US3668199A

US3668199A - 1,3-aminoalcohols

Info

Publication number: US3668199A
Application number: US85718A
Authority: US
Inventors: Jacob Szmuszkovicz
Original assignee: Upjohn Co
Current assignee: Pharmacia and Upjohn Co
Priority date: 1966-06-13
Filing date: 1970-10-30
Publication date: 1972-06-06
Anticipated expiration: 1989-06-06

Abstract

Novel 1,3-aminoalcohol of the formula

WHEREIN N HAS THE VALUE OF 1 TO 4, INCLUSIVE, WHEREIN R'', R'''', and R'''''' are hydrogen, halogen, alkyl of 1 to 6 carbon atoms, inclusive, and alkoxy of 1 to 6 carbon atoms, inclusive, or CF3, are prepared. The new compounds of formula IV per se as well as in the form of acid addition salts have diuretic activity and some of them have antihyperglycemic activity. Compounds of formula IV are thus useful to provide diuretics in mammals and are also useful as oral antidiabetic agents.

Description

United States Patent" Primary Examiner-Alton D. Rollins Attorney-Hans L. Berneis and John Kekich Szmuszkovicz [451 June 6, 1972 [541 1,3-AMINQALCOHOLS I [72] Inventor: Jacob Szmuszkoviez, Kalamazoo, Mich. [57] ABSTRACT [73] Assignee: The Upjohn Company, Kalamazoo, Mich. la'ammoalcohol oflhe formula [22] Filed: Oct. 30, 1970 v (CH: R 4 [2!] Appl. No.: 85,718 E Related U.S. Applicatlon'Data l [62] Division of Ser. No. 556,892, June 13, 1966, Pat. No. N 3,558,599, which is a division of Ser. No. 786,385,

Dec. 23, 1968, Pat. No. 3,595,867.

, [52] U.S.Cl.. ..260/239 B, 260/239 BF, 424/244 Int. Cl. ..C07d wherein n has h value of l to 4 inclusive wherein R1 n 0 Search B and R; are y g g alkyl of l to 6 carbon atoms I inclusive, and alkoxy of l to 6 carbon atoms, inclusive, or CF:,, [56] Reerences cued are prepared. The new compounds-of formula W per se as UNITED STATES PATENTS well as in the form of acid addition salts have diuretic activity and some of them have antihyperglycemic activity. Com- 3,257,413 6/1966 ShOft ..260/294.7 und of f ula IV are thus useful to provide diuretics in mammals and are also useful as oral antidiabetic agents.

10 Claims, No Drawings 1,3-AMINOALCOHOLS CROSS-REFERENCES TO RELATED APPLICATIONS This application is a division of application Ser. No.

556,892 filed June 13, 1966, now US. Pat. No. 3,558,599 and 5 represents hexamethyleneimino, wherein R is an alkyl containing from 1 to 6 carbon atoms, inclusive, wherein R, R, R are selected from the group of substituents consisting of hydrogen, halogen, alkyl and alkoxy containing from 1 to 6 carbon atoms, inclusive, and--CF and wherein Ac is the acyl radical of a hydrocarbon carboxylic acid containing from 2 to 12 carbon atoms, inclusive.

The invention further includes the compounds of formulae IV, [Va and IVb when in the form of the N-oxides, acid addition salts and quaternary alkyl ammonium halides in which the alkyl group has from 1 to 12 carbon atoms, inclusive, and the halogen can be chlorine, bromine and iodine. Also the acid addition salts of the compounds of formula III are embraced by this invention.

Examples of the cycloalkyl radical illustratively represented by the formula are cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

Examples of the heterocyclic amino radical having from 5 to 10 nuclear atoms, include: pyrrolidino, 2-

methylpyrrolidino, 2-ethylpyrrolidino, 2,2-dimethylpyrrolidino, 3,4-dimethylpyrrolidino, 2-isopropylpyrrolidino, 2- sec.butylpyrrolidino, and like alkylpyrrolidino groups, morpholino, 2-ethylmorpholino, 2-ethyl-5-methylmorpholino,

LII

3,3-dimethylmorpholino, thiamorpholino, 3- methylthiamorpholino, 2,3,6-trimethylthiamorpholino, 4- methylpiperazino, 4-butylpiperazino, piperidino, 2-methylpiperidino, 3-methylpiperidino, 4-methylpiperidino, 4-propylpiperidino, 2-pr0pylpiperidino, 4-isopropylpiperidino, and like alkylpiperidino groups, hexarnethyleneimino, 2-methylhexamethyleneimino, 3,-dimethylhexamethyleneimino, homomorpholino, 1,2,3 ,4-tetrahydroquinolyl, heptamethyleneimino, octamethyleneimino, 3-azabicyclo[3,2,2 ]nonan-3-yl, 2-azabicyclo-[2,2,2]octan-2-yl, and the like.

Illustrative examples of alkyl groups having from 1 to 6 carbon atoms are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, Z-methylbutyl, neopentyl, hexyl, 2- methylpentyl, 3-methylpentyl and the like. Alkyl groups for the quaternary ammonium halide salts include, in addition to the preceding alkyl groups, others such as heptyl, octyl, nonyl, decyl, undecyl, dodecyl and the like. The halogen moiety in such salts includes iodine, bromine and chlorine.

Illustrative examples of the acyl groups Ac of hydrocarbon carboxylic acids are particularly the acyl groups of alkanoic acids of 2 to 12 carbon atoms, e.g., acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, hexanoyl, octanoyl, decanoyl, ,B-cyclopentylpropionyl, lauroyl; of benzoic and aralkanoic acids, e.g., benzoyl, phenylacetyl, 3-phenylpropionyl, toluoyl, ethylbenzoyl, propylbenzoyl; of alkenoic acids, e.g., acryloyl, crotonoyl, chrysanthemummonocarbonyl, cinnamoyl, hexenoyl; of alkynoic acids, e.g., propioloyl, 2- and 3-butynoyl and the like.

Under halogen substitutents for R, R or R is understood fluorine, chlorine, bromine and iodine.

The novel compounds III, IV, Wu and IVb exist in different steroisomeric forms such as geometric and optically active forms (e.g., compounds of formula III have at least two asymmetric carbon atoms, while the final products, IV, IVa and IVb, have at least three asymmetric carbon atoms) as well as in racemic mixtures. These optically active forms and racemic mixtures and geometric isomers are also encompassed by this invention.

The process of the present invention comprises: heating a diketo compound of formula I in which one of the radicals on the central carbonyl group is a 2-oxocycloalkyl group having from 5 to 8 carbon atoms, inclusive, and the other group is substituted or unsubstituted phenyl, with a heterocyclic amine having from 5 to 10 nuclear atoms, inclusive, in the presence of an acidic catalyst, e.g., p-toluenesulfonic acid, to give the unsaturated keto compound of formula II; hydrogenating the thus-obtained compound II in the presence of a hydrogenation catalyst, preferably a noble metal catalyst such as platinum oxide, rhodium, palladium or the like to add stepwise one and thereupon two molar equivalents of hydrogen, thus yielding respectively (with 1 molar equivalent of hydrogen) the keto compound III and (with 2 molar equivalents of hydrogen) the alcohol IV. The thus-obtained l,3-amino alcohols IV can be converted to alcohol derivatives such as ethers (IVa) with an alkyl halide (l to 6 carbon atoms) in the presence of a base, or with a lower alkanol (1 to 6 carbon atoms) in the presence of anhydrous hydrogen chloride, and to esters (IVb) with an acid anhydride or acid halide in a suitable organic solvent.

The amino function in formulae lV, lVa and IVb compounds furthermore pennits the transformation of these compounds, by neutralization with inorganic and organic acids, into acid addition salts such as the hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, perchlorate, pamoate, cyclohexanesulfamate, methanesulfonate, ethanesulfonate, ptoluenesulfonate, benzenesulfonate, tartrate, citrate, lactate, and the like. By treatment of the compounds of formulae IV, Na and IVb with peracids such as m-chloroperbenzoic acid, peracetic acid, perbenzoic acid, perphthalic acid, and the like, the corresponding N-oxide derivatives are obtained. By treatment of the compounds of formulae 1V, IVa and IVb with alkyl halides, the corresponding quaternary ammonium halide salts are obtained.

The compounds of formulae IV, IVa and lVb, including the acid addition salts, the N-oxides, and the alkyl quaternary ammonium halides thereof, are compounds of significant diuretic activity. They may be administered to mammals and birds by both oral and parenteral routes in order to produce their pharmacological, that is, diuretic effects. For oral administration, the new compounds of formulae IV, IVa and IVb, as well as the acid addition salts, the N-oxides and the quaternary ammonium halide salts, can be compounded into solid and liquid unit dosage forms such as tablets, capsules, powders, granules, syrups, elixirs and the like, containing the appropriate amounts for treatment. For tablets, common pharmaceutically acceptable carriers are used such as starch, lactose, kaolin, dicalcium phosphate and the like. The compounds IV, IVa and lVb can also be given as powders, particularly in gelatin capsules with or without carriers such as methylcellulose, magnesium stearate, calcium stearate, talc and the like. For fluid preparations, these compounds may be dissolved or suspended in aqueous alcoholic vehicles with or without buffering agents and flavoring mixtures.

The thus-obtained pharmaceutical formulations are administered to edematous animals for the treatment of conditions associated with excess electrolyte retention and excess fluid retention. For example, the compositions are useful in treating the following conditions: edema associated with hepatic disease, edema and toxemia of pregnancy, hypertensive vascular disease, premenstrual fluid retention and congestive heart failure. Dosages between 0.5 and 30 mg./kg. of body weight are suitable to produce significantly increased diuresis. For example, the ether cis-l-[2-(a,p-dimethoxybenzyl)cyclohexyl]-piperidine of melting point 83-85 C. produced at 5 mg. dosage level per kg. of body weight ofrats a 73 percent increase in diuresis, as determined by the procedure of Lipschitz et al., J. Pharmacol Exp. Therap. 79, 97, 1943.

The compounds of Examples 38, 39, 48, 54, 55, 97, 99, 100 and 136A have demonstrated significant anti-hyperglycemic activity in rats. They are useful as oral antidiabetic agents.

As noted above, the new compounds of formulae IV, IVa and IVb can be used in the form of their acid addition salts with inorganic or organic acids, for example, hydrochlorides, lactates, sulfates, tartrates, hydroiodides, hydrobromides, and the like. Moreover, the fluosilicates of these compounds are useful moth-proofing agents according to U. S. Pat. Nos. 1,915,334 and 2,075,359. The thiocyanic acid addition salts of the same compounds can be condensed with formaldehyde to form resinous polymers which according to U. S. Pat. Nos. 2,425,320 and 2,606,155 are useful as pickling inhibitors. The trichloroacetic acid addition salts of the compounds of the same formulae IV, IVa and IV]; are useful as herbicides, for example, against Johnson grass, yellow foxtail, green foxtail, Bermuda grass and quack grass.

The alkyl quaternary ammonium halides of the compounds of formulae IV, [Va and Nb, such as a-(3,4,5-trimethoxyphenyl)-2-(hexahydro-l-methyl-l-azepinium)cyclohexanemethanol iodide (Example 142), possess high wetting power and electroconductivity and are thus suitable to prepare electrocardiographic jellies.

A suitable composition of an electrocardiographic jelly thus prepared comprises:

Parts Glycerol 5 Starch l0 Quaternary ammonium salt 60 Water 100 The jelly is prepared by mixing the starch, glycerol and water and then adding the quaternary ammonium salt. The mixture is then allowed to stand for at least two days with occasional agitation to allow the formation ofa gel.

The starting materials of formula I are known in part from the art, e.g., Campbell et al., J. Am. Chem. Soc. 82, 2389, (1960); Linn et al., J. Am. Chem. Soc. 78, 6066 (1956);

Eistert et al., Ann. 650, 133 (1961). An elegant method by which the 1,3-diones of the type of formula I are synthesized consists of the reaction of a selected cycloalkanone with pyrrolidine or piperidine to give the corresponding enamine and to react the enamine with a selected substituted or unsubstituted benzoyl chloride [Campbell et al., J. Org. Chem. 28, 379 (1963)]. This particular method is shown repeatedly in the Examples in order to synthesize hitherto unknown 1,3- diones of the type of formula I.

In carrying out the process of the present invention a 1,3- diketo compound (I) is reacted with heterocyclic amine in the presence of a acid catalyst and preferably under conditions in which the water produced in the condensation process is separated from the reaction mixture such as by employing an azeotropic separator together with the reflux condenser. As solvent, essentially water-free organic solvents are used such as benzene, toluene, xylene or the like. The heterocyclic amines used include particularly pyrrolidine, 2-methylpyrrolidine, 2-ethylpyrrolidine, 2,2-dimethylpyrrolidine, 3,4- dimethylpyrrolidine, 2-isopropylpyrrolidine, 2-sec.butylpyrrolidine and other like alkylpyrrolidines; morpholine, 2-ethylmorpholine, 2-ethyl-5-methylmorpholine, 3,3-dimethylmorpholine, thiamorpholine, 3-methylthiamorpholine, 2,3,6- trimethylthiamorpholine and other like alkylmorpholines and alkylthiamorpholines; 4-methylpiperazine, 4-butylpiperazine and other like alkylpiperazines; piperidine, Z-methylpiperidine, 3-methylpiperidine, 4-methylpiperidine, 4-propylpiperidine, 2-propylpiperidine, 4-isopropylpiperidine and other like alkylpiperidines; hexamethyleneimine, Z-methylhexamethyleneimine, 3,6-dimethylhexamethyleneimine and other like alkylhexamethyleneimines; homomorpholine, l,2,3,4-tetrahydroquinoline, heptamethyleneimine, octamethyleneimine, 3-azabicyclo-[3.2.2]nonane, 2-azabicyclo[2.2.2]octane,'and the like.

The reaction is generally carried out at temperatures between 50-l50 C. but lower or higher temperatures are operative. Preferably, the reaction is carried out at the reflux temperature of the reaction mixture. The time for completion of the reaction is between 1 hour and 48 hours, but if low temperatures are used, longer reaction times are necessary. When the reaction is terminated, the product is isolated in conventional manner such as evaporating the reaction mixture to dryness.

The keto product of formula II is then hydrogenated in the presence of a catalyst, preferably platinum oxide, at a hydrogen pressure between 40 and 60 pounds per square inch. Larger or smaller pressures can be used, but pressure between 50-55 pounds at the beginning of the reaction are found to be most convenient. The reaction can be followed by the hydrogen absorption and can be allowed to go to completion, that is, to the point of addition of 2 molar equivalents of "hydrogen to give the alcohol of formula IV, or alternatively may be interrupted after the addition of 1 molar equivalent of hydrogen to give the keto compound of formula III. In cases where the addition of hydrogen is slow, additional amounts of catalyst may be added after an interval of several hours. Other catalysts that can be used in this reaction are palladium and rhodium, and these catalysts can be used with catalyst carriers such as charcoal, alumina and the like. After the hydrogenation is completed, the product is isolated by filtering the mix- ,ture to remove the catalyst and evaporating the solvent to obtain either the keto compound of formula III or the alcohol of formula IV. The thus-isolated products are purified by conventional means such as by crystallization and recrystallization, chromatography, or the like. If desired, the keto product of formula III can be hydrogenated again to give the alcohol of formula IV.

The conversion of the alcohol of formula IV to an ether of formula IVa is usually achieved by two methods: (I) reacting the alcohol of formula IV in liquid ammonia containing sodium amide or potassium amide at low temperature with the selected alkyl halide, or (2) reacting the alcohol of formula IV with a lower alkanol in the presence of hydrogen chloride. The starting temperature of the first method is usually the temperature of a Dry Ice-acetone bath, that is, approximately --70 C. and'is completed at about room temperature. In the preferred embodiment of this invention, the selected alcohol (IV), is dissolved in ether and is added to liquid ammonia containing sodium amide under continuous stirring. When this mixture reaches the Dry Ice-acetone bath temperature, a solution of thealkyl halide, preferably an alkyl iodide, is added over a few minutes time to allow cooling. When the calculated amount of alkyl halide is consumed, the reaction mixture in the flask is removed from the Dry Ice-acetone bath and allowed to warm to room temperature under continuous stirring. Instead of sodium amide, other strong basic compounds can be used such as potassium amide, lithium amide, and the like. Instead of liquid ammonia and alkali metal amides, other reaction systems can be used, e.g., butyl lithium in the presence of tetrahydrofuran and a temperature range of about 70 to 25C. After the reactionis terminated, the ether thus produced (lVa) is isolated by conventional procedures such as extraction, evaporation of solvents, formation of amine addition salts such as the hydrochloride, and using the differential water solubility of the hydrochloride and the like. For purification, recrystallization andchromatography are usually employed. v

In the second method, the alcohol IV is stirred with a solution of hydrogen chloride gas in a lower alkanol, e.g.,

methanol, ethanol, propanol, l-butanol, 2-butanol and the like, usually at room temperature. Lower or higher temperatures are operative, however. The product is obtained as a hydrochloride of the amino ether. The free base is obtained by treating the hydrochloride witha base, e.g., 20 percent aqueous sodium hydroxide, extracting the free base with a waterimmiscible solvent, e.g., ether, methylene chloride, chloroform and the like and evaporating the solvent.

Esters (IVb) of the alcohol of formula IV are usually ob- I tained in conventional manner, that is, treatment of the alcohol with an acid anhydride or acid halide, preferably in solution at room temperature. The solvents used in this reaction are methylene chloride, tetrahydrofuran, pyridine and the like. The anhydrides used in this reaction are usually of hydrocarbon carboxylic acids, e.g., of alkanoic acids such as acetic, propionic,-butyric, isobutyric, valeric, hexanoic, heptanoic, octanoic acids and the like; of benzoic and aralkanoic acids such as benzoic acid, salicyclic acid, toluic acid, phenylacetic acid, 3-phenylpropionic acid and the like; of cycloalkanoic acids, e.g., of cyclohexanecarboxylic acid and the like. The acid halides used in this reaction can be of alkanoic acids, particularly higher alkanoic acids having from 6 to 12 carbon atoms, such as hexanoyl chloride, heptanoyl chloride, octanoyl chloride, decanoyl chloride, undecanoyl chloride, lauroyl chloride or the acid bromides thereof, but the chlorides and bromides of lower alkanoic acids are also useful. The invention also encompasses the use of the anhydrides and acid chlorides and bromides of unsaturated acids such as cinnamic acid, acrylic acid, crotonic acid propiolic acid, 2-butynoic acid, chrysanthemummonocarboxylic acid and the like. After termination of the reaction, the product is isolated by conventional procedures such as extraction, chromatography, crystallization and the like.

Acid addition salts of the amino alcohols (IV), amino ethers (Na) and amino esters (IVb) are synthesized in the usual manner, that is, by directly reacting the acid with the free amine, preferably in an aqueous or anhydrous solvent such as water, ether, methanol, ethanol, ethyl acetate or the like. Evaporation of the solvent provides the desired acid addition salt.

N-oxidesof the compounds of formulae (IV), (Na) and (IVb) are obtained by reacting the compound at a tempera ture between 0-30 C., preferably at the start of the reaction at a temperature between 0l0 C., with a peracid such as peracetic, perpropionic, perbenzoic, 'perphtahlic, mchloroperbenzoic or other organic peracids in a solvent such as methanol, ethanol, ether or the like. Evaporation of the solvent provides the desired N-oxide of the products of formulae IV, IVa and IVb.

The alkyl quaternary ammonium halides of products of formula IV, IVa and IVb are produced by conventional methods such as heating to reflux a solution of the selected compound IV, IVa or IVb in the presence of methanol, ethanol, acetonitrile or the like with a selected alkyl halide such as an iodide or bromide or, less desirably, a chloride of methyl, ethyl, propyl, butyl, isobutyl, isopropyl, pentyl, hexyl, heptyl, octyl, decyl, undecyl, dodecyl or isomers of these alkyl compounds. After the reaction is terminated, the reaction mixture is evaporated to dryness to give the product which can be purified by recrystallization from organic solvents such as methanol, ethanol, ether, Skellysolve B hexanes, mixtures thereof and the like.

It is obvious from the configuration of products III, IV, [Va and IVb that these products can exist in more than one isomeric structure, since the compounds of formula III have at least two asymmetric centers and those of formula IV, Na and IVb have at least three asymmetric centers,- as noted above. It will be seen from the Examples that many of the reactions are either stereo-specific giving only one single product (racemic) or are stereo-selective, that is, giving one major component with smaller amounts of other components. Thus, the hydrogenation of the compound II to the ketone III with platinum oxide appears to give only one single form of the cisketone. Heating the thus-obtained cis-ketone with a base, for example, refluxing it with piperidine, produces a single transketone (III), which according to thermodynamic principles of stability has the substituents on the cycloalkane moiety in the equatorial position.

Further hydrogenation of a cis-k'etone of formula III with platinum oxide as catalyst produces one single cis-alcohol form (racemate A). Heating this cis-alcohol of formula IV with trifluoroacetic acid produces another formula IV cis-alcohol (racemate B).

Further hydrogenation. of a trans-ketone of formula III with platinum oxide as catalyst produces one single formula IV trans-alcohol (racemate C) which can be converted to the other formula IV trans-alcohol (racemate D) with trifluoroacetic acid. Reduction of a trans-ketone of formula III with lithium aluminum hydride produces the two above-mentioned trans-alcohols of formula IV; The racemates can be resolved by standard methods. The subsequent Examples further illustrate the stereo-isomeric considerations.

The following Examples are illustrative of the process and the products of the present invention, but are not to be construed as limiting.

EXAMPLE I 2-( 3,4,5 -Trimethoxybenzoyl )cyclohexanone A mixture of 147 g. (1.5 moles) of cyclohexanone and 213.3 g. (3 moles) of pyrrolidine was refluxed in 2,250 ml. of benzene in a flask equipped with an azeotropic separator. After the water formed during the reaction was collected, the solution was evaporated to dryness in vacuo and the resulting crude oil, consisting of l-pyrrolidino-l-cyclohexene, was used directly for the next step.

A solution of 3,4,5-trimethoxybenzoyl chloride (138.3 g.; 0.6 mole) in 240 ml. of chloroform was added during a period of 2 hours to a solution of the crude l-pyrrolidino-1-cyc1ohexene in 630 ml. of chloroform, under a nitrogen atmosphere, with continuous stirring while keeping the temperature between 5 to 10 C. After the solution was stirred overnight (about 18 hours) at room temperature (about 22 to 25 C.), there was added 900 ml. of 10 percent aqueous hydrochloric acid, and the resulting mixture was stirred at room temperature for 2 hours. The aqueous layer was extracted with two 150 ml. portions of chloroform, and the chloroform extracts were combined with the chloroform layer above. The combined extracts were washed with water, saturated aqueous sodium bicarbonate solution, water and saturated salt solution. The thus-obtained chloroform solution was dried by passing it through anhydrous sodium sulfate and the dry solution was evaporated to give a residue which was crystallized Analysis:

Calcd. for C I-1 Found: C, 65.48; H, 6.84

EXAMPLE 2 2-(3,4,5-Trimethoxybenzoyl)cyclopentanone A mixture of 126 g. (1.5 moles) of cyclopentanone and 213.3 g. (3 moles) of pyrrolidine was refluxed in 2,250 ml. of benzene in a flask equipped with an azeotropic separator. After the calculated amount of water, produced during the condensation, had been collected, the reaction mixture was evaporated to give as an oil l-pyrrolidino-l-cyclopentene.

A solution of 3,4,5-trimethoxybenzoyl chloride (138.3 g.; 0.6 mole) in chloroform was added to a chloroform solution of the oily l-pyrrolidino-l-cyclopentene over a period of 1 hour. The reaction mixture was thereupon worked up as in Example 1 to give a brown oil weighing 190 g. This oil was dissolved in 500 ml. of ethanol and the ethanol solution was added to a solution of 172 g. of cupric acetate monohydrate in 2,600 ml. of water. The mixture was stirred for one-half hour, cooled and filtered, providing a crude copper complex of 2-(3,4,5- trimethoxybenzoyl) cyclopentanone. This product was crystallized from methylene chloride to give 70 g. of the pure copper complex melting at 206208 C.

Analysis:

Calcd. for C H CuO C, 58.29; H, 5.54; Cu, 10.28 Found: C, 58.58; H, 5.81; Cu, 9.49

The thus-obtained copper complex (70 g.) was dissolved in 350 ml. of chloroform and decomposed with 670 ml. of percent aqueous hydrochloric acid to give 60 g. (yield 36 percent) of 2-(3,4,5-trimethoxybenzoyl)cyclopentanone having a melting point of 8186 C. A sample of this material was recrystallized from Skellysolve B hexanes to give 2-(3,4,5- trimethoxybenzoly)cyclopentanone of melting point 9295 C.

Analysis:

Calcd. for C.,H...

Found: C,

In a run twice the size of the above synthesis, a yield of 47 percent was obtained.

EXAMPLE 3 2-( 3 ,4,5-Trimethoxybenzoyl )cycloheptanone A mixture of 500 g. of cycloheptanone (4.5 moles), 785 g. of morpholine (9 moles), 900 ml. of toluene and 5 g. of ptoluenesulfonic acid was refluxed for 23 hours, collecting the water produced in the reaction with an azeotropic separator. Ninety-eight ml. of a lower phase was collected and discarded. The remaining mixture was then evaporated in vacuo to give an oil which was distilled. The fraction boiling between 1 l9-125 C. consisting essentially of 262.7 g. of lmorpholino-1-cycloheptene (32 percent yield).

In the manner given in Example 1, 3,4,5-trimethoxybenzoyl chloride (92.5 g.; 0.4 mole) was reacted with 181.37 g. (1 mole) of l-morpholino-l-cycloheptene. The crude product was crystallized from 500 ml. of methanol and gave a first crop of 26 g. of 2 -(3,4,5-trimethoxybenzoyl)cycloheptanone of melting point 99-100 C. After two more recrystallizations from methanol, the product had a melting point of lO7-108 C.

Analysis:

Calcd. for C H O Found: From the above methanolic filtrate another 48.3 g. of 2- (3,4,5-trimethoxybenzoyl)cycloheptanone was obtained as a second crop. The total yield was 61 percent.

EXAMPLE 4 2-(p-Methoxybenzoyl)cyclohexanone A solution of 167 g. (0.98 mole) of p-anisoyl chloride in 480 ml. of chloroform was added during a period of 1.5 hours to a solution of 371.7 g. (2.46 moles) of distilled l-pyrrolidino-lcyclohexene in 1260 ml. of chloroform. The temperature was kept between 5-10 C. by cooling with ice. After stirring for a period of about 20 hours at room temperature, the mixture was decomposed by addition of 1,800 ml. of 10 percent aqueous hydrochloric acid over a period of 20 minutes. The mixture was then stirred for 2 hours, allowed to settle, the organic layer was separated and the aqueous layer extracted twice with 250-ml. portions of chloroform. The original organic layer and the chloroform extracts were combined, washed with water, saturated salt solution, and then dried by passage through sodium sulfate and evaporated. The residue resulting from the above evaporation was a brown oil which was dissolved in l l. of ethanol and added to a solution of 344 g. of cupric acetate monohydrate in 5,200 ml. of water, preheated to 65 C. The mixture was stirred for 0.5 hour, cooled to room temperature and filtered. The obtained precipitate was washed with water and then with ether. It was then dissolved in 800 m1. of chloroform and added to a solution of 300 ml. of concentrated hydrochloric acid in 1,100 ml. of water. The mixture was stirred for 1 hour. The organic layer was separated, and the aqueous layer was extracted once with chloroform. The combined chloroform original layer and extract were washed with water, saturated salt solution, dried by passing through anhydrous sodium sulfate and evaporated, to give a solid which was crystallized from 7 l. of methanol, yielding 136.5 g. of 2-(p-methoxybenzoyl)cyclohexanone having a melting point of 1 15-128 C. A second crop of 26 g., melting point 116-127 C., was obtained from the mother liquor; the total yield was 71 percent. A recrystallized sample from methanol of 2-(p-methoxybenzoyl) cyclohexanone had a melting point of l 17-l22 C.

Analysis:

Calcd. for c,,n,,o,;

Found:

EXAMPLE 5 2-(p-Methoxybenzoyl)cyclopentanone In the manner given in Example 2, 204 g. (1.2 moles) of panisoyl chloride was reacted with l-pyrrolidino-l-cyclopentene prepared from 252 g. (3 moles) of cyclopentanone. The crude product was converted to the copper complex as in Example 4, the complex being crystallized from chloroformether to give g. of copper complex of 2-(p-methoxybenzoyl)cyclopentanone with a melting point of 252 C. (dec.). The copper complex was decomposed with hydrochloric acid to give 67 g. of an oil which was crystallized from methanol to give 13.9 g. of 2-(p-methoxybenzoyl)cyclopentanone of melting point 82-83 C. The filtrate from the first crystallization was evaporated to dryness and the residue crystallized from ether-Skellysolve B hexanes to give 30.1 g. of a second crop of Z-(p-methoxybenzoyl)cyclopentanone of melting point 7677 C. (total yield 17 percent). Two recrystallizations from methanol gave 2-(p-methoxybenzoyl)cyclopentanone having a melting point of 83-87 C.

Analysis:

Calcd. for C I-I O Found:

2-(p-Ethoxybenzoyl)cyclohexanone In the manner given in Example 2, l-piperidino-l-cyclohex- EXAMPLE l4 2-[p-(Methylcarbamoyloxy)benzoyllcyclohexanone In the manner given in Example 2, l-piperidino-l-cyclohexene was reacted with p-ethoxybenzoyl chloride in chloroform 5 ene was reacted with p-methylcarbamoyloxybenzoyl chloride solution to give, after the copper complex purification procedure (Example 2), 2-(p-ethoxybenzoyl)cyclohexanone.

EXAMPLE 7 2-(p-Benzyloxybenzoyl)cyclohexanone In the manner given in Example 2, l-pyrrolidino-lcyclohexene 'wasreacted with p-benzyloxybenzoyl chloride in chloroform solution to give, after the copper complex purification procedure (Example 2), 2-(p-benzyloxybenzoyl)cyclohexanone of melting point I ll-l l 1.5 C.

EXAMPLE 8 EXAMPLE 9 2-(o-Methoxybenzoyl)cyclohexanone In the manner given in Example 2, l-piperidino-l-cyclohexene was reacted with o-methoxybenzoyl chloride in chloroform solution to give, after the copper complex purification procedure (Example 2), 2-(o-methoxybenzoyl)cyclohexanone of melting point 6568 C.

EXAMPLE 1O 2-(o-I-Iydroxybenzoyl)cyclohexanone In the manner given in Example 2, 1-piperidino-l-cyclohexene was reacted with o-acetoxybenzoyl chloride in chloroform solution to give, after the copper complex purification procedure (Example 2), 2-(0-acetoxybenzoyl)cyclohexanone. The thus-obtained 2-(o-acetoxybenzoyl)cyclohexanone was subjected to alkaline hydrolysis, the mixture acidified and the 2-( o-hydroxybenzoyl)cyclohexanone recovered by extraction.

EXAMPLE ll 2-( 2-Methoxy-4-methylbenzoyl)cyclohexanone In the manner given in Example 2, l-piperidino-l-cyclohexene was reacted with 2-methoxy-4-methylbenzoyl chloride in chloroform solution to give, after the copper complex purification procedure (Example 2), 2-( 2-methoxy-4-methylbenzoyl)cyclohexanone.

EXAMPLE l2 2-(p-Methoxybenzoyl)-4,4-dirnethylcyclohexanone In the manner given in Example 2, l-piperidino4,4- dimethyl-l-cyclohexene was reacted with p-methoxybenzoyl chloride in chloroform solution to give, after the copper complex purification procedure (Example 2), 2-(p-methoxybenzoyl)-4,4-dimethylcyclohexanone.

EXAMPLE l3 2-(3,5-Dimethyl-4-methoxybenzoyl)cyclohexanone In the manner given in Example 2, l-pyrrolidino-lcyclohexene was reacted with 3,5-dimethyl-4-methoxybenzoyl chloride in chloroform solution to give, after the copper complex purification procedure (Example 2), 2-(3,5' dimethyl-4-methoxybenzoyl)cyclohexanone of melting point l-l26 C.

in chloroform solution to give, after the copper complex purification procedure (Example 2), 2-[p-(methylcarbamoyloxy)benzoyl]cyclohexanone.

EXAMPLE l5 2-( 3,4-Methylenedioxybenzoyl )cyclohexanone In the manner given in Example 2, l-piperidino-l-cyclohexene was reacted with 3,4methylenedioxybenzoyl chloride in chloroform solution to give, after the copper complex purification procedure (Example 2), 2-(3,4-methylenedioxybenzoyl)cyclohexanone.

EXAMPLE l6 Z-(p-Trifluoromethylbenzoyl)cyclohexanone In the manner given in Example 2, l-piperidino-l-cyclohex ene was reacted with p-trifiuoromethylbenzoyl chloride in chloroform solution to give, after the copper complex purification procedure (Example 2), 2-(p-trifluoromcthylbenzoyl)cyclohexanone.

EXAMPLE l7 2-( p-Chlorobenzoyl)cyclohexanone In the manner given in Example 2, l-piperidinol-cyclohexene was reacted with p-chlorobenzoyl chloride in chloroform solution to give, after the copper complex purification procedure (Example 2), 2-(p-chlorobenzoyl)cyclohexanone.

EXAMPLE l8 2-(p-I-Iydroxybenzoyl)cyclohexanone In the manner given in Example 2, l-piperidinol-cyclohexene was reacted with p-acetoxybenzoyl chloride in chloroform solution to give, after the copper complex purification procedure (Example 2), 2-(p-acetoxybenzoyl)cyclohexanone. The thus-obtained 2-(p-acetoxybenzoyl)cyclohexanone was subjected to alkaline hydrolysis, the mixture acidified and the Z-(p-hydroxybenzoyl)cyclohexanone recovered by extraction.

EXAMPLE l9 2-(o-Methylbenzoyl)cyclohexanone In the manner given in Example,2, l-piperidino-l-cyclohexene was reacted with o-methylbenzoyl chloride in chloroform solution to give, after the copper complex purification procedure (Example 2), 2-(o-methylbenzoyl)cyclohexanone.

EXAMPLE 20 2-(p-Methylbenzoyl)cyclohexanone In the manner given in Example 2, l-pyrrolidino-lcyclohexene was reacted with p-methylbenzoyl chloride in chloroform solution to give, after the copper complex purification procedure (EXAMPLE 2), 2-(p-methylbenzoyl)cyclohexanone of melting point l08-l 10 C.

EXAMPLE 21 2-( 2,4-Dimethylbenzoyl )cyclohexanone In the manner given in Example 2, l-pyrrolidino-lcyclohexene was reacted with 2,4-dimethylbenzoyl chloride in chloroform solution to give, after the copper complex purification procedure (Example 2), 2-(2,4dimethylbenzoyl)c yclohexanone of melting point 5 l-52.5 C.

EXAMPLE 22 2-( 2-Methoxy'4-methylbenzoyl)cyclohexanone In the manner given in Example 2, l-piperidino-l-cyclohexene was reacted with 2-methoxy-4-methylbenzoyl chloride in chloroform solution to give, after the copper complex purification procedure (Example 2), 2-(2-methoxy-4-methylbenzoyl)cyclohexanone.

EXAMPLE 23 EXAMPLE 24 2-(p-Allyloxybenzoyl)cyclohexanone In the manner given in Example 2, l-piperidino-l-cyclohexene was reacted with p-allyloxybenzoyl chloride in chloroform solution to give after the copper complex purification procedure (Example 2), 2-(p-allyloxybenzoyl)cyclohexanone.

EXAMPLE 25 2-[p-(Carboxymethoxy)benzoyljcyclohexanone In the manner given in Example 2, l-piperidino-l-cyclohexene was reacted with p-(carboxymethoxy)benzoyl chloride in chloroform solution to give, after the copper complex purification procedure (Example 2), 2-[p-(carboxymethoxy)benzoyl]cyclohexanone.

EXAMPLE 26 2-(p-Benzyloxybenzoyl)cycloheptanone In the manner given in Example 2, l-pyrrolidino-lcycloheptene was reacted with p-benzyloxybenzoyl chloride in chloroform solution to give after the copper complex purification procedure (Example 2), 2-(p-benzyloxybenzoyl)cycloheptanone.

EXAMPLE 27 2-(p-Ethoxybenzoyl)cyclooctanone In the manner given in Example 2, l-morpholino-l-cyclooctene was reacted with p-ethoxybenzoyl chloride in chloroform solution to give, after the copper complex purification procedure (Example 2), 2-(p-ethoxybenzoyl)cyclooctanone.

EXAMPLE 28 2-(2,3,4-Trimethoxybenzoyl)cyclooctanone In the manner given in Example 2, l-piperidino-I-cyclooctene was reacted with 2,3,4-trimethoxybenzoyl chloride in chloroform solution to give, after the copper complex purification procedure (Example 2), 2-(2,3,4-trimethoxybenzoyl)cyclooctanone.

EXAMPLE 29 2-(p-Bromobenzoyl)cyclooctanone In the manner given in Example 2, l-piperidino-l-cyclooctene was reacted with p-bromobenzoyl chloride in chloroform solution to give, after the copper complex purification procedure (Example 2), 2-(p-bromobenzoyl)cyclooctanone.

EXAMPLE 30 to 10 nuclear atoms, inclusive, with a selected benzoyl chloride. Representative starting materials, thus prepared, include: 2-(3,5-diiodobenzoyl) cyclopentanone; 2-(pfluorobenzoyl)cyclohexanone; 2-( 2-methoxy-4- chlorobenzoyl )cyclohexanone; 2-( 2-methoxy-3-methylbenzoyl) cyclohexanone; 2(2-methyl-4-trifluoromethylbenzoyl)cyclohexanone; 2-(3,4-dipropylbenzoyl)cycloheptanone; 2-(2,5-dich1orobenzoyl) cycloheptanone; 2-(3,4- dichlorobenzoyl )cyclooctanone; 2-( p-propoxybenzoyl)cyclooctanone; 2-( 2,5-dii0dobenzoyl )cycloheptanone; 2-(3-fluorobenzoyl)cyclopentanone; 2-(pbromobenzoyl)cyclopentanone; 2-(p-hexylbenzoyl)cyclopentanone; 2-( 3-pentylbenzoyl )cyclohexanone; 2-( 2-bu tylbenzoyl)cyclohexanone; 2-( 2-propylbenzoyl)cycloheptanone; 2-( 3-ethylbenzoyl )cyclooctanone; 2-( 2-methoxy-5- bromo)cyclopentanone; 2benzoylcyclooctanone; 2-benzoylcycloheptanone; and the like.

EXAMPLE 31 3,4,5-Trimethoxyphenyl 2-piperidinol -cyclohexenl-yl ketone A mixture consisting of 35 g. (0.12 mole) of 2-(3,4,5- trimethoxybenzoyl)cyclohexanone, 30.6 g. (0.36 mole) of piperidine, 960 ml. of toluene, and 0.8 g. of p-toluenesulfonic acid was refluxed for 23 hours under nitrogen using an azeotropic separator (during this time 1.8 ml. of water was collected). The mixture was thereupon evaporated to dryness to give partially crystalline 3,4,5-trimethoxyphenyl 2- piperidino- 1 -cyclohexen- 1 -yl ketone.

EXAMPLE 3 2 a-( 3 ,4,5-Trimethoxyphenyl )-2-piperidinocyclohexanemethanol and its hydrochloride A solution of 3,4,5-trimethoxyphenyl 2-piperidino-1- cyclohexen-l-yl ketone prepared from 35 g. of 2-(3,4,5- trimethoxybenzoyl)cyclohexanone and 30.6 g. of piperidine, as in Example 31] in 300 ml. of ethanol was hydrogenated in the presence of 1.2 g. of platinum oxide at an initial pressure of 50.1 pounds of hydrogen. Two molar equivalents of hydrogen were taken up during 3.5 hours. The mixture was filtered through a filter aid and evaporated to dryness. The oily residue was dissolved in 400 ml. of ether and 400 ml. of 10 percent aqueous hydrochloric acid was added. The thus-obtained reaction mixture was stirred for 0.5 hour. A suspension was obtained which was filtered, yielding an original filtrate" and a solid which was washed with ether. The solid was twice recrystallized from methanol to give 14.7 g. of a-(3,4,5- trimethoxyphenyl-Z-piperidinocyclohexanemethanol hydrochloride of melting point 265-266 C. An analytical sample, prepared by additional recrystallization from methanol had a melting point of 266267 C. Ultraviolet: sh 228 (8,100); sh 232; A max. 269 (825); sh 278 (612).

Analysis:

Calcd. for C H NOJ'ICI:

C, 63.06; H, 8.57; Cl, 8.87; N, 3.50 Found: C, 62.99; H, 8.24; Cl, 8.66; N, 3.46

The above original filtrate was separated into layers, the aqueous layer was extracted with ether and then basified and extracted with methylene chloride. The extract was washed with water and saturated salt solution, then dried by pouring through anhydrous sodium sulfate and the water-free solution was evaporated to give 5.0 g. of an oil. The oil was converted to the hydrochloride with ethereal hydrogen chloride to give a second crop of 0.7 g. of a-(3,4,5-trimethoxyphenyl)-2- piperidinocyclohexanemethanol hydrochloride (total yield 32 percent; 15.4 g.).

The ether layer, after washing, drying and evaporation, gave 6.1 g. of an oil which was redissolved in ether and allowed to crystallize, yielding 0.5 g. of a-(3,4,5-trimethoxyphenyl)-2- hydroxycyclohexanemethanol of melting point -l31 C. (after additional recrystallization from ether).

Analysis:

Calcd. for c,,r-r,,o,=

Found: v c, 64.69; H, 8.29

EXAMPLE 33 3 ,4,5-Trimethoxyphenyl 2-morpholino- 1 -cyclohcxenl -yl EXAMPLE 34 a-( 3 ,4 ,5-Trimethoxyphenyl )-2-morpholinocyc1ohexanemethanol and its hydrochloride A solution of 3,4,5-trimethoxyphenyl 2-morpholino-lcyclohexen-l-yl ketone [produced as in Example 33 from 8.75 g. of 2,-(3,4,5-trimethoxybenzoyl)cyclohexanone] in 100 ml. of ethanol was hydrogenated in the presence of 0.3 g. of platinum oxide catalyst at an initial hydrogen pressure of 52.5 pounds. Two molar equivalents of hydrogen were taken up during a period of 6 ours. The mixture was filtered through diatomaceous earth (Filtercel) and evaporated to dryness. The resulting oil was dissolved in 100 ml. of 10 percent aqueous hydrochloric acid, 100 ml. of ether was added and the mixture was stirred for one-half hour. The aqueous layer was extracted twice with two 50-ml. portions of ether. The ether extracts were combined, washed with water, then with saturated salt solution, and finally dried by passage through anhydrous sodium sulfate. The thus-obtained solution was evaporated to give 2.3 g. of an oily material which after crystallization from ether gave 1 g. of 1-(3,4,5-trimethoxybenzoyl)-l-cyclohexene of melting point 73 74 C.

The above aqueous layer was cooled in ice, basified by adding sodium hydroxide solution and extracted with methylene chloride (three portions of 100 ml.). The extracts were combined, washed with water and saturated salt solution, and dried by passing through anhydrous sodium sulfate. The thusobtained solution was concentrated to give 7.89 g. of an oily material which was converted to the hydrochloride by adding a solution of hydrogen chloride in ether. The solid thus obtained was recrystallized frommethanol-ether to give 5 g. (42 percent yield) of a-(3,4,5-trimethoxyphenyl)-2-morpholinocyclohexanemethanol hydrochloride of melting point 20520 6 C.

Ultraviolet: sh 288 (8,150); sh 236 (6,350); A max. 269 (788); sh 278 (555).

Analysis:

Calcd. for C ,,H ,NO -HCl:

C, 59.76; H, 8.03; Cl, 8.82; N, 3.49 Found: C, 59.81; H, 8.52; l, 8.52; N, 3.57

Example 35 2-( 4-methyll -piperazinyl)- 1- Example 36 a-( 3 ,4,5-Trimethoxyphenyl )-2-(4-methyll -piperazinyl)cyclohexanemethanol dihydrochloride A solution of 3,4,5-trimethoxyphenyl 2-(4-methyl-lpiperazinyl)-l-cyclohexenl-yl ketone, prepared from 8.75 g. of 2-(3,4,5-trimethoxybenzoyl)cyclohexanone as in Example 35, was dissolved in ml. of methanol and then hydrogenated in the presence of 0.3 g. of platinum oxide at an initial pressure of 54 pounds. After 6.5 hours, the hydrogenation became sluggish, therefore, 0.03 mole of acetic acid and 0.3 g. of platinum oxide were added. After another period of 3 hours a total of 2 molar equivalents of hydrogen was absorbed. The mixture was filtered through diatomaceous earth (Filtercel) and evaporated to dryness. The resulting oil was dissolved in 100 ml. of 10 percent aqueous hydrochloric acid and 100 ml. of ether and the solution was stirred for 0.5 hour. The aqueous layer was extracted with three SO-ml. portions of methylene chloride. The extracts were discarded. The aqueous solution was then basified and extracted with four portions of 50 ml. each of methylene chloride. The methylene chloride extracts were combined, washed with water and with saturated salt solution, dried by passing through anhydrous sodium sulfate and evaporated to give 5.9 g. of oil. This oil was dissolved in ether and then acidified with 35 ml. of 2N ethereal hydrogen chloride. The resulting solid was recrystallized from methanol, yielding 4.4 g. (31 percent yield) of a-(3,4,5- trimethoxyphenyl )-2-(4-methyll -piperazinyl )cyclohexanemethanol dihydrochloride hemimethanol solvate of melting point 232-233 C.

Ultraviolet: sh 228 (8,400); sh 234.5 (6,850); A max. 270.5 (980); sh 278 (915).

Analysis:

Calcd. for C ,l-l N,O;2HCl' /& cruou;

C, 55.24; H, 8.19; Cl, 15.17; Found: C, 54.90; H, 8.05; CI, 15.30;

Example 37 p-Methoxyphenyl 2-piperidinol -cyclohexen- 1 -yl ketone In the manner given in Example 31, 23.2 g. (0.1 mole) of 2- (p-methoxybenzoyl)cyclohexanone was heated with 25.5 g. (0.3 mole) of piperidine in 800 ml. of toluene in the presence of 0.67 g. of p-toluenesulfonic acid to give p-methoxyphenyl 2-piperidino-l-cyclohexen-1-y1 ketone.

Example 38 Cis-A-a-(p-methoxyphenyl)-2-piperidinocyclohexanemethanol A solution of p-methoxyphenyl 2-piperidino-l-cyclohexenl-yl ketone (obtained from a synthesis of the same scale as shown in Example 37) in 300 m1. of ethanol was hydrogenated in the presence of l g. of platinum oxide under an initial hydrogen pressure of 51 pounds. Two molar equivalents of hydrogen were absorbed during a period of 2.5 hours. The mixture was filtered through Filtercei diatomaceous earth. The filtrate was then evaporated to dryness and the residue dissolved in 250 ml. of ether. The ether solution upon standing produced crystals which were recovered by filtration and washed with ether. One g. of material was obtained having a melting point l52-l68 C. This material after recrystallization from methanol-ether was found to be the p-toluenesulfonic acid salt of cis-A-a(p-methoxyphenyl)2-piperidinocyclohexanemethanol of melting point l82l 83 C. Ultraviolet: A max. 223 (21,800); sh 256 (705); sh 262 (980); sh 268 1,360); 275 (1,530); 282 (1,280).

Analysis:

Calcd. for CgeHa N0 5:

C, 65.66; H, 7.84; N, 2.95; S, 6.74

Found: C, 65.27; H, 7.88; N, 2.89; S, 6.86

The ethereal filtrate above was stirred with 200 ml. of percent aqueous acetic acid for 9% hour. The aqueous layer was separated, then extracted once with ether, and the ether extract discarded. The aqueous layer was then cooled, basified with aqueous sodium hydroxide solution and extracted with methylene chloride (four portions of 75 ml. each. The extracts were combined, washed with water, saturated salt solution, dried by passing the solution through anhydrous sodium sulfate and evaporated to give 22.5 g. of oily material. This material was recrystallized from petroleum ether to give 21.4 g. (71 percent yield) of cis-A-a-(p-methoxyphenyl)-2- piperidinocyclohexanemethanol of melting point 7880 C. Ultraviolet: A max. 225 (1 1,500); 275 (1,500); 283 (1,300).

Analysis:

Calcd. for C H NO C, 75.20; H, 9.63; N, 4.62 Found: C, 75.17; H 9.88- N 4.47

The above configurations are simplified. For example, a truer representation of the cis form above would be the configurations (X) and (Y) below.

cis trans In the configuration (X) the p-methoxybenzoyl group (at 1) is attached by an axial bond (a) to the cyclohexane moiety (chair form) and the piperidino group (at 2) by an equatorial bond (e). While this would indicate the existence of a cis isomer with reversed grouping, i.e., p-methoxybenzoyl on an equatorial bond and piperidino on an axial bond, such an isomer is thermodynamically less stable under ordinary conditions. However, the optical isomers (Y) and (X) of the cis form are stable and thus the simplified cis configuration represents a mixture of (X) and (Y). 1n the trans form, the equatorial-equatorial positions of the vicinal substituents is the thermodynamically stable configuration and thus only one trans-p-methoxyphenyl 2-piperidinocyclohexyl ketone consisting of two optical forms, as for the cis compound, is obtained.

EXAMPLE 39 Cis-p-methoxyphenyl 2-piperidinocyclohexyl ketone A mixture of 139 g. (0.6 mole) of 2-(p-methoxybenzoyl)cyclohexanone, 153 g. (1.8 moles) of piperidine,

4800 ml. of toluene and 4.02 g. of p-toluenesulfonic acid monohydrate was refluxed for 20 hours in a vessel equipped with an azeotropic separator. A total of 10.1 ml. of water was collected. The reaction mixture was evaporated to dryness on a steam bath to give a residue which was dissolved in 1,200 ml. of ethanol and the thus-obtained solution was divided into four equal parts. Each part was hydrogenated in the presence of 1.5 g. of platinum oxide at an initial pressure of 50 pounds of hydrogen. Hydrogenation was stopped after the uptake of 1 molar equivalent. The time required for this procedure was 25 minutes to 55 minutes. Thereafter, the combined mixture was filtered through diatomaceous earth, and the solution was evaporated to dryness. A deep yellow oil was obtained which was dissolved in 1,200 ml. of ether and allowed to stand for 15 minutes. The mixture was thereupon filtered and a precipitate was collected weighing 5.3 g. The ethereal filtrate was stirred with 1 l. of 10 percent aqueous hydrochloric acid for 45 minutes. The acidic layer was separated, filtered and basified with 20 percent aqueous sodium hydroxide solution. The resulting oil which solidified after a short time was extracted with methylene chloride (five portions of 200 ml. each), the extracts were combined, washed with water, then with saturated salt solution, dried over anhydrous sodium sulfate and evaporated to give a crude product of l 16 g. Recrystallization of this crude product from petroleum ether gave 75 g. (42 percent yield) of colorless needles of cis-p-methoxyphenyl Zpiperidinocyclohexyl ketone having a melting point of 8688 C. Further recrystallization from petroleum ether for analytical purposes gave cis-p-methoxyphenyl 2-piperidinocyclohexyl ketone of melting point 86.5-88 C.

Ultraviolet: A max. 217 (11,850 273 (15,800); 278 (15,500).

Analysis:

Calcd. for C H NO C, 75.71; H, 9.03; N, 4.65 Found: C, 76.19; H, 9.19; N, 4.88

EXAMPLE 40 Trans-p-methoxyphenyl 2-piperidinocyclohexy1 ketone A solution of 68.3 g. (0.227 mole) of cisp-methoxyphenyl 2-piperidinocyclohexyl ketone was refluxed for 68 hours in 683 m1. of piperidine. The reaction mixture was thereupon evaporated to dryness to give 55 g. of a residual oil which was dissolved in 500 ml. of ether and extracted with four portions of ml. each of 10 percent aqueous acetic acid. The acid extracts were combined, cooled in ice and basified with 20 percent aqueous sodium hydroxide solution and thereupon extracted with four portions of ml. each of methylene chloride. The methylene chloride extracts were combined, washed with saturated salt solution, dried over anhydrous sodium sulfate and evaporated to give 22 g. of a colorless solid which was crystallized from 150 m1. of petroleum ether (boiling range from 30-60 C.) to give 12.05 g. of trans-p-methoxyphenyl Z-piperidinocyclohexyl ketone of melting point 100-l01 C. A second crop of 3.5 g. of the same material was also obtained; a total of 23 percent yield. Ultraviolet: A max. 216 (12,900); 271 (15,350).

Analysis:

Calcd. for C ,H, NO

C, 75.71; H, 9.03; N, 4.65 Found: C, 75.28; H, 8.66; N, 4.62

The original ether layer above contained also l-(p-methoxy-benzoyl)-l-cyclohexene, a yellow oil boiling at l45-155 C.

Analysis:

Calcd. for C H O .7 EXAMPLE 41 Cis-A-a-( p-methoxyphenyl )-2-piperidinocyclohexanemethanol v H (in t A solution of 'cis-p-methoxyphenyl Z-piperidinocyclohexyl ketone (3.01 g.; 0.01 mole) in 100 ml. of ethanol was subjected to hydrogenation inthe presence of platinum oxide (0.3 g.) atan' initial pressure of 53 pounds of hydrogen. One molar equivalent was absorbed in 25 hours. The mixture was filtered, and the filtrate was evaporated to dryness, giving 3.1 g. of an oily material. A.2 .9-g. portion of this oil was chromatographed over 150 g. of Florisil (anhydrous magnesium silicate) using 150-m1. portions of an eluant of 6 percent acetone-94percent Skellysolve B hexanes. The first four fractions containing Since the carbon atom of the methanol group of a-(p- 'methoxyfphenyl)-2-piperidinocyclohexanemethanol is asymmetric, it is obvious that besides the cis-A-alcohol, the cis-B- alcohol is possible (Example 42).

EXAMPLE 42" Cis-A- I and cis-B-a-(p-methoxyphenyl)-2-piperidinocyclohexanemethanol 1 Solid cis-p-methoxyphenyl 2-piperidinocyclohexyl ketone (3.01 g.; 0.01 mole) was added, to an ice-cooled solution of sodium borohydride (3 g.) in 100 ml. of ethanol. The reaction mixture was then stirred at room temperature (22-25 C.) for a period of .16 hours. It was evaporated to dryness in vacuo at 40 C. To. the residue was added 100 ml. of water, and the mixture was then stirred for 30 minutes. The resulting oil was extracted three times with ether. The ether extracts were combined, washed with water, the water discarded, then washed with four 25-ml. portions of percent aqueous acetic acid. The acidic extract was washed once with ether, and the ether discarded. It was then cooled in ice and basified with percent sodium hydroxide solution. The reaction mixture was then extracted three times with ether, the extracts combined, washed with water, then with saturated salt solution, dried over anhydrous sodium sulfate and evaporated to give 3 g. of an oil. The oily material was crystallized from 50 ml. of petroleum ether (boiling range 30-60 C.) to give 1.8 g. of cis-A-a-(p-methoxyphenyl)-2-piperidinocyclohexanemethanol, melting point 78-80 C.

The filtrate was evaporated todryness, and the residue was chromatographed on 60 g. of Florisil (anhydrous magnesium silicate). The column of Florisil was eluted twice with 150-m1. portions ofan eluantconsisting of 6 percent acetone and 94 percent Skellysolve B hexanes; four times with 150-ml. portions of an eluant consisting of 12 percent acetone and 88 percent Skellysolve B hexanes; and finally three times with 150- ml; portions of a percent acetone-80 percent Skellysolve B hexanes solution, giving 0.576 g. of cis-A-alcohol, which after recrystallization from petroleum ether had a melting point of 80-81 C. Elution with 50 percent acetone-50percent Skellysolve B hexanes (four portions of 150 ml. each) and acetone (two portions of '250 ml. each) gave 0.316 g. of cis-B-a-(pmethoxyphenyl)-Z-piperidinocyclohexanemethanol, which after recrystallization from ether weighed 0.1 g. and had a melting point of 135-l 36 C.

These cis alcohols A and B can also be produced from cis-pmethoxyphenyl Z-piperidinocyclohexyl ketone by reduction with lithium aluminum hydride.

EXAMPLE 43 Cis-A- and cis-B-a-(p-methoxyphenyl)-2-piperidinocyclohexanemethanol A solution of 0.9 g. (Bmmoles) of cis-p-methoxyphenyl 2 piperidinocyclohexyl ketone in 25 ml. of ether was added dropwise during 5 minutes to a solution containing 1 g. of lithium aluminum hydride in 100 ml. of ether..The mixture was stirred during a period of 22 hours and was then decomposed by successive addition of 1 ml. of water, 1 ml. of 15 percent aqueous sodium hydroxide and 3 ml. of water. The resulting suspension was stirred for a period of 2 hours. It was then filtered and the solid washed with ether. The combined filtrate and washings were extracted with three portions of 30 ml. each of 10 percent aqueous acetic acid, and the combined acidic extracts were backwashed once with ether. The acidic extract was then basified with 15 percent aqueous sodium hydroxide and extracted three times with ether. The combined ether extracts were washed with water, saturated salt solution, and dried by passage through anhydrous sodium sulfate. The

resulting dried solution was evaporated to give 0.77 g. of a colorless oil. This oil was chromatographed over 35 g. of Florisil (anhydrous magnesium silicate) by eluting with an eluant consisting of 6 percent acetone and 94 percent Skellysolve B hexanes. The first four fractions of 150 ml. each gave 0.607 g. (67 percent yield) of cis-A-a-(p-methoxyphenyl)-2- piperidinocyclohexanemethanol(melting point -81 C.). Further elution with an eluant consisting of 12 percent acetone and 88 percent Skellysolve B hexanes gave, in four -ml. fractions, 0.209 g. of cis-B-a-(p-methoxypheny)-2- piperidinocyclohexanemethanol of melting point l34-l35 C. (23 percent yield).

EXAMPLE 44 Trans-C-a-(p-methoxyphenyl)-2-piperidinocyc1ohexanemethanol 1n the manner given in Example 41, trans-p-methoxyphenyl Z-piperidinocyclohexyl ketone (3.01 g.; 0.01 mole) was hydrogenated in ethanol solution in the presence of 0.5 g. of platinum oxide catalyst at 53 pounds initialhydrogen pressure. The solution after 138 minutes of hydrogenation was filtered through Filtercel diatomaceous earth. The filtrate was evaporated giving 3 g. of a solid of melting point 14l-l45 C. This solid was crystallized from methanol to give 2.5 g. of colorless needles of trans-C-a-(p-methoxyphenyl)-2- piperidinocyclohexanemethanol of melting point l48-l49 C. A second crop of 0.25 g. of product was obtained from the filtrate; the total yield was 91 percent. Ultraviolet: 225 (12,150); 275 (1,500); 281 (1,300).

Analysis:

Calcd. for G i-1 EXAMPLE 45 20; H, 9.63; N, 4.62 l

5. Found: 5. 8; H, 9.81; N, 4.82

thereupon extracted twice with methylene chloride. The combined extract was washed with water, saturated salt solution, dried by passage through anhydrous sodium sulfate and evaporated to give 0.6 g. of a colorless solid of melting point 129-l40 C. Crystallization from methanol yielded 0.325 g. of recovered starting material of melting point l45l47 C. The filtrate was evaporated to dryness and the residue was chromatographed over g. of Florisil (anhydrous magnesium silicate). The column containing the Florisil was eluted with 400 ml. of a solution containing 6 percent acetone and 94 percent Skellysolve B hexanes. The filtrates from the solution were combined and evaporated, and the residue was recrystallized from petroleum ether (boiling range 30-60 C.) to give 77 mg. of a product melting at 8l82 C., namely trans-D-a- (p-methoxyphenyl)-2-piperidinocyclohexanemethanol. Ultraviolet: 226 (1 1,000); 276 1,650); 282 1,450).

Analysis:

Calcd. for C H,,NO,:

EXAMPLE 46 Trans-C- and trans-D-a-(p-methoxyphenyl)-2-piperidinocyclohexanemethanol A solution of trans-p-methoxyphenyl 2-piperidinocyclohexyl ketone (23.9 g.; 0.0795 mole) in 575 ml. of ether was added to a solution of 24 g. of lithium aluminum hydride in 2,400 ml. of ether over a period of 30 minutes. The mixture was then stirred for about hours. It was thereupon decomposed successively with 24 ml. of water, 24 ml. of 15 percent aqueous sodium hydroxide and 72 ml. of water. The resulting mixture was filtered and the cake was washed with ether. The combined filtrate and washings were evaporated to dryness to give 22.5 g. of a colorless oily solid which upon crystallization from 75 ml. of ethanol gave 13.4 g. of trans-C-a-(p-methoxyphenyl)-2-pi eridinocyclohexanemethanol of melting point l45- 1 46 C.

The filtrate was evaporated to dryness. The residue was dissolved in 50 ml. of methylene chloride and chromatographed over 460 g. of Florisil (anhydrous magnesium silicate). The column containing the Florisil was eluted with 750 ml. of an eluant consisting of 3 percent acetone and 97 percent Skellysolve B hexanes. This fraction yielded 81 mg. of solid which was discarded; thereupon were taken 19 250-ml. portions using an eluant consisting of 6 percent acetone and 94 percent Skellysolve B hexanes. These fractions were combined and evaporated to give 5.31 g. of solid melting at 80-82 C. Further elution with an eluant consisting of 15 percent acetone and 85 percent Skellysolve B hexanes (4 fractions of 250 ml. each) gave 0.535 g. of solid melting at 808l C. Recrystallization of the combined material from petroleum ether afforded 4.6 g. of trans-D-a-(p-methoxyphenyl)-2- piperidinocyclohexanemethanol of melting point 8 l-82 C.

Nuclear magnetic resonance spectrum (in CDCl;,) showed methoxy at 229 cps; broad band for benzylic hydrogen centered at 278.5 cps.

Found:

EXAMPLE 47 Cis-B-a-(p-methoxyphenyl)-2-piperidinocyclohexanemethanol A solution was prepared having 30.3 g. (0.1 mole) of cis-A- a-(p-methoxyphenyl)-2-piperidinocyclohexanemethanol in 200 ml. of trifluoroacetic acid, under cooling with ice. The mixture was then stirred at room temperature for 20 minutes, giving a greenish solution which was again cooled in ice. To this solution was added 150 g. of ice followed by 500 ml. of water and then 500 ml. of 20 percent aqueous sodium hydroxide. The mixture was stirred for 15 minutes and was thereupon extracted with five portions of 200 ml. each of methylene chloride. The methylene chloride extracts were combined, washed with water, saturated salt solution, then dried by passage through anhydrous sodium sulfate and evaporated to Analysis:

Calcd. for C,,H ,NO,:

C, 75.20; H, 9.63; N, 4.62 Found: C, 74.96; H, 9.62; N, 4.55

EXAMPLE 48 a-( 3,4,5-Trimethoxyphenyl )-2-( hexahydrol H-azepinl yl)cyclohexanemethanol hydrochloride OCH;

H 60H; N

A mixture of g. (0.12 mole) of 2-(3,4,5-trimethoxybenzoyl)cyclohexanone, 35.6 g. (0.36 mole) of hexamethyleneimine, 960 ml. of toluene and 0.8 g. of ptoluenesulfonic acid was refluxed for 7.5 hours in a nitrogen atmosphere in a vessel equipped with an azeotropic separator. A total of 1.8 ml. of water was collected. The mixture was thereupon evaporated to dryness, the residue was dissolved in 250 ml. of ethanol and hydrogenated in the presence of 1.2 g. of platinum oxide at an initial pressure of 5 1.5 pounds of hydrogen. Two molar equivalents of hydrogen were absorbed during 5 hours. The reaction mixture was then filtered through diatomaceous earth (Filtercel), and the filtrate was evaporated to dryness. The thus-obtained residue was dissolved in 400 ml. of ether. The ether solution was stirred with 400 ml. of 10 percent hydrochloric acid for 0.5 hours, and the resulting suspension was filtered. The obtained solid was washed with ether to give 18.2 g. of material. This material was crystallized from 250 ml. of methanol to give 16.4 g. of a- 3 ,4,5-trimethoxyphenyl )-2-(hexahydrol l-l-azepinl yl)cyclohexanemethanol hydrochloride of melting point 244-246 C.

Ultraviolet: sh 288 (8,250); 268 (757); 276 (608).

Analysis:

Calcd. for C rr nza-H01;

C, 63.83; H, 8.77; Cl, 8.56; N, 3.38 Found: C, 63.95; H, 9.13; Cl, 8.47; N, 3.58 Workup of the aqueous hydrochloric acid filtrate above provided another 0.7 g. of a-(3,4,5-trimethoxyphenyl)-2- hexa-hydrol l-l-azepinl -yl)cyclohexanemethanol v hydrochloride of melting point 242-243 C.; thus a total yield of 34 percent.

EXAMPLE 49 l-l-azepinl reaction mixture was added a solution of 102 g. 0.6 mole) of 1 p-anisoyl chloride in 240 ml. of purified chloroform during a period of 2 hours while keeping the temperature between 5 to C. A suspension resulted which was stirred for a period of about hours at room temperature. The suspension was thereupon filtered, and the precipitate washed with ether, the ether wash being discarded. The precipitate was 46.8 g. of triethylamine hydrochloride of melting point 3-254 C.

' The chloroform filtrate was evaporated to dryness. The resulting residue was dissolved in 900 ml. of ethanol and hydrogenated in three portions, each in the presence of l g. of platinum oxide at a hydrogen pressure of about 50-52 pounds. After the absorption of about 80 percent of the hydrogen had taken place, the hydrogenation stopped and another 1 g. of platinum oxide was added. Two molar equivalents of hydrogenwere absorbed during 22 hours. The resulting thick suspension was filtered and the precipitate washed with ethanol. The moist cake was refluxed with 1,500 ml. of ethanol, .filtered and allowed to crystallize. The first crop of crystals amounted to 80.7 g.,of cis-A-a-(p-methoxyphenyl)-2- (hexahydrolH-azepinl -yl)cyclohexanemethanol hydrochloride of melting point of 230-23 1 C. A second crop of 20 g. was also collected. Further recrystallization did not change the melting point of the product.

Ultraviolet: )1 maxy226 12,150); 276 1,550); 282 1,350).

Analysis:

Calcd. for c,,,H ,,No,-Hcl= C, 67.87; H, 9. l2; Cl, 10.02; Found: C, 67.27; H, 9.14; Cl,

EXAMPLE 50 a(p-Trifluoromethylphenyl)-2-(hexahydro-lH-azepin-lyl)cyclohexanemethanol hydrochloride In the mariner given in Example 49, 0.1 mole of triethylamine and 0.1 mole of l-hexamethyleneimino-lcyclohexene was reacted irichloroform solution with 0.1 mole of p-trifluoromethylbenzoyl chloride. The resulting product was hydrogenated in 300 ml. of methanol in the presence of l g. of platinum oxide. Two molar equivalents of hydrogen were absorbed in 3.5 hours. The hydrogenation reaction mixture was filtered through diatomaceous earth (Filtercel) and the filtrate evaporated to dryness. The resulting solid was suspended in 200 ml. of ether and 200 ml. of 10 percent aque ous acetic acid, and the suspension was stirred for a period of 3.5 hours. The suspension was then filtered, and the solid washed with water followed by ether. Thirteen and four-tenths g. of solid was thus obtained which was recrystallized from methanol giving a-(p-trifluoromethylphenyl)-2-(hexa-hydro-1 H-azepin-l-yl)cyclohexanemethanol hydrochloride of melting point 263-264 C. v

Ultraviolet: A max. 216 (8,050); 252 (298); 257 (357); 263 (364);269(290).

Analysis:

Calcd. for C ,,H F NO-HC1:

C, 61.29; H, 7.46; Cl, 9.05; F, 14.54; found: C, 60.89; H, 7.58; Cl, 9.17;

EXAMPLE 51 N, 3.57 F, 13.96; N, 3.66

ml. of ethanol, heated to reflux, filtered and the solution allowed to crystallize. Filtration yielded 12.25 g. of a-(pchlorophenyl )-2-( hexa-hydrol H-azepin- 1 -yl)cyclohexanemethanol hydrochloride of melting point 274-275 C. Ultraviolet: A max. 221 (10,000); sh 226 (8,200); 252 (182); 258 (210); 267 (260); 275 (193).

Analysis:

Found: N, 3.98

EXAMPLE 52 a-Phenyl-2-( hexahydrolH-azepinl -yl)cyclohexanemethanol hydrochloride in the manner given in Example 49, 0.1 mole of triethylamine, 0.1 mole of l-hexamethylimino-l-cyclohexene and 0.1 mole 14 g.) of benzoyl chloride were reacted, and the reaction product hydrogenated in methanol in the presence of platinum oxide for a period of 2.5 hours. The mixture was filtered, evaporated to dryness and the solid residue was suspended in 200 ml. of ether and 200 ml. of 10 percent aq ueous acetic acid. The mixture was stirred for 0.5 hour and the resulting suspension filtered yielding a solid which was washed with water followed by ether. The thus-obtained product, 3.6 g., was recrystallized from methanol to give 2.8 g. of a-phenyl- 2-( hexahydro- 1 l-l-azepin- 1 -yl )cyclohexanemethanol hydrochloride of melting point 276277" C. Ultraviolet: A max. 247 (107.); 252 (130); 257 (178); 263 (130);267(91). 7

Analysis:

Calcd. for C H NO'HCl:

C, 70.45; H, 9.34; CI, 10.95; N, 4.33 Found: C, 70.22; H, 8.94; CI, 11.03; N, 4.45

EXAMPLE 53 a-( 3,4-Methylenedioxyphenyl )-2-(hexahydrol l-l-azepin- 1 yl)cyclohexanemethanol hydrochloride 1 A solution of piperonyloyl chloride in ml. of chloroform was added during 1.5 hours with cooling and stirring to a solution of l-hexamethyleneimino-l-cyclohexene (53.6 g.; 0.3 mole) and 30.3 g. (0.3 mole) of triethylamine in 126 ml. of chloroform at a'temperature below 10 C. The reaction mixture was then stirred for about 20 hours at a temperature between 23-26 C. The thus-obtained suspension was filtered to give 23 g. of triethylamine hydrochloride melting at 252254 C. The filtrate was evaporated to dryness, the residue was dissolved in 600 ml. of ethanol and hydrogenated in the presence of 3 g. of platinum oxide'at an initial pressure of 52.5 pounds of hydrogen. After 6 hours, a l g. quantity of platinum oxide catalyst was added and hydrogenation continued for another 16 hours. The resulting suspension was filtered and the solid, consisting of the product and catalyst, was refluxed in 1,800 ml. of ethanol; this suspension was. filtered, evaporated to 900 ml. and allowed to crystallize, yielding 50 g. of a-( 3 ,4-methylenedioxyphenyl)-2-(hexahydro-ll-l-azepin-1- yl)cyclohexanemethanol hydrochloride of melting point 235236 C.

Work-up of the filtrate by evaporation and stirring with 400 ml. of 10 percent aqueous acetic acid and 450 ml. of ether gave another 10 g. of solid material which after recrystallization from ethanol gave 5 g. of a-(3,4-methylenedioxyphenyl)- 2-(hexa-hydrol l-l-azepinl yl)cyclohexanemethanol hydrochloride of melting point 233-234 C.

Ultraviolet: A max. 235 (4,150); 286 (4,050).

Analysis:

Calcd. for c,,,i-l,,,No,-Hcl:

C, 65.29; H, 8.22; Cl, 9.64; N, 3.81

Found: C, 65.18; H, 8.38; CI, 9.93; N, 3.79

The above compound is useful as a diuretic and oral antidiabetic agent.

EXAMPLE 54 a-( 3 ,4-Dimethoxyphenyl )-2-( hexahydro- 1 H-azepin- 1 -yl) cyclohexanemethanol hydrochloride In the manner given in Example 53, l-hexamethyleneiminol-cyclohexene was reacted with 3,4-dimethoxybenzoyl chloride (53.6 g.; 0.3 mole) in the presence of triethylamine. The resulting product was hydrogenated in the presence of platinum oxide and the mixture was worked up as in Example 53 giving 52.2 g. of a-(3,4-dimethoxyphenyl)-2-(hexahydrolH-azepin-l-yl)cyclohexanemethanol hydrochloride of melting point 225-228 C. in the first crop. Additional material was obtained by the work-up of filtrates with acetic acid and ether. A total yield of about 50 percent was obtained. The analytical sample, prepared by recrystallization from ethanol, gave a-(3,4-dimethoxyphenyl)-2-(hexahydro-lH-azepin-lyl)cyclohexanemethano1 hydrochloride of melting point 225226 C. Ultraviolet: A max. 230 (8,550); 279 (2,950); sh 285 (2,550).

24; C, 65.88; H, 9.19; Cl, 3

9. Found: 9.

EXAMPLE 55 Cis-B-a-(p-methoxyphenyl)-2-(hexahydro-lH-azepin-lyl)cyclohexanemethanol and the hydrochloride thereof To 240 ml. of trifiuoroacetic acid, cooled to 5 C. was added, all at once, 38 g. (0.12 mole) of cis-A-a-(p-methoxyphenyl )-2-( hexahydrol H-azepin- 1 -yl)cyclohexanemethanol with stirring. The mixture was kept stirring for 20 minutes whereby the temperature reached about 40 C. Thereupon, the solution was cooled, ice was added, followed by 600 ml. of water and then 600 ml. of 20 percent aqueous sodium hydroxide. The mixture was then extracted with five 200-ml. portions of methylene chloride. The extracts were combined, washed with saturated salt solution, dried by passing through anhydrous sodium sulfate, and the filtrate evaporated to give 37.9 g. of a yellowish oil. This oil was dissolved in 150 ml. of petroleum ether (boiling range 30-60 C.) and allowed to crystallize in the refrigerator overnight; 13.6 g. of crystals were recovered by filtration. These crystals were recrystallized from 50 ml. of ether to give 10.1 g. of cis-B-a-(p-methoxyphenyl)-2-(hexahydro-1 H-azepin-l-y1)cyclohexanemethanol of melting point 94-95.5 C. Ultraviolet: A max. 225 (12,750); 275 (1,550); 281 (1,350).

Analysis:

Calcd. for C H NO Found:

The hydrochloride of cis-B-a-(p-methoxyphenyl)-2-(hexahydro-lI-I-azepin-l-yl)cyclohexanemethanol was prepared with 1.5 N ethereal hydrogen chloride. After two crystallizations from methanol-ether, colorless needles were obtained melting at 188-l 89 C.

Ultraviolet: A max. 226 (12,700); 275 (1,450); 281 (1,250).

Analysis:

Calcd. for C H ,N0,-HCl:

C, 67.87; H, 9.12; Cl, Found: C, 67.24; H, 9.36; Cl,

Analysis:

Calcd. for C H NO HCI:

C, 68.26; H, 8.59; Cl, 10.08; N, 3.98 Found: C, 67.92; H, 8.55; Cl, 10.06; N, 4.05

EXAMPLE 56 a-(3,4,5-Trimethoxyphenyl)-2-piperidinocycloheptane methanol hydrochloride A. l-Piperidino- 1 -cycloheptene.

A mixture of 224.2 g. (2 moles) of cycloheptanone, 340 g. (4 moles) of piperidine, 400 ml. of benzene and 2.2 g. of ptoluenesulfonic acid was refluxed for a period of 16 hours in a nitrogen atmosphere, using an azeotropic separator. A total of 5 ml. of water was collected. Since this was less than the calculated amount of water produced during the reaction, the separator was replaced with a Soxhlet extractor containing 322 g. of crystalline sodium aluminum silicate, Na [(Al o (SiO [Linde molecular sieve, Type 4A; see The Merck Index, Merck and Co., Inc. 1960, Seventh Edition, page 1,592], and the mixture was refiuxedfor 3 days. After the solvent was removed by distillation from the reaction mixture, 319.7 g. of l-piperidino-l-cycloheptene of boiling point -l3 1 C. at 17 mm. (89 percent yield) was obtained.

B. a-(3,4,5-Trimethoxyphenyl)-2-piperidinocyclohep tanemethanol hydrochloride In the manner given in Example 49, Part B, 23 g. (0.1 mole) of 3,4,5-trimethoxybenzoyl chloride, 17.9 g. (0.1 mole) of lpiperidino-l-cycloheptene and triethylamine (0.1 mole) were reacted at low temperature in a chloroform solution. The resulting product was hydrogenated in methanol for a period of 3 hours during which 2 molar equivalents of hydrogen were consumed. The resulting reaction mixture was then filtered and evaporated, and the residue stirred with ml. of water and 150 ml. of methylene chloride for a period of 0.5 hour. The methylene chloride layer was separated and stirred with 250 ml. of 10 percent aqueous hydrochloric acid for one-half hour. The resulting suspension was filtered and the solid washed with water to give 7.5 g. of a-(3,4,5-trimethoxyphenyl)-2-piperidinocycloheptanemethanol hydrochloride of melting point 237-238 C. This material was recrystallized from methanol to give a-(3,4,5-trimethoxyphenyl)-2-piperidinocycloheptanemethanol hydrochloride of melting point 243-244 C.

Ultraviolet: sh 266 (8,250); sh 234 (6,800); A max. 270 (782); sh 278 (546).

Analysis:

Calcd. for C,,H,,,,NO,-HC1:

C, 63.82; H, 8.77; Cl, 8.5 Found: C, 63.43; H, 8.85; Cl, 8.6

The work-up of the methylene chloride layer gave 1.5 g. of cycloheptyl 3,4,5-trimethoxyphenyl ketone of melting point 7677 C. in colorless crystalline plates.

Analysis:

Calcd. for C H O Found: C, 69.64; H, 8.24

EXAMPLE 5 7 a-( 3 ,4,5-Trimethoxyphenyl )2-( 1-pyrolidinyl)cyclohexanemethanol and hydrochloride A mixture of 17.5 g. (0.06 mole) of 2-(3,4,5-trimethoxybenzoyl)cyclohexanone, 12.8 g. (0.18 mole) of pyrrolidine and 480 ml. of benzene was refluxed for 1.25 hours using an azeotropic separator; 1.5 ml. of water was collected. The mixture was evaporated to dryness to give a yellow oil. A small sample was crystallized twice from ether to give yellow prisms melting at 1l8120 C. and constituting 3,4,5-trimethoxyphenyl 2-( 1-pyrrolidinyl)- l-cyclohexen-l-yl ketone. Ultraviolet: in ether A max. 262 (11,50 358 (5,500); in ethanol sh 220 17,000); 269 (7,700); 372 (7,050).

Analysis:

" Calcd. for C NO4 C, 69.54; H, 7.88; N. 495

Found: C, 69.91; H, 8.08; N, 3.76

The crude 3,4,5-trimethoxyphenyl 2-( l-pyrrolidinyl)-lcyclohexen-l-yl ketone was dissolved in 250 ml. of ethanol and hydrogenated in the presence of 0.6 g. of platinum oxide. Two molar equivalents of hydrogen were taken up in 6 hours. The mixture was then filtered through diatomaceous earth and the filtrate evaporated to dryness. The residue was stirred with 200 ml. of 10 percent aqueous hydrochloric acid and 250 ml. of ether for 0.5 hour. The aqueous layer was separated, extracted with ether, basified with sodium bicarbonate and extracted with four l25-ml. portions of methylene chloride. The methylene chloride extracts were combined, washed with water, then with saturated salt solution, dried by passing through anhydrous sodium sulfateand evaporated to give 16.5 g. of solid. This solid was recrystallized from ether to give 9.7 g. of a-(3,4,5-trimethoxyphenyl)-2-( l-pyrrolidinyl)cyclohexanemethanol of melting point l21-122 C. A second crop of 2 g. of the alcohol was obtained with a melting point of 1 l9l20 C. The total yield was 56 percent. Ultraviolet: .rh 226 (9,200); A max. 269 (744); sh 280 (542).

Analysis:

Calcd. for C,,,H ,NO

Found:

Analysis:

Calcd. for C,, H ,NO ,-HCI:

C, 62.24; H, 8.36; Cl, 9.19; N, 3.63 Found: C, 62.31; H, 8.82; Cl, 9.15 3.65

EXAMPLE 58 3 ,4,5 -Trimethoxy-a-( Z-pipe ridinocyclopentyl)benzyl alcohol [a-( 3 ,4,5-trimethoxyphenyl)-2-piperidinocyclopentanemethanol] A. 3,4,5-Trimethoxyphenyl ketone.

A solution of 15.1 g. (0.1 mole) of l-piperidino-l-cyclopentene was added, in a nitrogen atmosphere, with ice cooling, to a solution of 10.1 g. (0.1 mole) of triethylamine in 42 ml. of chloroform (purified by passage through a column of basic alumina). To this solution was added a solution of 23.0 g. (0.1 mole) of 3,4,5-trimethoxybenzoyl chloride in 40 ml. of chloroform, over a period of 1.5 hours, while the temperature of the reaction mixture was kept at 5-10 C. The mixture was then stirred overnight at room temperature (22-25 C.) and was filtered to give 6.91 g. of triethylamine hydrochloride. The filtrate was evaporated to dryness at 50 C. The residue was dissolved in 250 ml. of ethanol, 12 g. (0.2 mole) of acetic acid and 1 g. of platinum oxide were added and hydrogenation was carried out at an initial pressure of 51 pounds. Two moles of hydrogen were taken up during 1 hour and 28 minutes; more than 90 percent of the calculated hydrogen was absorbed in the first half hour. The mixture was then filtered and evaporated to dryness. A mixture of 100 ml. of ether and 100 ml. of percent aqueous hydrochloric acid was added, and the obtained reaction mixture was stirred for 1.5 hours. The layers were separated and the aqueous layer was extracted once with ether. The ether extracts were washed with water to give the neutral layer." The acidic layer was cooled in ice and basified with 20 percent aqueous sodium hydroxide. it was extracted twice with ether, the combined ether extract 2'piperidinocyclopentyl was washed with water, saturated salt solution, dried by passage through anhydrous sodium sulfate and evaporated to give 14.6 g. of a brown oil which solidified on standing in vacuo overnight. The solid was dissolved in 150 ml. of petroleum ether (boiling range between 30-60 C.) and 20 ml. of ether and cooled with ice for 2 hours. The resulting suspension was decanted, thus providing solid A and filtrate B. Filtrate B was evaporated to about half the volume and cooled. The resulting solid, 1.2 g. of melting point l20-l 30 C., was removed by filtration. Recrystallization of this solid from ether gave colorless needles of melting point 133.5-l 345 C. The melting point of this material was not changed by recrystallization from ether. Ultraviolet, infrared and NMR spectra and also carbon, hydrogen and nitrogen analysis indicated that this product was a mixture.

Solid A and the residue from filtrate B were combined to give 13.3 g. of a yellow solid. This solid was dissolved in 50 ml. of benzene and chromatographed over 400 g. of neutral alumina, taking six benzene fractions of 250 ml. each. Fraction 2 contained 2.378 g. of material which was crystallized from 20 ml. of Skellysolve B hexanes to give 1.5 g. of 3,4,5-trimethoxyphenyl Z-piperidinocyclpentyl ketone of melting point 7980 C. Ultraviolet: A max. 217 (29,400); 283 (10,700).

Analysis:

Calcd. for C, H,,,N0,:

Found:

The above neutral layer contained a solid fraction of 8.78 g. which after recrystallization from Skellysolve B hexanes gave 6.8 of cyclopentyl 3,4,5trimethoxyphenyl ketone of melting point 46-47.5 C.

B. 3,4,5-Trimethoxy-a-(Z-piperidinocyclopentyl)benzyl alcohol A solution of 1.2 g. (3.48 mmoles) of 3,4,5-trimethoxyphenyl 2-piperidinocyclopentyl ketone in 25 ml. of ether was added over a period of 5 minutes to a solution of 1.2 g. of lithium aluminum hydride in 100 ml. of ether, and the mixture was stirred for 21 hours. It was then decomposed by successive addition of 1.2 g. ofwater, 1.2 ml. of 15 percent aqueous sodium hydroxide and 3.6 ml. of water. The thus-obtained reaction mixture was stirred for a period of 2 hours giving a suspension. This suspension was filtered and the solid washed with ether. The ether washing and the ether filtrate were combined, dried by passage through anhydrous sodium sulfate and evaporated to give 1.2 g. of an oil. The oil was chromatographed over 48 g. of Florisil (anhydrous magnesium silicate). Elution with five 100-m1. portions of a mixture consisting of 10 percent acetone and 90 percent Skellysolve B hexanes gave 0.136 g. of an oil. Elution with five portions of 100 ml. each of 20 percent acetone-80 percent Skellysolve B hexanes mixture gave 0.582 g. of oil. After standing in vacuo for one week, the oil crystallized to give a solid of melting point -88 C. This solid was recrystallized from ether-petroleum ether to give a 3,4,5- trimethoxy-a-(Z-piperidinocyclopentyl)benzyl alcohol melting at 9 l-92 C. Ultraviolet: sh 224 (9,100); sh 234; sh 269 (849); sh 278 (660).

Analysis:

Calcd. for CZQHMNO4:

C, 68. Found: C, 68.

Further elution with 30 percent acetone-70 percent Skellysolve B hexanes (five portions of ml. each) gave 0.140 g. and elution with 50 percent acetone-50 percent Skellysolve B hexanes mixture (five portions of 100 ml. each) gave 0.170 g. of solids. A 75 percent acetone-25 percent Skelly-solve B hexanes mixture (five portions of 100 ml. each) gave 0.087 g. and elution with acetone (two portions of 100 ml. each) gave 0.154 g. of solids..These solid fractions were combined and recrystallized from petroleum ether (boiling range 30-60 C.)

EXAMPLE 59 3,4,5-Trimethoxy-a-(Zpyrrolidinocyclopentyl)benzyl alcohol [a-(3,4,5-trimethoxyphenyl)-2-pyrrolidino-cyclopentanemethanol] A mixture of 8.35 g. (0.03 mole) of 2-(3,4,5-trimethoxybenzoyl)cyclopentanone, 6.5 g. (0.09 mole) of pyrrolidine, 240 ml. of benzene and 0.2 g. of p-toluenesulfonic acid was refluxed under a nitrogen atmosphere for-21 hours using an azeotropic separator; 0.5 ml. of water was collected. The solution was evaporated to dryness, 3,4,5-trimethoxyphenyl 2-pyrrolidino-l-cyclopenten-1-y1 ketone being obtained as a residue. This residue was dissolved in 100 ml. of methanol and hydrogenated in the presence of 0.3 g. of platinum oxide at an initial pressure of 54 pounds. One molar equivalent of hydrogen was taken up over a period of 4 hours whereupon the hydrogenation was stopped. The mixture was filtered through diatomaceous earth, and the filtrate evaporated to dryness, 3,4,5-trimethoxyphenyl 2-pyrrolidinocyclopentyl ketone being obtained as a reside. One-half of this product (5 g.; 0.015 mole) was dissolved in 100 ml. of benzene. This solution was added during minutes to a solution of 5 g. of lithium aluminum hydride in 200 ml. of ether, and the mixture was refluxed with stirring for a period of 3 hours. It was then decomposed by successively adding 5 ml. of water, 5 ml. of percent aqueous sodium hydroxide and 15 ml. of water. The suspension was filtered, and the solid washed with ether. The filtrate and the ether washings were combined, extracted with 10 percent hydrochloric acid (four portions of 50 ml. each) and the acidic extracts were basified by the addition of aqueous sodium hydroxide. The basified solution was extracted with four portions (each 50 ml.) of methylene chloride. The methylene chloride extracts were combined, washed with water, then with saturated salt solution, dried by passage through anhydrous sodium sulfate and evaporated to give 4.5 g. of a yellow oil. This yellow oil was dissolved in ml. of methylene chloride and chromatographed over 200 g. of Florisil (anhydrous magnesium silicate). The elution was carried out with five portions of 200 ml. each of 50 percent acetone-50 percent Skellysolve B hexanes. The eluates were concentrated to give 0.41 g. of solid which was recrystallized from Skellysolve B hexanes to give 3,4,5-trimethoxy-a-(2-pyrrolidinocyclopentyl)benzyl alcohol of melting point 85-86 C Ultraviolet: sh 227 (9,300); A max. 269 (788); sh 278 (573). NMR showed H on carbon bearing the OH as a doublet centered at 316.5 cps 3 cps).

Analysis:

Calcd. for C, H NO,:

C, 68.03; H, 8.71; N, 4.18 Found: C, 67.50; H, 8.73; N, 4.43

Elution of the above column with five portions of 200 ml. each of acetone gave after evaporation 0.58 g. of a solid, which was crystallized from ether and thereupon from tetrahydrofuran-Skellysolve B hexanes to give isomeric 3,4,5- trimethoxy-a-(2-pyrrolidinocyclopentyl)benzyl alcohol of melting point 147-148 C.

Ultraviolet: sh 225 (8,950); A max. 270 1,100); sh 227 (567). NMR showed H on carbon bearing the OH as a doublet centered at 291 cps (j= 5 cps).

Analysis:

Calcd. for C H NQ:

C, 68.03; H, 8.71; N, 4.18 Found: C, 67.70; H, 8.90; N, 4.25

EXAMPLE 60 p-Ethoxyphenyl 2-piperidino-1-cyclohexen-1-yl ketone In the manner given in Example 31, Z-(p-ethoxybenzoyl)cyclohexanone was reacted with piperidine in the presence of p-toluene sulfonic acid to give p-ethoxyphenyl 21- piperidinol -cyclohexen- 1 -yl ketone.

EXAMPLE 61 p-Benzyloxyphenyl 2-pyrrolidino- 1 -cyclohexen- 1 -yl ketone In the manner given in Example 31, 2-(p-benzyloxybenzoyl)-cyclohexanone was reacted with pyrrolidine in the presence of p-toluenesulfonic acid to give p-benzyloxyphenyl 2-pyrrolidino-1-cyclohexen- 1 -yl ketone.

EXAMPLE 62 p-Benzyloxyphenyl Z-piperidino-l-cyclohexen1-yl ketone 1n the manner given in Example 31, Z-(p-benzyloxybenzoyl)-cyclohexanone was reacted with piperidine in the presence of p-toluenesulfonic acid to give p-benzyloxyphenyl Z-piperidino- 1 -cyclohexen 1 -yl ketone.

EXAMPLE 63 p-( 2-Hydroxyethoxy)phenyl 2-piperidino-1-cyclohexen l-yl ketone In the manner given in Example 31, 2-[p-(2-hydroxyethoxy)-benzoyl]cyclohexanone was reacted with piperidine in the presence of p-toluenesulfonic acid to give p-(2-hydroxyethoxy)phenyl 2-piperidinol-cyclohexen-l-yl ketone.

EXAMPLE 64 o-Methoxyphenyl Z-piperidino-l-cyclohexen-l-yl ketone In the manner given in Example 31, 2-(o-methoxybenzoyl)cyclohexanone was reacted with piperidine in the presence of p-toluenesulfonic acid to give o-methoxyphenyl 2- piperidino- 1 -cyclohexen- 1 -y1 ketone.

EXAMPLE 65 o-Hydroxyphenyl Z-piperidino-l-cyclohexen-l-yl ketone 1n the manner given in Example 31, Z-(o-hydroxybenzoyl)cyclohexanone was reacted with piperidine in the presence of p-toluenesulfonic acid to give o-hydroxyphenyl 2- piperidino- 1 -cyclohexen- 1 -yl ketone.

EXAMPLE 65A p-Hydroxyphenyl 2-piperidino- 1 -cyclohexen- 1 -yl ketone In the manner given in Example 31, 2-(p-hydroxybenzoyl)cyclohexanone was reacted with piperidine in the presence of p-toluenesulfonic acid to give p-hydroxyphenyl 2- piperidino-l-cyclohexen-1-yl ketone.

EXAMPLE 66 2-Methoxy-4-methylphenyl 2-piperidino- 1 -cyclohexenl -yl ketone.

In the manner given in Example 31, 2-(2-methoxy-4- methylbenzoyl)cyclohexanone was reacted with piperidine in the presence of p-toluenesulfonic acid to give 2-methoxy-4- methylphenyl Z-piperidino-l-cyclohexen-1-yl ketone.

EXAMPLE 67 EXAMPLE 68 p-Trifluoromethylphenyl ketone 2-piperidino- 1 -cyclohexenl -yl In the manner given in Example 31, Z-(p-trifluoromethylbenzoyl)cyclohexanone was reacted with piperidine in the presence of p-toluenesulfonic acid to give ptrifluoromethylphenyl 2-piperidino-l-cyclohexcnl-yl ketone.

EXAMPLE 69 p-Allyloxyphenyl Z-piperidino- 1 -cyclohexenl -yl ketone In the manner given in Example 31, 2-(p-allyloxybenzoyl)- cyclohexanone was reacted with piperidine in the presence of p-toluenesulfonic acid to give p-allyloxyphenyl Z-piperidinol-cyclohexen-1-yl ketone.

EXAMPLE 70 p-( Methylcarbamoyloxy)phenyl Z-piperidinol -cyclohexen- 1 -y1 ketone In the manner given in Example 31, Z-[p-(methylcarbamoyloxy)-benzoyl]cyclohexanone was reacted with piperidine in the presence of p-toluenesulfonic acid to give p- (methylcarbamoyloxy)phenyl 2-piperidinol -cyclohexenl -y] ketone.

EXAMPLE 7l 3 ,4-Methylenedioxyphenyl 2-( hexahydrol I-I-azepin l -yl l-cyclohexenl -yl ketone In the manner given in Example 31, 2-(3,4-methylenedioxybenzoyl)cyclohexanone was reacted with hexamethylencimine in the presence of p-toluenesulfonic acid to give 3 ,4-methylenedioxyphenyl Z-(hexahydrol I-l-azepin- 1- yl)- l -cycIohexen-l-yl ketone.

EXAMPLE 72 p-Chlorophenyl 2-(2-isopropylpyrrolidino)-l-cyclohexenl-yl ketone.

In the manner given in Example 31, 2-(p-chlorobenzoyl)- cyclohexanone was reacted with 2-ispropylpyrrolidine in the presence of p-toluenesulfonic acid to give p-chlorophenyl 2- (2-isopropylpyrrolidino 1 -cyclohexenl -yl ketone.

EXAMPLE 73 p-Hydroxyphenyl 2-octamethyleneimino- 1 -cyclohexenl -yl ketone v In the manner given in Example 31, 2-(p-hydroxybenzoyl)- cyclohexanone was reacted with octamethyleneimine in the presence of p-toluenesulfonic acid to give p-hydroxyphenyl 2- yl ketone; 3,5diiodophenyl 2-( 3-methylpiperidino)- I cyclohexen- 1 -y] ketone; 2-methoxy-4-chlorophenyl 2- piperidinol -cyclohexenl-yl ketone; 2-methyl-4- trifluoromethylphenyl 2-piperidinol-cyclohexen-1-yl ketone; 3,4-dipropylphenyl 2-pyrrolidino-l-cyclohepten-l-yl ketone; 2 ,5 -dichlorophenyl 2-(hexahydrol l-I-azepin- 1 -yl 1 cyclohepten-l-yl ketone; 3,4-dichlorophenyl 2-(3-methylpiperidino)-l-cycloocten-l-yl ketone; p-propoxyphenyl 2-(4- butylpiperazino)-l-cycloocten-l-yl ketone; 2,5-diiodophenyl 2-( 2-methylhexamethyleneimino)- l -cycloheptenl -yl ketone; 3-fluorophenyl 2-pyrrolidino-l-cyclopenten-l-yl ketone; 2- hexylphenyl 2-piperidino-l-cyclopenten-l-yl ketone; 3-pen- 30 tylphenyl Z-piperidino- 1 -cyclohexenl -yl ketone; 2-butylphenyl 2-morpholinol -cyclohexen- 1 -y] ketone; 2-

propylphenyl 2-( l,2,3,4-tetrahydro-l-quinolyl)-1-cyclohepten- 1 -yl ketone; 3-ethylpheny1 Z-pipen'dinol -cycloocten- 1 -yl ketone; 2-methoxy-5-bromophenyl 2-pyrrolidino-l-cyclopenten- 1 -y1 ketone; phenyl 2-octamethyleneiminol -cycloocten-l -yl ketone; phenyl 2-(2,3,6-trimethylmorpholino)-l-cyclohepten- 1 -yl ketone; and the like.

EXAMPLE 74 a-(p-Ethoxyphenyl)-2 hydrochloride In the manner given in Example 32, p-ethoxyphenyl 2- piperidino-l-cyclohexen-l-yl ketone was hydrogenated in the presence of platinum oxide to give a-(p-ethoxyphenyD-Z- piperidinocyclohexanemethanol recovered as hydrochloride;

-piperidinocyclohexanemethanol melting point 22 l -222 C.

EXAMPLE 75 a-(p-Benzyloxyphenyl)-2-pyrrolidinocyclohexanemethanol In the manner given in Example 32, p-benzyloxyphenyl 2- pyrrolidino-l-cyclohexen-l-yl ketone was hydrogenated in the presence of platinum oxide to give a-(p-benzyloXyphenyl)-2- pyrrolidinocyclohexanemethanol.

EXAMPLE 76 Cis-A-a-(p-benzyloxyphenyl)-2-piperidinocyclohexanemethanol In the manner given in Example 32, p-benzyloxyphenyl 2- piperidino-l-cyclohexen-l-yl ketone was hydrogenated in the presence of platinum oxide to give cis-A-a-(p-benzyloxyphenyl)-2-piperidinocyclohexanemethanol of melting point 148.5-149.5 C.

In the same manner, catalytic hydrogenation of cisbenzyloxyphenyl 2-piperidinocyclohexyl ketone (Example 88) gives the same product.

EXAMPLE 76A Cis-B-a-(p-benzyloxyphenyl)-2-piperidinocyclohexanemethanol and hydrochloride thereof In the manner given in Example 47, cis-A-a-(p-benzyloxyphenyl)-2 piperidinocyclohexanemethanol was converted by means of trifluoroacetic acid to cis-B-a-(p-benzyloxyphenyl)- 2-piperidinocyclohexanemethanol of melting point 129130 C.

This base was treated with ethereal hydrogen chloride, to obtain cis-B-a-(p-benzyloxyphenyl)-2-piperidinocyclohexanemethanol hydrochloride of melting point 238-240 C.

EXAMPLE 77 a-[ p-( 2-l-lydroxyethoxy)phenyl]-2-piperidinocyclohexanemethanol hydrochloride In the manner given in Example 32, p-(2-hydroxyethoxy)- phenyl Z-piperidino-l-cyclohexen-l-yl ketone was hydrogenated in the presence of platinum oxide to give a-[p- (2-hydroxyethoxy)-phenyl]-2-piperidinocyclohexanemethanol recovered as hydrochloride of melting point 196198 C.

The hydrochloride can be converted to the free base, and the latter can be reacted with trichloroacetic acid to give the corresponding trichloroacetic acid salt, useful as a herbicide, for example, against Johnson grass, yellow foxtail, green foxtail, Bennuda grass and quack grass.

EXAMPLE 78 a-(o-Methoxyphenyl)-2-piperidinocyclohexanemethanol hydrochloride In the manner given in Example 32, o-methoxyphenyl 2- piperidino-l-cyclohexen-l-y1 ketone was hydrogenated in the presence of platinum oxide to give a-(o-methoxypheny1)-2- piperidinocyclohexanemethanol recovered as hydrochloride.

EXAMPLE 79 a-(o-Hydroxyphenyl)-2-piperidinocyclohexanemethanol In the manner given in Example 32, o-hydroxyphenyl 2- piperidinol-cyclohexen-l-yl ketone was hydrogenated in the presence of platinum oxide to give a-(o-hydroxyphenyl)-2- piperidinocyclohexanemethanol of melting point l22-122.5 C.

The above compound is useful as a diuretic.

EXAMPLE 79A EXAMPLE 79B Cis-B-a-(p-hydroxyphenyl)-2-piperidinocycl0hexanemethanol In the manner given in Example 47, cis-A-a-(p-hydroxyphenyl)-2-piperidinocyclohexanemethanol was converted by means of trifluoroacetic acid to cis-B-a-(p-hydroxyphenyl)-2- cyclohexanemethanol of melting point l82l 83 C.

The above compound is useful as a diuretic.

EXAMPLE 8O a-(2-Methoxy-4-methylphenyl)-2-piperidinocyclohexanemethanol hydrochloride In the manner given in Example 32, 2-methoxy-4- methylphenyl Z-piperidino-l-cyclohexen-l-yl ketone was hydrogenated in the presence of platinum oxide to give a-(2- methoxy-4-methylphenyl)-2-piperidinocyclohexanemethanol recovered as hydrochloride; melting point 25 l252 C.

EXAMPLE 81 a-( 3 ,5-Dimethyl-4-methoxyphenyl )-2-piperidinocyclohexanemethanol hydrochloride In the manner given in Example 32, 3,5-dimethyl-4-methoxyphenyl 2-piperidin0-1-cyclohexen-l-yl ketone was hydrogenated in the presence of platinum oxide to give a- (3,5-dimethyl-4-meth0xyphenyl)-2-piperidinocyclohexanemethanol recovered as hydrochloride.

EXAMPLE 82 a-( p-Trifl uoromethylphenyl )-2-piperidinocyclohexanemethanol hydrochloride In the manner given in Example 32, p-trifluoromethylphenyl Z-piperidino-l-cyclohexen-l-yl ketone was hydrogenated in the presence of platinum oxide to give a-(ptrifluoromethylphenyl)-2-piperidinocyclohexanemethanol recovered as hydrochloride.

EXAMPLE 83 a-(p-Propoxyphenyl)-2-piperidinocyclohexanemethanol hydrochloride In the manner given in Example 32, p-allyloxyphenyl 2- piperidino-l-cyclohexen-l-yl ketone was hydrogenated in the presence of platinum oxide to give a-(p-propoxyphenyl)-2- piperidinocyclohexanemethanol recovered as hydrochloride.

EXAMPLE 83A Cis-A-a-(p-allyloxyphenyl)-2piperidinocyclohexanemet hanol A mixture of 11.6 g. (0.04 mole) of cis-A-a-(p-hydroxyphenyl)-2-piperidinocyclohexanemethanol and 1.8 g. of a 53.3 percent mineral oil dispersion of sodium hydride (0.04 mole of sodium hydride) in 100 ml. of dimethyl sulfoxide was stirred for a period of 1 hour. A solution of 4.9 g. (0.0404 mole) of allyl bromide in 15 ml. of ether was added to the mixture above during a period of 15 minutes and the obtained reaction mixture was stirred for 3 hours at room temperature and then poured in l l. of ice water. A white solid separated which was extracted three times with ether. The ether extracts were combined, washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to give a residue. This residue was twice recrystallized from ether-pentane to give a total of l 1.8 g. (89 percent) of cis-A-a-(p-allyloxyphenyl)-2-piperidinocyclohexanemethanol of melting point 70-72 C.

Analysis:

Calcd. for C I-I NO Found: 9.10 N, 4.20

The above compound is useful as an oral antidiabetic agent.

EXAMPLE 84 a-[p-(Methylcarbamoyloxy)phenyll-2-piperidinocyclohexanemethanol hydrochloride In the manner given in Example 32, p-(methylcarbamoyloxy)-phenyl 2-piperidino-l-cyclohexen-l-yl ketone was hydrogenated in the presence of platinum oxide to give a-[p- (methylcarbamoyloxy)-phenyl]-2-piperidinocyclohexanemethanol recovered as hydrochloride.

EXAMPLE 85 EXAMPLE 86 a-( p-Chlorophenyl )-2-( 2-isopropylpyrrolidino )cyclohexanemethanol hydrochloride In the manner given in Example 32, p-chlorophenyl 2-(2- isopropy1pyrrolidino)-l-cyclohexen-1-yl ketone was hydrogenated in the presence of platinum oxide to give oz-(pchlorophenyl)-2-(2-isopropylpyrrolidino)cyclohexanemet hanol recovered as hydrochloride.

EXAMPLE 87 a-(p-I-Iydroxyphenyl)-2-octamethyleneiminocyclohexanemethanol hydrochloride In the manner given in Example 32, p-hydroxyphenyl 2-0ctamethyleneiminol -cyclohexenl -yl ketone was hydrogenated in the presence of platinum oxide to give a-(phydroxyphenyl)-2-octamethyleneiminocyclohexanemethanol recovered as hydrochloride.

In the same manner given in Example 32, hydrogenating other keto compounds of formula II in the presence of platinum oxide gives the substituted methanols of the formula IV recovered as hydrochlorides. Representative hydrochlorides, thus obtained, include: the hydrochlorides of a-(o-methylphenyl)-2-pyrrolidinocyclohexanemethanol; a- (p-methylphenyl)-2-pyrrolidinocyclohexanemethanol; a-(2- methoxy-4-methylphenyl)- 2-morpholinocyclohexanemethanol; a-(2-hydroxy-5-chlorophenyl)-2- homomorpholinocyclohexanemethanol; a-[p-(carboxymethoxy)phenyl]-2-(3,6-dimethylhexamethyleneimino)cyclohexanemethanol; a-( 3,4- methylenedioxyphenyl)-2-(Z-methylpiperidino)cyclohexanemethanol; a-(p-ethoxyphenyl)-2-pyrrolidinocycloheptanemethanol; a-( 2,3 ,4-trimethoxyphenyl )-2-piperidinocyclooctanemethanol; a-( 3 ,5 -diiodophenyl)-2-( 3-methylpiperidino)cyclohexanemethanol; a-( 2- methoxy-4- chlorphenyl )-2-piperidinocyclohexanemethanol; a-( 2- methyl-4-trifluoromethylphenyl )-2-piperidinocyclohexanemethanol; a-(3,4-dipropylphenyl)-2-pyrrolidinocyc1oheptanemethanol; a-(2,5-dichlorophenyl)-2-(hexahydro-1H- azepinl -yl )cycloheptanemethanol; a-( 3 ,4-dichlorophenyl)-2 3-methylpiperidino )cyclooctanemethanol; a-( p-propoxyphenyl)-2-(4-butylpiperazino)cyclooctanemethanol; (Jr-(2,5- diiodophenyl)-2-( Z-methylhexaniethylneimino)cyclohepta nemethanol; a-( 3-fluorophenyl)-2-pyrrolidinocyclopentanemethanol; a-( 2-hexylphenyl)-2-piperidinocyclopentanemethanol; a-( 3-penty1phenyl )-2-piperidinocyclohexanemethanol; a-( Z-butylphenyl )-2-morpholinocyclohexanemethanol; a-( 2-propylphenyl)-2-( l,2,3,4-tetrahydro-lquinolyl)cycloheptanemethanol; a-(3-ethylphenyl)- 2- piperidinocyclooctanemethanol; a-(2-methoxy-5- bromophenyl)-2-pyrrolidinocyclopentanemethanol; a-pheny1-2 -octamethyleneim'inocyclooctanemethanol; a-phenyl-Z- (2,3,6-trimethylmorpholino)cycloheptanemethanol; and the like.

EXAMPLE 88 Cis-p-benzyloxyphenyl Z-piperidinocyclohexyl ketone In the manner given in Example 39, p-benzyloxyphenyl 2- piperidino-l-cyclohexen-l-yl ketone dissolved in ethanol was hydrogenated in the presence of platinum oxide until one molar equivalent of hydrogen was consumed (42 minutes) to give cis-p-benzyloxyphenyl Z-piperidinocyclohexyl ketone of melting point 87.588.5 C.

Analysis:

Calcd. for C H NO C, 79.53; H, 8.28; N, 3.71 Found: C, 78.88; H, 8.27; N, 3.65

In the same manner given in Example 39, selective catalytic reduction (preferably with platinum oxide) of other compounds of formula II produces cis-ketones of formula III, e.g., cis-3,4,5-trimethoxyphenyl 2-piperidinocyclohexyl ketone; cis-p-ethoxyphenyl Z-piperidinocyclohexyl ketone; cis-p-(2- hydroxyethoxy)-phenyl 2-piperidinocyclohexyl ketone; cis-ptrifluoromethylphenyl Z-piperidinocyclohexyl ketone; cis-pchlorophenyl 2-(2-isopropylpyrrolidino)cyclohexyl ketone; cis-3 ,4-methylenedioxyphenyl 2-( hexahydrol I-I-azepinl ketone; cis-2,3,4-trimethoxyphenyl 2- piperidinocyclooctyl ketone; cis-3,4 -dichlrophenyl 2-(3- methylpiperidino)cyclooctyl ketone; cis-2,5-dichlorophenyl 2-(hexahydro-1l-I-azepinyl-l-yl)cycloheptyl ketone; and the like.

In the manner given in Example 41, other cis-alcohols can be obtained by hydrogenating a compound of formula II or III in the presence of a catalyst such as platinum oxide, palladium or the like. Representative compounds thus obtained include: cis-a-(p-methylphenyl)-2-piperidinocyclohexanemethanol, melting point l02-l03 C., as hydrochloride melting point 25 l25 3 C.; cis-a-( p-methoxyphenyl )-2-( 4-methyll piperazinyl)cyclohexanemethanol, melting point 132133 C.; cis-a-( p-methoxyphenyl)-2-( 4-methylpiperidino)cyclohexanemethanol, melting point 93-94 C.; cis-a-(p-methoxyphenyl)-2-morpholinocyclohexanemethanol, melting point 1ll-112 C.; cis-a-(p-methoxyphenyl)-2-( 3-azabicyclo[ 3 ,2,2 ]nonan-3-yl )cyclohexanemethanol, melting point 114.5115.5 C.; cis-a (pmethoxyphenyl)-2-pyrrolidinocyclohexanemethanol, melting point l46-l47 C.; cis-a-(p-methoxyphenyl)-2-(2-methylpiperidino)cyclohexanemethanol, as perchlorate, melting point l081 1 1 C.; cisa-(p-methoxyphenyl)-3,3-dimethyl-6- piperidinocyclohexanemethanol, melting point l33l35 C.; cis-a-(4-methoxy-3,S-dimethylphenyl)-2-(hexahydro-1H- azepin-l-yl)cyclohexanemethanol, as hydrochloride, melting point 247248 C.; cis a-(2,4-dimethylphenyl)-2-piperidinocyclohexanemethanol, as hydrochloride, melting point 34 239-240 C.; cis-a-( 2,5-dichlorophenyl )-2-heptamethyleneiminocycloheptanemethanol; cis-a-( Z-butylphenyl)-2-morpholinocyclohexanemethanol; cis-a-(Z-propylphenyl)-2-( 1,2,3 ,4-tetrahydro- 1 -q uinolyl)cycloheptanemethanol; cisa (2,3,4 trimethoxyphenyl) Z-piperidinocyclooctanemethanol; and the like.

EXAMPLE 89 1-[2-(a,3,4,5-Tetramethoxybenzyl)cyclohexyl]piperidine hydrochloride (isomer cis-A hydrochloride) A solution of 4 g. (0.01 mole) of a-(3,4,5-trimethoxyphenyl)-2-piperidinocyclohexanemethanol hydrochloride in 160 ml. of water was basified by adding sufficient 10 percent aqueous sodium hydroxide solution. This solution was extracted three times with 100 ml. of methylene chloride. The methylene chloride solution was evaporated, leaving an oily free base.

A solution of the free base a-(3,4,5-trimethoxyphenyl)-2- piperidinocyclohexanemethanol in 25 ml. of ether was added to 100 ml. of liquid ammonia containing 0.01 mole of sodium amide and the mixture was stirred for a period of 50 minutes, while cooling in Dry Ice-acetone. A solution of 1.42 g. (0.01 mole) of methyl iodide in 5 ml. of ether was then added during 5 minutes; the Dry Ice bath was removed and the mixture allowed to stir at room temperature for a period of 7 hours. It was then allowed to evaporated overnight (about 20 hours). To this reaction mixture was then added 50 ml. of water, and the mixture was extracted with three portions of 50 ml. each of methylene chloride. The combined methylene chloride extracts were washed with water, saturated salt solution, dried by passing through anhydrous sodium sulfate and evaporated, to give 3.6 g. of an oily product. The oil was dissolved in methylene chloride and chromatographed on 108 g. of Florisil (anhydrous magnesium silicate). The column of Florisil was eluted with four portions, each 200 ml., of a 3 percent acetone-97 percent Skellysolve B hexanes solution, yielding 1.80 g. of an oil after evaporation of the solvents. The oil was dissolved in ether and treated with ethereal hydrogen chloride to give 1.4 g. of material melting at 227-228 C. This material was recrystallized from methanol-ether to give 1-[2-(a,3,4,5- tetramethoxybenzyl)cyclohexyl]hpiperidine hydrochloride (isomer cis-A hydrochloride) of melting point 224-225 C. Ultraviolet: A max. 212 (33,400); sh 235 (6,600); 271 (923); sh 279 (646).

Analysis:

calcd. for e igma-H01:

C, 63.82; H, 8.77; CI, 8.56;

Found: C, 63.70; H, 8.95; Cl, 8.25; N

Cis-B-l-[2-(a,p-dimethoxybenzyl)cyclohexyl]piperidine and hydrochloride thereof A. A solution of cis-A-a-(p-methoxyphenyl)-2-piperidinocyclohexanemethanol (3.0 g.; 0.01 mole) in 50 ml. of methanol was treated with a solution of 5 g. of hydrogen chloride in 50 ml. of methanol, and an additional 100 ml. of methanol was added. The solution was allowed to stand for 18 hours at about 25 C. and was then evaporated to dryness of 45 C. under reduced pressure. The oily residue was dissolved in 50 ml. of water; the solution was basified with aqueous sodium hydroxide solution and extracted with ether. The extract was washed with water, then with saturated sodium chloride solution, dried through anhydrous sodium sulfate, and evaporated to dryness, to obtain 3.0 g. percent yield) of cis-B- l 2-( a,p-dimethoxybenzyl)cyclohexyl]piperidine of melting point 7577 C. Recrystallization from ethanol gave 2.3 g. of this compound, melting point 8182 C. Ultraviolet: A max. 226 13,200); 275 (1,460); 282 (1,210).

Analysis:

Calcd. for C H NO C, 75.67; H, 9.84; N, 4.41 Found: C, 75.70; H, 10.06; N, 4.15

A solution of 10.7 g. (0.0354 mole) of cis-B-l-[2-(a,pdimethoxybenzyl)cyclohexyl]50 ml. of ether was treated with 40 ml. of 1.3 N ethereal hydrogen chloride solution. The resulting solid was crystallized from 25 ml. of methylene chloride and 50 ml. of ether to give 9.3 g. of cis-B- 1-[2-(a, p-dimethoxybenzyl)cyclohexyl]piperidine hydrochloride of melting point 20921 1 C. Ultraviolet: A max. 227 (12,500); 275 (1,400); 281 (1,200).

Analysis:

Calcd. for C H NO HClZ C, 67.87; H, 9.11;C 1 Found: C, 67.41; H, 9.31; C l,

B. In the manner given in Example 89, an ether solution of cis-B-a-(p-methoxyphenyl)-2-piperidinocyclohexanemethanol was treated in liquid ammonia with sodium amide and methyl iodide. The cis-B-1-[2-(a,p-dimethoxybenzyl)cyclohexyl1piperidine thus obtained was identical with the compound prepared by the above methanolhydrogen chloride etherification procedure.

EXAMPLE 91 Cis-B-l-[2-(a,p-methoxybenzyl)cyclohexyl]piperidine N- oxide hydrate To an lee-cooled solution of 2.2 g. (7 mmoles) of cis-B-1-[2 -(a,p-dimethoxybenzyl)cyclohexyl]piperidine in 50 ml. of methanol was added 2.4 g. (14 mmoles) of m-chloroperbenzoic acid. The resulting colorless solution was allowed to stand in ice for 6 hours and then at room temperature (23 to 25 C.) for about 18 hours. It was evaporated to dryness at 35 C. to give an oily residue. To this residue was added 25 ml. of water followed by 25 ml. of percent aqueous sodium hydroxide, and then the mixture was extracted three times with a total of 100 ml. of methylene chloride. The methylene chloride extracts were combined, washed twice with saturated salt solution, dried by passage through anhydrous sodium sulfate and evaporated to give 2.5 g. of an oil. The oil was dissolved in 25 ml. of hot ethyl acetate (saturated with water), and the cloudy solution was filtered through a sinter funnel. The resulting clear solution was evaporated to ml., cooled and seeded. The resulting crystals were recovered by filtration and washed with ether to give colorless prisms of cis-B-l-[2-(a,pdimethoxybenzyl)cyclohexyl]melting at l08-1 10 C.

Ultraviolet: A max. 227 (12,750); 275 (1,400); 282 (1,250).

N, 3. C, 68.66; H, 9. N, 3.

99 Found: 96

EXAMPLE 92 Cis-B- l -[2-(a,p-dimethoxybenzyl )cyclohexyl]piperidine and its methiodide A solution of 4 ml. of butyl lithium (0.01 mole) in hexane was added during 2 minutes to a solution of 3.03 g. (0.01 mole) of cis-B-a-(p-methoxyphenyl)-2-piperidinocyclohexanemethanol in 30 ml. of purified tetrahydrofuran. The mixture was stirred at room temperature for 30 minutes and then cooled in a Dry Ice bath at -70 C. To this solution was added a solution of methyl iodide (1.42 g.; 0.01 mole) in 10 ml. of tetrahydrofuran, dropwise, over a period of 10 minutes. The mixture was stirred at 70 C. for a period of 1.5 hours and then at room temperature for 19 hours. To the solution was thereupon added water (50 ml.) and the solution was then extracted with three portions of 75 ml. each of methylene chloride. The organic extracts were combined, dried by passage through anhydrous sodium sulfate and evaporated to give 2.7 g. of crude product. The crude product was dissolved in 20 ml. of methylene chloride and chromatographed over 135 g. of neutral alumina. The material was first eluted with eight portions of 250 ml. of a 5 percent ether-95 percent Skellysolve B hexanes solution. After evaporation of the combined eluates, 1.523 g. of solid material, melting between 82-84 C., was obtained. Further elution with two portions of 250 ml. of 25 percent ether-75 percent Skellysolve B hexanes, with two portions of 250 ml. each of 50 percent ether-50 percent Skellysolve B hexanes and with two portions of 250 ml. each of 75 percent ether-25 percent Skellysolve B hexanes gave a total of 0.204 g. of solid material after evaporation of the combined eluates. The above fractions were all combined and recrystallized from ethanol to give 0.644 g. of cis-B-l-[2-(a,pdimethoxybenzyl)cyclohexy|]84-85.5 C. This free base was identical with the free base obtained in Example 90, parts A and B.

Further elution of the column with 250 ml. of methanol gave 1.446 g. of material which was crystallized from methanol-ether overnight in the refrigerator to give 0.252 g. of the methiodide of cis-B-1-[2-(a,p-dimethoxybenzyl)cyclohexyl]piperidine, melting after another recrystallization from methanol-ether at 217218 C.

Ultraviolet: A max. 223 (24,000); 275 (1,390); 281 (1,280).

Analysis:

Calcd. for C H INO C, 54.90; H, 7.46; I, 27.63; Found: C, 55.03; H, 7.68; l, 27.63;

EXAMPLE 92A Analysis:

Calcd. for C H ,NO -CH OH-HCl:

C, 65.34; H, 9.40; Cl, 9.19; Found: C, 65.50; H, 9.28; Cl, 8.50;

EXAMPLE 93 Trans-C-l-[2-(a,p-dimethoxybenzyl)cyclohexyl] piperidine A solution of butyl lithium in hexane (5.25 ml., containing 0.01 mole) was added during a period of 10 minutes to a solution of a-(p-methoxyphenyl)-2-piperidinocyclohexanemethanol (3.03 g.; 0.01 mole of the trans-C alcohol) in 40 ml. of tetrahydrofuran in a nitrogen atmosphere. The reaction mixture was then stirred for 45 minutes. It was cooled to C. and thereto was added a solution of 1.41 g. (0.01 mole) of methyl iodide in 10 ml. of purified tetrahydrofuran over a period of 30 minutes. The mixture was then stirred at room temperature (about 25 C.) overnight for about 16 hours. The reaction mixture was thereupon evaporated to dryness and the resulting residue was dissolved in 50 ml. of water and 50 ml. of methylene chloride. The aqueous layer was extracted with methylene chloride and the methylene chloride extracts combined, washed with saturated salt solution, dried by passage through anhydrous sodium sulfate and evaporated, to give 3.2

Analysis:

Calcd. for C d-1 ,190,:

C N, 4.4 l N, 4.7 1

75.67; H, 9.84; Found: C, 75.80;1-1, 10.08;

The same product was obtained. when trans-C-a-(p-methoxy-phenyl)-2-piperidinocyclohexanemethanol in methanol solution was treated with anhydrous hydrogen chloride in methanol solution and the resulting hydrochloride was treated with 20 percent aqueous sodium hydroxide.

, EXAMPLE 94 Trans-D- 1 2-(a,p-dimethoxybenzyl)cyclohexyl1piperidine A hexane solution of butyl lithium 5.25 ml.; 0.01 mole) was added during minutes to a solution of trans-D-a-(p- 'methoxyphenyl)-2piperidinocyclohexanemethanol (3.03 g.;

0.01 mole) in 30 ml. of purified tetrahydrofuran in a nitrogen atmosphere. The mixture was stirred for a period of 40 minutes, then cooled to 70 C. and a solution of 1.42 (0.01 mole) of methyl iodide in 10 ml. of purified tetrahydrofuran was added over a period of 30 minutes. The mixture was then stirred for 18 hours at room temperature, evaporated to dryness and the residue dissolved in 50 ml. of water and 50 ml. of methylene chloride. The aqueous layer was extracted with methylene chloride and thecombined methylene chloride extracts were washed withsaturated salt solution, dried through sodium sulfate and evaporated. The crude product, amounting to 3.2 g., was chromatographed over 100 g. of neutral alumina using five fractions of 150 ml. each of 6 percent ether-94 percent Skellysolve B hexanes. The five fractions were combined and evaporated to give 1.145 g. of oily trans-D-l-[2-(a,p-

dimethoxybenzyl)cyclohexyl]Ultraviolet: A max. 228 (12,-

Analysis:

Calcd. for C H NO C, 75.67; H. 9.84; N, 4.41 Found: C, 75. 8; H, 9.93; N, 4.30

EXAMPLE 95 Trans-C- l 2-( a,p-dimethoxybenzyl)cyclohexyl1piperidine A solution of 2 g. of hydrogen chloride in ml. of methanol was added to a solution of 0.8 g. (2.64 moles) of a- (p-methoxyphenyl )-2-piperidinocyclohexanemethanol (trans- D isomer) in 40 ml. of methanol. The mixture was allowed to stand overnight. The resulting solution was basified with percent aqueous sodium hydroxide solution. The methanol was evaporated in vacuo, ml. of water was added, and the product was extracted with three portions of 25 ml. each of methylene chloride. The extracts were combined, washed with saturated salt solution, dried over magnesium sulfate and evaporated. The residue (0.08 g.) was dissolved in 3 percent ether-97 percent Skellysolve B hexanes and chromatographed over neutral alumina with the same solvent mixture. The column was eluted with ten portionsof ml. each of 3 percent ether-97 percent Skellysolve B hexanes and the fractions thus obtained were evaporated to give 0.351 g. of an oil, which was kept overnight at --l0 C. and thereupon solidified. The solidified material was crystallized from methanol to give trans-C-1-[2-(a,p-dimethoxybenzyl)cyclohexyl]piperidine of melting point 78-79 C., identical with the compound of Example 93.

EXAMPLE 96 1-[ 2-( a-Ethoxy-p-methoxybenzyl)cyclohexyl]piperidine (cis-A isomer) and the hydrochloride thereof A solution of cis-A-a-(p-methoxyphenyl)-2-piperidinocyclohexanemethanol (30.3 g.; 0.1 mole) in 250 ml. of ether was added during 45 minutes to a suspension of freshly prepared sodium amide (0.2 mole) in l l. of liquid ammonia. The mixture was stirred for 1 hour and then cooled in a Dry Ice-acetone bath. A solution of 31.2 g. (0.2 mole) of ethyl iodide in 100 ml. of ether was added dropwise over a period of 30 minutes, the mixture was then stirred'in the cold for 1 hour and allowed to stir without cooling for 2 hours. The solution was thereupon allowed to evaporate overnight. To the resulting product 500 ml. of water was added, and the mixture was extracted with 5 portions of 100 ml. each of methylene chloride. The extracts were combined, washed with water, then with saturated salt solution, dried by passage through anhydrous sodium sulfate and evaporated to give 30 g. of a yellow oil. A solution of this oil in 200 ml. of petroleum ether (boiling range 3060 C.) was allowed to crystallize overnight to give 15.8 g. (53 percent recovery) of starting alcohol as determined by mixed melting point (78-80 C.). The filtrate was evaporated, and the residue was chromatographed over 750 g. of neutral alumina. Elution with 6 percent ether-94 percent Skellysolve B hexanes (8 fractions 250 ml. each) gave 7.23 g. of oily cis-A-1-[2-(a-ethyoxy-p-methoxybenzyl)cyclohexyl]piperidine which was 98.9 percent pure as determined by vapor phase chromatography. Further elution with 25 percent ether-75 percent Skellysolve B hexanes (4 fractions of 250 ml. each) gave 0.546 g. of oil of one component; 50 percent ether-50 percent Skellysolve B hexanes (4 fractions 250 ml. each) gave 0.777 g. of oil and 2 fractions of 450 ml. each gave 0.396 g. of oil. Total yield from the ethyl ether fractions were 30 percent. This 011 did not crystallize. The oily cis-A-1-[2-(asethoxy-p-methoxybenzyl)cyclohexyl] piperidine had the following analysis: Ultraviolet: A max. 226.5 (12,000); sh 268, 276 (1,800); 284 (1,550).

Analysis:

Calcd. for C l-1 190,:

Found The hydrochloride of cis-A-l-[2-(a-ethoxy-p-methoxybenzyl)-cyclohexyl]piperidine was prepared by treatment of an ethereal solution of the above oily base with ethereal hydrogen chloride. Two recrystallizations from ethanol gave colorless prisms of the hydrochloride of cis-A-l-[2-(a-ethoxy' p-methoxybenzyl)cyclohexy11piperidine of melting point 203-204.5 C.

Ultraviolet: A max. 227 1 1,900); 275 (1,500); 282 (1,300).

Analysis:

Calcd. for C H NO -HCl:

C, 68.55; H, 9.31; Cl, 9.64; Found: C, 68.01; H, 9.42; Cl, 9.72;

EXAMPLE 97 1-[2-(a-Ethoxy-p-methoxybenzyl)cyclohexyllpiperidine (cis-B isomer)

Claims

2. The substituted methanol hydrochloride of claim 1, wherein n is 2, R'', R'''' and R'''''' are 3-, 4-, and 5- methoxy groups, which has a melting point of about 244*-246* C., and is therefore Alpha -(3,4,5-trimethoxyphenyl)-2-(hexahydro-1H-azepin-1-yl)cyclohexanemethanol hydrochloride.
3. The substituted methanol hydrochloride of claim 1, wherein n is 2, R'' and R'''' are hydrogen, R'''''' is p-methoxy, which has a melting point of about 230*-231* C. and is therefore cis-A- Alpha -(p-methoxyphenyl)-2-(hexahydro-1H-azepin-1-yl)cyclohexanemethanol hydrochloride.
4. The substituted methanol hydrochloride of claim 1, wherein n is 2, R'' and R'''' are hydrogen and R'''''' is p-trifluoromethyl, which has a melting point of about 263*-264* C. and is therefore Alpha -(p-trifluoromethylphenyl)-2-(hexahydro-1H-azepin-1-yl)cyclohexanemethanol hydrochloride.
5. The substituted methanol hydrochloride of claim 1, wherein n is 2, R, and R'''' are hydrogen, R'''''' is p-chloro, which has a melting point of about 274*-275* C. and is therefore Alpha -(p-chlorophenyl)-2-(hexahydro-1H-azepin-1-yl)-cyclohexanemethanol hydrochloride.
6. The substituted methanol hydrochloride of claim 1, wherein n is 2, R,, R'''', and R'''''' are hydrogen, which has a melting point of about 276*-277* C. and is therefore Alpha -phenyl-2-(hexahydro-1H-azepin-1-yl)cycloHexanemethanol hydrochloride.
7. The substituted methanol hydrochloride according to claim 1, wherein n is 2, R, and R'''' are 3- and 4-methoxy and R'''''' is hydrogen, which has a melting point of about 225*-226* C. and is therefore Alpha -(3,4-dimethoxyphenyl)-2-(hexahydro-1H-azepin-1-yl)cyclohexanemethanol hydrochloride.
8. The substituted methanol compound according to claim 1, wherein n is 2, R'', and R'''' are hydrogen and R'''''' is p-methoxy, which has a melting point of about 94*-95.5* C. and is therefore cis-B- Alpha (p-methoxyphenyl)-2-(hexahydro-1H-azepin-1-yl)cyclohexanemethanol.
9. A substituted methanol quaternary ammonium halide salt according to claim 1, which is Alpha -(3,4,5-trimethoxyphenyl)-2-(hexahydro-1H-azepin-1-yl)cyclohexanemethanol methiodide of melting point about 191*-193* C.
10. The substituted methanol hydrochloride compound according to claim 1, wherein n is 2, R'', is 4-methoxy and R'''' and R'''''' are 3-and 4-methyl groups, which has a melting point of about 247*-248* C. and is therefore cis- Alpha -(4-methoxy-3,5-dimethylphenyl)-2-(hexahydro-1H-azepin-1-yl)cyclohexanemethanol hydrochloride.