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Process for prepn. of racemic citalopram and/or S-or R-citalopram by separation of mixture of R-and S-citalopram

A technology for citalopram and its mixture, applied in the field of preparing racemic citalopram and/or S- or R-citalopram by separating R- and S-citalopram mixture, can solve the problem of not being able to meet the requirements of S-citalopram Citalopram specifications and other issues

Inactive Publication Date: 2004-08-11
H LUNDBECK AS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Other methods of stereoselective synthesis of S-citalopram also result in mixtures of R- and S-citalopram which do not meet the market-approved specifications for S-citalopram

Method used

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  • Process for prepn. of racemic citalopram and/or S-or R-citalopram by separation of mixture of R-and S-citalopram
  • Process for prepn. of racemic citalopram and/or S-or R-citalopram by separation of mixture of R-and S-citalopram

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0068] From R-4-[4-(dimethylamino)-1-(4'-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)benzonitrile by reaction with different acids in acetonitrile (R / S=95.7 / 4.3) Preparation of Citalopram

[0069] general method

[0070] R-4-[4-(dimethylamino)-1-(4'-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)benzonitrile (67.5g, R / S= 95.7 / 4.3) was dissolved in acetonitrile (37g), stirred at room temperature, added the mixture of acid and ice (or water) (the amount of acid and the amount of ice are listed in Table 1), and the reaction mixture was stirred at 78-85°C (reaction time Listed in Table 1), cooling the reaction mixture, adding water and toluene (315ml), then adding ammonia (25%, by weight), reaching pH9.5-10.5, the mixture was heated to 50-55 ° C (5-10 minutes), The phases were separated, toluene (50ml) was added to the aqueous phase, and stirred at 50-55°C (5-10 minutes). The phases were separated, the toluene phases were combined, washed 3 times with water (3 x 65 ml), and ...

Embodiment 2

[0074] From R-4-[4-(dimethylamino)-1-(4'-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)benzonitrile by reaction with different acids in toluene (R / S=95.7 / 4.3) Preparation of Citalopram

[0075] general method

[0076] R-4-[4-(dimethylamino)-1-(4'-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)benzonitrile (67.5g, R / S= 95.7 / 4.3) was dissolved in toluene (315ml), stirred at room temperature, added the mixture of acid and ice (or water) (the amount of acid and the amount of ice are listed in Table 2), and the reaction mixture was stirred at 78-85°C (reaction time Listed in Table 2), cooling the reaction mixture, adding water, and then adding ammonia (25%, by weight), to reach pH9.5-10.5, the mixture was heated to 50-55 ° C (5-10 minutes), phase separation, toluene The phase was washed 3 times with water (3 x 65 ml) and the toluene was removed under reduced pressure at up to 60°C to give the product as an oil.

[0077] Prepare citalopram acid by the above-mentioned general met...

Embodiment 3

[0080] From R-4-[4-(dimethylamino)-1-(4'-fluorophenyl)-1-hydroxybutyl]-3-(hydroxyl Methyl)benzonitrile (R / S=95.7 / 4.3) to prepare citalopram HBr

[0081] acid cyclization

[0082] R-4-[4-(dimethylamino)-1-(4'-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)benzonitrile (67.5g, R / S= 95.7 / 4.3) was dissolved in toluene (315ml), stirred at room temperature, added a mixture of sulfuric acid (26g, 96%) and ice (10g), stirred the mixture for 2 hours at 78-85°C, cooled the reaction mixture, added 40ml of water, and then Aqueous ammonia (25%, by weight) was added to reach pH 9.5-10.0, the mixture was heated to 55° C. (10 minutes), the phases were separated, the toluene phase was washed with water 3 times (3×65 ml), and the pressure was reduced at a maximum of 60° C. Removal of the toluene gave an oil (Oil A), yield 63 g (99%).

[0083] Basic Cyclization of Unstable Esters

[0084] R-4-[4-(dimethylamino)-1-(4'-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)benzonitrile (33.7g, R / S= 9...

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PUM

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Abstract

Disclosed is a process for the preparation of racemic citalopram free base or an acid addition salt thereof and / or R- or S-citalopram as the free base or an acid addition salt thereof by separation of a mixture of R- and S- citalopram with more than 50% of one of the enantiomers into a fraction consisting of racemic citalopram and a fraction of S-citalopram or R-citalopram characterised in that: i) citalopram is precipitated from a solvent as the free base or as an acid addition salt thereof; ii) the precipitate formed is separated from the mother liquor; iia) if the precipitate is crystalline it is optionally recrystallised one or more times to form racemic citalopram, and then optionally converted into an acid addition salt thereof; or iib) if the precipitate is not crystalline, steps i) and ii) are optionally repeated until a crystalline precipitate is obtained and the crystalline precipitate is optionally recrystallised one or more times to form racemic citalopram, and then optionally converted to an acid addition salt thereof; and iii) the mother liquor is optionally subjected to further purification and S-citalopram or R-citalopram is isolated from the mother liquor and optionally converted to an acid addition salt thereof.

Description

[0001] The present invention relates to a process for the preparation of racemic citalopram and / or S- or R-citalopram by separating a mixture of R- and S-citalopram in an amount greater than 50% of a certain enantiomer by The above R- and S-citalopram mixtures are separated into racemic citalopram fractions and / or S- or R-citalopram containing a minor amount of the other enantiomer. The present invention also relates to the preparation of racemic compound R-4-[4-(dimethylamino)-1-(4'-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)benzonitrile Method for obtaining enantiomerically pure citalopram. background of the invention [0002] S-citalopram (escitalopram) is the active ingredient of the product citalopram, which is a racemic mixture of R- and S-citalopram, the above compounds are of the selective serotonin re-release inhibitor (SSRI) type Useful antidepressants. [0003] Both racemic citalopram and S-citalopram are marketed as antidepressants. [0004] It has now surpr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/343A61P25/24C07B57/00C07C253/30C07DC07D307/87C07D307/93
CPCC07D307/87A61P25/00A61P25/24
Inventor R·E·亨布尔T·V·克里斯藤森M·H·罗克O·尼尔森H·彼得森R·丹瑟
Owner H LUNDBECK AS
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