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Method for preparing citalopram and S-citalopram

A technology for citalopram and a compound is applied in the field of preparing citalopram and S-citalopram, which can solve the problems of high pressure on production and environmental protection, and achieve the effects of less three wastes, high yield and high purity

Active Publication Date: 2009-09-23
ZHEJIANG HUAHAI PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to the use of a large amount of materials such as DEAD and triphenylphosphorus, this method also has the problem of high environmental protection pressure in industrial production.

Method used

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  • Method for preparing citalopram and S-citalopram
  • Method for preparing citalopram and S-citalopram
  • Method for preparing citalopram and S-citalopram

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Example 1 (S)-(+)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-cyanoisobenzo Preparation of furan (formula II) oxalate

[0028] Add 19.1g (S)-(-)-4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy Butyl]-3-(hydroxymethyl)-benzonitrile, 17.4gK 2 CO 3 , add 200mL toluene, 80mL water, start stirring, and cool the system to 0°C with an ice-salt bath; add a solution of 8.4g methanesulfonyl chloride and 70mL toluene dropwise to the reaction solution through a constant pressure funnel, and control the temperature in the reaction bottle to 0°C, 2 The dropwise addition was completed within 1 hour and the reaction was controlled to be complete by TLC (thin layer chromatography). After the reaction was completed, the filtrate was filtered, and the filtrate was separated. The water layer was extracted once with 100 mL of toluene. The toluene layers were combined and washed twice with 100 mL of water. Distill the toluene to dryness under reduced pressure, add 100m...

Embodiment 2

[0029] Example 2 (S)-(+)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-cyanoisobenzo Preparation of furan (formula II) oxalate

[0030] Add 28.8g (S)-(-)-4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy Butyl]-3-(hydroxymethyl)-benzonitrile, 20.8gNa 2 CO 3 , add 200mL toluene, 80mL water, start stirring, and cool the system to 0°C with an ice-salt bath; add a solution of 17g p-toluenesulfonyl chloride and 150mL toluene dropwise to the reaction solution through a constant pressure funnel, and control the temperature in the reaction bottle to 0°C, 2 The dropwise addition was completed within 1 hour and the reaction was controlled to be complete by TLC (thin layer chromatography). After filtering, the filtrate was separated into layers, and the water layer was extracted once with 100 mL of toluene. The toluene layers were combined and washed twice with 100 mL of water. Distill toluene to dryness under reduced pressure, add 110mL of absolute ethanol and 16g of ...

Embodiment 3

[0031] Example 3 (S)-(+)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-cyanoisobenzo Preparation of furan (formula II) oxalate

[0032]Add 19.5 g of (S)-(-)-4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy Butyl]-3-(hydroxymethyl)-benzonitrile, 3.36g NaOH, add 80mL toluene, 20mL water, start stirring, cool the system to 0°C with an ice-salt bath; mix 8.5g p-toluenesulfonyl chloride and 65mL toluene solution The reaction solution was added dropwise through a constant pressure funnel, and the temperature in the reaction bottle was controlled at 0°C. After 2 hours, the dropwise addition was completed and the reaction was controlled by TLC (thin layer chromatography). After the reaction was completed, the filtrate was filtered, and the filtrate was separated. The water layer was extracted once with 50 mL of toluene. The toluene layers were combined and washed twice with 100 mL of water. Distill toluene to dryness under reduced pressure, add 60mL of absolute ethan...

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Abstract

The invention provides a method for preparing citalopram and S-citalopram. In the method, 1-[2-(hydroxymethyl)-5-substituting group-]phenyl-4-(dimethylamino)-1-(4-fluorophenyl)-1- butyl alcohol undergoes a cyclization reaction with halogenated acylate in water and an organic solvent immiscible with water under the alkali condition to form a citalopram product. The method has high yield and high purity and is suitable for industrialized production.

Description

Technical field: [0001] The invention relates to medicinal chemistry, in particular to a method for preparing citalopram and S-citalopram. Background technique [0002] Citalopram, whose chemical name is 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-cyanoisobenzofuran, is a A new drug for the treatment of depression, which belongs to the class of selective serotonin reuptake inhibitors. Specifically, such as structural formula I, its S-configuration structural formula II is the main active ingredient. [0003] [0004] Citalopram was developed by LUNDBECK, Denmark, and was first disclosed in patent DE2657013. Corresponding to patent US4136193, the synthesis of S-citalopram was first disclosed in patent USRE34712. Afterwards, many patent reports studied the synthesis of citalopram. [0005] Patents US4136193, US4650884, WO9819512 and WO9819513 etc. have reported methods for preparing citalopram, such as Reaction Formula-1, wherein Z can be a cyano group, o...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/87
Inventor 赵国标俞灵军李胜永
Owner ZHEJIANG HUAHAI PHARMA CO LTD
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