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Method for splitting dihydropyrimidine racemic compound

A technology for dihydropyrimidines and compounds, which is applied in the field of resolution of organic racemic compounds, can solve the problems of high cost and difficulty in industrialization of resolution methods, and achieve the effects of enhanced diastereomer recognition, simple operation and high optical purity

Active Publication Date: 2010-12-29
SUNSHINE LAKE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the cost of the currently used splitting method is relatively high, and it is not easy to industrialize
According to Bayer and relevant domestic and foreign data, there is no other method for splitting new 2-heterocyclic substituted dihydropyrimidines other than chiral column splitting

Method used

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  • Method for splitting dihydropyrimidine racemic compound
  • Method for splitting dihydropyrimidine racemic compound
  • Method for splitting dihydropyrimidine racemic compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] (1) 1.0mol 4-(2-chlorophenyl)-6-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate racemic compound , its structural formula is as follows:

[0036]

[0037] and 0.50mol D-p-methyl-dibenzoyl tartaric acid (D-(+)-DTTA) into the reactor, followed by adding 2.5L dichloromethane and 2.5L petroleum ether under mechanical stirring;

[0038] (2) Stir at 23°C for 0.5h, rotate left and right methyl 4-(2-chlorophenyl)-6-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate Fully combined with D-p-methyldibenzoyl tartaric acid to form L-4-(2-chlorophenyl)-6-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine- Methyl 5-carboxylate D-p-methyldibenzoyl tartrate and D-4-(2-chlorophenyl)-6-methyl-2-(thiazol-2-yl)-1,4- Methyl dihydropyrimidine-5-carboxylate D-p-methyldibenzoyl tartrate;

[0039] (3) filtering, concentrating the mother liquor to 0.2 times the original volume, and then placing the concentrated mother liquor at 0°C overnight;

[0040] (4) Filter the mother ...

Embodiment 2

[0043] (1) 1.0mol 4-(2-bromo-4-fluorophenyl)-6-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid ethyl ester The racemic compound, its structural formula is as follows:

[0044]

[0045] and 1.0mol L-p-methyldibenzoyl tartaric acid (L-(-)-DTTA) into the reactor, followed by adding 4.5L dichloromethane and 32L petroleum ether;

[0046](2) Stir at 22°C for 1.0h, rotate 4-(2-bromo-4-fluorophenyl)-6-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5 -Ethyl carboxylate is fully combined with the resolving agent of L-p-methyldibenzoyl tartaric acid to form L-4-(2-bromo-4-fluorophenyl)-6-methyl-2-(thiazole-2- Base)-1,4-dihydropyrimidine-5-carboxylic acid ethyl ester L-p-methyldibenzoyl tartrate and D-4-(2-bromo-4-fluorophenyl)-6-methyl-2 -(Thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid ethyl ester L-p-methyldibenzoyl tartrate;

[0047] (3) Filtration, concentrating the mother liquor to 0.5 times the original volume, and then placing the concentrated mother liq...

Embodiment 3

[0051] (1) 0.40mol 4-(2-bromo-4-fluorophenyl)-6-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid ethyl ester The racemic compound and 1.2mol L-p-methoxydibenzoyl tartaric acid (L-(-)-DATA) are dropped into the reactor, and 2.5L acetone and 50L cyclohexane are added successively;

[0052] (2) Stir at 21°C for 3 hours, rotate 4-(2-bromo-4-fluorophenyl)-6-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate Ethyl acetate is fully combined with L-p-methoxydibenzoyl tartaric acid resolving agent to form L-4-(2-bromo-4-fluorophenyl)-6-methyl-2-(thiazol-2-yl )-1,4-Dihydropyrimidine-5-carboxylic acid ethyl ester L-p-methoxydibenzoyl tartrate and D-4-(2-bromo-4-fluorophenyl)-6-methyl-2 -(Thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid ethyl ester L-p-methoxydibenzoyl tartrate;

[0053] (3) filtering, concentrating the mother liquor to 0.6 times of the original volume, and then placing the concentrated mother liquor at room temperature for 48 hours;

[005...

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Abstract

The invention provides a method for splitting 2-heterocycle substituted dihydro pyrimidine racemic body, which comprises the following steps: (1) putting the 2-heterocycle substituted dihydro pyrimidine racemic body and O,O-diaroyl tartaric acid resolving agent with optical activity in a reactor, adding a solvent and stirring the mixture; (2) filtering the mixture, concentrating a mother solutionand standing the mother solution; (3) filtering and concentrating the mother solution to be dry, and obtaining a concentrate; and (4) refining the concentrate. The splitting method adopted for preparing single chiral 2-heterocycle substituted dihydro pyrimidine compounds has the product yield more than 20 percent and the optical purity above 98 percent; and the splitting method has the advantagesof stability, high yield, high optical purity, simple and convenient operation, strong practicability and easy industrialization.

Description

technical field [0001] The present invention relates to a resolution method for organic racemic compounds, in particular to a racemization of 2-heterocyclic substituted dihydropyrimidines using optically active O, O-di-p-aroyl tartaric acid as a resolution agent Compound resolution methods. Background technique [0002] Hepatitis B virus carriers account for more than 5% of the global population, and China is a high incidence area of ​​this infectious disease in the world, which has brought great harm to patients and society. In the treatment of hepatitis B, the global medical community has not yet made a breakthrough, and now foreign countries mainly use nucleoside therapeutic drugs and alpha interferon. Nucleoside drugs include entecavir, adefovir dipivoxil, tenofovir, lamivudine, clavudine, Telbivudine, Eluvcitabine, etc. Nucleoside drugs do have the effect of anti-HBV infection, but the biggest problem is the emergence of drug-resistant virus strains, virus resistance ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D417/04C07D417/14C07D413/04C07B57/00
Inventor 李静刘遗松卢轩林淘曦贺辙
Owner SUNSHINE LAKE PHARM CO LTD
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