Method for preparing chiral (1R,2S)-1-phenyl-2-(1-pyrrolidyl)propane-1-alcohol

A technology of pyrrolidinyl and propane, which is applied in the field of preparation of chiral-1-phenyl-2-propan-1-ol, can solve the problems of poor chiral selectivity and harsh reaction conditions, and can reduce costs and improve production. The effect of rate and atom economy

Active Publication Date: 2019-01-04
SUZHOU LEAD BIOTECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method uses a reducing agent to reduce The reaction conditions are harsh, the chiral selectivity is poor, and a large number of isomer by-products are produced

Method used

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  • Method for preparing chiral (1R,2S)-1-phenyl-2-(1-pyrrolidyl)propane-1-alcohol
  • Method for preparing chiral (1R,2S)-1-phenyl-2-(1-pyrrolidyl)propane-1-alcohol
  • Method for preparing chiral (1R,2S)-1-phenyl-2-(1-pyrrolidyl)propane-1-alcohol

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Experimental program
Comparison scheme
Effect test

Embodiment 1-5

[0035] The reaction path of embodiment 1-5 method is:

[0036]

Embodiment 1

[0038] Synthesis of (1R,2R)-1-Phenyloxypropylene (Compound Ⅱ)

[0039] Add 10 grams of 1-phenyl-2-chloro-1-propanone and 20ml of isopropanol to a 250ml reaction bottle, stir until the substrate is completely dissolved, then add 10ml of PBS buffer (0.4M, pH=7.5), 50ml of water , Ketoreductase powder (purchased from Suzhou Pilot Biotechnology Co., Ltd., commodity number is YH2011, here only provides the product of a kind of model to illustrate the effect of the present invention) 1 gram (dissolved in 10ml water), NADP + 0.2 g (dissolved in 10 ml of water), reacted with magnetic stirring at 35° C. for 20 h, then sampled for HPLC analysis, and the conversion rate was detected by HPLC >99%. Add 30ml of a pre-prepared 300g / L KOH solution to the system, raise the temperature to 40°C and continue stirring, monitor by TLC, and the reaction is completed in 3-4 hours. The system was filtered to remove enzymes, the aqueous phase was extracted 2-3 times with an equal volume of toluene, th...

Embodiment 2

[0041] Synthesis of (1R,2R)-1-Phenyloxypropylene (Compound Ⅱ)

[0042] Add 10 grams of 1-phenyl-2-bromo-1-propanone and 20 ml of isopropanol into a 250 ml reaction bottle, stir until the substrate is completely dissolved, then add 10 ml of PBS buffer (0.4M, pH=7.5), 50 ml of water , Ketoreductase powder (purchased from Suzhou Pilot Biotechnology Co., Ltd., commodity number is YH2011, here only provides the product of a kind of model to illustrate the effect of the present invention) 1 gram (dissolved in 10ml water), NADP +0.2 g (dissolved in 10 ml of water), reacted with magnetic stirring at 35° C. for 20 h, then sampled for HPLC analysis, and the conversion rate was detected by HPLC >99%. Add 30ml of a pre-prepared 300g / L KOH solution to the system, raise the temperature to 40°C and continue stirring, monitor by TLC, and the reaction is completed in 3-4 hours. The system was filtered to remove enzymes, the aqueous phase was extracted 2-3 times with an equal volume of toluene...

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Abstract

The invention provides a new method for simply and feasibly synthesizing (1R,2S)-1-phenyl-2-(1-pyrrolidyl)propane-1-alcohol through enzymatic catalysis. The method is easy to operate and mild in condition, an intermediate does not need to be separated, the production cost is greatly reduced, and the method is suitable for large-scale industrial production. According to the synthesis method, a first compound serves as a raw material, ketoreductase (KRD) is utilized for conducting an asymmetric reduction reaction on the first compound to obtain alpha-halohydrin, alpha-halohydrin is directly subjected to ring closing under the alkaline condition without separation to obtain a second compound (1R,2S)-1-phenyl epoxypropane, and tetrahydropyrrole is utilized for conducting a ring-opening reaction on the second compound to obtain (1R,2S)-1-phenyl-2-(1-pyrrolidyl)propane-1-alcohol.

Description

technical field [0001] The invention relates to a preparation method of chiral (1R,2S)-1-phenyl-2-(1-pyrrolidinyl)propan-1-ol, which belongs to the technical fields of biopharmaceutical and biochemical industry. Background technique [0002] (1R,2S)-1-phenyl-2-(1-pyrrolidinyl)propan-1-ol (structural formula ) is a chiral ligand widely used in the field of asymmetric organic synthesis. It is noteworthy that this compound has been successfully used as a chiral catalyst in the synthesis of the anti-AIDS drug efavirenz intermediate (J.Org.Chem.1998,63,8536-8543; EP0582455; WO9520389 and WO9637457, etc.), and Industrialized production has been realized. [0003] [0004] (1R,2S)-1-phenyl-2-(1-pyrrolidinyl)propan-1-ol is not only a very efficient chiral ligand itself, but also can be combined with other ligands to form new catalysts ( Journal of Organic Chemistry, 68(7), 2540-2546; 2003). In addition, it can also obtain a more widely used diamine ligand catalyst (Chemistry...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/06C12P7/22
CPCC12P7/22C07D207/06C07B2200/07
Inventor 谢新开黄晓飞徐伟
Owner SUZHOU LEAD BIOTECH CO LTD
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