# US 7,411,077 B2 · Process for the preparation of a cyano-isobenzofuran > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 7,411,077 B2 - Document ID: US7411077B2 - Status: Granted - Kind: B2 - Application number: 10/549,062 - Filed: 2004-03-09 - Published: 2006-08-17 - Granted: 2008-08-12 - Earliest claimed: 2003-03-13 - Assignees: Adorken Technology SpA - Inventors: Giovanni Cotticelli; Leone Dall'Asta; Gianluca Di Lernia - Web page: https://patentgrep.com/patent/US7411077B2 ## CPC - C07D 307/87: Benzo [c] furans; Hydrogenated benzo [c] furans - A61P 25/24: Antidepressants - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS ## Abstract A process for the preparation of citalopram and the pharmaceutically acceptable salts therof is disclosed by reacting 5-cyanophthalide with a 4-fluorophenyl magnesium halide, reducing the 3-hydroxymethyl-4-(4-fluorobenzoyl)benzonitrile with an agent reducing ketones to alcohols, submitting the thus-obtained 3-hydroxymethyl-4-[(4-fluorophenyl)hydroxymethyl)benzonitrile to a cyclization reaction to give 1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile without 1,1-bis(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile and treating 1,1-bis(4 fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile with a 3-(dimetylamino)propyl halide in the presence of a base. ## Claims ### Claim 1 A process for the preparation of pure 1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile which comprises: (a) reacting 5-cyanophthalide with a 4-fluorophenylmagnesium halide; (b) treating the mixture thus obtained, containing the 3-hydroxymethyl-4-(4-fluorobenzoyl)benzonitrile and the 3-hydroxymethyl-4-[bis-(4-fluorophenyl)hydroxymethyl]benzonitrile with a reducing agent of ketones to alcohols; (c) submitting the mixture thus obtained, containing the 3-hydroxymethyl-4-[(4-fluorophenyl)hydroxymethyl]benzonitrile (C) and the 3-hydroxymethyl-4-[bis-(4-fluorophenyl)hydroxymethyl]benzonitrile to a cyclization reaction and isolating a mixture containing the 1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile (B) and the 1,1-bis(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile; and (d) treating the mixture thus obtained with a solvent capable of dissolving the 1,1-bis(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile and in which the 1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile (B) is insoluble and recovering the pure 1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile (B), wherein said solvent is isopropanol or methyl-t-butylether. ### Claim 2 (depends on 1) A process according to claim 1, wherein, in step (b) the reduction is carried out with NaBH4 in water and sodium hydroxide. ### Claim 3 (depends on 1) A process according to claim 1, wherein, in step (c), the cyclization is carried out with phosphoric acid in a biphasic water/organic solvent medium. ### Claim 4 (depends on 3) A process according to claim 3, wherein said biphasic medium consists of water/ethyl acetate. ### Claim 5 (depends on 1, 2, 3, 4) A process according to any one of claims 1 to 4, wherein, in step (d), isopropanol or methyl-t-butylether is used as a solvent capable of dissolving the 1,1-bis(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile and in which the 1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile (B) is insoluble. ### Claim 6 (depends on 1, 2, 3, 4, 5) A process according to any one of claims 1 to 5, wherein the 1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile (B) is further reacted with a 3-(dimetylamino)propyl halide in the presence of a basic condensing agent and citalopram is isolated as free base or as a pharmaceutically acceptable salt thereof. ### Claim 7 (depends on 6) A process according to claim 6, wherein the chloride is used as an halide, sodium hydride is used as a basic condensing agent and the condensation is carried out in dimethylsulfoxide. ### Claim 8 A process for the preparation of citalopram or of a pharmaceutically acceptable salt thereof, which comprises: (a) reacting 5-cyanophthalide with a 4-fluorophenylmagnesium halide; (b) treating the mixture thus obtained, containing the 3-hydroxymethyl-4-(4-fluorobenzoyl)benzonitrile and the 3-hydroxymethyl-4-[bis-(4fluorophenyl)hydroxymethyl]benzonitrile with a reducing agent of ketones to alcohols; (c) submitting the mixture thus obtained, containing the 3-hydroxymethyl-4-[(4-fluorophenyl)hydroxymethyl]benzonitrile (C) and the 3-hydroxymethyl-4-[bis-(4-fluorophenyl)hydroxymethyl]benzonitrile to a cyclization reaction and isolating a mixture containing the 1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile (B) and the 1,1-bis(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile; (d) treating the mixture thus obtained with a solvent capable of dissolving the 1,1-bis(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile and in which the 1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile (B) is insoluble and recovering the pure 1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile (B), wherein said solvent is isopropanol or methyl-t-butylether; (e) treating the pure 1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile (B) with a 3-(dimethylamino)propyl halide in the presence of a basic condensing agent and isolating citalopram as free base or as a pharmaceutically acceptable salt thereof. ### Claim 9 (depends on 8) A process according to claim 8, wherein, in step (b) the reduction is carried out with NaBH4 in water and sodium hydroxide. ### Claim 10 (depends on 8) A process according to claim 8, wherein, in step (c), the cyclization is carried out with phosphoric acid in a biphasic water/organic solvent medium. ### Claim 11 (depends on 10) A process according to claim 10, wherein said biphasic medium consists of water/ethyl acetate. ### Claim 12 (depends on 8, 9, 10, 11) A process according to any one of claims 8 to 11, wherein, in step (d), isopropanol or methyl-t-butylether is used as a solvent capable of dissolving the 1,1-bis(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile and in which the 1-(4fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile (B) is insoluble.