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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 problems such as low yield, racemization or isomerization, and achieve high yield, mild conditions, and optical purity and the effect of high yield

Inactive Publication Date: 2009-12-23
SHANGHAI INST OF PHARMA IND +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
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  • Method for preparing escitalopram

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Example 1 Preparation of Escitalopram

[0031] In a reaction flask under nitrogen protection, add S-4-[4-(dimethylamino)-1-(4'-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-cyanide 34.2g (0.1mol) of benzene (S-diol ee value 98.5%) and 340ml of anhydrous tetrahydrofuran were added at room temperature with 57.6g (0.22mol) of triphenylphosphine and 10.2g (0.22mol) of 98% formic acid, Add 44.5 g (0.22 mol) of diisopropyl azodicarboxylate dropwise, react at room temperature of 20°C, wait for TLC to detect the end of the reaction (2 hours), evaporate the tetrahydrofuran to dryness under reduced pressure, and add toluene to the remaining oil. 200ml, cooled to 0 degrees and stirred, a large amount of white solid was precipitated, suction filtration, 200ml of 1N dilute hydrochloric acid was added to the filtrate, stirred, and the liquid was separated. Extract with ethyl acetate 100ml*3, combine the organic layers, wash with saturated brine, dry over anhydrous sodium sulfate, ...

Embodiment 2

[0034] Example 2 Preparation of Escitalopram

[0035] In a reaction flask under nitrogen protection, add S-4-[4-(dimethylamino)-1-(4'-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-cyanide 34.2g (0.1mol) of benzene (S-diol ee value 98.5%) and 340ml of anhydrous tetrahydrofuran were added at room temperature with 16.7g (0.22mol) of trimethylphosphine and 10.2g (0.22mol) of 98% formic acid, Add 44.5 g (0.22 mol) of diisopropyl azodicarboxylate dropwise, react at 30°C, wait for TLC to detect the end of the reaction (2 hours), evaporate the tetrahydrofuran to dryness under reduced pressure, and add 200 ml of toluene to the remaining oil. , cooled to 0 degrees and stirred, a large amount of white solid was precipitated, suction filtration, 200ml of 1N dilute hydrochloric acid was added to the filtrate, stirred, and the liquid was separated. Extract with 100ml*3 of ethyl ester, combine the organic layers, wash with saturated brine, dry over anhydrous sodium sulfate, filter with su...

Embodiment 3

[0037] Example 3 Preparation of Escitalopram

[0038]In a reaction flask under nitrogen protection, add S-4-[4-(dimethylamino)-1-(4'-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-cyanide 34.2g (0.1mol) of benzene (S-diol ee value 98.5%) and 340ml of anhydrous tetrahydrofuran were added at room temperature with 15.2g (0.2mol) of trimethylphosphine and 9.2g (0.2mol) of 98% formic acid, Add 19.2 g (0.2 mol) of diethyl azodicarboxylate dropwise, react at room temperature of 25°C, and wait for TLC to detect the end of the reaction (2 hours), evaporate the tetrahydrofuran to dryness under reduced pressure, and add 200 ml of toluene to the remaining oil. , cooled to 0 degrees and stirred, a large amount of white solid was precipitated, suction filtration, 200ml of 1N dilute hydrochloric acid was added to the filtrate, stirred, and the liquid was separated. Extract with 100ml*3 of ethyl ester, combine the organic layers, wash with saturated brine, dry over anhydrous sodium sulfate,...

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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 present invention relates to a preparation method of escitalopram. Background technique [0002] Citalopram is a well-known commercialized antidepressant that 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 molecule of citalopram, that is, the S-isomer, is at least 100 times stronger than that of its R-isomer. Compared with racemic citalopram, the S-isomer has higher 5-HT reuptake inhibition selectivity and lower affinity for other receptors, so it has better efficacy, fewer side effects, and simultaneous dose It can also be reduced by half. Therefore, since February 2002, the Danish Lingbi company has marketed its S-isomer in Switzerland and other European and American countries, with the common name of Escitalopram (escitalopram...

Claims

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Application Information

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IPC IPC(8): C07D307/87A61P25/24
Inventor 朱雪焱袁哲东王强潘红娟
Owner SHANGHAI INST OF PHARMA IND
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