JP2002525273A - Method for producing citalopram - Google Patents

Abstract

(57) Abstract: The present invention relates to a compound represented by the formula IV wherein R is C _1-6 alkyl, acyl, C _1-6 alkylsulfonyl or arylsulfonyl. -Dimethylamino) propylmagnesium halide to produce citalopram.

Description

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to the well-known antidepressant citalopram, namely 1- [3- (dimethylamino) propyl] -1- (4-fluorophenyl) -1,3-dihydro-5- The present invention relates to a method for producing isobenzofurancarbonitrile. BACKGROUND OF THE INVENTION Citalopram is a well-known antidepressant, which has been available on the market for several years,
Having the structure of formula I:

[0002]

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It is a selective, centrally active serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor with antidepressant activity. The antidepressant activity of this compound has been described in several publications, for example, J. Hyttel, Prog. Neuro-Psychopharmacol. & Biol. Psyc
hiat., 1982, 6, 277-295 and A. Gravem, Acta Psychiatr. Scand., 1987, 75,
478-486. Furthermore, it is disclosed in EP-A-474,580 that this compound is effective in treating dementia and cerebrovascular disorders.

Citalopram was first disclosed in German Patent No. 2,657,271 (US Pat. No. 4,136,193).
(Corresponding to the specification). This patent discloses the production of citalopram by one method, and outlines another method used to produce citalopram.

According to the process described therein, the corresponding 1- (4-fluorophenyl) -1,3-dihydro-5-isobenzofurancarbonitrile is prepared in the presence of methylsulphinylmethide as condensing agent. React with 3- (N, N-dimethylamino) propyl-chloride. The starting compound is prepared from the corresponding 5-bromo derivative by reaction with cuprous cyanide.

According to a method that is only generally outlined, citalopram has the formula I
Compound represented by I:

[0007]

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Is obtained by closing the ring in the presence of a dehydrating agent and then exchanging the 5-bromo group with cyanogen using cuprous cyanide. The starting compounds of the formula II are obtained from 5-bromophthalide by two successive Grignard reactions, respectively with 4-fluorophenylmagnesium chloride and N, N-dimethylaminopropylmagnesium chloride.

A new and surprising process for the preparation of citalopram and intermediates used in the preparation of cyclopram are described in US Pat. No. 4,650,884. According to the method, the compound of formula III

[0010]

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The intermediate represented by is subjected to a ring closure reaction by dehydration with strong sulfuric acid to obtain citalopram. The intermediate of formula III is prepared from 5-cyanophthalide by two successive Grignard reactions, namely with 4-fluorophenylmagnesium halide and N, N-dimethylaminopropylmagnesium halide, respectively.

Another process is described in International Patent Application Nos. WO 98/019511, WO 98/01951.
No. 019512 and (WO) 98/0151313.
International Patent Application Nos. (WO) 98/01951 and (WO) 98/01951
The invention described in the specification of Patent No. 3 discloses 5-amino-, 5-carboxy-, 5- (s-
Aminocarbonyl) phthalide was subjected to two successive Grignard reactions to give the resulting 1
, 3-Dihydroisobenzofuran derivatives to ring closure to convert to the corresponding 5-cyano compounds, ie, citalopram. International Patent Application No. (WO) 98 /
No. 0195511 discloses that (4-substituted-2-hydroxymethylphenyl- (4-fluorophenyl) methanol compound is ring-closed and the resulting 5-substituted 1- (4-fluorophenyl) -1 is obtained. Disclosed is a process for preparing citalopram, which comprises converting 2,3-dihydroisobenzofuran to the corresponding 5-cyano derivative and then alkylating it with (3-dimethylamino) propylhalogenide to obtain citalopram. .

Finally, a method for producing individual enantiomers of citalopram is described in US Pat. No. 4,943,59.
No. 0, from this patent it is also clear that the ring closure of the intermediate of formula III is carried out via a labile ester with a base.

The inventor has surprisingly found that citalopram can be prepared by a new advantageous and safe method using conventional starting compounds.

SUMMARY OF THE INVENTION Accordingly, the present invention provides a compound of formula IV

[0016]

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(Wherein R is C _1-6 alkyl, acyl, C _1-6 alkylsulfonyl or arylsulfonyl), a compound represented by the formula: 3- (N, N-dimethylamino) propyl magnesium halide; Reaction with 3- (N, N-dimethylamino) propylmagnesium chloride, preferably of formula I

[0018]

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[0019] The present invention relates to a novel method for producing citalopram, which comprises producing citalopram represented by and isolating it as its base or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides novel intermediates of formula IV.

In another aspect, the present invention relates to a method for preparing an intermediate of formula IV.

In another aspect of the invention, the compound of formula IV is of the formula III

[0023]

[Formula 16]

Used for the production of the racemic compound represented by

In another aspect, the present invention relates to an antidepressant pharmaceutical formulation containing citalopram produced by the method of the present invention.

According to the method of the present invention, citalopram has the formula IV

[0027]

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Wherein R is C _1-6 alkyl, acyl, C _1-6 alkylsulfonyl or arylsulfonyl. The compound is obtained by a one-step Grignard reaction.

Surprisingly, the product of the Grignard reaction spontaneously closes to citalopram and thus the reaction of the compound of formula IV with the Grignard reagent gives citalopram in one step.

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

One of these methods is based on Formula VI

[0032]

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Protection of (4-cyano-2-hydroxymethylphenyl) (4-fluorophenyl) methanol by hydroxymethyl alcohol followed by oxidation to a compound of formula IV wherein R is C _1-6 Alkyl, acyl, C _1-6 alkylsulfonyl or arylsulfonyl).

The oxidation of the compounds of the formula V is carried out with customary oxidizing agents, preferably with N 2
It is carried out by a ₂ WO _4.

The starting compound of the compound of formula VI is described in International Patent Application No. PCT / DK97
/ 00511 can be prepared.

Another process for the preparation of the compounds of the formula IV is to prepare 5-cyanophthalide and 4-fur
Orophenyl magnesium halide, preferably 4-fluorophenyl magnesium
Reaction with umbromide, then RX (wherein R has the meaning given above and X is
It is removal. ) ──── This RX is preferably pivaloyl chloride, 3,5 _- Dimethoxybenzoyl chloride, methyl iodide, ethyl bromide, tosyl chloride,
Me_TwoSO_FourOr MeSO_TwoIncluding the reaction with Cl, which is Cl.

The reaction is shown as follows:

[0038]

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The starting compound, 5-cyanophthalide, was obtained from Triouflet, J .; Bull. Soc. Sci. Bretagn.
e 26, 1959, 35.

According to a third process for the preparation of the compound of formula IV, one of the enantiomers of the compound of formula III, ie its R-enantiomer, is protected and dehydrated. , Equation V
The compound represented by II is converted to a ketone represented by the formula IV by oxidation.

[0041]

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In this way, the R-enantiomer of formula III can be used for the production of racemic citalopram.

The oxidative cleavage of the compounds of the formula VII is obtained by oxidation, preferably
It is performed by nO ₄ ⁻ (permanganate) or ozone, RuCl ₃ , OsO ₄ .

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

The active S-enantiomer of citalopram separates its S-enantiomer from the R-enantiomer as described in US Pat. No. 4,943,590, and It can be produced from the compound represented by the formula III by closing the palm form. Formula II
The R-enantiomer of the compound represented by I has not been used previously after separation.

Further, according to another aspect of the present invention, the R-enantiomer of formula III is converted to a non-optically active compound of formula IV followed by a racemic of formula III The compound can be prepared as shown in the following reaction formula.

[0047]

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The racemic compound of formula III is separated into optically active enantiomers by the method described in US Pat. No. 4,943,590, whereby the S of the compound of formula III -An enantiomer is obtained, which is used for the production of S-citalopram. The R-enantiomer of the compound of formula III can be recycled once more to the above process.

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

Other reaction conditions, solvents, and the like for the above reaction are the usual conditions for such a reaction, and can be easily determined by those skilled in the art.

Throughout the specification and claims, and throughout the specification and claims,
C _1-6 alkyl "the term branched or unbranched alkyl group 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
-Means methyl-1-propyl.

The term “aryl” refers to monocyclic or bicyclic carbocyclic aromatic groups, such as phenyl and naphthyl, especially phenyl or ring-substituted phenyl.

The term “heteroaryl” refers to monocyclic or bicyclic heterocyclic aromatic groups such as indolyl, thienyl, pyrimidyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, benzofuranyl, benzothienyl, pyridyl and furanyl, especially pyrimidinyl, Means indolyl and thienyl.

[0054] "Acyl" The term C _1-6 alkyl - or aryl - or it is used in the sense of heteroaryl carbonitrile nonyl, where C _1-6 alkyl - or aryl -
Or heteroaryl is as defined above.

Halogen means chlorine, bromine or iodine.

The leaving group preferably means a halide or a sulfonate.

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

The compounds of general formula I can be used as their free base or as their pharmaceutically acceptable acid addition salts. As such an acid addition salt, a salt formed with an organic acid or an inorganic acid can be used. Examples of such organic salts are maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, oxalic acid, bismethylene salicylic acid, methanesulfonic acid, ethanedisulfonic acid, acetic acid, propionic acid, tartaric acid,
Salicylic acid, citric acid, gluconic acid, lactic acid, malic acid, mandelic acid, cinnamic acid, citraconic acid, aspartic acid, stearic acid, palmitic acid, itaconic acid,
Glycolic acid, p-amino-benzoic acid, glutamic acid, benzenesulfonic acid and theophylline acetic acid, and salts with 8-haloteofiline, for example, 8-bromo-theophylline. Examples of such inorganic salts are the salts with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids.

The acid addition salts of this compound can be prepared by methods known in the art. The base is reacted with a calculated amount of acid in a water-miscible solvent such as acetone or ethanol and then concentrated and cooled to isolate the salt or a water-immiscible solvent such as ethyl ether, React with excess acid in ethyl acetate or dichloromethane and spontaneously isolate the salt.

The pharmaceutical preparations according to the invention can be administered parenterally in all suitable ways and in all suitable forms, for example orally in the form of tablets, capsules, powders, syrups or in the form of customary sterile solutions for injection. Can be administered.

[0061] The pharmaceutical preparations of the present invention can be manufactured by methods conventional in the art. For example, tablets can be prepared by mixing the active substance with customary adjuvants and / or diluents and then compressing this mixture on a conventional tablet press. Examples of adjuvants or diluents include: corn starch, potato starch, talc, magnesium stearate, gelatin, lactose, gum and the like. All other adjuvants or additives, such as colorants, fragrances, preservatives and the like may be used provided that they are compatible with the active ingredient.

The injectable solution is prepared by dissolving the active ingredient and usable additives in a part of an injectable solvent, preferably sterile water, adjusting the solution to a desired volume, sterilizing the solution, It can be manufactured by filling in a small ampoule or small bottle. All suitable additives commonly used in the art can be used, for example, tonicity agents.
), Preservatives, antioxidants and the like can be added.

EXAMPLES The present invention is further described by the following examples.

Example 1 2,2-Dimethyl-propionic acid 5-cyano-2- [1- (4-fluorophenyl) -1-hydroxy-methyl] -benzyl ester (4-cyano-2-hydroxymethylphenyl) (4-Fluorophenyl) methanol (9.2 g, 0.037 mol) and triethylamine (4.0 g, 0.1 g).
Pivaloyl chloride (4.2 g, 0.39 mol) is added to the stirred solution having the same concentration as in Example 1 (0.4 mol). After stirring for 60 minutes, the reaction mixture was poured onto ice, extracted with diethyl ether (2 × 75 ml), dried (MgSO ₄ ) and concentrated under reduced pressure to give a colorless oil (12.0 g). The obtained compound was purified by chromatography (eluent hexane / ethyl acetate 1: 9) to give the desired compound (8.2 g, 70 g).
%).

[0065]

[Outside 1]

Example 2 2,2-Dimethyl-propionic acid 5-cyano-2- [1- (4-fluorophenyl) -methanoyl] -benzyl ester 2,2-dimethyl-propionic acid in ethyl acetate (20 ml) 5-cyano-2
To a stirred solution containing-[1- (4-fluorophenyl) -1-hydroxy-methyl] -benzyl ester (8.0 g, 0.025 mol) was added a 30% wt hydrogen peroxide solution (10 g, 0 g). .079 _{mol), Na 2 WO 4. 2H 2} O (0.15g
, 0.0005 mol) and (n-octyl) 3NCH ₃ . HSO ₄ (0.23 g
, 0.0005 mol). The mixture was then heated at reflux for 4 hours, cooled to room temperature, poured into dilute HCl, extracted with diethyl ether (2 × 50 ml) and dried (
MgSO ₄ ) and concentrated under reduced pressure to obtain the desired ketone compound (7.8 g, 97.5%).

Example 3 5-Cyano-2- [4-dimethylamino-1- (4-fluoro-phenyl) -but-1-enyl] -benzyl acetate and its oxalate Method A. Acetic anhydride (103 g, 1 mol) was added to 4- [4-dimethylamino-1- (4-fluoro-phenyl) -1-hydroxy-butyl] -3-hydroxymethyl-benzonitrile (72 g) in acetonitrile (438 g). , 0.21 mol)
Is added dropwise at 20 ° C. to the stirred solution having As soon as the addition has ended, trimethylsilyl chloride (5.5 g, 0.05 mol) is added dropwise (giving an exothermic reaction temperature rising from 20 to 28 ° C.) and stirred overnight. Then concentrated H ₂ SO ₄ (14.5 g,
(0.14 mol) is added to the reaction mixture and the reaction mixture is heated at 50 ° C. for 30 minutes (HPLC indicates the end of the reaction). After cooling, the reaction mixture is concentrated under reduced pressure, neutralized with aqueous ammonia (23%) and extracted with toluene (twice). Dry the organic phase (MgSO ₄ ) and concentrate under reduced pressure to give the desired compound (69.5 g, 85%) as a pale orange oil.

Manufactured as oxalate. Oxalic acid (1 g, 0.0 g in methanol (50 ml))
(177 mol) is added to a stirred solution of the desired alkene compound (6.63 g, 0.0173 mol) in methanol (50 ml). After cooling, the crystals were isolated by filtration (7.4 g) and cold methanol (10 m
Wash in l). Melting point 168 [deg.] C.

[0069]

[Outside 2]

Acetic acid 5-cyano-2- [4-dimethylamino-1- (4-fluoro-phenyl) -but-1-enyl] -benzyl ester Method 3B. Acetic anhydride (1112 g, 10.8 mol) was added to acetonitrile (10
00g) in 4- [4-dimethylamino-1- (4-fluoro-phenyl) -1
-Hydroxy-butyl] -3-hydroxymethyl-benzonitrile (1000 g
(2.9 mol) is added dropwise at 20 ° C. (resulting in an exothermic reaction temperature rising from 20 to 50 ° C.) and stirred for 2 hours. Then concentrated H ₂ SO ₄ (300
g, 3 mol) is added to the reaction mixture and the reaction mixture is heated at 50 ° C. for 3 hours (H
PLC indicates the end of the reaction). After cooling, the reaction mixture was treated with an aqueous ammonia solution (25%
) And extract with toluene (2 times). The organic phase was dried (MgSO ₄ ) and concentrated under reduced pressure to give the desired compound as a pale orange oil (1023 g, 92%
) Is obtained.

Example 4 5-cyano-2- [4-dimethylamino-1,2-dimethyl-propionic acid
-(4-Fluoro-phenyl) -but-1-enyl] -benzyl ester and its oxalate salt Method 4A. A solution of pivaloyl chloride (26.0 g, 0.215 mol) was added to 4- [4-dimethylamino-1- (4-fluoro-phenyl) -1-hydroxy-butyl] -3-hydroxymethyl in acetonitrile (438 g). -Benzonitrile (
72 g, 0.21 mol) and triethylamine (25.0 g, 0.247 mol)
At 20 ° C. to the stirred solution having After 60 minutes, concentrated H ₂ SO ₄ (40 m
1) is added dropwise and the reaction mixture is heated at 70 ° C. for 180 minutes. The reaction mixture is cooled to room temperature, neutralized with aqueous ammonia solution (25%) and extracted with diethyl ether.
Dry the organic phase (MgSO ₄ ) and concentrate under reduced pressure to give the desired compound (82 g, 96%) as a yellow oil. Manufactured as oxalate. (Acetone) melting point 188 [deg.] C.

[0072]

[Outside 3]

5-Cyano-2- [4-dimethylamino-1,2-dimethyl-propionic acid
-(4-Fluoro-phenyl) -but-1-enyl] -benzyl ester and its hydrogen chloride salt Method 4B. A solution of pivaloyl chloride (30.1 g, 0.25 mol) was added to 4- [4-dimethylamino-1- (4-fluoro-phenyl) -1-hydroxy-butyl] -3-hydroxymethyl in acetonitrile (290 ml). -Benzonitrile (
(85.5 g, 0.21 mol) at 0 ° C. Before adding concentrated H ₂ SO ₄ (32.5 g, 0.33 mol), the reaction mixture was
Stir for a minute. As soon as the addition has ended, the reaction mixture is heated at 70 ° C. for 180 minutes. The reaction mixture is cooled to room temperature and acetonitrile (220 ml) is removed under reduced pressure before being neutralized with aqueous ammonia (23%) and extracted with diethyl ether. Dry the organic phase (MgSO ₄ ) and concentrate under reduced pressure to give the desired compound (102.1 g) as a pink oil.

A solution of alkene compound II (50.0 g, 0.11 mol) in methanol is added to a stirred solution of anhydrous HCl in methanol (200 ml). After stirring at room temperature for 30 minutes, the solvent was removed under reduced pressure, diethyl ether was added, the resulting white solid was filtered, washed with diethyl ether and the HCl salt (4.
8.1 g) are obtained. 165 ° C.

5-Cyano-2- [4-dimethylamino-1,2-dimethyl-propionic acid
-(4-Fluoro-phenyl) -but-1-enyl] -benzyl ester, sulfuric acid
Oxyhydrogen salt Method 4C. Pivaloyl chloride solution (29 g, 0.24 mol) was added to acetonitrile
(290 ml) in 4- [4-dimethylamino-1- (4-fluoro-phenyl).
) -1-Hydroxy-butyl] -3-hydroxymethyl-benzonitrile (85
. (5 g, 0.21 mol) at 0 ° C. Dark H_TwoSO _Four (32.5 g, 0.33 mol) before adding the reaction mixture for a further 60 minutes.
Stir. As soon as the addition has ended, the reaction mixture is heated at 70 ° C. for 180 minutes
. The reaction mixture was cooled to room temperature, acetonitrile was removed under reduced pressure and toluene (2
Of the desired compound (1) as a pink oil.
12.4 g) are obtained.

2,2-Dimethyl-propionic acid 5-cyano-2- [4-dimethylamino-1
-(4-Fluoro-phenyl) -but-1-enyl] -benzyl ester, hydrogen chloride Method 4D. A solution of pivaloyl chloride (7.6 g, 0.63 mol) was added to 4- [4-dimethylamino-1- (4-fluoro-phenyl) -1-hydroxy-butyl] -3-acetonitrile (21.35 g). Hydroxymethyl-benzonitrile (
(21.35 g, 0.052 mol) at room temperature. As soon as the addition was completed, methanesulfonyl chloride (50 ml) was dissolved in CH ₂ Cl ₂ (50 ml).
6.1 g (0.053 mol) was added, followed by triethylamine (
(10.6 g, 0.105 mol). The reaction mixture is stirred for a further 30 minutes, poured into water, extracted with CH ₂ Cl ₂ , the organic phase is dried (MgSO ₄ ) and concentrated under reduced pressure. The oil obtained was then dissolved in absolute ethanol / HCl, concentrated under reduced pressure, treated with diethyl ether, filtered and the alkene 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. Alkene 2,2-dimethyl-propionic acid 5-cyano-2- [4-dimethylamino-1- (4-fluoro-phenyl) in H ₂ O (1100 ml)
-But-1-enyl] -benzyl ester HCl salt (165 g, 0.337
Mol) into a stirred solution containing NaMnO ₄ (40% vv) (3%) in H ₂ O.
. Is added at a rate such that the reaction temperature is maintained at 45-50 ° C. As soon as the addition has ended, the reaction mixture is cooled to room temperature and filtered. The solid filtrate was washed with cold water (3 × 150 ml) and the solid residue was washed with acetone (2000
ml), filtered and evaporated to give the crude ketone. Silica plug (
Purification by filtration through a silica plug (eluent hexane: ethyl acetate 8: 2) yields 82 g (75%) of the desired ketone as a pure compound. Melting point 81 [deg.] C.

[0078]

[Outside 4]

2,2-Dimethyl-propionic acid 5-cyano-2- [1- (4-fluoro-phenyl) -methanoyl] -benzyl ester Method 5B. The ozone in O _{2 was} converted to water (1300 ml) and concentrated HCl (70 ml).
Alkene 2,2-dimethyl-propionic acid 5-cyano-2- [4-dimethylamino-1- (4-fluoro-phenyl) -but-1-enyl] -benzyl ester (38.0 g, 0.093) (Mol) while the reaction is monitored by HPLC. During the reaction, a white precipitate forms, and at the end of the reaction, the white solid is filtered, washed with water and dried under reduced pressure to give the protected ketone (22.5 g, 72%) as a pure compound.

2,2-Dimethyl-propionic acid 5-cyano-2- [1- (4-fluoro-
Enyl) -methanoyl] -benzyl ester Method 5C. Alkene 2, in water (250 ml) and ethyl acetate (100 ml)
2-dimethyl-propionic acid 5-cyano-2- [4-dimethylamino-1- (4
-Fluoro-phenyl) -but-1-enyl] -benzyl ester, H_TwoSO _Four (11.0 g, 0.022 mol) in NaIO_Four(30g, 0
. 14 mol) and RuCl_ThreeHydrate (0.35 g) is added. This suspension
Stir vigorously at ambient temperature for 16 hours. The resulting suspension is plugged with silica plug
Filter. Separate the organic phase and wash with water (50 ml). Evaporate the solvent under reduced pressure
The target compound is obtained as an oil. This is left to crystallize. Yield: 7
. 4 g (99%). Example 6 2,2-Dimethyl-propionic acid 5-cyano-2- [1- (4-fluoro-
Enyl) -methanoyl] -benzyl ester In dry THF (100 ml), 4-fluorobromobenzene (19.2 g,
0.11 mol) and magnesium turnings (3.2 g, 0.13 mol).
The solution with 4-fluorophenylmagnesium bromide in dry THF
Suspension containing 5-cyanophthalide (15.9 g, 0.1 mol) in water (150 ml).
Add dropwise to the suspension. Keep the temperature below 5 ° C. After the end of the addition, the reaction mixture is allowed to cool at room temperature.
Stir overnight.

A solution of pivaloyl chloride (13.3 g, 0.11 mol) is added to the reaction mixture and the temperature is raised to 60 ° C. for 2 hours at 60 ° C. The resulting solution was treated with NH ₄ Cl (100 m
1, aqueous solution) and ice (50 g). Diethyl ether (100 ml) is added and the phases are separated. The organic phase was washed with 0.1N NaOH (2 × 10
0 ml), then with water (100 ml) and the organic phase is dried with MgSO ₄ (20 g). The crude target compound (29.8) as an oil upon evaporation of the solvent.
g, 88%). This oil is considered sufficiently pure for the next reaction. Pure samples are obtained by crystallization from EtOAc / n-hexane (1: 9). The target 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 2,0-dimethyl-propionic acid 5-cyano-2- [1- (4-fluoride) in anhydrous THF (150 ml) at 0 ° C. -Phenyl) -methanoyl] -benzyl ester (28.5 g, 0.084 mol) was added to 3- (N, N-dimethylamino) propylmagnesium chloride (2.2 eq) and the reaction was terminated with HP
Track by LC. After 1 hour at 0 ° C., saturated magnesium chloride was added and the mixture was extracted with ethyl acetate, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give the desired compound as an oil (28.0 g, ( 87% HPLC)). This oxalate is obtained by crystallization from acetone.

Example 8 4- [1- (4-Fluoro-phenyl) -methanoyl] -3-hydroxymethyl-benzonitrile ketone 2,2-dimethyl-propionic acid 5-cyano-2- [1- (4-fluoro -Phenyl) -methanoyl] -benzyl ester (20 g, 0.061 mol) was added to freshly prepared Na methoxide (0.25 g sodium, 1 ml methanol).
(In 00 ml) and stirred at room temperature (HPLC indicates deprotection is complete).
. The methanol is then removed under reduced pressure, dissolved in MTBE, washed with saturated ammonium chloride, dried (MgSO ₄ ) and concentrated under reduced pressure to give the deprotected ketone of the target compound (14.6 g).

Example 9 4- [4-Dimethylamino-1- (4-fluoro-phenyl) -1-hydroxymethyl-butyl] -3-hydroxymethyl-benzonitrile The ketone 4- [1 in anhydrous THF at 0 ° C. To a solution having-(4-fluoro-phenyl) -methanoyl] -3-hydroxymethyl-benzonitrile (15.0 g, 0.046 mol) was added 3- (N, N-dimethylamino) propyl magnesium chloride (2. (2 eq.) Is added and the reaction is followed by HPLC. After 1 hour at 0 ° C., saturated ammonium chloride is added, the mixture is extracted with MTBE, dried (MgSO ₄ ) and concentrated under reduced pressure to give the desired compound as an oil. (16.7 g, (85% purity)).

[Procedure amendment]

[Submission date] April 9, 2002 (2002.4.9)

[Procedure amendment 1]

[Document name to be amended] Statement

[Correction target item name] Claims

[Correction method] Change

[Correction contents]

[Claims]

Embedded image (Wherein R is C _1-6 alkyl, acyl, C _1-6 alkylsulfonyl or arylsulfonyl). The compound represented by the following formula is reacted with 3- (N, N-dimethylamino) propyl magnesium halide. , Formula I

Embedded image A method for producing citalopram, which comprises producing citalopram represented by the formula: and isolating it as its base or a pharmaceutically acceptable salt thereof.

Embedded image (Wherein R has the meaning described in claim 1). The process according to claim 1, wherein the compound is prepared by oxidation of the corresponding compound represented by the formula:

Embedded image The process according to claim 3, which is produced by protecting (4-cyano-2-hydroxymethylphenyl) (4-fluorophenyl) methanol represented by the following formula with hydroxymethyl alcohol.

Embedded image (Wherein R has the meaning described in claim 1). The process according to claim 1, which is prepared by oxidative cleavage of the corresponding compound represented by the formula:

Embedded image 7. A process according to claim 5, wherein the compound of formula III is prepared by protection and dehydration of the corresponding compound of formula III, wherein the compound of formula III is the R-enantiomer.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) C07C 255/56 C07C 255/56 255/59 255/59 // C07B 61/00 300 C07B 61/00 300 ( 81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP , KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZA, ZW (72) Inventor Elegard Peter, 4174 Zistrup, Denmark Vay, 11F term (reference) 4C086 AA01 AA04 BA06 MA01 MA04 NA14 ZA12 4H006 AA01 AA02 AC44 AC48 AC52 AC54 BA02 BA14 BA23 BA30 BA37 BA51 BA60 BE05 QN30 4H039 CA62 CC20 CC60 CC60

Claims (12)

[Claims] 1. A compound of the formula IV (Wherein R is C _1-6 alkyl, acyl, C _1-6 alkylsulfonyl or arylsulfonyl). A compound represented by the formula: 3- (N, N-dimethylamino) propyl magnesium halide, preferably 3 -(N, N-dimethylamino) propylmagnesium chloride is reacted with a compound of formula I A method for producing citalopram, which comprises producing citalopram represented by the formula: and isolating it as its base or a pharmaceutically acceptable salt thereof. 2. An intermediate of the formula IV is converted to a compound of the formula V (Wherein R has the meaning described in claim 1). The process according to claim 1, wherein the compound is prepared by oxidation of the corresponding compound represented by the formula: 3. A compound of the formula V is converted to a compound of the formula VI The process according to claim 2, which is produced by protecting (4-cyano-2-hydroxymethylphenyl) (4-fluorophenyl) methanol represented by the formula: with hydroxymethyl alcohol. 4. An intermediate of the formula IV is converted to a compound of the formula VII (Wherein R has the meaning described in claim 1). The process according to claim 1, which is prepared by oxidative cleavage of the corresponding compound represented by the formula: 5. Oxidative cleavage of a compound of formula VII, preferably with MnO _Four ^- (Permanganate) or ozone, RuCl_Three, OsO_FourImplemented by
The method according to claim 4, which is performed by oxidation. 6. An intermediate alkene of the formula VII is converted to a compound of the formula III 6. The process according to claim 4, wherein the compound of formula III is prepared by protection and dehydration of the corresponding compound of formula III, wherein the compound of formula III is the R-enantiomer. 7. An intermediate of the formula IV is obtained by reacting 5-cyanophthalide with 4-fluorophenylmagnesium halide, preferably 4-fluorophenylmagnesium bromide, followed by RX (where R is Has the meaning described in 1, and X is a leaving group.) The R-X is preferably pivaloyl chloride, 3,5 _- dimethoxybenzoyl chloride, methyl iodide, ethyl bromide, chloride The process according to claim 1, prepared by reacting with tosyl, Me ₂ SO ₄ or MeSO ₂ Cl ───── to give a ketone compound of formula IV. (8) a) Formula IV: Wherein R has the meaning described in claim 1. b) the resulting compound of formula VIII Is reacted with 3- (N, N-dimethylamino) propylmagnesium halide, preferably 3- (N, N-dimethylamino) propylmagnesium chloride to give a compound of formula III A process for producing a racemic compound represented by the above formula III, which comprises producing a racemic compound represented by the formula: 9. A process according to claim 1, wherein R is acyl, preferably pivaloyl, acetyl or optionally substituted benzoyl. 10. A compound of formula IV (Wherein R is C _1-6 alkyl, acyl, C _1-6 alkylsulfonyl or arylsulfonyl, preferably pivaloyl, acetyl or optionally substituted benzoyl). 11. An antidepressant pharmaceutical composition containing citalopram produced by the method according to any one of claims 1 to 9. 12. A method for using the intermediate according to claim 10 for producing citalopram or S-citalopram.