US3499033A - Ethers of alpha-phenyl-2-aminocycloalkanemethanols - Google Patents

Ethers of alpha-phenyl-2-aminocycloalkanemethanols Download PDF

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US3499033A
US3499033A US607627A US3499033DA US3499033A US 3499033 A US3499033 A US 3499033A US 607627 A US607627 A US 607627A US 3499033D A US3499033D A US 3499033DA US 3499033 A US3499033 A US 3499033A
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give
ether
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cyclohexanemethanol
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Jacob Szmuszkovicz Kalamazoo
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Pharmacia and Upjohn Co
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/56—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/56—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds
    • C07C45/562—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds with nitrogen as the only hetero atom

Definitions

  • This invention relates to new organic compounds and is particularly concerned with new central nervous system stimulating 1,3-amino alcohols, the intermediates thereof, the ethers, esters, N-oxides, acid addition salts and quaternary ammonium salts thereof as well as the process for production therefor.
  • n has the value of 1 to 4, inclusive; wherein R 3,499,033 Patented Mar. 3, 1970 ice R4 is selected from the group consisting of the combinations H alk d v alk an 9.12
  • each alk is an alkyl of from 1 to 6 carbon atoms, inclusive
  • alk is an alkyl radical having from 1 to 6 carbon atoms, inclusive
  • alkoxyalkyl in which alkoxyalkyl is defined as above,
  • R, R and 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 III, IV, Na and IV b when in the form of the N-oxides, acid addition salts and 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.
  • alkyl groups having from 1 to 6 carbon atoms are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, 2-methylbutyl, neopentyl, hexyl, 2-methylpentyl, 3-methylpentyl and the like.
  • Alkyl groups for the quaternary alkyl 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.
  • 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, undecanoyl, dodecanoyl; of cycloalkanoic acids, e.g., cyclohexane-carbonyl, B-cyclopentylpropionyl; of benzoic and aralkanoic acids, e.g., benzoy-l, phenylacetyl, 3-phenylpropionyl, mand ptoluoyl, p-ethylbenzoyl, p-propylbenzoyl; of alkenoic acids, e.g., acryloyl, crotonyl,
  • R, R", or R' is understood fluorine, chlorine, bromine and iodine.
  • hydroxyalkyl groups are 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, S-hydroxypentyl, 6- hydroxyhexyl, 2-hydroxypropyl, 2-hydroxybutyl, 3-hydroxypentyl and the like.
  • Representative alkoxyalkyl groups comprise such radicals as methoxymethyl, Z-methoxyethyl, 3-methoxypropyl, 4-methoxybutyl, S-methoxypentyl, 3-methoxypentyl, 2,2- diethoxyethyl, and the like.
  • R is selected from the group consisting of halogen, alkyl and alkoxy containing from 1 to 6 carbon atoms, inclusive, and -CF for example, o-, m-, and pch-lorophenyl, o-, m-, and p-fluorophenyl, o-, m-, and ptolyl, o-, m-, and p-butylphenyl, o-, m-, and p-anisyl, 0-, m-, and p-butoxyphenyl, o-, m-, and p-ethylphenyl, 0-, m-, and p-bromophenyl, o-, mand p-trifluoro-methylphenyl, and the like.
  • substituents R and R by definition include the substituents R and R
  • 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 grouphaving from 5 to 8 carbon atoms, inclusive, and the other group is substituted or unsubstituted phenyl, with an amine of formula:
  • R and R are defined as above, in the presence of an acidic catalyst, e.g., benzenesulfonic acid, pchlorobenzene-sulfonic acid, 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 meta-1 catalyst such as platinum oxide, rhodium, palladium or the like to add at least two molar equivalents of hydrogen, thus yielding the corresponding compound Ill.
  • an acidic catalyst e.g., benzenesulfonic acid, pchlorobenzene-sulfonic acid, p-toluenesulfonic acid
  • Those compounds of Formula II in which R or R is benzyl can be submitted to hydrogenation-either simultaneously or consecutively-4o split off the benzyl group and thus to give primary or secondary amines, which can be alkylated, or acylated to give the range of compounds represented by Formula IV.
  • the thus-obtained 1,3-amino alcohols III or 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 arbon a om n h p esen e of anhydrous, hy-
  • the Formula III compounds, and the amino compounds of Formulae IV, IVa and TV] can be transformed by neutralization with inorganic and organic acids, into acid addition salts such as the hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, perchlorate, pamoate, cyclohexanesulfamate, methane-sulfonate, ethanesulfonate, p-toluenesulfonate, benzenesulfonate, t artrate, citrate, lactate, and the like.
  • acid addition salts such as the hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, perchlorate, pamoate, cyclohexanesulfamate, methane-sulfonate, ethanesulfonate, p-toluenesulfonate, benzenesulfonate, t artrate,
  • the compounds of Formula IVa including N-oxides, quaternary alkyl ammonium halide salts and acid addition salts thereof are useful stimulating agents, which act on the central nervous system. They can be used for stimulation of the respiratory, medullary, vagal and vasomotoric centers of mammals and birds.
  • the new compounds of Formula IVa 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, elixers and the like, containing the appropriate amounts for treatment.
  • common pharmaceutically acceptable carriers are used such as starch, lactose, kaolin, dicalcium phosphate and the like.
  • the compound IVa 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.
  • 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 animals for the treatment of conditions associated with respiratory diificulties, e.g., pneumonia, bronchitis, asthma or with heart insulficiencies.
  • these compounds are useful as geriatric stimulants for pet animals. Dosages between 0.110 mg./kg. of body weight per day produce significant stimulation.
  • the compounds of Formulae IV, IVa and IVb which are primary amines (R and R are hydrogen) are also useful as intermediates for the production of highly active diuretic compounds, namely, when reacted with 1,5- dibromoor -diiodopentane, these Z-amino-cycloalkane compounds become 2-piperidinocycloalkane compounds.
  • the new compounds of Formula HI, and the amino 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.
  • the fluosilicates of these compounds are useful mothproofing agents according to 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 pickling inhibitors.
  • the trichloroacetic acid addition salts of the same compounds are useful as herbicides, for examples,
  • the quaternary alkyl ammonium halides of the tertiary amino compounds of Formulae III, IV, IVa and IVb possess high wetting power and electroconductivity and are thus suitable to prepare electrocardiographic jellies.
  • a suitable composition of an electrocardiographic jelly thus prepared comprises:
  • 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 of a gel.
  • the starting materials of Formula I are known in part from the art, e.g., Campbell et al., I. Am. Chem. Soc. 82, 2389 (1960); Linn et al., I. 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 reduction 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., I. ()rg. Chem. 28, 379 (1963)]. This particular method is shown repeatedly in the preparations in order to synthesize hitherto unknown 1,3-diones of the type of Formula I.
  • a 1,3-diketo compound (I) is reacted with an amine (V) in the presence of an 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.
  • solvent essentially water-free organic solvents are used such as benzene, toluene, xylene or the like.
  • the amines used include particularly N- methylbenzylamine, N-ethylbenzylamine, N-propylbenzyl amine, N-butylbenzylamine, ethylamine, isopropylamine, butylamine, pentylamine, hexylamine, dimethylamine, (iiethylamine, dipropylamine, N-methylpentylamine, dibutylamine, dihexylamine, benzylamine, aniline, o-, m-, and ptoluidine, p-butylaniline, 0-, m-, and p-anisidine, o-, m-, and p-chloroaniline, o-, m-, and p-trifluoromethylaniline, Z-hydroxyethylamine, 3-hydroxypropylamine, 2-hydroxypropylamine, 3 hydroxypentylamine, 4 hydroxybutylamine, 6-hydroxyhexyl
  • the reaction is generally carried out at temperatures between 30-150 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.
  • the product is isolated in conventional manner such as evaporating the reaction mixture.
  • the keto product of Formula II is then hydrogenated in the presence of a catalyst, e.g., platinum oxide, rhod-.
  • a catalyst e.g., platinum oxide, rhod-.
  • ium and the like palladium on a carrier, e.g., alumina or charcoal, at a hydrogen pressure between 40 and 60 pounds per square inch. Larger or smaller pressures can be used, but pessures between 5-60 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 FormulaIII.
  • the product is isolated by filtering the mixture to remove the catalyst and evaporating the solvent to obtain the alcohol of formula III.
  • the thus-isolated product is purified by conventional means such as by crystallization and recrystallization, chromatography or the like.
  • the conversion of the alcohol of Formula IV to an ether of Formula IVa is usually achieved by two methods: 1) 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) re acting the alcohol of Formula IV with a lower alkanol in the presence of hydrogen chloride.
  • the starting tempera ture 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.
  • the selected alcohol (IV) is dissolved in ether and is added to liquid ammonia containing sodium amide, under continuous stirring.
  • a solution of the alkyl halide preferably an alkyl iodide
  • the reaction mixture in the flask is removed from the Dry Ice-acetone bath and allowed to warm to room temperature under continuous stirring.
  • sodium amide other strong basic compounds can be used such as potassium amide, lithium amide and the like.
  • liquid ammonia and alkali metal amides other reaction systems can be used, e.g., butyl lithium in the presence of tetrahydrofuran at a temperature range of about 70 to 25 C.
  • the ether thus produced (IVa) 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 and chromatography are usually employed.
  • 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 with a base, e.g., 20% aqueous sodium hydroxide, extracting the free base with a water-immiscible solvent, e.g., ether, methylene chloride, chloroform and the like and evaporating the solvent.
  • Esters (lVb) of the alcohol of Formula IV are usually obtained 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-pheny1- propionic acid and the like; of cycloalkanoic acids, e.g., of cyclohexanecarboxylic acid, ocand fl-cyclopentylpropionic acid and the like.
  • hydrocarbon carboxylic acids e.g., of alkanoic acids, such as acetic, propionic, butyric, isobutyric, valeric, hexanoic, heptanoic, octanoic acids and the like; of
  • 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, chrysanthenummonocarboxylic acid and the like.
  • unsaturated acids such as cinnamic acid, acrylic acid, crotonic acid, propiolic acid, 2-butynoic acid, chrysanthenummonocarboxylic acid and the like.
  • Acid addition salts of the amino alcohols (III) and (IV), amino ethers (IVa) 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-oxides of the tertiary amino compounds of Formulae III, IV, IVa and IVb are obtained by reacting the compound at a temperature between -30 C., preferably, at the start of the reaction at a temperature between 0-10 C., with a peracid such as performic, peracetic, perpropionigperbenzoic, perphthalic, m-chloroperbenzoic 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 III, IV, IVa and IVb.
  • a peracid such as performic, peracetic, perpropionigperbenzoic, perphthalic, m-chloroperbenzoic or other organic peracids
  • a solvent such as methanol, ethanol, ether or the like.
  • the quaternary alkyl ammonium halides of tertiary amino compounds of Formulae III, IV, IVa and IVb are produced by conventional methods such as heating to reflux a solution of the selected compound III, 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.
  • a selected alkyl halide such as an iodide or bromide or, less desirably, a chloride of methyl, ethyl, propyl, butyl, isobutyl,
  • 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.
  • 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 from methanol to yield 100 g. of long, colorless needles of 2-(3,4,5-trimethoxybenzoyl)cyclohexanone of melting point l4l142 C.
  • PREPARATION 6 2- (p-ethoxybenzoyl cyclohexzmone
  • l-piperidino-lcyclohexene was reacted with p-ethoxybenzoyl chloride in chloroform solution to give, after the copper complex purification procedure (Preparation 2), Z-(p-ethoxybenzoyl)cyclohexanone.
  • PREPARATION 8 2- (2-meth0xy-4-methylbenzoyl)cyclohexanone
  • 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-methy1benzoyl)cyclohexanone.
  • PREPARATION 9 2-(3,5-dimethyl-4-meth0xybenz0yl)cycl0hexan0ne
  • PREPARATION 10 2-(p-lrifluoromethylbenzoyl) cyclohexanone
  • l-piperidino-lcyclohexene was reacted with p-trifluoromethylbenzoyl chloride in chloroform solution to give, after the copper complex purification procedure (Preparation 2), 2-(ptrifluoromethylbenzoyl) cyclohexanone.
  • PREPARATION 1 2- (p-chlorobenzoyl) cyclohexanone
  • 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 13 2- (p-metlzylbenzoyl)Icyclohexanone
  • l-pyrrolidino-lcyclohexene was reacted with p-methylbenzoyl chloride in chloroform solution to give, after the copper complex purification procedure (Preparation 2), 2- (p-methylbenzoyl)cyclohexanone of melting point 108-1l0 C
  • l-pyrrolidino-L cyclohexene was reacted with 2,4-dimethylbenzoyl chloride in chloroform solution to give, after the copper complex purification (Preparation 2) 2-(2,4-dimethylbenzoyl) cyclohexanone of melting point 5152.5 C
  • PREPARATION 15 2- (2-meth0xy-4-methylbenzoyl) cyclahexanone
  • 1-piperidino-1- cyclohexene 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 18 2- (p-bromobenzoyl cyclooctanone
  • l-piperidino-lcyclooctene was reacted with p-bromobenzoyl chloride in chloroform solution to give, after the copper complex purification procedure (Preparation 2), Z-(p-bromobenzoyl) cyclooctanone.
  • PREPARATION 19 2- (m-methylbenzoyl cycloo'ctanone
  • l-piperidino-lcyclooctene was reacted with rn-methylbenzoyl chloride in chloroform solution to give, after the copper complex purification procedure (Preparation 2), Z-(m-methylbenzoyl)cyclooctanone.
  • starting compounds are prepared by reacting a l-cyclicaminol-cycloalkene, wherein the cycloalkene moiety has from to 8 nuclear carbon atoms, inclusive, and the cyclicamino moiety has from 5 to 10 nuclear atoms, inclusive, e.g. morpholino, pyrrolidino, piperidino, and the like with a selected benzoyl chloride.
  • Representative starting materials, thus prepared include:
  • CisA-a-(p-methoxyphenyl)-2 (methylamin0) cyclohexanemethanol A solution of 58 g. (0.25 mole) of Z-(p-methoxybenzoyl)cyclohexanone, 91 g. (0.75 mole) of N-methylbenzylamine and 1.6 g. of p-toluenesulfonic acid monohydrate in 2 l. of toluene was heated at reflux for 20 hours, collecting 4 ml. of water in a Dean-Stark trap. The mixture was then concentrated in vacuo to give a residue which was taken up in 400 ml. of ethanol and hydrogenated in the presence of 2.5 g.
  • the catalyst was then removed by filtration, the filtrate concentrated in vacuo, the resulting residue dissolved in 200 ml. of 10% aqueous acetic acid-300 ml. of ether and stirred for a period of 30 minutes.
  • the acid layer was then separated, basified with 20% sodium hydroxide solution and the mixture extracted with methylene chloride.
  • the methylene chloride extracts were combined, washed with water, saturated sodium chloride solotion and finally dried over anhydrous magnesium sulfate. After evaporation of the solution, there was left 25.61 g.
  • EXAMPLE 6 a-(3,4,5-trimeth0vcyphenyl) -2-(bulylamin0) cyclopentane methanol
  • 2-(3,4,5-trimethoxybenzoyl)cyclopentanone was refluxed with butylamine in benzene; and the resulting product was hydrogenated in the presence of platinum oxide catalyst to give lit-(3,4,5- trimethoxyphenyl) 2 (butylamino)cyclopentanemethanol.
  • EXAMPLE 7 a-(3,4,5-trimeth0xyphenyl) -2-(hexylamlzno) cycloheptanemethanol
  • 2-(3,4,5-trimethoxybenzoyl)cycloheptanone was refluxed with hexylamine in benzene; and the resulting product was hydrogenated in the presence of platinum oxide catalyst to give a-(3,4,5- trimethoxyphenyl)-2-(hexylamino)cycloheptanemethanol.
  • EXAMPLE 8 u-(p-Methoxyphenyl)-2-(6-hydroxyhexylamin0) cyclopentanemethanol
  • Z-(p-methoxybenzoyl)cyclopentanone was refluxed with 6-aminohexanol in benzene; and the resulting product was hydrogenated in the presence of platinum oxide catalyst to give a-(pmethoxyphenyl) -2 (6 hydroxyhexylamino)cyclopentame-methanol.
  • EXAMPLE 9 0L- (p-Ethoxyphenyl) -2-(ethylamino)cyclohexanemethanol
  • Z-(p-ethoxybenzoyl) cyclohexanone was refluxed with N-ethylbenzylamine in benzene; and the resulting product was hydrogenated first in the presence of platinum oxide catalyst and then in the presence of palladium-on-carbon catalyst to give a-(pethoxyphenyl)-2-(ethylamino)cyclohexanemethanol.
  • EXAMPLE 11 a- (Z-methoxy-4-methylphenyl -2-anilin0qicl0hexane methanol u-(3,5-dimethyl-4-metho-xyphenyl -2- (propylamino) cyclohexanemethanol
  • 2-(3,5-dimethyl-4- methoxybenzoyl)cyclohexanone was refluxed with N-propylbenzylamine in benzene; and the resulting product was hydrogenated first in the presence of platinum oxide catalyst and then in the presence of palladium-on-carbon catalyst to give u-(3,5-dimethylA-methoxyphenyl)2-(propylamino) cyciohexanemethanol
  • EXAMPLE 13 ot- (p-Trifluoromethfl-phenyl) -2- (pen tylam ino) cyclohexanemeth anal In the manner given in Example 5, 2-(2-(
  • EXAMPLE 14 a-(p-Chlorophe'nyl) -2-(isopropylamino)cyclohexanemethanol
  • 2- (p-chlorobenzoyl) cyclohexanone was refluxed with N-isopropylamine in benzene; and the resulting product was hydrogenated first in the presence of platinum oxide catalyst and then in the presence of palladium-on-carbon catalyst to give a-(pchlorophenyl) -2- iso pro pylamino) cyclohexanemethanol.
  • EXAMPLE 15 a-(o-Methylphenyl)-2-amin0cyclohexanemethdnol
  • 2-(o-methylbenzoyl) cyclohexanone was refluxed with benzylamine in benzene; and the resulting product was hydrogenated first in the presence of platinum oxide catalyst and then in the presence of palladium-on-carbon catalyst to give u-(omethylphenyl) -2-aminocyclohexanemethanol.
  • EXAMPLE 16 m-(p-Methylphenyl) -2-(ethylaminokyblohexana methanol
  • Z-(p-methylbenzoyl)cyc10hexanone was refluxed with N-ethylbenzylamine in benzene; and the resulting product was hydrogenated first in the presence of platinum oxide catalyst and then in the presence of palladium-on-carbon catalyst to give a-(p-methylphenyl)-2-(ethylamino)cyclohexanemethanol.
  • EXAMPLE 18 a- (2-m ethoxy-4-methylphenyl -2-(Z-ezhOxyethyIaminO) cyclohexanemethanol
  • 2-(2-rnethoxy-4- rnethylbenzoyl)cyclohexanone was refluxed with 2-eth0xyethylarnine in benzene; and the resulting product was hydrogenated in the presence of platinum oxide catalyst to give u-(2-methoxy-4-methylphenyl) 2 (2 ethoxyethylamino) cyclohexanemethanol.
  • a-(2,3,4-trimethoxybenzoy1)cyclooctanone was refluxed with 4-hydroxybutylamine in benzene; and the resulting product was hydrogenated in the presence of platinum oxide catalyst to give a-(2,3,4-trimethoxyphenyl)-2 (4 hydroxybutylamino) cyclooctanemethanol.
  • EXAMPLE 21 a- (p-Bromoph enyl -2- (isobuty lamrino) -cyclaocfan emethanol
  • 2-(p-bromobenzoyl)cyclooctanone was refluxed with isobutylamine in benzene; and the resulting product was hydrogenated in the presence of platinum oxide catalyst to give a-(p-bro mophenyl -2- (isobutylamino) cyclooctanemethanol.
  • EXAMPLE 22 OL- (m-Methylphenyl) -2- (o-toluidin'o) cyclooctanemethanol
  • 2-(m-methylbenzoyl)cyclooctanone was refluxed with o-toluidine in benacne; and the resulting product was hydrogenated in the presence of platinum oxide catalyst to give a-(m-methylphenyl) -2- (o-toluidino) cyclooctanemethanol.
  • EXAMPLE 23 ap-Fluorophenyl) -2-aminocyclohexan emethano l
  • Z-(p-fluorobenzoyl)cyclohexanone was refluxed with benzylamine in benzene; and the resulting product was hydrogenated first in the presence of platinum oxide catalyst and then in the presence of palladium-on-carbon catalyst to give a-(p-fluorophenyl -2-aminocyclohexanemethanol.
  • EXAMPLE 24 a-(2,5-dii0d0phenyl)-2-(methylamin0)cyclaheptanemethanol
  • 2-(2,5-diiodobenzoyl)-eycloheptanone was refluxed with N-methylbenzylamine in benzene; and the resulting product was hydrogenated first in the presence of platinum oxide catalyst and then in the presence of palladium-on-carbon catalyst to give a-(2,5-diiodophenyl) -2- (methylamino cycloheptanemethanol.
  • EXAMPLE 25 a-(p-Bromophenyl) -2-(ethylamin0)cycl0pentanemethan0l
  • 2-(p-bromobenzoyl) cyclopentanone was refluxed with N-ethylbenzylamine in benzene; and the resulting product was hydrogenated first in the presence of platinum oxide catalyst and then in the presence of palladium-on-carbon catalyst to give u-(pbromophenyl) -2- ethylamino cyclopentanemethanol.
  • EXAMPLE 26 a-(p-Hexylphenyl) -2-(4-eth0xybutylamin0)cyclopentanemethanol
  • Z-(p-hexylbenzoyl) cyclopentanone was refluxed with 4-ethoxybutylamine in benzene; and the resulting product was hydrogenated in the presence of platinum oxide catalyst to give a-(p-hexylphenyl) -2- (4-ethoxybutylamino -cyclopentanemethanol.
  • EXAMPLE 27 a-(3,4-dipropylphenyl)-2-(S-hydroxypmpylamino) cycloheptanemethanol
  • 2-(3,4-dipropylbenzoyl)cycloheptanone was refluxed with 3-hydroxypropylamine in benzene; and the resulting product was hydrogenated in the presence of platinum oxide catalyst to give a (3,4-dipropylphenyl)-2-(3-hydroxypropy1amino)cycloheptanemethanol.
  • EXAMPLE 28 a-(2,4-diiodophenyl)-2-(ethylamin0) cycloheptanemethanol
  • 2-(2,4-diiodobenzoyl)cycloheptanone was refluxed with N-ethylbenzylamine in benzene; and the resulting product was hydrogenated first in the presence of platinum oxide catalyst and in the presence of palladium-on-carbon catalyst to give u (2,4 diiodophenyl) 2 (ethylamino)cycloheptanemethanol.
  • 1,3-amino alcohols of Formula III are obtained by reacting a 1,3-diketo compound I with a primary or secondary amine (V) and hydrogenating.
  • Representatiave 1,3-amino alcohols thus obtained include:
  • ether was allowed to stand at room temperature for 3 days. During this time, a solid separated from the solution. The mixture was taken up into additional ether and aqueous sodium bicarbonate solution.
  • EXAMPLE 30 Cis-A-a- (gr-methoxyphenyl) -2-aminocyclohexanemethanol and its hydrochloride
  • the hydrochloride was treated with aqueous sodium hydroxide and the mixture extracted with methylene chloride, the methylene chloride extracts were washed with aqueous sodium chloride and thereupon evaporated to give the free base, cis-A-a-(p-methoxyphenyl)-2-aminocyclohexane methanol of melting point 86-87 C.
  • the oxalate (1.3 g.) was converted to the free base by dissolving the salt in methanol and adding excess sodium methoxide in methanol. The mixture was diluted with water and extracted several times with methylene chloride. The methylene chloride extract was washed with saturatde sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated to give 1.03 g. of an oil which after trituration with pentane gave a solid. Recrystallization of this material from Skellysolve B hexanes gave 0.43 g. of cis-B-w(p-methoxyphenyl)-2-aminocyclohexanemethanol melting at 86-87 C.
  • EXAMPLE 33 Cis-A -a-(0-meth0xyphenyl) -2-amin0cycl0hexanemethanol
  • a mixture of 23 g. (0.099 mole) of 2-(o-methoxybenzoyl)cyclohexanone and 11 g. (0.103 mole) of benzylamine in ml. of benzene was heated at reflux for 1.5 hours using a water trap (Dean-Stark). A total of 1.5 ml. of water was collected. The mixture was thereupon evaporated in vacuo, and the resulting residue was dissolved in 150 ml. of ethanol and hydrogenated in the presence of 1.5 g.
  • the acetic acid layer was separated, basified with 20% aqueous sodium hydroxide solution whereupon an oil separated which was extracted with methylene chloride.
  • the methylene chloride extracts were washed with water, saturated aqueous sodium chloride solution and finally dried over anhydrous sodium sulfate. Evaporation of the solution resulted in a solid which was recrystallized from ether-Skellysolve B hexanes several times to give cis-A-a-(o-methoxyphenyl)-2-aminocyclohexanemethanol of melting point 122123 C.
  • EXAMPLE 35 a-(p-ethoxyphenyl) -2-aminocyclohexanemethanol
  • Z-(p-ethoxy-benzoyl)cyclohexanone was treated with benzylamine; the resulting product was hydrogenated consecutively in the presence of platinum oxide catalyst and then in the presence of palladium-on-carbon catalyst to give 11- (p-ethoxyphenyl -2-aminocyclohexanemethanol,
  • EXAMPLE 36 u-(3,4,5-trimetlzoxyphenyl) -2-amin0cycl0pentanemethanol
  • 2-(3,4,5- trimethoxybenzoyl)cyclopentanone was treated with benzylamine; the resulting product was hydrogenated consecutively in the presence of platinum oxide catalyst and then in the presence of palladium-on-carbon catalyst to give a-(3,4,5-trimethoxyphenyl) 2 aminocyclopentanemethanol.
  • EXAMPLE 37 ot-(3,4,5-trimethoxyphenyl) -2-amin0cycl0heptanemethanol
  • 2-(3,4,5- trimethoxybenzoyl)cycloheptanone was treated with benylamine; the resulting product was hydrogenated consecutively in the presence of platinum oxide catalyst and then in the presence of palladium-on-carbon catalyst to give a-( 3,4,5 trirnethoxyphenyl) 2 aminocycloheptanemethanol.
  • EXAMPLE 38 a-(p-Methoxyphenyl) -2-amin0cycl0pentanemethanol
  • 2-(pmethoxybenzoyl)cyclopentane was treated with benzylamine; the resulting product was hydrogenated consecutively in the presence of platinum oxide catalyst and then in the presence of palladium-on-carbon catalyst to give no (p-methoxyphenyl -2-aminocyclopentanemethanol.
  • EXAMPLE 39 tx-(2-methoxy-4-methylphenyl)-2-amin0cycl0hexanemethanol
  • 2-(2- methoxy 4 methylbenzoyl)cyclohexanone was treated with benzylamine; the resulting product was hydrogenated consecutively in the presence of platinum oxide catalyst and then in the presence of palladium-on-carbon catalyst to give u: (2-methoXy-4-methylphenyl)-2-aminocyclohexanemethanol.
  • EXAMPLE 40 u-(3,5-dimethyl-4-meth0xyphenyl -2-amin0cycl0- hexanemethanol
  • 2-(3,5- dimethyl 4-methoxybenzoyl)cyclohexanone was treated with benzylamine; the resulting product was hydrogenated consecutively in the presence of platinum oxide catalyst and then in the presence of palladium-on-carbon catalyst to give u-(3,5-dimethyl-4-methoxyphenyl)-2-aminocyclohexanemethanol.
  • EXAMPLE 41 u-( p-Trifluoromethylphenyl )-2-amin0cycl0hexanemethanol
  • 2-(p-trifluoromethylbenzoyl)cyclohexanone was treated with benzylamine; the resulting product was hydrogenated consecutively in the presence of platinum oxide catalyst and then in the presence of palladium-on-carbon catalyst to give a (p trifluorornethylphenyl)-2-aminocyclohexanemethanol.
  • EXAMPLE 42 ap-Chlorophenyl) -2-amin0cycl0hexanonemethanol
  • 2-(pchlorobenzoyl)cyclohexanone was treated with benzylamine; the resulting product was hydrogenated consecutively in the presence of platinum oxide catalyst and then in the presence of palladium-on-carbon catalyst to give a (p chlorophenyl)-2-aminocyclohexanemethanol.
  • EXAMPLE 43 a-(p-Ethoxyphenyl)-2-aminocyclooctanemethanol
  • 2-(pethoxybenzoyl)cyclooctanone was treated with benzylamine; the resulting product was hydrogenated consecutively in the presence of platinum oxide catalyst and then in the presence of palladium-on-carbon catalyst to give a- (p-ethoxyphenyl) -2-aminocyclooctanemethanol.
  • EXAM LE 44 a-(2,3,4-trimethoxyphenyl)-2-amin0cycl0octanemethanol
  • 2-(2,3,4- trimethoxybenzoyl)cyclooctanone was treated with benzylamine; the resulting product was hydrogenated consecutively in the presence of platinum oxide catalyst and then in the presence of palladium-on-carbon catalyst to give u-(2,3,4-trimethoxyphenyl) 2 aminocyclooctanemethanol.
  • Example 30 In the manner given in Example 30 (Part 2), condensing a diketo compound I with benzylamine and hydrogenating in the presence of platinum oxide catalyst, following .by hydrogenation with palladium-on-carbon catalyst, yields the corresponding a phenyI-Z-aminocycloalkanemethanols (IV, when R -R hydrogen).
  • Representative ot-phenyl-2-aminocycloalkanemethanols thus obtained include:
  • EXAMPLE 46 Cis-A-a-(p-methoxyphenyl)-2-pr0pi0namid0cycl0- hexanemethanol
  • equimolar quantities of cis-A-a-(p-methoxyphenyl)-2-aminocyclohexanemethanol and propionic anhydride were reacted together at about 24-26 C. in ether to give cis-A-a-(p-methoxyphenyl)-2-propionamidocyclohexanemethanol.
  • EXAMPLE 47 Cis-A-u-(p-meth0xyphenyl) -2-butyramidocycl0- hexanemethanol
  • equimolar quantities of cis-A-a-(p-methoxyphenyl)-2-aminocyclohexanemethanol and butyric anhydride were reacted together at about 24-26 C. in ether to give cis-A-a-(p-methoxyphenyl)-2-butyramidocyclohexanemethanol.
  • EXAMPLE 48 Cis-A-a- (p-methoxyphenyl)-2-decan0amidocyclohexanemethanol
  • equimolar quantities of cis-A-w(p-methoxyphenyl)-2-aminocyclohexanemethanol and decanoic anhydride were reacted together at about 24-26 C. in ether to give cis-A-a-(p-methoxyphenyl )-2-decanoamidocyclohexanemethanol.
  • EXAMPLE 49 CiS-u- (3,4,5-trimeth0xyphenyl )-2-valeramid0cyclohexanemethanol
  • equimolar quantities of cis-a-(3,4,5-trirnethoxypheny1)-2-aminocyclohexanemethanol and valeric anhydride were reacted together at about 24-26 C. in ether to give cis-a-(3,4,S-trimethoxyphenyl) -2-valeramidocyclohexanemethanol.
  • EXAMPLE 50 u-(3,4,5-trimethoxyphenyl) -2-benzamid0cycl0- pentanemethanol
  • equimolar quantities of a-(3,4,5-trimethoxyphenyl)-2-arninocyc1opentanemethanol and benzoic anhydride were reacted together at about 24-26 C. in ether to give a-(3,4,5-trimethoxyphenyl -2-benzamidocyclopentanemethanol.
  • EXAMPLE 51 a-(3,4,5-trimethoxyphenyl) -2-hexanoamid0cycl0- heptanemethanol
  • equimolar quantities of u-(3,4,5-trimethoxyphenyl)-2-arninocyc1oheptanemethanol and hexanoic anhydride were reacted together at about 24-26 C. in ether to give a-(3,4,5-trimethoxyphenyl) -2-hexanoamidocycloheptanemethanol.
  • EXAMPLE 52 a- (p-Methoxyphenyl) -2-0ctan0amid0cycl0- pentanemethanol
  • equimolar quantities of a-(p-methoxyphenyl)-2-aminocyclopentanemethanol and octanoic anhydride were reacted together at about 24-26 C. in ether to give a-(p-methoxyphenyl)-2- octanoamidocyclopentanemethanol.
  • EXAMPLE 5 3 xp-Eth oxypheny l -2-n0n anoamidacycloh exanemeth anol
  • equimolar quantities of u-(p-ethoxyphenyl)-2-aminocyclohexanemethan0l and nonanoic anhydride were reacted together at about 2426 C. in ether to give a-(p-ethoxyphenyl)-2-nonanoamidocyclohexanemethanol.
  • EXAMPLE 54 00- p-Fluorophenyl) -2- (phenylacetamido) cyclehexanemethanol
  • equimolar quantities of u-(p-fluorophenyl)-Z-aminocyclohexanemethanol and phenylacetic anhydride were reacted together at about 24-26 C. in ether to give u-(p-fiuorophenyl)-2- (phenylacetamido)cyclohexanemethanol.
  • EXAMPLE 55 0c- (m-Trifluoromethylphenyl) -2-h eptanoamidocyclopentanemethanol
  • equimolar quantities of u-(m-trifluoromethylphenyl)-2-a.minocyclopentanemethanol and heptanoic anhydride were reacted together at about 2426 C. in ether to give a-(m-trifluoromethylphenyl -2-heptanoamidocyclopentanemethanol.
  • EXAMPLE 56 a-(2,4-dieth0xyphenyl)-2-(3-phenylpr0pion amido)cycl0- octanemethanol oc- (o-Fluorophenyl -2-bu'ty ramidocyclooctwnemethanol
  • equimolar quantities of u-(o-fluorophenyl)-2-aminocyclooctanemethanol and butyric anhydride were reacted together at about 24-26 C. in ether to give u-(o-fluorophenyl)-2-butyramidocyclooctanemethanol.
  • EXAMPLE 58 a-(3,5-dipr0pylphenyl) -2-benzamidocyclooctanemethanol
  • equimolar quantities of a-(3,5-dipropylphenyl)-2-aminocyclooctanemethanol and benzoic anhydride were reacted together at about 24-26 C. in ether to give a-(3,5-dipropylphenyl)- 2-benza'midocyclooctanemethanol.
  • equimolar quantities of a-(p-butoxyphenyl)-2-aminocyclooctanemethanol and decanoic anhydride were reacted together at about 24-26 C. in ether to give ot-(p-butoxyphenyl)-2-decanoamidocyclooctanemethanol.
  • EXAMPLE 60 a- (p-Methoxyphenyl) -2-propionamidocyclooctanemethanol
  • a-(p-methoxyphenyl)-2-aminocyclooctanemethanol and propionic anhydride were reacted together at about 24-26 C. in ether to give a-(p-methoxyphenyD-2- propionamidocyclooctanemethanol.
  • EXAMPLE 61 u- (p-Methoxyphenyl)Z-(N-ethylbenzamido)cyclohexanemelhanol
  • approximately equimolar amounts of a-(p-methoxyphenyl)-2-(ethylamino)cyc1ohexanemethanol and benzoic anhydride were reacted in ether solution at about 2426 C. for three days to give ot-(p-rnethoxyphenyl)-2-(N-ethylbenzamido) cyclohexanemethanol.
  • EXAMPLE 62 a-(3,5-dimethyl-4-methoxyphenyl) -2-(N-pr0pylacetzrmido) cyclohexanemethanol
  • approximately equimolar amounts of a-(3,5-dimethyl-4-methoxyphenyl)- 2-(propylamino)cyclohexanemethanol and acetic anhydride were reacted in ether solution at about 2426 C. for three days to give e-(3,5-dimethyl-4-methoxyphenyl)- 2-(N-propylacetamido)cyclohexanemethanol.
  • EXAMPLE 63 ec-(p-Trifluoromethylphenyl)-2- (N-pentyldecanoamido) cyclohexanemethanol
  • approximately equimolar amounts of a-(p-trifiuoromethylphenyl)-2- (pentylamino)cyclohexanemethanol and decanoic anhydride were reacted in ether solution at about 2426 C. for three days to give a-(p-trifluoromethylphenyl)-2-(N- pentyldecanoamido cyclohexanemethanol.
  • EXAMPLE 64 et-(pChlorophenyl) -2-(N-isopropyloctanoamido)cyclohexanemethanol
  • approximately equimolar amounts of a-(p-chlorophenyl)-2-(isopropylamino)cyclohexanemethanol and octanoic anhydride were reacted in ether solution at about 2426 C. for three days to give u-(p-chlorophenyl)-2-(Nisopropyloctanoamido) cyclohexanemethanol.
  • EXAMPLE 65 ap-M ethy Iph enyl -2- (N -ethyl-3 pheny l propioruamido) cyclohexanem ethanol
  • approximately equimolar amounts of u-(p-methylphenyl)-2-(ethylamino)cyclohexanemethanol and 3-pheny1propionic anhydride were reacted in ether solution at about 2426 C. for three days to give a-(p-methylphenyl)-2-(N-ethyl-3- phenylpropionamido cyclohexanemethanol.
  • EXAMPLE 66 oc- (p-Ethoxyphenyl) -2-(N-methylacetamido) cyclooctanemethanol
  • approximately equimolar amounts of a-(p-ethoxyphenyl)-2-(methy1- amino)cyclooctanemethanol and acetic anhydride were reacted in ether solution at about 24-26 C. for three days to give a-(p-ethoxyphenyl)-2-(N-methylacetamido) cyclooctanemethanol.
  • EXAMPLE 67 a- (p-Bromophenyl) -2-(N-isobzttylhexanoamido) cyclooctanemethanol
  • approximately equimolar amounts of tx-(p-bromophenyl)-2-(isobutylamino)cyclooctanemethanol and hexanoic anhydride were reacted in ether solution at about 24-26 C. for three days to give u-(p-bromophenyl)-2-(N-isobutylhexanoamidot cyclooctanemethanol.
  • EXAMPLE 68 a-(2,5-'dii0d0phenyl)-2-(N-methylbenzamido) cycloheptanemethanol
  • EXAMPLE 69 oc-( p-Bromophenyl -2- (N -ethylphenylacetamido) cyclopentanemethanol
  • approximately equimolar amounts of a (p-bromophenyl)-2-(ethylamino)cyclopentanemethanol and phenylacetic anhydride were reacted in ether solution at about 24-26 C. for three days to give a-(p-bromophenyl)-2-(N-ethylphenylacetamido)cyclopentanemethanol.
  • EXAMPLE 70 0t.- (p-Hexylphenyl)-2-[N-(4-ethoxybutyl) butyramido]- cyclopentanemethanol
  • approximately equimolar amounts of a-(p-hexylphenyl)-2-(4-ethoxybutylamino)cyclopentanemethanol and butyric anhydride were reacted in ether solution at about 24-26 C. for three days to give ot-(p-hexylphenyl)-2-[N-(4-ethoxybutyl butyramido] cyclopentanemethanol.
  • the ether-Skellysolve B hexane fractions contained no product.
  • the 2 l. of ether fractions were evaporated and gave 1.85 g. of oil.
  • the fraction of 5% methanol-% ether contained 1.8 g. of oil and the fraction 10% methanol-90% ether contained 0.38 g. of oil.
  • the 1.85 g. of oil obtained from the ether fractions was triturated with Skellysolve B hexanes to give a gummy solid, which was not further characterized.
  • EXAMPLE 72 Cis-2-(a,p-dimethoxybenzyl) cyclohexylamine and maleate thereof
  • a solution of 1.18 g. (0.005 mole) of cis-A-(p-me' thoxyphenyl)-2-aminocyclohexanemethanol in 100 ml. of methanol containing 2.5 g. of anhydrous hydrogen chloride was kept at room temperature for a period of 20 hours. The mixture was then concentrated in vacuo to give a residue which was diluted with ice water, basified with 20% aqueous sodium hydroxide and extracted with methylene chloride which was washed with water, saturated aqueous sodium chloride solution and concentrated finally to 1.48 g.
  • EXAMPLE 73 2- a,3,4,5-retramethoxybenzyl) -N-methylcyclohexylamine and its hydrochloride
  • a solution of 0.01 mole of a-(3,4,5-trimethoxyphenyl)-2-(methylamino)cyclohexanemethanol hydrochloride in ml. of water was basified by adding sufficient 10% aqueous sodium hydroxide solution. This solution was ex tracted three times with 100 ml. of methylene chloride. The methylene chloride solution was evaporated, leaving as an oily free base a-(3,4,5-trimethoxyphenyl)-2-(methylamino) cyclohexanemethanol.
  • ExAMPLE 74 2-(m,3,4,5-tetramethoxybenzyl)-N-butylcyclopentylamine and hydrochloride thereof
  • a solution of a-(3,4,5-trimethoxyphenyl)-2-(butylamino)cyclopentanemethanol (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 at 45 C.
  • EXAMPLE 75 2-(wethoxy-3,4,5-trimeth0xybenzyl)-N-hexylcycloheptylamine and its hydrochloride
  • u-(3,4,5-trimethoxyphenyl)-2-(hexylamino)cycloheptanemethanol in ethanol solution containing hydrogen chloride was allowed to react for a period of 20 hours at room temperature to give 2- a-ethoxy-3 ,4,5-trimelthoxybenzyl -N-hexfylcytzloheptylamine hydrochloride.
  • EXAMPLE 76 2-(a-propoxy-p-methoxybenzyl)-N-(6-hydroxyhexyl)- cyclopentylamine and its hydrochloride
  • a-(p-methoxyphenyl) 2-( 6-hydroxyhexylamino)cyclopentanemethanol in propanol solution containing hydrogen chloride was alowed to react for a period of 20 hours at room temperature to give 2-(a-propoxy-p-methoxybenzyl)-N-(6- hydroxyhexyl)cyclopentylamine hydrochloride.
  • EXAMPLE 78 2-(cap-diethoxybenzyl)-N-methylcycl00ctylatmine and its hydrochloride
  • Example 74 a-(p-ethoxyphenyl)-2-(methylamino)cyclooctanemethanol in ethanol solution containing hydrogen chloride was allowed to react for a period of 20 hours at room temperature to give 2-(a,p-diethoxybenzyl)-N-methylcyclooctylamine hydrochloride.
  • EXAMPLE 79 2-(a-is0pr0p0xy-2,3,4-trimethoxybenzyl)-N-(4-hydr0xybutyl)cyclooctylamine and its hydrochloride
  • a-(2,3,4-trimethoxyphenyl) 2-(4-hydroxybutylamino)cyclooctanemethanol in isopropyl alcohol solution containing hydrogen chloride was allowed to react for a period of 20 hours at room temperature to give 2-(u-isopropoXy-2,3,4-trimethoxybenzyl) N (4-hydroxybutyl)cyclooctaylamine hydrochloride.
  • EXAMPLE 8O 2- a-hexyl0xy-2,5-diiodobenzyl) -N-methylcycloheptylamine and the hydrochloride thereof
  • a-(2,5-diiodophenyl)-2-(rnethylamino)cycloheptanemethanol in ether was added to a solution of sodium amide is liquid ammonia at about -70 C., and thereto was added an ether solution of hexyl iodide to give 2-(a-hexyloxy-2,5-diiodobenzyl)- N-methycycloheptylamine.
  • Treatment .of the free base with etheral hydrogen chloride yielded the hydrochloride of 2- a-hexyloxy-2,S-diiodobenzyl -N-methylcyc1oheptylamine.
  • ethers of Formula IVa are prepared by reacting a lower alkanol, e.g., methanol, ethanol, propanol, 2-propanol, butanol or the like, with an alcohol of Formula IV or III in the presence of an acidic reagent, e.g., gaseous hydrogen chloride or hydrogen bromide.
  • a lower alkanol e.g., methanol, ethanol, propanol, 2-propanol, butanol or the like
  • an alcohol of Formula IV or III in the presence of an acidic reagent, e.g., gaseous hydrogen chloride or hydrogen bromide.
  • an acidic reagent e.g., gaseous hydrogen chloride or hydrogen bromide.
  • ether compounds of Formula IVa can be obtained by reacting an alcohol of Formula IV, particularly one in which R is acyl with an alkyl halide in the presence of a strong base, at low temperature.
  • Ethers thus obtained include:
  • the material was first eluted with eight portions of 250 ml. of a 5% ether-95% Skellysolve B hexanes solution. After evaporation of the combined eluates, solid material was obtained. Further elution with two portions of 250 ml. of 25% ether-75% Skellysolve B hexanes, with two portions of 250 ml. each of 50% ether-50% Skellysolve B hexanes and with two portions of 250 ml. each of 75% ether-25% Skellysolve B hexanes gave solid material after evaporation of the combined eluates. The above fractions were all combined and re crystallized from ethanol to give 2-(a,p-dimethoxyben zyl)-N-methylcyclohexylamine.
  • EXAMPLE 83 Cis-B-Z-(u,p-dimethoxybenzyl)-N,N-dimethylcycl0hexylamine and its methanesmlfonate
  • the reaction mixture was extracted with ether, and the combined ether extracts were washed in succession with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution.
  • the ether layer was dried and concentrated in vacuo to give a yellow oil.
  • the yellow oil was treated with methanesulfonic acid in ether to form cis-B-2-(a,p-dimethoxybenzyl)-N,N dimethylcyclohexylamine methanesulfonate which was recrystallized from methyl ethyl ketone, yielding 12.1 g. of melting point Ill-113 C. After re crystallization from isopropanol-ether, the salt had a melting point of 112-114 C.
  • Cis-A-a-(p-methoxyphenyl)-2-(methylamin0)cycl0- hexanemethanol acetate ester A solution was prepared containing ml. of pyridine, 5 ml. of acetic anhydride, and 0.5 g. of CiS-A-ot-(P-IIIB- thoxyphenyl) -2- (methylamino cyclohexanemethanol. The mixture was allowed to stand at room temperature (24- 26 C.) for a period of 3 days. The mixture was thereupon treated with ether and aqueous sodium bicarbonate solution. The ether layer was separated, washed with water and extracted with 5% hydrochloric acid.
  • the acid layer was separated from the ether layer, basified with 10% aqueous sodium carbonate solution and thereupon extracted with methylene chloride.
  • the methylene chloride layers were washed with aqueous sodium chloride solution, water and thereupon dried over anhydrous sodium sulfate.
  • the dried solution was concentrated to give a whitish solid which was several times recrystallized from isopropanol to give cis-A-a-(p-methoxyphenyl-2-(methylamino)cyclohexanemethanol acetate ester.
  • EXAMPLE 86 Cis-A-a-(p-methoxyphenyl) 2 (benzylamin0)cyclohexane-methanol butyrate ester
  • cis A a-(pmethoxyphenyD-Z (benzylamino) cyclohexanemethanol was treated in pyridine solution with butyric anhydride, the mixture after 3 days was extracted first with ether, then the ether solution with dilute hydrochloric acid, the hydrochloric acid extracts were separated, neutralized with dilute aqueous sodium carbonate solution, extracted with methylene chloride, the methylene chloride extracts evaporated and the resulting residue recrystallized to give cis-A a (p-methoxyphenyl) 2 (benzylamino) cyclohexamethanol butyrate ester.
  • EXAMPLE 89 a- (p-ethoxyphenyl -2-valeramidocycl00ctan emethanol heptarzemethanol phenylacetate ester
  • Ot'(3,4,5 trimethoxyphenyl)-2-(hexylamino)cycloheptanemethanol was reacted with phenylacetyl chloride in pyridine, the resulting reaction mixture worked up as in Example 87 to yield a-(3,4,5-trimethoxyphenyl) 2 (hexylamino)- cycloheptanemethanol phenylacetate ester.
  • EXAMPLE 90 ao-Methoxyphenyl) -2- (3-meth0xypropylamin0) cyclohexanemethanol 3-phenylpropi0nate ester
  • a-(o-methoxyphenyl) 2 .(3 methoxypropylamino)cyclohexanemethanol was reacted with 3 phenylpropionyl chloride in pyridine, the resulting reaction mixture Worked up as in Example 87 to yield u-(o-methoxyphenyl)-2-(3- methoxypropylamino)cyclohexanemethanol 3 phenylpropionate ester.
  • EXAMPLE 91 ec- (p-Trifluoromethylphenyl) -2- (pentylamino) cyclohexanemethanol propionate ester
  • a-(p-trifluoromethylphenyl) 2 (pentylamino)cyclohexanemethanol was reacted with propionic anhydride in pyridine, the resulting reaction mixture worked up as in Example 87 to yield 1x-(p-trifluoromethylphenyl)-2-(pentylamino)cycylohexanemethanol propionate ester.
  • EXAMPLE 92 oz- (2,3,4-trimeth0xyphenyl) -2- (4-hydroxybutylamino cyclooctanemethanol diacetate ester
  • oc-(2,3,4-trirnethoxyphenyl) -2- 4-hydroxybutylamino cyclooctanemethanol was reacted with acetyl bromide in pyridine, the resulting reaction mixture worked up as in Example 87 to yield a-(2,3,4-trimethoxyphenyl) 2 (4 hydroxybutylamino) cyclooctanemethanol diacetate ester.
  • EXAMPLE 94 a- (2,5 -diiodophenyl -2-(methy lamina) eyeloheptanemethanol hexanoate ester
  • a-.(2,5-diiodophenyl) -2-(methylamino)cycloheptanemethanol was reacted with hexanoyl chloride in pyridine, the resulting reaction mixture worked up as in Example 87 to yield a- (2,5-diiodophenyl) 2 (methylamino) cycloheptanemethanol hexanoate ester.
  • EXAMPLE 95 a- (p-Bromophenyl) -2- (ethylamino)eyclopentanemethanol heptanoate ester
  • a-(p-brornophenyl)-2-(ethylarnino)cyclopentanemethanol was reacted with heptanoyl chloride in pyridine, the resulting reaction mixture worked up as in Example 87 to yield a-(p-bromophenyl)-2-(ethylamino) cyclopentanernethanol heptanoate ester.
  • EXAMPLE 96 Cis-a-(3,4,5-trimethoxyphenyl)-2-benzamidoeyclohexanemethanol benzoate ester A mixture of 5 mmoles of cis-a-(3,4,5-trimethoxyphenyl) -2-aminocyclohexanemethanol and 20 mmoles of benzoyl chloride in '8 ml. of pyridine was allowed to stand at room temperature(23-26 C.) for a period of 50 hours.
  • EXAMPLE 97 a-(3,4,5-trimethoxyphenyl)-2-ar:etamidocyelopentanemethanol acetate ester
  • a (3,4,5 trimethoxyphenyl) 2 aminocyclopentanemethanol was reacted with acetic anhydride in pyridine, the resulting reaction mixture worked up as in Example 96 to yield cc- (3,4,S trimethoxyphenyl) 2 acetamidocyclopentanemethanol acetate ester.
  • EXAMPLE 99 a-(3,4,5-trimethoxyphenyl)-2-(butyramid0) cycloheptanemethanal butyrate ester
  • a (3,4,5 trimethoxyphenyl)-2-aminocycloheptanemethanol was reacted with butyric anhydride in pyridine to yield a-(3,4,5- trimethoxyphenyl) 2 (butyramido)cycloheptanemethanol butyrate ester.
  • EXAMPLE 100 a-(p-Ethoxyphenyl) -2-valeramidocyclooctanemethanol valerate ester
  • a-(p-ethoxyphenyl)-2-arninocyclooctanemethanol was reacted with valeric anhydride in pyridine solution to give a-(p-ethoxyphenyn- 2-valeramidocyc1ooctanemethanol valerate ester.
  • EXAMPLE 101 41- (2,3,4-trimethoxyphenyl) 2 -deca'noamidocyclooctanemethanol decanoate ester
  • EXAMPLE 102 u-(p-EthOxyphenyD-Z-(3-phenylpr0pionamid0)cyclooctanemethanol S-phenylpropionate ester
  • a-p-ethoxyphenyl)-2-aminocyclooctanemethanol was reacted with 3- phenylpropionyl chloride in pyridine solution to give a-(pethoxyphenyl) 2 (3-phenylpropionamido)cyclooctane methanol 3-phenylpropionate ester.
  • esters of Formula IVb in which at least one of the parameters R or R is other than hydrogen, can be obtained by reacting a compound of Formula IV with an acylating reagent selected from the group of acid anhydrides and acid halides, particularly of alkanoic acids, cycloalkanoic and phenylsubstituted alkanoic acids containing up to and including 12 carbon atoms.
  • an acylating reagent selected from the group of acid anhydrides and acid halides, particularly of alkanoic acids, cycloalkanoic and phenylsubstituted alkanoic acids containing up to and including 12 carbon atoms.
  • Representative compounds thus obtained include:
  • esters of Formula IVb in which one of the R or R groups is an acyl group are provided in Example 96, in which one of the R or R groups is an acyl group,
  • EXAMPLE 104 Cis-A-a-(p-methoxyphenyl) -2-piperidin0cycl0- hexanemethanol
  • the mixture was concentrated in vacuo, the residue was taken up into methylene chloride-water and the organic layer was separated, washed with water, saturated sodium chloride solution and finally dried over anhydrous magnesium sulfate.
  • the dried solution was thereupon evaporated to give an oily material which was chromatographed on a column containing g. of silica.
  • the column was eluted with five portions of 100 ml. each of methylene chloride, then with ten portions of methylene chloride containing 2.5% methanol (each portion 100 ml), then with ten 100-ml. portions containing 5% methanol, and then with ten portions containing 10% methanol.
  • cis-A-ot-(p-methoxyphenyl)-2- piperidinocyclohexanemethanol can be prepared from cis- A a (p-methoxyphenyl)-2-aminocyclohexanemethanol with 1,5-dibromopentane.
  • EXAMPLE C is-B-a-(p-methoxy phenyl )-2-piperidinocycl0- hexanemethanol
  • 1.1 g. of cis-B- a (p-methoxyphenyl)-2-aminocyclohexanemethanol, 1.6 g. of 1,5-diiodopentane and 7 g. of anhydrous potassium carbonate in 75 ml. of methyl ethyl ketone was stirred for a period of 23 hours to give a total of 363 mg. (26 of cis-B-a-(p-methoxyphenyl) -2-piperidinocyclohexanemethanol of melting point 136-138 C. having diuretic activity.
  • EXAMPLE 106 Cis-B-a-(3,4,5-trimethoxyphenyl)-2-piperidinocycl0- hexanemethanol
  • cis-B-ot-(3,4,5-trimethoxyphenyl)-2-aminocyclohexanemethanol was reacted with 1,5-cliiodopentane in the presence of potassium carbonate to give cis B a (3,4,5-trimethoxyphenyl)-2- piperidinocyclohexanemethanol, a diuretic.
  • ExAMPLE 107 a-(p-Fluorophenyl) -2-piperidin0cyclopentanemethanol
  • a-(p-fluorophenyl)-2-aminocyclopentanemethanol was treated with 1,5-dii0dopentane in the presence of potassium carbonate to give diuretically active a-(p-fiuorophenyl)-2-piperidinocyclopentanemethanol.
  • EXAMPLE 108 a- (2,4-dimethylphenyl)-2-piperidin0cyclohexanemethanol
  • a-(ZA-dimethylphenyl)-2-aminocyclohexanemethanol was treated with 1,5-diiodopentane in the presence of potassium carbonate to give diuretically active on (2,4 dimethylphenyl) 2- piperidinocyclohexanemethanol.
  • EXAMPLE 109 a- (2,5-dii0a'0phenyl) -2-piperidin0cycloheptanemethanol
  • 0L-(2,5-dll0d0- phenyl)-2-aminocycloheptanemethanol was treated with 1,5-dibromopentane in the presence of potassium carbonate to give diuretically active a-(2,5-diiodophenyl)-2- piperidinocycloheptanemethanol.
  • EXAMPLE 1'10 .a- (p -Butoxyphenyl)-2-piperidinocyclooctanemethanol
  • a-(p-butoxyphenyl)-2-aminocyclooctanemethanol was reacted with 1,5-diiodopentane in the presence of potassium carbonate to give diuretically active ot-(p-butoxyphenyl)-2-piperidinocyclooctanemethanol.
  • 2- piperidinocycloalkanemethanols can be made by reacting a selected 2-aminocycloalkanemethanol with 1,5-diiodoor 1,5-dibromopentane in the presence of a. strong base such as potassium carbonate, sodium carbonate or the like.
  • a. strong base such as potassium carbonate, sodium carbonate or the like.
  • ethers and esters of such Z-aminocycloalkanemethanols can be converted to the corresponding 2-piperidinocycloalkanemethanol esters or ethers.
  • Representative compounds thus obtained which have diuretic activity include:
  • EXAMPLE 112 a-(3,4,5-trimetlzoxyphenyl) -2-(N-ethylbnzYlamino)- cyclohexanemethauol
  • Example 111 treating tit-(3,4,5- trimethoxyphenyl -2- benzylamino) cyclohexanemethanol with ethyl iodide and potassium carbonate in methanol produces a (3,4,S-trimethyoxyphenyl)-2-(N-ethylbenzylamino) cyclohexanemethanol.
  • EXAMPLE 113 ap-F l uorophenyl -2- (N -prpyl-p-t0luidi n0) cyclopentanemethanol
  • a-(pfluorophenyl) -2- p-toluidino cyclopentanem ethanol with propyl iodide and potassium carbonate in methanol pro- 40 considers a (p-fiuorophenyl)-2- (N-propyl-p-toluidino) cyclopentanemethanol
  • EXAMPLE 1 14 ct- (3 ,4,5 -trieth0xy phenyl -2- (diethylamino cycloheptanem ethanol
  • treating lit-(3,4,5- triethoxyphenyl) 2 (ethylamino)cycloheptanemethanol with ethyl iodide and potassium carbonate in methanol produces
  • EXAMPLE 1 16 Cis-2-(a,p-dimetho,xybenzyl)-N-methyl-N-butylcyclohexylamine
  • Example 111 heating 0.01 mole of cis-Z-(u,p-dimethoxybenzyl)-N-methylcyclohexylamine
  • butyl iodide in ethanol
  • potassium carbonate yields cis-2-(a,pdimethoxybenzyl)-N-methyl-N-butylcyclohexylamine.
  • EXAMPLE 1'17 a-(p-Methoxyphenyl)-2-(N-me'thylbenzylamino)cyclohexanemerhanol benzoate ester
  • heating in waterfree methanol solution 0.01 mole of u-(p-methoxyphenyl)-2-(methylamino)cyclohexanemethanol benzoate ester, 0.01 mole of benzyl chloride and 0.01 mole of potassium carbonate yields a-(p-methoxyphenyD-Z-(N- methylbenzylamino)cyclohexanemethanol benzoate ester.

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4098904A (en) * 1976-11-12 1978-07-04 The Upjohn Company Analgesic n-(2-aminocycloaliphatic)benzamides
US4179501A (en) * 1976-11-12 1979-12-18 The Upjohn Company Analgesic N-(2-aminocycloaliphatic)azidobenzamides
US4540690A (en) * 1982-02-09 1985-09-10 The Upjohn Company 2-(Phenylmethylene)cycloalkylamines and -azetidines
US4652559A (en) * 1982-08-16 1987-03-24 The Upjohn Company 2-(Phenylmethylene)cycloalkyl-azetidines

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CN111574445B (zh) * 2020-06-19 2021-02-26 湖北精瑜材料有限公司 一种水溶性硫化二聚体喹啉季铵盐缓蚀剂及其制备方法和应用

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2854483A (en) * 1954-10-06 1958-09-30 American Home Prod Bronchodilator compounds
US3252996A (en) * 1962-10-02 1966-05-24 Ciba Geigy Corp Alpha-pyrrolidinomethyl valero and caprophenones

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2854483A (en) * 1954-10-06 1958-09-30 American Home Prod Bronchodilator compounds
US3252996A (en) * 1962-10-02 1966-05-24 Ciba Geigy Corp Alpha-pyrrolidinomethyl valero and caprophenones

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4098904A (en) * 1976-11-12 1978-07-04 The Upjohn Company Analgesic n-(2-aminocycloaliphatic)benzamides
US4152459A (en) * 1976-11-12 1979-05-01 The Upjohn Company Analgesic N-2-(aminocycloaliphatic)-hydroxy, alkoxy and (allylic)alkenyloxy-benzamides
US4179501A (en) * 1976-11-12 1979-12-18 The Upjohn Company Analgesic N-(2-aminocycloaliphatic)azidobenzamides
US4540690A (en) * 1982-02-09 1985-09-10 The Upjohn Company 2-(Phenylmethylene)cycloalkylamines and -azetidines
US4652559A (en) * 1982-08-16 1987-03-24 The Upjohn Company 2-(Phenylmethylene)cycloalkyl-azetidines

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