BG65271B1 - Method for the preparation of citalopram - Google Patents

Abstract

The invention relates to a method for the preparation of citalopram comprising reaction of a compound of formula wherein R is acyl, with 3-(N,N-dimethylamino)-propyl magnesium halide, to prepare citalopram.

Description

Technical field

The present invention relates to a process for the preparation of the known antidepressant drug citalopram, 1- [3- (dimethylamino) propyl] -1- (4-fluorophenyl) -1,3-dihydro-5 isobenzofurancarbonitrile.

BACKGROUND OF THE INVENTION

Citalopram is a well-known antidepressant drug that has been on the market for several years and has the following structural formula:

Formula I

It is a selective centrally acting serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor having antidepressant activity. The antidepressant activity of the compound has been reported in a number of publications, for example J. Hyttel, Prog. NeuroPsychopharmacol. & Biol. Psychiat., 1982,6,277295 and A. Gravem, Acta Psychiatr. Scand., 1987, 75, 478-486. The compound is also disclosed to have an effect in the treatment of dementia and cardiovascular disorders, EP-A 474580.

Citalopram was first disclosed in DE 2,657,271 corresponding to US 4,136,193. This patent publication describes the preparation of citalopram by one method and sets forth a second method that can be used to prepare citalopram.

According to the method described, the corresponding 1 (4-fluorophenyl) -1,3-dihydro-5-isobenzofurancarbonitrile is reacted with

3- (and, dimethylamino) propyl chloride in the presence of methylsulfinylmetide as a condensing agent. The starting material is obtained from the corresponding 5-bromo derivative by reaction with copper cyanide.

According to the generally described method, citalopram may be prepared by ring closure of the compound:

formula II in the presence of a dehydrating agent and subsequent replacement of the 5-bromo group with cyano using copper cyanide. The starting material of formula II is obtained from 5-bromophthalide in two successive Grignard reactions, namely 4-fluorophenylmagnesium chloride and N, N-dimethylaminopropylmagnesium chloride.

A novel and unexpected method and intermediate for the preparation of citalopram are described in US 4,650,884, according to which an intermediate of formula

Formula III is subjected to a ring closure reaction by dehydration with strong sulfuric acid in order to obtain citalopram. The intermediate of Formula III is prepared from 5-cyanophthalide by two successive Grignard reactions, namely 4-fluorophenylmagnesium halide and N, N-dimethyl nopropyl magnesium halide.

Other methods are disclosed in WO 1998/019511, WO 1998/019512 and WO 1998/019513, WO 1998/019512 and WO 1998/019513 refer to methods in which 5-amino-, 5-carboxy- or 5- (sec. -aminocarbonyl) phthalide is subjected to two sequential Grignard reactions - ring closure and conversion of the 1,3-dihydroisobenzofuran derivative obtained into the corresponding 5-cyano compound, i. citalopram. WO 1998/019511 discloses a method for the manufacture of citalopram wherein the (4-substituted-2-hydroxymethylphenyl- (4-fluorophenyl) methanol compound is subjected to ring closure, the resulting 5-substituted 1- (4fluorophenyl) -1. The 3-dihydroisobenzofuran is converted to the corresponding 5-cyan derivative and alkylated with (3-dimethylamino) propyl halide to give citalopram.

US 4,943,590 discloses methods for the preparation of the individual enantiomers of citalopram, which show that ring closure of the intermediate of formula III can be carried out with a base through a labile ester.

It has been found that citalopram can be obtained in high yield as a very pure product by a new favorable and safe method that uses appropriate starting materials.

SUMMARY OF THE INVENTION

Accordingly, the present invention relates to a novel process for the preparation of citalopram comprising the reaction of a compound of formula IV

wherein R is acyl with 3- (L, N-dimethylamino) propylmagnesium halide, preferably not 3- (N, N-dimethylamino) propylmagnesium chloride to give citalopram

Formula I which is isolated in the form of a base or a pharmaceutically acceptable salt thereof.

In another aspect, the invention relates to methods of preparing intermediates of formula IV.

According to the method of the invention, citalopram is prepared by a one-step ginning reaction of the compounds of formula IV

The surprisingly ginger reaction ring is closed spontaneously and directly in citalopram, and therefore the reaction of the compound of formula IV with the ginger glue results in citalopram in one step.

In addition, the compounds of formula IV can be prepared by three different methods according to the invention.

One of these methods involves protecting the hydroxymethyl alcohol of (4-cyano-2-hydroxymethylphenyl) (4-fluorophenyl) methanol of formula IV;

followed by oxidation to give the compounds of formula IV wherein R is acyl.

The oxidation of the compounds of formula V can be carried out with any suitable oxidizing agent, preferably with Na ₂ WO ₄ .

The starting material for the compound of formula VI can be prepared as described in PCT / DK 1997/000511.

Another method of preparing the compounds of formula IV involves reacting 5-cyanophthalide with 4-fluorophenyl-magnesium halide, preferably 4-fluorophenylmagnesium bromide, followed by reaction with R-X, where R is as defined above, and X is leaving group

The reaction is shown below.

The starting compound 5-cyanophthalide can be prepared as described by 35 Tirouflet, I, Bull.Soc.Sci. Brittany 26, 1959, 35.

According to the third process for the preparation of the compound of formula IV, one of the enantiomers of the compound of formula III, namely the R-enantiomer, is protected and dehydrated to give the compound of formula VII, which is oxidized to give the ketone of formula IV.

Thus the R-enantiomer of formula III can be used to prepare racemic citalopram.

The oxidative cleavage of the compound of formula VII is carried out by oxidation, preferably caused by MnO ₄ '(permanganates) or ozone, RuCl ₃ , OsO ₄ .

Other reaction conditions, solvents, etc. for the reactions described above, the conditions are traditional for such reactions and can be readily determined by one of ordinary skill in the art.

In the specification and claims the term C] _b alkyl refers to a branched or unbranched alkyl group having from one to six carbon atoms, including methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl -2-propyl, 2,2-dimethyl-1-ethyl and 2-methyl-1-propyl.

The term aryl refers to a mono- or bicyclic carbocyclic aromatic group such as phenyl and naphthyl. and in particular phenyl or ring-substituted phenyl.

The term heteroaryl refers to a mono- or bicyclic heterocyclic aromatic group such as indolyl, thienyl, pyrimidyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, benzofuranyl, benzothienyl, pyridyl and pyranyl-phenyllyl.

Acyl is used in the determination of C ₁₆ alkyl- or aryl- or heteroarylcarbonyl, where C _1-4 alkyl, aryl and heteroaryl are as defined above.

Halogen means chloro, bromo or iodo.

A preferred leaving group is halogenide or sulfonate.

In a preferred embodiment of the invention R is acyl, preferably pivaloyl, acetyl or optionally substituted benzoyl.

The compound of general formula I can be used as the free base or as a pharmaceutically acceptable acid addition salt thereof. Salts obtained with organic or inorganic acids may be used as acid addition salts. Examples of such organic salts are those with maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bismethylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, milky, apple, citricene, apple stearic, palmitic, igaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic and theophylline acetic acids, as well as 8-haloteophilins, for example 8-bromoteophilin. Examples of such inorganic salts are those with hydrochloric, bromo, 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 either with a calculated amount of acid in a water miscible solvent such as acetone or ethanol, followed by isolation of the salt by concentration and cooling, or with excess acid in a water miscible solvent such as ethyl ether, ethyl acetate or dichloromethane , with natural salt separation.

The pharmaceutical compositions of the invention can be administered in any suitable manner and in any convenient form, for example orally in the form of tablets, capsules, powders or syrups, or parenterally in the form of conventional sterile injectable solutions.

The pharmaceutical compositions of the invention can be prepared by conventional methods in the art. For example, tablets may be prepared by mixing the active ingredient with ordinergic adjuvants and / or diluents and subsequently compressing the mixture of conventional tabletting machines. Examples of adjuvants or diluents include corn starch, potato starch, talc, magnesium stearate, gelatin, lactose, resins, and the like. Any other adjuvants or additives may be used - coloring agents, flavors, preservatives, etc., provided they are compatible with the active ingredients.

Injectable solutions can be prepared by dissolving the active ingredient and any additives in part of the injection solvent, preferably sterile water, filling the solution to the desired volume, sterilizing the solution and filling it in suitable ampoules or vials. Any suitable additives commonly used in the art can be added, such as tonics, preservatives, antioxidants, and the like.

Examples of carrying out the invention

The invention is further illustrated by the following examples:

Example 1.

2,2-Dimethylpropionic acid 5-cyano-2- [1- (4-fluoro-phenyl) -1-hydroxy-methyl] -benzyl ester

To a stirred solution of (4-cyano-2-hydroxymethylphenyl) (4-fluorophenyl) methanol (9.2 g, 0.037 mol) and triethylamine (4.0 g, 0.04 mol) was added pivaloyl chloride (4.2 g, 0.39 mol). After stirring for 60 min, the reaction mixture was poured onto ice, extracted with diethyl ether (2 x 75 ml), dried (MgSO ₄ ) and concentrated under reduced pressure to give a colorless oil (12.0 g). The compound was purified by chromatography (eluenthexane / ethyl acetate 1: 9) to give the title compound (8.2 g, 70%).

Ή NMR (DMSO-D ₆ ): 1.1 (s, 9H), 5.15 (m, 2H), 6 (bs, 1H), 6.25 (d, J = 6 Hz, 1H), 7.1-7.2 (m, 2H) , 7.3-7.4 (m, 2H), 7.7-7.9 (m, 3H).

Example 2.

2,2-Dimethyl-propionic acid 5-cyano-2- [1- (4-fluoro-phenyl) -methanoyl] -benzyl ester

To a stirred solution of 5-cyano-2 [1- (4-fluoro-phenyl) -1-hydroxy-methyl] -benzyl ester of 2,2-dimethyl-propionic acid (8.0 g, 0.025 mol) in ethyl acetate (20 ml) was added a solution of hydrogen peroxide, 30% by weight (10 g, 0.079 mol), Na ₂ WO ₄ .2H ₂ O (0.15 g, 0.0059 mol) and (H-oKTnn) 3NCH ₃ .HSO ₄ (0.23 g, 0.0005 mol). The mixture was heated at reflux for 4 hours, allowed to cool to room temperature and poured into dilute HCl, extracted with diethyl ether (2 x 50 ml), dried (MgSO ₄ ) and concentrated under reduced pressure. to give the title ketone (7.8 g, 97.5%).

Example 3.

-cyano-2- [4-dimethylamino-1- (4-fluoro-phenyl) -but-1-enyl] -acetic acid benzyl ester and its oxalate salt

Method FOR. To a stirred solution of

4- [4-Dimethyl amino-1- (4-fluoro-phenyl) -1-hydroxy-6-butyl] -3-hydroxymethyl-benzonitrile (72 g, 0.21 mol) in acetonitrile (43 8 g) at 20 ° C dropwise acetic anhydride (103 g, 1 mol) was added. After the addition of acetic anhydride was completed, trimethylsilyl chloride (5.5 g, 0.05 mol) was added dropwise (resulting in an exothermic temperature increase from 20 to 28 ° C) and stirred overnight.

Concentrated H ₂ SO ₄ (14.5 g, 0.14 mol) was then added to the reaction mixture and the mixture heated for 30 min at 50 ° C (HPLC) indicated completion of the reaction). After cooling, the reaction mixture was concentrated under reduced pressure, neutralized with aqueous ammonia (23%) and extracted with toluene (twice). The organic phase was dried (MgSO ₄ ) and concentrated under reduced pressure to give the title compound as an orange oil (69.5 g, 85%).

Characterization of the oxalate salt. To a stirred solution of the alkene title compound (6.63 g, 0.0173 mol) in methanol (50 ml) was added a warm solution of oxalic acid (1 g, 0.0177 mol) in methanol (50 ml). The mixture was allowed to cool and the crystals were isolated by filtration (7.4 g) and washed with cold methanol (10 ml). Melting point 168 ° C.

Ή NMR (DMSO-D _6): 1.9 (s, H), 2.2 (m, 2H) , 2.62 (s, 6H), 3.1 (t, J = 6.2 Hz, 2H), 4.8 (s, 2H), 6.35 (t, J = 7 Hz, 1H), 7.1-7.25 (m, 4H), 7.42 (d, J = 7 Hz, 1H), 7.9-8 (m, 2H).

^ CNMRQMSO-De): 20.35,24.98,42.16,55.54, 62.51, 111.17, 115.25, 115.59, 118,51, 124.85, 128.0, 128.18, 131.32, 132.43, 132.73, 135.65, 135.99, 138.68, 142.9, 164.72, 169.96.

Analysis: Calculated for C ₂₄ H ₂₅ N ₂ O ₆ F: C, 63.14, H, 5.53, N, 6.14. Found: C, 63.1, H, 5.58, N, 6.12.

-cyano-2- [4-dimethylamino-1- (4-fluoro-phenyl) -but-1-enyl] -acetic acid benzyl ester

The method of SV. To a stirred solution of 4- [4-dimethylamino-1- (4-fluoro-phenyl) -1-hydroxy-butyl] -3-hydroxymethyl-benzonitrile (1000 g, 2.9 mol) in acetonitrile (1000 g) at 20 ° C Acetic anhydride (1112 g, 10.8 mol) (resulting in an exothermic temperature increase from 20 to 50 ° C) was added dropwise and stirred for 2 h. To the reaction mixture was added kH ₂ SO ₄ (300 g, 3 mol) and heated for 3 h at 50 ° C (HPLC showed completion of the reaction). After cooling, the reaction mixture was neutralized with aqueous ammonia (25%) and extracted with toluene (twice).

The organic phase was dried (MgSO ₄ ) and concentrated under reduced pressure to give the title compound as a pale orange oil (1023 g, 92%).

Example 4.

Cyano-2- [4-dimethylamino-1- (4-fluoro-phenyl) -but-1-enyl] -benzyl ester of 2,2-dimethylpropionic acid and its oxalate salt

Method 4A. To a stirred solution of 4- [4-dimethylamino-1- (4-fluoro-phenyl) -1-hydroxy-butyl] -3-hydroxymegyl-benzonitrile (72 g, 0.21 mol) and triethylamine (25.0 g, 0.247 mol) in acetonitrile (438 g) at 20 ° C was added dropwise a solution of pivaloyl chloride (26.0 g, 0.215 mol). After 60 min concentrated H ₂ SO ₄ (40 ml) was added dropwise and the reaction mixture was heated at 70 ° C for 180 min. It was allowed to cool to room temperature, neutralized with aqueous ammonia (25%) and extracted with diethyl ether. The organic phase was dried (MgSO ₄ ) and concentrated under reduced pressure to give the title compound as a yellow oil (82 g, 96%).

Characterization of the oxalate salt. (acetone) Melting point 168 ° C.

Ή NMR (DMSO-D _6): 1.07 (s, 9H) , 2.2 (m, 2H), 2.6 (s, 6H), 3.05 (t, J = 6.2 Hz, 2H), 4.735 (d, J = 12 Hz , 1H), 4.85 (d, J = 12 Hz, 1H), 6.3 (t, J = 6.3 Hz, 1H), 7.1-7.3 (m, 4H), 7.42 (d, J = 7 Hz, 1H), 7.9 -8 (m, 2H).

¹³ C NMR (DMSO-D ₆ ): 25.1, 26.71, 42.3, 55.67, 62.55, 111.21, 115.3, 115.64, 128.17, 131.33,

132.28, 136.13, 138.58, 142.76, 164.4.

Analysis: Calculated for C ₂₇ H ₃₁ N ₂ O ₆ F: C, 65.04, H,

6.28, N, 5.62. Found: C, 64.86, H, 6.63, N, 5.6.

Cyano-2- [4-dimethyl amino-1- (4-fluoro-phenyl) -but-1-enyl] -benzyl ester of 2,2-dimethylpropionic acid and its hydrogen chloride salt

Method 4B. To a stirred solution of 4- [4-dimethylamino-1- (4-fluoro-phenyl) -1-hydroxy-butyl] -3-hydroxymethyl-benzonitrile (85.5 g, 0.21 mol) in acetonitrile (290ml) at 0 ° C was added a solution of pivaloyl chloride (30.1 g, 0.25 mol). The reaction mixture was stirred for a further 60 min before the addition of concentrated H ₂ SO ₄ (32.5 g, 0.33 mol). After the addition was complete, the reaction mixture was heated at 70 ° C for 180 min. The mixture was allowed to cool to room temperature and the acetonitrile (220 ml) was removed under reduced pressure before the mixture was neutralized with aqueous ammonia (23%) and extracted with diethyl ether. The organic phase was dried (MgSO ₄ ) and concentrated under reduced pressure to give a rose oil of the title compound (102.1 g).

To a stirred solution of anhydrous hydrochloric acid in methanol (200 ml) was added a solution of the alkene compound II of the title. After stirring at room temperature for 30 min, the solvent was removed under reduced pressure, diethyl ether was added and the resulting white solid was filtered and washed with diethyl ether to give the hydrochloride salt (48.1 g). Melting point = 165 ° C.

2,2-Dimethylpropionic acid 5-cyano-2- [4-dimethylamino-1- (4-fluoro-phenyl) -but-1-enyl] -benzyl ester, hydrogen sulfate

Method 4C. To a stirred solution of 4- [4-dimethylamino-1- (4-fluoro-phenyl) -1-hydroxy-butyl] -3-hydroxymethyl-benzonitrile (85.5 g, 0.21 mol) in acetonitrile (290 ml) at 0 ° C a solution of pivaloyl chloride (29 g, 0.24 mol) was added. The reaction mixture was stirred for a further 60 min before the addition of concentrated H ₂ SO ₄ (32.5 g, 0.33 mol). After the addition was complete, the reaction mixture was heated at 70 ° C for 180 min. The mixture was allowed to cool to room temperature, the acetonitrile was removed under reduced pressure, toluene (200 ml) was added and the mixture was removed under reduced pressure to give the title compound as a pale pink oil (H2.4 g). .

5-Cyano-2- [4-dimethylamino-1- (4-fluoro-phenyl) -but-1-enyl] -benzyl ester of 2,2-dimethylpropionic acid, hydrogen chloride Method 4D. To a stirred solution of 4- [4-dimethylamino-1- (4-fluoro-phenyl) -1-hydroxy-butyl] -3-hydroxymethyl-benzonitrile (21.35 g, 0.052 mol) in acetonitrile (21.35 g) at room temperature added pivaloyl chloride (7.6 g, 0.63 mol). After the addition was complete, a solution of methanesulfonyl chloride (6.1 g, 0.053 mol) in CH ₂ Cl ₂ (50 ml) was added, followed by triethylamine (10.6 g, 0.105 mol). The reaction mixture was stirred for a further 30 min, poured into water, extracted with CH ₂ Cl ₂ , the organic phase was dried (MgSO ₄ ) and concentrated under reduced pressure. The resulting oil was dissolved in anhydrous ethanol / HCl, concentrated under reduced pressure, treated with diethyl ether and filtered to give the alkene hydrochloride salt (22.6 g, 98%).

Example 5.

2,2-Dimethylpropionic acid-cyano-2- [1- (4-fluoro-phenyl) -methanoyl] -benzyl ester

Method 5A. To a stirred solution of the alkene hydrochloride salt of 5-cyano-2- [4-dimethylamino-1- (4-fluoro-phenyl) -but-1-yl] benzyl ester of 2,2-dimethylpropionic acid (165 g, 0.337 mol) in H ₂ O (1100 ml) a solution of NaMnO ₄ in H ₂ O (40% v / v) (3.7 mol) was added at such a rate that the temperature was maintained between 45 and 50 ° C. After the addition was complete, the reaction mixture was allowed to cool to room temperature and filtered. The solid was washed with cold water (3x150 ml), the solid was stirred in acetone (2000 ml) and filtered to give the crude ketone which was purified by filtration over silica gel (eluent hexane: ethyl acetate 8: 2) to give the title ketone as the pure compound (82 g, 75%). Melting point = 81 ° C. 1 H NMR (DMSO-D ₆ ): 0.9 (s, 9H), 5.1 (s, 2H), 7.357.5 (m, 3H), 7.65 (d, J = 1 Hz, 1H), 7.8-7.9 (m. 2H), 8.0 (m, 1H), 8.1 (s, 1H).

¹³ CNMR (DMSO-D ₆ ): 26.5,63.01,113,183,116.0, 116.36, 118.02, 129.35, 132.19, 132.58, 133.03, 133.18, 133.34, 135.98, 141.7, 163.62, 167.65, 176.87, 193.94.

Analysis: Calculated for C ₂₀ H _lg NO ₃ F: C, 70.79, H, 5.35, N, 4.13. Found: C, 70.49, H, 5.30, N, 4.07.

2,2-Dimethylpropionic acid 5-cyano-2- [1- (4-fluoro-phenyl) -methanoyl] -benzyl ester

Method 5B. To a stirred solution of the alkene hydrochloride salt of 5-cyano-2- [4-dimethylamino-1- (4-fluoro-phenyl) -but-1-enyl] benzyl ester of 2,2-dimethylpropionic acid (38.0 g, 0.093 mol) in H ₂ O (1300 ml) and HCl (70 ml), ozone is passed into O ₂ , the reaction being followed by HPLC. A white precipitate formed during the reaction and at the end of the reaction this white precipitate was filtered off, washed with water and dried under reduced pressure to give the protected ketone as a pure compound (22.5 g, 72%).

2,2-Dimethylpropionic acid 5-cyano-2- [1- (4-fluoro-phenyl) -methanoyl] -benzyl ester

Method 5C. To a stirred solution of the alkene hydrochloride salt of 5-cyano-2- [4-dimethylamino-1- (4-fluoro-phenyl) -but-1-enyl] -benzyl ester of 2,2-dimethylpropionic acid, H ₂ SO ₄ ( 11.0 g, 0.022 mol) in H ₂ O (250 ml) and ethyl acetate (100 ml) were added Na ₂ O ₄ (30 g, 0.14 mol) and RuCl ₁ hydrate (0.35 g). The suspension was stirred vigorously at room temperature for 16 h. The resulting suspension was filtered through a pad of silica gel. The organic phase was separated and washed with water (50 ml). Evaporation of the solvent in vacuo gave the title compound as an oil which crystallized on standing. Yield: 7.4 g (99%).

Example 6

2,2-Dimethylpropionic acid-cyano-2- [1- (4-fluoro-phenyl) -methanoyl] -benzyl ester

To a suspension of 5-cyanophthalide (15.9 g, 0.1 mol) in dry tetrahydrofuran (150 ml) was added dropwise a solution of 4-fluorophenylmagnesium bromide obtained from 4-fluorobromobenzene (19.2 g, 0.11 mol) and magnesium chips (3.2 g, 0.13 mol). The temperature was maintained at 5 ° C. After the addition was complete, the reaction mixture was stirred overnight at room temperature. To the reaction mixture was added pivaloyl chloride (13.3 g, 0.11 mol) and the temperature increased over 2 hours to 60 ° C. The resulting solution was added to saturated NH ₄ Cl (100 ml) and ice (50 g). Diethyl ether (1000 ml) was added and the phases were separated. The organic phase was washed with 0.1 N NaOH (2 x 100 ml) and water (100 ml) and the organic phase was dried with MgSO ₄ (20 g). Evaporation of the solvent gave the crude title compound (29.8 g, 88%) as an oil, which was considered sufficiently pure to be used in the next reaction. A pure sample was obtained by crystallization in EtOAc / n-heptane (1: 9). The title compound was obtained in the form of white crystals.

Example 7.

- (3-dimethylamino-propyl) -1- (4-fluoro-phenyl) -1,3-dihydro-isobenzofuran-5-carbonitrile and its oxalate salt

To a solution of 5-cyano-2- [1- (4-fluoro-phenyl) -methanoyl] -benzyl ester of 2,2-dimethylpropionic acid (28.5 g, 0.084 mol) and anhydrous tetrahydrofuran (15 0 ml) at 0 A solution of 3- (N, N-dimethylamino) propyl magnesium chloride (2.2 eq) was added, and the reaction was followed by HPLC. After 1 h at 0 ° C, saturated ammonium chloride solution was added and the mixture was extracted with ethyl acetate, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give the title compound as an oil (28.0 g , (purity 87% HPLC)). Recrystallization in acetone gives the oxalate salt.

Claims (10)

Claims A process for the preparation of citalopram comprising the reaction of a compound of formula IV wherein R is acyl with 3- (L, N-dimethylamino) propylmagnesium halide to give citalopram, Formula I which is isolated in the form of a base or a pharmaceutically acceptable salt thereof. A method according to claim 1, characterized in that the intermediate of formula IV is prepared by oxidation of the corresponding compound of formula V: wherein R is as defined in claim 1. 3. The process of claim 2, wherein the compound of formula V is prepared by protecting the hydroxymethyl alcohol of (4-cyano-2-hydroxymethylphenyl) (4-fluorophenyl) methanol of formula VI: A method according to claim 1, characterized in that the intermediate of formula IV is prepared by oxidative cleavage of the corresponding compound of formula VII: Formula VII wherein R is as defined in claim 1. 5. The method of claim 4, wherein the oxidative cleavage of the compound of formula VII is carried out by oxidation induced preferably by MnO ₄ '(permanganates) or ozone, RuCl ₃ , OsO ₄ . A process according to claims 4-5, characterized in that the intermediate alkene of formula VII is prepared by protecting and dehydrating the corresponding compound of formula III: Formula III wherein the compound of formula III is the Renantiomer. A method according to claim 1, characterized in that the intermediate of formula IV is prepared by reacting 5-cyanophthalide with 4-fluorophenyl-magnesium halide, followed by reaction with R-X, to obtain a ketone of formula IV, wherein R is as defined in claim 1 and X is a leaving group. The method of claim 1, wherein the compound of general formula IV is reacted with 3- (b1, N-dimethylamino) -propylmagnesium chloride. A method according to claim 7, characterized in that the compound of formula IV is prepared by reacting 5cyanophthalide with 4-fluorophenyl-magnesium bromide. A method according to any one of claims 1 to 9, wherein R is pivaloyl, acetyl or optionally substituted benzoyl.