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Method for asymmetric synthesis of (S)-2-chloro-1-phenylethanol derivative

A technology of phenylethanol and derivatives, applied in the field of biosynthesis, can solve the problems of high price and high cost of resolving agents, and achieve the effects of easy realization of reaction conditions, low cost and simple operation

Inactive Publication Date: 2009-08-12
GUANGDONG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

At present, 2-chloro-1-phenylethanol derivatives are mainly synthesized by chemical methods at home and abroad. The single-configuration 2-chloro-1-phenylethanol derivatives are prepared by chemical resolution or enzymatic resolution. These The resolving agent is relatively expensive, and the maximum yield of the obtained optically pure substance is only 50%, and it needs to repeat the resolution many times to obtain a relatively pure single enantiomer, and the cost is relatively high

Method used

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  • Method for asymmetric synthesis of (S)-2-chloro-1-phenylethanol derivative
  • Method for asymmetric synthesis of (S)-2-chloro-1-phenylethanol derivative
  • Method for asymmetric synthesis of (S)-2-chloro-1-phenylethanol derivative

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Experimental program
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Effect test

Embodiment 1

[0022] Add 25 mL of pH 6.8 phosphate buffer, 3.0 g (120 g / L) of dry baker’s yeast and 1.25 g (50 g / L) of glucose into the Erlenmeyer flask, and vibrate at a certain temperature in a temperature-controlled shaker (140 r / L) min) 0.5h to activate the baker's yeast. Then add substrate 2,2', 4'-trichloroacetophenone 33.5mg (0.006mol / L) and auxiliary substrate methyl alcohol (5%, V 辅底物 / V 缓冲溶液 ), placed on a shaker (140r / min) at 30°C for 48 hours. After the reaction is over, add n-hexane to the reaction solution, place it in a shaker and extract it by shaking at 100r / min for 10 minutes, then transfer it to a separatory funnel, shake it again to make the extraction complete, and take the upper layer solution after standing for layers Carry out centrifugation, then take the supernatant after centrifugation and use anhydrous Na 2 SO 4 After drying, the substrate, product concentration and reaction stereoselectivity were analyzed by gas chromatography. The yield of the product (S)-...

Embodiment 2

[0024] Add 25 mL of pH 6.8 phosphate buffer, 2.5 g (100 g / L) of dry baker’s yeast and 1.25 g (50 g / L) of glucose into the Erlenmeyer flask, and vibrate at a certain temperature in a temperature-controlled shaker (140 r / L). min) 0.5h to activate the baker's yeast. Then add substrate 2,2', 4'-trichloroacetophenone 55.9mg (0.01mol / L) and auxiliary substrate ethanol (5%, V 辅底物 / V 缓冲溶液 ), placed on a shaker (140r / min) at 30°C for 24 hours. After the reaction is over, add n-hexane to the reaction solution, place it in a shaker and extract it by shaking at 100r / min for 10 minutes, then transfer it to a separatory funnel, shake it again to make the extraction complete, and take the upper layer solution after standing for layers Carry out centrifugation, then take the supernatant after centrifugation and use anhydrous Na 2 SO 4 After drying, the substrate, product concentration and reaction stereoselectivity were analyzed by gas chromatography. The yield of the product (S)-2-chlor...

Embodiment 3

[0026] Add 25 mL of pH 7.0 phosphate buffer, 2.25 g (90 g / L) of dry baker’s yeast and 1.25 g (50 g / L) of glucose into the Erlenmeyer flask, and vibrate at a certain temperature in a temperature-controlled shaker (140 r / L). min) 0.5h to activate the baker's yeast. Then add substrate 2,2', 4'-trichloroacetophenone 335.3mg (0.06mol / L) and auxiliary substrate methyl alcohol (5%, V 辅底物 / V 缓冲溶液 ), placed on a shaker (140r / min) at 30°C for 36 hours. After the reaction is over, add n-hexane to the reaction solution, place it in a shaker and extract it by shaking at 100r / min for 10 minutes, then transfer it to a separatory funnel, shake it again to make the extraction complete, and take the upper layer solution after standing for layers Carry out centrifugation, then take the supernatant after centrifugation and use anhydrous Na 2 SO 4 After drying, the substrate, product concentration and reaction stereoselectivity were analyzed by gas chromatography. The yield of the product (S)...

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Abstract

The invention discloses a method for asymmetrically synthesizing a derivative of (S)-2-clorine-1-phenyl ethanol. In the method, the bakery yeast is used for biologically catalyzing a derivative of 2-clorine-1-acetophenone shown in a formula (II) to asymmetrically synthesize the derivative of (S)-2-clorine-1-phenyl ethanol shown in a formula (I), wherein R1 and R2 are any two of H, F, Cl, Br, CH3 or C2H5. In the method, the bakery yeast is used as a catalyst to biologically asymmetrically catalyze the derivative of (S)-2-clorine-1-phenyl ethanol with single optical rotation property, the yield of the target product of the derivative of (S)-2-clorine-1-phenyl ethanol is over 74 percent, the enantioselectivity e.e is over 97 percent, thereby the method greatly simplifies the following split separation step; moreover, the method also has the advantages of simple step, high reaction stereoselectivity, mild reaction conditions, low cost and suitability for mass production.

Description

technical field [0001] The invention belongs to the technical field of biosynthesis. Specifically, the present invention relates to the biological asymmetric synthesis of (S)-2-chloro-1-phenylethanol derivatives shown in formula (I), and the prepared formula (I) is a method for industrial production of chiral antifungal drug compounds key intermediates. [0002] Background technique [0003] Phenylethylimidazole antifungal drugs, such as miconazole, econazole, tioconazole, isoconazole, sulconazole, voriconazole, ketoconazole and fenticonazole, are broad-spectrum antifungal drugs commonly used in clinical practice. Fungal drugs are highly effective, safe, and almost all have effects on pathogenic fungi. However, the antifungal activity of such drugs has a great relationship with their three-dimensional structure. The configuration of the key intermediate 2-chloro-1-phenylethanol in this synthesis step is the determinant of the configuration of phenethylimidazole antifun...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P7/22C12R1/865
Inventor 方岩雄张金玲赵建红周蓓蕾张焜谭伟黄宝华黄华荣赵肃清杜志云霍延平郑杰吕红
Owner GUANGDONG UNIV OF TECH
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