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Method for preparing escitalopram

A coordination and phosphine compound technology, which is applied in nervous system diseases, organic chemistry, drug combination, etc., can solve the problems of racemization or isomerization, low yield, etc., and achieve mild conditions, high yield, and optical purity and the effect of high yield

Inactive Publication Date: 2011-09-28
SHANGHAI INST OF PHARMA IND CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] The technical problem to be solved by the present invention is to provide a simple method, mild reaction conditions and yield High efficiency, high optical purity, easy to apply to a new method of large-scale industrial production

Method used

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  • Method for preparing escitalopram
  • Method for preparing escitalopram
  • Method for preparing escitalopram

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Example 1 Preparation of Escitalopram

[0031] In the reaction flask under the protection of nitrogen, add S-4-[4-(dimethylamino)-1-(4'-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-cyanide Benzene (S-type diol ee value 98.5%) 34.2g (0.1mol), anhydrous tetrahydrofuran 340ml, add triphenylphosphine 57.6g (0.22mol) at room temperature, 98% formic acid 10.2g (0.22mol), Add 44.5 g (0.22 mol) of diisopropyl azodicarboxylate dropwise, and react at room temperature at 20°C. After the reaction is detected by thin-layer chromatography (TLC) (2 hours), evaporate the tetrahydrofuran to dryness under reduced pressure, and add toluene to the remaining oil 200ml, cooled to 0°C and stirred, a large amount of white solids precipitated, suction filtered, added 200ml of 1N dilute hydrochloric acid to the filtrate, stirred, separated, the water layer was washed once with 100ml of ethyl acetate, adjusted to pH=10 with dilute aqueous sodium hydroxide solution, Ethyl acetate was extracted...

Embodiment 2

[0034] Example 2 Preparation of Escitalopram

[0035] In the reaction flask under the protection of nitrogen, add S-4-[4-(dimethylamino)-1-(4'-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-cyanide Add 16.7 g (0.22 mol) of trimethylphosphine and 10.2 g (0.22 mol) of 98% formic acid to 34.2 g (0.1 mol) of benzene (S-type diol ee value 98.5%) and 340 ml of anhydrous tetrahydrofuran. Add 44.5 g (0.22 mol) of diisopropyl azodicarboxylate dropwise and react at 30°C. After the reaction is detected by TLC (2 hours), evaporate THF to dryness under reduced pressure and add 200 ml of toluene to the remaining oil. , cooled to 0°C and stirred, a large amount of white solids precipitated, filtered with suction, added 200ml of 1N dilute hydrochloric acid to the filtrate, stirred, and separated, the water layer was washed once with 100ml of ethyl acetate, adjusted to pH=10 with dilute aqueous sodium hydroxide solution, acetic acid Ethyl ester 100ml*3 was extracted, the organic layers were ...

Embodiment 3

[0037] Example 3 Preparation of Escitalopram

[0038]In the reaction flask under the protection of nitrogen, add S-4-[4-(dimethylamino)-1-(4'-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-cyanide Add 15.2 g (0.2 mol) of trimethylphosphine and 9.2 g (0.2 mol) of 98% formic acid to 34.2 g (0.1 mol) of benzene (S-type diol ee value 98.5%) and 340 ml of anhydrous tetrahydrofuran. Add 19.2 g (0.2 mol) of diethyl azodicarboxylate dropwise and react at room temperature at 25°C. After the end of the reaction (2 hours) as detected by TLC, evaporate the tetrahydrofuran to dryness under reduced pressure and add 200 ml of toluene to the remaining oil , cooled to 0°C and stirred, a large amount of white solids precipitated, filtered with suction, added 200ml of 1N dilute hydrochloric acid to the filtrate, stirred, and separated, the water layer was washed once with 100ml of ethyl acetate, adjusted to pH=10 with dilute aqueous sodium hydroxide solution, acetic acid Ethyl ester 100ml*3 wa...

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Abstract

The invention discloses a method for preparing escitalopram represented by a formula (I), which comprises the following step: reacting S-diol represented by a formula (II) in an aprotic organic solvent under the action of a phosphine complex compound, an azo reagent and a proton supplying agent in an atmosphere of an inert gas to obtain the escitalopram represented by the formula (I). The method uses a Mitsunobu reaction in the cyclization preparation of escitalopram represented by the structural formula (I) for the first time and has the unexpected advantages of excellent product configuration retention, prevention of racemization in a cyclization process and high optical purity and yield. In addition, the method of the invention is simple in operation, mild in condition, simple and convenient in post processing and suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to a preparation method of escitalopram. Background technique [0002] Citalopram, a well-known commercially available antidepressant, is a selective serotonin reuptake inhibitor. Commercially available citalopram is a racemate, and its structure is as follows: [0003] [0004] Formula III [0005] It is currently known that the antidepressant effect of the dextrorotatory optical isomer in the citalopram molecule, that is, the S-isomer is at least 100 times stronger than that of the R-isomer. The S-isomer has higher 5-HT reuptake inhibitory selectivity than racemic citalopram, and has lower affinity to other receptors, so it has better curative effect and fewer side effects. It can also be reduced by half. Therefore, since February 2002, the Danish Lingbi Company has listed and sold its S-type isomer in Switzerland and other European and American countries. The general name is Escitalopram (escitalopram), and its structure...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D307/87A61P25/24
Inventor 朱雪焱袁哲东王强潘红娟
Owner SHANGHAI INST OF PHARMA IND CO LTD
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