Title of Invention	METHOD FOR THE PREPARATION OF CITALOPRAM
Abstract	A method for the preparation of citalopram comprising reaction of a compound of formula 5-aminomethyl-1-(3-dimethylamino-propyl)-1-(4-fluoro-phenyl)-1,3-dihydro-isobenzofuran with an oxidising agent to prepare citalopram.

Full Text

Method for the Preparation of Citalopram The present invention relates to a method for the preparation of the well-known anti¬depressant drug citalopram, l-[3-(dimethylamino)propyl]-l-(4-fluorophenyl)-l,3-dihydro-5-isobenzofurancarbonitrile. Background of the Invention It is a selective, centrally acting serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor, accordingly having antidepressant activities. The antidepressant activity of the compound has been reported in several publications, eg. J. Hyttel Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1982, 6, 277-295 and A. Gravem, Acta Psychiatr. Scand. 1987, 75, 478-486. The compound has further been disclosed to show effects in the treatment of dementia and cerebrovascular disorders, EP-A 474580. Citalopram was first disclosed in DE 2,657,013, corresponding to US 4,136,193. This patent publication describes the preparation of citalopram by one method and outlines a further method, which may be used for preparing citalopram. According to the process described, the corresponding l-(4-fluorophenyl)-l,3-dihydro-5-isobenzofurancarbonitrile is reacted with 3-(N,N-dimethylamino)propyl-chloride in the presence of methylsulfinylmethide as condensing ^ent. The starting material was prepared from the corresponding 5-bromo derivative by reaction with cuprous cyanide. According to the method, which is only outlined in general terms, citalopram may be obtained by ring closure of the compoimd: Fxirther processes are disclosed in International patent application Nos. WO 98019511, WO 98019512 and WO 98019513. WO 98019512 and WO 98019513 relate to methods wherein a 5-amino-, 5-carboxy- or 5-(sec: aminocarbonyl)phthalide is subjected to two successive Grignard reactions, ring closure and conversion of the resulting 1,3-dihydroisobenzofuran derivative to the corresponding 5-cyano compoimd, i.e. citalopram. Intemational patent application No. WO 98019511 discloses a process for the manufacture of citalopram wherein a (4-substituted-2-hydroxymethylphenyl-(4-fluorophenyl)methanol compoimd is subjected to ring closure and the resulting 5-substituted l-(4-fluorophenyl)-1,3-dihydroisobenzofuran converted to the corresponding 5-cyano derivative which is alkylated with a (3-dimethylamino)propylhalogenide in order to obtain citalopram. Finally, methods for preparing the individual enantiomers of citalopram are disclosed in US Patent No 4,943,590 from which it also appears that the ring closure of the intermediate of Formula III may be carried out via a labile ester with a base. It has now, surprisingly, been found that citalopram may be manufactured by a novel favourable and safe procedure using convenient starting materials. Furthermore, according to the invention, the compounds of Formula IV may be prepared by different methods. The resulting compound of Formula VII is reacted with a reducing agent such as LiAlH^, Red-Al, AIH3 or activated forms of NaBH4, e.g. NaBH4, Me2S04; NaBH4, l^, NaBH^, BF3. EtjO; or BjH^; followed by treatment with acid or another dehydrating agent to perform ring closure to form the compound of Formula VIII. The alcohol of Formula VIII is conveniently activated by tosylchloride or mesylchloride to form the corresponding substituted sulphonate; or the alcohol is converted into the corresponding benzyUc halide. This conversion is preferably carried out with SOBrj or SOCI2. The corresponding sulphonate or halide is either converted directly to the compound of Formula FV by reaction with liquid ammonia; or by a reaction with a metal salt of phthalimide, preferably potassium phthalamide followed by treatment with NHjNHj or ^y treatment with an amine in an alcohol, i.e. R"NHj/R"-OH, wherein R^ and R® are lower alkyl, preferably methyl or ethyl, e.g. methylamine in ethanol; or by a reaction with metal azide, MN3, M preferably being Na or K; followed by treatment with a reducing agent such as Pd/C and H2 or a hydrate source such as LiAlH4 or NaBH4 or an activated form of it. Another method for preparing the compound of Formula IV includes the follovmg steps: The alcohol of Formula XV is conveniently activated by tosylchloride or mesylchloride to fonn the corresponding substituted sulphonate; or the alcohol is converted into the corresponding benzylic halide. This conversion is preferably carried out with SOBrj or SOCl,. The corresponding sulphonate or halide is either converted directly to the compound of Formula XVII by reaction with hquid ammonia; or by a reaction with a metal salt of phthalimide, preferably potassium phthalamide, followed by treatment with NH2NH2 or by treatment with an amine in an alcohol, i.e. R^"NHz/R"-OH, wherein R* and R" are lower alkyl, preferably methyl or ethyl, e.g. methylamine in ethanol; or by a reaction with metal azide MN3, M preferably being Na or K; followed by treatment with a reducing agent such as Pd/C and H2 or a hydride source such as LiAlH4 or NaBH4 or an activated form thereof The resulting compound of Formula XVII is alkylated with wherein X is a leaving group in the presence of a suitable base. X is preferably halogen or sulphonate. Optionally, the alkylating reaction is a stepwise alkylation analogous to the stepwise aUcylation described above. Optionally the steps of the alkylation and the conversion to the cyano derivative are in opposite order so the conversion to the cyano derivative is performed before the alkylation. Throughout the specification and claims; the terms lower aUcyl or Cj^ alkyl refer to a branched or unbranched alkyl grouphaving from one to six carbon atoms inclusive, such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl, 2,2-dimethyl-l-ethyl and 2-methyl-l-propyl. Similarly, alkenyl and alkynyl, respectively, designate such groups having from two to six carbon atoms, including one double bond and triple bond respectively, such as ethenyl, propenyl, butenyl, ethynyl, propynyl, and butynyl. The term aryl refers to a mono- or bicyclic carbocyclic aromatic group, such as phenyl and naphthyl, in particular phenyl. The term aralkyl refers to aryl-alkyl, wherein aryl and alkyl are as defined above. .ialogen means chloro, bromo or iodo. The compoimd of general Fomiula I may be used as the free base or as a pharmaceutically acceptable acid addition salt thereof. As acid addition salts, such salts formed with organic or inorganic acids may be used. Exemplary of such organic salts are those with maleic, ftimaric, benzoic, ascorbic, succinic, oxalic, bismethylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycohc, p-aminobenzoic, glutamic, benzene sulfonic and theophylline acetic acids, as well as the 8-halotheophyllines, for example 8-bromotheophylline. Exemplary of such inorganic salts are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids. The acid addition salts of the compounds may be prepared by methods known in the art. The base is reacted with either the calculated amount of acid in a water miscible solvent, such as acetone or ethanol, with subsequent isolation of the salt by concentration and cooung, or with an excess of flie acid in a water immiscible solvent, such as ethylether, ethylacetate or dichloromethane, with the salt separating spontaneously. The phamiaceutical compositions of the invention may be administered in any suitable way and in any suitable form, for example orally in the form of tablets, capsules, powders or syrups, or parenterally in the form of usual sterile solutions for injection. The pharmaceutical formulations of the invention may be prepared by conventional methods in the art. For example, tablets may be prepared by mixing the active ingredient with ordinary adjuvants and/or diluents and subsequently compressing the mixture in a conventional tabletting machine. Examples of adjuvants or diluents comprise: Com starch, potato starch, talcum, magnesium stearate, gelatine, lactose, gums, and the like. Any other adjuvant or additive, colouring, aroma, preservative etc. may be used provided that they are compatible with the active ingredients. Solutions for injections may be prepared by dissolving the active ingredient and possible additives in a part of the solvent for injection, preferably sterile water, adjusting the solution to the desired volume, sterilising the solution and filUng it in suitable ampoules or vials. Any suitable additive conventionally used in the art may be added, such as tonicity agents, preservatives, antioxidants, etc. Examples The invention is further illustrated by the following examples. Example 1 5-Aminomethyl-l -(3-dimethylamino-propyl)-l -(4-fluoro-phenyl)-l, 3-dihydro-isohenzofuran l-(3-Dimethylamino-propyl)-l-(4-fluoro-phenyl)-3-oxo-l,3-dihydro-isobenzofuran-5-carbonitrile (5.4 g, 16.2 mmol) was dissolved in dry THF (5 mL) and diluted with dry ether (50 mL). This solution was added dropwise to a refluxing suspension of Kthium aluminium hydride (2.5 g, 65 mmol) in dry ether (150 mL) over 10 - 15 minutes, after which the resulting suspension was heated at reflux for a further 4 h. The solution was allowed to cool to room temperature and was stirred at room temperature overnight. The reaction was quenched with a minimum of water, and the resulting solution/suspension was dried over anhydrous magnesium sulfate. The mixture was filtered, and the soUd cake was washed with THF. The combined filtrates were ev^orated to give an oil. The oil was dissolved in toluene (200 mL) and was stirred with an aqueous solution of sulfiiric acid (10 ml, 70 % v/v) for 3 h. The mixture was diluted with water, and the pH was adjusted to >9 by the addition of aqueous ammonia solution (25% w/v). The toluene was separated, and the aqueoiis phase was extracted with further toluene. The combined toluene extracts were dried over anhydrous magnesium sulfate, filtered and evaporated to give the title compound as a yellow oil (4.4 g, 84%). "H NMR (CDCI3): 6 1.25-1.40 (m, IH), 1.40-1.55 (m, IH), 2.11 (ddd, IH), 2.13 (t, 3H), 2.15 (ddd, IH), 2.21 (t, 2H), 3.85 (s, 2H), 5.11 (d, IH), 5.14 (d, IH), 6.96 (t, 2H), 7.15 (s, IH), 7.21 (d, IH), 7.22 (d, IH), 7.45 (dd, 2H). Example 2 Citalopram, HBr A mixture of 5-aminomethyl-l -(3-dimethylaniino-propyl)-l-(4-fluoro-phenyl)-l,3-dihydro-isobenzofuran (10 g, 30 mmol) and 5A molecular sieves (24 g) in pyridine (150 mL) was stirred at 60 °C under an atmosphere of oxygen. Copper(I) chloride (1.8 g, 1.8 mmol) was added, and the mixture was stured for 3 h. Further copper(I) chloride (1.8 g, 1.8 mmol) was added, and the mixture was stirred overnight. The mixture was poured onto ice, and the pH of the mixture was adjusted to >9 by the addition of aqueous ammonia solution (25% w/v). The solution was diluted with toluene and filtered. The organic phase was separated, and the aqueous was washed with further toluene. The combined organic extracts were washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was treated with heptane and was evaporated to give an oil (11.1 g). This oil was dissolved in acetone and treated with aqueous hydrobromic acid (7 ml, 47% w/v). The solution was evaporated, and the residue was dissolved in wo-propanol (100 mL). The solution was stirred overnight. The resulting precipitate was filtered and dried to give the HBr salt of citalopram as a white powder (8.2 g, 66%). The filtrate was evaporated, and the oily residue was shaken with ether and allowed to stand overnight. Filtration of the solution gave further HBr salt of citalopram as a brown solid (1.7 g, 14%). "H NMR (d*- DMSO): 6 1.35-1.50 (m, IH), 1.50-1.60 (m, IH), 2.25 (t, 2H), 2.69 (s, 3H), 3.00-3.10 (m, 2H), 5.17 (d, IH), 5.25 (d, IH), 7.18 (t, 2H), 7.61 (dd, 2H), 7.77 (d, IH), 7.82 (d, IH), 7.83 (s, IH), 9.27 (bs, IH). Example 3 l-(4-Fluoro-phenyl)-3-oxo-l,2-dihydro-isobenzofiiran-5-carboxylic acid methyl ester A stirred suspension of l-(4-fluoro-phenyl)-3-oxo-l,3-dihydro-isobenzofuran-5-carboxylic acid (1 g, 3.7 mmol) in thionyl chloride (25 mL) was heated at reflux for 25 min, during which time the solid dissolved. The thionyl chloride was then evaporated, and the residue was dissolved in toluene, and again evaporated. The residue was stirred in methanol (25 mL) overnight, during which time a heavy precipitate formed. The solvent was evaporated, and the residue was partitioned between aqueous ammonia solution (25% w/v) and toluene. The organic phase was separated, dried over magnesium sulfate and evaporated to give the title compound as a white solid (0.97 g, 92%). "H NMR (d^- DMSO): S 3.92 (s, 3H), 6.85 (s, IH), 7.26 (t, 2H), 7.42 (dd, 2H), 7.61 (d, IH), 8.31 (dd, IH), 8.36 (s, IH). Example 4 l~(4-Fluoro-phenyl)-3-oxo-l, 3-dihydro-isobenzofuran-5-carboxylic acid amide A stirred suspension of l-(4-fluoro-phenyl)-3-oxo-l,3-dihydro-isobenzofuran-5-carboxylic acid (1 g, 3.7 mmol) in thionyl chloride (25 mL) was heated at reflux for 25 min, during which time the soHd dissolved. The thionyl chloride was then evaporated, and the residue was dissolved in toluene, and again evaporated. The residue was dissolved in toluene (15 mL) and was treated with a solution of ammonia in ether and a heavy precipitate formed. The mixture was stirred overnight, diluted with toluene and aqueous ammonia solution, and fihered. The residue was dried to give the title compound as a white solid (0.80 g, 80%). "H NMR (d*-DMSO): 5 6.81 (s, IH), 7.25 (t, 2H), 7.40 (dd, 2H), 7.54 (d, IH), 7.59 (bs, IH), 8.24 (bs, IH), 8.24 (dd, IH), 8.42 (s, IH). Example 5 l-(4-Fluoro-phenyl)-3-oxo-l,3-dihydro-isobenzofuran-5-carbonitrile A suspension of l-(4-fIuoro-phenyl)-3-oxo-l,3-dihydro-isobenzofuran-5-carboxylic acid amide (13.6 g, 0.05 mole) in thionyl chloride (40 mL) and DMF (0.25 mL) was heated at reflux for 2 hours. The thionyl chloride was then evaporated, and the residue was dissolved in hot BPA (100 mL). On cooling, crystals of the title compound was formed. Yield: 7.8 g (62%). "HNMR (d^"-DMSO): 6 6.87 (s, IH), 7.26 (t, 2H), 7.42 (dd, 2H), 7.58 (d, IH), 8.18 (dd, IH), 8.48 (s, IH). Example 6 5-Bromomethyl-l-(4-fluoro-phenyl)-l,3-dihydro-isobenzofuran A suspension of 5-hydroxymetliyl-l-(4-fluoro-phenyl)-l,3-dihydro-isobenzofuran (2 g, 8.2 mmol) in toluene (20 mL) was heated until the solid dissolved. Heating was then stopped. Thionyl bromide (2.2 g, 10.6 mmol) was added, and the mixture was stirred for 1 h. Silica (25 g) was added, and the mixture was filtered, and the residue was washed with a 1:1 v/v solution of ethyl acetate and heptane. The filtrate was evaporated to give the title compound as a red-orange oil (2.6 g, 90%). "H NMR (d*-DMSO): 6 4.72 (s, 2H), 5.11 (d, IH), 5.28 (d, IH), 6.17 (s, IH), 7.04 (d, IH), 7.17 (t, 2H), 7.33 (d, IH), 7.38 (dd, 2H), 7.45 (s, IH). 5-Aminomethyl-l"(4-Fluoro-phenyl)-l,3-dihydro-isobenzofiiran A suspension of 5-bromomethyl-l-(4-fluoro-phenyl)-l,3-dihydro-isobenzofliran (1.96 g, 6.4 mmol) was stirred in liquid re-distilled ammonia (200 mL) under nitrogen/ammonia at -33 °C for 2"/2 days. The ammonia was allowed to evaporate, and the residue was stirred with a mixture of ethyl acetate and aqueous sulfuric acid (2 M). The aqueous phase was separated and was washed with ether. The aqueous phase was then basified to pH > "9 using aqueous ammonium hydroxide solution (25% w/v), and was extracted with toluene. The toluene extracts were dried over anhydrous magnesium sulfate and evaporated to give the title compound as a yellow-orange oil (0.63 g, 40%). "H NMR (d*-DMSO): 5 3.72 (s, 2H), 5.09 (d, IH), 5.25 (dd, IH), 6.14 (s, IH), 6.96 (d, IH), 7.17 (t, 2H), 7.20 (d, IH), 7.32 (s, IH), 7.36 (dd, 2H). Example 8 Citalopram To a stirred solution of 5-aminomethyl-l-(3-dimethylamino-propyl)-l-(4-fluoro-phenyl)-1,3-dihydro-isobenzofuran (0.5 g, 1.5 mmol) in dichloromethane (10 mL) was added an aqueous solution of potassium bisulfate and sodiiun hydroxide (19 mL; 0.2 M in KjSjOg, 3.8 mmol; 0.4 M in NaOH, 7.6 mmol), followed by an aqueous solution of nickel sulfate (1.5 mL, 40 mM, 61 famol). The mixture was stirred vigorously for 4 days, and was then filtered through celite. The filtrate was partitioned between aqueous sulfuric acid (2 M) and toluene. The aqueous layer was separated, and the pH of the mixture was adjusted to >9 by the addition of aqueous ammonia solution (25% w/v). The solution was extracted with toluene, and this latter toluene extract was dried over magnesium sulfate and evaporated to give the firee base of citalopram as a very pale yellow oil (0.35 g, 70%). Example 9 l-(4-Fluoro-phenyl)-3-oxo-l,3-dihydro-isobenzofuran-5-carboxylicacid Zink (38 g, 0.58 mol) was suspended in acetic acid (400 mL). The mixture was heated to 60 °C. 2,4-dicarboxy-4"-fluoro-benzophenone (21 g, 0.075 mol) was added in portions of 5 grams. After addition, the reaction mixture was heated at reflux temperature for two hours. The suspension was filtered while it was still hot. The filtrate was added to ice-water (1 kg) and the title compound was isolated by filtration. Yield 17.8 g (90%). "H NMR (d*- DMSO): 5 6.84 (s, IH), 7.17 (t, 2H), 7.43 (dd, 2H), 7.59 (d, IH), 8.31 (d, IH), 8.35 (s, IH). WE CLAIM: 1. A method for the preparation of citalopram comprising reaction of a compound of Formula IV which is isolated as the base or a pharmaceutically acceptable salt thereof 2. The method as claimed in claim 1, wherein the oxidizing agent is a copper (I) salt such as copper (I) chloride, CuCl, in the presence of a stoichiometric oxidant. 3. The method as claimed in claim 2, wherein the stoichiometric oxidant is oxygen. 4. The method as claimed in claim 1, wherein the oxidizing agent is a nickel (II) salt such as nickel (II) sulfate, NiS04, in the presence of a stoichiometric oxidant. 5. The method as claimed in claim 4, wherein the stoichiometric oxidant is potassium persulfate, K2S2O8. 6. The method as claimed in claim 1, wherein the citalopram is isolated as the base. 7. The method as claimed in claim 1, wherein the citalopram is isolated as an acid addition salt, such as the hydrobromide.

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