MXPA99011854A - Method for the preparation of citalopram - Google Patents

Abstract

A method for the preparation of citalopram comprising the steps of reacting a compound of Formula (IV) wherein R1 is C1-6 alkyl and X is O or NH, successively with a Grignard reagent of 4-halogen-fluorophenyl and a Grignard reagent of 3-halogen-N,N-dimethyl-propylamine, respectively, effecting ringclosure of the resulting compound of Formula (V) wherein R1 and X are as defined above, and converting the resulting 1,3-dihydroisobenzofuran compound to the corresponding 5-cyano derivative, i.e. citalopram.

Description

METHOD FOR THE PREPARATION OF CITALOPRAM DESCRIPTION OF THE INVENTION The present invention relates to a method for the preparation of the known drug an ti es es va citalopram, l- [3- (dimethylamino) -propyl] -1- (4-fluorfenyl) -1,3 -dihidro-5 - is oben z of ur ancarboni tri 1 oe intermediaries used in the method.

BACKGROUND OF THE INVENTION Citalopram is a well-known and widespread drug that has been commercialized for some years and has the following structure: Formula I It is a centrally active inhibitor of serotonin reuptake (5-hydroxytryptamine, 5-HT), therefore it has anti-deprivation activities. The anti-depot activity of the compound has been reported in several publications, for example, J. Hyttel, Prog. Neur o-P s and chopha rma c ol, & Biol. Psychiat., 1982, 6, 277-295 and A. gravem, Acta Psychiatr. Scand., 1987, 75, 478-486. The compound has further been disclosed to show the effects in the treatment of dementia and vascular disorders, European Patent No. A-474580. Citalopram was first disclosed in DE 2,657,271 corresponding to US Patent No. 4,136,193. This patent publication describes the preparation of citalopram and also points out a method that can be used to prepare citalopram. According to the process described, the corresponding 1 - (4 - f 1 uo rf eni 1) - 1, 3 -dihi dr o - 5 - is oben zo fur ancarboni tri 1 or with 3- (N, N -di eti 1 amino) pr op i 1 - cl orur or in the presence of me ti 1 its 1 as a condensing agent. The starting material was prepared from the corresponding 5-bromo derivative by reaction with cuprous cyanide. According to the method, which is only delineated in general terms, citalopram can be obtained by ring closure of the compound: Formula II in the presence of a shidr agent and subsequent exchange of the 5-bromine group with cuprous cyanide. The starting material of Formula II is obtained from 5-bromine-1-one by two successive Grignard reactions, ie, with 4-f-1-chloro-phenylmagnesium chloride and N, N-dimethylaminopropylmagnesium chloride, respectively. A new and surprising method and an intermediary for the preparation of citalopram is described in US Pat. No. 4,650,884, according to which an intermediary of the F or rmu l a Formula III It is subject to a ring closure reaction by hydration with strong sulfuric acid in order to obtain citalopram. The intermediate of Formula III was prepared from 5-cyanalpha lure or by two successive Grignard reactions, that is, with halogenide of 4-f luor f eni lmagne sioy halogenide of N, N-dime ti 1 aminop r op i Ima gne sio, respectively. Finally, methods for preparing the individual enantiomers of citalopram are disclosed in US Pat. No. 4,943,590, which also shows that the ring closure of the intermediate of Formula III can be carried out under basic conditions. It has surprisingly been found that citalopram can be manufactured by a favorable and safe procedure using convenient starting materials.

Summary of the Invention Accordingly, the present invention relates to a novel method for the preparation of citalopram comprising the steps of reacting a compound of Formula IV Formula IV which is characterized in that R is alkyl C? ~ C? and X is O or NH, successively with a Grignard reagent of 4-halogen-f1 or f, so that a compound of Formula IVa is obtained Formula IVa which is characterized in that R1 and X are as defined above, and a Grignard reagent of 3-hal or non-N, N-dimime ti 1-pr op i 1 amine, effect ring closure of the resulting compound of the Formula V Formula V characterized in that R and X are as defined above, and converting the compound Formula VI where R and X are as defined above, for the cor porate derived from 5-cyano, ie, citalopram, which is separated as a base or pharmaceutically acceptable salt thereof. In another aspect, the present invention provides novel intermediates of Formula IV and V, respectively. In another aspect, the present invention relates to novel intermediates of Formula VI. In another aspect, the present invention relates to. a depot-containing pharmaceutical composition comprising the citalopram manufactured by the process of the invention. In the specification and in the Claims, C? -C6 alkyl refers to a branched or unbranched alkyl group having from one to six carbon atoms inclusive, such as methyl, ethyl, 1-propyl, 2-propyl, 1- butyl, 2-butyl, 2-methyl-1-propyl-1, 2, 2-dimethyl-1- 1 -eti-1, and 2-methyl-1-propyl. The 4-halogen-fluorophenyl Grignard reagents that can be used in the first step are the magnesium halides, such as chloride, bromide or iodide. Magnesium bromide is preferably used. The Grignard reagents of 3-halogen-N, N-dime t-ylpr or i-amine which can be used are the magnesium halides, such as chloride, bromide or iodide, preferably magnesium bromide. The I termediario of Formula IVa may or may not be separated. Preferably, the two reactions develop successively without separation of the intermediate. The ring closure of the compound of Formula V is effected by an acid or via a labi-1 ester with a base. Closure of acidic rings is carried out by an inorganic acid, such as sulfuric or phosphoric acid, or an organic acid, such as the acids me ti 1 su 1 f óni co, pt ol uens ul f óni co or acid trif luor ac ti co. The basic ring closure is developed via a labile ester, such as methane sulfonyl esters, p-toluene sulfonyl, 10-to-1 canf or sulfonyl, or triforpholipid 1 or with the addition of a base such as triethylamine, dime ti 1 ani 1 i na, pyridine, etc. The reaction is carried out in an inert solvent, preferably with cooling, in particular at about 0 ° C and is preferably carried out by a pot method, that is to say with simultaneous theri fi cation and addition of the base. When X is O, the conversion of the group R1-X-CO- into cyano is preferably carried out via the corresponding amide or rupture, which is then converted to the cyano group in the same manner as compounds of Formula VI which is characterized in that X is NH. The reaction of R1-X-CO- (X = 0) to amide is carried out by hydrolysis with an acid or a base and subsequent conversion into acid chloride and amidation by reaction with ammonia or an alkylamine, preferably t -bu t i 1 amine. Acid hydrolysis can be carried out by use of any suitable acid, such as HBr, HCl, HBr / acetic acid. The basic hydrolysis can be carried out by any suitable base, such as K2C03, NaOH, KOH, etc. The conversion to amide can also be obtained by reaction of the ester (X = 0) with ammonia or an alkylamine under pressure and heat. The amide is converted to the cyano group by conventional nitrile synthesis. Therefore, the resulting amide or the amide of Formula V where X is NH, is preferably converted to the cyano compound, ie citalopram, by reaction with a dehydrating agent, more preferably thionyl, chloride, phosphorus pentachloride, etc. . Alternatively, an ester, that is, a compound of Formula VI, which is characterized in that X is O, can be hydrolyzed and then reacted with isocyanate of chlorophyl or or to form the nitrile. The process of the invention can be carried out with or without separation of the intermediates. The process of the invention can be further carried out to prepare the active (S) enantiomer of citalopram. Then, the compound of Formula V is separated into optically active enantiomers, by a procedure analogous to that described in US Patent No. 4,943,590, whereby the (S) -enantiomer of the compound of Formula V is obtained which is used in the ring closing reaction in step c). Accordingly, the individual enantiomers of the intermediates of Formula V and VI, respectively, are included in the Formulas. Other reaction conditions, solvents, etc., are conventional conditions for such reactions and can be readily determined by those skilled in the art. The starting materials of Formula IV are commercially available or can be prepared from 5-caboxylate to the ur or by reaction with thionyl chloride and then C 1 -C 6 alkanol or alkylamine. Ci-Cß 5 - ca rb or i f t a 1 u r o is commercially available and can be prepared by well-known procedures (Tirouflet, J; Bull. Soc. Sci. Bretagne 26, 1959, 35). In one embodiment of the invention X is 0, and R1 is ethyl, propyl, or butyl, preferably ethyl, 2-propyl or t-butyl. In another embodiment of the invention X is NH and R is ethyl, propyl or butyl, preferably ethyl, 2-propyl or t-butyl, more preferably t-butyl. The compound of the general Formula I can be used as the free base or as a pharmacologically acceptable acid addition salt thereof. As acid addition salts, said salts formed with organic or inorganic acids can be used. Examples of such organic salts are those with the following acids: maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bis-me-thi-ens al-i-1, co-morphine, et al. f oni co, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, mellic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-ami n enzoic, glutamic, benzene sulfuric, and theophylline acetic, as well as the 8 - ha 1 oteofi 1 ino s, for example, 8 -br orno teofi 1 ino. Examples of such inorganic salts are those with hydrochloric, hydroxy, sulfuric, sulfamic, phosphoric and nitric acids. The acid addition salts of the compounds can 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 removal of the salt by concentration and cooling, or with an excess of the acid in a solvent immiscible with water. water, such as ethyl ether, ethyl acetate or dichloromethane, with the salt that separates spontaneously. The pharmaceutical compositions of the invention can be administered in any suitable manner and in suitable form, for example, orally by tablets, capsules, powders or syrups or in parenteral form by sterile solutions common for injections. Pharmaceutical formulations of the V-0 invention can be prepared by methods conventional in the art. For example, the tablets can be prepared by mixing the active ingredient with common adjuvants and / or diluents and subsequently compressing the mixture in a conventional machine to make tablets. Examples of adjuvants or diluents comprise; corn starch, potato starch, talcum, magnesium stearate, gelatin, lactose, gums and the like. Any other adjuvant or coloring additive, The flavorant, preservative, etc. may be used as long as they are compatible with the active ingredients. Solutions for injections can be prepared with a solution of the active ingredient and possible additives in a part of the solvent for injection, preferably sterile water, adjusting the solution to the desired volume, sterilizing the solution and filling in suitable ampoules or flasks. Any conventionally suitable additive used in the art can be added, such as tonicity agents, preservatives, antioxydants, etc.

E emplos Example 1 5-tert. bu t ox i ca rbon i 1 f t 1 u ro Suspend 5-ca r ox i f t a 1 ur (100 g-, 0.56 mol) in pyridine (1,200 ml); p-t chloride or 1-olonic acid (211 g, 1.12 mol) is added and the mixture is stirred for 30 minutes at room temperature. Tert-butanol (54 g, 0.73 mol) is added and the reaction mixture is allowed to stand at room temperature with efficient stirring for 3 days. The clear solution is poured into ice water and the precipitated crystals are filtered. The product is reacted with 2-propanol (500 ml.). Yield: 123 g., 94%. Decomposition temperature: 151, 5 ° C.

EXAMPLE 2 5- (2-prop i 1 oxycarbonyl) phthalide Method A): 5-C rboxi f t the ur (36 g, 0.2 mol) is suspended in thionyl chloride (100 ml). DMF (1.5 ml.) Is added and the mixture is refluxed for one hour. Toluene (200 ml.) Is added and the solvents are evaporated in vacuo. 2-Propanol (200 ml.) Is added and the mixture is refluxed for 30 minutes. After cooling to 0 ° C the crystals are filtered and washed with cold 2-propanol (50 ml.). Yield: 38 g. 87%. Decomposition temperature: 144 ° C. Method B): Suspend 5-e t oxi ca rboni 1 f t a 1 ur (52 g, 0.25 mol) in 2-propanol (1000 ml). Ti (iPrO) 4 (38 g, 0.14 mol) is added and the mixture refluxes for 3 hours. The reaction mixture is cooled to 0 ° C and the crystals are filtered and washed with cold 2-propanol (70 ml.). Yield 47 g., 85%. Decomposition temperature: 144 ° C.

Example 3 5-tert-butylca rb my Iftalide 5-C arbox i f t a 1 ur (36 g / 0.2 mol) is suspended in thionyl chloride (100 ml). It is added DMF (1.5 ml.) And the mixture is refluxed for one hour. Toluene (200 ml.) Is added and the solvents are evaporated in vacuo. The residue is dissolved in THF (200 ml.) And added to a solution of tert-butylamine (31 g., 0.42 mol.) In THF (200 ml.) At 5 ° C. The mixture can be heated to room temperature and stirred overnight. Then, the reaction is poured into ice water (400 ml.) And the precipitated crystals are filtered and washed with water (100 ml.). Yield: 41 g., 87%. Decomposition temperature: 189, 5 ° C.

EXAMPLE 4 Tert-butyl 1- (3-dimethyl-ylaminopr-opyl) -1- (4-fl uo-ffen-1) -1,3-dihydroisobenzofuran-5-ca boxyl-oxalate A solution of 4-bromide is added f 1 uo rf enylmagnesium, prepared from 4-f luorbr or obencene (31.5 g., 0.18 mol.) and magnesium (5.1 g., 0.21 mol.) in anhydrous THF ( 150 ml.), Dropwise to a suspension of 5-tert-butyloxy carbonyl phthalide (35.1 g., 0.15 mol.) In anhydrous THF (150 ml.). The temperature is kept below 5 ° C. After completing the addition, the reaction mixture is stirred for 3 hours at room temperature. A second Grignard solution is prepared from 3-dime thi 1 aminop r or i or 1 (21.9 g, 0.18 mol) and magnesium chloride (5.1 g, 0.21 mol). in anhydrous THF (150 ml.) and added to the reaction mixture. The temperature is kept below 10 ° C during the addition. The reaction is allowed to stand overnight at room temperature while stirring. The reaction mixture is poured into ice-cold water (300 ml.) And a saturated solution of ammonium chloride (100 ml.). THF is evaporated in vacuo. Ethyl acetate (300 mL) ^ H-0 is added and the organic phase is separated and washed with water (2 x 100 mL) and brine (50 mL). The organic phase is extracted with 2M HCl (2 x 100 ml.). 4 M NaOH (100 mL) is added to the aqueous phase to give a final pH of 9 or greater. The water layer is extracted with acetate Ethyl (400 ml.) And the organic phase is washed with water (100 ml.), Brine (50 ml.) And dried with MgSO.sub.0 (20 g.). Triethylamine (45.5 g, 0.45 mol) is added to the organic phase and the solution is cooled to 5 ° C. Methanesulfonyl chloride (19.5 g, 0.17 mol) in ethyl acetate (100 ml) is added dropwise and after the addition, the reaction mixture is allowed to stand for one hour with stirring. The reaction mixture is washed with 0.1 M NaOH (2 x 100 mi. ) and the organic phase is dried (MgSO4, 10 g.) and the solvent is evaporated in vacuo. The material thus obtained (15 grams of the compound titled as its free base) is dissolved in acetone (120 ml.) And treated with anhydrous oxalic acid (13.5 g., 0.15 mol.) Dissolved in acetone (120 ml. .). The mixture is allowed to stand at room temperature overnight and the precipitated oxalate is filtered. Yield: 34 g., 43%. Decomposition temperature: 172 ° C. 1 H NMR (DMS0-d 6, 500 MHz): 1.43 (1H, m); 1.47-1.57 (10H, s + m); 2.21 (2H, t, J = 10HZ); 2.63 (6H, s); 2.97 (2H, t, J = 10 Hz); 5,14 (1H, d, J = 12.5 Hz), 5.22 (1H d, J = 12.5 Hz), 7.16 (2H, t, J = 8.5 Hz); 7.56 (2H, dt, J = 1, 2 Hz J = 8.5 Hz); 7.60 (1H, d, J = 8.5 Hz); 7.82 (1H, s); 8.86 (1H, d, J = 8.5 Hz). Analysis calculated for C 26 H 32 N F F 07 07; C, 63.78: H, 6.60: N, 2.86. Found C, 63.95: H, 6.51: N, 3.14. Similarly, the following compounds were prepared from 5 - (2-pr opyloxycarbonyl 1) - phthalide and from 5 - (et oxy ca rboni 1) ft to ur or, respectively: 2-propyl 1-oxalate - (3-dimethyl-ylpropyl) -1- (4-fluoro-phenyl) -1,3-dihydroisobenzofuran-5-ca-rboxi lato Yield 20 g. , (42%) from acetone. Decomposition temperature: 79 ° C. H1 NMR (DMSO-de, 250 MHz); 1.40 (6H, d, J = 6.5 Hz); 1.40-1.60 (2H, m); 2, 20 (2H, t, J = 10Hz); 2, 63 (6H, s); 2.98 (2H, t, J = 10 Hz), 5.12 (1H, heptet, J = 6.5 Hz); 5, 15 (1H, d, J = 12, 5 Hz); 5, 24 (1H, d, J = 12, 5 Hz), 7, 18 (2H, t, J = 8.5 Hz); 7, 57 (2H, dt, J = 1, 2 Hz J = 8, 5Hz); 7, 63 (1H, d, J = 8.5 Hz); 7, 88 (1H, s); 8, 90 (1H, d, J = 8, 5 Hz). Analysis calculated for C23H28N1 F1O3, 1, 1 (COOH) 2; C, 62, 41: H, 6, 27: H, 6, 27; N, 2, 90. Found C, 62, 41: H; 6, 34: N, 3, 21.

Oxalate of ethyl 1 - (3-dimethyl t i laminoprop i 1) -1- (4 -fl uo rfen il) -1,3-dihydro i s oben z o fur an-5-ca rboxi lato Yield 14,1 g. (30%) from acetone. Decomposition temperature: 148 ° C. H1 NMR (DMSO-d6, 500 MHz); 1.31 (3H, t, J = 7.5 Hz), 1.44 (1H, m); 1.55 (1H, m), 2.22 (2H, t, J = 10Hz); 2.64 (6H, s); 3.00 (2H, t, J = 10Hz); 4.39 (2 H, q, J = 7.5 Hz); 5.15 (1H, d, J = 12.5 Hz); 5.23 (1H, d, J = 12.5 Hz); 7.15 (2H, t, J = 8.5 Hz); 7.58 (2H, dt, J = 1.2 Hz J = 8.5 Hz); 7.65 (1H, d, J = 8.5 Hz); 7.89 (1H, s); 8.92 (1H, d, J = 8.5 Hz). Analysis calculated for C 26 H 32 F? 07, 1.5 H 2 O; C, 59, 00: H, 6, 40: N, 2, 86. Found C, 58, 99: H; , 93: N, 2, 92.

Example 5 Oxalate of 5 - (tert-but i 1 carbami 1) - 1 - (3-dimethylamin oprop i 1) - 1 - (4-fluorophenyl) -1,3-dihydric acid is added to the furnace. solution of bromide of 4-f 1 or f-magnesium, prepared from a mixture of 4-f-1-one-two-ene (42 g., 0.24 mol.) and magnesium (7 g., 0.29 g. mol.) in anhydrous THF (120 ml.), dropwise to a suspension of 5-tert-butylcarbamylcarbamide (23.3 g., 0.1 mol.) in anhydrous THF (120 ml.). The temperature is kept below 5 ° C. After completing the addition, the reaction mixture is stirred for three hours at room temperature. A second Grignard solution is prepared from a mixture of 3-dimethylaminopropyl chloride (14.6 g, 0.12 mol) and magnesium (3.4 g, 0.14 mol) in anhydrous THF ( 100 ml.), And added to the reaction mixture. The temperature is maintained below 10 ° C during the addition. The addition is allowed to stand overnight at room temperature with stirring. The reaction mixture is poured into ice water (250 ml.) And a saturated solution of ammonium chloride (100 ml.). The THF is evaporated in vacuo. Ethyl acetate (300 ml.) Is added and the organic phase is separated and washed with water (2 x 100 ml.) And brine (50 ml.). The organic phase is extracted with 2M HCl (2 x 100 ml.). To the aqueous phase 4M NaOH (100 ml.) Is added to give a final pH of 9 or greater. The water layer is extracted with ethyl acetate (400 ml.) And the organic phase is washed with water (100 ml.)Brine (50 ml.) and dry with MgSO.sub.4 (20 g.) - Triethylamine (45.5 g, 0.45 mol.) is added to the organic phase and the solution is cooled to 5 ° C. Methanesulfonyl chloride (19.5 g, 0.17 mol) in ethyl acetate (100 ml) is added dropwise and after addition, the reaction mixture is allowed to stand for one hour with stirring. The reaction mixture is washed with 0.1 M NaOH (2 x 100 ml.) And the organic phase is dried (MgSO.10 g.) And the solvent is evaporated in vacuo. The material thus obtained (15 grams of the compound titled as free base) is dissolved in acetone (100 ml) and treated with anhydrous oxalic acid (10 g, 0.11 mol) dissolved in acetone (100 ml). The mixture is allowed to stand at room temperature with stirring for 3 days and the precipitated oxalate is filtered. Yield: 7 g. 14% Decomposition temperature: 167 ° C. 1 R NMR (DMS0-d6, 500 Hz); 1.35 (9H, s), 1.37-1.58 (2H, m + m); 2.21 (2H, t, J = 10 Hz); 2.61 (6H, s); 2.96 (2H, t, J = 10Hz); 5.12 (1H, d, J = 12.5 Hz); 5.20 (1H, d, J = 12.5 Hz), 7.15 (2H, t, J = 8.5Hz); 7.52 (1H, d, J = 8.5Hz), 7.57 (2H, dt, J = 1, 3Hz J = 8.5 Hz); 7.67-7.75 (3H, s + br s + d, J = 8.5Hz). Analysis calculated for C26H32N? F? 07, C, 63.91: H, 6.82: N, 5.73. Found C, 63.53: H; 6.82: N, 5.81.

E xample 6 Oxalate of 1 - (3-dimetholaminoprop i 1) - 1 - (4-f 1 or phenyl) -1,3-dihyd or i s oben z or fur an - 5 - ca rbon itril Method A): Tert.butyl-1- (3-dimethylaminopropyl) -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carboxylate oxalate is dissolved. (20 g, 0.048 mol.) In acetic acid (100 ml.). HBr (20 ml., 33% in AcOH) is added and allowed to stand with stirring for 10 minutes. The solvents are extracted in vacuo and the residue coevaporated with toluene (100 ml). The residue is dissolved in toluene (80 ml.) And thionyl chloride (80 ml.). DMF (1 ml.) Is added and the mixture is allowed to reflux for one hour. The solvents are removed in vacuo and the residue is dissolved in ethyl acetate (100 ml.). NH 4 OH (100 mL, 25% in water) is added and ice (100 g) is added; then let stand with good agitation for 30 minutes. The organic phase is washed with water (50 ml.) And brine (20 ml.) And dried with MgSO.sub.0 (10 g.). The solvents are removed in vacuo and the residue is dissolved in thionyl chloride (40 ml.) And allowed to reflux for 2 hours. Toluene (100 ml.) Is added and the solvents are removed in vacuo. Toluene is added (100 mL) and the organic phase is washed with 2N NaOH. (100 mi.) And water (50 mi.). The solvents are removed in vacuo. The product thus obtained is purified by flash chromatography, which makes it possible to obtain the titled product as a free base in the form of an oil. The oxalic acid salt is crystallized from acetone. Yield: 9.0 g. (43%). Decomposition temperature: 156 ° C. 1 H NMR (DMSO-d 6, 500 MHz): 1.40 (1H, m); 1.50 (1H, m); 1.50 (1 H, m); 2.21 (2H, t, J = 10Hz); 2.61 (6H, s); 2.95 (2H, t, J = 10Hz); 5.15 (1H, d, J = 12.5 Hz); 5.22 (1H, d, J = 12.5 Hz); 7.17 (2H, t, J = 8.5 Hz); 7.58 (2H, dt, J = 1, 2Hz J = 8.5 Hz); 7.63 (1H, d, J = 8.5 Hz); 7.80 (1H, d, J = 8.5 Hz); 8.82 (1H, s). Analysis calculated for C 22 H 23 N 2 F 1 O 5; C, 63, 75: H, 6, 59: N, 6, 76. Found C, 63, 12: H; 6, 59: N, 6, 66.

Method B): 5- (tert-butylcarbamyl) -1- (3-dimethylaminopropyl) -1- (4-f-1-phenyl) -1,3-dihi dr oi s oben zof ur-oxalate (lg 0.002 mol.) is dissolved in thionyl chloride (10 ml.) and the mixture is refluxed for two hours. Toluene (10 ml.) Is added and the solvents are removed in vacuo. The residue is dissolved in ethyl acetate (15 mi.). NH40H (5 ml., 25% in water) and ice (5 g.) Are added and the phases are separated and separated. The organic phase is washed with water (10 ml.) And dried with MgSO.sub.4. The solvent is then extracted in vacuo.

The titled compound is crystallized from acetone. Yield: 0.66 g. 78%. Decomposition temperature: 156 ° C.

Claims (21)

1. A method for the preparation of citalopram comprising the steps of reacting a compound of Formula IV Formula IV which is characterized in that R1 is C alquilo-Cß alkyl and X is O or NH, successively with a Grignard reagent of 4-halogen-fl uor f or 1, whereby a compound of Formula IVa is obtained. Formula IVa which is characterized in that R1 and X are as defined above, and a Grlgnard reagent of 3 -ha 1 O-N, N-dime thi 1 -pr op i 1 amine, effecting the ring-closure of the resulting compound of Formula V Formula V which is characterized in that R and X are as defined previously, and converting the resulting compound of Formula VI Formula VI which is characterized in that R1 and X are as defined above, in the corresponding 5-cyano derivative, ie citalopram, which is separated as a base or as a pharmaceutically acceptable salt thereof.

2. The method of claim 1 characterized in that X is 0.

3. The method of claim 1 characterized in that X is NH.

4. The method of claim 2 or 3 characterized in that R1 is ethyl, propyl, or butyl, preferably ethyl, 2-propyl or t-butyl, more preferably t-butyl.

5. The method of claim 1-4, characterized in that the Grignard reagent used is a magnesium halide, preferably chloride, bromide or iodide.

6. The method of re-indication 5, which is characterized in that the Grignard reagent used in the first step is magnesium bromide salt.

7. The method of claim 5, characterized in that the Grignard reagent used in the second step is magnesium chloride.

8. The method of any of claims 1-6, characterized in that ring closure of the compound of Formula V, is effected by an acidic ring closure developed by an inorganic acid, such as a sulfuric or phosphoric acid, or a organic acid, such as acidic acid, acid or acid or acid trifluoric acid.

9. The method of any of claims 1-6, characterized in that ring closure of the compound of Formula V, is developed by a basic ring closure via 5 a labile ester referentially with simultaneous s i f i cation and base addition.

10. The method of claim 8, characterized in that the labile ester is ester ^ BLO methanesulfonyl, p-toluene sulfonyl, 10- to 1-camphor sulfonyl, t r i f 1 uorace t i 1, or trifluorose-tanosulfonyl, and the base is triethylamine, dimethoxylane or pyridine.

11. The method of the rei indications 2, which is characterized in that X is 0 and the conversion of the group R1 -X-Co- in cyano develops via the corresponding amide group.

12. The method of claim 10, characterized in that the reaction of R1-X-Co- to the amide is carried out by hydrolysis with an acid or a base, subsequent conversion into acid chloride and amidation by reaction with ammonia or a Alkylamine, preferably t-buyl-nama.

13. The method of claim 11, characterized in that the hydrolysis is carried out by use of a suitable acid, such as HBr, HCl, HBr / acetic acid.

14. The method of claim 11, characterized in that the hydrolysis is carried out by use of a suitable base preferably, K2C03, NaOH or KOH.

15. The method of claim 8, characterized in that the reaction of R1-X-CO to amide is carried out by reaction of the ester with ammonia or an alkylamine under pressure and heat.

16. The method of any of claims 9-14 characterized in that the amide is converted to the cyano group by reaction with a dehydrating agent, preferably thionyl chloride or phosphorus pentachloride.

17. A process of any of claims 1-15 characterized in that before being used in the ring closure reaction, the compound of Formula V is separated into optically active enantiomers, thus obtaining the (S) enantiomer.

18. An intermediary for the preparation of citalopram with Formula IVa. Formula IVa which is characterized in that R 'is Ci-C6 alkyl and X is O or NH.

19. An intermediary for the preparation of citalopram with Formula V Formula V which is characterized in that R 'is alkyl Cj.-C5 and X is O or NH.

20. An intermediary for the preparation of citalopram with Formula VI Formula VI which is characterized in that R1 is Ci-C6 alkyl and X is O or NH.

21. An antidepressant pharmaceutical composition comprising citalopram manufactured by the process of any of claims 1-16. p: H. LUNDBECK A / S