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Preparation method of IV intermediate S-diol

A type of diol and ethanol technology, which is applied in the field of preparation of D-citalopram intermediate S-type diol, can solve the problems of poor purity and low product yield, and achieve high yield, high purity and low cost Effect

Active Publication Date: 2011-09-21
ZHEJIANG HUAHAI PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

This method requires the addition of seed crystals to induce crystallization, and the yield of the obtained product is generally low and the purity is poor

Method used

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  • Preparation method of IV intermediate S-diol
  • Preparation method of IV intermediate S-diol
  • Preparation method of IV intermediate S-diol

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Add 100g of racemic 4-(4-dimethylamino-1-p-fluorophenyl-1-hydroxybutyl)-3-(hydroxymethyl)cyanobenzene, 700ml ethyl acetate in the reaction flask, Heat to 55°C and stir to dissolve, add D-(+) di-p-toluoyl tartaric acid ethanol solution (59g D-(+) di-p-toluoyl tartaric acid dissolved in 140mL absolute ethanol) and stir to react 2 hours, slowly cooled to 50 DEG C and stirred for 2 hours, then slowly cooled to 0 DEG C, continued to stir for 2 hours, decompressed suction filtration to separate the crystal slurry, washed crystals with ethyl acetate, and obtained S-type diol D-( +) Di-p-methylbenzoyl tartrate 60.5g, yield 38.7%, chiral purity (as determined by HPLC): 98.2%.

[0024] The obtained S-type diol D-(+) di-p-methylbenzoyl tartrate is freed in ammonia water and extracted with toluene to obtain the S-type diol.

Embodiment 2

[0026] Add 100g of racemic 4-(4-dimethylamino-1-p-fluorophenyl-1-hydroxybutyl)-3-(hydroxymethyl)cyanobenzene, 700ml ethyl acetate in the reaction flask, Heat to 55°C and stir to dissolve, add D-(+) di-p-toluoyl tartaric acid in acetonitrile solution (59g D-(+) di-p-toluoyl tartaric acid dissolved in 175mL acetonitrile) and stir for 2 hours , slowly cooled to 50°C and stirred for 2 hours, then slowly cooled to 0°C, continued to stir for 2 hours, vacuum filtered to separate the crystal slurry, washed crystals with ethyl acetate, and obtained S-type diol D-(+) after vacuum drying 52.6 g of di-p-methylbenzoyl tartrate, yield 33.6%, chiral purity (as determined by HPLC): 98.9%.

[0027] The obtained S-type diol D-(+) di-p-methylbenzoyl tartrate is freed in ammonia water and extracted with toluene to obtain the S-type diol.

Embodiment 3

[0029] Add 100g of racemic 4-(4-dimethylamino-1-p-fluorophenyl-1-hydroxybutyl)-3-(hydroxymethyl)cyanobenzene, 900ml ethyl acetate in the reaction flask, Heat to 55°C and stir to dissolve, add D-(+) di-p-toluoyl tartaric acid ethanol solution (59g D-(+) di-p-toluoyl tartaric acid dissolved in 225mL absolute ethanol) and stir to react 2 hours, slowly cooled to 50 DEG C and stirred for 2 hours, then slowly cooled to 0 DEG C, continued to stir for 2 hours, decompressed suction filtration to separate the crystal slurry, washed crystals with ethyl acetate, and obtained S-type diol D-( +) 60 g of di-p-methylbenzoyl tartrate, yield 32.6%, chiral purity (as determined by HPLC): 99.0%.

[0030] The obtained S-type diol D-(+) di-p-methylbenzoyl tartrate is freed in ammonia water and extracted with toluene to obtain the S-type diol.

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Abstract

The invention provides a method for splitting 4-(4-dimethylamino-1-p-fluorophenyl-1-hydroxyl butyl)-3-(hydroxymethyl) cyanobenzene (II) of racemic to obtain high purity S-diol (I). The preparation method comprises steps of performing crystallization in a mixed solvent containing ethyl acetate and ethanol or a mixed solvent containing ethyl acetate and acetonitrile to obtain S-diol D-(+) di p-methyl-benzoyl-tartaric acid salts. The splitting method provided in the invention has advantages of low cost and high yield; besides, the S-diol that is obtained by splitting has high purity. Therefore, the preparation method of the IV intermediate S-diol is especially suitable for industrialized large-scale production.

Description

technical field [0001] The invention relates to a preparation method of D-citalopram intermediate S-type diol. Background technique [0002] D-citalopram (IV) (also known as S-citalopram) is the active isomer of citalopram, which has a highly selective inhibitory effect on the reabsorption of 5-hydroxytryptamine (5-HT) The reabsorption of hormones and dopamine has little effect. Increases the concentration of 5-HT in the synaptic cleft by preventing 5-HT reabsorption, thereby producing antidepressant effects. Mainly applicable to the treatment of severe depression. [0003] [0004] The preparation method of D-citalopram has been reported for a long time, mainly through the cyclization of the chiral intermediate S-type diol. [0005] US Pat. No. 4,943,590 describes the resolution of racemic 4-(4-dimethylamino-1-p-fluorophenyl-1 -Hydroxybutyl)-3-(hydroxymethyl)cyanobenzene, to obtain S-type diol D-(+) di-p-toluoyl tartrate. The S-type diol D-(+) di-p-methylbenzoyl tar...

Claims

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Application Information

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IPC IPC(8): C07C255/59C07C253/34
Inventor 周世伟甘立新张军蹇峰
Owner ZHEJIANG HUAHAI PHARMACEUTICAL CO LTD
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