CZ292992B6 - 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

Technical field

The invention relates to a process for the preparation of the known antidepressant citalopram, which is 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, 5-HT) reuptake inhibitor with antidepressant activity. 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 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 Π

Br

In the presence of a dehydrating agent followed by a bromine atom exchange at the 5-position with copper (I) cyanide. The starting material of formula Π 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.

closes the ring by dehydration reaction with strong sulfuric acid to form citalopram. The intermediate of formula ΙΠ is prepared from 5-cyanophthalide by two consecutive Grignard reactions, first with 4-fluorophenylmagnesium chloride and then with N, N-dimethylaminopropylmagnesium halide.

Other processes have been described in WO 98 019511, WO 98 019512 and WO 98 019513. WO 98 019512 and WO 98 019513 disclose processes in which 5-aminophthalide, 5-carboxyphthalide or 5- (secaminocarbonyl) phthalide are disclosed. subjected to two successive Grignard reactions, ring closure and conversion of the resulting 1,320 dihydroisobenzofuran derivative into the corresponding 5-cyano compound, i.e., citalopram. International patent application WO 98 019511 discloses a process for the manufacture of citalopram, in which a ring is closed in 4-substituted 2-hydroxymethylphenyl- (4-fluorophenyl) methanol and the resulting 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 give 25 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 and its pharmaceutically acceptable salts by reacting a compound of formula IV

-2GB 292992 B6

wherein R is acyl, with 3- (N, N-dimethylamino) propylmagnesium halide, preferably 3 (N, N-dimethylamino) propylmagnesium chloride, to form citalopram of formula I

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

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 acyl

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

-3GB 292992 B6

followed by oxidation of the resulting intermediate of formula V to give a compound of formula IV wherein R is acyl.

The oxidation of the compounds of formula (V) may be accomplished by any suitable oxidizing agent, preferably Na ₂ WO ₄ .

The starting material of formula VI can be prepared by the method of International Patent Application No. 10 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 R-X wherein R is as defined above and X is a leaving group 15.

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 producing a compound of formula IV is to protect one of the enantiomers of the compound of formula ΙΠ, the R-enantiomer, with a protecting group and then dehydrate to form a compound of formula VH which is then oxidized to the ketone of formula IV according to the following scheme:

-4GB 292992 B6

In this way, the R-enantiomer of the compound of formula Π 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 OsO ₄ .

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 a compound of formula ΠΙ by separating the Senantiomer 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 Π was previously not used.

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.

In the text of the application and the claims, the term C1-C6alkyl refers to straight or branched chain alkyl having 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.

In the specification, 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 the form of a pharmaceutically acceptable acid addition salt. Of the acid addition salts, organic and inorganic acid salts may be used. Examples of organic salts are those with maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bismethylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartar, salicylic, citric, gluconic, lactic, malic, citric, cinnamon aspartic, stearic, plasma, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic and theo

Also useful are salts with 8-halotheophyllins, for example with 8-bromotheophyllin. For example, inorganic salts include those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids.

The acid addition salts may be prepared in a manner known per se. This is done by reacting the free material with a calculated amount of acid in a water-miscible solvent such as acetone or ethanol, followed by isolating the salt by concentrating the solution and cooling, or adding an excess of acid in a water-immiscible solvent such as ethyl ether, ethyl acetate or dichloromethane and the salt spontaneously precipitates.

r 10

The pharmaceutical composition containing citalopram obtained according to the invention can 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 containing citalopram obtained according to the invention can 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 25 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-Dimethylpropinic acid 5-cyano-2- [1- (4-fluorophenyl) -1-hydroxymethyl] 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). The mixture was stirred for 60 minutes, then poured into 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), δ (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).

-6GB 292992 B6

Example 2

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

To a stirred solution of 2,2-dimethylpropionic acid 5-cyano-2- [1- (4-fluorophenyl) -1-hydroxymethyl] benzyl ester in 20 ml of ethyl acetate is added 10 g, 0.079 mol of a 30% solution. hydrogen peroxide, 0.15 g, 0.0005 mol of Na ₂ WO ₄ .2H ₂ O and 0.23 g, 0.0005 mol (noctyl) of 3NCH 3. HSO4. The mixture was refluxed for 4 hours, then allowed to cool to room temperature, poured into dilute hydrochloric acid and extracted with 2x50 mL diethyl ether, dried over magnesium sulfate and evaporated under reduced pressure to yield 97.5% yield. 7.8 g of the resulting ketone are obtained.

Example 3

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

Procedure 3 A. 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 and the reaction mixture was heated to 50 ° C for 30 minutes, after which time HPLC showed complete reaction. 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 evaporated under reduced pressure to give 69.5 g (85%) of the title product as a pale orange oil.

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 methanol. After cooling, the formed crystals were collected by filtration and the resulting 7.4 g of the 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 = 7Hz, 1H), 7.1-7.25 (m, 4H), 7.42 (d, J = 7Hz, 1H) 7.9-8 (m, 2H).

^B 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, 135.65, 135.99, 138.68, 142.9, 164.72, 169.96.

Analysis for C ₂₄ H ₂₅ N ₂ O ₍ , F:

calculated: C 63.14 H 5.53 N6.14% found: C63.1 H 5.58 N6.12%

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

Procedure 3B. 1112 g, 10.8 mol of acetic anhydride are added dropwise to a stirred solution of 1000 g, 2.9 mol of 4- [4-dimethylamino-1- (4-fluorophenyl) -1-hydroxybutyl] -3-hydroxymethylbenzonitrile in 1000 g. of acetonitrile at 20 ° C, an exothermic reaction occurs where the temperature rises from 20 to 50 ° C, then the mixture is stirred for 2 hours. After this time, 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 showed that the reaction was complete. After cooling, the mixture was neutralized with aqueous ammonia solution (25%) and then extracted twice with toluene. The organic phase is dried

The magnesium sulfate was evaporated under reduced pressure to give the title compound (1023 g, 92%) 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 pivaloyl chloride (26.0 g, 0.215 mol) was added to a stirred solution of 4- [4-dimethylamino-1- (4-fluorophenyl) -1-hydroxybutyl] -3-hydroxymethylbenzonitrile (72 g, 0.21 mol) and 25.0 g, 0.247 mol of triethylamine in 438 g of acetonitrile 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 to give the title compound (82%) as a yellow oil (96%). This product was characterized as recrystallized from acetone as the oxalate, m.p. 188 ° C.

1 H NMR (DMSO-D ₆ ): 1.07 (s, 9H), 2.2 (m, 2H), 2.6 (s, 6H), 3.05 (t, J = 6.2Hz, 2H) ), 4.725 (d, J = 12 Hz, 1H), 4.85 (d,> 12 Hz, IH), 6.3 (t, J = 6.3 Hz, IH), 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, 115.3, 115.64, 128.17, 131.33 , 132.28.136.13, 138.58.142.76, 164.4

Analysis for C ₂₇ H3iN O6F _2: Calculated: C, 64.04 H6,28 N5,62% Found: C 64.86% H6,63 N5,6

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 pivaloyl chloride (30.1 g, 0.25 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 290 ml of 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 50.0 g (0.11 mol) of the product of formula Π in methanol is 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 added

-8EN 292992 B6

Concentrated sulfuric acid (32.5 g, 0.33 mol). 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. 7.6 g (0.63 mol) of pivaloyl chloride are added dropwise to a stirred solution of 21.35 g (0.052 mol) of 4- [4-dimethylamino-1- (4-fluorophenyl) -1-hydroxybutyl] -3-hydroxymethylbenzonitrile in 21, 35 g of 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

2,2-Dimethylpropinic acid 5-cyano-2- [1- (4-fluorophenyl) methynoyl] benzyl ester

Procedure 5A. To a stirred solution of 5-cyano-2- [4-dimethylamino-1- (4-fluorophenyl) -but-1-enyl] -benzyl 2,2-dimethylpropionate hydrochloride (165 g, 0.337 mol) in 1,100 ml of water is added 3.7 moles of NaMnCl 4 in water (40% by volume) at a rate such that the reaction mixture is maintained at a temperature in the range of 45-50 ° C. After the addition was complete, the mixture was allowed to cool to room temperature and filtered. The solid was 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 was 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.

^! 1 H NMR (DMSO-D ₆ ): 0.9 (s, 9H), 5.1 (s, 2H), 7.35-7.5 (m, 3H), 7.65 (d, J = 7Hz, 1H), 7.87.9 (m, 2H), 8.0 (m, 1H), 8.1 (s, 1H) ¹³ C, NMR (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 for C20H18NO3F:

calculated: C 70.79 H5.35 N4.13% found: C 70.49 H5.30 N4.07%

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

Procedure 5B. Oxygen was bubbled through a stirred solution of 5-cyano-2- [4-dimethylamino-1- (4-fluorophenyl) -but-1-enyl] -benzyl 2,2-dimethylpropinate in 3800 g, 0.093 mol in 1300 ml of water and 70 ml of concentrated hydrochloric acid, the progress of the reaction is monitored by HPLC. A white precipitate is formed during the reaction, after completion of the reaction, the white solid is filtered off, washed with water and dried under reduced pressure to give 22.5 g of pure protected resulting ketone in 72% yield.

-9EN 292992 B6

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

Procedure 5C. To a suspension of 2,2-dimethylpropionic acid 5-cyano-2- [4-dimethylamino-1- (4-fluorophenyl) -but-5-enyl] -benzyl ester as a 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 vigorously stirred at room temperature for 16 hours. The resulting suspension is 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

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

A solution of 4-fluorophenylmagnesium bromide prepared from 19.2 g (0.11 mol) of 4-fluorobromobenzene and 3.2 g (0.13 mol) of magnesium turnings in 100 ml of anhydrous THF is added dropwise to a suspension of 15.9 g. 1 mol of 5-cyanophthalide in 150 ml of anhydrous THF. The temperature is maintained below 5 ° C. After the addition was complete, the reaction mixture was stirred overnight at 20 room temperature.

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 25 N sodium hydroxide and 100 ml of water and then dried with 20 g of magnesium sulphate. 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 dirty white crystals.

Example 7 1- (3-Dimethylaminopropyl) -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile and oxalate thereof

To a solution of 2,2-dimethylpropionic acid 5-cyano-2- [1- (4-fluorophenyl) methanoyl] benzyl ester in 150 ml of anhydrous THF at 28 ° C was added a solution of 2.2 equivalents of 40 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.

Claims (10)

PATENT CLAIMS A process for the preparation of citalopram and pharmaceutically acceptable salts thereof, comprising reacting a compound of formula IV wherein R is acyl with 3- (N, N-dimethylamino) -propylmagnesium halide to form citalopram of formula I which is isolated in in free form or in the form of a pharmaceutically acceptable salt. A process according to claim 1, characterized in that an intermediate of formula (IV) prepared by oxidation of a corresponding compound of formula (V) wherein R is as defined in claim 1 is reacted. -11EN 292992 B6 Process according to Claim 2, characterized in that a compound of formula V, prepared by introducing a protective group on the hydroxymethyl alcohol group of (4-cyano-2-hydroxymethylphenyl) - (4-fluorophenyl) methanol of formula VI, is used. A process according to claim 1, characterized in that the intermediate of formula (IV) prepared by oxidative cleavage of the corresponding compound of formula (vn) wherein R is as defined in claim 1 is reacted. 15 Dec Process according to claim 4, characterized in that the oxidative cleavage of the compound of formula VII is preferably carried out by oxidation with MnO ₄ - or ozone, RuCl ₃ or OsO ₄ . Process according to any one of claims 4 to 5, characterized in that an alkene of formula VII, prepared by introducing a protective group R, wherein R is as defined in claim 1, is used. 20 and dehydrating the corresponding compound of formula ΙΠ as the R-enantiomer. -12GB 292992 B6 The process of claim 1, wherein the reaction is an intermediate of formula IV, prepared by reacting 5-cyanophthalide with 4-fluorophenylmagnesium halide followed by reaction with a compound of formula RX to form a ketone of formula IV, wherein R is as defined in of claim 1, and X is a leaving group. 8. The process of claim 1 wherein the compound of formula IV is reacted with 3- (N, N-dimethylamino) propylmagnesium chloride. A process according to claim 7, wherein the compound of formula (IV), prepared by reacting 5-cyanophthalide with 4-fluorophenylmagnesium bromide, is used. The process of claims 1-9 wherein R is pyvaloyl, acetyl or optionally substituted benzoyl.