# US 5,710,277 A · Process for R (+) 1,2,3,6-tetrahydro-4-phenyl-1-›(3-phenyl-3-cyclohexen-1-yl)methyl!pyridi ne, a central nervous system agent > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 5,710,277 A - Document ID: US5710277A - Status: Granted - Kind: A - Application number: 08/304,074 - Filed: 1994-09-12 - Granted: 1998-01-20 - Earliest claimed: 1994-09-12 - Assignees: Warner-Lambert Company - Inventors: Donald Eugene Butler; Jodette Gailey; Tung Van Le; William John Smith, III; David Juergen Wustrow - Web page: https://patentgrep.com/patent/US5710277A ## CPC - C07D 211/70: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms - C07C 51/487: by treatment giving rise to chemical modification (by chemisorption C07C51/47) - C07C 69/757: having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, [IMAGE cpc-sch-C07C-0958.gif] groups,[IMAGE cpc-sch-C07C-0959.gif] groups, or[IMAGE cpc-sch-C07C-0960.gif] in the acid moiety - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) - C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS ## Abstract An improved process for the preparation of R(+)1,2,3,6-tetrahydro-4-phenyl-1-›(3-phenyl-3-cyclohexen-1-yl)methyl!pyri dine by a novel synthesis is described where 5-oxo-3-phenyl-3-cyclohexene-carboxylic acid is converted in five operations to the desired product, as well as processes for the resolution of 5-oxo-3-phenyl-3-cyclohexenecarboxylic acid using cinchonidine to afford (S)5-oxo-3-phenyl-3-cyclohexenecarboylic acid or .alpha.-chymotrypsin to selectively hydrolyze n-butyl 5-oxo-3-phenyl-3-cycohexenecarboxylate to afford (S)5-oxo-3-phenyl-3-cyclohexenecarboxylic acid as well as other valuable intermediates used in the processes. ## Claims ### Claim 1 A process for the preparation of the compound of Formula I ##STR40## and pharmaceutically acceptable salts thereof which comprises: Step (a) treating the racemic compound of Formula VIII ##STR41## with cinchonidine in a solvent to afford the compound of Formula VII ##STR42## Step (b) treating the compound of Formula VII with a base in a solvent to afford after acidification the compound of Formula VI ##STR43## Step (c) treating the compound of Formula VI with the compound of Formula V ##STR44## in the presence of a coupling reagent and a solvent to afford the compound of Formula IV ##STR45## Step (d) treating the compound of Formula IV with a reducing reagent in a solvent to afford a mixture of compounds of Formula IIIa and Formula IIIb ##STR46## Step (e) treating the mixture of compounds of Formula IIIa and Formula IIIb with a mixture of zinc chloride, and sodium cyanoborohydride in a solvent followed by a solution of a carboxylic acid in a solvent to afford the compound of Formula II ##STR47## Step (f) treating the compound of Formula II with a metal hydride reducing agent in a solvent to afford the compound of Formula I; Step (g) and, if desired, converting the resulting compound of Formula I to a corresponding pharmaceutically acceptable acid addition salt by conventional means, and if so desired, converting the corresponding pharmaceutically acceptable acid addition salt to a compound of Formula I by conventional means. ### Claim 2 (depends on 1) A process according to claim 1 wherein the solvent in Step (a) is an alcohol. ### Claim 3 (depends on 2) A process according to claim 2 wherein the solvent is isopropanol. ### Claim 4 (depends on 1) A process according to claim 1 wherein the base in Step (b) is an alkali metal hydroxide. ### Claim 5 (depends on 4) A process according to claim 4 wherein the base is sodium hydroxide. ### Claim 6 (depends on 1) A process according to claim 1 wherein the solvent in Step (b) is methanol. ### Claim 7 (depends on 1) A process according to claim 1 wherein the coupling reagent in Step (c) is selected from the group consisting of: carbonyl diimidazole; and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, 1-hydroxybenzotriazole hydrate, and triethylamine. ### Claim 8 (depends on 7) A process according to claim 7 wherein the coupling reagent is carbonyl diimidazole. ### Claim 9 (depends on 1) A process according to claim 1 wherein the solvent in Step (c) is selected from the group consisting of: acetonitrile; and tetrahydrofuran. ### Claim 10 (depends on 9) A process according to claim 9 wherein the solvent is acetonitrile. ### Claim 11 (depends on 1) A process according to claim 1 wherein the reducing reagent in Step (d) is a cation borohydride. ### Claim 12 (depends on 11) A process according to claim 11 wherein the reducing reagent is sodium borohydride. ### Claim 13 (depends on 1) A process according to claim 1 wherein the solvent in Step (d) is selected from the group consisting of: an alcohol; and an aqueous alcohol. ### Claim 14 (depends on 13) A process according to claim 13 wherein the solvent is ethanol. ### Claim 15 (depends on 1) A process according to claim 1 wherein the solvent in Step (e) is selected from the group consisting of: hexane; and heptane. ### Claim 16 (depends on 15) A process according to claim 15 wherein the solvent is heptane. ### Claim 17 (depends on 1) A process according to claim 1 wherein the carboxylic acid in Step (e) is selected from the group consisting of: glacial acetic acid; propanoic acid; butyric acid; and pivalic acid. ### Claim 18 (depends on 17) A process according to claim 17 wherein the carboxylic acid is glacial acetic acid. ### Claim 19 (depends on 1) A process according to claim 1 wherein the carboxylic acid in Step (e) is added as a solution in a solvent selected from the group consisting of: hexane; heptane; and tetrahydrofuran. ### Claim 20 (depends on 19) A process according to claim 19 wherein the solvent is tetrahydrofuran. ### Claim 21 (depends on 1) A process according to claim 1 wherein the metal hydride reducing agent in Step (f) is lithium aluminum hydride. ### Claim 22 (depends on 1) A process according to claim 1 wherein the solvent in Step (f) is tetrahydrofuran. ### Claim 23 (depends on 1) A process according to claim 1 wherein the compound of Formula I is R(+)1,2,3,6-tetrahydro-4-phenyl-1-›(3-phenyl-3-cyclohexen-1-yl)methyl!-pyr idine maleate. ### Claim 24 A process for the preparation of the compound of Formula VI ##STR48## which comprises: Step (a) treating the racemic compound of Formula VIII ##STR49## with cinchonidine in a solvent to afford the compound of Formula VII ##STR50## and Step (b) treating the compound of Formula VII with a base in a solvent to afford after acidification the compound of Formula VI. ### Claim 25 (depends on 24) A process according to claim 24 wherein the solvent in Step (a) is an alcohol. ### Claim 26 (depends on 25) A process according to claim 25 wherein the solvent is isopropanol. ### Claim 27 (depends on 24) A process according to claim 24 wherein the base in Step (b) is an alkali metal hydroxide. ### Claim 28 (depends on 27) A process according to claim 27 wherein the base is sodium hydroxide. ### Claim 29 (depends on 24) A process according to claim 24 wherein the solvent in Step (b) is methanol. ### Claim 30 A process for the preparation of the compound of Formula VI ##STR51## which comprises treating the racemic compound of Formula IX ##STR52## in a solvent at about pH 5 with .alpha.-chymotrypsin to afford after separation of unreacted ester and acidification the compound of Formula VI. ### Claim 31 (depends on 30) A process according to claim 30 wherein the solvent is water. ### Claim 32 A process for the preparation of the compound of Formula II ##STR53## which comprises: Step (a) treating the racemic compound of Formula VIII ##STR54## with cinchonidine in a solvent to afford the compound of Formula VII ##STR55## Step (b) treating the compound of Formula VII with a base in a solvent to afford after acidification the compound of Formula VI ##STR56## Step (c) treating the compound of Formula VI with the compound of Formula V ##STR57## in the presence of a coupling reagent and a solvent to afford the compound of Formula IV ##STR58## Step (d) treating the compound of Formula IV with a reducing reagent in a solvent to afford a mixture of compounds of Formula IIIa and Formula IIIb ##STR59## Step (e) treating the mixture of compounds of Formula IIIa and Formula IIIb with a mixture of zinc chloride, and sodium cyanoborohydride in a solvent followed by a solution of a carboxylic acid in a solvent to afford the compound of Formula II. ### Claim 33 A process for the preparation of the compounds of Formula IIIa and Formula IIIb ##STR60## which comprises: Step (a) treating the racemic compound of Formula VIII ##STR61## with cinchonidine in a solvent to afford the compound of Formula VII ##STR62## Step (b) treating the compound of Formula VII with a base in a solvent to afford after acidification the compound of Formula VI ##STR63## Step (c) treating the compound of Formula VI with the compound of Formula V ##STR64## in the presence of a coupling reagent and a solvent to afford the compound of Formula IV ##STR65## and Step (d) treating the compound of Formula IV with a reducing reagent in a solvent to afford a mixture of compounds of Formula IIIa and Formula IIIb. ### Claim 34 A process for the preparation of the compound of Formula IV ##STR66## which comprises: Step (a) treating the racemic compound of Formula VIII ##STR67## with cinchonidine in a solvent to afford the compound of Formula VII ##STR68## Step (b) treating the compound of Formula VII with a base in a solvent to afford after acidification the compound of Formula VI ##STR69## and Step (c) treating the compound of Formula VI with the compound of Formula V ##STR70## in the presence of a coupling reagent and a solvent to afford the compound of Formula IV. ### Claim 35 The compound of Formula IX ##STR71## ### Claim 36 A compound selected from the group consisting of Formula IIIa and Formula IIIb ##STR72## ### Claim 37 The compound of Formula IV ##STR73## ### Claim 38 The optically pure compound of Formula VI ##STR74## ### Claim 39 The compound of Formula VII ##STR75##