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A kind of levorotatory corey lactone diol intermediate, its preparation method and its pharmaceutical application

A technology of lactone diol and intermediate, applied in the field of pharmaceutical preparation, can solve the problems of low enantiomeric yield and low enantiomeric excess, and achieve high enantiomeric yield and high enantiomeric excess. , the effect of mild reaction conditions

Active Publication Date: 2022-03-18
厦门欧瑞捷生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In order to solve the problems of low enantiomeric excess value and low enantiomeric yield in the existing process of preparing L-Corey lactone diol intermediate L-compound VI by bio-enzyme resolution mentioned in the background technology

Method used

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  • A kind of levorotatory corey lactone diol intermediate, its preparation method and its pharmaceutical application
  • A kind of levorotatory corey lactone diol intermediate, its preparation method and its pharmaceutical application
  • A kind of levorotatory corey lactone diol intermediate, its preparation method and its pharmaceutical application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Example 1: Effects of different esterases on the resolution selectivity and activity of compound I.

[0039] In parallel, take ten parts of the prepared buffer solution of disodium hydrogen phosphate and sodium dihydrogen phosphate (pH=8.0) 10mL into a 50mL reaction bottle, and place them in a shaker at 30°C; then add different Enzyme 1g; then weigh 20g of racemic compound I and 69g of vinyl acetate into 100mL of ethyl acetate solution, then divide the above mixed solution into ten parts in parallel and add to the reaction system, start the shaker, and start the reaction. The reaction was sampled at intervals of 1 h. When sampling, it was allowed to stand for stratification, and 500 μL of the upper organic layer was taken out for chiral detection. The results are shown in Table 1.

[0040] Table I

[0041]

[0042] It can be seen from the comparison of the impact of different enzymes on the resolution selectivity and activity in Table 1: the reaction temperature is ...

Embodiment 2

[0043] Example 2: Effects of different reaction temperatures on the resolution selectivity and activity of Lipase AK.

[0044]In parallel, take five prepared buffer solutions of disodium hydrogen phosphate and sodium dihydrogen phosphate (pH=8.0) from 10mL to 50mL in reaction bottles, and place them at 20°C, 30°C, 40°C, 50°C , in a shaker at 60°C; then add 1 g of Lipase AK enzyme to the above system; then weigh 4 g of racemic compound I and 35 g of vinyl acetate to prepare 50 mL of ethyl acetate solution, then divide it into 5 parts in parallel and add to In the reaction system, start the shaker to start the reaction. The reaction was sampled at intervals of 1 h. When sampling, it was allowed to stand for stratification, and 500 μL of the upper organic layer was taken out for chiral detection. The results are shown in Table 2.

[0045] Table II

[0046]

[0047] From Table 2, the comparison of the effects of different reaction temperatures on the resolution selectivity an...

Embodiment 3

[0048] Example 3: Effects of different pH buffer solutions on the resolution selectivity and activity of Lipase AK.

[0049] Prepare buffer solutions of disodium hydrogen phosphate and sodium dihydrogen phosphate with different pH values ​​(pH = 6.0, 7.0, 8.0, 9.0, 10.0), and then measure 10mL to 50mL reaction flasks, and place them at 30°C Then add 1 g of LipaseAK enzyme to the above system; then weigh 4 g of racemic compound I and 35 g of vinyl acetate to prepare 50 mL of ethyl acetate solution, then divide it into 5 parts in parallel and add to the reaction system, Start the shaker and start the reaction. The reaction was sampled at intervals of 1 h. When sampling, the samples were allowed to stand for stratification, and 500 μL of the upper organic layer was taken out for chiral detection. The results are shown in Table 3.

[0050] Table three

[0051]

[0052] It can be seen from the comparison of the effects of different pH buffer solutions in Table 3 on the separat...

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Abstract

A kind of L-Corey lactone diol intermediate, its preparation method and pharmaceutical application thereof, wherein, a kind of method for preparing L-Corey lactone diol intermediate comprises the alkaline buffer solution containing esterase and hydrophobic organic solvent mixing and reacting; the hydrophobic organic solvent contains vinyl carboxylate compounds and racemic compound I; the organic layer is separated from the reaction system, and the levorotatory compound VI is extracted from the organic layer. The present invention splits the racemic compound I by esterase, and can directly prepare the levorotatory compound VI, which has the advantages of mild reaction conditions, no use of amine compounds, environmental friendliness, high enantiomeric excess value, and high enantiomeric yield. .

Description

technical field [0001] The invention relates to the field of medicine preparation, in particular to a L-Corey lactone diol intermediate, its preparation method and its pharmaceutical application. Background technique [0002] The chemical name of L-Corey lactone diol is: (1S,5R,6R,7R)-6-hydroxymethyl-7-hydroxy-2-oxabicyclo[3.3.0]-octan-3-one, referred to as CLA, it is an important intermediate in the synthesis of prostaglandin drugs. The compound has four chiral centers, and the racemic Corey lactone should theoretically be a mixture of eight enantiomers and sixteen configurations, but the L-Corey lactone diol usually referred to is only these sixteen types One of the configurations. The chemical synthesis of L-Corey lactone diol must involve many steps and high cost. And because it is a key intermediate in the synthesis of prostaglandin drugs, the price of prostaglandin drugs is expensive. Therefore, the development of a new L-Corey lactone synthesis process can effectiv...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C12P41/00C12P17/04C07D307/935
CPCC12P17/04C12P41/001C07D307/935
Inventor 郑飞剑李刚赵欢蔡金柱陈思涵万明张立军王萍高伟
Owner 厦门欧瑞捷生物科技有限公司
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