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Method for preparing (S)-citalopram intermediate S-type glycol

A technology of dextrocitalopram, type diol, applied in the directions of organic chemistry methods, chemical instruments and methods, organic racemization, etc., can solve the problems of high cost, poor stability and reproducibility, great difficulty, etc. Simple, stable and reproducible results at low cost

Active Publication Date: 2008-09-17
ZHEJIANG AOTUOKANG PHARMA GROUP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0026] The present invention aims at the disadvantages of high cost, low yield, cumbersome operation, high difficulty, poor stability and reproducibility, and unsuitability for industrialized production in the existing method for preparing single optical isomer D-citalopram The purpose is to provide a method for resolution of the D-citalopram intermediate S-type diol with low cost, easy operation, good stability and reproducibility, and suitable for industrial production.

Method used

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  • Method for preparing (S)-citalopram intermediate S-type glycol
  • Method for preparing (S)-citalopram intermediate S-type glycol
  • Method for preparing (S)-citalopram intermediate S-type glycol

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] 55.1g 4-[4-(dimethylamino)-1-(4'-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-cyanobenzene in 100ml dichloromethane solution and D - Mix 32.5 g of p-methyldibenzoyl tartaric acid in 500 ml of absolute ethanol and heat until the solids are completely dissolved. Slowly lowered to room temperature, then lowered to 0°C, stirred for 1h. Filter and wash with a small amount of dichloromethane: absolute ethanol (1:5). dry. 32.1 grams of 4-[4-(dimethylamino)-1-(4'-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-cyanobenzene.1 / 2DTTA salt was obtained, yield 36.7%.

[0040] The above solid was dissolved in 400 ml of a mixed solvent of dichloromethane and absolute ethanol (ratio 1:5) for recrystallization to obtain 29.1 g of solid, with a yield of 93%.

[0041] After detection: the total yield of resolution: 34.1%; the optical degree is 99.4% (HPLC).

Embodiment 2

[0043] 55.1g 4-[4-(dimethylamino)-1-(4'-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-cyanobenzene in 150ml dichloromethane solution and D - Mix 32.5 g of p-methyldibenzoyl tartaric acid in 350 ml of absolute ethanol and heat until the solids are completely dissolved. Slowly lowered to room temperature, then lowered to 0°C, stirred for 1h. Filter and wash with a small amount of dichloromethane: absolute ethanol (3:5). dry. 34.5 grams of 4-[4-(dimethylamino)-1-(4'-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-cyanobenzene.1 / 2DTTA salt was obtained, yield 39.4%.

[0044] The above solid was dissolved in 350 ml of a mixed solvent of dichloromethane and absolute ethanol (ratio 3:5) for recrystallization to obtain 32.8 g of solid, with a yield of 95%.

[0045] After detection: the total yield of resolution: 37.4%; the optical degree is 99.6% (HPLC).

Embodiment 3

[0047] 55.1g of 4-[4-(dimethylamino)-1-(4'-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-cyanobenzene in 450ml of dichloromethane solution and D - Mix 32.5 g of p-methyldibenzoyl tartaric acid in 150 ml of absolute ethanol and heat until the solids are completely dissolved. Slowly lowered to room temperature, then lowered to 0°C, stirred for 1h. Filter and wash with a small amount of dichloromethane: absolute ethanol (3:1). dry. 40.5 g of 4-[4-(dimethylamino)-1-(4'-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-cyanobenzene.1 / 2DTTA salt was obtained, yield 46.3%.

[0048] The above solid was dissolved in 350 ml of a mixed solvent of dichloromethane and absolute ethanol (ratio 3:1) for recrystallization to obtain 39.0 g of solid, with a yield of 96%.

[0049]After testing: the total yield of resolution: 44.4%; the optical degree is 99.0% (HPLC).

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Abstract

The invention relates to a method of preparing S-type diol that is a dextral citalopram intermediate product. Aiming at the disadvantages of high cost, low yield rate, fussy operation, high difficulty, and bad stability and repeatability in the existing method of preparing dextral citalopram that has single optical isomers, the invention provides a separation method of the S-type diol that is the dextral citalopram intermediate product which has low cost, convenient operation, and good stability and repeatability. The method is completed by the following way: racemic glycols (IV) are separated by adopting a separation method; resolving agent used for separation is organic acid that has the single optical isomers; resolving solvent used for separation is mixed solvent composed of halogenated hydrocarbon and absolute ethyl alcohol, or the mixed solvent composed of acetone and the absolute ethyl alcohol, or the acetone and isopropanol; when in separation, the racemic glycols (IV) are put in the mixed solution composed of the resolving agent and the resolving solvent, the salt of the S-type diol is crystallized and precipitated, and the S-type diol (I) which has single optical configurations is obtained through dissociation.

Description

technical field [0001] The invention relates to a preparation method of citalopram intermediate diol, in particular to a preparation method of D-citalopram intermediate S-type diol. Background technique [0002] Citalopram, a well-known antidepressant that has been on the market for many years, is a selective serotonin reuptake inhibitor, and the antidepressant activity of this compound has been reported in various publications, such as: prog. Neuro-Psychopharmacol. & Biol.Psychiat.1982 (6): 277-295, Acta Psychiatr. Scand., 1987 (75): 478-486. In EP474580, it is further disclosed that this compound is used in the treatment of dementia and cerebrovascular diseases The effect shown. At present, it has been listed in more than 60 countries and regions in the world. The commercially available citalopram is a racemate, and its structure is as follows: [0003] [0004] Formula (II) [0005] The patents for the first synthesis of citalopram are US Patent US4136193 in 1977 an...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C255/59C07C253/34C07B57/00
Inventor 朱雪焱叶晓秧吴新建袁哲东施华琴王强
Owner ZHEJIANG AOTUOKANG PHARMA GROUP
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