Indian Patents. 210129:A METHOD FOR THE PREPARATION OF 5 - AMINOMETHYL -1 -(3 - DIMETHLYAMINO - PROPYL) - 1 - (4 - FLUORO - PHENYL) -1,3

Title of Invention	A METHOD FOR THE PREPARATION OF 5 - AMINOMETHYL -1 -(3 - DIMETHLYAMINO - PROPYL) - 1 - (4 - FLUORO - PHENYL) -1,3 - DIHYDROISOBENZOFURAN
Abstract	The present invention relates to a method for the preparation of a compound of Formula IV is prepared by activating the alcohol of Formu.1a VIII by a substituted sulphonate or converting the alcohol into a benzylic halide or another activated derivative followed by aminolysis to form the compound of Formula IV

Full Text	Method for the Preparation of Citalopram The present invention relates to a method for the preparation of the well-known antidepressant drug citalopram, l-[3-(dimethylamino)propyl]-l-(4-fluorophenyl)-l,3- Background of the Invention Citalopram is a well-known antidepressant drug that has now been on the market for some years and has the following structure: 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 Pr-og. Neuro-Psychopharmacol & Biol Psychiat 1982, (5, 277-295 and A. Gravem, Acta Psychiati: 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-isobenzoforancarbonitrile is reacted with 3-(N,N-diinethylamino)propyl-chloride in the presence of methylsulfinyhnethide as condensing agent. The starting material was prepared firom 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: in the presence of a dehydrating agent and subsequent exchange of the 5-bromo group with cuprous cyanide. The starting material of Formula II is obtained jfrom 5-bromophthalide by two successive Grignard reactions, i.e. with 4-fluorophenyl magnesium chloride and N,N-dimethylaminopropyl magnesium chloride, respectively. A new and surprising method and an intermediate for the preparation of citalopram were described in US Patent No 4,650,884, according to which an interaiediate of the formula is subjected to a ring closure reaction by dehydration with strong sulfuric acid in order to obtain citalopram. The intermediate of Formula III was prepared from 5-cyanophthalide by two successive Grignard reactions, i.e. with 4-fluorophenyl magnesium halogenide and N,N-dimethylaminopropyl magnesium halogenide, respectively. Further 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-dihydroisobenzofiiran derivative to the corresponding 5-cyano compound, i.e. citalopram. International patent appHcation No. WO 98019511 discloses a process for the manufacture of citalopram wherein a (4-substituted-2-hydroxyinethylphenyl-(4-fluorophenyl)methanol compound 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 iMividual 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 HI 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. Summary of the invention Accordingly, the present invention relates to a novel metliod for the preparation of citalopram comprising reaction of a compound of Formula TV with an appropriate oxidising agent such as copper(I) and O2; or NiS04 and KsS^Og to afford citalopram which is isolated as the base or a pharmaceutically acceptable salt thereof hi another aspect, the invention relates to methods for preparing the intermediates of Formula IV. In yet another aspect, the present invention relates to an antidepressant pharmaceutical composition comprising citalopram as the base or any convenient salt thereof / manufactured by the process of the invention. Furthermore, according to the invention, the compounds of Formula IV may be prepared by different methods. One of these methods includes the following steps: 6-carboxy-3-(4-fluorophenyl)phthalide is reacted with an alcohol, R-OH, wherein R is preferably lower alkyl, most preferably Me, in the presence of a dehydrating agent, preferably SOCU. The resulting compound of Formula VI is alkylated with wherein X is a lea\dng gioup in the presence of a suitable base. X is preferably halogen or sulphonate. Optionally, the alkylating reaction is a stepwise alkylation. In this case, the resulting compoimd of Formula VI is alkylated with a compound having the formula wherein X' is a suitable leaving group and R' is -CHs-O-Pg, -CH2-NPgiPg2, -CO-N(CH3)o. -CH(OR^)(OR'), -C(OR')(OR')(OR') or -COOR^ wherein Pg is a protection group for an alcohol group, Pg^ and Pg2 are protection groups for an amino group, R' and R^ are alkyl groups or R and R^ together form a chain of 2 to 4 carbon atoms and R^ R\ R^ and R^ are allcyl, alkenyl, alkynyl, aryl or aralkyl; to form a compound of Formula XVIII wherein R' is as defined above; followed by conversion of the group R' to a dimethylaminomethyl group. The resulting compound of Formula VII is reacted with a reducing agent such as LiAlH4, Red-Al, AIH3 or activated forms of NaBH4, e.g. NaBEt, Me2S04; NaBH4,1.; NaBH4, BF3. EtjO; or B2H6; followed by treatment with acid or another dehydrating agent to perform ring closure to form tlie compound of Formula VHI. The alcohol of Formula Vin is conveniently activated by tosylchloride or mesylchloride to form the corresponding substituted sulphonate; or the alcohol is converted into the corresponding benzyhc hahde. This conversion is preferably carried out with SOBrs or SOCI2. The corresponding sulphonate or haiide is either converted directly to the compound of Fomiula FV by reaction with liquid ammonia; or by a reaction with a metal salt of phthalimide, preferably potassium phthalamide followed by treatment with NH^NH, or by treatment with an amine in an alcohol, i.e. R^NH2/R^-0H, wherein R^ and R^ are lower allcyl, 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 LiAIH4 or NaBH4 or an activated form of it. Another method for preparing the compound of Formula IV includes the following steps: 6-carboxy-3-(4-fluorophenyl)phthalide is conveniently reacted with a dehydrating agent such as thionylchloride, followed by aminolysis of the resulting activated acid derivative. The resulting compound of Formula IX 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 alkylation described above. The resulting compound of Formula X is reacted with a reducing agent such as LiAlH^, Red-Al, AlHs or activated fonns of NaBH^, e.g. NaBH4, Me2S04; NaBH4, I.; NaBH^, BF3.Et20; or BsH^; followed by treatment with acid or another dehydrating agent to perform ring closure to form the compound of Formula IV. According to a third method for preparing the compound of Formula TV, the corresponding 6-cyano substituted derivative of 6-carboxy-3-(4-fiuorophenyl)phthalide is prepared. n n n Th^ carboxy derivative is either reacted with SOCI2 followed by treatment with ammonia and finally a dehydrating agent such as SOCI2 to prepare the cyano derivative of Formula XI; or reacted with an alcohol R-OH in the presence of acid followed by ti-eatment with ammonia and finally reacted with SOCI2; or reacted in a one-pot process such as with S02(NH2)25 SOCl. and sulfolane, or with ?err-butylainine, a dehydrating agent such as POCI3 and a suitable solvent, such as toluene. The resulting compound of Formula XI 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 alkylation described above. The resulting compound of Formula XII is reacted with a reducing agent such as LiAlH4, Red-Al, AIH3 or activated forms of NaBH4, e.g. NaBH^, Me2S04; NaBH4, I,; NaBH4, BF3.Et20; or B2H6; followed by treatment with acid to perform ring closure to form the compound of Formula IV. Other reaction conditions, solvents, etc. for the reactions described above ai-e conventional conditions for such reactions and may easily be determined by a person sldlled in the art. In another aspect, the present invention provides the novel intermediate of Formula V. In a further aspect, the invention relates to methods for preparing the intermediate of Formula V. One stepwise process for preparing the intermediate of Formula V is illustrated below: m-xylene and p-fluorobenzoyl chloride, which are commercially available compounds are reacted in the presence of AICI3 to afford the compound of Fommla XIV. Tliis compound is oxidised wth permanganate, preferably KMn04 or NaMn04, giving the resulting compound of Formula XIII, which is finally reacted conveniently with Zn in acid, preferably acetic acid. Alternatively, the compound of Formula IV is prepared from the compound of Formula Xin by the following stepwise process: The compound of Formula XIII is reacted with a reducing agent such as LiAlH4, Red-Al, AIH3 or activated forms of NaBH4, e.g. NaBH^, Me^SO,; NaBH4, I^; NaBH,, BFs.EtoO; or BsH^; followed by treatment with acid to perform ring closure to form the compound of Formula XV. The alcohol of Formula XV is conveniently activated by tosylchloride or mesylchloride to form the corresponding substituted sulphonate; or the alcohol is converted into the corresponding benzylic hahde. This conversion is preferably carried out with SOBr2 or SOCl.. The corresponding sulphonate or hahde is either converted directly to the compound of Formula XVII by reaction with Uquid ammonia; or by a reaction with a metal salt of phthaUmide, preferably potassium phthalamide, followed by treatment with NH2NH2 or by treatment with an amine in an alcohol, i.e. R^NH^/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 IvWj, M preferably being Na or K; followed by ti-eatn^ent with a reducing agent such as Pd/C and Hj or a hydride source such as LiAlH4 or NaBH4 or an activated form thereof The resulting compound of Formula XVn 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 analogoiis to the stepwise allcylation 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 perfomied before the alkylation. Tlxroiighont the specification , the tenns lower allc}^ or C,.^ ^'iHO'I ^'efer to a branched or unbranched alkyl group having from one to six carbon atoms inclusive, such as methyl, ethyl, I-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methy]-2-propyI, 2,2-dimethyM-etfayI and 2-methyl~l-prop34. SimilarlVj allcenyl and alkynyl, respectively, designate such groups having from hvo to six carbon atoms, including one double bond and tiiple bond respectively, such as etlienyl, propenyl, buten}'-!, eth\niyh propynyl, and hvtynyl The term ar>d refers to a mono- or bicyclic carbocyclic ai'omatic group, such as phenyl and naphthyL in particular phenyl. The tenn aralkyl refers to ar)d-allcyl, wherein aryl and alkyl are as defined above. Halogen means chloro, bromo or iodo. The compomrd of general Foimula 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 orgainc or inorganic acids may be used. Exemplary of such organic salts are those with maleic, liunaric, benzoic, ascorbic, succinic, oxalic, bismethylenesalicylic, methanesulfoiiic, etiianedisulfonic, acetic, propionic^ tartaric, salicylic, citric, gluconic, lactic, laialic, niandelic, ciimamic, citraconiCj aspartic, stearic, palmitic, itaconic, glycohc, p-aminobenzoic, glutamic, benzene sulfonic and theophylline acetic acids, as well as the 8-halotheophyllines, for example 8-bromotheophylhne. Exemplary of such inorgamc salts are those with hydrochloric, hydrobromic, sulfiiric, sulfamic, phosphoric and nitric acids. The acid addition salts of the compounds may be prepared by methods laiown 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 a3id cooling, or with an excess of the 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: Corn 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 ingi'edient 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 EUing 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 fmHier illustrated by the following examples. Example 1 5-Aminometh-yl'l -(3-dmethylamino-propyl)'l -(4-fliioro~phe7tyl)-l, S-dihydro-isobenzofuran 1 -(3 -Dimethylamino-propyl)-1 -(4-fluoro-phenyl)-3-oxo-1,3-dih3^dro-isobenziofuran-5-carbonitrile (5.4 g, 16.2 mmol) was dissolved in dry THF (5 mL) and diluted with dry ether (50 mL). Tins solution was added dropwise to a refluxing suspension of lithium aluminium hydride (2.5 g, 65 mmol) m dry ether (150 mL) over 10-15 mmutes, after wliich 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 solid cake was washed with THF. The combined filtrates were evaporated to give an oil. The oil was dissolved in toluene (200 mL) and was stirred with an aqueous solution of sulfiuic 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 ajtxinionia solution (25% w/v). The toluene was separated, and the aqueous 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): 5 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 mixtui-e of 5-aminomethyl-1 -(3-dimethylaniino-propyl)-1 -(4-fluoro-phenyl)-1,3-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 nmiol) was added, and the mixture was stirred for 3 h. Furflier 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 jjo-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): 5 1.354.50 (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-Fliioro~phenyl)-3-oxo-l, 3-dihydro~isobenzofuran-5'Carbox)dic acid methyl ester A stirred suspension of l-(4-fluoro-phenyl)-3-oxo-l,3-dihydro-isobenzofuran-5-carboxyhc 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 m 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 nhaap WAR RRnarated. dried over magnesium sulfate and evaporated to give the title compound as a white soUd (0.97 g, 92%). ^H NMR (d^-DMSO): 5 3.92 (s, 3H), 6.85 (s, IH), 7.26 (t, 2H), 7.42 (dd, 2H), 7.61 (d, IH), 8.31 (dd, IH), 836 (s, IH). Example 4 l-(4-Fluoro-phe7tyl)-3-oxo~l,3-dihydro~isobenzofuran-5-carboxylic acidamid^ 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 dissolved in toluene (15 niL) and was treated with a solution of ammonia in ether and a hea-s^ precipitate formed. The mixture was stirred overnight, diluted with toluene and aqueous ammonia solution, and filtered. The residue was dried to give the title compound as a white sohd (0.80 g, 80%). ^HNMR (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-L3-dihydro-isobenzofura7i-5-carbonit}'ile A suspension of l-(4-fluoro-phenyl)-3-oxo-l,3-dihydro-isobenzofiuan-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 EPA (100 mL). On cooling, crystals of the title compound was formed. Yield: 7.8 g (62%). 'HNMR (d'-DMSO): 5 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-hydroxymethyl-l-(4-fluoro-phenyl)-l,3-dihydro-isobenzofaran (2 g, 8.2 mmol) in toluene (20 niL) was heated until the sohd 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): 5 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). Example 7 5-Aminomethyl-I-(4-Fluoro-phenyl)~l,3-dihydro-isobenzofura7i A suspension of 5-bromomethyl-l-(4-fluoro-pheiiyl)-l,3- -33 °C for 2y2 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 annnomum hydroxide solution (25% w/v), and was extracted with toluene. The toluene extracts were dried over anhydi'ous magnesium sulfate and evaporated to give the title compound as a yellow-orange oil (0.63 g, 40%). ^H NMR (d^-DMSO): S 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, lH),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-isobenzofliran (0.5 g, 1.5 mmol) in dichloromethane (10 mL) was added an aqueous solution of potassium bisulfate and sodium hydroxide (19 mL; 0.2 M in K2S20g, 3.8 mmol; 0.4 M inNaOH, 7.6 mmol), followed by an aqueous solution of nickel sulfate (1.5 roL, 40 mM, 61 \|a.mol). 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 anrnionia 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 fi:ee 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-carboxylic acid Zinlc (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 gi-ams. 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: L A method for the preparation of a compound of Formula IV comprising activating the alcohol of Formula VIII by a substituted sulphonate or converting the alcohol into a benzylic halide or another activated derivative, followed by aminolysis to form the compound of Formula IV 2. The method of Claim 1, wherein the intermediate of Formula VIII is prepared by reacting the compound of Formula VII with a reducing agent followed by treatment with acid or another dehydrating agent to perform ring closure 3. The method of Claim 2, wherein the intermediate of Formula VII is prepared by alkylating the compound of Formula VI optionally by stepwise alkylation. 4. The method of Claim 3, wherein the intermediate of Formula VI is prepared by reacting the compound of Formula V with an alcohol R-OH in the presence of a dehydrating agent. 5. The method of Claim 4 wherein the intermediate of Formula V is prepared by a ring closure reaction of a compound of Formula XIII with a suitable reducing agent. 6. The method of Claim 5, wherein the reducing agent is Zn in acid, preferably acetic acid.

Full Text

Method for the Preparation of Citalopram
The present invention relates to a method for the preparation of the well-known antidepressant drug citalopram, l-[3-(dimethylamino)propyl]-l-(4-fluorophenyl)-l,3- Background of the Invention
Citalopram is a well-known antidepressant drug that has now been on the market for some years and has the following structure:

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 Pr-og. Neuro-Psychopharmacol & Biol Psychiat 1982, (5, 277-295 and A. Gravem, Acta Psychiati: 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-isobenzoforancarbonitrile is reacted with 3-(N,N-diinethylamino)propyl-chloride in the presence of methylsulfinyhnethide as condensing agent. The starting material was prepared firom 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:

in the presence of a dehydrating agent and subsequent exchange of the 5-bromo group with cuprous cyanide. The starting material of Formula II is obtained jfrom 5-bromophthalide by two successive Grignard reactions, i.e. with 4-fluorophenyl magnesium chloride and N,N-dimethylaminopropyl magnesium chloride, respectively.
A new and surprising method and an intermediate for the preparation of citalopram were described in US Patent No 4,650,884, according to which an interaiediate of the formula

is subjected to a ring closure reaction by dehydration with strong sulfuric acid in order to obtain citalopram. The intermediate of Formula III was prepared from 5-cyanophthalide by two successive Grignard reactions, i.e. with 4-fluorophenyl magnesium halogenide and N,N-dimethylaminopropyl magnesium halogenide, respectively.
Further 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-dihydroisobenzofiiran derivative to the corresponding 5-cyano compound, i.e. citalopram. International patent appHcation No. WO 98019511 discloses a process for the manufacture of citalopram wherein a (4-substituted-2-hydroxyinethylphenyl-(4-fluorophenyl)methanol compound 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 iMividual 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 HI 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.
Summary of the invention
Accordingly, the present invention relates to a novel metliod for the preparation of citalopram comprising reaction of a compound of Formula TV

with an appropriate oxidising agent such as copper(I) and O2; or NiS04 and KsS^Og to afford citalopram

which is isolated as the base or a pharmaceutically acceptable salt thereof
hi another aspect, the invention relates to methods for preparing the intermediates of Formula IV.
In yet another aspect, the present invention relates to an antidepressant pharmaceutical composition comprising citalopram as the base or any convenient salt thereof / manufactured by the process of the invention.

Furthermore, according to the invention, the compounds of Formula IV may be prepared by different methods.
One of these methods includes the following steps:

6-carboxy-3-(4-fluorophenyl)phthalide is reacted with an alcohol, R-OH, wherein R is preferably lower alkyl, most preferably Me, in the presence of a dehydrating agent, preferably SOCU.
The resulting compound of Formula VI is alkylated with

wherein X is a lea\dng gi*oup in the presence of a suitable base. X is preferably halogen or sulphonate.
Optionally, the alkylating reaction is a stepwise alkylation. In this case, the resulting compoimd of Formula VI is alkylated with a compound having the formula

wherein X' is a suitable leaving group and R' is -CHs-O-Pg, -CH2-NPgiPg2, -CO-N(CH3)o. -CH(OR^)(OR'), -C(OR')(OR')(OR') or -COOR^ wherein Pg is a protection group for an alcohol group, Pg^ and Pg2 are protection groups for an amino

group, R' and R^ are alkyl groups or R* and R^ together form a chain of 2 to 4 carbon atoms and R^ R\ R^ and R^ are allcyl, alkenyl, alkynyl, aryl or aralkyl;
to form a compound of Formula XVIII

wherein R' is as defined above; followed by conversion of the group R' to a dimethylaminomethyl group.
The resulting compound of Formula VII is reacted with a reducing agent such as LiAlH4, Red-Al, AIH3 or activated forms of NaBH4, e.g. NaBEt, Me2S04; NaBH4,1.; NaBH4, BF3. EtjO; or B2H6; followed by treatment with acid or another dehydrating agent to perform ring closure to form tlie compound of Formula VHI.
The alcohol of Formula Vin is conveniently activated by tosylchloride or mesylchloride to form the corresponding substituted sulphonate; or the alcohol is converted into the corresponding benzyhc hahde. This conversion is preferably carried out with SOBrs or SOCI2.
The corresponding sulphonate or haiide is either converted directly to the compound of
Fomiula FV by reaction with liquid ammonia;
or by a reaction with a metal salt of phthalimide, preferably potassium phthalamide
followed by treatment with NH^NH, or by treatment with an amine in an alcohol, i.e.
R^NH2/R^-0H, wherein R^ and R^ are lower allcyl, 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 LiAIH4 or NaBH4 or
an activated form of it.
Another method for preparing the compound of Formula IV includes the following steps:

6-carboxy-3-(4-fluorophenyl)phthalide is conveniently reacted with a dehydrating agent such as thionylchloride, followed by aminolysis of the resulting activated acid derivative.
The resulting compound of Formula IX 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 alkylation described above.
The resulting compound of Formula X is reacted with a reducing agent such as LiAlH^, Red-Al, AlHs or activated fonns of NaBH^, e.g. NaBH4, Me2S04; NaBH4, I.; NaBH^, BF3.Et20; or BsH^; followed by treatment with acid or another dehydrating agent to perform ring closure to form the compound of Formula IV.
According to a third method for preparing the compound of Formula TV, the corresponding 6-cyano substituted derivative of 6-carboxy-3-(4-fiuorophenyl)phthalide is prepared.
n n n
Th^ carboxy derivative is either reacted with SOCI2 followed by treatment with ammonia
and finally a dehydrating agent such as SOCI2 to prepare the cyano derivative of Formula
XI;
or reacted with an alcohol R-OH in the presence of acid followed by ti-eatment with
ammonia and finally reacted with SOCI2; or reacted in a one-pot process such as with

S02(NH2)25 SOCl. and sulfolane, or with ?err-butylainine, a dehydrating agent such as
POCI3 and a suitable solvent, such as toluene.
The resulting compound of Formula XI 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 alkylation described above.
The resulting compound of Formula XII is reacted with a reducing agent such as LiAlH4, Red-Al, AIH3 or activated forms of NaBH4, e.g. NaBH^, Me2S04; NaBH4, I,; NaBH4, BF3.Et20; or B2H6; followed by treatment with acid to perform ring closure to form the compound of Formula IV.
Other reaction conditions, solvents, etc. for the reactions described above ai-e conventional conditions for such reactions and may easily be determined by a person sldlled in the art.
In another aspect, the present invention provides the novel intermediate of Formula V.
In a further aspect, the invention relates to methods for preparing the intermediate of Formula V.
One stepwise process for preparing the intermediate of Formula V is illustrated below:

m-xylene and p-fluorobenzoyl chloride, which are commercially available compounds are reacted in the presence of AICI3 to afford the compound of Fommla XIV. Tliis compound is oxidised wth permanganate, preferably KMn04 or NaMn04, giving the resulting compound of Formula XIII, which is finally reacted conveniently with Zn in acid, preferably acetic acid.

Alternatively, the compound of Formula IV is prepared from the compound of Formula Xin by the following stepwise process:

The compound of Formula XIII is reacted with a reducing agent such as LiAlH4, Red-Al, AIH3 or activated forms of NaBH4, e.g. NaBH^, Me^SO,; NaBH4, I^; NaBH,, BFs.EtoO; or BsH^; followed by treatment with acid to perform ring closure to form the compound of
Formula XV.
The alcohol of Formula XV is conveniently activated by tosylchloride or mesylchloride to form the corresponding substituted sulphonate; or the alcohol is converted into the corresponding benzylic hahde. This conversion is preferably carried out with SOBr2 or SOCl..
The corresponding sulphonate or hahde is either converted directly to the compound of
Formula XVII by reaction with Uquid ammonia;
or by a reaction with a metal salt of phthaUmide, preferably potassium phthalamide,
followed by treatment with NH2NH2 or by treatment with an amine in an alcohol, i.e.
R^NH^/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 IvWj, M preferably being Na or K; followed by ti-eatn^ent
with a reducing agent such as Pd/C and Hj or a hydride source such as LiAlH4 or NaBH4 or
an activated form thereof
The resulting compound of Formula XVn 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 analogoiis to the stepwise allcylation 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 perfomied before the alkylation.
Tlxroiighont the specification , the tenns lower allc}^ or C,.^ ^'iHO'I ^'efer to a
branched or unbranched alkyl group having from one to six carbon atoms inclusive, such as methyl, ethyl, I-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methy]-2-propyI, 2,2-dimethyM-etfayI and 2-methyl~l-prop34.
SimilarlVj allcenyl and alkynyl, respectively, designate such groups having from hvo to six carbon atoms, including one double bond and tiiple bond respectively, such as etlienyl, propenyl, buten}'-!, eth\niyh propynyl, and hvtynyl
The term ar>d refers to a mono- or bicyclic carbocyclic ai'omatic group, such as phenyl and naphthyL in particular phenyl.
The tenn aralkyl refers to ar)d-allcyl, wherein aryl and alkyl are as defined above.
Halogen means chloro, bromo or iodo.
The compomrd of general Foimula 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 orgainc or inorganic acids may be used. Exemplary of such organic salts are those with maleic, liunaric, benzoic, ascorbic, succinic, oxalic, bismethylenesalicylic, methanesulfoiiic, etiianedisulfonic, acetic, propionic^ tartaric, salicylic, citric, gluconic, lactic, laialic, niandelic, ciimamic, citraconiCj aspartic, stearic, palmitic, itaconic, glycohc, p-aminobenzoic, glutamic, benzene sulfonic and theophylline acetic acids, as well as the 8-halotheophyllines, for example 8-bromotheophylhne. Exemplary of such inorgamc salts are those with hydrochloric, hydrobromic, sulfiiric, sulfamic, phosphoric and nitric acids.
The acid addition salts of the compounds may be prepared by methods laiown 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 a3id

cooling, or with an excess of the 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: Corn 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 ingi'edient 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 EUing 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 fmHier illustrated by the following examples.
Example 1
5-Aminometh-yl'l -(3-dmethylamino-propyl)'l -(4-fliioro~phe7tyl)-l, S-dihydro-isobenzofuran
1 -(3 -Dimethylamino-propyl)-1 -(4-fluoro-phenyl)-3-oxo-1,3-dih3^dro-isobenziofuran-5-carbonitrile (5.4 g, 16.2 mmol) was dissolved in dry THF (5 mL) and diluted with dry ether (50 mL). Tins solution was added dropwise to a refluxing suspension of lithium aluminium hydride (2.5 g, 65 mmol) m dry ether (150 mL) over 10-15 mmutes, after wliich 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 solid cake was washed with THF. The combined filtrates were evaporated to give an oil. The oil was dissolved in toluene (200 mL) and was stirred with an aqueous solution of sulfiuic 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 ajtxinionia solution (25% w/v). The toluene was separated, and the aqueous 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): 5 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 mixtui-e of 5-aminomethyl-1 -(3-dimethylaniino-propyl)-1 -(4-fluoro-phenyl)-1,3-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 nmiol) was added, and the mixture was stirred for 3 h. Furflier 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 jjo-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): 5 1.354.50 (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-Fliioro~phenyl)-3-oxo-l, 3-dihydro~isobenzofuran-5'Carbox)dic acid methyl ester A stirred suspension of l-(4-fluoro-phenyl)-3-oxo-l,3-dihydro-isobenzofuran-5-carboxyhc 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 m 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 nhaap WAR RRnarated. dried over magnesium sulfate and

evaporated to give the title compound as a white soUd (0.97 g, 92%). ^H NMR (d^-DMSO): 5 3.92 (s, 3H), 6.85 (s, IH), 7.26 (t, 2H), 7.42 (dd, 2H), 7.61 (d, IH), 8.31 (dd, IH), 836 (s, IH).
Example 4
l-(4-Fluoro-phe7tyl)-3-oxo~l,3-dihydro~isobenzofuran-5-carboxylic acidamid^ 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 dissolved in toluene (15 niL) and was treated with a solution of ammonia in ether and a hea-s^ precipitate formed. The mixture was stirred overnight, diluted with toluene and aqueous ammonia solution, and filtered. The residue was dried to give the title compound as a white sohd (0.80 g,
80%). ^HNMR (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-L3-dihydro-isobenzofura7i-5-carbonit}'ile A suspension of l-(4-fluoro-phenyl)-3-oxo-l,3-dihydro-isobenzofiu*an-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 EPA (100 mL). On cooling, crystals of the title compound was formed. Yield: 7.8 g
(62%). 'HNMR (d'-DMSO): 5 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-hydroxymethyl-l-(4-fluoro-phenyl)-l,3-dihydro-isobenzofaran (2 g, 8.2 mmol) in toluene (20 niL) was heated until the sohd 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): 5 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).

Example 7
5-Aminomethyl-I-(4-Fluoro-phenyl)~l,3-dihydro-isobenzofura7i
A suspension of 5-bromomethyl-l-(4-fluoro-pheiiyl)-l,3- -33 °C for 2y2 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 annnomum hydroxide solution (25% w/v), and was extracted with toluene. The toluene extracts were dried over anhydi'ous magnesium sulfate and evaporated to give
the title compound as a yellow-orange oil (0.63 g, 40%). ^H NMR (d^-DMSO): S 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, lH),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-isobenzofliran (0.5 g, 1.5 mmol) in dichloromethane (10 mL) was added an aqueous solution of potassium bisulfate and sodium hydroxide (19 mL; 0.2 M in K2S20g, 3.8 mmol; 0.4 M inNaOH, 7.6 mmol), followed by an aqueous solution of nickel sulfate
(1.5 roL, 40 mM, 61 |a.mol). 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 anrnionia 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 fi:ee 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-carboxylic acid
Zinlc (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 gi-ams. 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:
L A method for the preparation of a compound of Formula IV comprising activating the alcohol of Formula VIII

by a substituted sulphonate or converting the alcohol into a benzylic halide or another activated derivative, followed by aminolysis to form the compound of Formula IV

2. The method of Claim 1, wherein the intermediate of Formula VIII is prepared by reacting the compound of Formula VII

with a reducing agent followed by treatment with acid or another dehydrating agent to perform ring closure
3. The method of Claim 2, wherein the intermediate of Formula VII is prepared by
alkylating the compound of Formula VI

optionally by stepwise alkylation.
4. The method of Claim 3, wherein the intermediate of Formula VI is prepared by
reacting the compound of Formula V

with an alcohol R-OH in the presence of a dehydrating agent.
5. The method of Claim 4 wherein the intermediate of Formula V is prepared by a
ring closure reaction of a compound of Formula XIII

with a suitable reducing agent.
6. The method of Claim 5, wherein the reducing agent is Zn in acid, preferably acetic acid.

Documents:

1009-che-2004-abstract.pdf

1009-che-2004-claims filed.pdf

1009-che-2004-claims grand.pdf

1009-che-2004-correspondnece-others.pdf

1009-che-2004-correspondnece-po.pdf

1009-che-2004-description(complete) filed.pdf

1009-che-2004-description(complete) grand.pdf

1009-che-2004-form 1.pdf

1009-che-2004-form 18.pdf

1009-che-2004-form 26.pdf

1009-che-2004-form 3.pdf

1009-che-2004-form 5.pdf

1009.jpg

« Previous Patent

Next Patent »

Patent Number

210129

Indian Patent Application Number

1009/CHE/2004

PG Journal Number

50/2007

Publication Date

14-Dec-2007

Grant Date

21-Sep-2007

Date of Filing

30-Sep-2004

Name of Patentee

M/S. H.LUNDBECK A/S

Applicant Address

9,OTTILIVEJ,DK-2500 VALBY-COPENHAGEN

Inventors:

#	Inventor's Name	Inventor's Address
1	PETERSEN HANS	9,OTTILIVEJ,DK-2500

PCT International Classification Number

C 07 D 307/87

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	PA20000078	2000-05-12	Denmark

A METHOD FOR THE PREPARATION OF 5 - AMINOMETHYL -1 -(3 - DIMETHLYAMINO - PROPYL) - 1 - (4 - FLUORO - PHENYL) -1,3 - DIHYDROISOBENZOFURAN

Documents:

Inventors:

PCT Conventions: