FI118765B - Preparation of citalopram as antidepressant drug and for treating dementia and cerebrovascular disorders comprises reaction of a new intermediate with 3-(N,N-dimethylamino)propyl magnesium halide - Google Patents

Abstract

Preparation of citalopram (I) comprises reacting a diphenylketone derivative (IV) with 3-(N,N-dimethylamino)propyl magnesium halide preferably 3-(N,N-dimethylamine)-propyl magnesium chloride and isolating (I) as the base or its salt. Preparation of citalopram of formula (I) comprises reacting a diphenylketone derivative of formula (IV) with 3-(N,N-dimethylamino)propyl magnesium halide preferably 3-(N,N-dimethylamine)-propyl magnesium chloride and isolating (I) as the base or its salt. [Image] R : 1-6C alkyl, 1-6C alkylsulfonyl or arylsulfonyl. Independent claims are included for the following: (1) preparation of a racemic compound of formula (III) which comprises deprotecting (IV) and reacting the obtained compound of formula (VIII) with 3-(N,N-dimethylamino)propyl magnesium halide, preferably 3-(N,N-dimethylamine)-propyl magnesium chloride and (2) new compounds (IV). [Image] ACTIVITY : Antidepressant; nootropic. MECHANISM OF ACTION : Serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor.

Description

, 118765

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

Background of the Invention

Citalopram is a well-known antidepressant that has been on the market for several years and has the following structure: ncYva 1 °

Formula I F

It is a selective CNS-active serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor and thus has anti-depressive activities. The antidepressant activity of the compound is described in several publications, for example, J. Hyttel, Prog. Neuro-Psychopharmacol. &

Biol. Psychiat., 1982, 6, 277-295 and A. Gravem, Acta Psychiatr. Scand., 1987,:: *; 20 75, 478-486. Further, the compound has been described as having effects in the treatment of dullness and cerebral vascular disorders, EP-A 474580.

Citalopram was first described in DE 2 657 271, which corresponds to U.S. Patent 4,136,193. This patent describes the preparation of citalopram by one method and outlines another method that can be used to prepare citalopram.

According to the method described, the corresponding 1- (4-fluorophenyl) -1,3-dihydro-5-isobenzofuranecarbonitrile is reacted with 3- (N, N-dimethyl: * ·· amino) propyl chloride in the presence of methylsulfinylmethide. present as a condensing agent. The starting material was prepared from the corresponding 5-bromo derivative by reaction with copper (2) cyanide.

Only according to the method outlined citalopram. can be obtained by ring closure of the compound: • * · · ··· · · 118765 2

BR 'v ^ v ^ cH5OH

5

Formula II

in the presence of a dehydration reagent and subsequent exchange with a 5-bromo group copper (2) cyanide. The starting material of formula II is obtained from 5-bromo-phthalide by two successive Grignard reactions, i.e., 4-fluorophenylmagnesium chloride and N, N-dimethylaminopropylmagnesium chloride, respectively.

A novel and astonishing process and intermediate for the preparation of citalopram was described in U.S. Patent No. 4,650,884, according to which an intermediate of formula 15 nc ^^ ch2oh YX \ oh i 20 is subjected to a ring closure reaction by removal of water with strong sulfuric acid to give citalopram . The intermediate of formula III was prepared from 5-cyanophthalide by two successive Grignard reactions, i.e., 4-fluorophenylmagnesium halide and N, N-dimethylaminopropylmagnesium halide, respectively.

i ”]: Other methods are described in international patent applications

WO 98019511, WO 98019512 and WO 98019513

· * ... 98019512 and WO 98019513 relate to processes wherein 5-amino, 5-carboxy. **. 30 or 5- (sec-aminocarbonyl) phthalide is subjected to two successive Grignard reactions, ring closure, and conversion of the resulting 1,3-dihydroisobenzofuran derivative to the corresponding 5-cyano compound, i.e., citalopram.

*

International patent application WO 98019511 describes a method of - ***; citalopram wherein the (4-substituted-2-hydroxymethylphenyl- (4-fluorophenyl) -methanol compound is subjected to ring closure and the resulting 5-substituted 1- (4-fluorophenyl) -1,3-dihydroisobenzofuran is converted to the corresponding 118765 3-cyanide which is alkylated with (3-dimethylamino) propyl halide to give citalopram.

Finally, methods for preparing the single enantiomers of citalopram are described in U.S. Patent No. 4,943,590, which also discloses that the intermediate of Formula III may be ring annealed via an unstable ester with a base.

It has now surprisingly been found that citalopram can be prepared by a new inexpensive and safe procedure using conventional starting materials.

Summary of the Invention

Accordingly, the present invention relates to a novel process for the preparation of citalopram, which comprises reacting a compound of formula IV

CN

15 (Tl?

Formula IV

20 F

Wherein R is C 1-6 alkyl, acyl, C 1-6 alkylsulfonyl or arylsulfonyl, with 3- (N, N-dimethylamino-propyl-magnesium halide, preferably 3- (N, N-dimethyl-amino) -N-propyl-magnesium chloride , to give citalopram

* · **; 25 | J jj o I

• · IN / \ »· {I ^ • ** In. 1

* ... # Formula I

30 F

which is isolated as a base or a pharmaceutically acceptable salt thereof.

* ϊ ** ·: In another aspect, this invention provides, ···. new intermediates of formula IV.

• ·

In another aspect, the invention relates to processes for the preparation of intermediates of formula IV.

118765 4

In yet another aspect of the invention, the compounds of formula IV are used to prepare a racemic compound of formula III.

nc \ ^^ ch, oh 5

Formula III

10 F

In yet another aspect, the present invention relates to a pharmaceutical antidepressant composition comprising citalopram prepared by the process of the invention.

Citalopram is obtained by a one-step Grignard reaction according to the invention from compounds of formula IV wherein R is C 1-6 alkyl, acyl, C 1-6 alkylsulfonyl or arylsulfonyl

CN

lii R

20 • · 1 · / Ν2λ • · · n * «· s

VJ Formula IV

• · ♦ £

:. · F

* · 3 · 25 Surprisingly, the product of the Grignard reaction undergoes spon- * 3: ethane and a direct ring closure to citalopram, and thus the reaction of the compound of formula IV with the Grignard reagent results in a single step of citalopram.

·. In addition, compounds of formula IV may be prepared according to the invention. 30 by three different methods.

* ·

One of these methods involves protecting the hydroxymethyl alcohol of (4-cyano-2-hydroxymethylphenyl) (4-fluorophenyl) methanol of formula IV: 1 3 • · 118765 5

χ χ CN

Salting Oxidation [Γ ^ Ι ^ fj0H ΓΓ ™ | -γγ> fX ^ VI V rXJ w 5 followed by oxidation to give compounds of formula IV wherein R is C 1-6 alkyl, acyl, C 1-6 alkylsulfonyl or arylsulfonyl.

The oxidation of the compounds of formula V may be carried out with any conventional oxidizing reagent, preferably Na 2 CO 4. The starting material of the compound of formula IV may be prepared as described in International Patent Application PCT / DK97 / 00511.

Another process for the preparation of compounds of formula IV involves the reaction of 5-cyanophthalide with 4-fluorophenylmagnesium halide, preferably 4-fluorophenylmagnesium bromide, followed by reaction with RX wherein R is as defined above and X is a leaving group, preferably RX. is pivaloyl chloride, 3,5-dimethoxybenzoyl chloride, methyl iodide, ethyl libromide, tosyl chloride, Me 2 SO 4 or Me SO 2 Cl.

The reaction is described below:

ΦΜ0Μ8Ι OH OR

®yV

Jl J s ° {I JL .o ··.:. · * "~ YV \> —1- *: *: \\ \\ o * ♦ ··· nl- ~ • · 25 - - Starting material, 5- cyanophthalide may be prepared in the manner described: **]: in Tirouflet, J.; Bull. Soc. Sci. Bretagne 26, 1959, 35.

According to a third method, one of the enantiomers of the compound of formula III, i.e.

. ···. The R enantiomer is subjected to deprotection and dehydration to give a compound of formula VII, which is oxidized to give a ketone of formula IV.

XX ™ O CjL.OH .Security OL -S Oxidation || ^ | ? . ·. J 35 hoJ J. Dewatering [| In this way, the R enantiomer of formula III can be used in the preparation of racemic citalopram.

The oxidative cleavage of the compound of formula VII is accomplished by oxidation, preferably with MnO 4 '(permanganates), or Ozone-5, RuCl 3, OsO 4.

Citalopram is sold as an antidepressant in the form of a racemate. The active S-enantiomer of citalopram will also be launched in the near future.

The active S-enantiomer of citalopram can be prepared from a compound of formula III 10 by separation of the S-enantiomer and the R-enantiomer, followed by ring closure of the S-enantiomer as described in U.S. Patent 4,943,590. The R enantiomer of the compound of formula III has not previously been used after separation.

In addition, according to a further aspect of the invention, after conversion of the R-enantiomer of Formula III to a non-optically active compound of Formula IV, the racemic compound of Formula III can be prepared as described below:

cn cn CN

„Λ Unblocking Grignard 20 1 -► Λ 1 ----- ► un T l iTr ° rr °

: IV Fruit III

The racemic compound of formula III can be optically resolved into its active enantiomers by the procedure described in U.S. Patent No. 4,943,590, thus providing the S-enantiomer of formula III: *; which is used in the preparation of S-citalopram The R-enantiomer of the compound of formula IIi can be recycled according to the process cycle described above.

Iillä.

·. In this way, the R enantiomer of Formula III can be converted to * S · citalopram.

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

. ·· *. Throughout the specification and claims, the term C 1-4 alkyl refers to 35 branched or unbranched alkyl groups having one

• »S

to six carbon atoms including these, such as methyl, ethyl, 1-propyl, 1187657 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 monocyclic or bicyclic carbocyclic aromatic group such as phenyl and naphthyl, especially phenyl or ring-substituted phenyl.

The term heteroaryl refers to a one or two ring heterocyclic aromatic group such as indolyl, thienyl, pyrimidyl, oxazolyl, iso-xazolyl, thiazolyl, isothiazolyl, imidazolyl, benzofuranyl, benzothienyl, pyridyl and furanyl, especially pyrimidyl,

Acyl is used to mean C 1-6 alkyl or aryl or heteroarylcarbonyl wherein C 1-6 alkyl and aryl and heteroaryl are as defined above.

Halogen means chlorine, bromine or iodine.

The leaving group preferably represents a halide 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. Acid addition salts may be those formed with organic or inorganic acids. Exemplary such organic salts include salts of maleic, fumaric, benzoic, ascorbic, amber, oxalic, bismethylene salicyl, methanesulfone, ethane disulfone, vinegar, propionic, wine, *: *: salicyl, lemon -, Glucone, Milk, Apple, Almond, Cinnamon, Citracone, Aspa: * · *: Ragin, Stearin, Palmitine, Itacone, Glycol, p-aminobenzo, glutamine, ····· 25 benzenesulfonic and theophyllineacetic acids, as well as 8-halo-theophyllines, for example 8-bromo-theophylline. Exemplary of such inorganic salts are salts with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids.

The acid addition salts of the compounds may be prepared by methods known in the art. The base is reacted with either a calculated amount of acid in a water-miscible solvent such as acetone or ethanol, followed by isolation of the ·: ··· salt by subsequent concentration and cooling, or excess acid in a water-immiscible solvent such as ethyl ether, ethyl acetate, whereby the salt separates spontaneously.

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

The pharmaceutical formulations of the invention may be prepared by methods conventional in the art. For example, tablets may be prepared by mixing the active ingredient with conventional excipients and / or diluents and subsequently compressing the mixture in a conventional tablet making machine. Examples of excipients or diluents include: corn starch, potato starch, talc, magnesium stearate, gelatin, lactose, gums and the like. Any other coloring, flavoring, preservative and similar excipients or additives may be used, provided they are compatible with the active ingredients.

Solutions for injection may be prepared by dissolving the active ingredient and any additives in a portion of the solvent for injection, preferably sterile water, adjusting the volume of the solution as desired, sterilizing the solution and filling into suitable ampoules or vials. Any suitable excipients conventionally used in the art, such as tonicity regulators, preservatives, antioxidants and the like, may be added.

eXAMPLES

The invention is further illustrated by the following examples.

. Example 1 * · · *: **: 2,2-Dimethyl-propionic acid 5-cyano-2- [1- (4-fluorophenyl) -1-hydroxymethyl] benzyl ester A mixed solution of (4-cyano-2-hydroxymethylphenyl) (4-fluorophenyl) methanol (9.2 g, 0.037 mol) and triethylamine (4.0 g, 0). , 04 mol), pivaloyl chloride (4.2 g, 0.39 mol) was added. After stirring for 60 minutes, 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). The compound was purified by chromatography (eluent hexane / ethyl acetate 1: 9) to give the title compound (8.2 g, 70%).

30-NMR (DMSO-D6): 1.1 (s, 9H), 5.15 (m, 2H), 6 (bs, 1H), 6.25 (d, JJ = 6 Hz, 1H ), 7.1-7.2 (m, 2H), 7.3-7.4 (m, 2H), 7.7-7.9 (m, 3H).

• · • M ♦ · • · ··· • 9 9 9 m \

Example 2 9 118765 2,2-Dimethyl-propionic acid 5-cyano-2- [1- (4-fluoro-phenyl) -methanoyl] -benzyl ester

To a stirred solution of 5-cyano-5-cyano-2- [1- (4-fluorophenyl) -1-hydroxymethyl] -benzyl ester of 2,2-dimethylpropionic acid (8.0 g, 0.025 mol) in ethyl acetate (20 mL), 30% w / w hydrogen peroxide solution (10 g, 0.079 mol), NazO 4 O 2 H 2 O (0.15 g, 0.0005 mol), and (n-octyl) 3NCH 3 HSO 4 (0.23 g) were added. 0.0005 mol). The mixture was then heated at reflux for 4 hours, allowed to cool to room temperature and poured into dilute 10 HCl, extracted with diethyl ether (2 x 50 mL), dried (MgSO 4) and concentrated under reduced pressure to give the ketone title compound (7.8 g, 97.5). %).

Example 3

Acetic acid 5-cyano-2- [4-dimethylamino-1- (4-fluoro-phenyl) -but-1-en-yl] -benzyl ester, and its oxalate salt

Method 3A. Acetic anhydride (103 g, 1 mol) was added dropwise to a stirred solution of 4- [4-dimethylamino-1- (4-fluorophenyl) -1-hydroxybutyl] -3-hydroxymethylbenzonitrile (72 g, 0.21 mol). ) in acetonitrile (438 g) at 20 ° C. At the end of the addition, trimethylsilylchloride, 20 rides (5.5 g, 0.05 mol) were added dropwise (followed by an exothermic reaction raising the temperature from 20 to 28) and stirring overnight. Concentrated H 2 SO 4 (14.5 g, 0.14 mol) was then added to the reaction mixture, and then the reaction mixture was heated to 50 ° C for 30 minutes (HPLC indicated the reaction was complete).

'** · * The reaction mixture was cooled, then concentrated under reduced pressure: ** and the pH adjusted to neutral pH 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 a pale orange solid. as a blue oil (69.5 g, 85%).

. ♦ ··. Characterized as the oxalate salt. To a stirred solution of ♦ · · · * 30 alkene title compound (6.63 g, 0.0173 mol) in methanol (50 mL) was added a warm solution of oxalic acid (1.0 g, 0.0177 mol) in methanol ( 50 ml).

After allowing to cool, the crystals were isolated by filtration (7.4 g) and washed with water.

. ···. was cooled with cold methanol (10 mL). Sp. 168 ° C

* ··· 87 118765 δ NMR (DMSO-D6): 1.9 (s, 3H), 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).

13 C NMR (DMSO-D 6): 20.35, 24.98, 42.16, 55.54, 62.51, 111.17, δ 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.

Elemental Analysis calculated for C 13 H 13 N 3 O 6 F: C, 63.14; H, 5.53; N, 6.14. Found: C, 63.1; H, 5.58; N, 6.12

Acetic acid 5-cyano-2- [4-dimethylamino-1- (4-fluoro-phenyl) -but-1-enyl-10] -yl] -benzyl ester

Method 3B. Acetic anhydride (1112 g, 10.8 mol) was added dropwise to a stirred solution of 4- [4-dimethylamino-1- (4-fluorophenyl) -1-hydroxybutyl] -3-hydroxymethylbenzonitrile ( 1000 g, 2.9 mol) in acetonitrile (1000 g) at 20 ° C (followed by an exothermic reaction whereby the temperature rose from 20 to 50 ° C) and stirred for 2 hours. Concentrated H 2 SO 4 (300 g, 3 mol) was added to the reaction mixture, and then the reaction mixture was heated for 3 hours at 50 ° C (HPLC indicated the reaction was complete). The reaction mixture was cooled, then adjusted to pH neural with aqueous ammonia (25%), and extracted with toluene (twice). The organic phase was dried (MgSO 4) and concentrated under reduced pressure to give my title *: compound as a light orange oil (1023 g, 92%).

*. * Example 4 • · · 2,2-Dimethyl-propionic acid 5-cyano-2- [4-dimethylamino-1- (4-fluoro-phenyl) -but-1-enyl] -benzyl ester, and its oxalate salt «••• s! .. * 25 Method 4A. A solution of pivaloyl chloride (26.0 g, 0.215 mol) was added to a stirred solution of 4- [4-dimethylamino-1- (4-fluoro-phenyl) -1-hydroxy-butyl ] -3-hydroxymethylbenzonitrile (72 g, 0.21 mol) and triethyl: * ··· lamine (25.0 g, 0.247 mol) in acetonitrile (438 g) at 20 ° C. After 60 minutes, concentrated H2SO4 (40 mL) was added dropwise and the reaction mixture was heated for 180 minutes at 70 ° C. The reaction mixture was allowed to cool to room temperature, the pH was adjusted to neutral with aqueous ammonia (25%). pH 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 V-j oil (82 g, 96%).

35 Characterized as oxalate salt (acetone) m.p. 188 ° C.

118765 11 @ 1 H-NMR (DMSO-d6): 1.07 (s, 9H), 2.2 (m, 2H), 2.6 (s, 6H), 3.05 (t, J = 6.2 Hz) , 2H), 4.725 (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 = 7Hz, 1H), 7.9-8 (m, 2H).

13 C NMR (DMSO-D 6): 25.1, 26.71, 42.3; 55.67, 62.55, 111.21, δ 115.3, 115.64, 128.17, 131.33, 132.28, 136.13, 138.58, 142.76, 164.4

Elemental 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 2,2-Dimethyl-propionic acid 5-cyano-2- [4-dimethylamino-1- (4-fluoro-phenyl) -but-1-enyl] -benzyl ester, and hydrochloride salt Method 4B. A solution of pivaloyl chloride (30.1 g, 0.25 mol) was added to a stirred solution of 4- [4-dimethylamino-1- (4-fluorophenyl) -1-hydroxybutyl] -3-hydroxymethyl benzonitrile (85.5 g, 0.21 mol) in acetonitrile (290 ml) at 0 ° C. The reaction mixture was stirred for an additional 60 minutes before adding concentrated H2SO4 (32.5 g, 0.33 mol). After the addition was complete, the reaction was stirred for 180 minutes at 70 ° C. The reaction mixture was allowed to cool to room temperature, and acetonitrile (220 mL) was removed under reduced pressure before the pH was adjusted to neutral with aqueous ammonia (23%) and extracted with diethyl ether. The organic phase was dried (MgSO 4) and concentrated under reduced pressure to give the title compound as a light pink oil (102.1 g).

: A solution of the alkylene title compound II (50.0 g, 0.11 mol) in methanol was added to a stirred solution of anhydrous HCl in methanol (200 mL). After stirring for 30 minutes at room temperature, 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 HCl salt (48.1 g). Sp. = 165 ° C.

• ··· 2,2-Dimethyl-propionic acid 5-cyano-2- [4-dimethylamino-1- (4-fluorophenyl) -but-1-enyl] -benzyl ester, hydrogen sulfate

Method 4C. A solution of pivaloyl chloride (29 g, 0.24 mol) was added to a stirred solution of 4- [4-dimethylamino-1- (4-fluorophenyl) - *. 1-Hydroxy-butyl] -3-hydroxymethyl-benzonitrile (85.5 g, 0.21 mol) in acetonitrile (290 ml) at 0 ° C. The reaction mixture was stirred for an additional 60 minutes before adding concentrated H2SO4 (32.5 g, 0.33 mol). After the addition was complete, the reaction was heated at 70 ° C for 180 minutes. The reaction mixture was allowed to cool to room temperature and acetonitrile was removed under reduced pressure, added toluene (200 mL) and removed under reduced pressure to give the title compound as a pink oil (112.4 g).

2,2-Dimethyl-propionic acid 5-cyano-2- [4-dimethylamino-1- (4-fluoro-phenyl) -but-1-enyl] -benzyl ester, hydrochloride Method 4D. Pivaloyl chloride (7.6 g, 0.63 mol) was added dropwise to a stirred solution of 4- [4-dimethylamino-1- (4-fluorophenyl) -1-hydroxybutyl] -3-hydroxymethylbenzonitrile (21.35 g, 0.052 mol) in acetonitrile (21.35 g) at room temperature. 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 an additional 30 minutes, poured into water, extracted with CH 2 Cl 2, the organic phase dried (MgSO 4) and concentrated under reduced pressure. The resulting oil was then dissolved in anhydrous ethanol / HCl, concentrated under reduced pressure and treated with diethyl ether and filtered to give al-15 Kene HCl salt (22.6 g, 98%).

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

Method 5A. To a stirred solution of 5-cyano-2- [4-dimethylamino-1- (4-fluoro-phenyl) -but-1-enyl] -alkene-2,2-dimethyl-propionic acid *: ··· * HCl salt of benzyl ester (165 g, 0.337 mol) in H 2 O (1100 mL), a solution was added, * · * · containing NaMnO 4 in H 2 O (40% v / v) (3.7 mol) at such a rate that the reaction temperature remained between 45 and 50 ° C. After the addition was complete, the reaction mixture was allowed to cool to room temperature and filtered. The solid filtrate was washed with cold water (3 x 150 mL), and the solid residue was stirred in acetone (2000 mL) and filtered to give crude ketone, which was purified by filtration through a pad of silica (hexane eluent: ethyl acetate 8: 2) to give 82 g (75%) of the ketone title compound as pure, mp = 81 ° C.

Δ: ··· Ή 30 NMR (DMSO-D 6): 0.9 (s, 9H), 5.1 (s, 2H), 7.35-7.5 (m, 3H), ... : 7.65 (d, J = 7Hz, 1H), 7.8-7.9 (m, 2H), 8.0 (m, 1H), 8.1 (s, 1H) 13 C- NMR (DMSO-D6): 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 118765 13

Elemental Analysis calculated for C20H18NO3F: C, 70.79; H, 5.35; N, 4.13. Found: C, 70.49; H, 5.30; N, 4.07 2,2-Dimethyl-propionic acid 5-cyano-2- [1- (4-fluoro-phenyl) -methanoyl] -benzyl ester 5 Method 5B. Ozone 02 was bubbled through a stirred solution of 5-cyano-2- [4-dimethylamino-1- (4-fluoro-phenyl) -but-1-enyl] -benzyl ester of alkene-2,2-dimethyl-propionic acid ( 38.0 g, 0.093 mol) in H 2 O (1300 mL) and concentrated HCl (70 mL) followed by reaction on HPLC. A white precipitate formed during the reaction, and at the end of the reaction, the white precipitate was filtered, washed with water and dried under reduced pressure to afford the title compound, protected ketone (22.5 g, 72%).

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

Method 5C. To a suspension of 5-cyano-2- [4-dimethylamino-1- (4-fluoro-phenyl) -but-1-enyl] -benzyl ester of 5-cyano-2- (4-dimethyl-propionic acid), , 0 g, 0.022 mol) in water (250 ml) and ethyl acetate (100 ml) were added NalO 4 (30 g, 0.14 mol) and RuCl 3 hydrate (0.35 g). The suspension was stirred vigorously at ambient temperature for 16 hours. The resulting suspension was filtered through a pad of silica. The organic phase was separated: 20 and washed with water (50 mL). The solvent was evaporated in vacuo to give the title compound as an oil which crystallized on standing. Yield: 7.4 g (99%).

Example 6 * 2,2-Dimethyl-propionic acid 5-cyano-2- [1- (4-fluoro-phenyl) -methanoyl] - '* "** benzyl ester *** • m * ··· * A solution of 4-fluorophenylmagnesium bromide in dry THF made from 4-fluorobromobenzene (19.2 g, 0.11 mol) and magnesium turnings (3.2 g, 0.13 mol) (100 mL) was added dropwise to a suspension of: ** ** cyanophthalide (15.9 g, 0.1 mol) in dry THF (150 mL) The temperature was kept below 5 ° C. After the addition was complete, the reaction mixture was stirred for «30 nights at room temperature.

Pivaloyl chloride (13.3 g, 0.11 mol) was added to the reaction mixture, and the temperature of M M was raised to 60 ° C for 2 hours. The resulting solution was added to saturated NH 4 Cl solution (100 mL, in water) and ice (50 g). Diethyl ether (100 mL) was added and the phases were separated. The organic phase was washed with 0.1 N NaOH 118765 14 (2 x 100 mL) and water (100 mL) and the organic phase was dried over MgSO 4 (20 g). The solvents were evaporated to give the crude title compound (29.8 g, 88%) as an oil which was considered sufficiently pure for further reaction.

The pure sample is obtained by crystallization from EtOAc / n-heptane (1: 9). The Ot-5 fatty compound is obtained as off-white crystals.

Example 7 1- (3-Dimethylamino-propyl) -1- (4-fluoro-phenyl) -1,3-dihydro-isobenzofuran-5-carbonitrile, and its oxalate salt

To a solution of 2,2-dimethyl-propionic acid 5-cyano-2- [1- (4-10 fluoro-phenyl) -methanoyl] -benzyl ester (28.5 g, 0.084 mol) in anhydrous THF (150 mL) At 0 ° C, a solution of 3- (N, N-dimethylamino) propylmagnesium chloride (2.2 equivalents) was added and the reaction was monitored by HPLC. After 1 hour at 0 ° C, saturated ammonium chloride 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, (87% purity by HPLC)]. The oxalate salt is obtained by crystallization from acetone.

Example 8 4- [1- (4-Fluoro-phenyl) -methanoyl] -3-hydroxymethyl-benzonitrile. ·. 5-Cyano-2- [1- (4-fluoro-phenyl) -methanoyl] -benzyl ester of ketone-2,2-dimethyl-propionic acid (20 g, 0.061 mol) was added to the freshly prepared Na-meth. ... oxide (0.25 g of sodium in 100 ml of methanol) and stirred at room temperature (HPLC showed complete deprotection). Methanol was then removed under reduced pressure, dissolved in MTBE, washed with saturated ammonium chloride and dried (MgSO 4), and concentrated under reduced pressure to give the title compound, unprotected ketone (14.6 g).

Example 9 4- [4-Dimethylamino-1- (4-fluoro-phenyl) -1-hydroxy-butyl] -3-hydroxymethyl-benzonitrile • ·

To a solution of ketone 4- [1- (4-fluoro-phenyl) -methanoyl] -3-hydroxy-methyl-benzonitrile (15.0 g, 0.046 mol) in anhydrous THF at 0 ° C, A solution of 3- (N, N-dimethylamino) propylmagnesium chloride (2.2 equivalents *) was added and the reaction was monitored by HPLC. After 1 hour at 0 ° C, 118765 saturated ammonium chloride was added and the mixture was extracted with MTBE, dried (MgSO 4) and concentrated under reduced pressure to give the title compound as an oil [16.7 g (85% purity)].

• · • · · ··· 9 • «M 9

• 1 I

• 9 • 9 9 9 9 9 9 9 99 9 9 9 • 99 • 9 • 9 • 9 9 • 9 9 9 • 99 9 • 9 9:: • 99 9 9 • 9 9 9 9 9 • 99 9 9 • 9 9 ·· 9 9 9 9 • 9 · • 9

Claims (11)

A process for the preparation of citalopram comprising reacting a compound of formula IV, CN όυ Formula IV F wherein R is C 1-6 alkyl, acyl, C 1-6 alkylsulfonyl or arylsulfonyl, with a 3- (N, N- dimethylamino) propylmagnesium halide, preferably 3- (N, N-dimethylamino) propylmagnesium chloride, whereby citalopram is obtained, TX> i * · · I * a · JL u * I Formula I * 1 · or a pharmaceutically acceptable site thereof:]] 1: 2. A process according to claim 1, characterized in that the intermediate product of formula IV is prepared by oxidation of the corresponding compound of formula V: · ··· ♦ ♦ · • ♦ a ·· • · • ♦ · • · · • «· 2 • ♦ 118765 CN άυ ΛϊΛοη Forme! V F where R is as defined in claim 1. A process according to claim 2, characterized by the compound of formula V being prepared by protecting the hydroxymethanol of (4-5 cyano-2-hydroxymethylphenyl) (4-fluorophenyl) methanol of formula VI: CN Formula! VI F ^ · * · ϊ: 4. A process according to claim 1, characterized in that the intermediate product of Formula IV is prepared by oxidative cleavage of the corresponding compound of Formula VII: :: (i ^ i R lii II ***** \ \:: ··: Z 'Formula VII F • · where R is as defined in claim 1. • · • · · «♦ 1 · * · · • ·· • «118765 5. A process according to claim 4, characterized by the deoxidative digestion of the compound of formula VII by oxidation, preferably carried out with MnO4 '(permanganates), or ozone, RuCl3, Os04. 6. A process according to any one of claims 4-5, characterized in that the alkene intermediate of formula VII is prepared by protecting and dehydrating the corresponding compound of formula III: CN Formula II F where the compound of formula III is the R enantiomer. 10 Process according to claim 1, characterized in that the intermediate product of formula IV is prepared by reacting 5-cyanphthalidine with a 4-fluorophenylmagnesium halide, preferably 4-fluorophenylmagnesium bromide, and subsequently reacting with RX to form the ketone compound. , wherein R is as defined in claims 1 and X is a leaving group, preferably RX is pivaloyl chloride, 3,5-dimethoxybenzoyl, soyl chloride, methyl iodide, ethyl bromide, tosyl chloride, Me 2 SO 4 or MeSO 2 Cl. • 1 · • · • 1 • · • · • · *** • · • · * · · • m • ·· * «· • · • 1 • · 9 · ··· • ·% · ··· · · · ··