gm. (65% yield) of 4-(N-allyl-N-methylamino)-4-phenylcyclohexanone, ethylene ketal hydrochloride having a melting range from 163 to Analysis:
Calc'd. for Cl8H26ClN02:
C, 64.94; H, 8.17; N, 4.21.
Found: C, 65.33; H, 7.93, N, 4.03.
Example 34 Preparation of 4-(N-allyl-N-methylamino)-4-phenylcyclohexanone hydroiodide A reaction solution consisting of 1.82 gm. (0.0058 mole) of 4-(N-allyl-N-methylamino)-4-phenylcyclohexanone, ethylene ketal hydrochloride (prepared in Example 33, abcYe), 8.0 ml. of 2.5 N hydrochloric acid and 16.0 ml.
methanol is set aside in a stoppered reaction vessel at S~3~

25 C. for sixty-six (66) hours. After removing most of the solvent by evaporation under reduced pressure, the concentrate thus obtained is extracted with methylene chloride. The methylene chloride solution is washed first with saturated aqueous sodium bicarbonate, then with water, and finally with 10% hydroiodic acid. The methylene chloride solvent is then removed by evaporation, and the residue obtained is recrystallized two times from a mix-ture of methylene chloride and ethyl acetate. There is thus obtained 0.88 gm. (42% yield) of 4-(N-allyl-N-methyl-amino)-4-phenylcyclohexanone hydroiodide having a melting point at 182 to 183 C.
Analysis Calc'd. for C,6H22IN0:
C, 51.76; H, 5.97; N, 3:77.
Found: C, 51.73; H, 5.96; N, 3.84.
Example 35 Preparation of 4-[~(ethoxycarbonyl)methyl]-methylamino]-4-phenylcyclohexanone, ethylene ketal, p-toluenesulfonate A reaction mixture consisting of 8.77 gm. (0.031 mole) of 4-methylamino-4-phenylcyclohexanone, ethylene ketal hydrochloride (prepared as in Example 17, Part G, above), 5.16 gm. (3.42 ml.) ethyl bromoacetate, 4.29 gm. potassium carbonate, and 120 ml. dimethylformamide is heated in an oil bath to 100 C. and then held at that temperature with stirring for eighteen (18) hours. After removing the solvent medium by evaporation under reduced pressure, the residue obtained is dissolved in a mixture of 25 ml. water and 150 ml. benzene. The benzene layer is allowed to separate from the water and is recovered. It is washed 3?3~3 with water and then with brine. The benzene is then re-moved by evaporation under reduced pressure. The residue thus obtained is dissolved in diethyl ether and to the ether solution is added 5.9 gm. p-toluenesulfonic acid dissolved in the minimum possible amount of diethyl ether.
A gummy precipitate forms which is recrystallized two times from a mixture of methylene chloride and ethyl acetate.
There is thus obtained 10.0 gm. (63% yield) of 4-[[(ethoxy-carbonyl)methyljmethylamino]-4-phenylcyclohexanone, ethylene ketal, p-toluenesulfonate having a melting range from 108 to 115 C. An analytical sample melts from 115 to 117 C.
Analysis:
Calc'd. for C26H3sN08S:
C, 59.86i H, 6.76; N, 2.68.
Found: C, 60.90, H, 7.16; N, 2.58.
Example 36 Preparation of 4-[(2-hydroxyethyl)methyl-amino]-4-phenylcyclohexanone, ethylene ketal hydrochloride A solution consisting of 4.52 gm. (0.0136 mole) of 4-~[(ethoxycarbonyl)methyl]methylamino]-4-phenylcyclohex-anone, ethylene ketal, p-toluenesulfonate (prepared in Example 35, above), and 100 ml. tetrahydrofuran is added to a suspension of 0.52 gm. lithium aluminum hydride in 10 ml. tetrahydrofuran. This reaction is heated at the reaction mixture is heated at the reflux temperature for four (4) hours, after which heating it is allowed to cool and then chilled in an ice bath. To the chilled solution is added 0.52 ml. water followed by 0.52 ml. of 15% aqueous sodium hydroxide, and finally followed by another 1.56 ml.

3~

water. A gel fo~ms and the gelatinous liquid is poured through a filter. The filtrate is collected and the liquids removed by evaporation under reduced pressure. The residue thus obtained is chromatographed on a 400 ml.
column of silica gel and the chromatogram is developed by elution with a 3% solution of methanol in methylene chlo-ride which has been saturated with ammonia. The fractions containing the prospective product, as determined by th;n layer chromatography, are combined and the solvents re-moved by evaporation under reduced pressure. The residuethus obtained is dissolved in diethyl ether and then hydrogen chloride saturated diethyl ether is added.- A
precipitate forms which 1S collected on a filter and recrystallized from a mixture of methylene chloride and 15ethyl acetate. There is thus obtained 2.56 gm. (58% yield) of 4-[(2-hydroxyethyl)methylamino]-4-phenylcyclohexanone ethylene ketal hydrochloride having a melting range from 184 to 186 C. A second crop of crystals obtained by removing some of the solvent mixture from the mother liquors by evaporation under reduced pressure weighs 0.56 gm. and has a melting range from 176 to 182 C.
Analysis:
Calc'd. for Cl7H26ClN03:
C, 62.28; H, 7.99; N, 4.27.
25Found: C, 62.14; H, 8.21; N, 4.10.
Example 37 Preparation of 4-[(2-hydroxyethyl)methylamino]-4-phenylcyclohexanone A reaction mixture consisting of 1.50 gm. (0.0046 mole) of 4-[(2-hydroxyethyl)methylamino]-4-phenylcyclo-hexanone, ethylene ketal, hydrochloride (prepared in ~5v~3~

Example 36, above), 3 ml. of 2.5 N hydrochloric acid, and 30 ml. acetone is stirrçd at 25 C. for eighteen (18) hours. After removing most of the acetone by evaporation under reduced pressure, the concentrate thus obtained is basified with sodium bicarbonate. The basic mixture is then extracted three times with 25 ml. portions of methyl-ene chloride. The methylene chloride extracts are com-bined and the solvent is removed by evaporation under reduced pressure. The residue thus obtained is recrystal-lized two times from a mixture of acetone and technical hexane to give 0.71 gm. (62% yield) of 4-[(2-hydroxyethyl)-methylamino]-4-phenylcyclohexanone having a melting range from 139 to 141 C.
Analysis:
Calc'd. for ClsH2lN02 C, 72.84; H, 8.56; N, 5.66.
Found: C, 72.80; H, 8.68i N, 5.56.
Example 38 Preparation of 4-~ethylacetamido-4-phenylcyclo-hexanone, ethylene ketal A reaction solution consisting of the free base from 1.08 gm. (0.0038 mole) of 4-methylamino-4-phenylcyclo-hexanone, ethylene ketal hydrochloride (prepared in Example 17, Part G, above), 6.0 ml. pyridine, and 2.0 ml. acetic anhydride is set aside for eighteen (18) hours at 25 C.
and then poured into ice:water. The ice:water mixture is then extracted three times with 25 ml. portions of methylene chloride. The combined methylene chloride extracts are first washed with ice-cold 2.5 N hydrochloric acid, followed by a washing with water, and finally a washing with saturated aqueous sodium bicarbonate. The methylene ~13~

chloride is then removed by evaporation under reduced pressure, and the residue thus obtained is chromatographed on a 100 ml. column of silica gel. The chromatogram is developed with a solvent mixture consisting of 15% ethyl acetate in methylene chloride. The appropriate fractions are combined, and the solvents are removed by evaporation under reduced pressure. The residue thus obtained is recrystallized from a mixture of methylene chloride and technical hexane to give 0.57 gm. (52% yield) of 4-methyl-acetamido-4-phenylcyclohexanone, ethylene ketal having a melting point at 98 to 99.5 C.
Analysis:
Calc'd. for Cl7Hz3NO3:
C, 70.56; H, 8.01; N, 4.84.
; 15 Found: C, 70.78; H, 7.93; N, 4.98.
Example 39 Preparation of 4-Methylamino-4-phenylcyclo-hexanone hydrochloride A reaction mixture consisting of 1.0 gm. (0.0035 mole) of 4-methylamino-4-phenylcyclohexanone, ethylene ketal, hydrochloride (prepared in Example 17, Part G, above) 2.0 ml. of 2.5 N hydrochloric acid, and 20 ml. acetone is stirred continuously for eighteen (18) hours, at 25 C.
The reaction mixture is then made basic by adding solid sodium bicarbonate, and most of the solvent is removed by evaporation under reduced pressure. The concentrated material thus obtained is ectracted four times with 20 ml.
portions of methylene chloride. The extracts are combined and the methylene chloride is removed by evaporation under reduced pressure. A gummy residue is obtained that is dissolved in diethyl ether. The ether solution is treated 5~;38 with hydrogen chloride in ether. A precipitate forms which is collected on a filter and recrystallized from a mixture of methylene chloride and ethyl acetate. There is thus obtained 0.53 gm. (74% yield) of 4-methylamino-4-phenylcyclohexanone hydrochloride having a melting range from 218 to 220 C.
Analysis:
Calc'd, for C,3H,8ClN0:
C, 65.12; H, 7.56; N, 5.84.
Found: C, 64.35; H, 7.64i N, 5.85.
Example 40 Preparation of 4-(m-hydroxyphenyl)-4-(methyl-n-butylamino)cyclohexanone Part A 4-Cyano-4-(m-hydroxyphenyl)cyclohexan-1-one To an ice-cooled solution of 10.0 9. (0.044 mole) of 4-cyano-4-(m-anisyl)cyclohexan-1-one (prepared in Example 11, Part C), in 125 ml. methylene chloride there is added dropwise 13 ml. of boron tribromide. Following 4 hours stirring in the cold the mixture is poured onto ice and diluted with 50 ml. chloroform. The organic layer is washed with water, aqueous sodium bicarbonate and brine, and taken to dryness. The residual solid is recrystallized from acetone:Skellysolve B to give 7.60 9.
of 4-cyano-4-(m-hydroxyphenyl)cyclohexan-1-one, m.p.
130-133 C.
Analysis:
Calc'd. for Cl3HI3NO2:
C, 72.54; H, 6.09; N, 6.51.
Found: C, 72.50; H, 6.14; N, 6.35.
Part e 4-Cyano-4-(m-hydroxyphenyl)cyclohexan-1-one, ethylene ketal 5~;~$

A mixture of 8.80 9. (0.041 mole) of 4-cyano-4-(m-hydroxyphenyl)cyclohexan-l-one, 2.50 ml. ethylene glycol and 0.26 9. p-toluenesulfonic acid in 170 ml. benzene is heated at reflux under a Deane-Stark trap for 4 hours.
The mixture is then allowed to cool, washed with aqueous sodium bicarbonate and taken to dryness. The residual solid is recrystallized from methylene chloride:Skellysolve B to give 9.85 9. of 4-cyano-4-(m-hydroxyphenyl)cyclohex-an-l-one, ethylene ketal, m.p. 109-110.5 C.
Analysis:
Calc'd. for C,sH~7N03:
C, 69.48; H, 6.61; N, 5.32.
Found: C, 59.23; H, 6.69; N, 5.32.
Part C 4-Cyano-4-(m-benzyloxyphenyl)cyclohexan-l-one, ethylene ketal To a solution of 9.85 9. of 4-cyano-4-(m-hydroxy-phenyl)cyclohexan-l-one, ethylene ketal (prepared in Part B, above) in 40 ml. DMF and 80 ml. benzene there is added 1.85 9. of a 50% dispersion of sodium hydride in mineral oil. The mixture is stirred for 15 mins. at room temper-ature and 1 hour at reflux. Benzyl chloride (6.53 9.) is then added, the mixture heated for an additional 4 hours and allowed to cool. The reaction mixture is washed in turn with water and brine and taken to dryness. The residual solid is recrystallized from ether:petroleum ether to gi~e 11.70 9. of 4-cyano-4-(m-benzyloxyphenyl)-cyclohexan-l-one, ethylene ketal, m.p. 67-69 C.
Analysis:
Calc'd. for C22H23N03:
C, 75.62; H, 6.63; N, 4.01 ~ 3~ 3286 Found: C, 75.34; H, 6.66i N, 4.01.
Part D 4-(m-benzyloxyphenyl)cyclohexan-1-one-4-carboxylic acid, ethylene ketal A mixture of 7.00 g. (0.020 mole) of 4-cyano-4-(m-benzyloxyphenyl)cyclohexan-l-one, ethylene ketal (prepared in Part C, above) and 1.20 9. sodium hydroxide in 50 ml.
ethylene glycol is heated at reflux for 17 hours. The solution is allowed to cool, diluted to 300 ml. with water and covered with 100 ml. ether. The aqueous layer is acidified with 5 ml. concentrated hydrochloric acid and the organic layer separated. The aqueous layer is then extracted with 100 ml. portions of ether and methylene chloride. The organic layer and extracts are combined, washed with water and brine and taken to dryness. There is obtained 7.22 9. of 4-(m-benzyloxyphenyl)cyclohexan-l-one-4-carboxylic acid, ethylene ketal, m.p. 108-110.5 C. A small sample is recrystallized from ether to give the analytical sample, m.p. 118.5-120.5 C.
Analysis:
Calc'd. for C22H2405:
C, 71.72; H, 6.57.
Found: C, 71.80; H, 6.89.
Part E 4-(m-benzyloxyphenyl)-4-(methylamino)cyclo-hexan-l-one, ethylene ketal A mixture of 7.22 9. (0.020 mole) of 4-(m-benzyloxy-phenyl)cyclohexan-l-one-4-carboxylic acid, ethylene ketal, (prepared in Part D, above) 5.52 9. of diphenylphosphoryl-azide and 2.8 ml. triethylamine in 50 rnl. anisole is heated in an oil bath at 90 for 2 hours. The bulk of the solver,t is then rernoved in vacuum and the residue chromato-~S~

graphed over 600 ml. silica gel. the column is eluted with 2% ethyl acetate in methylene chloride and those fractions which contain product as determined by tlc are combined. There is obtained 4.97 9. of the intermediate isocyanate as an oil.
A solution of this oil (isocyanate) in 80 ml. THF
is added to a suspension of 0.78 9. lithium aluminum hydride in 10 ml. THF. Following 6 hours heating at re-flux the mixture is cooled in an ice bath and treated in turn with 0.7 ml. water, 0.7 ml. 15% sodium hydroxide and 2.4 ml. water. The inorganic gel is separated on a filter and the filtrate taken to dryness. The residual solid is recrystallized from petroleum ether to afford - 3.31 9. of 4-(m-ben7yloxyphenyl)-4-(methylamino)cyclo-hexan-l-one, ethylene ketal, m.p. 64-66 C.
Analysis:
Calc'd. for Cz2H27N03:
C, 74.75; H, 7.70; N, 3.96.
Found: C, 75.03; H, 7.53; N, 3.93.
20 : Part F 4-(Methyl-n-butylamino)-4-(m-benzyloxy-phenyl)cyclohexan-l-one, ethylene ketal To an ice cold solution of 3.31 9. (9.4 mmole) of 4-methylamino-4-(m-benzyloxyphenyl)cyclohexan-1-one, ethylene ketal (prepared in Part E, above) and 1.30 ml.
triethylamine in 40 ml. THF there is added dropwise 1.0 9.
(1.10 ml.) butyryl chloride. Following 6 hours' standing in the cold the bulk of the solvent is removed in vacuum.
The residual is diluted with ice-water and ether. The --~
organic layer is separated and washed in turn with water, sa~urated sodium bicarbonate and brine. The solution is ~ t~

taken to dryness to give the amide as a gum. Infrared spectrum is consistent with the structure assigned (ab-sorption at 1660 cm~I). A solution of the crude amide thus obtained in 80 ml. THF is added to a suspension of 0.50 9. lithium aluminum hydride in 10 ml. THF. Following 6 hours' heating at reflux the mixture is cooled in ice and treated in turn with 0.50 ml. water, 0.50 ml. 15%
sodium hydroxide and 1.5 ml. water. The inorganic gel is collected on a filter and the filtrate taken to dryness.
There is obtained 3.50 9. of 4-(methyl-n-butylamino)-4-(m~enzyloxyphenyl)cyclohexan-1-one, ethylene ketal as an amorphous gum which shows a single spot on thin layer chromatography (tlc).
Part G 4-(Methyl-n-butylamino)-4-(m-hydroxyphenyl)-cyclohexan-l-one, ethylene ketal hydrochlo-ride A mixture of 3.56 9. of the crude tertiary amine (prepared in Part F, above), 3.6 ml. 3 N ethereal hydrogen chloride and 1.78 9. 10% palladium on charcoal in 150 ml.
ethyl acetate is shaken in an atmosphere of hydrogen for 18 hours. The catalyst and some precipitated product are then collected on a filter. The collected solid is washed thoroughly with chloroform. The combined filtrate and washes are then taken to dryness. The residual solid is recrystallized from methylene chloride:acetone to give 2.00 9. of 4-(methyl-n-butylamino)-4-(m-hydroxyphenyl)-cyclohexan-l-one, ethylene ketal hydrochloride, m.p.
208-210 C.i m.m.p. (mixed melting point) with authentic material (prepared in Example 42) 208-210 C.
Part H Preparation ot 4-(m-hydroxyphenyl)-4-(methyl-~5~

n-butylamino)cyclohexanone Following the procedure of Example 2, but substitut-ing 4-(m-hydroxyphenyl)-4-(methyl-n-butylamino)cyclohexan-l-one, ethylene ketal hydrochloride (prepared in Part G, above) for the 4-(p-chlorophenyl)-4-dimethylaminocyclo-hexanone, ethylene ketal hydrochloride there is obtained the object compound 4-(m-hydroxyphenyl)-4-(methyl-n-butylamino)cyclohexanone. Recrystallization from ether:
petroleum ether gives an analytical sample, m.p. 89-91 C.
Analysis:
Calc'd. for Cl7H2sNO2:
C, 74.14; H, 9.15~ N, 5.08.
Found: C, 74.32; H, 9.04; N, 5.26.
Example 41 Alternative preparation for a preferred com-pound 4-(p-Chlorophenyl)-4-dimethylaminocyclo-hexanone, ethylene ketal free base and the hydrochloride thereof Part A Preparation of precursor Cyclohexane-1,4-di-one, ethylene monoketal A reaction mixture consisting of 10 gm. (0.085 mole) 4-hydroxycyclohexanone, 4.75 ml. ethylene glycol, 0.20 gm.
p toluenesulfonic acid, and 100 ml. benzene is heated at the reflux temperature in a reaction vessel fitted with a Dean and Stark trap for 2 hours. After the reaction mix-ture has cooled, it is washed first with water and then with brine. The benzene is then removed by evaporation under reduced pressure giving the intermediate 4-hydroxy-cyclohexanone ethylene monoketal as a viscous oil weighing 14.12 gm. The 4-hydroxycyclohexanone ethylene monoketal is dissolve~ in 100 ml. methylene chloride and added with ~ 3286 stirring to a suspension consisting of 55.0 gm. chromium trioxide (predried for 24 hours under reduced pressure over phosphorous pentoxide), one liter dry methylene chloride, and 52.8 gm. 3,5-dimethylpyrazole. After con-tinued stirring for ten (10) min. this dark reaction mix-ture is poured onto a two liter column of silica gel.
When the reaction mixture has been completely adsorbed, the chromatogram is developed with a 1:1 mixture of ethyl acetate and technical hexane (Skellysolve B - a mixture of isomeric hexanes having a boiling range between 60 and 70 C.). The appropriate fractions as determined by TLC are collected and combined, after which the solvents are removed by evaporation under reduced pressure. The crystals thus obtained are recrystallized from technical lS hexane, and there is thus obtained 10.82 gm. (91% yield) of the desired cyclohexane - l,4-dione, ethylene monoketal having a melting point at 68 to 69 C. [The literature value is 71.5 to 72.5 C.]
Part B Preparation of first intermediate 4-Cyano-4-dimethylaminocyclohexanone,-ethylene ketal A reaction mixture consisting of 3.0 gm. (0.019 mole) of the cyclohexane-1,4-dione, ethylene monoketal prepared in Part A, above, 3.0 gm. potassium cyanide, 4.5 gm. di-methylamine hydrochloride, 3.0 ml. methanol, and 25 ml.
saturated aqueous dimethylamine is stirred at 25 C. for 48 hours. The reaction mixture is then extracted succes-sively with Five 40 ml.-portions of diethyl ether. The ether extracts are combined and the ether is removed by evaporation under reduced pressure. The residue thus ~1~5~3~3 obtained is dissolved in methylene chloride. Some small amount of water present is separated, and the organic sol vent portion is conserved for removal of the methylene chloride by evaporation under reduced pressure. The residual solid thus obtained is recrystallized from technical hex-ane to give 3.6 gm. (78% yield) of the desired intermediate 4-cyano-4-dimethylaminocyclohexanone ethylene ketal having a melting point at 79 to 81 C.
Analysis: Calc'd~ for CllHl7N 2 2 10C, 62.83, H, 8.63; N, 13.33.
Found: C, 62.92, H, 8.66; N, 13.58.
Part C Preparation of object compound, 4-(p-Chloro-phenyl)-4-dimethylaminocyclohexanone, ethylene ketal hydrochloride 15To a Grignard reagent prepared from 2.73 gm. of p-chloro-bromobenzene, 0.35 gm. magnesium and 30 ml. tetrahydrofuran tTHF), is added 1.50 9. (0.071 mole) of 4-cyano-4-dimethyl-aminocyclohexanone ethylene ketal (prepared in Part B) in 40 ml. of THF. The reaction mixture is heated for three (3) days at the refiux temperature. It is then cooled, chilled in an ice bath and 20 ml. saturated ammonium chloride in ben- ---zene added. The organic phase is separated. It is washed initially with water and then with brine. Finally, the sol-vents are removed by evaporation under reduced pressure. The residue thus obtained is dissolved in diethyl ether and 4 N
ethereal hydrogen chloride is added until precipitation is complete. The salt thus obtained is collected on a filter as a gummy material. It is suspended in methylene chloride and one N aqueous sodium hydroxide is added. The organic layer is separated and the methylene chloride is removed by 32~6 ~ ;5~3~

evaporation under reduced pressure. The residue thus obtained is added onto a 200 ml. column of silica gel, the chromatogram is developed with methylene chloride containing 4% methanol and 20-ml. fractions are collected.
The solvent is removed by evaporation under reduced pres-sure and the residue is dissolved in diethyl ether. the ether solution is treated with 4 N ethereal hydrogen chlo-ride until precipitation vf the desired 4-(p-chlorophenyl)-4-dimethylaminocyclohexanone ethylene ketal hydrochloride is complete. The precipitate is collected on a filter and crystallized from a mixture of methylene chloride and ethyl acetate to give 0.80 gm. (34% yield) of pure 4-(p-chlorophenyl)-4-dimethylaminocyclohexanone ethylene ketal hydrochloride having a melting point at 252 to 254 C.
Example 42 Alternative preparation for a preferred com-pound 4-(m-hydroxyphenyl)-4-(methyl-n-butyl-amino)cyclohexanone, ethylene ketal hydrochlo-rlde Part A 4-(methyl-n-butylamino)-4-cyanocyclohexan-l-one, ethylene ketal A mixture of 2.05 9. (15 mmole) of 1,4-cyclohexane-dione ethylene monoketal (prepared as in Example 41, Part A), 2.05 g. potassium cyanide, 5.40 9. methyl-n-butylamine, in 8 ml. water and 12 ml. 2.5 N hydrochloric acid is stirred at room temperature for 5 days. The mixture is then extracted thoroughly with 5 portions, of 40 ml. each, methylene chloride. The extracts are combined and taken to dryness. To a solution of the residual gum in 50 ml.
ether there is added sufficient 3 N ethereal hydrogen chloride to precipitate all the basic material. That ~S~3~

precipitate is recrystallized from methylene chloride:
ethyl acetate to give 2.65 9. o-f 4-(methyl-n-butylamino)-4-cyanocyclohexan-1-one, ethylene ketal (hydrochloride salt), m.p. 114-120 C.
Analysis:
Calc'd. for Cl4H~sClN202-1~H~0 C, 53.23; H, 4.93; N, 8.87.
Found: C, 53.62; H, 8.67; N, 8.71.
A suspension of the salt in 50 ml. of methylene chlo-ride is shaken with 40 ml. 1 N sodium hydroxide. The organic layer is separated and taken to dryness to give 2.49 g. of the 4-(methyl-n-butylamino)-4-cyanocyclohexan-l-one, ethylene ketal as an oil.
Part B 4-(methyl-n-butylamino)-4-(m-hydroxyphenyl)-cyclohexan-l-one, ethylene ketal hydrochlo-ride To the Grignard reagent prepared from the tetrahydro-pyranyl ether of 4.80 g. of m-bromophenol, 0.81 g. mag-nesium and 60 ml. THF there is added a solution of 2.49

9. 4-(methyl-n-butylamino)-4-cyanocyclohexan-1-one, ethylene ketal (prepared in Part A, above) in 25 ml. THF.
Following 24 hours' heating at reflux the mixture is cooled in an ice bath and treated with 25 ml. each satur-ated aqueous ammonium chloride and benzene. The organic layer is washed with water and brine and taken to dryness.
The residue is dissolved in 25 ml. ether and treated with just sufficient 3 N ethereal hydrogen chloride to pre-cipitate the basic material. This gum is dissolved in 40 ml. water. Following 5 mins. standing at room temper-ature the solution is neutralized with solid sodium bicar-~5~

bonate. The mlxture is then extracted with 3 portions (40 ml. each) of ~ethylene chloride. The extracts are then taken to dryness. The residual gum is chro~atographed on a 1" x 48" column of tlc grade silica gel (elution with 7.5% methanol in chloroform). Those fractions which contain product (as determined by tlc analysis) are combined and taken to dryness. The residual gum is con-verted to the hydrochloride salt and this is recrystallized from methylene chloride:acetone. There is obtained 152 mg. of 4-(methyl-n-butylamino)-4-(m-hydroxyphenyl)cyclo-hexan-l-one, ethylene ketal hydrochloride, m.p. 206-208 C.
Analysis:
Calc'd. for C, gH3 oCl NO3:
C, 64.11; H, 8.51; N, 3.94.
Found: C, 64.46; H, 8.44; N, 3.75.
Example 43 Preparation of 4-(m-hydroxyphenyl)-4-dimethyl-aminocyclohexanone, ethylene ketal A reaction solution consisting of 5.0 gm. (0.029 mole) m-bromophenol, 5.0 gm. dihydropyran, 0.30 gm. p-toluene-sulfonic acid, and 80 ml. anhydrous diethyl ether isstirred at 25 C. for four (4) hours. The mixture is washed successively with 25 m~. portions of 1 N aqueous sodium hydroxide, with water, and with brine. The thus washed organic layer is taken to dryness by removing the solvent by evaporation under reduced pressure. There is thus obtained 7.42 gm. of m-(tetrahydropyranyl-2-oxy)-bromobenzene which is converted to the corresponding Grignard reagent by dissolving in 60 ml. of tetrahydro-furan and adding the solution to 0.70 gm. magnesium. To this Grignard is added 1.50 gm. (0.0071 mole) of 4-cyano-r~3 4-dimethylaminocyclohexanone ethylene ketal (prepared in Example 41, Part B, above) dissolved in 30 ml. tetrahydro-furan. This reaction mixture is heated at the reflux temperature for 22 hours. After cooling, the mixture is treated with 10 ml. saturated ammonium chloride in benzene.
The organic solvent portion is initially washed with water and then with brine. The organic solvent is then removed by evaporation under reduced pressure. The residue thus ob-tained is dissolved in diethyl ether and treated with 4 N
ethereal hydrogen chloride until precipitation of the hydro-chloride salt is complete. The salt is collected on a fil-ter and then suspended in 25 ml. water containing 1 ml.
2.5 N hydrochloric acid. The acidified mixture is stirred at 25 C. for one hour, when sodium bicarbonate (solid) is added until the pH is 8. This slightly basic mixture is extracted thoroughly with diethyl ether. The ether extracts are combined and the ether removed be evaporation under reduced pressure. The residue thus obtained is transferred to a column of the grade silica gel 1" in cross section by 48" in length. The chromatogram is developed with a solvent medium cor.sisting of 0.5% ammonia and 7.5% methanol in chloroform, and 20-ml. fractions are collected. Those fractions which contain product (as determined by tlc anal-ysi~) are combined. The solvent is removed by evaporation under reduced pressure to give 0.96 gm. (48% yield) of crude 4-(m-hydroxyphenyl)-4-dimethylaminocyclohexanone, ethylene ketal having a melting point at 169 to 175 C. An analyt-ical sample is obtained by recrystallization from a mixture of ethyl acetate and cyclohexane. The melting point is 175 to 177 C.

Analysis:
Calc'd. for Cl6H~3N03:
C, 69.28; H, 8.36i N, 5.05.
Found: C, 69.08; H, 8.13; N, 5.02.
Example 44 Preparation of 4-(m-hydroxyphenyl)-4-dimethyl-aminocyclohexanone A reaction mixture consisting of 1.92 gm. (0.0069 mole) of 4-(m-hydroxyphenyl)-4-dimethylaminocyclohexanone, ethylene ketal (prepared in Example 43, above), 15 ml. 2.5 N hydro-chloric acid, and 30 ml. methanol is stirred continuouslyfor three (3) days (72 hours). The bulk of the solvent is then removed by evaporation under reduced pressure, and solid sodium bicarbonate is added until the pH is brought to 8. This basic mixture is then extracted with six 20 ml.
portions of chloroform. The extracts are combined and the chloroform removed by evaporation under reduced pressure.
The residue thus obtained is recrystallized from a mixture of acetone and technical hexane to give 0.48 gm. (30%
yield) of 4-(m-hydroxyphenyl)-4-dimethylaminocyclohexanone having a melting point at 127 to 130 C.
Analys~s:
Calc'd. for C,4HIgNO2:
C, 72.07; H, 8.21; N, 6.01.
Found: C, 72.02; H, 8.13; N, 5.87.
2~ Example 45 Part A
Following the procedure of Example 40, Part F, but separately substituting acetyl chloride, 2,2-dimethylpro-pionyl chloride, cyclohexanecarbonyl chloride, cyclopentane-carbonyl chloride and 2-cyclopentylacetyl chloride for f~ 5~

n-butyryl chloride there are prepared the corresponding:
4-(m-benzyloxyphenyl)-4-(ethylmethylamino)cyclohex-anone ethylene ketal, 4-(m-benzyloxyphenyl)-4-(pivalylmethylamino)cyclo-hexanone ethylene ketal, 4-(m-benzyloxyphenyl)-4-(N-cyclohexylmethyl-N-methyl-amino)cyclohexanone ethylene ketal, and 4-(m-benzyloxyphenyl)-4-(N-cyclopentylmethyl-N-methyl-amino)cyclohexanone ethylene ketal, respectively.
Part B
Following the procedure of Example 40, Part G, but substituting the compounds obtained in Part A (above) for 4-(methyl-n-butylamino)-4-(m-benzyloxyphenyl)cyclohexanone ethylene ketal there are obtained 4-(m-hydroxyphenyl)-4-(ethylmethylamino)cyclohexanone ethylene ketal hydrochloride, . 4-(m-hydroxyphenyl)-4-(pivalylmethylamino)cyclohexa-none ethylene ketal hydrochloride, 4-(m-hydroxyphenyl)-4-(N-cyclohexylmethyl-N-methyl-amino)cyclohexanone ethylene ketal hydrochloride, and 4-(m-hydroxyphenyl)-4-(N-cyclopentylmethyl-N-methyl-amino)cyclohexanone ethylene ketal hydrochloride, respect-ively.
Part C
Following the procedure of Example 44 but substituting the compounds prepared in Part B (above) for the 4-(m-hydroxyphenyl)-4-(dimethylamino)cyclohexanone ethylene ketal there are prepared the object compounds 4-(m-hydroxyphenyl)-4-(ethylmethylamino)cyclohexanone, 4-(m--hydroxyphenyl)-4-(pivalylmethylamino)cyclohexa-~ ~ S~ 3 none, 4-(m-hydroxyphenyl)-4-(N-cyclohexylmethyl-N-methyl-amino)cyclohexanone, and 4-(m-hydroxyphenyl(-4-(N-cyclopentylmethyl-N-methyl-amino)cyclohexanone, respectively.
Example 46 Preparation of 4-(p-hydroxyphenyl)-4-(methyl-n-butylamino)cyclohexanone Part A
Following the procedure of Example 40, Parts A-E, but initially substituting 4-p-anisyl-4-cyanocyclohexanone (prepared in Exampie 7, Part C) for the 4-m-anisyl-4-cyano-cyclohexanone and subsequently substituting the appropriate intermediates in appropriate quantities there is obtained 4-methylamino-4-(p-benzyloxyphenyl)cyclohexanone ethylene . 15 ketal.
- Part B
Following the procedure of Example 40, Part F, but substituting the appropriate quantity of 4-(p-benzyloxy-phenyl)-4-methylaminocyclohexanone ethylene ketal for 4-(m-benzyloxyphenyl)-4-methylaminocyclohexanone ethylene ketal there is obtained 4-(n-butylmethylamino)-4-(p-benzyl-oxyphenyl)cyclohexanone ethylene ketal.
Part C
Fvllowing the procedure of Example 40, Part G, but 2i substituting 4-(p-benzyloxyphenyl)-4-(n-butylmethylamino)-cyclohexanone ethylene ketal (prepared in Part B, above) for 4-(m-benzyloxyphenyl)-4-(n-butylmethylamino)cyclohex-anone ethylene ketal there is obtained 4-(p-hydroxyphenyl)-4-(n-butylmethylamino)cyclohexanone ethylene ketal hydro-chloride.

S~J~

Part D
Following the procedure of Example 44, but substitut-ing 4-(p-hydroxyphenyl)-4-(n-butylmethylamino)cyclohexanone ethylene ketal hydrochloride (prepared in Part C, above) for the 4-(m-hydroxyphenyl)-4-dimethylaminocyclohexanone, ethylene ketal there is obtained 4-(p-hydroxyphenyl)-4-(n-butylmethylamino)cyclohexanone.
Example 47 ~
Part A
Follo~ing the procedure of Example 42, Part A, but substituting an appropriate quantity of diethylamine for n-butylmethylamine there is obtained 4-cyano-4-diethylamino-cyclohexanone ethylene ketal.
Part B
Following the procedure of Example 42, Part B, but substituting the appropriate quantities of the compound prepared above in Part A for 4-(methyl-n-butylamino)-4-cyanocyclohexanone, ethylene ketal, and of the tetrahydro-pyranyl ether of p-bromophenol for the corresponding ether of m-bromophenol, there is obtained 4-(p-hydroxyphenyl)-4-diet.hylaminocyclohexanone ethylene ketal hydrochloride.
Part C
Following the procedure of Example 44, but substituting an appropriate quantity of the compound prepared above (Part B) for 4-(m-hydroxyphenyl)-4-dimethylaminocyclohexanone ethylene ketal there is obtained 4-(p-hydroxyphenyl)-4-di-ethylaminocyclohexanone.
Exampl_e 48 Following the procedure of Example 1, Part A; Example 3, Part A; and Example 17, Part A, but separately substituting ~S1~33 (2-bromo-5-methoxyphenyl)acetonitrile, (3-bromo-4-phenethyl)acetonitrile, (5-bromo-4-anisyl)acetonitrile, [5-bromo-3-(n-propoxy)phenyl]acetonitrile, (3-chloro-4-fluorophenyl)acetonitrile, (3-chloro-6-methoxyphenyl)acetonitrile, (2,6-dichlorophenyl)acetonitrile, (3,5-diisopropylphenyl)acetonitrile, (4,5-dimethoxyphenyl)acetonitrile, (o-ethylphenyl)acetonitrile, for (p-chlorophenyl)- r acetonitrile, there are prepared the corresponding:
dimethyldiester of 4-(2-bromo-5-methoxyphenyl)-4-cyano-pimelic acid, ~ 4-(3-bromo-4-phenethyl)-4-cyanopimelic acid, `~ 15 4-(5-bromo-4-anisyl)-4-cyanopimelic acid, 4-(5-bromo-3-n-propoxyphenyl)-4-cyanopimelic acid, 4-(3-chloro-4-fluorophenyl)-4-cyanopimelic acid, 4-(3-chloro-6-methoxyphenyl)-4-cyanopimelic acid, 4-(2,6-dichlorophenyl)-4-cyanopimel;c acid, 4-(3,5-diisopropylphenyl)-4-cyanopimelic acid, 4-(4,5-dimethoxyphenyl)-4-cyanopimelic acid, 4-(o-ethylphenyl)-4-cyanopimelic acid, respectively.
Example 49 _ Following the procedure of Examples 1, 4, and 17, Parts B, C, D, E, F, G, and H, but substituting as indicated a ~riori the intermediates prepared in Example 48, above, and those intermediates thus sequentially prepared, there are prepared finally the corresponding:
4-(2-bromo-5-methoxyphenyl)-4-dimethylaminocyclohex-3n anone, ethylene ketal free base and the HCl salt thereof, 32~6 ~5,C~3~3 4-(3-bromo-4-phenethyl)-4-dimethy1aminocyclohexanone, ethylene ketal free base and the HCl salt thereof, 4-(5-bromo-4-anisyl)-4-dimethylaminocyclohexanone, ethylene ketal free base and the HCl salt thereof, 4-(5-bromo-3-n-propoxyphenyl)-4-dimethylaminocyclo-hexanone, ethylene ketal free base and the HCl salt thereof, 4-(3-chloro-4-fluorophenyl)-4-dimethylaminocyclohex-anone ethylene ketal free base and the HCl salt thereof, 4-(3-chloro-6-methoxyphenyl)-4-dimethylaminocyclo-hexanone ethylene ketal free base and the HCl salt thereof, 4-(2,6-dichlorophenyl)-4-dimethylaminocyclohexanone, :
ethylene ketal free base and the HCl salt thereof, 4-(3,5-diisopropylphenyl)-4-dimethylaminocyclohexanone, ethylene ketal free base and the HCl salt thereof, 4-(4,5-dimethoxyphenyl)-4-dimethylaminocyclohexanone, ethylene ketal free base and the HCl salt thereof, : 4-(o-ethylphenyl)-4-dimethylaminocyclohexanone, ethylene ketal free base and the HCl salt thereof, Example 50 Part A
Following the procedure of Example 41, Part A, but separately substituting trimethylene glycol (1,3-propane-diol), 2,2-dimethyl-1,3-propanediol [prepared as described in ~. Amer. Chem. Soc. 70, 946 (1948)], 2-phenyl-1,3-propane-diol, 2-allyl-1,3-propanediol, for the ethylene glycol, there are prepared the corresponding precursors:
cyclohexane-1,4-dione, trimethylene monoketal, cyclohexane-1,4-dione, (2,2-dimethyltrimethylene)mono-ketal, cyclohexane-1,4-dione, (2-phenyltrimethylene)monoketal, 5~B

cyclohexane,-1,4-dione, (2-allyltrimethylene)mono-ketal, respectively.
Part B
Following the procedure of Example 41, Part B, but substituting cyclohexane-1,4-dione, trimethylene monoketal, cyclohexane-1,4-dione, (2,2-dimethyltrimethylene)monoketal, cyclohexane-1,4-dione, (2-phenyltrimethylene)monoketal, and cyclohexane-1,4-dione, (2-allyltrimethylene)monoketal for the cyclohexane-1,4-dione, ethylene monoketal, there are prepared the corresponding intermediates:
4-cyano-4-dimethylaminocyclohexanone, trimethylene ketal, 4-cyano-4-dimethylaminocyclohexanone, (2,2-dimethyl-trimethylene) ketal, 4-cyano-4-dimethylaminocyclohexanone, (2-phenyltri-. methylene) ketal, and 4-cyano-4-dimethylaminocyclohexanone, (2-allyltri-methylene) ketal respectively. -:
Part C
Following the procedure of Example 41, Part C? but separately substituting each intermediate prepared in Part B, above 'or the 4-cyano-4-dimethylaminocyclohexanone, ethylene ketal, there are prepared the corresponding object compounds:
4-(p-chlorophenyl)-4-dimethylaminocyclohexanone, tri-methylene ketal hydrochloride, 4-(p-chlorophenyl)-4-dimethylaminocyclohexanone, (2,2-dimethyltrimethylene) ketal hydrochloride, 4-(p-chlorophenyl)-4-dimethylaminocyclohexanone, (2-phenyltrimethylene) ketal hydrochloride, 5~3~3 and 4-(chlorophenyl)-4-dimethylaminocyclohexanone, .
(2-allyltrirnethylene) ketal hydrochloride, respectively.
Example 51 Part A
Following the procedure of Example 42, Part A, but separately substituting each intermediate prepared in Example 50, Part A, for the cyclohexane-1,4-dione ethylene monoketal there are prepared the corresponding intermed;ates:
4-cyano-4-n-butylmethylaminocyclohexanone, trimethylene ketal, 4-cyano-4-n-butylmethylaminocyclohexanone, (2,2-di-methyltrimethylene) ketal, 4-cyano-4-n-butylmethylaminocyclohexanone, (2-phenyl-trimethylene) ketal, and 4-cyano-4-n-butylmethylaminocyclohexanone, (2-allyl-trimethylene) ketal, respectively.
Part B
Following the procedure of Example 42, Part B, but separately substitut;ng each intermediate prepared in Part A (above) for 4-cyano-4-(methyl-n-butylamino)cyclohexanone, ethylene ketal, there are prepared the corresponding object compounds:
4-(m-hydroxyphenyl)-4-n-butylmethylaminocyclohexanone, trimethylene ketal hydrochloride, 4-(m-hydroxyphenyl)-4-n-butylmethylaminocyclohexanone, (2,2-dimethyltrimethylene) ketal hydrochloride, 4-(m-hydroxyphenyl)-4-n-butylmethylaminocyclohexanone, (2-phenyltrimethylene) ketal hydrochloride, and 4-(rn-hydroxyphenyl)-4-n-butylmethylaminocyclohexanone, (2-allyltrimethylene) ketal hydrochloricle, respectively.

~!5~

Example 52 Following the procedure of Example 42, Part A, but sep-arately substituting diethylamine, di-n-propylamine, N-allyl-N-ethylamine, di-n-butylamine, n.butylethylamine, and N-methyl-N-cyclopropylamine, for n-butylmethylamine, there are prepared the corresponding intermediates:
4-cyano-4-diethylaminocyclohexanone, ethylene ketal, 4-cyano-4-di-n-propylaminocyclohexanone, ethylene ketal, 4-cyano-4-(N-allyl-N-ethylamino)cyclohexanone, ethylene ketal, 4-cyano-4-di-n-butylaminocyclohexanone, ethylene ketal, 4-cyano-4-(n-butylethylamino)cyclohexanone, ethylene ketal, and 4-cyano-4-(N-methyl-N-cyclopropylamino)cyclohexanone, ethylene ketal, respectively.
Example 53 Following the procedure of Example 42, Part B, but separately substituting each intermediate prepared as in Example 52, for the 4-cyano-4-n-butylmethylaminocyclohex-anone, ethylene ketal, there are prepared the corresponding object compounds:
~-~m-hydroxyphenyl)-4-diethylaminocyclohexanone, ethylene ketal hydrochloride, 4-(m-hydroxy?henyl)-4-di.n-propylaminocyclohexanone, ethylene ketal hydrochloride, 4-(m-hydroxyphenyl)-4-(N-allyl-N-ethylamino)cyclo-hexanone, ethylene ketal hydrochloride, 4-(m;hydroxyphenyl)-4-di-n-butylaminocyclohexanone, B0 ethylel7e ketal hydrochloride, 5~~3 :

4-(m-hydroxyphenyl)-4-(n-butylethylamino)cyclohexanone, ethylene ketal hydrochloride, and 4-(m-hydroxyphenyl)-4-(N-methyl-N-cyclopropylamino)-cyclohexanone, ethylene ketal hydrochloride, respectively.
Example _ Following the procedure of Example 44, but separately substituting each compound prepared in Example 53 for the 4-(m-hydroxyphenyl)-4-dimethylaminocyclohexanone, ethylene ketal, there are prepared the corresponding:
4-(m-hydroxyphenyl)-4-diethylaminocyclohexanone, 4-(m-hydroxyphenyl)-4-di-n-propylaminocyclohexanone, 4-(m-hydroxyphenyl)-4-(N-allyl-N-ethylamino)cyclo-hexanone, 4-(m-hydroxyphenyl)-4-di-n-butylaminocyclohexanone, 4-(m-hydroxyphenyl)-4-(n-butylethylamino)cyclohexanone, and 4-(m-hydroxyphenyl)-4-(N-methyl-N-cyclopropylamino)-cyclohexanone, respectively.
~xample 55 Preparation of 4-(m-trifluoromethylphenyl)-4-dimethylaminocyclohexanone ethylene ketal hydrochloride A Grignard reagent is prepared using 4.79 gm. (0.024 mole) m-trifluoromethylbromobenzene, 0.59 gm. magnesium and 50 ml. tetrahydrofuran; to this is added 1.50 gm.
(.0071 mole) 4-cyano-4-dimethylaminocyclohPxanone ethylene ketal (prepared in Example 41, Part B, dissolved in 40 ml.
tetrahydrofuran. This reaction mixture is heated at the reflux temperature for 17 hours. It is then cooled, chilled in ice, and 20 ml. saturated aqueous ammonium chloride and benzene are added. The organic solution is then separated, initially washed with water, and then washed with brine.

32~6 The solvents are then removed by evaporation under reduced pressure. The residue thus obtained is dissolved in diethyl ether, and 4 N ethereal hydrogen chloride is added until precipitation o~ the hydrochloride salt as a gum is complete.
The supernatant liquid is decanted and the remaining gum is dissolved in methylene chloride. One N aqueous sodium hydroxide is added. The organic layer is then separated and the methylene chloride is removed by evaporation under ; reduced pressure. The residue thus obtained is transferred onto a 200 ml. column o~ silica gel and the chromatogram is developed with methylene chloride containing 3% metahnol.
The appropriate fractions, as determined by TLC, are col-lected and combined. The solvent is removed by evaporation under reduced pressure, and the gummy residue thus obtained is dissolved in diethyl ether. The ether solution is treated with 4 N ethereal hydrogen chloride until precipi-tation of the hydrochloride salt is complete. The precipi-tate is collected on a filter and then recrystallized from a mixture of methylene chloride and ethyl acetate to give 0.63 gm. (24% yield) of 4-(m-trifluoromethylphenyl)-4-dimethylam,nocyclohexanone ethylene ketal hydrochloride having a melting point at 231 to 232 C.
- Analysis:
Calc'd. for C,7H23ClF3NO2:
C, 55.81; H, 6.33; N, 3.83.
Found: C, 55.63; H, 6.66; N, 3.94.
Example 56 Preparation of 4-(p-trifluoromethylphenyl)-4-dimethylaminocyclohexanone, ethylene ketal hydrochloride 3U Following substantially the same procedure as described in Example 55, but substituting 4.79 gm. (0.024 mole) p-trifluoromethylbromobenzene for the 4.79 gm. (0.024 mole) m-trifluoromethylbromobenzene, there is prepared 0.90 gm.
(34% yield) of 4-(p-trifluoromethylphenyl)-4-dimethylamino-cyclohexanone, ethylene ketal hydrochloride having a melt-ing point at 243 to 244 C.
Analysis:
Calc'd. for Cl7H23ClF3N02 ~H20:
C, 54.47; H, 6.45; N, 3.74.
Found: C, 54.56; H, 6.24; N, 4.13.
Example 57 Preparation of 4-(p-chlorophenyl)-2-methyl-4-dimethylaminocyclohexanone A solution consisting of 0.51 gm. (0.005 mole) diiso-propylamine in 10 ml. tetrahydrofuran is chilled in an ice:
methanol bath and 3 ml. of 1.68 N butyllithium in pentane is added. To this mixture is then added a solution con-sisting of 1.25 gm. (0.005 mole) 4-(p-chlorophenyl)-4-di-methylaminocyclohexanone (prepared in Example 2) in 20 ml.
tetrahydrofuran. After 5 min. stirring, 1.42 gm. methyl iodide is added. This reaction is stirred for another 30 min. in the cold, and then it is allowed to warm up to j~r.n 25 C. ~triri-~ is continued for 2~2 hours, when 20 ml.
saturated aqueous ammonium chloride is added. Benzene is also added. The organic solvents are removed by evaporation under reduced pressure. The residue thus obtained is transferred to a chromatographic column containing 200 ml.
silica gel. The chromatogram is developed with 2 liters of a mixture of 3% methanol in methylene chloride followed by 2 liters of a mixture of 5% methanol in methylene chlo-ride. The appropriate fractions as determined by TLC are -1 ~1 -5~r~

combined. The solvent is removed by evaporation under reduced pressure giving the desired 4-(p-chlorophenyl)-2-methyl-4-dimethylaminocyclohexanone. The compound is recrystallized from diethyl ether to give an analytical sample having a melting point at 110 to 111 C. This is recognized to be the cis isomer by NMR spectroscopy.
Analysis:
Calc'd. for ClsH20clNo:
C, 67.78; H, 7.59; N, 5.27.
Found: C, 67.75; H, 7.59; N, 5.56.
The corresponding trans isomer is obtained by combining the later series of fractions in the same manner. It is recrystallized from a mixture of diethyl ether and technical hexane to give 0.52 gm. of the isomer having a melting point at 103 to 105 C.
Analysis:
Calcrd. for Cl sH2 oCl NO:
C, 67.7~; H, 7.59; N, 5.27.
Found: C, 68.03; H, 7.61; N, 5.11.
Following the same procedure, but substituting, e.g., ethyl iodide, n-propyl iodide, n-butyl iodide, and n-pentyl iodide, for methyl iodide, there are prepared the correspond-ing:
4-(p-chlorophenyl)-2-ethyl-4-dimethylaminocyclohexa-none, 4-(p-chlorophenyl)-4-dimethylamino-2-n-propylcyclo-hexanone, 2-n-butyl-4-(p-chlorophenyl)-4-dimethylaminocyclo-hexanone, 4-(p-chlorophenyl)-4-dirnethylamino-2-n-pentylcyclohex-~5-~3~3 anone, respectively.
Example 58 Preparation of 2-methyl-4-dimethylamino-4-(p-tolyl)cyclohexanone A solution consisting of 1.02 gm. (0.010 mole) diiso-propylamine in 20 ml. tetrahydrofuran was chilled in an ice:methanol bath before 6 ml. of 1.68 N butyllithium in pentane is added. To this mixture is then added a solution consisting of 2.31 gm. (.010 mole) of 4-dimethylamino-4-(p-tolyl)cyclohexanone (prepared in Example 14) and 40 ml.
tetrahydrofuran. Five minutes later, 2.82 gm. methyl iodide is added, and the mixture is stirred for 45 min. in the cold.
It is allowed to warm to 25 C. and stirring is continued for 5 hours, when the reaction mixture is diluted with a mixture of water and benzene. The organic layer is separated and washed first with water and then with brine. The organic solvents are removed by evaporation under reduced pressure, and the residual waxy solid thus obtained is transferred to a column of the grade silica gel 1" by 48". The chrom-atogram is developed with a solvent medium consisting of 7.5% methanol in chloroform and 20-ml. fractions are collected.
The fractions which contain product (as determined by TLC) are combined. The solvent is removed by evaporation under reduced pressure, and the residue thus obtained is recrystal-lized from diethyl ether. There is thus obtained 1.01 gm.
(39% yield) of the object compound 2-methyl-4-dimethylamino-4-(p-tolyl)cyclohexanone having a melting point at 102 to 104.5 C. NMR suggests assignment of c~s relationship of 2-methyl to 4-N(CH3)2.
Analysis:
Calc'd. for Cl6H23N0:

~ 3286 C, 78.32; H, 9.45; N, 5.71.
Found: C, 78.03; H, 9.51; N, 5.65.
Example 59 Following the procedure oF Example 58, but separately substituting 4-(p-chlorophenyl)-4-diethylaminocyclohexanone, 4-(p-chlorophenyl)-4-dipropylaminocyclohexanone, 4-(p-chlorophenyl)-4-di-n-butylaminocyclohexanone, and 4-(p-chlorophenyl)-4-(N-methyl-N-cyclopropylamino)-cyclohexanone, for the 4-dimethylamino-4-(p-tolyl)cyclo-hexanone, there are prepared the corresponding objectcompounds:
4-(p-chlorophenyl)-4-diethylamino-2-methylcyclohex-anone, 4-(p-chlorophenyl)-4-dipropylamino-2-methylcyclohex-anone, 4-(p-chlorophenyl)-4-di-n-butylamino-2-methylcyclohex-anone, and 4-(p-chlorophenyl)-4-(N-methyl-N-cyclopropylamino)-2-methylcyclohexanone, respectively.
Example 60 Preparation of 4-(m-hydroxyphenyl)-4-n-propyl-.
methylaminocyclohexanone ethylene ketal hydro-chloride Following the procedure of Example 40, Parts F and G, but substituting the appropriate quantity of propionyl chloride for butyryl chloride, and the appropriate inter-mediate subsequently, the title compound is obtained as a crystalline solid (m.p. 204-207 C.).
Analysis:
Calc'd. for C, 8 H 2 8 0 3 NCl:
3C C, 63.23; H, 8.25; N, 4.10.

-1~4-~5~3i3 Found: C, 63.13; H, 8.42; N, 3.95.
Example 61 Preparation of 4-(m-hydroxyphenyl)-4-(methyl-n-pentylamino)cyclohexanone ethylene ketal hydrochloride Following the procedure of Example 40, Parts F and G, but substituting the appropriate quantity of valeryl chlo-ride (pentanoyl chloride) for butyryl chloride, and the appropriate intermediate subsequently, the title compound is obtained as a gum.
Analysis:
Calc'd. for C 2 oH3 2 03NCl-~H 2 C, 63.68; H, 8.78; N, 3.70.
Found: C, 63.61; H, 8.92; N, 3.50.
Example 62 Preparation of 4-(m-hydroxyphenyl)-4-(N-methyl-N-~-phenylethylamino)cyclohexanone ethylene ketal hydrochloride Following theprocedure of Example 40, Parts F and G, but substituting the appropriate quantity of phenylacetyl chloride for n-butyryl chloride, and the appropriate inter-mediate subsequently, the title compound is obtained as an amorphous solid. The NMR and mass spectra are consistent with the assigned structure.
Analysis:
Calc'd. for C2 3H3003NCl:
C, 71.20; H, 7.80; N, 3.61.
Found: C, 66.64; H, 7.47; N, 3.46.
Example 63 Preparation of 4-(m-hydroxyphenyl)-4-(i-butyl-methylamino)cyclohexanone ethylene ketal hydro-chloride Following the procedure of Example 40, Parts F and G, ~ 3~ 3286 but substituting the appropriate quantity of 2-methylpro-panoyl chloride for n-butyryl chloride, and the appropriate intermediate subsequently, the title compound is obtained as a crystalline solid (m.p. 203-204 C.).
Analysis:
Calc'd. for ClgH3003NCl:
C, 64.12; H, 8.57; N, 3.94.
Found: C, 64.14; H, 8.66; N, 4.30.
Exarnple 64 Preparation of 4-(m-hydroxyphenyl)-4-(N-methyl-N-cyclopropylmethylamino)cyclohexanone ethylene ketal hydrochloride Following the procedure of Example 40, Parts F and G, but substituting the appropriate quantity of cyclopropane-carbonyl chloride for n-butyryl chloride, and the appropriate intermediate subsequently, the title compound is obtained as a crystalline solid (m.p. 214-215 C.).
Analysis:
Calc'd. for ClgH2aO3NCl:
C, 64.48; H, 7.97; N, 3.96.
Found: C, 64.21; H,~8.08; N, 3.86.
Exanlple 65 Part A 4-(m-benzyloxyphenyl)-4-(N-methyl-N-ethylamino)-cyclohexanone ethylene ketal hydroiodide Following the procedure of Example 40, Part F, but substituting the appropriate quantity of acetyl chloride for n-butyryl chloride, there is obtained a material which is dissolved in methylene chloride and this solution is washed witll 20% aqueous hydrogen iodide. The solid which remains when the solution is taken to dryness is recrystallized frorn methylene chloride:ethyl acetate to give crystalline ~ al~ 3286 4-(m-benzyloxyphenyl)-4-(N-methyl-N-ethylamino)cyclohexanone ethylene ketal hydroiodide, m.p. 195-196.5 C.
Anal~sis:
Ca1c'd. for C24H32IN0:
C, 56.60; H, 6.33; N, 2.75.
Found: C, 56.53; ~I, 6.48i N, 2.93.
Part B
Hydrogenolysis of the compound prepared in Part A, over inert catalyst, gives the corresponding 4-(m-hydroxy-lG phenyl)-4-(N-methyl-N-ethylamino)cyclohexanone ethylene ketal.
- Example 66 Part A 4-(m-benzyloxyphenyl)-4-(N-methyl-N-~-phenoxy-ethylamino)cyclohexanone, ethylene ketal hydrochloride Following the procedure of Example 40, Part F but sub-stituting phenoxyacetyl chloride for n-butyryl chloride there is obtained the title compound. Recrystallization from methylene chloride-ethyl acetate gives the product, m.p. 173-174 C.
20 - Analysis:
Calc'd. for C30H34ClN04:
C, 70.92; H, 6.75; N, 2.76.
Found: C, 70.81; H, 7.08; N, 2.62.
Part B
Hydrogenolysis of the compound prepared in Part A, over inert catalyst, gives the corresponding 4-(m-hydroxyphenyl)-4-(N-methyl-N-~-phenoxyethylamino)cyclohexanone, ethylene ketal.
Example 67 4-(m-acetoxyphenyl)-4-dimethylaminocyclohexan-l-one 3~

To a solution of 0.96 g. (4.1 mmole) of 4-(m-hydroxy-phenyl)-4-dimethylaminocyclohexan-1-one (prepared in Example 44) in 20 ml. THF there is added 0.46 9. (0.63 ml.) tri-ethylamine and 0.46 9. (0.42 ml.) acetic anhydride. Follow-ing 6 hours standing at room temperature the mixture isconcentrated in vacuum and the residue diluted with ice:
water. The precipitated gum is extracted with methylene chloride. The extract is washed with saturated sodium bicarbonate and brine and taken to dryness. The residue is chromatographed over a 1" x 48" column of TLC grade silica gel. These fractions shown by TLC to contain product are collected and taken to dryness. The solid which remained is recrystallized from petroleum ether to give 0.30 g. of 4-(m-acetoxyphenyl)~4-dimethylaminocyclohexan-1-one, m.p.
1551-53 C.
- Analysis:
Calc'd. for C,6H21N03:
C, 69.79; H, 7.69; N, 5.09.
Found: C, 69.47; H, 7.89; N, 5.21.
Example 68 Following the procedure of Example 67, but substituting 4-(m-hydroxyphenyl)-4-(methyl-n-butylamino)cyclohexanone (prepared in Example 40, Part H) for 4-(m-hydroxyphenyl)-4-(dimethylamino)cyclohexanone there is obtained the desired 4-(m-acetoxyphenyl)-4-(methyl-n-butylamino)cyclohexanone as the hydrochloride.
Analysis:
Calc'd. for ClgH27N03-HCl-2/3H20:
C, 62.36; H, 8.17; N, 3.82.
3CFound: C, 62.07; H, 7.81i N, 3.80.

-1~8-3~3 Example 69 Preparation of 4-phenyl-~-(1-pyrrolidinyl)-cyclohexanone, ethylene ketal, hydrochloride A reaction mixture consisting of the free base from 2.69 gm. (0.01 mole) of 4-amino-4-phenylcyclohexanone, ethylene ketal hydrochloride (prepared in Example 32, above) 2.16 gm. of 1,4-dibromobutane, 2.76 gm. potassium carbonate, and 15.0 ml. ethanol is heated at the reflux temperature, with stirring, for eighteen (18) hours. The volatile compo-nents are then substantially removed by evaporation under reduced pressure, and the concentrate thus obtained diluted with water. A precipitate forms which is collected on a filter and dissolved in diethyl ether. The ether solution is treated with an equivalent of 3 N hydrogen chloride in diethyl ether. A precipitate that forms is collected on a filter and recrystallized from a mixture of methylene chlo-ride and ethyl acetate. ,There is thus obtained 1.57 gm.
(49% yield) of 4-phenyl-4-(1-pyrrolidinyl)cyclohexanone, ethylene ketal hydrochloride hav;ng a melting range from 238 to 239.5 C.
~ Analysis:
Calc'd. for C,aH2 6Cl N02:
C, 66.75; H, 8.09; N, 4.33.
Found: C, 66.38; H, 8.25; N, 4.30.
Example 70 Preparation of 4-phenyl-4-(1-pyrrolidinyl)cyclo-hexanone A reaction solution consisting of 1.57 gm. (0.0049 mole) 4-phenyl-4-(1-pyrrolidinyl)cyclohexanone, ethylene ketal hydrochloride (prepared in Example 69, above), 7.0 ml.
of 2.5 N hydrochloric acid, and 14.0 ml. methanol is set aside at 25 C. for sixty-six (66) hours. After cooling g5~3~3 and removing most of the liquid and volatiles by evaporation under reduced pressure, the residue is made strongly basic with 50% aqueous sodium hydroxide. A precipitate that forms is collected on a filter and then recrystallized from petroleum ether. There is thus obtained 0.77 gm. (65% yield) of 4-phenyl-4-(1-pyrrolidinyl)cyclohexanone having a melting point at 75 to 76.5 C.
Analysis:
Calc'd. for C,6H2lN0:
10C, 78.97; H, 8.70; N, 5.76.
Found: C, 79.03; H, 8.73; N, 5.75.
Example 71 Preparation of 4-phenyl-4-(1-piperidinyl)-cyclohexanone, ethylene ketal hydrochloride A reaction mixture consisting of the free base from 152.88 gm. (0.011 mole) of 4-amino-4-phenylcyclohexanone ethylene ketal hydrochloride (prepared in Example 32, above), 3.47 gm. 1,5-diiodopentane, 2.95 gm. potassium carbonate, and 25 ml. ethanol is heated at the reflux temperature, with stirring, for eighteen (18) hours. After cooling and removing most of the liquid and volatiles by evaporation under reduced pressure, the residue thus obtaihed is dis-persed in a mixture of 100 ml. of diethyl ether and 10 ml.
of water. The ether layer is allowed to separate and is recovered. It is washed with water and with brine, before removing the ether by evaporation under reduced pressure.
The residue thus obtained is dissolved in diethyl ether and an amount of 3 N hydrogen chloride in diethyl ether is added so as to form the hydrochloride acid addition salt which precipitates. The salt is collected on a filter and then recrystalli~ed from a mixture of methylene chloride and ~ 5 ~ ~ 3286 ethyl acetate. There is thus obtained 2.26 gm. (61% yield) of 4-phenyl-4~ piperidinyl)cyclohexanone, ethylene ketal hydrochloride having a melting range from 228 to 231 C.
An analytical sample has a melting point at 234 to 235.5 C.
Analysis:
Calc'd. for ClgH28ClN02:
C, 67.54; H, 8.35; N, 4.14.
Found: C, 67.24; H, 8.12; N, 3.97.
Example 72 Preparation of 4-phenyl-4-(1-piperidinyl)cyclo-hexanone A reaction solution consisting of 2.26 gm. (0.0067 -~
mole) of ~-phenyl~4-(1-piperidinyl)cyclohexanone, ethylene h~, roch/or, ~
ketal h~drochloirdc (prepared in Example 71, above), 10 ml.
,~." ~ .
of 2.5 N hydrochloric acid and 20 ml. methanol is set aside in a stoppered reaction vessel at 25 C. for four (4) days.
After removing most of the solvent by evapration under reduced pressure, the residue is made strongly basic with 50% aqueous sodlum hydroxide. A precipitate forms which is collected on a filter and recrystallized two times from a mixture of acetone and technical hexane. There is thus obtained 0.94 gm. (55% yield) of 4-phenyl-4-(1-piperidinyl)-cyclohexanone having a melting range from 114 to 117 C.
Analysis:
Calc'd. for Cl7H23N0:
C, 79.33; H, 9.01; N, 5.44.
Found: C, 79.16; H, 9.15; N, 5.31.
Example 73 Part _ Following the procedure of Example 32 but substituting the appropriate quantity of 4-isocyanato-4-(m-methoxyphenyl)-~ t~

cyclohexanone ethylene ketal (prepared in Example 11, Part F, above) for 4-phenyl-4-isocyanatocyclohexanone ethylene ketal there is obtained 4-amino-4-(m-methoxyphenyl)cyclo-hexanone, ethylene ketal hydrochloride (alternate name:
4-amino-4-(m-anisyl)cyclohexanone, ethylene ketal hydro-chloride).
Part B
Following the procedure of Example 69 but substituting the appropriate quantity of 4-amino-4-(m-methoxyphenyl)-cyclohexanone ethylene ketal hydrochloride (prpeared in PartA, above) for the 4-amino-4-phenylcyclohexanone, ethylene ketal hydrochloride there is obtained 4-(1-pyrrolidinyl)-4-(m-methoxyphenyl)cyclohexanone ethylene ketal hydrochloride.
Part C
Following the procedure of Example 70 but substituting an appropriate quantity of 4-(m-anisyl)-4-(1-pyrrolidinyl)-cyclohexanone ethylene ketal hydrochloride (prepared in Part B, above) for 4-phenyl-4-(1-pyrrolidinyl)cyclohexanone ethylene ketal hydrochloride there is obtained 4-(m-anisyl)-4-(~pyrrolidinyl)cyclohexanone.
Part D
Following the procedure of Example 40, Part A, but suhstituting an appropriate quantity of 4-(m-anisyl)-4-(1-pyrrolidinyl)cyclohexanone (prepared in Part C, above) for the 4-cyar,o-4-(m-anisyl)cyclohexanone there is obtained 4-(m-hydroxyphenyl)-4-(1-pyrrolidnyl)cyclohexanone.
Part E
Following the procedure of Example 40, Part B, but substituting an appropriate quantity of 4-(m-hydroxyphenyl)-~0 4-(1-pyrrolidinyl)cyclohexanone (prepared in Part D, above) ~,5rA3~3 for 4-cyano-4-(m-hydroxyphenyl)cyclohexanone there is ob-tained 4-(m-hydroxyphenyl)-4-(1-pyrrolidinyl)cyclohexanone, ethylene ketal.
Part F
Following the procedure of Example 67, Part A, but substituting an appropriate quantity of 4-(m-hydroxyphenyl)-4-(1-pyrrolidinyl)cyclohexanone (prepared in Part D, above) for 4-(m-hydroxyphenyl)-4-(dimethylamino)cyclohexanone there is obtained 4-(m-acetoxyphenyl)-4-(1-pyrrolidinyl)-cyclohexanone.
Example 74 Part A
Following the procedure of Example 32 but separately substituting the appropriate quantity of each of the 4-iso-cyanato intermediates prepared in Examples 1-27 (Parts F) and Example 31, Part A, for 4-isocyanato-4-phenylcyclo-hexanone ethylene ketal there is obtained, respectively, each corresponding 4-aryl-4-aminocyclohexanone, ethylene ketal hydrochloride.
Part B
Following the procedure of Example 69 but separately substituting each amino compound prepared in Part A above for 4-phenyl-4-aminocyclohexanone ethylene ketal hydrochlo-chloride and 2-methyl-1,4-dibromobutane for 1,4-dibromo-butane there is prepared, respectively, each corresponding 4-aryl-4-(3-methyl-1-pyrrolidinyl)cyclohexanone ethylene ketal hydrochloride.
Part C
Each product compound prepared in Part B, above, can be hydrolyzed to the corresponding ketone, following the ~1~5~

procedure of Example 70 but substituting an appropriate quantity of each ethylene ketal hydrochloride (Part B, above) for 4-(phenyl)-4-(1-pyrrolidinyl)cyclohexanone ethylene ketal hydrochloride.
Example 75 Part A
Following the procedure of Example 71 but separately substituting appropriate quantities of each amino compound prepared in Example 74 ? Part A, for 4-phenyl-4-aminocyclo-hexanone ethylene ketal hydrochloride, and 3-ethyl-1,5-di-iodopentane for the l,5-diiodopentane there are prepared, respectively, the corresponding 4-aryl-4-(4-ethyl-1-piper-idinyl)cyclohexanone ethylene ketal hydrochlorides.
Part B
Following the procedure of Example 72 but separately substituting an appropriate quantity of each ketal prepared in Part A, above, for 4-phenyl-4-(1-piperidinyl)cyclohex-anone, ethylene ketal hydrochloride there are obtained, respecti~ely, the corresponding 4-aryl-4-(4-ethyl-1-piper-idinyl)cyclohexanones.
Example 76 Following the procedure of Example 42, Part B, but separately substituting the appropriate quantity of each intermediate prepared in Example 50, Part B, for the 4-cyano-4-(methyl-n-butylamino)cyclohexanone ethylene ketal there are prepared the corresponding compounds:
4-(m-hydroxyphenyl)-4-dimethylaminocyclohexanone tri-methylene ketal (m.p. 147-150 C.) Analysis:
Calc'd. for Cl 7H2 sNO3: ;.

~P~35~3~ 3286 C, 70.07; H, 8.65; N, 4.81.
Found: C, 69.67; H, 8.45; N, 5.07.
4-(m-hydroxyphenyl)-4-dimethylaminocyclohexanone (2,2-dimethyltrimethylene) ketal Analysis:
Calc'd. for ClgH29N03:
C, 71.44; H, 9.15j N, 4.39.
Found: C, 70.76; H, 9.22; N, 4.57.
4-(m-hydroxyphenyl)-4-dimethylaminocyclohexanone, (2-phenyltrimethylene) ketal Analysis:
Calc'd. for C23H29N03:
C, 75.17; H, 7.95; N, 3.81.
Found: C, 74.79; H, 8.04; N, 4.09.
4-(m-hydroxyphenyl)-4-dimethylaminocyclohexanone, (2-allyltrimethylene) ketal Analysis:
Calc'd. for C20H29N03:
C, 72.47; H, 8.82; N, 4.23.
Found: C, 72.15; H, 9.01; N, 4.42.
Example 77 Part A
Following the procedure of Example 42, Part A, but substituting the appropriate quantity of allylmethylamine 2S for methyl-n butylamine, stirring at room temperature for 2 days and extracting the reaction mixture with diethyl ether there is obtained, on recrystallization from petroleum ether, crystalline product, 4-cyano-4-(N-methyl-N-allyl-amino)cyclohexanone ethylene ketal, m.p. 47-50 C. (Mass spec. m/e-~ (M ) = 236).

-15~-ll~S~38 Analysis:
Calc'd. for Cl3H20N202:
C, 66.07; H, 8.53; N, 11.86.
Found: C, 66.85; H, 8.65; N, 11.69.
Part B
- Following the procedure of Example 42, Part B, but substituting 4-cyano-4-(N-methyl-N-allylamino)cyclohexanone ethylene ketal (prepared in Part A) for 4-cyano-4-(methyl-n-buty1amino)cyclohexanone ethylene ketal, and purifying by high-pressure liquid chromatography followed by recrys-tallization there is obtained the object compound 4-(m-hydroxyphenyl)-4-(N-allyl-N-methylamino)cyclohexanone ethylene ketal.
Analysis:
Calc'd. for Cl8H2sN03-2/3H20:
C, 68.54; H, 8.40; N, 4.44.
Found: C, 68.62; H, 8.45; N, 4.32.
Example 78 Part A
Following the procedure of Example 1, Parts A-H, but initially substituting l-naphthylacetonitrile for p-chloro-phenylacetonitrile and subsequently substituting each inter-mediate appropriately there is obtained 4-(1-naphthyl)-4-dimethylaminocyclohexanone ethylene ketal, m.p. 132-135 C.
Analysis:
Calc'd. for C2~H2sNO2: -C, 77.13; H, 8.09; N, 4.50.
Found: C, 76.93; H, 8.40; N, 4.48.
Part ~
Following the procedure of Example 2 but substituting ~5~ 3286 the product from Part A for 4-(p-chlorophenyl)-4-dimethyl-aminocyclohexanone ethylene ketal hydrochloride there is obtained 4-(1-naphthyl)-4-dimethylaminocyclohexanone.
Analysis:
Calc'd. for C,8H21N0 1/4H20:
C, 79.52; H, 7.97i N, 5.15.
Found: C, 79.76; H, 8.04; N, 5.22.
Example 79 Following the procedure of Example 44, but separately substituting the appropriate quantities of the final com-pounds prepared in Examples 60 through 64 for 4-(m-hydroxy-phenyl)-4-dimethylaminocyclohexanone, ethylene ketal there are prepared 4-(m-hydroxyphenyl)-4-(n-propylmethylamino)cyclohex-anone (m.p. 116-118 C.) Analysis:
Calc'd. for C,6H23N02:
C, 73.53; H, 8.87; N, 5.36.
Found: C, 73.29; H, 8.96; N, 5.67.
4-(m-hydroxyphenyl)-4-(n-pentylmethylamino)cyclohexanone, 4-(m-hydroxyphenyl)-4-(N-~-phenylethyl-N-methylamino)-cyclohexanone, 4-(m-hydroxyphenyl)-4-(i-butylmethylamino)cyclohexanone, and 4-(m-hydroxyphenyl)-4-(N-cyclopropylmethyl-N-methyl-amino)cyclohexanone, Example 80 Following the procedure of Example 67, but substituting 4-(m-hydroxyphenyl)-4-(N-~-phenylethyl-N-methylamino)-cyclohexanone, 4-(m-hydroxyphenyl)-4-(n-propyllnethylamino)cycl~hexanone, ~'5~ 3286 4-(m-hydroxyphenyl)-4-(n-pentylmethylamino)cyclohex-anone, 4-(m-hydroxyphenyl)-4-(isobutylmethylamino)cyclohex-anone, and 4-(m-hydroxyphenyl)-4-(cyclopropylmethylmethylamino)-- cyclohexanone prepared in Example 79 (above) for 4-(m-hydroxyphenyl)-4-dimethylam;nocyclohexanone there are obtained, respectively, 4-(m-acetoxyphenyl)-4-(N-~-phenyl-ethyl-N-methylamino)cyclohexanone, 4-(m-acetoxyphenyl)-4-(N-propylmethylamino)cyclohexa-none, 4-(m-acetoxyphenyl)-4-(n-pentylmethylamino)cyclohex-anone, 4-(m-acetoxyphenyl)-4-(isobutylmethylamino)cyclohexa- :
none, and 4-(m-acetoxyphenyl)-4-(cyclopropylmethylamino)cyclo-hexanone.
Example 81 Following the procedure of Example 67 but substituting propionic anhydride and butyric anhydride for acetic anhydride there are prepared 4-(m-propionoxyphenyl)-4-dimethylaminocyclohexanone, 4-(m-n-butyroxyphenyl)-4-dimethylaminocyclohexanone.
Example 82 Following the procedure o-f Example 68 but substituting propionic anhydride and n-butyric anhydride for acetic anhydride, there are obtained 4-(m-propionoxyphenyl)-4-(methyl-n-butylamino)cyclo-hexanone, and 4-(m-n-butyroxyphenyl)-4-(methyl-n-butylamino)cyclo-hexanone, respectively.
Example 83 Preparation of 4-phenyl-4-diethylaminocyclo-hexanone hydrochloride Part A
Following the procedure for Example 47, Part B, but substituting bromobenzene for the tetrahydropyranyl ether of m-bromophenol, there is obtained 4-phenyl-4-diethylamino-cyclohexanone ethylene ketal.
Part B
Following the procedure of Example 44, but substituting an appropriate quantity of the compound prepared in Part A
(above~ for 4-(m-hydroxyphenyl)-4-dimethylaminocyclohexanone ethylene ketal, there is obtained the 4-phenyl-4-diethyl-aminocyclohexanone as the hydrochloride salt, m.p. l75-177.5 C.
Analysis:
Calc'd. for Cl6H24NOCl ~H20:
C, 66.07; H, 8.66; N, 4.81.
Found: C, 65.78; H, 8.88; N, 4.98.
Example 84 Preparation of 4-dimethylamino-4-(3-hydroxy-4-methylphenyl)cyclohexanone ethylene ketal Part A
; Following the procedure of Example 42, Part B, but substituting the appropriate quantities of 4-cyano-4-di-methylaminocyclohexanone ethylene ketal, prepared in Example 41, Part B, and of the tetrahydropyranyl ether of 3-hydroxy-4-methylbro~obenzene for the corresponding ether of m-bromo-phenol, there is ob~ained 4-(3-hydroxy-4-methylphenyl)-4-dimethylaminocyclohexanone ethylene ketal which is re-3G crysta71ized fron1 chloroform/ethyl acetate; m.p. 196-200 C.

~5~

Analysis:
Calc'd. for Cl7H2s~03-~H20;
C, 67.96; H, 8.72; N, 4.66.
Found: C, 68.28; H, 8.73; N, 4.90.
The compounds of the Formula I have analgetic activity and can be used for the relief of pain without loss of con-sciousness. The compounds can be used to treat the pain of headache, muscle spasm, arthritis and other musculoskeletal conditions, e.g., bursitis, relieve mild to moderate post-operative and postpartum pain; dysmenorrhea and pain of traumatic origin. Additionally, the compounds of Formula I can be administered for the treatment of severe pain, e.g., pain associated with adenocarcinoma, amputation of a limb, and third degree burns over a major portion of the body in animals and humans.
Additionally selected compounds of Formula I have activ-ity as narcotic antagonists. They can be used to counteract or prevent excessive central nervous system depression and respiratory depression resulting from the administration of morphine or other morphine like drugs, e.g., hydromorphone, oxymorphone, methadone and meperidine. The compounds are also ;
capable of inducing an abstinence syndrome in narcotic ad-dicted subjects, i.e., induce withdrawal effects for diagnostic purposes.
The dosage of the compound of the Formula I for analgetic purposes is from about 0.01 to about 7 mg~/kg. body weight of the patient. The compounds of the Formula I are conveniently prepared in 5,10,25,50,75,100and 200 mg. dosage units for ad-ministration for 1 to ~ times a day. Preferred unit dosages are from 0.05 to 4 mg./kg. body weight of the patient.

~$~ 3 3286 The compounds are administered orally, parenterally and rectally for systemic action.
Tlle compositions of the present invention are presented for administration to humans and animals in unit dosage forms, such as tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, and oral solu-tions or suspensions, and oil-water emulsions containing suitable quantities of a compound of Formula I or its pharmacologically acceptable salts.
Pharmaceutical dosage unit forms are prepared in accordance with the subsequerlt general specific descriptions to provide from about 0.5 mg. to about 500 mg. of the essential active ingredient per dosage unit form (pre-ferred 2.5 - 300 mg.).
Oral pharmaceutical dosage forms are either solid or li~uid. The solid dosage forms are tablets, capsules, granules, and bulk powders. Types of oral tablets are, for example, compressed (including chewable and lozenge), ; tablet triturates, enteric-coated~ sugar-coated, film-coated, and multiple compressed. Capsules are either hard or scft elastic gelatin. Granules and powders are either effervescent or non-effervescent.
Pnarmaceutically acceptable substances utilized in compressed tablets are binders, lubricants, diluents, dis-; 25 integrating agents, coloring agents, flavoring agents, flow inducing agents, and wetting agents. Tablet triturates (either molded or compressed) utilize diluents and binders.
Enteric-coated tablets, due to their enteric-coating, resist the action oF stomach acid and dissolve or disintegrate in the alkaline intestine. Sugar-coated tablets are compressed ~5~3~ 3286 tablets to which usually four different layers of pharma-ceutically acceptable substances have been applied. Film-coated tablets are compressed tablets which have been coated with a water soluble cellulose polymer. Multiple compressed tablets are compressed tablets made by more than one compression cycle utilizing the pharmaceutically accept-able substances previously mentioned. Coloring agents are utilized in the above dosage forms. Flavoring and sweeten-ing agents are utilized in compressed tablets, tablet triturates, sugar coated, multiple compressed and chewable tablets. Flavoring and sweetening agents are especially useful in the formation of chewable tablets and lozenges.
Examples of binders include glucose solution (25-50%), acacia mucilage (10-20%), gelatin solution (10-20%p sucrose and starch paste. Lubricants include, for example, talc, starch, magnesium or calcium stearate, lycopodium and stearic acid. Diluents include, for example, lactose, su-crose, starch, kaolin, salt, mannitol and dicalcium phosphate.
Disintegrating agents include, for example, corn starch, potato starch, bentonite, methylcellulose, agar and carboxy-methylcellulose. Coloring agents include, for example, any of the approved certified water soluble FD and C dyes, mixtures thereof, and water insoluble FD and C dyes suspended on alumia hydrate. Sweetening agents include, for example, sucrose, lactose, mannitol, and artificial sweetening agents such as sodium cyclamate and saccharin, and any number of spray dried flavors. Flavoring agents include natural flavors extracted from plants such as fruits and synthetic blends of compounds which produce a pleasant sensation. Flow inducing agents include, for example, silicon dioxide and ~ 5~ 3286 talc. Wetting agents include, for example, propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene laural ether. Enteric-coatings include, for example, fatty acids, fats, waxes, shellac, ammoniated shellac and cellulose acetate phthal-ates. Pharmaceutically acceptable substances for the first layer, an undercoating, of sugar-coated tablets, include, for example, dextrin and gelatin. The second layer, an opaque zone, includes, for example, starch, talc, calcium carbonate, magnesium oxide and magnesium carbonate. The third layer, a translucent zone, includes, for example, sucrose. The fourth layer, a glaze, includes, for example, beeswax, carnauba wax, or a mixture of these waxes. Film coatings include, for example, hydroxyethylcellulsoe, sodium carboxymethylcellulose, polyethylene glycol 4000 and cellu-lose acetate phthalate.
~ lard gelatin capsules, sizes 5 through 1000, are made largely from gelatin and may be either clear or colored.
These capsules may be filled with either a powder or coated pellets (sustained release).
The diluents utilized in powder filled capsules are the same as those illustrated above for tablets. Pharma-ceutically acceptable substances utilized for coatiny pellets include, for example, stearic acid, palmitic acid, glyceryl myristate, cetyl alcohol, fats, waxes, polymeric substances sensitive to small changes in pH of the gastrointestinal tract, polyvinyl alcohol, ethyl cellulose and mixtures of beeswax, carnauba wax or bayberry wax with glyceryl mono-stearate.
Soft elastic selatin capsules contain sufficient ~ S~ ~ ~ 3286 glycerin so that they are permanently flexible. Pharma-ceutically acceptable liquid diluents used in soft elastic gelatin capsules are those which do not dissolve or harm the capsule and which are non-toxic? including, for example, corn oil, cottonseel oil, polysorbate 80, DMA and triacetin.
Pharmaceutically acceptable substances utilized in non-effervescent granules, for solution and/or suspension, include diluents, wetting agents, flavoring agents and coloring agents. Examples of diluents, wetting agents, flavoring agents and coloring agents include those previously exemplified.
Pharmaceutically acceptable substances utilized in ---effervescent granules and powders include organic acids, a source of carbon dioxide, diluents, wetting agents, lS flavoring agents and coloring agents.
Examples of organic acids include, for example, citric acid and tartaric acid. Sources of carbon dioxide include, for example, sodium bicarbonate and sodium carbonate. Exam-ples of sweetening agents include, for example, sucrose, calcium cyclamate and saccharin. Examples of diluents, wetting agents and coloring agents include those previously exen;plified.
Bulk powders have the compound of the Formula I uniformly dispersed throughout a pharmaceutically acceptable powdered carrier diluent. Examples of the diluent include those previously exemplified.
The individual oral solid pharmaceutical dosage forms, tablets and capsules, are packaged individually, unit-dose, or in quantity, multiple-dose containers, for example, hottles of 50, 100, 500, 1000, or 5000.

~35~3i~3 The amount of compound of the Formula I analog per dose unit is adjusted so that it provides the patient with an effective amount. The exact dose depends on the age, weight and condition of the patient or animal as is known in the art. For example, tablets and capsules are given in sufficient number and frequency to obtain the desired pharmacological effect.
The sustained release tablets and capsules provide an effective amount upon ingestion and continue to release a sufficient amount of the active material to keep the concen-tration at an effective level for increased periods of time, for example, 12 hours.
Non-effervescent granules and powders are packages in predetermined amounts, such that when reconstituted with a , 15 specified quantity of an appropriate liquid vehicle?
usually distilled water, a solution and/or suspension results, providing a uniform concentration of the compound of the Formula 1 after shaking, if necessary. The concentration of the solution is such that a teaspoonful (5 ml.), a table-spoonful (one-half ounce or 15 ml.) or a fraction or a ~ult;ple thereof will provide an effective amount to produce the desired pharmacological effect. The exact dose depends on the age, weight and condition of the patient or animal, as is known in the art.
Effervescent granules and powders are packaged either in unit-dose, for example, tin foil packets, or in bulk, for example, in 4 o~. and 8 o~. amounts, such that a specific amount, either a unit-dose or, For example, a teaspoonful, tablespoonful or a fraction or a mul~iple thereof of bulk 3~ granules, when added to a specific amount of 1i4uid vehicle, :, :
-~5~ ~3 3286 for example, water, yields a container of liquid dosageform to be ingested. The concentration of the active material in the granules is adjusted so that a specified amount when mixed with a specific amount of water yields S an effective amount of the active material and produces the desired pharmacological effect. The exact amount of granules to be used depends on age, weight and condition of the patient as is known in the art.
Liquid oral dosage forms include, for example, aqueous

10 solutions, emulsions, suspensions, solutions and/or sus- ;
pensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules. Aqueous solutions include, for example, elixirs and syrups. Emulsions are either oil-in-water (o/w) or water-in-oil (w/o).
Elixirs are clear, sweetened, hydroalcoholic prepara-tions. Pharmaceutically acceptable substances utilized in elixirs include, for example, solvents. Syrups are con-centrated aqueous solutions of a sugar, for example, sucrose, and may contain a preservative. An emulsion is a two-phase system in which one liquid is dispersed in the form of small globules throughout another liquid. ~/w emulsions are much preferred for oral administration over w/o emulsions. Phar-maceutically acceptable substances utilized in emulsions are non-aqueous liquids, emulsifying agents and preservatives.
Syspensions utilize pharmaceutically acceptable suspending agents and preservatives. Pharmaceutically acceptable sub-stances utilized in non-effervescent granules, to be recon-stituted into a liquid oral dosage form, include, for example, diluents, sweeteners, and wetting agents. Pharma-~l~'S~ 3286 ceutically acceptable substances utilized in effervescent granules, to be reconstituted into a liquid oral dosage form, include, for example, organic acids and a source of carbon diox;de. Coloring and flavoring agents are utilized in all of the above dosage forms.
Solvents include, for example, glycerin, sorbitol, ethyl alcohol and syrup. Examples of preservatives include glycerin, methyl and propylparaben, benzoic acid, sodium benzoate and alcohol. Examples of non-aqueous liquids ut;li~ed in emulsions include, for example, mineral oil and cottonseed oil. Examples of emulsifying agents include for example, gelatin, acacia, tragacanth, bentonite, and sur-factants such as polyoxyethylene sorbitan monooleate.
Suspending agents include, for example, sodium carboxy-methylcellulose, pectin, tragacanth, Veegum and acacia.Diluents include, for example, lactose and sucrose. Sweet-ening agents include, for example, sucrose, syrups, glycerin, and artificial sweetening agents such as sodium cyclamate and saccharin. Wetting agents include, for example, propyl-ene glycol monostearate, sorbitan monooleate, diethyleneg7ycol mGnolaurate and polyoxyethylene lauryl ether. Organic acids include, for example, citric and tartaric acid.
Sources of carbon dioxide include, for example, sodium bicarbonate and soidum carbonate. Coloring agents include, for example, any of the approved, certified water soluble FD and C dyes, and mixtures thereof. Flavoring agents includie, for example, natural flavors extracted from plants such as fruits, and synthetic blends of compounds which produce a pleasant taste sensation.
~he concentration of the compound of the Formula I

~ ~iS ~ ~ 3286 throughout the solutions must be uniform. llpon shaking, the concentration of the compound of the Formula l throughout the emulsions and suspensions must be uniform.
The concentration of the compound of the ~ormula I is adjusted so that a teaspoonfu1 (5 ml.), a tablespoonful (one-half ounce or 15 ml.) or a fraction or multiple thereof, will provide an effective amount to produce the desired pharmacological effect. The exact dose depends on the age, weight and condition of the patient or animal as is known in the art.
The liquid oral dosage forms may be packaged, for - example, in unit-dose sizes of 5 ml. (teaspoonful), 10 ml., 15 ml. (tablespoonful) and 30 ml. (one ounce), and multiple dose containers, including, for example, 2 oz., 3 oz., 4 oz., 6 oz., 8 oz., pint, quart, and gallon sizes.
Non-effervescent granules are packaged in predetermined amounts such that when reconstituted with a specified quantity of an appropriate liquid vehicle, usually distilled water, a solution and/or suspension results providing a uniform concentration of the compound of the Formula I after shaking, if necessary. The concentration of the solution is such that a teaspoonful (5 ml.), a tablespoonful (one-half ounce or 15 ml.) or a fraction or multiple thereof will provide an effective amount to produce the desired pharma-cological effect. The exact does depends on the age, weisht,and condition of the patient or animal as is known in the art.
Effervescent granules are packaged either in unit-dose, for example, tin foil packets or in bulk, for example, in 3~ 4 oz. and 8 oz. amounts such that a specific amount, either ~ ~35 ~ 3~ 3286 a unit-dose or for example, a teaspoonful, tablespoonful or a fraction or multiple thereof of bulk granules when added to a sp~cific amount of liquid vehicle, for example, water yields a container of liquid dosage form to be ingested.
The concentration of the compound of the Formula I in the granules is adjusted so that a specified amount when mixed with a specific amount of water yields an effective amount of the active material to produce the desired pharmacological effect. The exact amount of granules to be used depends on age, weight and condition of the patient as it known in the art.
Parenteral administration includes intravenous, sub-cutaneous, intramuscular, and the like.
Preparations for parenteral administration include sterile solutions ready for injection, sterile dry soluble products ready to be combined with a solvent just prior to use, including hypodermic tablets, sterile suspensions ready for injection, sterile dry insolbule products ready to be combined with a vehicle just prior to use and sterile emulsions. The solutions may be either aqueous or non-aqueous.
Pharmaceutically acceptable substances utilized in parenteral preparations include aqueous vehicles, non-aqneous vehicles, antimicrobial agents, isotonic age~ts, buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifying agents, sequestering or chelating agents and other pharmaceutical necessities.
Examples of aqueous vehicles include Sodium Chloride Injection, Ringers Injection, Isotonic (5 percent) Dextrose Injection, Sterile ~ater for Injection, Dextrose and Sodium ~5~3~ 3286 Chloride Injection and Lactated Ringers Injection. Non-aqueous parenteral vehicles include fixed oils of vegetable origin, for example, cottonseed oil, corn o;l, sesame oil and peanut oil. Antimicrobial agents in bacteriostatic or fungistatic concentrations must be added to parenteral preparations packaged in multiple-dose containers (vials) which include phenol or cresols, mercurials, benzyl alcohol9 - chlorobutanal, methyl and propyl p-hydroxybenzoic acid esters, thimerosal, benzalkonium chloride and benzethonium chloride. Isotonic agents include, for example, sodium ; chloride and dextrose. Buffers include, for example, phos-phate and citrate. Antioxidants include, for example, sodium bisulfiate. Local anesthetics include, for example, procaine hydrochloride. Suspending and dispersing agents include, for example, sodium carboxymethylcellulsoe, hydroxy-propyl methylcellulose and polyvinylpyrrolidone. Emulsifying - agents include, for example, Polysorbate 80 (Tween 80). A
sequestering or chelating agent of metal ions include, for example, EDTA (ethylenediaminetetraacetatic acid). Pharma-ceutical necessities include9 for example, ethyl alcohol, polyethylene glycol and propylene glycol for water miscible - vehicles and sodium hydroxide9 hydrochloric acid, citric acid or lactic acid for pH adjustment.
The concentration of the pharmaceutically active ingredient is adjusted so that an injection, for example, 0.5 ml., 1.0 ml., 2.0 ml.9 and 5.0 ml. or an intraarterial or intravenous infusion9 for example9 0.5 ml./min., 1.0 ml./mln., 1.0 ml./min.9 and 2.0 ml./min. provides an effective amount to produce the desired pharmacological 3Q effect. The exact dose depends on the age, weight and -17~-~f 3 ~35~ 3286 condition of the patient or animal as is known in the art.
The unit-dose parenteral preparations are packaged, for example, in an ampul or a syringe with a needle. The multiple-dose package, for example, is a vial.
All preparations for parenteral administration must be sterile, as is known and practiced in the art.
Illustratively, intravenous or intraarterial infusion of a sterile aqueous solution containing an active material is an effective mode of administration. Another embodiment is a sterile aqueous or oily solution or suspension con-taining an active material injected as necessary to produce the desired pharmacological effect.
Pharmaceutical dosage forms for rectal administration -are rectal suppositories, capsules, tablets for systemiceffect.
Rectal suppositories are used herein mean solid bodies for insertion into the rectum which melt or soften at body temperature releasing one or more pharmacologically or therapeutically active ingredients.
Pharmaceutically acceptable substances utilized in rectal suppositories are bases or vehicles and agents to raise the melting point.
Examples of bases or vehicles include, for example, 25 COC03 butter (theobroma oil), glycerin-gelatin, carbowax, (polyoxyethylene glycol) and appropriate mixtures of mono-, di- and triglycerides of fatty acids. Combinations of the various bases may be used. Agents to raise the melting point of suppositories include, for example, spermaceti and wax.
Rectal suppositories may be prepared either by the compressed ~ rol~ 3286 ~ w .;:7~ ~

method or by molding. The usual weight of a rectal suppository is about 2.0 gm.
Tablets and capsules for rectal administration are manufactured utilizing the same pharmaceutically acceptable substance and by the same methods as for formulations for oral administration.
Rectal suppositories, tablets or capsules are packaged either individually, in unit-dose, or in quantityt, multiple dose, for example, 2, 6, or 12.
The pharmaceutically therapeutically active compounds of the Formula I are administered orally, parenterally or rectally in unit-dosage forms or multiple-dosage forms.
Unit-dose forms as used in the specification and claims refers to physically discrete units suitable for human and animal subjects and packaged individually as is known in the art.
Each unit-dose contains a predetermined quantity of the therapeutically active compound sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical carrier, vehicle or diluent. Examples of unit-dose forms include ampuls and syringes (parenteral), individually packaged tablet or capsule (oral-solid) or individually packaged teaspoonful or tablespoonful (oral-liquid). Unit-dose forms may be administered in fractions or multiples thereof. A multiple-dose form is a plurality of identica1 unit-dosage forms packaged in a single container to be administered in segregated unit-dose form. Examples of multiple-dose forms include vials (parenteral), bottles of tablets or capsules (oral-solid) or bottles of pints or gallons (oral-liquid). Hence, multiple dose form is a multiple of unit-doses which are not segregated in packaging.

~ 5-c~ ~ 3286 The specificat;ons for the unit-dosage form and the multiple-dosage form are dictated by and directly dependent on (a) the unique characteristics of the therapeutically active compound and the particular therapeutic effect to be achieved and (b) the limitations inherent in the art of compounding such a therapeutically active compound for ther-apeutic or prophylactic.
In addition to the administration of a compound of Formula I as the principal active ingredient of compositions for the treatment of the conditions described herein, the said compound can be included with other types of compounds to obtain advantageous combinations of properties. Such - combinations include a compound of Formula I with other analgesics such as aspirin, phenacetin acetaminophen, pro-poxyphene, pentazocine, codeine, meperidine, oxycodone,mefenamic acid, and ibuprofen; muscle relaxants such as methocarbamol, orphenadrine, carisoprodol, meprobamate, chlorphenesin carbamate, diazeDam, chlordiazepoxide, and chlorzoxazone; analeptics such as caffeine, methylphenidate and pentylenetetrazol; corticosteroids such as methylpred-nisolone, prednisone, prednisolone and dexamethasone; anti-histamines such as chlorpheniramine, cyproheptadine, pro-methazine and pyrilamine.
Example 85 Capsules One thousand two-piece hard gelatin capsules for oral use, each containing 0.5 mg. of 4-(methyl-n-butylamino)-4-(m-hydroxyphenyl)cyclohexan-1-one ethylene ketal hydro-chloride are prepared from the following types and amounts of materials: -4-(methyl-n-butylamino)-~ 5 ~ ~ 3286 4-(m-hydroxyphenyl)cyclo-hexan-l-one ethylene ketal hydrochloride 0.5 gm.
Lactose 150 gm.
Corn Starch 25 gm.
Talc 20 gm.
Magnesium stearate 2.0 gm.
The materials are thoroughly mixed and then encap-sulated ;n the usual manner.
The foregoing capsules are useful for the treatment of headache in adult humans by the oral administration of 1 capsule every 4 hours.
Using the procedure above, capsules are similarly prepared containing 4-(methyl-n-butylamino)-4-(m-hydroxy-phenyl)cyclohexan-l-one ethylene ketal hydrochloride in 50, 75, 100, and 200 mg. amounts by substituting 50, 75, 100, and 200 gm. of 4-(methyl-n-butylamino)-4-(m-hydroxyphenyl)-cyclohexan-l-one ethylene ketal hydrochloride for the 25 gm.
used above.
Example 86 Capsules One thousand two-piece hard gelatin capsules for oral use, each containing 100 mg. of 4-(methyl-n-butylamino)-4-(m-hydroxyphenyl)cyclohexan-1-one ethylene ketal hydro-chloride and 325 mg. of aspirin, are prepared from the following types and amounts of ingredients:
4-(methyl-n-butylamino)-4-(m-hydroxyphenyl)-cyclohexan-l-one ethylene ketal hydrochloride 100 gm.
I~spirin 325 gm.

~ 3~ 3286 Talc 35 gm.
Magnesium stearate 2.5 gm.
The ingredients are thoroughly mixed and then encap-sulated in the usual manner.
The foregoing capsules are useful for the treatment of headache in adult humans by the oral admin;stration of 1 capsule every 6 hours.
Example 87 Tablets One thousand tablets for oral use, each containing 200 mg. of 4-(methyl-n-butylamino)-4-(m-hydroxyphenyl)cyclo-hexan-l-one ethylene ketal hydrochloride are prepared from the follo~ing types and amounts of materials:
4-(methyl-n-butylamino)-4-(m-hydroxyphenyl)cyclohexan-l-one ethylene ketal hydro-chloride 200 gm.
Lactose 125 gm.
Corn Starch 65 gm.
Magnesium stearate 2.5 gm.
Light liquid petrolatum 3 gm.
The ingredients are thoroughly mixed and slugged. The slugs are broken down by forcing through a number sixteen screen. The resulting granules are then compressed into tablets, each tablet containing 200 mg. of 4-(methyl-n-butylamino)-4-(m-hydroxyphenyl)cyclohexan-1-one ethylene ketal hydrochloride.
The foregoing tablets are useful for treatment of arthritic pain in adult humans by oral administration of 1 tablet every 4 hours.
~0 Exa~ple 88 Tablets One thousand oral tablets, each containing 100 mg. of 4-(methyl-n-butylamino)-4-(m-hydroxyphenyl)cyclohexan-l-one ethylene ketal hydrochloride and a total of 400 mg.
of chlorphenesin carbamate are prepared from the following types and amounts of materials:
4-(methyl-n-butylamino)-4-~m-hydroxyphenyl)cyclohexan-l-one ethylene ketal hydro-chloride 100 gm.
Chlorphenesin Carbamate 400 gm.
Lactose 50 gm.
Corn starch 50 gm.
Calcium stearate 2.5 gm.
Light liquid petrolatum 5 gm.
The ingredients are thoroughly mixed and slugged. The slugs are broken down by forcing through a number sixteen screen. The resulting granules are then compressed into tablets, each containing 100 mg. of 4-(methyl-n-butylamino)-4-(m-hydroxyphenyl)cyclohexan-1-one ethylene ketal hydro-chloride and 400 mg. of chlorphenesin carbamate.
The foregoing tablets are useful for treatment of low back pain by the oral administration of 1 tablet every six hours.
Example 89 Oral Syrup One thousand ml. of an aqueous suspension for oral use, containing in each 5 ml. dose, 100 mg. of 4-(methyl-n-butylamino)-4-(m-hydroxyphenyl)cyclohexan-1-one ethylene ketal hydrochloride is prepared from the followint types and amounts of ingredients:
4-(methyl-n-butylamino)-4-~ 3~ 3286 (m-,hydroxyphenyl)cyclohexan-l-one,ethylene ketal hydro-chloride 20 gm.
Citric acid 2 gm.
Benzoic acid l gm.
Sucrose 700 gm.
Tragacanth 5 gm.
Lemon oil 2 ml.
Deioniz'ed water q.s. lO00 ml.
The citric acid, benzoic acid, sucrose, tragacanth, and lemon oil are dispersed in sufficient water to make 850 ml. of solution. The 4-(methyl-n-butylamino)-4-(m-hydroxyphenyl)cyclohexan-l-one ethylene ketal hydrochloride is stirred into the syrup until uniformly distributed.
Sufficient water is added to make lO00 ml.
The composition so prepared is useful in the treatment of headache in adult humans at a dose of 1 teaspoonful 4 times a day.
Example 90 Parenteral solution A sterile aqueous solution for intramuscular use, containing in l ml. 25 mg. of 4-(methyl-n-butylamino)- , 4-(m-hydroxyphenyl)cyclohexan-l-one ethylene ketal hydro-chloride is prepared from the following types and amounts of Materials: ' 4-(methyl-n-butylamino)-4-(m-hydroxyphenyl)cyclohexan-l-one ethylene ketal hydro-chloride 25 gm.
Lidocaine hydrochloride 4 gm.
Methylparaben 2.5 gm.

' Propylparaben 0.17 gm.
Water for injection q.s. 1000 ml.
The ingredients are dissolved in the water and the solution sterilized by filtration. The sterile solution is filled into vials and the vials sealed.
Example 91 Suppository, rectal One thousand suppositories, each weighing 2.5 gm. and containing 100 mg. of 4-(methyl-n-butylamino)-4-(m-hydroxy-phenyl)cyclohexan-l-one ethylene ketal hydrochloirde are prepared from the following types and amounts of ingredients:
4-(methyl-n-butylamino)-4-(m-hydroxyphenyl)cyclohexan-l-one ethylene ketal hydro-chloride 100 gm.
Propylene glycol 162.5 gm.
Polyethylene glycol 4000 q.s. 2500 gm.
The 4-(methyl-n-butylamino)-4-(m-hydroxyphenyl)cyclo-hexan-l-one ethylene ketal hydrochloride is added to the propylene glycol and the mixture milled until the powders are finely divided and uniformly dispersed. The poly-ethylene glycol 4000 is melted and the propylene glycol dispersion added slowly with stirring. The suspension is poured into unchilled molds at 40 C. The composition is allowed to cool and solidify and then removed from the mold and each suppository foil wrapped.
The suppositories are useful in the treatment of headache by the insertion rectally of 1 suppository every six hours.
Examp_e 92 ~5~3~3 Compositions are similarly prepared following the procedure of the preceding Examples 85 through 91 substi-tuting an equimolar amount each of 4-(p-chlorophenyl)-4-dimethylaminocyclohexanone, ethylene ketal free base;
4-(p-chlorophenyl)-4-dimethylaminocyclohexanone, ethylene ketal hydrochloride;
4-(p-chlorophenyl~-4-dimethylaminocyclohexanone;
4-(p-fluorophenyl)-4-dimethylaminocyclohexanone, ethylene ketal free base;
4-(p-fluorophenyl)-4-dimethylaminocyclohexanone, ethylene ketal hydrochloride;
4-(p-fluorophenyl)-4-dimethylaminocyclohexanone;
4-(p-anisyl)-4-dimethylaminocyclohexanone, ethylene ketal free base;
4-(p-anisyl)-4-dimethylaminocyclohexanone, ethylene ~ !
ketal hydrochloride;
4-(p-anisyl)-4-dimethylaminocyclohexanone free base;
4-(o-chlorophenyl)-4-dimethylaminocyclohexanone, ethylene ketal free base;
4-(o-chlorophenyl)-4-dimethylaminocyclohexanone, ethylene ketal hydroiodide;
4-(o-chlorophenyl)-4-dimethylaminocyclohexanone;
4-(m-anisyl)-4-dimethylaminocyclohexanone, ethylene ketal free base;
4-(m-anisyl)-4-dimethylaminocyclohexanone, ethylene ketal hydrochloride;
4-(m-anisyl)-4-dimethylaminocyclohexanone;
4-dimethylamino-4-(p-tolyl)cyclohexanone, ethylene ketal free base;

4-dimethylamino-4-(p-tolyl)cyclohexanone, ethylene ketal hydrochloride;
4-dimethylamino-4-(p-tolyl)cyclbhexanone;
4-dimethylamino-4-phenylcyclohexanone;
4-(p-bromophenyl)-4-dimethylaminocyclohexanone, ethylene ketal free base;
4-(p-bromophenyl)-4-dimethylaminocyclohexanone, ethylene ketal hydrochloride;
4-(p-bromophenyl)-4-dimethylaminocyclohexanone;
4-(2,4-dichlorophenyl)-4-dimethylaminocyclohexanone, ethylene ketal free base;
4-(2,4-dichlorophenyl)-4-dimethylaminocyclohexanone, ethylene ketal hydrochloride;
4-dimethylamino-4-(2-thienyl)cyclohexanone, ethylene ketal;
4-(m-tolyl)-4-dimethylaminocyclohexanone free base;
4-(methyl-n-butylamino)-4-(m-hydroxyphenyl)cyclohexan-l-one, ethylene ketal free base;
4-(methyl-n-butylamino)-4-(m-hydroxyphenyl)cyclohexan-l-one, ethylene ketal hydrochloride;
4-(m-hydroxyphenyl)-4-(methyl-n-butylamino)cyclohex-anone;
4-(m-hydroxyphenyl)-4-dimethylaminocyclohexanone, ethylene ketal;
4-(m-hydroxyphenyl)-4-dimethylaminocyclohexanone;
4-(p-hydroxyphenyl)-4-(n-butylmethylamino)cyclohexanone ethylene ketal free base;
4-(p-hydroxyphenyl)-4-(n-butylmethylamino)cyclohexanone ethylene ketal.hydrochloride;
4-(p-hydroxyphenyl)-4-(n-butylmethylamino)cyclohexanone;

~5~3~ 3286 4-(p-trifluoromethylphenyl)-4-dimethylaminocyclo-hexanone, ethylene ketal free base;
4-(p-trifluoromethylphenyl)-4-dimethylaminocyclo-hexanone, ethylene ketal hydrochloride, 4-(p-chlorophenyl)-cis-2-methyl-4-dimethylaminocyclo-hexanone;
4-(p-chlorophenyl)-trans-2-methyl-4.dimethylamino-cyclohexanone;
4-(m-hydroxyphenyl)-4-(n-propylmethylamino)cyclohex-anone ethylene ketal free base;
4-(m-hydroxyphenyl)-4-(n-propylmethylamino)cyclo-hexanone, ethylene ketal hydrochloride;
4-(m-hydroxyphenyl)-4 (methyl-N-pentylamino)cyclohex-anone ethylene ketal free base;
4-(m-hydroxyphenyl)-4-(methyl-n-pentylamino)cyclo-hexanone ethylene ketal hydrochloride;
4-(m-hydroxyphenyl)-4-(i-butylmethylamino)cyclohex-anone ethylene ketal free base;
4-(m-hydroxyphenyl)-4-(i-butylmethylamino)cyclohex-anone ethylene ketal hydrochloride;
4-(m-acetoxyphenyl)-4-dimethylaminocyclohexan-1-one;
4-(m-acetoxyphenyl)-4-(methyl-n-butylamino)cyclohex-anone;
4-(m-hydroxyphenyl)-4-(1-pyrrolidinyl)cyclohexanone;
4-(m-hydroxyphenyl)-4-(1-pyrrolidinyl)cyclohexanone, ethylene ketal;
4-(m-acetoxyphenyl)-4-(1-pyrrolidinyl)cyclohexanone;
4-(m-hydroxyphenyl)-4-dimethylaminocyclohexanone tri-methylene ketal;
4-(m-acetoxyphenyl)-4-(n-propylmethylamino)cyclohexanone;

~ 3286 4-(m-acetoxyphenyl)-~-(isobutyllllethylanlino)cyclo-hexanone;
4-(m-acetoxyphenyl)-4-(n-pentylmethylamino)cyclohex-anone;
4-(m-hydroxyphenyl)-4-dimethylaminocyclohexanone trimethylene ketal;
4-(m-acetoxyphenyl)-4-(n-butylmethylamino)cyclohex-anone hydrochloride; and 4-(m-hydroxyphenyl)-4-(n-propylmethylamino)cyclohex-anone for the 4-(methyl-n-butylamino)-4-(m-hydroxyphenyl)-cyclohexan-l-one ethylene ketal hydrochloride of the examples.
Example 93 The compositions prepared in the preceding Examples 85, 87, 89, 90 and 91 can be used for testing for narcotic dependence by inducing withdrawal symptoms in drug addicts.
Also, they are useful for counteracting respiratory and central nervous system depression induced by morphine or related analgesics.
Although compounds of Formula VIII can induce analgesia, the;r additional activity of being at the same time narcotic antagonists considerably diminishes the risk of addiction to the particular drug. One can say that the narcotic antagonist activity of the compounds of this inven-tion acts as an internal safety device directed toward moderating any inherent properties of physical dependence of the medication caused by its narcotic-type analgetic action.
As a result, one can use the free bases or salts to obtain narcotic type analgesia with minimal risk of physical dependence.

-1~2-

Claims

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 of the formula:

wherein Ar' is n is zero or one, R1 is alkyl of 1 to 8 carbon atoms, inclusive;
R2 is alkyl of 1 to 8 carbon atoms, inclusive, cycloalkylalkyl wherein cycloalkyl is of 3 to 6 carbon atoms, inclusive, and alkyl is of 1 to 3 carbon atoms, inclusive, cycloalkyl of 3 to 6 carbon atoms, inclusive, , or wherein Y' is halogen, CF3, alkyl of 1 to 4 carbon atoms, inclusive, or alkoxy of 1 to 4 carbon atoms, inclusive, and m is 0, 1 or 2 comprising:
(a) reacting a compound of the formula with a diol of the formula:

wherein n is zero or one and R4 is hydrogen or methyl; R5 is hydrogen, phenyl, -CH2-alkenyl wherein alkenyl is of 2 to 4 carbon atoms, inclusive, or methyl; in the presence of acid in an inert solvent to obtain a compound of the formula:

(b) oxidation of the above compound to obtain a compound of the formula:

(c) reacting the above compound with HCN and an amine of the formula to obtain a compound of the formula:

(d) reacting the above compound with a Grignard Reagent of the formula Ar'MgX wherein Ar' is in anhydrous organic solvent to obtain a compound of the formula:

wherein Ar', R1, R2, R4 and R5 are defined hereinbefore

2. A 4-amino-4-arylcyclohexanone ketal of the formula:

wherein Ar', R1, R2, R4 and R5 are as defined in claim 1, whenever prepared or produced by the process defined in claim 1 or by the obvious chemical equivalent.