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A method for preparing chiral (1r, 2s)-1-phenyl-2-(1-pyrrolidinyl)propan-1-ol

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 harsh reaction conditions, poor chiral selectivity, etc., and achieves improved yield and atomic Economical, cost-reducing effect

Active Publication Date: 2022-05-17
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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  • A method for preparing chiral (1r, 2s)-1-phenyl-2-(1-pyrrolidinyl)propan-1-ol
  • A method for preparing chiral (1r, 2s)-1-phenyl-2-(1-pyrrolidinyl)propan-1-ol
  • A method for preparing chiral (1r, 2s)-1-phenyl-2-(1-pyrrolidinyl)propan-1-ol

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Experimental program
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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 present invention provides a simple and easy enzyme-catalyzed new method for synthesizing (1R, 2S)-1-phenyl-2-(1-pyrrolidinyl)propane-1-alcohol. The body does not need to be separated, which greatly reduces the production cost and is suitable for large-scale industrial production. The synthesis method of the present invention is that, using compound I as a raw material, using ketoreductase (KRED) to carry out asymmetric reduction reaction on compound I, the obtained α-halohydrin is directly subjected to α-halohydrin under alkaline conditions without separation. Alcohol ring closure gives (1R,2R)-1-phenyl propylene oxide (compound Ⅱ), compound Ⅱ is subjected to ring-opening reaction with tetrahydropyrrole to obtain (1R,2S)-1-phenyl-2-(1-pyrrole Alkyl) 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 Patents(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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