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A method for preparing (s)-2-chloro-1-(3,4-difluorophenyl)ethanol

A technology of p-toluenesulfonyl and triethylamine, which is applied in the field of preparation of intermediate-2-chloro-1-ethanol, can solve the problems of large amount of diphenylprolinol, high odor, high price and the like, and achieves protection Effects on health and environment, mild reaction conditions, low system toxicity

Active Publication Date: 2020-07-21
JIANGSU VCARE PHARMATECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The shortcoming of this method is: (1) the consumption of (S)-diphenylprolinol is bigger, and price is expensive, has improved production cost; (2) reductant borane dimethyl sulfide is expensive, and smell is big, And the toxicity is high, also is unfavorable for cost control and industrialized production

Method used

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  • A method for preparing (s)-2-chloro-1-(3,4-difluorophenyl)ethanol
  • A method for preparing (s)-2-chloro-1-(3,4-difluorophenyl)ethanol
  • A method for preparing (s)-2-chloro-1-(3,4-difluorophenyl)ethanol

Examples

Experimental program
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Effect test

Embodiment 1

[0024] Preparation of (S)-2-chloro-1-(3,4-difluorophenyl)ethanol

[0025] 2-Chloro-1-(3,4-difluorophenyl)ethanone (38g, 0.2mol, 1eq), catalyst of formula (IIIa) (0.098g, 0.000132mol, 0.00066eq), toluene (400ml) were added to the reaction In the bottle, at room temperature, add the premixed solution of formic acid and triethylamine (triethylamine: 97g, formic acid: 110g) to the reaction bottle twice, after the addition is complete, add 10g of formic acid, stir for 10 minutes, then heat up and reflux React overnight. The next day, almost complete disappearance of starting material was found by TLC analysis. Add 120 ml of water to quench the reaction, stir well and then separate into layers. The organic phase is dried, concentrated, and then purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 10:1) to obtain a yellow oily product 26.9 grams, 1 H-NMR (300MHz, CDCl 3 )δ7.07~7.28(m,3H), 4.86~4.89(m,1H), 3.69~3.74(dd,1H, J=3.3Hz, J=11.1Hz), 3.55...

Embodiment 2

[0027] Preparation of (S)-2-chloro-1-(3,4-difluorophenyl)ethanol

[0028] 2-Chloro-1-(3,4-difluorophenyl)ethanone (3.8g, 20mmol, 1eq), formula (IIIa) catalyst (9.8mg, 0.0132mmol, 0.00066eq), dichloromethane (40ml) Add it into the reaction flask, at room temperature, add the premixed solution of formic acid and triethylamine (triethylamine: 9.7g, formic acid: 11g) to the reaction flask twice, after the addition is complete, add 2g of formic acid, and stir for 10 minutes , heated up to 30°C and reacted overnight. The next day, almost complete disappearance of starting material was found by TLC analysis. Add 20 ml of water to quench the reaction, stir well and then separate into layers. The organic phase is dried, concentrated, and then purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 10:1) to obtain a yellow oily product 2.6 grams, e.e=98.3% (chiral HPLC analysis conditions: Chiralpak IC 4.6mm×250mm; column temperature: 35°C; mobile phase:...

Embodiment 3

[0030] Preparation of (S)-2-chloro-1-(3,4-difluorophenyl)ethanol

[0031] 2-Chloro-1-(3,4-difluorophenyl)ethanone (3.8g, 0.02mol), formula (IIIb) catalyst (9mg), toluene (40ml) were added in the reaction flask, at room temperature, to Add the premixed solution of formic acid and triethylamine (triethylamine: 9.7g, formic acid: 11g) to the reaction flask twice, after the addition is complete, add 2g of formic acid, stir for 10 minutes, then heat up to 30°C for overnight reaction. The next day, almost complete disappearance of starting material was found by TLC analysis. Add 20 ml of water to quench the reaction, stir well and then separate into layers. The organic phase is dried, concentrated, and then purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 10:1) to obtain a yellow oily product 2.7 grams, e.e=98.0% (chiral HPLC analysis conditions: Chiralpak IC 4.6mm×250mm; column temperature: 35°C; mobile phase: n-hexane:isopropanol=99:1; flow r...

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Abstract

The invention relates to a preparation method of (S)-2-chloro-1-(3,4-difluorophenyl)ethanol. In the method, optically-pure (S)-2-chloro-1-(3,4-difluorophenyl)ethanol is obtained by carrying out catalytic hydrogen transfer reduction on 2-chloro-1-(3,4-difluorophenyl)ethyl ketone by taking metal as a catalyst and taking formic acid, triethylamine and the like as hydrogen donors. The method is low incost, simple and convenient to operate and suitable for industrial production.

Description

technical field [0001] The invention relates to the field of pharmacy, in particular to a preparation method of an intermediate (S)-2-chloro-1-(3,4-difluorophenyl)ethanol of an antiplatelet drug ticagrelor. Background technique [0002] Ticagrelor (Ticagrelor) is a new antiplatelet drug developed by AstraZeneca, which was approved by the FDA in 2011. (S)-2-Chloro-1-(3,4-difluorophenyl)ethanol is a useful intermediate for the preparation of ticagrelor. So far, only Chinese patent applications 200780028775.8 and 200780028624.2 and their related patents disclose the preparation method of (S)-2-chloro-1-(3,4-difluorophenyl)ethanol, which uses (S)-difluorophenyl Asymmetric reduction of 2-chloro-1-(3,4-difluorophenyl)ethanone using the complex of phenylprolinol and trimethyl borate as a chiral catalyst, using borane dimethyl sulfide as a reducing agent . The shortcoming of this method is: (1) the consumption of (S)-diphenylprolinol is bigger, and price is expensive, has improve...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C33/46C07C29/143
Inventor 江宁刘源逸任英梅龚彦春刘永强
Owner JIANGSU VCARE PHARMATECH