Method for splitting 2-heterocycle substituted dihydropyrimidine racemic compound

A technology of dihydropyrimidine and compound is applied in the field of splitting of racemic compounds and achieves the effects of strong practicability, high yield and stable splitting method

Active Publication Date: 2011-06-08
SUNSHINE LAKE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

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 2-heterocycle substituted dihydropyrimidine racemic compound
  • Method for splitting 2-heterocycle substituted dihydropyrimidine racemic compound
  • Method for splitting 2-heterocycle substituted dihydropyrimidine racemic compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] (1) 1.0mol 4-(4-fluorophenyl)-6-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate racemic compound , its structural formula is as follows:

[0034]

[0035] and 0.50mol L-binaphthol phosphate are dropped into the reactor, and 2.5L dichloromethane and 2.5L sherwood oil are added successively under mechanical stirring;

[0036] (2) Stirring at room temperature for 0.5h, left and right rotation of methyl 4-(4-fluorophenyl)-6-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate Fully combined with L-binaphthol phosphate resolving agent to form L-4-(4-fluorophenyl)-6-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5 -Methyl carboxylate L-binaphthol phosphate and D-4-(4-fluorophenyl)-6-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5- Methyl carboxylate L-binaphthol phosphate;

[0037] (3) filtering, concentrating the mother liquor to 0.2 times the original volume, and then placing the concentrated mother liquor at 0°C overnight;

[0038] (4) and then fil...

Embodiment 2

[0041] (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:

[0042]

[0043] Put into reactor with 1.0mol L-binaphthol phosphate ester, add 4.5L dichloromethane and 32L sherwood oil successively;

[0044] (2) Stirring at room temperature for 1.0h, rotating 4-(2-bromo-4-fluorophenyl)-6-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5- Ethyl carboxylate and L-binaphthol phosphate resolving agent are fully combined to form L-4-(2-bromo-4-fluorophenyl)-6-methyl-2-(thiazol-2-yl)-1 , Ethyl 4-dihydropyrimidine-5-carboxylate L-binaphthol phosphate and D-4-(2-bromo-4-fluorophenyl)-6-methyl-2-(thiazol-2-yl )-1,4-dihydropyrimidine-5-carboxylic acid ethyl ester L-binaphthol phosphate;

[0045] (3) Filtration, concentrating the mother liquor to 0.5 times the original volume, and then placing the concentrated mother liquor at -5°C for 8 hours;

[0046](4) and the...

Embodiment 3

[0049] (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 d-binaphthol phosphate are dropped into the reactor, and 2.5L acetone and 50 L hexanaphthene are added successively;

[0050] (2) Stir at room temperature for 3 hours, rotate 4-(2-bromo-4-fluorophenyl)-6-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate Acetate ethyl ester is fully combined with D-binaphthol phosphate resolving agent to form L-4-(2-bromo-4-fluorophenyl)-6-methyl-2-(thiazol-2-yl)-1 , 4-dihydropyrimidine-5-carboxylic acid ethyl ester dex-binaphthol phosphate and dex-4-(2-bromo-4-fluorophenyl)-6-methyl-2-(thiazole-2- Base)-1,4-dihydropyrimidine-5-carboxylic acid ethyl ester D-binaphthol phosphate;

[0051] (3) Filtrate, concentrate the mother liquor to 0.6 times the original volume, and then place the concentrated mother liquor at 25°C for 48h;

[0052] (4) and then filtered, and then the filtered...

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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 1,1'-Binaphthyl-2,2'-diyl hydrogenphosphate resolving agent with optical activity in a reactor, and adding a solvent; (2) stirring the mixture; (3) filtering the mixture, concentrating a mother solution and standing the mother solution; (4) filtering and concentrating the mother solution to be dry; and (5) refining. The single chiral 2-heterocycle substituted dihydro pyrimidine compounds prepared by the splitting method has the product yield about 20 percent and the optical purity above 98 percent; and the splitting method has the advantages of 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 racemic compounds, in particular to a method for resolution of 2-heterocyclic substituted dihydropyrimidine racemic compounds using optically active binaphthol phosphate as a resolution agent . 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. [0003] Nucleoside drugs do have the effect of anti-HBV infection, but the biggest problem is the emergence of drug-resistant virus strains, virus resistance and rebou...

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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