JP3365764B2 - Method for producing citalopram - Google Patents

Description

Detailed Description of the Invention

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

[0002]

[Chemical 11]

It is a selective, centrally active serotonin (5-hydroxytryptamine; 5-HT) with antidepressant activity.
It is a reuptake inhibitor. The antidepressant activity of this compound is
Some literature, eg J. Hyttel, Prog. Neuro-Ps
ychopharmacol. & Biol. Psychiat., 1982, 6, 277-295
And A. Gravem, Acta Psychiatr. Scand., 1987, 75, 47.
Reported at 8-486. Further, it is disclosed in European Patent Publication (EP-A) 474,580 that this compound is effective for treating dementia and cerebrovascular disorder.

Citalopram was first published in German Patent No. 2,657,27.
No. 1 (corresponding to US Pat. No. 4,136,193). This patent specification discloses the production of citalopram by one method and outlines another method used to make citalopram.

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

According to the method generally only outlined, citalopram is a compound of formula II:

[0007]

[Chemical 12]

Is obtained by ring closure in the presence of a dehydrating agent and then exchanging the 5-bromo group for cyan with cuprous cyanide. The starting compound of formula II is obtained from 5-bromophthalide by two successive Grignard reactions, namely with 4-fluorophenylmagnesium chloride and N, N-dimethylaminopropylmagnesium chloride respectively.

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

[0010]

[Chemical 13]

The intermediate represented by ## STR1 ## 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 halogenide and N, N-dimethylaminopropylmagnesium halogenide, respectively.

Another treatment is International Patent Application No. (WO) 98 /
No. 019511, (WO) 98/019512 and (WO) 98/019513. The inventions described in International Patent Application Nos. (WO) 98/019512 and (WO) 98/019513 describe 5-amino-, 5-carboxy-, 5- (s-aminocarbonyl) phthalide as 2 The present invention relates to a method in which two 1,3-dihydroisobenzofuran derivatives thus obtained are subjected to two consecutive Gruniard reactions to ring-close them into corresponding 5-cyano compounds, that is, citalopram. In International Patent Application No. (WO) 98/019511, a (4-substituted-2-hydroxymethylphenyl- (4-fluorophenyl) methanol compound was ring-closed to obtain 5
-Substituted 1- (4-fluorophenyl) -1,3-
A process for the preparation of citalopram is disclosed, characterized in that dihydroisobenzofuran is converted into the corresponding 5-cyano derivative and then alkylated with (3-dimethylamino) propyl halogenide to give citalopram.

Finally, a method for producing the individual antipodes of citalopram is described in US Pat. No. 4,943,590, from which the ring closure of the intermediate of formula III is not possible with a base. It is also clear that this is done via a stable ester.

The inventor has surprisingly found that citalopram can be prepared with the usual starting compounds by a new advantageous and safe process.

Summary of the invention Accordingly, the present invention provides formula IV

[0016]

[Chemical 14]

(Wherein R is C _1-6 alkyl, acyl, C
_1-6 alkylsulfonyl or arylsulfonyl. ) Is a 3- (N, N-dimethylamino) propyl magnesium halide, preferably 3-
Reacting with (N, N-dimethylamino) propyl magnesium chloride to give a compound of formula I

[0018]

[Chemical 15]

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 invention provides novel intermediates of formula IV.

In another aspect, the invention relates to a method of making the intermediate of formula IV.

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

[0023]

[Chemical 16]

It is used for producing a racemic compound represented by

In another aspect, the present invention relates to antidepressant pharmaceutical formulations containing citalopram prepared by the method of the present invention.

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

[0027]

[Chemical 17]

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

Surprisingly, the product of the Grignard reaction spontaneously cyclizes to the immediate citalopram, thus the reaction of the compound of formula IV with the Grignard reagent yields citalopram in one step.

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

One of these methods is described by Formula VI

[0032]

[Chemical 18]

Protecting (4-cyano-2-hydroxymethylphenyl) (4-fluorophenyl) methanol represented by ## STR3 ## with hydroxymethyl alcohol and then oxidizing it to give a compound of formula IV (wherein R is C
_1-6 alkyl, acyl, C _1-6 alkylsulfonyl or arylsulfonyl. ) And to include.

Oxidation of the compounds of formula V is carried out with conventional oxidants, preferably Na ₂ WO ₄ .

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

Another method for preparing the compound of formula IV is the reaction of 5-cyanophthalide with 4-fluorophenylmagnesium halide, preferably 4-fluorophenylmagnesium bromide, followed by RX (wherein R
Has the meaning given above and X is a leaving group. ) ---- The R-X is preferably pivaloyl chloride, 3,5 _{_}
Dimethoxybenzoyl chloride, methyl iodide, ethyl bromide, tosyl chloride, Me ₂ SO ₄ or MeSO ₂ Cl
----- is included.

The reaction is shown as follows:

[0038]

[Chemical 19]

The starting compound, 5-cyanophthalide, is Triouf
It can be prepared as described in let, J .; Bull. Soc. Sci. Bretagne 26, 1959, 35.

According to a third process for the preparation of compounds of formula IV, one of the enantiomers of the compound of formula III, ie its R-enantiomer, is protected and dehydrated. ,
To obtain a compound of formula VII, which is oxidized to form compound of formula I
Let it be a ketone represented by V.

[0041]

[Chemical 20]

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

The oxidative cleavage of the compound of formula VII is obtained by oxidation, preferably MnO ₄ ^- is performed by (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 has the S-enantiomer separated from the S-enantiomer and the R-enantiomer as described in US Pat. No. 4,943,590. It can be prepared from the compound of formula III by ring closure of the palm. R- of the compound of formula III
The antipode was not previously used after separation.

Further in accordance with another aspect of the invention, Formula II
After converting the R-enantiomer represented by I into a non-optically active compound represented by Formula IV, a racemic compound represented by Formula III can be produced as shown in the following reaction scheme.

[0047]

[Chemical 21]

The racemic compound of formula III is separated into its optically active antipodes by the method described in US Pat. No. 4,943,590, whereby formula III
The S-enantiomer of the compound represented by the following formula 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 step.

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

Other reaction conditions for the above reactions, solvents, etc. are conventional conditions for such reactions and can be readily determined by one skilled in the art.

Throughout this specification and claims, the term "C _1-6 alkyl" refers to a branched or unbranched alkyl group having 1 to 6 carbon atoms. , For example, 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,
In particular, it means phenyl or ring-substituted phenyl.

The term "heteroaryl" is a monocyclic or bicyclic heterocyclic aromatic radical such as indolyl, thienyl, pyrimidyl, oxazolyl, isoxazolyl,
Means thiazolyl, isothiazolyl, imidazolyl, benzofuranyl, benzothienyl, pyridyl and furanyl, especially pyrimidinyl, indolyl and thienyl.

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

Halogen means chlorine, bromine or iodine.

Leaving groups preferably mean halides or sulfonates.

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 include maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, oxalic acid, bismethylenesalicylic 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 8-halotheophylline, for example 8-bromo
-It's a salt with theophylline. Examples of such inorganic salts are
It is a salt with hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid.

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, then concentrated and cooled to isolate the salt or a water-immiscible solvent such as ethyl ether, The salt is spontaneously isolated by reaction with excess acid in ethyl acetate or dichloromethane.

The pharmaceutical preparations according to the invention are parenterally administered 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 conventional sterile injectable solutions. It can be administered.

The pharmaceutical preparations of the present invention can be manufactured by methods conventional in the art. For example, tablets with active substance and / or usual adjuvants and / or
It can be prepared by mixing with a diluent and then pressing the mixture on a conventional tabletting machine. Examples of adjuvants or diluents include: corn starch, potato starch, talc, magnesium stearate, gelatin, lactose, gums and the like. All other adjuvants or additives such as colorants, aromatics, preservatives and the like may be used provided they are compatible with the active ingredient.

Injectable solutions are prepared by dissolving the active ingredient and usable additives in a part of the injectable solvent, preferably sterile water,
It can be prepared by adjusting the solution to the desired volume, sterilizing the solution and filling in suitable ampoules or vials. All suitable additives commonly used in the art may be used, for example tonicity agents.
t), preservatives, antioxidants, etc. can be added.

Example The invention is further illustrated by the following example.

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, 0.04 mol) to a stirred solution containing pivaloyl chloride (4.2
g, 0.39 mol). After stirring for 60 minutes,
The reaction mixture was poured onto ice and washed with diethyl ether (2 x 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%).

[0065]

[Outer 1]

Example 2 2,2-Dimethyl-propionic acid 5-cyano-2- [1]
-(4-Fluorophenyl) -methanoyl] -benzyl ester 5-cyano-2- [1- (4-fluorophenyl) -1-hydroxy- 2,2-dimethyl-propionic acid in ethyl acetate (20 ml). To a stirred solution with methyl] -benzyl ester (8.0 g, 0.025 mol), 30% wt hydrogen peroxide solution (10 g, 0.079 mol), Na ₂ WO _4.2 H ₂ O (0. 15g, 0.000
5 mol) and (n- octyl) 3NCH _3. HSO ₄
(0.23 g, 0.0005 mol) is added. 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), dried (MgSO ₄ ) and concentrated under reduced pressure to give the desired ketone compound (7.8 g, 97.5%) is obtained.

Example 3 Acetic acid 5-cyano-2- [4-dimethylamino-1- (4
-Fluoro-phenyl) -but-1-enyl] -benzyl ester and its oxalate method A. Acetic anhydride (103 g, 1 mol) was added to 4- [4-dimethylamino-1-in acetonitrile (438 g).
(4-Fluoro-phenyl) -1-hydroxy-butyl] -3-hydroxymethyl-benzonitrile (72
g, 0.21 mol) is added dropwise at 20 ° C. to the stirred solution. As soon as the addition was complete, trimethylsilyl chloride (5.5 g, 0.05 mol) was added dropwise (20 to 2
Stir overnight, resulting in an exothermic reaction temperature rising to 8 ° C). Then concentrated H ₂ SO ₄ (14.5 g, 0.14 mol)
Is added to the reaction mixture and the reaction mixture is heated for 30 minutes at 50 ° C. (HPLC indicates completion of reaction). After cooling, the reaction mixture was concentrated under reduced pressure and the aqueous ammonia solution (23
%) And extract with toluene (twice). The organic phase was dried (MgSO _4), and concentrated under reduced pressure, the objective compound (69.5 g, 85%) is obtained as a pale orange oil.

Produced as oxalate salt. Methanol (50
A warm solution of oxalic acid (1 g, 0.0177 mol) in ml) is added to a stirred solution of the desired alkene compound (6.63 g, 0.0173 mol) in methanol (50 ml). After cooling, crystals were isolated by filtration (7.4g) and cold methanol (10m).
Wash with 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)
Agitated with 4- [4-dimethylamino-1- (4-fluoro-phenyl) -1-hydroxy-butyl] -3-hydroxymethyl-benzonitrile (1000 g, 2.9 mol) in acetonitrile (100 g). The solution 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 for 3 hours at 50 ° C. (HPLC shows the reaction is complete). After cooling, the reaction mixture was treated with an aqueous ammonia solution (25
%) And extract with toluene (twice). The organic phase was dried (MgSO _4), and concentrated under reduced pressure, the target compound (1023g, 92%) is obtained as a pale orange oil.

Example 4 2,2-Dimethyl-propionic acid 5-cyano-2- [4
-Dimethylamino-1- (4-fluoro-phenyl)-
But-1-enyl] -benzyl ester and its oxalate method 4A. Pivaloyl chloride solution (26.0 g, 0.21
5 mol) in acetonitrile (438 g) 4- [4
-Dimethylamino-1- (4-fluoro-phenyl)-
1-Hydroxy-butyl] -3-hydroxymethyl-benzonitrile (72 g, 0.21 mol) and triethylamine (25.0 g, 0.247 mol) are added at 20 ° C. to a stirred solution. After 60 minutes, concentrated H ₂ SO ₄
(40 ml) was added dropwise and the reaction mixture was heated at 70 ° C for 180 minutes.
Heat with. The reaction mixture is cooled to room temperature, neutralized with aqueous ammonia solution (25%) and extracted with diethyl ether. The organic phase was dried (MgSO _4), and concentrated under reduced pressure, the target compound (82 g, 96%) as a yellow oil. Manufactured as oxalate. (Acetone) melting point 1
88 ° C.

[0072]

[Outside 3]

2,2-Dimethyl-propionic acid 5-cyano-2- [4-dimethylamino-1- (4-fluoro-
Phenyl) -but-1-enyl] -benzyl ester and its hydrogen chloride salt Method 4B. Pivaloyl chloride solution (30.1 g, 0.25
Mol) in acetonitrile (290 ml) 4- [4
-Dimethylamino-1- (4-fluoro-phenyl)-
1-Hydroxy-butyl] -3-hydroxymethyl-benzonitrile (85.5 g, 0.21 mol) is added at 0 ° C. to a stirred solution. Concentrated H ₂ SO ₄ (32.
The reaction mixture is stirred for a further 60 minutes before adding 5 g, 0.33 mol). Once the addition is complete, the reaction mixture is heated for 180 minutes at 70 ° C. The reaction mixture is cooled to room temperature, acetonitrile (220 ml) is removed under reduced pressure and extracted with diethyl ether before being neutralized with aqueous ammonia solution (23%). The organic phase is dried (MgSO 4
₄ ) and concentrated under reduced pressure to obtain the target compound (102.1 g) as a pink oily substance.

Alkene compound II (5
0.0 g, 0.11 mol) is 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, the resulting white solid was filtered, washed with diethyl ether and the HCl salt (4
8.1 g) are obtained. Melting point 165 [deg.] C.

2,2-Dimethyl-propionic acid 5-cyano-2- [4-dimethylamino-1- (4-fluoro-
Phenyl) -but-1-enyl] -benzyl ester, hydrogensulfate Method 4C. A solution of pivaloyl chloride (29 g, 0.24 mol) in acetonitrile (290 ml) 4- [4-
Dimethylamino-1- (4-fluoro-phenyl) -1
-Hydroxy-butyl] -3-hydroxymethyl-benzonitrile (85.5 g, 0.21 mol) is added to the stirred solution at 0 <0> C. Concentrated H ₂ SO ₄ (32.5
g, 0.33 mol), the reaction mixture is stirred for a further 60 minutes. Once the addition is complete, the reaction mixture is heated for 180 minutes at 70 ° C. The reaction mixture was cooled to room temperature, acetonitrile was removed under reduced pressure, toluene (200 ml) was added, and the mixture was removed under reduced pressure to obtain the target compound (112.4 g) as a pink oily substance.

2,2-Dimethyl-propionic acid 5-cyano-2- [4-dimethylamino-1- (4-fluoro-
Phenyl) -but-1-enyl] -benzyl ester, hydrogen chloride method 4D. Pivaloyl chloride solution (7.6 g, 0.63 mol) was added to 4- [4] in acetonitrile (21.35 g).
-Dimethylamino-1- (4-fluoro-phenyl)-
1-Hydroxy-butyl] -3-hydroxymethyl-benzonitrile (21.35 g, 0.052 mol) is added dropwise at room temperature to a stirred solution. As soon as 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) is added. 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 resulting oil was then dissolved in absolute ethanol / HCl, concentrated under reduced pressure, treated with diethyl ether, filtered and alkene H was added.
The Cl salt (22.6 g, 98%) is obtained.

Example 5 2,2-Dimethyl-propionic acid 5-cyano-2- [1
-(4-Fluoro-phenyl) -methanoyl] -benzyl ester Method 5A. Alkenes 2,2 in H ₂ O (1100 ml)
-Dimethyl-propionic acid 5-cyano-2- [4-dimethylamino-1- (4-fluoro-phenyl) -but-
HCl salt of 1-enyl] -benzyl ester (165
g, 0.337 mol), H ₂
A solution of NaMnO ₄ (40% vv) (3.7 mol) in O is added at a rate such that the reaction temperature is maintained at 45-50 ° C. Once the addition is complete, the reaction mixture is cooled to room temperature and filtered. The solid filtrate was washed with cold water (3 x
150 ml) and the solid residue was washed with acetone (200 ml).
0 ml), filtered and evaporated to give the crude ketone. 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. Ozone in O ₂ was alkene 2,2-dimethyl-in water (1300 ml) and concentrated HCl (70 ml).
Propionic acid 5-cyano-2- [4-dimethylamino-
1- (4-Fluoro-phenyl) -but-1-enyl]
-Benzyl ester (38.0 g, 0.093 mol)
Bubbling the reaction through HPLC with a stirred solution having. During the reaction, a white precipitate formed and at the end of the reaction the white solid was filtered, washed with water and dried under reduced pressure to give the desired ketone (2
2.5 g, 72%).

2,2-Dimethyl-propionic acid 5-cyano-2- [1- (4-fluoro-phenyl) -methanoyl] -benzyl ester Method 5C. Water (250 ml) and ethyl acetate (100 m
l) in the alkene 2,2-dimethyl-propionic acid 5-
Cyano-2- [4-dimethylamino-1- (4-fluoro-phenyl) -but-1-enyl] -benzyl ester, into a suspension with H ₂ SO ₄ (11.0 g, 0.022 mol). , NaIO ₄ (30 g, 0.14 mol) and RuCl ₃ , hydrate (0.35 g) are added. The suspension is vigorously stirred for 16 hours at ambient temperature. The suspension obtained is filtered through a plug of silica. The organic phase is separated and washed with water (50 ml). The solvent is evaporated under reduced pressure to obtain the target compound as an oily substance. This is left to crystallize. Yield: 7.4 g (99%). Example 6 2,2-Dimethyl-propionic acid 5-cyano-2- [1
4- (4-Fluoro-phenyl) -methanoyl] -benzyl ester 4-Fluorobromobenzene (19.2 g, 0.11 mol) and magnesium shavings (3.2 g, 0.13) in dry THF (100 ml). 4) produced from
The solution with fluorophenyl magnesium bromide is added to a suspension of 5-cyanophthalide (15.9 g, 0.1 mol) in dry THF (150 ml). Keep the temperature below 5 ° C. After the addition is complete, the reaction mixture is stirred at room temperature overnight.

Pivaloyl chloride solution (13.3 g, 0.1
1 mol) is added to the reaction mixture and the temperature is raised to 60 ° C. for 2 hours to 60 ° C. The resulting solution was added to NH ₄ Cl (10
0 ml, aqueous solution) and to a saturated solution with ice (50 g). Diethyl ether (100 ml) was added,
Separate the phases. The organic phase is 0.1N NaOH (2 x 100
ml) and then with water (100 ml) and the organic phase is washed with M
Dry with gSO ₄ (20 g). The crude target compound (29.8 g, 88) was obtained as an oil by evaporation of the solvent.
%) Is obtained. This oil is believed to be sufficiently pure for the next reaction. Pure sample is EtOA
Obtained by crystallization from c / 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 anhydrous THF at 0 ° C. 2,2-Dimethyl-propionic acid 5-cyano-2- [1- (4-fluoro-phenyl) -methanoyl] -benzyl ester (2
8.5 g, 0.084 mol), 3-
(N, N-Dimethylamino) propylmagnesium chloride (2.2 eq) is added and the reaction is followed by HPLC. After 1 hour at 0 ° C., saturated magnesium chloride was added, the mixture was extracted with ethyl acetate, dried (Na ₂
SO ₄ ) and concentrated under reduced pressure to give the target compound as an oil (28.0 g, (purity 87% HPLC)). This oxalate is obtained by crystallizing from aceton.

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 (sodium 0.25
g, in 100 ml of methanol) and stirred at room temperature (HPLC indicates completion of deprotection). The methanol was 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 (14.6) of the desired compound.
g) is obtained.

Example 9 4- [4-Dimethylamino-1- (4-fluoro-phenyl-)-1-hydroxymethyl-butyl] -3-hydroxymethyl-benzonitrile Ketone 4- [in anhydrous THF at 0 ° C. 1- (4-Fluoro-phenyl) -methanoyl] -3-hydroxymethyl-
To a solution with benzonitrile (15.0 g, 0.046 mol) is added a solution with 3- (N, N-dimethylamino) propylmagnesium chloride (2.2 eq) and the reaction is followed by HPLC. After 1 hour at 0 ° C., saturated ammonium chloride was added and the mixture was mixed with MTBE.
Extracted with, dried (MgSO ₄ ), concentrated under reduced pressure,
The target compound is obtained as an oil. (16.7g,
(Purity of 85%)).

─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Elegard Peter, 4174 Gistrupp, Knut Lavartswäi, Denmark, 11 (56) References JP 61-87654 (JP, A) WO 98/19511 (WO, A1) (58) Fields investigated (Int. Cl. ⁷ , DB name) C07D 307/87 CAPLUS (STN) REGISTRY (STN)

Claims (11)

(57) [Claims] 1. Formula IV: (In the formula, R is C _1-6 alkyl, acyl, C _1-6 alkylsulfonyl or arylsulfonyl.) The compound represented by the formula 3- (N, N-dimethylamino)
Reaction with propylmagnesium halide to give formula I A process for producing citalopram, which comprises producing citalopram represented by the formula and isolating the citalopram as a base or a pharmaceutically acceptable salt thereof. 2. The 3- (N, N-dimethylamino) propyl magnesium halide is 3- (N, N-dimethylamino) propyl magnesium chloride.
The method described. 3. An intermediate of formula IV can be converted to a compound of formula V (Wherein R has the meaning described in claim 1) and is produced by oxidation of the corresponding compound represented by:
The method of claim 1. 4. A compound of formula V can be converted into a compound of formula VI The process according to claim 3, which is prepared by protecting (4-cyano-2-hydroxymethylphenyl) (4-fluorophenyl) methanol represented by the formula (4) with hydroxymethyl alcohol. 5. The intermediate of formula IV can be converted to formula VII: The method according to claim 1, which is produced by oxidative cleavage of a corresponding compound represented by the formula: wherein R has the meaning described in claim 1. The oxidative cleavage of 6. A compound of the formula VII MnO ₄ ^- (permanganates), or ozone, RuCl
Method according to claim 5, carried out by oxidation carried out by ₃ , OsO ₄ . 7. An intermediate alkene of formula VII is represented by formula III: 7. A process according to claim 5 or 6 which is prepared by protection and dehydration of the corresponding compound of formula I, wherein the compound of formula III is the R-enantiomer. 8. An intermediate of formula IV reacts 5-cyanophthalide with 4-fluorophenylmagnesium halide and then R--X, wherein R has the meaning stated in claim 1, X Is a leaving group.)
A process according to claim 1 prepared by forming a ketone compound of formula IV. 9. The method according to claim 8, wherein the 4-fluorophenyl magnesium halide is 4-fluorophenyl magnesium bromide. 10. RX is pivaloyl chloride, 3,5
-Dimethoxybenzoyl chloride, methyl iodide, ethyl bromide, tosyl chloride, Me ₂ SO ₄ or MeSO ₂ C
9. The method of claim 8, which is l. 11. A process according to any of claims 1 to 10 wherein when R is acyl it is pivaloyl, acetyl or optionally substituted benzoyl.