CZ20012246A3 - Process for preparing citalopram - Google Patents

Abstract

The present invention relates to a method for the preparation of citalopram and pharmaceutically acceptable thereof comprising reaction of a compound of the general formula IV, wherein R represents acyl, with 3-(N,N-dimethylamino)-propyl magnesium halide, preferably 3-(N,N-dimethylamino)propyl magnesium chloride to prepare citalopram of the general formula I and isolating the obtained citalopram in its free form or in the form of a pharmaceutically acceptable salt thereof.

Description

(57)

A process for the preparation of citalopram comprising reacting a compound of formula IV wherein R is C 1 -C 6 alkyl, acyl, C 1 -C 6 alkylsulfonyl or arylsulfonyl with 3 (N, N-dimethylamino) propylmagnesium halide, preferably 3- (N, N (dimethylamino) propylmagnesium chloride to give citalopram of formula I which is isolated in free form or form or in pharmaceutically acceptable salt form. Compounds of formula IV wherein the substituents are as defined above, their use as intermediates and their preparation.

CZ 2001 - 2246 A3

Process for producing citalopram

Technical field

The invention relates to a process for the preparation of the known antidepressant citalopram, chemically

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 available for several years and can be represented by the following formula I

It is a selective, centrally acting serotonin (5-hydroxytriptamine) reuptake inhibitor,

5-HT) with antidepressant effect. The antidepressant effect of the compound has been described in a number of publications, for example J. Hyttel, Prog. Neuro-Psychopharmacol. & Biol. Psychiat., 1982, 6, 277-295 and by A. Gravem, Acta Psychiatr. Scand. 1987, 75, 478-486. It has also been shown to have beneficial effects in the treatment of dementia and cerebrovascular disorders according to EP-A 474580.

• ·

Citalopram was first disclosed in DE 2657271, which corresponds to US 4136193. This patent discloses one method of producing citalopram and proposes a further process applicable to the production of citalopram.

According to the described procedure, the corresponding 1- (4-fluorophenyl) -1,3-dihydro-5-isobenzofurancarbonitrile is reacted with 3- (N, N-dimethylamino) propyl chloride in the presence of methylsulfinylmethide as a condensing agent. The starting material is prepared from the corresponding 5-bromo derivative by reaction with cuprous cyanide.

According to the process proposed in said patent, citalopram can be prepared by ring closure in a compound of formula II

in the presence of a dehydrating agent followed by replacement of the bromine atom at the 5-position with cuprous cyanide. The starting material of formula II is prepared from 5-bromophthalide by two consecutive Grignard reactions, first with 4-fluorophenylmagnesium chloride and then with N, N-dimethylaminopropylmagnesium chloride.

A novel and surprising process for the production of citalopram, including the corresponding intermediate, has been described in U.S. Pat. No. 4,650,884.

it closes the dehydration reaction with a strong sulfuric acid to form citalopram. The intermediate of formula III is prepared from 5-cyanophthalide by two consecutive Grignard reactions, and firstly with

4-fluorophenylmagnesium chloride and then with N, N-dimethylaminopropylmagnesium halide.

Other processes have been described in International Patent Applications WO 98119511, WO 98019512 and WO 98019513. WO 98119512 and WO 98019513 disclose processes in which 5-aminophthalide, 5-carboxyphthalide or 5- (sec. Aminocarcinyl) phthalide is subjected to two following Grignard. by reaction, ring closure and conversion of the resulting 1,3-dihydrobenzofuran derivative into the corresponding 5-cyano compound, i.e., citalopram. International patent application WO 98019511 discloses a process for the production of citalopram comprising:

4-substituted 2-hydroxymethylphenyl

- (4-fluorophenyl) methanol closes the ring and results

The 5-substituted 1- (4-fluorophenyl) -1,3-dihydroisobenzofuran is converted to the corresponding 5-cyano derivative, which is then

alkylated with (3-diethylamino) propyl halide to form citalopram.

Finally, further processes for making the individual enantiomers of citalopram are described in US 4943590, it is also clear from this patent that the ring closure of the intermediate of formula 3 can be accomplished via a labile ester by treatment with a base.

It has now surprisingly been found that citalopram can be prepared by a novel convenient and safe process using preferred starting materials.

SUMMARY OF THE INVENTION

The present invention provides a process for the preparation of citalopram by reacting a compound of formula IV

wherein R is C 1 -C 6 alkyl, acyl, C 1 -C 6 alkylsulfonyl or arylsulfonyl, with 3- (N, N-dimethylamino) -propylmagnesium halide, preferably 3- (N, N-dimethylamino) -propylmagnesium chloride, to form citalopram of formula I

which is isolated in free form or in the form of a pharmaceutically acceptable salt.

The present invention also provides novel intermediates of formula (IV).

The invention also relates to a process for the preparation of intermediates of formula IV.

According to another embodiment of the invention, compounds of formula IV are used for the preparation of the racemic compound of formula III

The invention also relates to a pharmaceutical composition having an antidepressant effect, which comprises as its active ingredient citalopram produced by the process according to the invention.

According to the process of the invention, citalopram can be prepared in a single step by Grignard reaction from compounds of formula IV wherein R is C 1 -C 6 alkyl, acyl, C 1 -C 6 alkylsulfonyl or arylsulfonyl

Surprisingly, in the Grignard reaction product, the ring self-closes to directly form citalopram, so that the reaction of the compounds of formula IV with the Grignard reagent leads to citalopram in a single step.

In addition, the compounds of formula (IV) may be prepared by three different methods.

One of these methods is to protect the hydroxymethyl alcohol group in (4-cyano-2-hydroxymethylphenyl) (4-fluorophenyl) methanol of formula VI

followed by oxidation of the resulting intermediate of formula V to give a compound of formula IV wherein R is C 1 -C 6 alkyl, acyl, C 1 -C 6 alkylsulfonyl or arylsulfonyl.

Oxidation of compounds of formula V may be any suitable oxidizing agent, the preferred reagent is Na2WO _fourth

The starting material of formula VI can be prepared by the method of International Patent Application PCT / DK 97/00511.

Another process for preparing compounds of formula IV comprises reacting 5-cyanophthalide with 4-fluorophenylmagnesium halide, preferably 4-fluorophenylmagnesium bromide followed by reaction with a compound of formula 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 bromide, tosyl chloride, Me ₂ SO ₄ or MeSC-Cl.

The reaction can be illustrated by the following reaction scheme:

The starting material, 5-cyanophthalide, can be prepared according to Tirouflet, J. Bull. Soc. Sci.

Bretagne 26, 1959 35.

A third process for the preparation of a compound of formula (IV) is to protect one of the enantiomers of the compound of formula (III), the R-enantiomer, with a protecting group and then dehydrate to form a compound of formula (VII). the following scheme:

In this way, the R-enantiomer of the compound of formula III can be used to produce racemic citalopram.

The oxidative cleavage of a compound of formula VII is effected by oxidation, preferably by treatment with permanganate or ozone, RuCl 3 or 0s0 _fourth

Citalopram is commonly supplied as an antidepressant in the form of a racemate. However, the active S-enantiomer of citalopram should also be marketed in the near future.

The active S-enantiomer of citalopram can be prepared from the compound of formula III by separation of the S-enantiomer and

The R-enantiomer followed by ring closure of the S-enantiomer by the method of US 4943590. The R-enantiomer of the compound of formula III was not previously used after separation.

According to another embodiment of the invention, it is after conversion

The R-enantiomer of formula III to an optically inactive compound of formula IV can be prepared by a racemic compound of formula III according to the following scheme

The racemic compound of formula III can be resolved into the optically active enantiomers by the method of US 4943590 to give the S-enantiomer of the compound of formula III, which is used for the preparation of S-citalopram. The R-enantiomer of compound III can be reused in the above procedure.

In this way, the R-enantiomer of the compound of formula III can be converted to S-citalopram.

The reaction conditions, solvents and other reaction conditions for the above reactions are conventional conditions readily determined by one of ordinary skill in the art.

Throughout the application and claims, the term C1-C6alkyl refers to straight or branched chain alkyl of 1 to 6 carbon atoms such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2- methyl-2-propyl, 2,2-dimethyl-1-ethyl and 2-methyl-1-propyl.

Aryl means a carbon aromatic group having one or two rings, for example phenyl or naphthyl, especially phenyl, optionally substituted on the ring.

The term heteroaryl refers to a heterocyclic aromatic group with one or two rings such as indolyl, thienyl, pyrimidyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, benzofuranyl, benzothienyl, pyridyl and furanyl, particularly suitable are pyrimidyl, indolyl and thienyl.

Acyl means C1-C6alkyl- or aryl- or heteroarylcarbonyl, wherein C1-C6alkyl, aryl and heteroaryl are as defined above.

Throughout this application, a halogen atom means a chlorine, bromine or iodine atom.

A preferred leaving group is a halide or sulfonate residue.

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

The compound of formula (I) may be used in free form or in pharmaceutically acceptable acid addition salt form. Of the acid addition salts, organic and inorganic acid salts may be used. Examples of organic salts include those with maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bismethylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartar, salicylic, citric, gluconic, mandelic, malic, cinnamic, salts with aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic and theophylline acetic acid, salts with 8-halo theophylins, for example with 8-bromohophylline, may also be used. Examples of inorganic salts are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids.

The acid addition salts may be prepared in a manner known per se. To do this, the free material is reacted with a calculated amount of acid in a water-miscible solvent such as acetone or ethanol followed by isolation of the salt by concentration of the solution and cooling, or an excess of acid in a water-immiscible solvent such as ethyl ether is added. ethyl acetate or dichloromethane and the salt spontaneously precipitates.

The pharmaceutical composition of the invention may be administered by any suitable means, 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 may be prepared by conventional methods. For example, tablets may be prepared by mixing the active ingredient with conventional excipients and / or diluents followed by compression of the resulting mixture on a conventional tabletting machine. Examples of excipients or diluents include conventional ingredients such as corn starch, potato starch, talc, magnesium stearate, gelatin, lactose, gums and the like. Otherwise, any other adjuvant, coloring agent, flavoring agent, preservative and the like may be used provided that they are compatible with the active ingredient.

Injectable solutions may be prepared by dissolving the active ingredient and adding other ingredients and a portion of the solvent for injection, preferably sterile water, making up to the desired volume, sterilizing and filling into suitable ampoules or vials. Also in this case any conventional adjuvant may be added, for example osmotic pressure adjusting agents, preservatives, antioxidants and the like.

The following examples are intended to illustrate the invention.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

2,2-dimethylpropionic acid 5-cyano-2- [1- (4-fluorophenyl) -1-hydroxymethyl] benzyl ester.

• · · * _{Λ Λ Λ Λ Λ Λ}

Ival 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 with pivaloyl chloride (4.2 g, 0.39 mol). The mixture was stirred for 60 minutes, then poured onto ice and extracted with ethyl acetate (2.times.75 ml), dried (MgSO4) and evaporated under reduced pressure to give 12.0 g of a colorless oil. The resulting product was purified by chromatography, eluting with hexane / ethyl acetate 1: 9 to give the title compound (8.2 g, 70%).

1 H-NMR (DMSO-D 6): 1.1 (s, 9H), 5.15 (m, 2H), 6 (bs, 1H),

6.25 (d, J = 6Hz, 1H), 7.1-7.2 (m, 2H), 7.3-7.4 (m, 2H), 7.7-7.9 (m, 3H).

Example 2

5-Cyano-2- [1- (4-fluorophenyl) meshanoyl] benzyl ester

2,2-dimethylpropionic

To a stirred solution of 8.0 g of 0.025 mol of 5-cyano-2- [1- (4-fluorophenyl) -1-hydroxymethyl; benzylic acid ester

2,2-dimethyl in 20 ml of ethyl acetate was added 10 g, 0.079 mol of 30% hydrogen peroxide solution, 0.15 g, 0.0005 mol Na2WO ₄ .2H ₂ O and 0.23 g, 0.0005 mol (n- octyl) 3NCH ₃ . HSO ₄ . The mixture was refluxed for 4 hours, then allowed to cool to room temperature, poured into dilute hydrochloric acid and extracted with 2 x 50 mL diethyl ether, dried over magnesium sulfate and evaporated under reduced pressure to yield 97.5 yield. % yields 7.8 g of the resulting ketone.

Example 3

Acetic acid 5-cyano-2- [4-dimethylamino-1- (4-fluorophenyl) -but-1-enyl] -benzyl ester and its oxalate.

Procedure 3A. 103 g, 1 mol of acetic anhydride are added dropwise to a stirred solution of 72 g, 0.21 mol of 4- [4-dimethylamino-1- (4-fluorophenyl) -1-hydroxybutyl] -3-hydroxymethylbenzonitrile in 438 g. of acetonitrile at 20 ° C. After completion of the addition, trimethylsilyl chloride (5.5 g, 0.05 mol) was added dropwise, resulting in an exothermic reaction at which the temperature rose from 20 to 28 ° C, then the reaction mixture was stirred overnight. After this time, concentrated sulfuric acid (14.5 g, 0.14 mol) was added to the reaction mixture, and the reaction mixture was heated to 50 ° C for 30 minutes, at which time HPLC indicated the reaction was complete. After cooling, the reaction mixture was evaporated under reduced pressure, neutralized with aqueous ammonia solution (23%) and extracted twice with toluene. The organic phase was dried (MgSO4) and dried under reduced pressure to give 69.5 g (85%) of the title product as a pale organotreatment.

The product was characterized as the oxalate salt. A warm solution of 1 g, 0.0177 mol of oxalic acid in 50 ml of methanol was added to a stirred solution of 6.63 g, 0.0173 mol of the resulting product in 50 ml of mechanol. After cooling, the crystals formed were separated by filtration and the obtained 7.4 g of crystals were washed with 10 ml of cold methanol. Mp 168 ° C.

¹ H NMR (DMSO-D 6): 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, 115.25, 115.59, 118,51, 124.85, 128.0, 128.18 131.32, 132.43, 132.73, 164.72, 169.96. Analysis for C ₂₄ H ₂₅ N ₂ O _S F 135,65, 135, 99, 138.68, 142.9 calculated 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-fluorophenyl) -but-1-enyl] -benzyl ester

Procedure 3B. 1112 g, 10.8 moles of acetic anhydride are added dropwise to a stirred solution of 1000 g, 2.9 moles of 4- [4-dimethylamino-1- (4-fluorophenyl) -1-hydroxybutyl] -3-hydroxymethylbenzonitrile in 1000 q of acetonitrile at 20 ° C, an exothermic reaction occurs, increasing the temperature from 20 to 50 ° C, then stirring for 2 hours. Thereafter, 300 g (3 mol) of concentrated sulfuric acid was added and the reaction mixture was heated to 50 ° C for 3 hours, at which time HPLC indicated completion of the reaction. After cooling, the mixture was neutralized with aqueous ammonia solution (25%) and then extracted twice with toluene. The organic phase was dried (MgSO4) and evaporated under reduced pressure to give 1023 g (92%) of the title product as a pale orange oil.

Example 4 2,2-Dimethylpropionic acid 5-cyano-2- [4-dimethylamino-1- (4-fluorophenyl) -but-1-enyl] -benzyl ester and its oxalate

Procedure 4A. A solution of 26.0 g, 0.215 mol of pivaloyl chloride was added to a stirred solution of 72 g, 0.21 mol of 4- [4-dimethylamino-1- (4-fluorophenyl) -1-hydroxybutyl] -3-hydroxymethylbenzonitrile, and 25.0 g. Triethylamine (0.247 mol) in acetonitrile (438 g) at 20 ° C. After 60 minutes, 40 ml of concentrated sulfuric acid was added dropwise and the reaction mixture was heated to 70 ° C for 180 minutes. The reaction mixture was allowed to cool to room temperature, neutralized with aqueous ammonia (25%) and extracted with diethyl ether. The organic phase was dried (MgSO4) and evaporated under reduced pressure as a yellow oil. This product for recrystallization from

188 [deg.] C.

oxalate with a melting point of acetone of ³ H NMR (DMSO-D ₆ ): 1.07 was characterized

3.05

J = 6.2Hz, 2H)

J = 12

J = 6.3 Hz,

7.42 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,

142.76, 164.4

Analysis for

C27H31N2O6F requires

C, 65.04

H, 6.28

N, 5.62%

N 5,6%

2,2-Dimethylpropionic acid 5-cyano-2- [4-dimethylamino-1- (4-fluorophenyl) -but-1-enyl] -benzyl ester and its hydrochloride

Procedure 4B. A solution of 30.1 g, 0.25 mol of pivaloyl chloride is added to a stirred solution of 85.5 g, 0.21 mol of 4- [417 •

-dimethylamino-1- (4-fluorophenyl) -1-hydroxybutyl] -3-hydroxymethylbenzonitrile in 290 ml acetonitrile at 0 ° C. The reaction mixture was stirred for 60 minutes and then concentrated sulfuric acid (32.5 g, 0.33 mol) was added. After the addition was complete, the reaction mixture was heated to 70 ° C for 180 minutes. The reaction mixture was allowed to cool to room temperature and acetonitrile (220 ml) was evaporated under reduced pressure, then neutralized with aqueous ammonia (23%) and extracted with diethyl ether. The organic phase was dried (MgSO4) and evaporated under reduced pressure to give the title compound (102.1 g) as a pink oil.

A solution of the resulting product of formula II (50.0 g, 0.11 mol) in methanol was added to a stirred solution of anhydrous hydrogen chloride in 200 ml of methanol. The mixture was stirred at room temperature for 30 minutes, then the solvent was evaporated under reduced pressure, diethyl ether was added and the resulting white solid was filtered off and washed with diethyl ether to give 48.1 g of the hydrochloride, m.p. 165 ° C.

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

Procedure 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-hydroxybutyl] -3-hydroxymethylbenzonitrile (85.5 g, 0.21 mol) in acetonitrile (290 mL). at 0 ° C. The reaction mixture was stirred for an additional 60 minutes and then concentrated sulfuric acid (32.5 g, 0.33 mol) was added. After the addition was complete, the reaction mixture was heated.

180 min at 70 ° C. The reaction mixture was allowed to cool to room temperature, the acetonitrile was evaporated under reduced pressure, 200 ml of toluene was added, which was also evaporated under reduced pressure to give 112.4 g of the product as a pale pink oil.

2,2-Dimethylpropionic acid 5-cyano-2- [4-dimethylamino-1- (4-fluorophenyl) -but-1-enyl] -benzyl ester as hydrogen chloride

Procedure 4D. Pivaloyl chloride (7.6 g, 0.63 mol) was added dropwise to a stirred solution of 21.35 g (0.052 mol)

4- [4-dimethylamino-1- (4-fluorophenyl) -1-hydroxybutyl] -3-hydroxymethylbenzonitrile in 21.35 g acetonitrile at room temperature. After the addition was complete, a solution of 6.1 g (0.053 mol) of methanesulfonyl chloride in 50 ml of methylene chloride was added, followed by 10.6 g (0.105 mol) of triethylamine. The reaction mixture is stirred for a further 30 minutes, then poured into water, extracted with methylene chloride, the organic phase is dried over magnesium sulphate and evaporated under reduced pressure. The resulting oil was then dissolved in a mixture of anhydrous ethanol and hydrogen chloride, evaporated under reduced pressure, diethyl ether was added, and the mixture was filtered to give 22.6 g of the hydrochloride of the title product in 98% yield.

Example 5

5-Cyano-2- [1- (4-fluorophenyl) methanoyl] benzyl ester

2,2-dimethylpropionic

Procedure 5A. To a stirred solution of 5-cyano-2- [4-dimethylamino-1- (419) hydrochloride (165 g, 0.337 mol)

-fluorophenyl) -but-1-enyl] -benzyl 2,2-dimethylpropionate in 1100 ml of water is added a solution of 3.7 mol of NaMnO ₄ in water (40% by volume) at such a rate that the reaction mixture is maintained at a temperature in the range Mp 45 ° C. After the addition was complete, the mixture was allowed to cool to room temperature and filtered. The solid is washed with 3 x 150 ml of cold water and then treated with 2000 ml of acetone and filtered to give a crude ketone which is purified by filtration through silica, eluting with hexane / ethyl acetate 8: 2. yielding 82 g of pure ketone with a melting point of 81 ° C in 75% yield.

^{Χ Η} NMR _(DMSO-d6): 0.9 (s, 9H), 5.1 (s, 2H), 7.35-7.5 (m,

3H), 7.65 (d, J = 7H) Hz, 1H) , 7,8-7 9 (m, 2H), 8.0 (m, 1 H), 8.1 (with, 1H) ¹³ c, NMR (DMSO-D3) : 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 for C 20 H 18 NO 3 F calculated C, 70.79 H 5.35 N 4.13% found C, 70.49 H 5.30 N 4.07%

5-Cyano-2- [1- (4-fluorophenyl) methanoyl] benzyl ester

2,2-dimethylpropionic

Procedure 5B. Oxygen was bubbled through a stirred solution of 2,2-dimethylpropionic acid 5-cyano-2- [4-dimethylamino-1- (4-fluorophenyl) -but-1-enyl] -benzyl ester in 1300 (38.0 g, 0.093 mol) ml of water and 70 ml of concentrated hydrochloric acid are monitored by HPLC. A white precipitate is formed during the reaction, after completion of the reaction a white solid is formed. It is filtered, washed with water and dried under reduced pressure to give 22.5 g of pure protected resulting ketone in 72% yield.

5-Cyano-2- [1- (4-fluorophenyl) meshanoyl] benzyl ester

2,2-dimethylpropionic

Procedure 5C. To a suspension of 11.0 g, 0.022 mol of 2,2-dimethylpropionic acid 5-cyano-2- [4-dimethylamino-1- (4-fluorophenyl) -but-1-enyl] -benzyl ester as sulfate in 250 ml of water and 100 ml ethyl acetate was added 30 g, 0.14 mol _NaIO4 hydrate and 0.35 g of RuC1 _third The mixture was stirred vigorously for 16 hours at room temperature. The resulting slurry was filtered through a pad of silica. The organic phase is separated and washed with 50 ml of water. The solvent was removed in vacuo to give 7.4 g (99%) of an oil which crystallized on standing.

Example 6

5-Cyano-2- [1- (4-fluorophenyl) mechanoyl] benzyl ester

2,2-dimethylpropionic

4-Fluorophenylmagnesium bromide solution prepared from

4-fluorobromobenzene (19.2 g, 0.11 mol) and magnesium turnings (3.2 g, 0.13 mol) in anhydrous THF (100 ml) were added dropwise to a suspension of 5-cyanophthalide (15.9 g, 0.1 mol) in 150 ml. of anhydrous THF. The temperature is maintained below 5 ° C. After the addition was complete, the reaction mixture was stirred at room temperature overnight.

Pivaloyl chloride (13.3 g, 0.11 mol) was added to the reaction mixture and the mixture was heated to 60 ° C for 2 hours.

• ·

The resulting solution was added to a saturated solution of ammonium chloride (100 mL in water) and 50 g of ice. 100 ml of diethyl ether are added and the phases are separated. The organic phase is washed twice with 100 ml of 0.1 N sodium hydroxide and 100 ml of water and then dried with 20 g of magnesium sulfate. Evaporation of the solvents afforded 29.8 g (88% yield) of a crude product of sufficient purity for the next reaction.

A pure sample was prepared by crystallization from a 1: 9 mixture of ethyl acetate and n-heptane. The resulting product was obtained as off-white crystals.

Example 7

1- (3-dimethylaminopropyl) -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonizrile and its oxalate

To a solution of 28.5 g, 0.084 ml of 2,2-dimethylpropionic acid 5-cyano-2- [1- (4-fluorophenyl) methanoyl] benzyl ester in 150 ml of anhydrous THF at 0 ° C is added a solution of 2.2 equivalents of 3 - (N, N-dimethylamino) propylmagnesium chloride and the progress of the reaction was monitored by HPLC. After 1 hour at 0 ° C, saturated ammonium chloride solution was added and the mixture was extracted with ethyl acetate, dried over sodium sulfate and evaporated under reduced pressure to give 28.0 g of the title product as an oil with 87% purity by HPLC. The oxalate is obtained by crystallization from acetone.

Example 8

- [1- (4-Fluorophenyl) -methanoyl] -3-hydroxymethylbenzonitrile g, 0.061 mol of 5-cyano-2- [1- (4-fluorophenyl) methanoyl] benzyl ketone-2,2-dimethyl-22-propionate is added to the fresh prepared sodium methoxide containing 0.25 g of sodium in 100 ml of methanol and stirred at room temperature, monitoring the complete deprotection by HPLC. The methanol was then removed under reduced pressure, the residue dissolved in MTBE, washed with saturated ammonium chloride solution and high magnesium sulfate, and then evaporated under reduced pressure to give 14.6 g of deprotected title compound.

Example 9

4- [4-dimethylamino-1- (4-fluorophenyl) -1-hydroxybutyl] -3-hydroxymethylbenzonitrile

To a solution of 15.0 g, 0.046 mole of cecon-4- [1- (4-fluorophenyl) -methanoyl] -3-hydroxymethylbenzonitrile in anhydrous THF at 2.2 ° C was added 2.2 equivalents of 3- (N, N-) solution. dimethylamino) propylmagnesium chloride and the reaction is monitored by HPLC. Saturated ammonium chloride solution was added at 0 ° C for one hour, the mixture was extracted with MTBE, dried over magnesium sulfate and evaporated under reduced pressure to give 16.7 g of the product as an oil with 85% purity.

Claims (12)

PATENT CLAIMS CLAIMS 1. A process for the preparation of citalopram comprising reacting a compound of formula IV wherein R is C1-C6alkyl, acyl, C1-C6alkylsulfonyl or arylsulfonyl, with 3- (N, N-dimethylamino) -propylmagnesium halide, with preferably with 3- (N, N-dimethylamino) -proplymagnesium chloride to give citalopram of formula I which is isolated in free form or in pharmaceutically acceptable salt form. • · 2. A process according to claim 1, wherein the intermediate is reacted IV, prepared by oxidation of the corresponding compound of formula V wherein R is as defined in claim 1. Process according to claim 2, characterized in that a compound of formula V, prepared by introducing a protective group on the hydroxymethyl alcohol of (4-cyano-2-hydroxymethylphenyl) (4-fluorophenyl) methanol of formula VI, is used. 4. A process according to claim 1, wherein the intermediate of the formula is reacted IV, prepared by oxidative cleavage of the corresponding compound of formula VII wherein R is as defined in claim 1. Method according to claim 4, characterized in that the oxidative cleavage of the compound of formula VII is preferably carried out by oxidation with MnCl 2 or ozone, RUC 13 or OSO 4. Process according to one of Claims 4 to 5, characterized in that an alkene of formula VII, prepared by introducing a protective group and dehydrating the corresponding compound of formula III in the form of the R-enantiomer, is used. Process according to claim 1, characterized in that the reaction is carried out using an intermediate of formula IV, prepared by reacting 5-cyanophthalide with 4-fluorophenylmagnesium halide, preferably 4-fluorophenylmagnesium bromide, followed by reaction with a compound of formula RX to form a ketone of formula IV. wherein R is as defined in claim 1 and X is a leaving group, the compound of formula RX is preferably pivaloyl chloride, 3,5-dimethoxybenzoyl chloride, methyl iodide, ethyl bromide, tosyl chloride, Me ₂ SO ₄ or MeSO ₂ Cl. 8. A process for the preparation of a racemic compound of the formula III, characterized in that it is: a) deprotecting a compound of formula IV wherein R is as defined in claim 1, b) reacting the resulting compound of formula VIII with 3- (N, N-dimethylamino) propyl magnesium halide. Preferably with 3- (N, N-di-methylamino) propylmagnesium chloride to give the racemic compound of formula III ř * 9. Process according to one of Claims 1 to 8, characterized in that R represents acyl, preferably pivaloyl, acetyl or optionally substituted benzoyl. A compound of formula IV wherein R is C 1 -C 6 alkyl, acyl C 1 -C 6 alkylsulfonyl or arylsulfonyl, preferably pivoyl, acetyl or optionally substituted benzoyl, as an intermediate to carry out the process of claim 1. Pharmaceutical composition for the treatment of depressive conditions, characterized in that it contains as its active ingredient citalopram, prepared by a process according to any one of claims 1 to 9. Use of an intermediate according to claim 10, for the manufacture of Citalopram or S-citalopram.