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Method for asymmetrically catalyzing and synthesizing (R)-(+)-3-chlorine-phenylpropanol

An asymmetric, phenylpropanol technology, applied in the field of preparation of pharmaceutical intermediates, can solve the problems of difficulty in the source and storage of reactants, increase the reaction cost, and the product yield is less than 50%, and achieves high yield and product optical properties. Purity, reduced production and storage costs, improved catalytic activity

Active Publication Date: 2012-07-18
GUANGXI XINJING TECH +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Thereafter, Brazilian patent BR2003006242 utilized chiral boroxazolidine for the synthesis of (R)-(+)-3-chloro-phenylpropanol, and U.S. patent US.20080200672 synthesized its single-helical body, the reaction system uses borane solution as the reducing agent, the source and storage of reactants are difficult, and the reaction cost is increased
Chinese patent CN100591649C has tried sodium borohydride as reducing agent and chiral amino acid derivative, inorganic Lewis acid effect, obtains (R)-(+)-3-chloro-phenylpropanol without resolution, but product yield is not good to 50%

Method used

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  • Method for asymmetrically catalyzing and synthesizing (R)-(+)-3-chlorine-phenylpropanol
  • Method for asymmetrically catalyzing and synthesizing (R)-(+)-3-chlorine-phenylpropanol
  • Method for asymmetrically catalyzing and synthesizing (R)-(+)-3-chlorine-phenylpropanol

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Weigh catalyst Cat.2, 0.544g (1.75nmol) and KBH 4 Put 0.55g (12.5mmol) in a 100ml three-necked flask, add 15ml tetrahydrofuran solution and mix, add glacial acetic acid dropwise to the flask until the pH value of the reaction solution is 1.0, stir the reaction to turn the mixed solution into a clear and transparent liquid. Put 25ml of 3-chloro-propiophenone tetrahydrofuran solution (0.8mol / L) into the constant pressure funnel, slowly drop it into the reaction bottle at a rate of 2S / drop, and drop it for about 0.5h. After 4h of reaction, add ice water to terminate the reaction . The resulting solution was analyzed by chiral column gas chromatography to obtain a conversion rate of 92% and an optical purity e.e. value of 96%.

[0027] The reaction solution was washed with 2.0mol / L hydrochloric acid solution, the organic layer was left to pass through the column, and the effective eluent was decompressed and rotary evaporated to remove 3.0 g of off-white solid (R)-(+)-3-c...

Embodiment 2

[0030] Weigh catalyst Cat.6, 0.81g (2.5nmol) and NaBH 4 , 0.95g (25mmol) in a 100ml three-necked flask, add 15ml tetrahydrofuran solution and mix, add glacial acetic acid dropwise to the bottle until the pH value of the reaction solution is 5.0, stir the reaction to make the mixed solution become a clear and transparent liquid. Put 20ml of 3-chloro-propiophenone tetrahydrofuran solution (1.25mol / L) into the constant pressure funnel, and slowly drop it into the reaction bottle at a rate of 2S / drop. The dropwise addition is completed in about 0.5h. After 5h of reaction, add ice water to terminate the reaction. The resulting solution was analyzed by chiral column gas chromatography to obtain a conversion rate of 95% and an optical purity e.e. value of 94%.

[0031] The reaction solution was washed with 2.0 mol / L hydrochloric acid solution, and the organic layer was left for rotary evaporation under reduced pressure, and the obtained crude product was recrystallized with cyclohexa...

Embodiment 3

[0034] Weigh catalyst Cat.3 (see chemical formula) 1.6275g (7.5nmol) and LiBH 4 1.1g (50mmol) in a 100ml three-necked flask, add 15ml tetrahydrofuran solution and mix, add glacial acetic acid dropwise to the bottle until the pH of the reaction solution is 0.2, stir the reaction to make the mixed solution become a clear and transparent liquid. Put 18ml of tetrahydrofuran solution (1.5mol / L) of 3-chloro-propiophenone into the constant pressure funnel, and slowly drop it into the reaction bottle at a rate of 2S / drop. After about 0.5h, the dropwise addition is completed. After 2h of reaction, add ice water to terminate the reaction . The resulting solution was analyzed by chiral column gas chromatography to obtain a conversion rate of 98% and an optical purity e.e. value of 93%.

[0035] The reaction solution was washed with 2.0 mol / L hydrochloric acid solution, the organic layer was left for decolorization, and the crude product obtained by rotary evaporation under reduced pres...

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Abstract

The invention provides a method for asymmetrically catalyzing and synthesizing (R)-(+)-3-chlorine-phenylpropanol. The method is implemented as follows: metal hydroboron is taken as a reducing agent and organic acid is taken as an accessory ingredient to asymmetrically catalyze and reduce 3-chlorine-propiophenone; spiroborate and hydroboron are mixed by a tetrahydrofuran solvent, a certain quantity of organic acid is added and stirred until mixed solution is clear and transparent, tetrahydrofuran solution of the 3-chlorine-propiophenone is dropped slowly and stirred to reaction at the 50 degrees below zero to 30 DEG C, reaction liquid is purified to obtain the (R)-(+)-3-chlorine-phenylpropanol mono-spin-body. The optical purity of undetached (R)-(+)-3-chlorine-phenylpropanol is more than 90%e.e..

Description

technical field [0001] The invention relates to a preparation method of a pharmaceutical intermediate, in particular to a method for synthesizing an important intermediate (R)-(+)-3-chloro-phenylpropanol of cetine antidepressants by using an asymmetric catalytic reduction method. Background technique [0002] "World Health Report 2002" pointed out that depression has become the fourth most common disease in the world, and it may become the second largest disease after heart disease by 2020. Depression is becoming a serious global problem. [0003] Antidepressants mainly refer to drugs used to treat depression and negative depression for depression. Its development began with isoniazid in the 1950s. Isapiatide is a monoamine oxidase inhibitor (MAOD), which is gradually eliminated because it is easy to cause serious toxic and side effects such as liver damage after medication. Subsequently, tricyclic and tetracyclic antidepressants have been developed. At present, the internat...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C33/46C07C29/143
Inventor 袁芳爱孙果宋韦志明蒲国荣向忠权
Owner GUANGXI XINJING TECH
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