US3506670A - 2-hetero-amino-alpha,alpha-diaryl-cycloalkone-methanols and esters thereof - Google Patents

Description

United States Patent Upjohn Company, Kalamazoo, Mich., a corporation of Delaware No Drawing. Filed Sept. 26, 1966, Ser. No. 581,730

Int. Cl. 'C07d 13/22, 57/36 US. Cl. 260294.7 3 Claims ABSTRACT OF THE DISCLOSURE Novel 1,3-aminoalcohols of the Formula II:

j RIII (0112):; [\TH K C 1 R wherein n is 1 to 4,

is a heterocyclic amino radical, R, R and R are hydrogen, halogen, lower alkyl, lower alkoxy or -CF and R R and R are hydrogen, lower alkyl and --CF are produced by treating a ketone of Formula I:

R, R", R are defined as above, with a phenyl or substituted phenyl Grignard, The alcohols II, their ethers and esters, N-oxides, acid addition salts are useful as oral parenteral diuretics in mammals.

This invention relates to new organic compounds and is particularly concerned with tertiary 1,3-aminoalcohols and the ethers, esters, N-oXides, acid addition salts, and quaternary alkyl ammonium halide salts as well as the process of production thereof.

The novel compounds and the process of invention can ice be illustratively represented by the following sequence of formulae:

R! RI! (onz).,' R R (onz n (Ina/[j C C R!!! A R1 R2 N RI! N r CZ) \z) y I II R3 I II RI RI! (0112),, OR anon 0A0 L R R!!! R1 R2 R1 R2 N N G I 111 R 1v R3 wherein n has the value of 1 to 4, inclusive; wherein represents a heterocyclic amino radical containing from 5 to 10 nuclear atoms, inclusive; wherein R is an alkyl containing from 1 to 4 carbon atoms, inclusive; wherein R, R" and R' are selected from the group of substituents consisting of hydrogen, halogen, alkyl and alkoxy in which the alkyl group contains from 1 to 6 carbon atoms, inelusive, and --CF wherein R R and R are selected from the group of substituents consisting of hydrogen, CF alkyl and alkoxy in which the alkyl group contains from 1 to 6 carbon atoms, inclusive; and wherein Ac signifies the acyl radical of a straight-chain alkanoic acid having from 2 to 8 carbon atoms, inclusive, benzoic acid, monosubstituted benzoic acids, and phenylacetic and phenylpropionic acids.

The invention further includes the novel compounds of Formulae II, III, and IV in the form of the N-oxides, acid addition salts and the quaternary alkyl ammonium halide salts in which the alkyl group has from 1 to 12 carbon atoms, inclusive, and the halogen can be chlorine, bromine and iodine.

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, Z-ethylpyrrolidino, 2,2-dimethylpyrrolidino, 3,4-dimethylpyrrolidino, 2-isopropylpyrrolidino, 2-sec. butylpyrrolidino, and like alkylpyrrolidino groups, morpholino, Z-ethylmorpholino, Z-ethyl-S-methylmorpholino, 3,3-dimethylmorpholino, thiamorpholino, 3-methylthiamorpholino, 2,3,6-trimethylthiamorpholino, 4-methylpiperazino, 4-butylpiperazino, piperidino, Z-methylpiperidino, 3-methylpiperidino, 4-methylpiperidino, 4-propylpiperidino, 2-propylpiperidino, 4-isopropylpiperidino, and like alkylpiperidino groups, hexamethylene imino, 2-methylhexamethyleneimino, 3,6-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 4 carbon atoms are methyl, ethyl, propyl, isopropyl, butyl, and isobutyl. Illustrative examples of alkyl groups having from 1 to 6 carbon atoms, in addition to those already named, are tert.butyl, pentyl, 2-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, decyl, undecyl, dodecyl, branched-chain isomers thereof, and the like. The halogen moiety in such salts includes iodine, bromine and chlorine.

Illustrative examples of acyl groups Ac of straight-chain alkanoic acids of 2 to 8 carbon atoms, inclusive, are acetyl, propionyl, butyryl, valeryl, hexanoyl, heptanoyl and octanoyl.

The monosubstituted benzoic acids herein used comprise mainly the o,mand p-nitrobenzoic, -methoxybenzoic, -chloro and bromobenzoic acids.

Under halogen substituents for R, R", and R, is understood fluorine, chlorine, bromine and iodine.

The novel compounds II, III, and IV exist in different stereoisomeric forms such as geometric and optically active forms, as well as in racemic mixtures. For example, compounds for Formulae II, III, and IV have at least two asymmetric carbon atoms and three when the aromatic rings differ from each other. These optically active forms and racemic mixtures and geometric isomers are also encompassed by this invention.

The process of the present invention comprises: treating a keto compound of Formula I with a selected aromatic Grignard reagent in an inert organic solvent to give the tertiary 1,3-aminoalcohol of Formula II. Compound II can be converted to an ether of Formula III under basic conditions, e.g., sodium amide in liquid ammonia and an alkyl halide, e.g., methyl iodide, ethyl bromide and the like. Esters (Formula IV) of these tertiary alcohols II can be prepared by the methods of Nevitt et al., J. Amer. Chem. Soc., 76, 4124 (1954) and Bartlett et al., J. Amer. Chem. 500., 77, 2804 (1955) as shown in detail in the examples.

With inorganic acids such as hydrochloric, hydrobromic, hydroiodic, perchloric, sulfuric and the like, and also with organic acids, e.g., lactic acid, tartaric acid, citric acid, oxalic acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid and the like, acid addition salts are produced of the compounds of Formulae II, III, and IV. With peracids, e.g., performic, peracetic, perphthalic m-chloroperbenzoic perbenzoic acid and the like the N- oxides of the compounds of Formulae II, III, and IV can be produced. With alkyl halides, particularly iodides and bromides of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl and the well-known branched-chain isomers thereof, quaternary alkyl ammonium halide salts are produced as shown in detail in the examples.

The compounds of Formulae II, III and IV including the acid addition salts, the N-oxides and the quaternary alkyl ammonium halide salts thereof are compounds of significant diuretic activity. They can be administered to mammals and birds by both oral and parenteral routes in order to produce their pharmacological, that is, di-

uretic effects. For oral administration, the new compounds of Formulae II, III and IV, as well as the acid addition salts, the N-oxides and the quaternary alkyl 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 II, III, and IV 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 can 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. per kg. body weight are suitable to produce significantly increased diuresis. For example, trans-u,a-bis(p-methoxyphenyl) -2 piperidinocyclohexanemethanol of melting point of 112-115 C. produced, at 5 mg. dosage level per kg. of body weight of rats, a 46% increase in diuresis, as determined by the procedure of Lipschitz et al., J. Pharmacol, Exp. Therap., 79, 97 (1943).

As noted above, the new compounds of Formulae II, III and IV can be used in the form of their acid addition salts with inorganic and organic acids, for example, hydrochlorides, oxalates, lactates, sulfates, tartrates, hydroiodides, hydrobromides, and the like. Thus, for example, the oxalate of trans-a,a-bis(p-methoxyphenyl)-2-piperidinocyclohexanemethanol increased the diuretic activity in rats, at a dosage level of 5 mg./kg., by 84%.

The fluosilicates of these compounds are useful mothproofing agents as described in U.S. Patents 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. Patents 2,425,320 and 2,606,155 are useful as pickling inhibitors. The trichloroacetic acid addition salts of the compounds of the same Formulae II, III and IV are useful as herbicides, for example against Johnson grass, yellow foxtail, green foxtail, Bermuda grass and quack grass.

The quaternary alkyl ammonium halide salts of the compounds of Formulae II, III and IV possess high wetting powder and electroconductivity and are thus suitable to prepare electrocardiographic jellies.

A suitable composition of an electrocardiographic jelly thus prepared comprises:

Parts Glycerol 5 Starch 1O Quaternary ammonium salt 60 Water 100 The jelly is prepared by mixing the starch, glycerol and water and then adding the quaternary alkyl ammonium halide salt. The mixture is then allowed to stand for at least two days with occasional agitation to allow the formation of gel.

The starting materials of Formula I are prepared by reacting a cycloalkanone with a heterocyclic amine such as pyrrolidine to form the corresponding enamine and reacting the enamine with a selected benzoyl chloride, the acyl radical of which attaches itself to the 2-position of the cycloalkenyl moiety of the enamine. If at the end of this reaction the amino portion of the enamine is split off by hydrolysis, it is reestablished by reacting the obtained Z-(benzoyl or substituted benzoyl) cycloalkanone with a heterocyclic amine containing from 5 to nuclear atoms as defined above. This second method is preferred in some instances because of better yields. The thus-obtained unsaturated compound, a (phenyl or substituted phenyl) (2 heterocyclicamino-l-cycloalken-l-yl) ketone, is then selectively hydrogenated with 1 molar equivalent of hydrogen per molar equivalent of unsaturated ketone in the presence of a platinum oxide catalyst to give the starting material of Formula I. The production of such starting material is shown in detail under preparations.

In carrying out the process of the present invention, a selected keto compound of Formula I is submitted to a Grignard reaction under conventional conditions in which the Grignard is of an aromatic nature, having the formula:

wherein X is bromine or iodine and R R and R are defined as before.

The reaction is generally carried out in an inert organic solvent such as ether, tetrahydrofuran, benzene or the like under anhydrous conditions and at a temperature between 0 C. and the boiling point of diethyl ether (34-35 C.) or in other solvents up to 50 C. In the preferred embodiment of this invention, the Grignard reaction is carried out simply at the prevailing room temperature. The desired Grignard reagent is generally prepared in the usual manner by reacting a bromoor iodosubstituted phenyl compound with magnesium in either solution. The Grignard reagent, itself, is generally employed in excess, e.g., from 1.2 to 4 molar equivalents for each molar equivalent of compound I, but larger or smaller quantities can be used. The reaction period is generally between 1 and 6 hrs. at room temperature with longer periods required if the reaction is conducted at particularly low temperatures. At the termination of the reaction, water is added to the reaction mixture, thereby decomposing any remaining Grignard reagent and terminating further reaction. The product is isolated from the ether layer of the reaction mixture; the water layer is discarded. The isolation is carried out in conventional manner such as freeing the ether layer from solid, suspended particles, for example by filtration, and evaporating the ether layer to obtain the crude compound. This compound is then purified by standard methods such as recrystallization, extraction of impurities with solvents, chromatography, and the like.

The conversion of the thus-obtained tertiary alcohol (II) to the corresponding tertiary ether (III) is generally done by procedures in alkaline media. Thus, ethers are generally made by reacting the tertiary alcohol in liquid ammonia solution containing sodium amide or potassium amide with a solution of an alkyl bromide or iodide at a temperature between and 80 C.

Esters (IV) of these tertiary alcohols (II), are prepared by methods known in the art, e.g., by the methods of Nevitt et a1. and Bartlett et al., supra.

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

PREPARATION 1 2-(3,4,5-trimethoxybenz0yl) cyclohexanone A mixture of 147 g. (1.5 moles) of cyclohexanone and 213.3 g. (3 moles) of pyrrolidine was refluxed in 2250 ml. of benzene in a flask equipped with an azeotropic separator. After the calculated amount of 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 hrs. to a solution of the crude l-pyrrolidinol-cyclohexene 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 hrs.) at room temperature (about 22 to 25 C.), there was added 900 ml. of 10% aqueous hydrochloric acid and the resulting mixture was stirred at room temperature for 2 hrs. The aqueous layer was extracted with two l50-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 thusobtained chloroform solution was dried by passing it through anhydrous sodium sulfate and the dry solution was evaporated to give a residue which was crystallized from methanol to yield g. of long, colorless needles of 2-(3,4,5 trimethoxybenzoyl)cyclohexanone, melting point 141142 C.

Analysis.Calcd. for O -H 0 (percent): C, 65.74; H, 6.90. Found (percent): C, 65.48; H, 6.84.

PREPARATION 2 2- (3,4,5-trimerhoxybenzoyl) cyclopentanone A mixture of 126 g. (1.5 moles) of cyclopentanone and 213.3 g. (3 moles) of pyrrolidine was refluxed in 2250 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 1-pyrrolidino-l-cyclopentene over a period of 1 hr. The reaction mixture was thereupon worked up as in Preparation 1 to give a brown oil weighing 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 2600 ml. of water. The mixture was stirred for one-half hr., 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 cupric complex melting at 206208 C.

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

The thus-obtained cupric complex (70* g.) was dissolved in 350 ml. of chloroform and decomposed with 670 ml. of 10% aqueous hydrochloric acid to give 60 g. (36% yield) of 2-(3,4,5-trimethoxybenzoyl)cyclopentanone having a melting point of 81-86 C. A sample of this material was recrystallized from Skellysolve B hexanes to give 2-(3,4,5-trimethoxybenzoyl)cyclopentanone of melting point 9295 C.

Analysis.-Calcd. for 0 11 0 (percent): C, 64.73; H, 6.52. Found (percent): C, 64.95; H, 6.52.

PREPARATION 3 2-(3,4,S-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 p-toluenesulfonic acid was refluxed for 23 hrs., 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 to dryness in vacuo to give an oil which was distilled. The fraction boiling between 119-125 C. consisted essentially of 262.7 g. of l-morpholino-l-cycloheptene (32% yield).

In the manner given in Preparation 1, 3,4,5-trimethoxybenzoyl chloride (92.5 g.; 0.4 mole) was reacted with 181.37 g. (1 mole) of 1-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 107108 C.

Analysis.--Calcd. for C H O (percent): C, 66.65; H, 7.24. Found (percent): C, 66.16; H, 7.48.

PREPARATION 4 2- (p-met/zoxybcnzoyl 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 hrs. to a solution of 371.7 g. (2.46 moles) of distilled l-pyrrolidino-l-cyclohexene 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 hrs. at room temperature, the mixture was decomposed by addition of 1800 ml. of aqueous hydrochloric acid over a period of minutes. The mixture was then stirred for two hrs, 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 anhydrous sodium sulfate and evaporated. The residue resulting from the evaporation was a brown oil which was dissolved in 1 1. of ethanol and added to a solution of 344 g. of cupric acetate monohydrate in 5200 ml. of water, preheated to 65 C. The mixture was stirred for 0.5 hr., cooled to room temperature and filtered. The obtained precipitate was washed with water and then with ether. It was then dissolved in 800 ml. of chloroform and added to a solution of 300 ml. of concentrated hydrochloric acid in 100 ml. of water. The mixture was stirred for 1 hr. 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 1. of methanol, yielding 136.5 g. of Z-(p-methoxybenzoyl) cyclohexanone having a melting point of 115-128 C. A recrystallized sample (from methanol) of 2-(p-methoxybenzoyl)cyclohexanone had a melting point of 117- 122 C.

Analysis.-Calcd. for C H O (percent): C, 72.39; I

In the manner given in Preparation 2, 204 g. (12 moles) of p-anisoyl 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 Preparation 4, the complex being crystallized from chloroform-ether to give 80 g. of copper complex of Z-(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 8283 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 2-(p-methoxybenzoyl)cyclopentanone of melting point 7677 C. (total yield 17% Two recrystaL lizations from methanol gave 2-(p-methoxybenzoyl)cyclopentanone having a melting point of 8387 C.

Analysis. Calcd. for C H O (percent): C, 71.54; H, 6.47. Found (percent): C, 71.83; H, 6.48.

8 PREPARATION 6 2- (p-erhoxybenzoyl cycIo/zexanone In the manner given in Preparation 2, l-piperidino-lcyclohexene was reacted with p-ethoxybenzoyl chloride in chloroform solution to give, after the copper complex purification procedure (Preparation 2), 2-(p-ethoxybenzoyl) cyclohexanone.

PREPARATION 7 2-(o-methoxybenzoyf)cyclohexanone In the manner given in Preparation 2, l-piperidino-lcyclohexene was reacted with o-methoxybenzoyl chloride in chloroform solution to give, after the copper complex purification procedure (Preparation 2), 2-(o-methoxybenzoyl)cyclohexanone of melting point 6568 C.

PREPARATION 8 2- (2-meth0xy-4-metlzylbenz0yl cyclo/zexanone In the manner given in Preparation 2, l-piperidino-lcyclohexene was reacted with 2-methoxy-4-methylbenzoyl chloride in chloroform solution to give, after the copper complex purification procedure (Preparation 2), 2-(2- methoxy-4-methylbenzoyl -cyclohexanone.

PREPARATION 9 2- (3,5 -dimetlzyl-4-melhoxybenzoyl cyclollexanone In the manner given in Preparation 2, l-pyrrolidino-lcyclohexene was reacted with 3,5-dimethyl-4-methoxybenzoyl chloride in chloroform solution to give, after the copper complex purification procedure (Preparation 2), 2-(3,5-dimethyl-4-methoxybenzoyl)cyclohexanone of melting point 126 C.

PREPARATION 10 2- p-tri fluoromelh y l benzoyl cycloh exanone In the manner given in Preparation 2, l-piperidino-lcyclohexene was repeated with p-trifluoromethylbenzoyl chloride in chloroform solution to give, after the copper complex purification procedure (Preparation 2), 2-(ptrifluoromethylbenzoyl)cyclohexanone.

PREPARATION 1 1 2- (p-chlorobcnzoyl) cyclohexanone In the manner given in Preparation 2, l-piperidino-lcyclohexene was reacted with p-chlorobenzoyl chloride in chloroform solution to give, after the copper complex purification procedure (Preparation 2), 2-(p-chlorobenzoyl)cyclohexanone.

PREPARATION 12 2-(0-methylbenz0yl)cyclolzexanone In the manner given in Preparation 2, l-piperidino-lcyclohexene was reacted with o-methylbenzoyl chloride in chloroform solution to give, after the copper complex purification procedure (Preparation 2), 2-(o-methylbenzoyl)cyclohexanone.

purification procedure (Preparatio 2), 2-(p-methylbenzoyl)cyclohexanone of melting point 1081l0 C PREPARATION 14 2-(2,4-dimethylbenzoyI) cyclohexanone In the manner given in Preparation 2, l-pyrrolidino-lcyclohexene was reacted with 2,4-dimethylbenzoyl chloride in chloroform solution to give, after the copper complex purification procedure (Preparation 2), 2-(2,4-di- 9 methylbenzoyl)cyclohexanone of melting point 51- 52.5 C.

PREPARATION 15 2-(2-meth0xy-4-methylbenz0yl) cyclohexanone In the manner given in Preparation 2, l-piperidino-lcyclohexene was reacted with 2-methoxy-4-methylbenzoy1 chloride in chloroform solution to give, after the copper complex purification procedure (Preparation 2), 2-(2- methoxy-4-methylbenzoyl) cyclohexanone.

PREPARATION 16 2-(p-ethoxybenz0yl) cyclooctanone In the manner given in Preparation 2, l-morpholino-lcyclooctene was reacted with p-ethoxybenzoyl chloride in chloroform solution to give, after the copper complex purification procedure (Preparation 2), 2-(p-ethoxybenzo yl cyclooctanone.

PREPARATION 17 2-(2,3,4-trimethoxybenz0yl) cyclooctanone In the manner given in Preparation 2, l-piperidino-lcyclooctene was reacted with 2,3,4-trimethoxybenzoyl chloride in chloroform solution to give, after the copper complex purification procedure (Preparation 2), 2-(2,3,4- trimethoxyb enzoyl cyclooctanone.

PREPARATION 18 2- (p-bromobenzoyl) cyclooctanone PREPARATION l9 2- (3-merhy [benzoyl cyclooctanone In the manner given in Preparation 2, l-piperidino-lcyclooctene was reacted with 3-rnethylbenzoyl chloride in chloroform solution to give, after the copper complex purification procedure (Preparation 2), 2(3-methylbenzoyl)cyclooctanone.

In the same manner given in the foregoing preparations, other 2-benzoylcycloalkanones are prepared by reacting a l-cyclicamino-l-cycloalkene, wherein the cycloalkene moiety has from 5 to 8 nuclear carbon atoms, inclusive, and the cyclicamino moiety has from 5 to 10 nuclear atoms, inclusive, with a selected benzoyl chloride. Representative compounds, thus prepared, include: 2-(3,5-diiodobenzoyl)cyclopentanone; 2 (p-fluorobenzoyl)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 -dichlorobenzoyl) cycloheptanone; 2 (3,4-dichlorobenzoyl)cyclooctanone; 2 (p propoxybenzoyl)cyclooctanone; 2-(2,5-diiodobenzoyl)cycloheptanone; 2 (3 fluorobenzoyl)cyclopentanone; 2-(p-bromobenzoyl)cyclopentanone; 2-(p-hexylbenzoyl)cyclopentanone; 2 (3 pentylbenzoyl)-cyclohexanone; 2-(2-butylbenzoyl)cyclohexanone; 2-(2-propylben- Zoyl)cycloheptanone; 2 (3-ethylbenzoyl)cyclooctanone; 2 (2 methoxy 5 bromobenzoyl)cyclopentanone; 2- benzoylcyclooctanone; Z-benzoylcycloheptanone and the like.

PREPARATION 20 3,4,5-trimeth0xyphenyl 2-piperidin0-1-cyclohexen-1-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 hrs. under nitrogen using an azeotropic separator (during this time, 1.8 ml. of water was collected). The mixture was thereupon evapo- 10 rated to dryness to give partially crystalline 3,4,5-trimethoxyphenyl Z-piperidino-l-cyclohexen-1-yl ketone.

PREPARATION 21 3,4,5-trimezh0xyphenyl Z-morpholino-J-cycl0hexen-1 -yl ketone In the manner given in Preparation 20, 8.75 g. of 2- (3,4,5-trimethoxybenzoyl)cyclohexanone, 7.84 g. of morpholine, 240 ml. of benzene and 0.2 g. of p-toluenesulfonic acid was refluxed under nitrogen for a period of 23 hrs. whereby 0.49 ml. of water was collected. The solution was evaporated to dryness, to give 3,4,5-trimethoxyphenyl 2-morpholino-lcyclohexen-1-yl ketone.

PREPARATION 22 3,4,5-trimethoxyphenyl 2-(4-methyl-1 -piperazinyl)-1- cyclohexen-Iyl ketone A mixture of 8.75 g. (0.03 mole) of 2-(3,4,5-trimethoxybenzoyl)cyclohexanone, 9 g. (0.09 mole) of N- methylpiperazine, 240 ml. of toluene and 0.2 g. of ptoluenesulfonic acid was refluxed in a nitrogen atmosphere for a period of 7 hrs. After 7 hrs. 0.6 mole of water had been collected in an azeotropic separator. The reaction mixture Was thereupon evaporated to dryness to give 3,4,5 trimethoxyphenyl 2 (4-methyl-l-piperazinyl)-1- cyclohexen-l-yl ketone.

PREPARATION 23 p-Methoxyphenyl Z-piperidino-J-cycl0hexen-1-yl ketone In the manner given in Preparation 20, 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-yl ketone.

PREPARATION 24 Cis-p-methoxyphenyl Z-piperidinocyclohexyl ketone A mixture of 139 g. (0.6 mole) of 2.-(p-methoxyben zoyl)-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 hrs. 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 1200 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 of hydrogen. 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 1200 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% aqueous hydrochloric acid for 45 minutes. The acidic layer was separated, filtered and basified with 20% 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 116 g. Recrystallization of this crude product from petroleum ether gave 75 g. (42% yield) of colorless needles of cisp-methoxyphenyl Z-piperidinocyclohexyl ketone having a melting point of 86-88" C. Further recrystallization from petroleum ether for analytical purposed gave cis-p-methoxyphenyl 2-piperidinocyclohexyl ketone of melting point 86.588 C.

1 1 Ultraviolet: Amax, 217 (11,850); 273 (15,800); 278 (15,500).

Analyris.Calcd. for C19H27NO2 (percent): C, 75.71; H, 9.03; N, 4.65. Found (percent): C, 76.19; H, 9.19; N, 4.88.

PREPARATION 25 T rans-p-metlzoxyphenyl Z-piperidinocyclohexyl ketone A solution of 68.3 g. (0.227 mole) of cis-p-methoxyphenyl Z-piperidinocyclohexyl ketone was refluxed for 68 hrs. in 683 ml. 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 100 ml. each of 10% aqueous acetic acid. The acid extracts were combined, cooled in ice, and basified with 20% aqueous sodium hydroxide solution and thereupon extracted with four por tions of 150 ml. each of methylene chloride. The methylene chloride extracts were combined, washed with satu rated salt solution, dried over anhydrous sodium sulfate and evaporated to give 22 g. of a colorless solid which was crystallized from 150 ml. of petroleum ether boiling range from 30-60 C.) to give 12.05 g. of trans-p-methoxyphenyl 2-piperidinocyclohexyl ketone of melting point 100-101 C. A second crop of 3.5 g. of the same material was also obtained; a total of 23% yield.

Ultraviolet: x 216 (12,900); 271 (15,350). A1zalysis.-Calcd. for C19H27N02 (percent): C, 75.71; H, 9.03; N, 4.65. Found (percent): C, 75.28; H, 8.66; N, 4.62.

PREPARATION 26 3,4,5-trz'meth0xyphenyl 2-piperidin0cycl0pentyl ketone A solution of 15.1 g. (0.1 mole) of l-piperidino-lcyclopentene 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 hrs., while the temperature of the reaction mixture was kept at -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. The mixture was filtered and evaporated to dryness. A mixture of 100 ml. of ether and 100 ml. of aqueous hydrochloric acid were added and the obtained reaction mixture was stirred for 1.5 hrs. The layers were separated and the aqueous layer was extracted once with ether. The ether extracts were washed to give a neutral layer. The acidic layer was cooled in ice and basified with 20% aqueous sodium hydroxide. It was extracted twice with ether, the combined ether extract 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 hrs. 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 120-130 C., was removed by filtration. Recrystallization of this solid from ether gave colorless needles of melting point l33.5-134.5 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 2Fpiperidinocyclopentyl ketone of melting point 79-80 C.

Ultraviolet: A 217 (29,400); 283 (10,700).

Analysis.-Calcd. for C H NO (percent): C, 69.13; H, 8.41; N, 4.03. Found (percent): C, 69.21; H, 8.58; N, 4.14.

PREPARATION 27 p-Ethoxyphenyl Z-piperfdino-I -cyclohexen-I-yl-ketone In the manner given in Preparation 20, 2-(p-ethoxybenzoyl)cyclohexanone was reacted with piperidine in the presence of p-toluenesulfonic acid to give p-ethoxyphenyl 2-piperidinol-cyclohexenl-yl ketone.

PREPARATION 28 o-Metlzoxyphenyl Z-piperidino-I-cycl0hexen-1-yl ketone In the manner given in Preparation 20, 2-(o-methoxybenzoyl)cyclohexanone was reacted with piperidine in the presence of p-toluenesulfonic acid to give omethoxyphenyl 2-piperidino-l-cyclohexen-l-yl ketone.

PREPARATION 29 2-methoxy-4-metlzylphenyl Z-piperidino-I-cyclw hexen-l-yl ketone In the manner given in Preparation 20, 2-(2-methoxy- 4-methylbenzoyl)cyclohexanone was reacted with piperidine in the presence of p-toluenesulfonic acid to give 2- methoxy 4 methylphenyl 2-piperidino-l-cyclohexen-lyl ketone.

PREPARATION 3O 3,5-dimethyl-4-methoxyphenyl Z-piperidino-l-cyclohexen-I-yl ketone In the manner given in Preparation 20, 2-(3,5-dimethyl- 4-methoxybenzoyl)cyclohexanone was reacted with piperidine in the presence of p-toluenesulfonic acid to give 3,5- dimethyl-4-methoxyphenyl 2 piperidino-l-cyclohexen-lyl ketone.

PREPARATION 31 p-Trifluoromelhylphenyl Z-piperidino-I-cyclohexen-I-yl ketone In the manner given in Preparation 20, 2-(p-trifluoromethylbenzoyl)cyclohexanone was reacted with piperidine in the presence of p-toluenesulfonic acid to give ptrifluoromethylphenyl 2-piperidino-1-cyclohexen 1 yl ketone.

PREPARATION 32 p-Chlorophenyl 2- (Z-isopropylpyrrolidino) -1- cyclohexen-I-yl ketone o-methylphenyl 2-pyrrolidino-l-cyclohexen-l-yl ketone;

p-methylphenyl 2-pyrrolidino-l-cyclohexen-l-yl ketone;

2,4-dimethylphenyl 2-(4-methyl-l-piperazinyl) -1-cyc1ohexen-l-yl ketone; v

2-methoxy-4-methylphenyl 2-morpholino-l-cyclohexen- 1-yl ketone;

p-ethoxyphenyl Z-pyrrolidino-l-cyclohepten-l-yl ketone;

2,3,4-trimethoxyphenyl 2-piperidino-l-cycloocten-l-yl ketone;

p-bromophenyl 2-(4-butyl-l-piperazinyl)-1-cycloocten-1- yl ketone;

3,5-diiodophenyl 2-(3-methylpiperidino)-1-cyc1ohexen-1- yl ketone;

2-methoxy-4-chlorophenyl 2-piperidino-l-cyclohexen-l-yl ketone;

2-methyl-4-trifluoromethylphenyl-2-piperidino-l-cyclohexen-l-yl ketone;

3,4-dipropylpheny1 Z-pyrrolidino-l-cyclohepten-l-yl ketone;

2,5-dich1orophenyl 2-(hexahydro-1H-azepin-1-yl)-1-cyc1ohepten-l-yl ketone;

3,4-dichlorophenyl 2-(3-methylpiperidino)-1-cyclooctenl-yl ketone;

p-propoxyphenyl 2-(4-butylpiperazino)-1-cycloocten-1-y1 ketone;

2,5 -diiodophenyl 2-(Z-methylhexamethyleneimino)-1- cyclohepten-l-yl ketone;

3-fluorophenyl 2-pyrro1idino-l-cyclopenten-1-y1 ketone;

p-bromophenyl 2-(4-ethyl-l-piperazinyl)-l-cyclopentenl-yl ketone;

2-hexylphenyl 2-piperidino-l-cyclopenten-l-yl ketone;

3-pentylphenyl 2-piperidino-l-cyclohexen-l-yl ketone;

2-butylphenyl 2-morpholino-l-cyclohexen-l-yl ketone;

2-propylpheny1 2-( 1,2,3,4-tetrahydro-l-quinolyl) -1-cyclohepten-l-yl ketone;

3-ethylphenyl 2-piperidino-l-cycloocten-l-yl ketone;

2-methoxy-5-bromophenyl Z-pyrrolidino-l-cyclopenten-lyl ketone;

phenyl Z-octarnethyleneimino-l-cycloocten-l-yl ketone;

phenyl 2-(2,3,6-trimethylmorpholino)-1-cyc1ohepten-1-yl ketone;

and the like.

In the same manner given in Preparation 24, catalytic reduction (preferably with platinum oxide) of the beforementioned unsaturated ketones produces ketones of Formla I, i.e., starting compounds, e.g.,

cis-3,4,5-trimethoxyphenyl Z-piperidinocyclohexyl ketone;

cis-p-ethoxyphenyl 2-piperidinocyclohexyl ketone;

cis-2-methoxy-5-bromopheny1 2-pyrro1idinocyclopentyl ketone;

cis-3,4-dipropylphenyl 2-pyrrolidinocyclohepty1 ketone;

cis-ptrifluoromethylphenyl Z-piperidinocyclohexyl ketone;

cis-2-propylpheny1 2-( 1,2,3,4-tetrahydrol-quinolyl) cycloheptyl ketone;

cis-p-chlorophenyl 2-(2-isopropy1pyrro1idino) cyclohexyl ketone;

cis-2,3,4-trimethoxyphenyl Z-piperidinocyclooctyl ketone;

cis-p-bromophenyl 2-(4-rnethyl-1-piperaziny1)cyclooctyl ketone;

cis-3,5-diiodophenyl 2-(3-methylpiperidino)cyclohexyl ketone;

cis-2,5-dichlorophenyl 2-(hexahydro-lH-azepin-l-yl)cycloheptyl ketone;

cis-p-bromophenyl 2-(4-butyl-1-piperaziny1)cyclopentyl ketone;

cis-2,3,4-trimethoxyphenyl 2-morpholino-cyclooctyl ketone;

cis-3,4-dichlorophenyl 2-(3-methylpiperidino)cyclooctyl ketone;

cis-2,5-dichlorophenyl 2-(hexahydro-1H-azepin-l-yl) cycloheptyl ketone;

cis-phenyl 2-octamethylenimino-cyc1ooctyl ketone;

and the like.

l 4 EXAMPLE 1 Cis-a,ot-bis p -metho xyph enyl -2- pi peridinocyclohexanemethanol g o- 00H. GHQ-@MgBr 11 A solution of 9.03 g. (0.03 mole) of cis-p-methoxyphenyl-Z-piperidinocyclohexyl ketone in ml. of anhydrous ether was added over a 25-minute period to a solution of p-methoxyphenylmagnesium bromide, prepared by reacting 11.2 g. (0.06 mole) of p-bromoanisole and 1.45 g. (0.06 mole) of magnesium turnings in ml. of anhydrous ether. The mixture was stirred for a period of 3 hrs. and was then decomposed by the addition of 50 m1. of water. The solution was decanted from an amorphous solid, which was washed with ether. The combined ether solution and washings were washed with water, then with saturated salt solution, dried over anhydrous sodium sulfate and evaporated to give 15 g. of crude product. This product was crystallized from ether-petroleum ether (boiling range 30-60 C.) to give 5 g. of colorless prisms of melting point -136 C. and 3 g. of a second crop of melting point 134-135" C.; total yield 59%. Recrystallization from ether gave pure cis-a,a-bis(p-rnethoxyphenyl) 2 piperidinocyclohexanemethanol of melting point 136-137 C.

Ultraviolet: sh 224 (13,600); k 235.5 (17,650); 273 (3,100); sh 283 (1,800).

Analysis.Calcd. for C H NO (percent): C, 76.24; H, 8.61; N, 3.42. Found (percent): C, 75.92; H, 8.96; N, 3.61.

EXAMPLE 2 Trans-a,a-bis (p-methoxyph enyl -2-piperidin0cycl0 hexanemethano-l water. The solution was decanted from an amorphous solid, which was washed with ether. The ether fraction and ether washings were combined, washed with water, saturated salt solution, dried over anhydrous sodium sulfate and evaporated to give 4.8 g. of crude material. This crude material was first purified by extraction with 10% aqueous acetic acid, four portions of 75 ml. each; the acetic acid extracts were combined and basified with 20% aqueous sodium hydroxide solution, and the oil which separated was extracted with four portions of methylene chloride of 50 ml. each. The methylene chloride extracts were combined, washed with water, then with saturated sodium chloride solution, and finally dried with anhydrous sodium sulfate. The dried solution was evaporated to give 3.8 g. of material which was chromatographed over 190 g. of Florisil (synthetic anhydrous magnesium silicate): five eluates of 250 ml. each of 6% acetone, 94% Skellysolve B hexanes. Combining and evaporating the fractions gave 2.9 g. (71% yield) of trans-a,a-bis(p-methoxyphenyl)-2- piperidinocyclohexanemethanol as an amorphous, colorless solid which had a melting point of about 100 C. with effervescence.

Ultraviolet: A 228 (19,350); 275 (3,050); 281.5 (2,750).

AnaIysis.-Calcd. for C H NO (percent): C, 76.24; H, 8.61; N, 3.42. Found (percent): C, 76.01; H, 8.69; N, 3.56.

This product was converted to the oxalate. Basification of ethis salt gave crystalline trans-a,a-bis (p-methoxyphenyl)-2-piperidinocyclohexanemethanol of melting point 112-115 C.

EXAMPLE 3 C is-a,a-bis (Z-methoxy-S -methy lphenyl -2-p iperid inocyclohexanem ethanol In the manner given in Example 1, solution of cis-2- methoxy-5-methylphenyl-2-piperidinocyclohexyl ketone in diethyl ether was reacted with 2-methoxy-5-methylphenylmagnesium bromide (synthetized from 2-bromo-4-methylanisol and magnesium turnings) and the mixture was decomposed with water to give cis-u,a-bis(2-methoxy- 5 methylphenyl) 2-piperidinocyclohexanemethanol, obtained n recrystallization from ethanol as an ethanol solvate of melting point 169-170 C.

Ultraviolet: A sl sh 230 (12,240); 282 (4,880); 288 (4,815).

Analysis.-Calcd. for C H NO -(CH H OH) (percent): C, 76.09; H, 9.11; N, 3.10; C H OH, 3.1. Found (percent): C, 75.67; H, 9.52; N, 3.18; C H OH, 3.29.

The above ethanol solvate was dried at 0.1 mm. mercury pressure and 80 C. for 48 hours, in the presence of calcium chloride, to obtain cis-u,a-bis(2-methoxy-5-methylphenyl)-2-piperidinocyclohexanemethanol.

EXAMPLE 4 Cis-a,a-bis(p-ethoxyphenyl) -2-piperidin0cycl0- h exanemethanol A Grignard reagent was prepared from 40 g. (0.2 mole) of 1-bromo-4-ethoxybenzene and 4.9 g. (0.02 mole) of magnesium turnings in 100 ml. of tetrahydrofuran.

To the stirred Grignard mixture at room temperature was added, over a period of 30 minutes, a solution of 12 g. of cis-p-ethoxyphenyl Z-piperidinocyclohexyl ketone. The mixture was stirred for 1.5 hrs. and allowed to stand overnight. It was decomposed with 25 ml. of water and then filtered through Celite (diatomaceous earth). The filtrate was concentrated and taken to dryness in vacuo and the thus-obtained residue taken up in ether-water; the ether layer was separated, washed repeatedly with water, then with saturated sodium chloride solution and finally dried over anhydrous sodium sulfate. The ether layer was then evaporated and the residue was dissolved in methylene chloride and chromatographed over 1 kg. of Florisil (synthetic anhydrous magnesium silicate) column with methylene chloride. The column was eluted with 500 ml. fractions of 10% aqueous acetic acid. The aqueous acid extracts were basified with 20% aqueous sodium hydroxide solution and the oil which separated was extracted with methylene chloride. The methylene chloride extracts were washed with water, then with saturated sodium chloride solution, and dried over anhydrous sodium sulfate, then concentrated in vacuo to give a solid which was twice recrystallized from Skellysolve B hexanes to give cis-u,a-bis(p-ethoxyphenyl)-2- piperidinocyclohexanemethanol of melting point 164- 165 C.

Ultraviolet: 8 sh 231 (10,950); 236 (13,160); 274 (2,230); sh 284 (1,310).

Analysis.Calcd. for C H NO (percent): C, 76.85; H, 8.98; N, 3.20. Found (percent): C, 76.97; H, 9.12; N, 3.22.

EXAMPLE 5 Cis-a,a-bis(m-meflzoxyphenyl)-2-piperidin0cyclohexancmethanol In the manner given in Example 1, a solution of cism-methoxyphenyl Z-piperidinocyclohexy ketone in diethyl ether was reacted with 3-methoxyphenylmagnesium bromide (synthetized from 3-bromoanisole and magnesium turnings in ether) and the mixture was decomposed with water to give cis-ogwbis(m-methoxyphenyl) 2 piperidinocyclohexanemethanol of melting point 145-146 C.

Ultraviolet: Amax, 274 (4,135); 282 (3,740).

Analysis.Calcd. for C H NO (percent): C, 76.24; H, 8.61; N, 3.42. Found (percent): C, 76.48; H, 8.88; N, 3.53.

EXAMPLE 6 Cis-tz,a-bis(0-meth0xyphenyl) -2-pipcridin0cyclohexanemethanol In the manner given in Example 1, a solution of cis-omethoxyphenyl Z-piperidinocyclohexyl ketone in diethyl ether was reacted with o-methoxyphenylmagnesium bromide (synthetized from 2-bromoanisole and magnesium turnings) and the mixture was decomposed with water to give cisa,o-bis(o-methoxyphenyl) 2 piperidinocyclohexanemethanol of melting point 197l98 C.

Ultraviolet: A sl sh 227 (9,200); 274 (4,150); 281 (4,200).

Analysis.Calcd. for C H NO (percent): C, 76.24; H, 8.61; N, 3.42. Found (percent): C, 76.04; H, 8.48; N, 3.34.

EXAMPLE 7 Cis-a,a-bis(o-etlzoxyphenyl)-2-piperidin0k:ycl0- hexanemethanol In the manner given in Example 1, a solution of cis-oethoxyphenyl 2 piperidinocyclohexyl ketone in diethyl ether was reacted with 2-ethoxyphenylmagnesium bromide (synthetized from 2 bromophenetole and magnesium turnings) and the mixture was decomposed with water to give cis-a,tx-bis(o-ethoxyphenyl) 2 piperidinocyclohexanemethanol of melting point 187 C.

Ultraviolet: k sl sh 228 (12,150); 275 (4,700); 282 (4,900).

Analysis.Calcd. for C H NO (percent): C, 76.85; H, 8.98; N, 3.20. Found (percent): C, 77.04; H, 9.06; N, 3.11.

EXAMPLE 8 a,ot-BiS( o-methoxyphenyl -2-piperidz'n0cy clopentanemethanol In the manner given in Example 1, a solution of cis-(omethoxyphenyl) Z-piperidinocyclopentyl ketone in diethyl ether was reacted with 2-methoxyphenylmagnesium bromide (synthetized from o-bromoanisole and magnesium turnings) and the mixture was decomposed with water to give a,a-bis(p-methoxyphenyl) 2 piperidinocyclopentanemethanol of melting point l23126 C. (after recrystallization several times from ethanol).

Ultraviolet: A sh-233 (14,080); 273 (3,830); 279.5 (3,780).

Analysis.Calcd. for C H NO (percent): C, 75.91; H, 8.41; N, 3.54. Found (percent): C, 75.83; H, 8.37; N, 3.40.

Concentrating the ethanol mother liquors gave an iso meric a,a-bis(o-methoxyphenyl) 2 piperidinocyclopentanemethanol of melting point 129130 C. (recrystallized from Skellysolve B hexanes).

Ultraviolet: A s1 sh-225 (13,160); 273 (4,330); 279 (4,270).

Analysis.Calcd. for C H NO (percent): C, 75.91; H, 8.41; N, 3.54. Found (percent): C, 75.80; H, 8.27; N, 3.59.

EXAMPLE 9 Cis-a- (p hydroxyphenyl) -ap-methoxyph enyl) -2- piperidinocyclohexanemethanol In the manner given in Example 1, a solution of cis-(pmethoxyphenyl) Z-piperidinocyclohexyl ketone in tetrahydrofuran was reacted with p-(2-tetrahydropyranyl)- phenylmagnesium bromide (synthetized from p-(Z-tetrahydropyranyl)bromophenol and magnesium turnings) and the mixture was decomposed with water to give cis-a- (p-hydroxyphenyD-a-(p-methoxyphenyl) 2 piperidinocyclohexanemethanol, obtained as a hydrate shown in the molecular formula below; melting point 215216 C. (after recrystallization from ethanol and then from =benzene-Skellysolve B hexanes).

Ultraviolet: Amax' 225 (13,150); 235 (16,450); 274 (3,100); sl sh 283 (1,850).

Analysis.Calcd. for C H NO AH O (percent): C, 75.06; H, 8.44; N, 3.50; H O, 1.12. Found (percent): C, 74.80; H, 8.18; N, 3.73; H O, 1.06.

Mother liquors were combined and concentrated in vacuo and the thus-obtained residue was dissolved in methylene chloride and chromatographed over Florisil with 80% Skellysolv B hexanes-20% acetone mixture. The product thus obtained was recrystallized from benzene to give cis-a-(p-hydroxyphenyl)-a-(p-methoxyphenyl)-2- piperidinocyclohexanemethanol of melting point 219- 220 C.

Ultraviolet: Amax, sh 224 (11,700); 236 (15,200); 274 (2,900); sh 284 (1,750).

Analysis.Calcd. for C H NO (percent): C, 75.91; H, 8.41; N, 3.54. Found (percent): C, 75.85; H, 8.52; N, 3.93.

The products of this example have diuretic activity.

EXAMPLE 10 t- (p-Elhylphenyl) -oz- (2-meth0xy-4-methylphenyl) -2- piperidinocyclohexanemethano l In the manner given in Example 1, a solution of 2- methoxy-4-methylphenyl Z-piperidinocyclohexyl ketone was reacted with p-ethylphenylmagnesium bromide and the resulting product decomposed with water to give a- (p ethylphenyl)-u-(2-methoxy-4-methylphenyl) 2 piperidinocyclohexanemethanol.

EXAMPLE 11 u- (3,4,5-trimethoxyphenyl -a-p-trifluo ramethyl) phiemyl -2-m0rpholin0cylohexanemethanol In the manner given in Example 1, a solution of 3,4,5- trimethoxyphenyl Z-morpholinocyclohexyl ketone was reacted with p-trifluoromethylphenylmagnesiurn bromide and the resulting product decomposed with water to give a (3,4,5 trimethoxyphenyl)-ot-(p-trifluoromethylphenyl) -2- (4-methy1- l-piperazinyl) cyclohexanemethanol.

EXAMPLE 12 a-(3,4,5-trimethoxyphenyl)-a-(m-pr0pylphenyl)-2- 4 -methyl-1 -piperazinyl) cyclohexanem ethanol In the manner given in Example 1, a solution of 3,4,5- trimethoxyphenyl 2 (4 methyl-l-piperazinyl)cycloheX- yl ketone was reacted with m-propylphenylmagnesium bromide and the resulting product decomposed with water to give a-(3,4,5-trimethoxyphenyl)-a-(m-propylphenyl) -2- (4-mehty1-1-piperazinyl) cyclohexanemethanol.

EXAMPLE 13 a-(2,5-dichlorophenyl) -a- (p-b'utylphenyl) -2-(hexahydr0- 1 H -azepin-1 -yl )cycloheptane methanol In the manner given in Example 1, a solution of 2,5-dichlorophenyl 2 (hexahydro-lH-azepin-l-yl)cycloheptyl ketone was reacted with p-butylphenylmagnesium bromide and the resulting product decomposed with water to give u (2,5 dichlorophenyl)-u-(p-butylphenyl)-2- hexahydro- 1H- azepin- 1 -yl cycloheptanemethanol.

EXAMPLE 14 Cis-a-(2,5-dichlorophenyl)-a-(3,4,5-trimethoxyphenyl)- 2-0ctamethyleniminocyclooctanemethanol In the manner given in Example 1, a solution of cis-2,5- dichlorophenyl 2 octamethyleneiminocyclooctyl ketone was reacted with 3,4,S-trimethoxyphenylmagnesium bromide and the resulting product decomposed with water to give cisx(2,5-dichlorophenyl)-a-(3,4,5-trimethoxyphenyl) -2-octamethyleniminocyclooctanemethanol.

EXAMPLE 15 oz- (3,5-dii0d0phenyl) -0c- (3,5-dimiethylphengyl) -2-(3- methyl piperz'dinzo) cyclohexanemethanol In the manner given in Example 1, a solution of 3,5 diiodophenyl 2-(3-methylpiperidino)cyclohexyl ketone was reacted with 3,S-dimethylphenylmagnesium bromide and the resulting product decomposed with water to give a-(3,5-diiodopheny1) a (3,5 dimethylphenyl)-2-(3- methylpiperidino) cyclohexanemethanol.

EXAMPLE 16 oz- (2-methoxy-S-bromophenyl) -x- (3-butylp henyl) -2 pyrrolidinocyclopen mnemethanol In a manner given in Example 1, a solution of 2- methoxy-S-bromophenyl 2-pyrrolidinocyclopentyl ketone was reacted with 3-butylphenylmagnesium bromide and the resulting product decomposed with water to give a- (2-methoxy-5-bromophenyl)-a-(3-butylphenyl) 2 pyrrolidinocyclopentanemethanol.

EXAMPLE 17 a-(3,4-dipropylphenyl)-a-(o-ethylphenyl) -2- pyrrolidinocycloheptwnemethanol In the manner given in Example 1, a solution of 3,4-di- 'propylphenyl 2-pyrrolidinocycloheptyl ketone was reacted with o-ethylphenylmagnesium bromide and the resulting product decomposed with water to give a-(3,4- dipropylphenyl)-u-(o-ethylphenyl) 2 pyrrolidinocycloheptanemethanol.

In the manner given in Example 1, other 1,3-aminoketones of Formula I are converted to the tertiary 1,3- aminoalcohols of Formula II. Representative compounds of Formula II include: agar-bis(2,4-dimethylphenyl)-2-(4- methyl-l-piperazinyl)cyclohexanemethanol; u-(2,3,4-trimethoxyphenyl)-u-(2,4-diethoxyphenyl) 2 piperidinocyclooctanemethanol; a- (p-bromophenyl -u- Z-methoxy- 4 methyl)-2-(4-b'utyl-1-piperazinyl)cyclooctanemethanol; a (3,5-diiodophenyl)-a-(4-isobutylphenyl)-2-(3-methypiperidino cyclohexamethanol; a- 2,5 -dichlorophenyl) -a- (2,5 dimethoxyphenyl)-2-hexahydro-1H-azepin-1-yl)cycloheptanemethanol; u-(p-methoxyphenyl) a o-propylphenyl)-2-(1,2,3,4-tetrahydro 1 quinolyl)cycloheptanemethanol; ot-(p-bromophenyl)-u-(3,5-dipropylphenyl)-2- (4-ethyl piperazinyl)cyclopentanemethanol; 0t,Ot-biS(3- ethylphenyl) 2 piperidinocyclooctanemethanol; a-(Z- methoxy-5-bromophenyl)-a-(o-butylphenyl) 2 pyrrolidinocyclopentanemethanol; 0:,0: diphenyl-Z-piperidinocyclohexanemethanol, and the like.

EXAMPLE 18 Cis-I- [2- [methoxybis(p-meth;typhenyl) methyl] cyclohexyl] piperidine To 75 ml. of liquid ammonia was added the minium amount of sodium metal which gave a lasting blue color. A crystal of ferric nitrate was added and then 0.23 g. (0.01 mole) of sodium metal. After a few minutes, the blue solution changed to a brown suspension. To the above stirred suspension was added a solution of 4.0 g. of cis-a,a-bis(p methoxyphenyl)-2-piperidinocyclohexanemethanol in ml. of dry tetrahydrofuran over a period of 10 minutes. The mixture was stirred for one hour, cooled to -70 C. in an acetone-Dry Ice bath, and a solution of 1.42 g. (0.01 mole) of methyl iodide in 10 ml. of dry ether was added over 10 minutes. The mixture was stirred at 70 C. for 30 minutes and the acetone-Dry Ice bath was removed. The material was stirred for 4 hrs. and then left overnight to allow the ammonia to evaporate. The residue was then dissolved in 150 ml. of a solvent mixture consisting of 50 ml. of water and 100 ml. of methylene chloride and the resulting aqueous layer Was separated and extracted with methylene chloride (two portions of 75 ml. each). The original methylene chloride layer and the washings were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated in vacuo to give 4.38 g. of a gum-like material. Trituration of this material with 100 ml. of ether gave 0.90 g. of recovered starting material. Removal of the ether in vacuo and recrystallization of the remaining gum (3.51 g.) from Skellysolve B hexanes gave 1.95 g. of starting material. Concentration of the mother liquors gave 0.80 g. of a viscous oil which darkened on standing. This oil was chromatographed over 75 g. of neutral alumina suspended in Skellysolve B hexanes. The column was eluted with 50 ml. of Skellysolve B hexanes, then with 1.5 l. of 5% ether- 95% Skellyslove B hexanes, collecting fractions of 100 ml. each. Fractions 8 through were combined, dissolved in Skellysolve B hexanes, filtered to eliminate some brown material and the filtrate was concentrated in vacuo to give 260 mg. of cis-l-[2-[methoxybis(methoxyphenyl) methyl]cyclohexyl]piperidine as a gum.

Ultraviolet: A 229 (17,200); 275 (3,500); sh 283 (3,050).

Analysis.Calcd. for C27H37NO3 (percent): C, 76.56; H, 8.81; N, 3.31. Found (percent): C, 76.56; H, 8.72; N, 3.44.

In the same manner given in Example 18, the ethyl, propyl and butyl ethers of cis-a,a-bis(p-methoxyphenyl)- 2-piperidinocyclohexanemethanol can be produced by substituting methyl iodide with ethyl iodide, propyl iodide, butyl iodide, ethyl bromide, propyl bromide or butyl bromide in Example 18.

EXAMPLE 19 Cis-I-[2-[ethoxybis(2-methylphenyl)methyl]cyclohexyl] piperidine In the same manner given in Example 18, C1S-a,otbiS- (2-methoXy-5-methylphenyl) 2 piperidinocyclohexanemethanol in liquid ammonia was treated with ethyl bromide in the presence of sodium amide (prior formed in situ) to give cis-l-[2-[ethoxybis(2-methoxy-5-methylphenyl)methyl]cyclohexyl]piperidine.

EXAMPLE 20 Cis-I- [2- [propoxybis(Z-methoxyphenyl) methyl] eyel0hexyl]piperidine In the same manner given in Example 18, cis-a,ot-bis- 2-methoxyphenyl) piperidinocyclohexanemethanol in liquid ammonia was treated with propyl iodide in the presence of sodium amide (prior formed in situ) to give cis- 1- [2- [propoxybis (2 methoxyphenyl) methyl] cyclohexyl] piperidine.

EXAMPLE 21 1- [2-[methoxy(3,4,5-trimeth0xyphenyl) (m-propylphenyl) methyl] cyclohexyl] -4-methylpiperazine In the same manner give in Example 18, a-(3,4,5-trimethoxyphenyl) a (m-propylphenyl) 2 (4-methyl-lpiperazinyl)cyclohexanemethanol in liquid ammonia was treated with methyl iodide in the presence of sodium amide (prior formed in situ) to give 1-[2-[methoxy(3,4, S-trimethoxyphenyl) (m propylphenyl)methyl] cyclohexyl]-4-methylpiperazine.

EXAMPLE 22 1- [2- [ethoxy (2-meth0xy-5-br0m0phenyl) (3-butylphenyl) methyl] cyclopentyl] pyrrolidine In the same manner given in Example 18, a-(2-methoxy 5 bromophenyl)-a-(3-butylphenyl) 2 pyrrolidinocyclopentanemethanol in liquid ammonia was treated with ethyl iodide in the presence of sodium amide (prior formed in situ) to give 1-[2-[ethoxy(Z-methoxy-S-bromophenyl) (3-butylphenyl)methyl] cyclopentyl] pyrrolidine.

EXAMPLE 23 1-[2- [methoxy (2,5-dichl0r0phenyl) (p-butylphenyl) methyl] cycloheptyl] hexahydro-IH-azepine In the same manner give in Example 18, a-(2,5-dichlorophenly) a (p-butylphenyl)-2-(hexahydro-1H-azepin- 1yl)cycloheptanemethanol in liquid ammonia was treated with methyl bromide in the presence of sodium amide (prior formed in situ) to give 1-[2-[methoXy(2,5-dichlorophenyl)(p butylphenyl)methyl]cycloheptyl1hexahydro-lH-azepine.

In the manner given in Example 18, other Formula III ethers of the beforementioned Formula II tertiary 1,3- amino-alcohols can be obtained by reacting the tertiary alcohol in liquid ammonia in the presence of sodium amide or potassium amide with a methyl, ethyl, propyl, butyl iodide or bromide. Representative compounds thus obtained include:

and the like.

EXAMPLE 24 Cis-ot,ot-bis(p-methoxyphenyl)-2-piperidin0cycl0- hexanemethanol acetate ester A solution was prepared containing 4.09 g. (0.01 mole) of cis-e,ot-bis(p-methoxyphenyl)-2-piperidinocyclohexanemethanol in 50 ml. cyclohexane. To this solution was added under rapid stirring in a nitrogen atmosphere, 5.6 ml. of a 1.9 molar solution of butyllithium in hexane (0.01 mole). The reaction was carried out at a temperature between to C. and thereafter the mixture was stirred for an additional hour. The cooling bath was thereupon removed and the liquid evaporated in vacuo at room temperature.

The thus-obtained residue, a crude lithium salt of cisoc,oc bis(p methoxyphenyl) 2 piperidinocyclohexanemethanol was taken up With ether at 0 C. and under stirring 0.015 mole of acetyl chloride was added. The stir- Cis-a,a-bis(Z-methoxy-S-methylphenyl)-2-piperidin0- cyclohexanemethanol propionate ester In the manner given in Example 24, cis-a,a-bis(2-methoxy-S-methylphenyl) 2 piperidinocyclohexanemethanol was treated with butyllithium to form the lithium salt of the alcohol which was thereupon reacted with propionyl chloride to give the desired cis-a,a-bis(2-methoxy methylphenyl)-2-piperidinocyclohexanemethanol propionate ester.

EXAMPLE 26 Cis-u,u-bis(0-meth0xyphenyl)-2-piperidin0cyclopentanemethanol hexanoate ester In the manner given in Example 24, cis-u,a-bis(o-me thoxyphenyl)-2-piperidinocyclopentanemethanol was reacted with butyllithium to give the lithium salt of the alcohol and thereupon the salt was reacted with hexanoyl bromide to give cis-u,a-bis(o-methoxyphenyl)-2-piperidinocyclopentanemethanol hexanoate ester.

EXAMPLE 27 w (p-Ethylphenyl) -u- (2-meth0xy-4-methylphenyl) -2- piperidinocyclohexanemethanol butyrate ester In the manner given in Example 24, ot-(p-ethylphenyD- (IL-(2 methoxy 4 methylphenyl) -2-piperidinocyclohex anemethanol was treated with butyllithium to give the lithium salt of the alcohol which was thereupon treated with butyryl chloride to give u-(p-ethylphenyl)-a-(2-methoxy-4 methylphenyl) 2 piperidinocyclohexanemethanol butyrate ester.

EXAMPLE 28 a-(ZJ-dichlorogahenyl) a (p butylphenyl) 2 (hexahydro -1H wzepin-l-yl)cyelohe ptwnemethanol valerate ester In the manner given in Example 24, m-(2,5-dichlorophenyl) a (p butylphenyl) 2 (hexahydro 1H- azepin-l-yl)cycloheptanemethanol was treated with butyllithium to give the lithium salt of the alcohol Which was en treated with valeryl chloride to give u-(2,5-dichlorophenyl) oz (p butylphenyl) 2 (hexahydro 1H- azepin-l-yl)cycloheptanemethanol valerate ester.

EXAMPLE 29 a (p Bromophenyl) 0c (2 methoxy 4 methylphenyl) 2 (4 methyl 1 piperazinyl) cyclooctanemethanol acetate ester In the manner given in Example 24,,a-(p bromophenyl) oz (2 methory 4 methylphenyl) 2 (4- methyl-l-piperazinyl)cyclooctanemethanol was treated with butyllithium to give the lithium salt of the alcohol which was reacted with acetyl chloride to give a-(p-bromophenyD-a-(Z methoxy 4 methylphenyl) 2 (4- methyl-l-piperazinyl)-cyclooctanemethanol acetate ester.

In the same manner given in Example 24, other Formula IV esters of Formula II tertiary 1,3-aminoalcohols can be produced by reacting the alcohol first with butyllithium to obtain the lithium salt and reacting the lithium salt with an acid chloride or bromide of the selected acid. In this manner, the acetates, propionates, butyrates, valerates, hexanoates, benzoates, phenylacetates, p-nitrobenzoates, p-chlorobenzoates, m-bromobenzoates, or the like can be produced from the before-exemplified alcohols. Representative esters thus obtained include: trans-a,a-bis(p-methoxyphenyl)-2-piperidinocyclohexanemethanol propionate ester, tit-(3,4,5 trimethoxyphenyl) 0c (p-trifluoromethylphenyl) 2 morpholinocyclohexanemethanol benzoate ester; 11,0; bis(3 ethylphenyl)-2-piperidinocyclooctanemethanol phenylacetate ester; a-(2-methoxy-5-bromophenyl) or (o-butylphenyl)-2-pyrrolidinocyclopentanemethanol hexanoate ester and the like.

EXAMPLE 30 C iS-oc,oc-l1iS( p-methoxyphenyl -2-plperidin0cyclahexanemethanol N-oxide hydrate A solution of 4.1 g. (0.01 mole) of cis-a,a-bis(p-methoxyphenyl)-2-piperidinocyclohexanemet-hanol and 3.45 g. (0.02 mole) of m-chloroperbenzoic acid in 150 ml. of chloroform was allowed to stand at room temperature for a period of 16 hrs. The chloroform layer Was thereupon extracted with saturated aqueous sodium bicarbonate solution and saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. Evaporation left a dark, gum-like material which was extracted with boiling ether and the ether extract was filtered, diluted with Skellysolve B hexanes and allowed to stand overnight. The solid which separated was recrystallized from absolute ethanol to obtain 0.9 g. of product of melting point l45153 C. This solid was recrystallized from absolute ethanol containing one drop of water to give cisa,a-bis(p methoxyphenyl) 2 piperidinocyclohexanemethanol N-oxide hydrate of melting point 145l48 C.

Ultraviolet: k 237 (17,050); 274 (3,150); s l sh 284 (1,950).

Analysis.Calcd. for C H NO .H O (percent): C, 70.40; H, 8.41; N, 3.16; H O, 4.06. Found (percent): C, 70.04; H, 8.61; N, 3.11; H O, 3.81.

EXAMPLE 31 Cis-I- [2-[methovcybis(p-meth0xyphenyl) methyl] cyclohexyl]piperidine N-o xide To an ice-cooled solution of cis-l-[2-[methoxybis(pmethoxyphenyl)methyl]cyclohexyl]piperidine in methanol was added m-chloroperbenzoic acid. The resulting colorless solution was allowed to stand in ice for 6 hrs. and then at room temperature for about 18 hrs. It was evaporated to dryness at 35 C. to give an oily residue. To this residue was added water followed by aqueous 5% sodium hydroxide, and then the mixture was extracted three times with methylene chloride. The methylene chloride extracts were combined, washed twice with saturated salt solution, dried by passage through sodium sulfate and evaporated. The resulting product was dissolved in hot ethyl acetate, saturated with water, and the cloudy solution was filtered through a sintered funnel. The resulting clear solution was evaporated to 10 ml. and the residue recrystallized several times from ethyl acetate to give crystals of cis 1 [2 methoxy-bis(p-methoxyphenyl)methyl] cyclohexyl]piperidine N-oxide.

EXAMPLE 32 Cis-a,a-bis(p-methoxyphenyl) -2-pip'eridin0cycl0 hexanemethanol acetate ester N-oxide To a solution of cis-a,oc-bis(p-methoxyphenyl)-2-piperidinocyclohexanemethanol acetate ester in methanol was added under cooling (in ice) m-chloroperbenzoic acid. The resulting reaction mixture was allowed to stand in ice for 7.5 hrs. and thereupon at room temperature for 16 hrs. It was then evaporated to dryness in vacuo at 40 C. To thethus-obtained residue was added water, followed by 50 ml. of 5% aqueous sodium hydroxide and ml. of methylene chloride. The mixture was shaken until solution resulted. The aqueous layer Was extracted with methylene chloride; the combined organic layers were washed with saturated salt solution, dried by passage through sodium sulfate and evaporated to give a residue. This residue was dissolved in 100 ml. of ethyl acetate, saturated with water, and the solution was refluxed for 5 minutes during which time a suspension resulted. It Was allowed to cool and was then filtered, and the precipitate was washed with ethyl acetate, then with ether, and the resulting product was recrystallized from ethyl acetate to give cis (1,11 bis(p-methoxyphenyl)-2-piperidinocyclohexanemethanol acetate ester N-oxide.

EXAMPLE 33 Cis-a,a-bis(Z-met/zoxy-S-methylphenyl) -2-piperidinocyclolzexanemethanol N-oxide In the manner given in Example 31, CiS-oc,ot-biS(2 methoxy 5 methylphenyl) 2 piperidinocyclohexanemethanol was reacted with m-chloroperbenzoic acid to give cis ;,00 bis(2 methoxy methylphenyl) 2- piperidinocyclohexanemethanol N-oxide.

EXAMPLE 34 Cis-I-[Z-[elhoxybis(Z-met/zoxy-S-methylphenyl) methyl]cyclolzexyl]piperidine N-oxide In the manner given in Example 31, cis-1-[2-[ethoxybis- (Z-methoxy 5 methylphenyDmethyl]cyclohexyl]piperidine was treated with peracetic acid to give cis-l-[Z- [ethoxybis(2 methoxy 5 methylphenyl)methyl]cyclohexyl]piperidine N-oxide.

EXAMPLE 35 Cis-a,tat-bis(Z-methoxy-S-methy[phenyl)-2-piperidinocyeIohexa/zemethanol propionate ester N-oxide In the manner given in Example 31, cis-a,a-bis(2- methoxy 5 methylphenyl) 2 piperidinocyclohexanemethanol propionate ester was reacted with perbenzoic acid to give cis u,m-blS(2 methoxy 5 methylphenyl)- 2 piperidinocyclohexanemethanol propionate ester N- oxide.

In the same manner given in Example 31, other tertiary 1,3-amino alcohols, ethers or esters thereof can be treated with an organic peracid, e.g., performic, peracetic, perpropionic, perbenzoic, m-chloroperbenzoic, perphthalic acid and the like to give the corresponding N-oxide. Representative N-oxides thus produced include: cis a,a-bis(mmethoxyphenyl) 2 piperidinocyclohexanemethanol N- oxide; cis a,a-bis(o-methoXy-phenyl) 2 piperidinocyclohexanemethanol N-oxide; cis Q a bis(p-ethoxyphenyl) 2 piperidinocyclohexanemethanol N-oxide; trans 0:,0: bis(p methoxyphenyl) 2 piperidincyclohexanemethanol N-oxide; a (3,4,5 trimethoxyphenyl)- 0c (2,4-diethoxyphenyl) 2 piperidinocyclooctanemethanol N-oxide; oz (p bromophenyl) o: (2 methoxy- 4 methylphenyl) 2 (4 methyl 1 piperazinyl)- cyclooctanemethanol N-oxide; a (3,5 diiodophenyl)- lit-(4 isobutylphenyl) 2 (3-methylpiperidino)cyclohexanemethanol N-oxide; a (2,5 dichlorophenyl) oc- (2,5 dimethoxyphenyl) 2 (hexahydro 1H azepin- 1-yl)cycloheptanemethanol N-oxide; cis 1 [2 [propoxybis(2 methoxyphenyl)methyl]cyclohexyl]piperidine N-oxide; 1 [2 methoxy( 3,4,5 trimethoxyphenyl)(rnpropylphenyl)methyl]cyclohexyl] 4 butylpiperazine N- oxide; 1 [2 [ethoxy(2 methoxy 5 bromophenyl)- (3 butylphenyl)methyl]cyclopentyl1pyrrolidine N-oxide; 1 [2 [methoxy(2,5 dichlorophenyl) (p butylphenyl)- cycloheptyl]heptamethyleneimine N-oxide; the acetate, propionate, butyrate, valerate, and hexanoate esters of the beforementioned tertiary 1,3-aminoalcohols, and like compounds.

EXAMPLE 36 Cir-a,u-bis(p-methoxyphenyl) -2-pt'peridt'lzoeyclolze.\'anemethatzol methiodide A solution of CiS-ot,a-bi$( p methoxyphenyl) 2 piperidinocyclohexanemethanol in methanol was refluxed with 5 molar equivalents of methyl iodide for a period of 8 hrs. The mixture was thereupon evaporated to dryness and the residual material was recrystallized several times from a mixture of methanol and ether to give cis-a,a-bis(p-methoxyphenyl) 2 piperidinocyclohexanemethanol methiodide.

By substituting methyl iodide with ethyl iodide or bromide, propyl iodide or bromide, butyl iodide or bromide, pentyl iodide or bromide, hexyl iodide or bromide, the corresponding cis 0t, bis(p methoxyphenyl) 2- piperidinocyclohexanemethanol quaternary alkyl iodides or bromides are obtained in which the alkyl group is ethyl, propyl, butyl, pentyl or hexyl depending on the selected alkyl halide.

EXAMPLE 37 TI'at1s-ot,a-bis( p-methoxyphenyl )-2-piperidinocyel0- hexanemethanol ethiodide In the manner given in Example 36, trans u,a-bis(pmethoxyphenyl) 2 piperidinocyclohexanemethanol was reacted with ethyl iodide to give trans 0:,0: bis(p-methoxyphenyl) 2 piperidinocyclohexanemethanol ethiodide.

EXAMPLE 38 Cis-a,a-bis(2-methoxy-5-methylphenyl)-2-piperidinocyclohexanemethanol met/ziodide In the manner given in Example 36, cis-a,a-bis(2-methoxy 5 methylphenyl) 2 piperidinocyclohexanemethanol was reacted with methyl iodide to give ClS-ot,a bis(2-methoxy 5 methylphenyl) 2 piperidinocyclohexanemethanol methiodide.

EXAMPLE 39 Cis-I-[2-[ethoxybis(2-nzethoxy-5-methylphenyl)methyl] cycloh-exyl]piperidine butyl iodide In the same manner given in Example 36, cis-1-[2- [ethoxy-bis( 2 methoxy 5 methylphenyl)methyl]cyclo hexyllpiperidine was reacted with butyl iodide to give cis 1 [2 [ethoxybis(2 methoxy 5 methylphenyl)- methyl]cyclohexyl]piperidine butyl iodide.

EXAMPLE 40 Cis-I- [2- [methoxybis(p-methoxyplzenyl) methyl] cyclolzexyl]piperidine propyl bromide In the same manner given in Example 36, cis-1-[2-[methoxy bis(p methoxyphenyl)methyl]cyclohexyl]piperidine was reacted with propyl bromide to give cis 1 [2- [methoxybis(p methoxyphenyl)methyl]cyclohexyl]piperidine propyl bromide.

EXAMPLE 41 Cir-oeu-bis(p-methoxyphenyl)-2-piperidinocyclo hexanenzethanol acetate ester ethiodide In the manner given in Example 36, cis 06,0: bis(pmethoxyphenyl) 2 piperidinocyclohexanemethanol acetate ester was reacted with ethyl iodide to give CiS-u,a-biS- (p methoxyphenyl) 2 piperidinocyclohexanemethanol acetate ester ethiodide.

EXAMPLE 42 T rans-a,a-bis( p-methoxyphenyl -2-piperidinoeyclohexanemethanol propionate ester octyl bromide In the manner given in Example 36, trans (1,06 bis (p methoxyphenyl) 2 piperidinocyclohexanemethanol propionate ester was reacted with octyl bromide to give trans 04,0; bis(p methoxyphenyl) 2 piperidinocyclohexanemethanol propionate ester octyl bromide.

EXAMPLE 43 a (3,4,5-trimethoxyphenyl) -a-(p-trifluoromethylpllenyl)- Z-nzorplzolinocyclohexanemethanol benzoate ester d0- decyl iodide In the manner given in Example 36, a-(3,4,5-trimethyl- 25 phenyl) (p trifluoromethylphenyl) 2 morpholinocyclohexane-methanolbenzoate ester was reacted with dodecyl iodide to give a (3,4,5 trimethoXyphenyD-a-(ptrifiuoromethylphenyl) 2 morpholinocyclohexanemethanol benzoate ester dodecyl iodide.

In the manner given in Example 36, other quaternary alkyl amonium halide salts can be prepared from the compounds of Formulas II, III and IV, e.g., a-(2,5- dichlorophenyl)-u-(3,4,5 trimethoxyphenyl) 2 octamethyleneiminocyclooctanemethanol ethiodide; 0C,t1'biS- (o-ethoxyphenyl)-2-piperidinocyclohexanemethanol butyl iodide; 00- 2-methoXy-5-bromophenyl -a- 3 -butylphenyl Z-pyrrolidinocyclopentanemethanol methobromide; 41,0:- bis(2-methoxy methylphenyl) 2 piperidinocyclohexanemethanol propyl iodide; cis-u,a-bis(m-methoxyphenyl)-2-piperidinocyclohexanemethanol butyl iodide; cis-a,a-bis(omethoxyphenyl) 2 piperidinocyclohexanemethanol ethobromide; CiS-nt,ocbiS (o-methoxyphenyl -2- piperidinocyclopentanemethanol methiodide; the acetate, propionate, butyrate, valerate, hexanoate, benzoate and phenylacetate esters thereof; the methyl, ethyl, propyl and butyl ethers thereof, and the like.

EXAMPLE 44 Cis-a,a-bis(p-methoxyphenyl)-2-piperidin0cycl0- hexanemethanol methanesulfonate To a solution of 0.82 g. (0.002 mole) of cis-u,a-bis- (p-methoxyphenyl)-2-piperidinocyclohexanemethanol in 100 ml. of ether was added a solution of 0.19 g. (0.002 mole) of methanesulfonic acid in 100 ml. of ether. The mixture was shaken for 5 minutes; a white solid was produced which was recovered by filtration. The white solid was recrystallized twice from acetonitrile-ether by dissolving it in acetonitrile, filtering the solution, and adding ether until recrystallization was initiated. The mixture was then cooled in the refrigerator at 5 C. to give 0.45 g. of cis-u,a-bis(p-methoxyphenyl)-2-piperidinocyclohexanemethanol methanesulfonate of melting point 20l202 C.

Analysis.Calcd. for C H NO -CH SO H (percent) C, 64.13; H, 7.77; N, 2.77. Found (percent): C, 63.63; H, 7.99; N, 2.90.

EXAMPLE 45 C is-a,a-bis( o-methoxy pherzyl -2-piperidz'nocycl0hexanemethanol hydrochloride Five grams of cis-a,a-bis(o-methoxyphenyl)-2-piperidino-cyclohexanemethanol was dissolved in 50 ml. of pure tetrahydrofuran. A slight excess of ethereal hydrogen chloride was added and the hydrochloride was precipitated with additional ether. The solid was filtered, washed With ether, and recrystallized from methyl ethyl ketoneether to give 5.4 g. of product melting at 217220 C. This material was recrystallized fro-m warm water (60 C.) and recovered by filtration to give 4 g. (80% yield) of cis-a,a-bis (o-methoxyphenyl) -2-piperidinocyclohexanemethanol hydrochloride of melting point 107-l09 C.

Analysis.Calcd. for C H NO -HCl(I-I O) (percent): C, 61.34; H, 8.51; N, 2.75; H O, 12.4. Found (percent): C, 60.93; H, 8.13; N, 2.62; H O, 12.20, 12.65.

The above hydrate was dried at 0.1 mm. mercury pressure and 80 C. in the presence of calcium chloride to obtain CiS-ut,o bis(o-methoxyphenyl)-2-piperidinecyclohexanemethanol hydrochloride.

EXAMPLE 46 T1'ans-a,u-bis( p-methoxyphenyl -2-piperidin0cycl0 hexanemethanol oxalate A solution of 8.06 g. of trans-a,ot-bis(p-methoxyphenyl)-2-piperidinocyclohexanemethanol in 30 ml. of isopropyl alcohol was mixed with 1.8 g. (one equivalent) of oxalic acid in 20 ml. of isopropyl alcohol. The solu- 26 tion was diluted with 200 ml. of ether and left to stand overnight. A white solid precipitated which was recovered by filtration, recrystallized from a solvent mixture consisting of ml. of absolute ethanol and 250 ml. of ether and allowed to precipitate, while standing in a refrigerator at 5 C. (The solid (4.9 g.) was recovered by filtration, recrystallized from a mixture of 100 ml. of methanol and 900 ml. of ether at 5 C. to give 2.88 g. of product melting at 147149 C. This material was recrystallized from a mixture of 50 ml. of absolute ethanol and 325 ml. of ether at 5 C. and again recrystallized from methyl ethyl ketone to give 0.95 g. of translX,OL-biS(p methoxyphenyl) 2 piperidinocyclohexanemethanol oxalate of melting point 164.5 to 165.5 C.

Anrzlysis.Calcd. for C H NO -C H O (percent): C, 67.31; H, 7.47; N, 2.80. Found (percent): C, 67.41; H, 7.53; N, 2.72.

A second crop of the same material was obtained having a melting point of 166166.5 C. after recrystallization from isopropanol-ether, ethanol-ether and methyl ethyl ketone.

A part of the oxalate salt was converted to the free base with aqueous sodium carbonate solution in the presence of methylene chloride. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to give a gummy material. This material was triturated with Skellysolve B hexanes, leaving a solid which was dissolved in Skellysolve B hexanes and seeded to give a colorless crystalline material melting at 112-115 C. which was trans-a,u-bis(p-methoxyphenyl)-2-piperidinocyclohexanemethanol.

EXAMPLE 47 T raIzs-a,a-bis( p-melhoxyphenyl 2-piperidin0cycl0- hexanemethano l methanesulfonate To a solution of 4.1 g. of trans-a,a-bis(p-methoxyphenyl)-2-piperidinocyclohexanemethanol in 250 ml. of ether was added a solution of 0.965 g. of methanesulfonic acid in 20 ml. of ether. The white solid which separated was filtered, washed well with ether and recrystallized from methyl ethyl ketone-ether to give 3.2 g. of transu,a-bis(p methoxyphenyl) 2 piperidinocyclohexanemethanol methanesulfonate of melting point 181-183 C.

Ultraviolet: k 230.5 (22,570); inflection 268 (3,050); 282 (2,750).

Analysis.Calcd. for C H NO -CH SO H (percent) C, 64.13; H, 7.77; N, 2.77. Found (percent): C, 64.05; H, 7.96; N, 2.75.

EXAMPLE 48 Cis-a,a-bis(p-methoxyphenyl)-2-piperidin0cycl0- hexan'emethanol p-tolu'enesulfonate A mixture of 4.1 g. of cis-u,a-bis(p-methoxyphenyl)- 2-piperidinocyclohexanemethanol and 5.6 g. (0.03 mole) of methyl -p-toluenesulfonate was heated on the steam bath for 2 hrs. The reaction mixture was cooled and diluted with ether, whereby a white solid separated. This white solid was collected by filtration, and twice recrystallized from absolute ethanol-ether to give CiS-a,abis(p-methoxyphenyl) 2-piperidinocyclohexanemethanol p-toluenesulfonate (acid addition salt) of melting point 2l8.5219.5 C.

Analysis.-Calcd for C H NO S (percent): C, 68.14; H, 7.45; N, 2.41. Found (percent): C, 68.60; H, 7.81; N, 2.51.

The product of this example has diuretic activity.

EXAMPLE 49 Cisa,or-bis(Z-methoxy-5-methylphenyl) -2-piperidin0- cyclohexanemethanol hydroiodide In the manner given in Example 47, cis-a,u-bis(2-methoxy 5 methylphenyl)-2-piperidinocyclohexanemethanol was reacted with hydrogen iodide to give CiS-u,oc-

27 bis(2 methoxy S-methylphenyl) (2-piperidino)cyclohexanemethanol hydroiodide.

EXAMPLE O Cis-a,a-bis(2-methoxy-S-methyIphenyl)-2-piperidin0- cyclolz xanemethanol hydrobromide In the manner given in Example 47, cis-a,a-bis(2-methoxy 5 methylphenyl)-2-piperidinocyclohexanemethanol was reacted with hydrogen bromide to give CiS-rx,otbis(2 methoxy 5 methylphenyl)-2-piperidinocycloheX anemethanol hydrobromide.

EXAMPLE 51 Cis-a,a-bis(Z-methoxy-S-methylphenyl) -2-piperidin0- cyclohexanemethanol acetate In the manner given in Example 47, cis-a,a-bis(2- methoxy 5 methylphenyl)-2-piperidinocyclohexanemethanol was reacted with acetic acid to give ClS-a,otbis(2 methoxy 5 methylphenyl)-2-piperidinocyclohexanemethanol acetate.

EXAMPLE 52 Cis-a,ot-bis(2-methoxy-5-methylphenyl)-2-piperidin0- cyclohexanemethanol perchlorate In the manner given in Example 47, CIS-ot,a-bIS(2- methoxy 5 methylphenyl) 2 piperidinocyclohexanemethanol was reacted with perchloric acid to give cisot,a bis(2-methoxy-S-methylphenyl)-2-piperidinocyclohexanemethanol perchlorate.

EXAMPLE 53 C is-a,a-bis (2 -me thoxy-S -m ethy 1 pk any I -2-piperid inocyclohexanemethanol sulfate In the manner given in Example 47, CIS-Ot,Oc-bi5(2- methoxy 5 methylphenyl) 2 piperidinocyclohexanemethanol was reacted with sulfuric acid to give cisa,ot bis(2 methoxy-S-methylphenyl)-2-piperidinocyclohexanemethanol sulfate.

EXAMPLE 5 4 C is-a,a-bis(2-meth0xy-5 -methylphenyl )-2-piperidin0- cyclohexanemethanol propionate In the manner given in Example 47, CiS-oc,ct-biS(2- methoxy 5 methylphenyl) 2 piperidinocyclohexanemethanol was reacted with propionic acid to give cis- 04,04 bis(2-methoxy-S-methylphenyl)-2-piperidinocyclohexanemethanol propionate.

EXAMPLE 55 Cis-a,tat-bis(2-meth0xy-5-methylphenyl) -2-piperidin0- cyclohexanemethanol methanesulfonate In the manner given in Example 47, cis-a,a-bis(2- methoxy 5 methylphenyl) 2 piperidinocyclohexanemethanol was reacted with methanesulfonic acid to give cis oz,ot bis(2-methoxy-5-methylphenyl)-2-piperidinocyclohexanernethanol methanesulfonate.

EXAMPLE 5 6 Cis-a,a-l1is( Z-metlzoxy-S-methy lphenyl )-2-piperidin0- cyclolzexanemethanol benzoate In the manner given in Example 47, CiS-ct,abi$(2- methoxy 5 methylphenyl) 2 piperidinocyclohexanemethanol was reacted with benzoic acid to give cistx,m bis(2 methoxy-S-methylphenyl)-2-piperidinocyc ohexanemethanol benzoate.

EXAMPLE 57 Cis-a,a-bis(2-methoxy-S-methylphenyl)-2-piperidin0- cyclohexalzemetllanol lactate In the manner given in Example 47, ClS-oz,ctbiS(2- methoxy 5 methylphenyl) 2 piperidinocyclohexanemethanol was reacted with lactic acid to give cis-u,-

28 bis(2 methoxy- S-methylphenyl)-2-piperidinocyclohexanemethanol lactate.

EXAMPLE 58 C iS-a,a-bis(2-met]z0xy-5-methyl phenyl )-2-pi per-idinocyclohexanemethanol tartrate In the manner given in Example 47, ClS-ot,zx-bl$(2- methoxy 5 methylphenyl) 2 piperidin0cyclohexanemethanol was reacted with tartaric acid to give cis-a tbis(2 methoxy 5 methylphenyl) 2 piperidinocyclohexanemethanol tartrate.

EXAMPLE 59 Cis-a,a-bis(Z-methoxy-S-methylphenyl) -2-piperidin0- cyclohexanemethanol citrate In the manner given in Example 47, CIS-oz,ablS(2- methoxy 5 methylphenyl) 2 piperidinocyclohexanemethanol was reacted with citric acid to give cis-a 1- bis(2 methoxy 5 methylphenyl) 2 piperidinocyclohexanemethanol citrate.

EXAMPLE 60 Cis-a,a-bis(2-methoxy-S-methylphenyl)-2-piperidinocyclohexanemethanol benzenesulfonate EXAMPLE 6 1 Cis-a,a-bis(Z-methoxy-S-methylphenyl) -2-piperidin0- cyclohexanemethanol phosphate In the manner given in Example 47, cis-a,ot-bis(2- methoxy 5 methylphenyl) 2 piperidinocyclohexanemethanol was reacted with phosphoric acid to give cisa, x bis(2 methoxy-S-methylphenyl)-2-piperidinocyclohexanemethanol phosphate.

In the manner given in the preceding examples for the synthesis of acid addition salts of compounds of the Formula II (tertiary 1,3-aminoalcohols), the acid addition salts of compounds of Formula III ethers, and Formula IV esters of the tertiary 1,3-aminoalcohols are prepared; such as hydrochlorides, hydrobromides, hydroiodides, perchlorates, sulfates, methanesulfonates, phosphates, acetates, propionates, laurates, lactates, tartrates, citrates, benzenesulfonates and the like.

I claim:

1. A compound selected from the group consisting of a tertiary amino ester of the formula:

(|)Ac l 2)n O wherein n has the value of 1 to 4, inclusive, wherein represents a heterocyclic amino radical containing from 5 to 10 nuclear atoms, inclusive, selected from the group consisting of pyrrolidino and alkylpyrrolidino, morpholino and alkylmorpholino, thiamorpholino and alkylthiamorpholino, 4-alkylpiperazino, piperidino and alkylpiperidino, hexamethyleneimino, alkylhexamethyleneimino, homomorpholino, heptamethyleneimino, octarnethyleneimino, 3-azabicyclo[3.2.2.]nonan-3-yl and Z-azabicyclo [2.2.2.]octan-2-yl, in which the alkyl group is of 1 to 4 carbon atoms, inclusive; wherein R, R and R are selected from the group of substituents consisting of hydrogen, halogen, alkyl and alkoxy in which the alkyl group is of 1 to 6 carbon atoms, inclusive, and --CF;,; wherein R R and R are selected from the group consisting of hydrogen, CF alkyl and alkoxy in which alkyl is of 1 to 6 carbon atoms, inclusive; and wherein Ac signifies the acyl radical of a straight-chain alkonoic acid having from 2 to 8 carbon atoms, inclusive, benzoic acid, monosubstituted mand p-nitro-, -methoxy-, -chloro-, and bromobenzoic acids and phenylacetic and phenylpropionic acids; the pharmaceutically acceptable acid addition salts thereof, N-oxides thereof, and quaternary alkyl ammonium halide salts thereof in which the alkyl group is of 1 to 12 carbon atoms, inclusive.

2. The compound according to claim 1, wherein n=2;

F\ -N Z is piperidino; R and R are Z-methoxy groups, R" and R are S-rnethyl groups and R and R are hydrogen; and the compound is therefore cis-u,a-bis(2methoxy-5- methylphenyl -2-piperidinocyclohexan emethanol.

3. Cis a (p-hydroxyphenyl) 0c (p-methoxyphenyl)-2-piperidinocyclohexanemethanol having a melting point of about 219220 C.

References Cited UNITED STATES PATENTS 2,989,533 6/1961 Stein et a1. 3,078,275 2/1963 Moffett et al. 260--326.3 3,157,656 11/1964 Krapcho. 3,190,920 6/ 1965 Spickett et al.

FOREIGN PATENTS 230,052 10/ 1958 Australia.

956,615 4/1964 Great Britain.

HENRY R. JILES, Primary Examiner S. D. WINTERS, Assistant Examiner US. Cl. X.R.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 5,506,6YO Dated Apr i l 1 1970 Inventor(s) Jacob Szmuszkovlcz It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 1, formula I I shou ld appear as fol lows Rl RI! Rlll Column 1, l ine 55, for "Grigna rd, read Grlgna rd l ine 56-57, for "oral parenteral" read oral and parenteral Column 5, l l ne 10, for "hexamethylene imino read hexamethyleneimlno l ine 65 for "m-ch loroperbenzoi c" read m-ch loroperbenzoic, Column 4, l ine 53, for "powder" read power l ine 67, for "of gel" read of a gel Column 10, l ine 17, for "-1 yl ketone" read l-yl ketone l ine 65, for "ch lorlde five" read chloride (five Column 11, l ine 22, for ether boi l lng" read ether (boi l ing l ine 57, For "purified" read gpurified Column 15, line 46, for "(CH H OH)" read C2H 0H) Column 16, l ine 22, for "2-plperidinocyclohexy" read 2-piperld i nocyclohexyl Column 17, l ine 61,

FORM PO-105O (10-69) UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 5,5 7 Dated Apr i 1 14, 1970 l Jacob Szmuszkovicz Page 2 It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

for "oa-p-trifluoromethyl)-phenyl)-" read a- (p-tri fluoromethyl phenyl I I ne 69, for "2- I-methyll-piperazinyl )cyc lohexanemethanol read 2-morphol Inocyclohexanemethanol Column 18, I ine 40, for I n a manner" read l n the manner I ine 65-66, for (B-methypiperidino)" read -methyl pi peridino) I ine 68-69 for "-o-o-propylphenyl read -on- (oropylphenyl Column 19, I ine 56, for (2-methylphenyl5 read (2- methoxy-B-methylphenyl Column 22, I ine 60, for [2- methoxy-b is" read [2-[methoxy-bis Column 23, l ine 62, for "-[2-methoxy" read -[2-[methoxy Column 26,

l ine 6, for (The sol id l.9" read The sol id (4.9

:IGNB AN F'IIF DESI-m (SEAL) Alien:

Mum," WILLIAM x. 5mm. 38- Attesting Officer I oomissionmof Patents FORM PO-1050 (l0-69)