A kind of preparation method of (s)-2-chloro-1-(6-fluoro-1-chroman-2-yl)-ethanol

A chroman and ethanol technology, applied in the directions of organic chemistry methods, chemical instruments and methods, organic chemistry, etc., can solve the problems of irrespective of chiral selectivity, low chiral purity of products, difficulty in separation and purification, and the like, Achieve high chiral selectivity, high chiral purity, high yield, and high chiral purity

Active Publication Date: 2020-04-07
江苏八巨药业有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The method has a large heat release and a violent reaction, and potassium borohydride needs to be added in batches. The operation is complicated and the process is cumbersome, and the reaction basically does not consider the problem of chiral selectivity. The product obtained by it has low chiral purity and is difficult to separate and purify. low yield

Method used

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  • A kind of preparation method of (s)-2-chloro-1-(6-fluoro-1-chroman-2-yl)-ethanol
  • A kind of preparation method of (s)-2-chloro-1-(6-fluoro-1-chroman-2-yl)-ethanol
  • A kind of preparation method of (s)-2-chloro-1-(6-fluoro-1-chroman-2-yl)-ethanol

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Experimental program
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Effect test

Embodiment 1

[0031] Take 22.87g (0.1mol) of (S)-(6-fluoro-3,4-dihydro-2H-chroman-2-methanol-2-yl)ethanone chloride into the reaction flask, add 230mL of dichloromethane, stirred at room temperature, then added 30g (0.5mol) isopropanol, continued to stir and mix evenly, then, added 6.0g (0.03mol) aluminum isopropoxide, stirred until uniform. Slowly raise the temperature of the water bath to 30°C, and control the temperature at 30°C to 35°C to keep warm for catalytic reduction reaction for 4 hours. After the reaction, add 5wt% dilute hydrochloric acid to wash with water, let stand to separate the liquid, collect the organic phase, and then After adding water and washing once, the organic phase was dried with anhydrous sodium sulfate for 0.5 hours, filtered, and the collected filtrate was subjected to vacuum distillation to remove the solvent to obtain the corresponding finished product (S)-2-chloro-1-((S)-6-fluoro -1-chroman-2-yl)-ethanol 19.38g, yield 84.03%, content 97.58%, chiral purity 9...

Embodiment 2

[0033]Take 22.87g (0.1mol) of (S)-(6-fluoro-3,4-dihydro-2H-chroman-2-methanol-2-yl)ethanone chloride into the reaction flask, add 250mL of toluene, stirred at room temperature, then added 36g (0.6mol) isopropanol, continued to stir, then added 8.0g (0.04mol) aluminum isopropoxide, stirred until uniform, then slowly raised the temperature to 60°C in a water bath, and controlled the reaction system The temperature is kept at 58°C-60°C for 4 hours of catalytic reduction reaction. After the reaction, add 5wt% dilute hydrochloric acid to wash with water, stand to separate the liquid, collect the organic phase, and then add water to wash once. The organic phase is anhydrous Sodium sulfate was dried for 0.5 hours, filtered, and the collected filtrate was subjected to vacuum distillation to remove the solvent to obtain the corresponding finished product (S)-2-chloro-1-((S)-6-fluoro-1-chroman- 2-yl)-ethanol 20.24g, yield 87.76%, content 98.02%, chiral purity 96.63%.

Embodiment 3

[0035] Take 22.87g (0.1mol) of (R)-(6-fluoro-3,4-dihydro-2H-chroman-2-methanol-2-yl)ethanone chloride into the reaction flask, add 300mL of toluene, stirred at room temperature, then added 24g (0.4mol) isopropanol, continued to stir, then added 4.0g (0.02mol) isobutyl aluminum, stirred until uniform, then slowly raised the temperature to 80°C in a water bath, and controlled the reaction system The temperature was kept at 75°C to 80°C to carry out the catalytic reduction reaction for 3 hours. After the reaction, add 5wt% dilute hydrochloric acid to wash, stand to separate the liquid, collect the organic phase, and then add water to wash once. Add 2g of organic phase to the organic phase dried over sodium sulfate for 0.5 hours, filtered, and the collected filtrate was distilled under reduced pressure to remove the solvent to obtain the corresponding finished product (S)-2-chloro-1-((R)6-fluoro-1-chroman- 2-yl)-ethanol 21.12g, yield 91.6%, content 98.51%, chiral purity 97.63%.

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Abstract

The invention relates to a preparation method of (S)-2-chloro-1-(6-fluoro-1-chromanone-2-yl)-ethanol and belongs to the technical field of synthesis of drug intermediates. Aiming at solving the existing problems that the chiral purity is low and the separation is difficult, the invention provides the preparation method of the (S)-2-chloro-1-(6-fluoro-1-chromanone-2-yl)-ethanol; the preparation method comprises the following step: carrying out catalytic reduction reaction on a substrate in a mixed solvent of isopropyl alcohol and a non-proton weak-polarity solvent under the catalysis effect oforganic aluminum salt, so as to obtain the product (S)-2-chloro-1-(6-fluoro-1-chromanone-2-yl)-ethanol. According to the preparation method provided by the invention, an isopropyl alcohol and non-proton weak-polarity solvent system is combined and the organic aluminum salt is used for carrying out the catalytic reaction, so that the high chiral selectivity can be realized, and the preparation method has the effects of high chiral purity and high yield.

Description

technical field [0001] The invention relates to a preparation method of (S)-2-chloro-1-(6-fluoro-1-chroman-2-yl)-ethanol, belonging to the technical field of pharmaceutical intermediate synthesis. Background technique [0002] Hypertension is one of the most common cardiovascular diseases in the world today. Epidemiological studies have shown that the incidence rate of hypertensive patients in China is 12%, while it reaches 20% in some developed countries in Europe and America. At present, the percentage of sales of cardiovascular and cerebrovascular drugs in the total drug sales has risen from 15% in the 1980s to about 20% at present. According to market research firm Kalorama Information's research report, the cardiovascular market will exceed the $100 billion mark by 2008. Therefore, attention should be paid to drug research for cardiovascular diseases. [0003] Historically, β-blockers have been used as anti-ischemic, anti-arrhythmic, and antihypertensive drugs. Nebi...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D311/58
CPCC07B53/00C07B2200/07C07D311/58
Inventor 王福军程祖福刘玉坤杨泽心陈恬蒲通王家洪钟惺周映
Owner 江苏八巨药业有限公司
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