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Enzymatic chemical preparation method of (S)-5-azaspiro[2.4]heptane-6-carboxylic acid and derivative thereof

A technology of carboxylic acid derivatives and azaspirocycles, applied in the field of medicine, can solve the problems of low yield, large organic waste, and high product separation cost, and achieves the effects of high reaction conversion rate, convenient post-processing, and reduced production cost

Inactive Publication Date: 2017-12-19
南京方生和医药科技有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But the yield is low, and a large amount of organic waste is produced, and the cost of product separation is high

Method used

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  • Enzymatic chemical preparation method of (S)-5-azaspiro[2.4]heptane-6-carboxylic acid and derivative thereof
  • Enzymatic chemical preparation method of (S)-5-azaspiro[2.4]heptane-6-carboxylic acid and derivative thereof
  • Enzymatic chemical preparation method of (S)-5-azaspiro[2.4]heptane-6-carboxylic acid and derivative thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Example 1: Synthesis of (S)-5-azaspiro[2.4]heptane-6-carboxylic acid precursor (racemic mixture 1)

[0035] Referring to the method described in US 20130324740, the azaspiro compound was obtained through 6 steps using 2-cyclopropyl-1,3-propanediol as a raw material. It was identified as the target compound by mass spectrometry, hydrogen spectrometry and other analytical methods.

Embodiment 2

[0036] Embodiment 2: Preparation of (S)-5-azaspiro[2.4]heptane-6-carboxylic acid

[0037] Reaction formula:

[0038] The specific steps are:

[0039] 1) adding lipase to the buffer solution, dissolving the racemic mixture 1 in a solvent to form a solution;

[0040] 2) Mix the two solutions and adjust the pH to react at 6.9.

[0041] 3) a. After the reaction is finished, filter to obtain filtrate 1; b. use NaHCO 3 The precipitate was washed with aqueous solution to obtain filtrate 2; c. the obtained precipitate was washed with MTBE, and the MTBE layer was washed with NaHCO 3 The aqueous solution rinses again. Discard the organic layer and keep the water layer to obtain filtrate 3; d. Mix the filtrates 1, 2, and 3, add MTBE, adjust the pH to less than 2 with hydrochloric acid, and add MgSO to the product 4 , product 3 was obtained by filtration and distillation.

[0042] The lipase described in the above step 1) is Novozyme435; step 2) after mixing, the concentration of th...

Embodiment 3

[0047] Embodiment 3: Preparation of (S)-5-azaspiro[2.4]heptane-6-carboxylic acid

[0048] Reaction formula:

[0049] The specific steps are:

[0050] 1) adding lipase to the buffer solution, dissolving the racemic mixture 1 in a solvent to form a solution;

[0051] 2) Mix the two solutions and adjust the pH to react at 7.1.

[0052] 3) a. After the reaction is finished, filter to obtain filtrate 1; b. use NaHCO 3 The precipitate was washed with aqueous solution to obtain filtrate 2; c. the obtained precipitate was washed with MTBE, and the MTBE layer was washed with NaHCO 3 The aqueous solution rinses again. Discard the organic layer and keep the water layer to obtain filtrate 3; d. Mix the filtrates 1, 2, and 3, add MTBE, adjust the pH to less than 2 with hydrochloric acid, and add MgSO to the product 4 , product 3 was obtained by filtration and distillation.

[0053] The lipase described in the above step 1) is Novozyme435; step 2) after mixing, the concentration of ...

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Abstract

The invention provides an enzymatic chemical preparation method of (S)-5-azaspiro[2.4]heptane-6-carboxylic acid and a derivative thereof. The enzymatic chemical preparation method comprises: 1) adding lipase into a buffer solution, and dissolving a precursor compound in a solvent to prepare a solution; 2) mixing the two solutions, adjusting the pH value to 6.9-7.1, and carrying out a reaction; and 3) after completing the reaction, filtering, extracting, distilling, and carrying out other operations to obtain the product. According to the present invention, the method uses the biological enzyme so as to provide advantages of safety and environment protection, the reaction is rapid, the yield is high, the purity of the product is high, and the biological enzyme can be recycled so as to reduce the production cost.

Description

technical field [0001] The invention relates to the field of medicines, in particular to a key intermediate (S)-5-azaspiro[2.4]heptane-6-carboxylic acid and its derivatives of a genotype 1 hepatitis C drug, Ledipasvir Preparation methods based on enzyme chemistry of substances; Background technique [0002] Ledipasvir, an NS5A protease inhibitor developed by Gilead Sciences, is an approved drug for an all-oral treatment regimen for hepatitis C, eliminating the need for the traditional injectable drug interferon (IFN). The synthesis method of ledidevir is relatively simple. According to the empirical analysis of segmentation, the bond between carbon atoms and heteroatoms is cut off. The synthetic route of ledidevir can be divided into two parts, one part is 6-[5-(9H- Fluorene-2-yl)-1H-imidazolyl]-5-azaspiro[2.4]heptane derivatives; the other part is 2-{2-bicyclo[2.2.1]heptyl-3-yl}-1H- Benzopyridine derivatives. In its synthetic route, (S)-5-azaspiro[2.4]heptane-6-carboxyli...

Claims

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Application Information

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IPC IPC(8): C12P17/10
CPCC12P17/10Y02P20/582
Inventor 王欢吕伏生
Owner 南京方生和医药科技有限公司
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