Method for preparing single-configuration 3-aminocyclopentanol through chiral resolution

A technology for the separation of aminocyclopentanol and chirality, which is applied in the direction of organic chemical methods, chemical instruments and methods, and the preparation of organic compounds, and can solve problems such as high cost, low optical purity, and low yield

Inactive Publication Date: 2019-07-09
SHANGHAI DESANO PHARMA INVESTMENT +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0011] The purpose of the present invention is to provide a new preparation method for preparing single-configuration 3-aminocyclopentanol, to enrich the preparation method of optically pure 3-aminocyclopentanol, to overcome the low yield and low optical purity of the prior art, High cost, not conducive to industrial promotion, to better meet market demand

Method used

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  • Method for preparing single-configuration 3-aminocyclopentanol through chiral resolution
  • Method for preparing single-configuration 3-aminocyclopentanol through chiral resolution
  • Method for preparing single-configuration 3-aminocyclopentanol through chiral resolution

Examples

Experimental program
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Effect test

Embodiment 1

[0073] The cis-3-aminocyclopentanol racemic mixture (50 g, 0.495 mol) was dissolved in 400 mL of isopropanol, and the resolution reagent D-tartaric acid (59.4 g, 0.396 mol) was added, stirred at room temperature, and a large amount of solids precipitated. After continuing to stir for 1 to 2 hours, filter with suction, and rinse the filter cake once with isopropanol to obtain crude (1R,3S)-3-aminocyclopentanol tartrate as a white solid, with a wet weight of 80.76 g and an ee value of 92.1%. .

[0074] Suspend the crude product of (1R,3S)-3-aminocyclopentanol tartrate obtained above in 300ml of 95% ethanol, raise the temperature to reflux to dissolve the liquid, slowly lower the temperature to room temperature, and further cool down to 10-15°C, keep stirring After 1 to 2 hours, filter to obtain a refined solid, and its ee value is measured to be 98.5%.

[0075] Repeat the refining step to obtain 52.4 g of refined (1R,3S)-3-aminocyclopentanol tartrate, and its ee value is 99.2%....

Embodiment 2

[0077] The cis-3-aminocyclopentanol racemic mixture (50 g, 0.495 mol) was dissolved in 400 mL of absolute ethanol, and the resolution reagent D-tartaric acid (74.2 g, 0.495 mol) was added, stirred at room temperature, and a large amount of solids precipitated. After continuing to stir for 1 to 2 hours, filter with suction, and rinse the filter cake once with absolute ethanol to obtain (1R,3S)-3-aminocyclopentanol tartrate as a white solid crude product, with a wet weight of 82.3g and an ee value of 91.2%. .

[0078] Suspend the crude product of (1R,3S)-3-aminocyclopentanol tartrate obtained above in 300ml of absolute ethanol, raise the temperature to reflux to dissolve the liquid, slowly lower the temperature to room temperature, and further cool down to 10-15°C, keep stirring After 1 to 2 hours, filter to obtain a refined solid whose ee value was measured to be 98.6%.

[0079] The above refining steps were repeated to obtain 53.0 g of (1R,3S)-3-aminocyclopentanol tartrate af...

Embodiment 3

[0082] Dissolve cis-3-aminocyclopentanol racemic mixture (50g, 0.495mol) in 400mL of 95% ethanol, add resolution reagent D-di-p-toluoyl tartaric acid (152.8g, 0.396mol), heat up to 40°C and keep stirring After 2 hours, a large amount of solid precipitated. After lowering to room temperature and continuing to stir for 1-2 hours, suction filtration, the filter cake was rinsed once with 95% ethanol to obtain white solid (1R,3S)-3-aminocyclopentanol tartrate, wet weight 140.2g, ee value 92.1%.

[0083] Suspend the crude product of (1R,3S)-3-aminocyclopentanol tartrate obtained above in 400ml of 95% ethanol, raise the temperature to reflux to dissolve the liquid, slowly lower the temperature to room temperature, and further cool down to 10-15°C, keep stirring After 1 to 2 hours, filter to obtain a refined solid whose ee value was measured to be 94.3%.

[0084] The above refining steps were repeated twice to obtain 48.8 g of (1R,3S)-3-aminocyclopentanol di-p-toluoyl tartrate after...

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Abstract

The invention relates to a method for preparing a single-configuration 3- aminocyclopentanol through chiral resolution. Specifically, the invention discloses a chiral splitting method of 3-aminocyclopentanol. The preparation method is simple to operate, a used resolving reagent is low in price, the reaction condition is mild, the resolving yield can reach 40%, the optical purity is not lower than99.5%, and the preparation method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a preparation method of optically pure 3-amino-cyclopentanol. Background technique [0002] Bictegravir is an innovative once-daily integrase strand transfer inhibitor developed by Gilead, which is currently in phase III clinical trials. The phenamine combination is used in the treatment of HIV infection. [0003] [0004] 3-Amino-cyclopentanol is an important intermediate for the synthesis of anti-HIV drug Bictegravir, as well as an important intermediate for the synthesis of other antiviral drugs and pharmaceutical raw materials. Currently, the methods for synthesizing cis-3-amino-cyclopentanol are as follows. [0005] Method 1: Patent CN201210090148X discloses the preparation method of cis-3-amino-cyclopentanol using benzyl chloroformate as the starting material. The synthesis route is short and the synthesis process is simple and easy to operate, ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C213/10C07C215/44
CPCC07B2200/07C07C213/10C07C215/44
Inventor 李金亮赵楠靳家玉孟江
Owner SHANGHAI DESANO PHARMA INVESTMENT
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