# US 4,399,284 A · Process for the optical resolution of mixtures of D- and L-2-(6-methoxy-2-naphthyl)-propionic acids > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 4,399,284 A - Document ID: US4399284A - Status: Granted - Kind: A - Application number: 06/282,440 - Filed: 1981-07-13 - Granted: 1983-08-16 - Earliest claimed: 1980-07-30 - Assignees: Alfa Farmaceutici S.p.A. - Inventors: Vincenzo Cannata; Graziano Zagnoni - Web page: https://patentgrep.com/patent/US4399284A ## CPC - C07D 453/04: having a quinolyl-4, a substituted quinolyl-4 or a alkylenedioxy-quinolyl-4 radical linked through only one carbon atom, attached in position 2, e.g. quinine - C07C 51/487: by treatment giving rise to chemical modification (by chemisorption C07C51/47) - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) - C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS ## Abstract A new process for the optical resolution of mixtures of d- and 1-2-(6-methoxy-2-naphthyl)-propionic acids, which comprises preparing a solution of a mixture of d-and 1-2-(6-methoxy-2-naphthyl)-propionic acids and an optically active organic base in a predetermined organic solvent, slowly cooling the obtained solution and seeding with crystals of a salt of d-2-(6-methoxy-2-naphthyl)-propionic acid with the optically active organic base containing a certain amount by weight of the organic solvent, and treating the obtained product with mineral acids in suitable organic solvents to obtain the free d-2-(6-methoxy-2-naphthyl)-propionic acid. ## Claims ### Claim 1 A process for the resolution into the optically active isomers of mixtures of d- and l-2-(6-methoxy-2-naphthyl)-propionic acids, which consists of: (a) preparing a solution of a mixture of d- and l-2-(6-methoxy-2-naphthyl)-propionic acids and the optically active organic base cinchonidine in an organic solvent selected from the group consisting of formamide, monomethylformamide, dimethylformamide, monoethylformamide, diethylformamide, monomethylacetamide and diethylacetamide, at a temperature between about 70.degree. and about 90.degree. C. to obtain a solution; (b) gradually cooling said solution and, at a predetermined temperature, seeding with crystals of a salt of d-2-(6-methoxy-2-naphthyl)-propionic acid and cinchonidine, said salt having a content by weight of the organic solvent used in step (a) which content is between 9.5% and about 14%, and further gradually cooling, whereby the salt of d-2-(6-methoxy-2-naphthyl)-propionic acid with cinchonidine precipitates, which salt has a content by weight of said organic solvent used in step (a) between about 9.5% and 14% and filtering said salt; (c) reacting said salt from step (b) with a mineral acid in an organic solvent whereby the free d-2-(6-methoxy-2-naphthyl)-propionic acid is obtained. ### Claim 2 (depends on 1) A process as defined in claim 1, wherein said organic solvent is dimethylformamide or dimethylacetamide. ### Claim 3 (depends on 1) A process as defined in claim 1, wherein about 0.5 molar equivalent of cinchonidine is reacted for each molar equivalent of said mixture of d- and l-2-(6-methoxy-2-naphthyl)-propionic acid. ### Claim 4 (depends on 1) A process as defined in claim 1, wherein the mixture of d- and l-2-(6-methoxy-2-naphthyl)-propionic acids is a substantially racemic mixture. ### Claim 5 (depends on 1) A process as defined in claim 1, wherein the seeding temperature is between about 50.degree. and 70.degree. C. ### Claim 6 (depends on 1) A process as defined in claim 1 wherein cooling is continued to a temperature between about room temperature and about 0.degree. C. ### Claim 7 (depends on 1) A process as defined in claim 1, wherein the product obtained from step (b) is subjected to a further recrystallization from the same solvent. ### Claim 8 A process for the resolution into the optically active isomers of a substantially racemic mixture of d- and l-2-(6-methoxy-2-naphthyl)-propionic acids which consists of: (a) preparing a solution of a molar equivalent of said mixture and about 0.5 molar equivalent of cinchonidine, in an organic solvent which is dimethylformamide or dimethylacetamide, at a temperature of about 75.degree.-80.degree. C.; (b) gradually cooling the obtained solution and, at a temperature between about 60.degree. and 66.degree. C., seeding with crystals of the cinchonidine salt of d-2-(6-methoxy-2-naphthyl)-propionic acid containing 9.5%-12% by weight of dimethylformamide or 10.5%-14% of dimethylacetamide, and continuing to cool to a temperature between about room temperature and about 0.degree. C., whereby the cinchonidine salt of d-2-(6-methoxy-2-naphthyl)-propionic acid containing from about 9.5% to about 14% by weight of dimethylformamide or dimethylacetamide precipitates; (c) treating the said product from step (b) with hydrochloric acid in the presence of ethyl acetate to obtain the free d-2-(6-methoxy-2-naphthyl)-propionic acid. ### Claim 9 The cinchonidine salt of d-2-(6-methoxy-2-naphthyl)-propionic acid containing 10.6% by weight of dimethylformamide. ### Claim 10 The cinchonidine salt of d-2-(6-methoxy-2-naphthyl)-propionic acid containing 11.2% by weight of dimethylacetamide. ### Claim 11 A process for preparing the cinchonidine salt of d-2-(6-methoxy-2-naphthyl)-propionic acid containing from about 9.5%-12% by weight of dimethylformamide or 10.5%-14% of dimethylacetamide, which consists of dissolving a molar amount of d-2-(6-methoxy-2-naphthyl)-propionic acid and a molar equivalent of cinchonidine in dimethylformamide or dimethylacetamide at a temperature between about 55.degree. and about 65.degree. C., slowly cooling the resulting solution to about 20.degree. C., letting the product precipitate and filtering the product. ### Claim 12 (depends on 11) A process as defined in claim 11 wherein said solvent is dimethylacetamide and d-2-(6-methoxy-2-naphthyl)-propionic acid is reacted with cinchonidine in the molar ratio of 1:1 and the cinchonidine salt of d-2-(6-methoxy-2-naphthyl)-propionic acid having 11.2% by weight of dimethylacetamide is obtained.