Method for refining alogliptin benzoate

A purification method and technology of benzoic acid, applied in the direction of organic chemistry and the like, can solve the problems such as inability to remove alogliptin benzoate isomers, and achieve the effect of ensuring safety and effectiveness and easy operation.

Inactive Publication Date: 2017-05-31
湖南千金湘江药业股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method also cannot remove the alogliptin benzoate isomer

Method used

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  • Method for refining alogliptin benzoate
  • Method for refining alogliptin benzoate
  • Method for refining alogliptin benzoate

Examples

Experimental program
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Embodiment 1

[0037] A method for refining alogliptin benzoate, comprising the following steps:

[0038] Put 10 g of alogliptin benzoate crude product and 60 mL of acetone into the reaction flask, raise the temperature to 45-55° C., and stir until all the solids are dissolved. Add 40 mL of 1.5 mol / L d-tartaric acid aqueous solution to the reaction flask, and continue to stir and react at 45-55° C. for 1 h.

[0039] Cool the reaction solution with ice-salt water to 0-5°C, stir and crystallize for 2-3 hours, filter, remove tartaric acid from the solid through subsequent operations, and then salt and crystallize with benzoic acid, filter, and dry the filter cake under reduced pressure to constant weight. Obtain 9.42 g of alogliptin benzoate.

[0040] The refined alogliptin benzoate is detected by HPLC, and the purity is 99.98%, and the impurity content of the alogliptin benzoate enantiomer is 0.02%. The liquid chromatograms of alogliptin benzoate before and after refining are shown in figur...

Embodiment 2

[0042] Put 10 g of alogliptin benzoate crude product and 60 mL of tetrahydrofuran into a reaction flask, raise the temperature to 40-45° C., and stir until all the solids are dissolved. Add 40 mL of 1.5 mol / L d-tartaric acid aqueous solution to the reaction flask, and continue to stir and react at 40-45° C. for 1 h.

[0043] Cool the reaction solution with ice-salt water to 0-5°C, stir and crystallize for 1 hour, filter, remove tartaric acid through subsequent operations, and then salt and crystallize with benzoic acid, filter, and dry the filter cake under reduced pressure to constant weight to obtain benzoic acid Alogliptin 9.33g.

[0044] The refined alogliptin benzoate is detected by HPLC, and the purity is 99.95%, and the impurity content of the alogliptin benzoate enantiomer is 0.05%.

Embodiment 3

[0046] Put 10 g of alogliptin benzoate crude product and 100 mL of acetonitrile into the reaction flask, raise the temperature to 50-60° C., and stir until all the solids are dissolved. Add 40 mL of 1.5 mol / L d-tartaric acid aqueous solution to the reaction flask, and continue to stir and react at 50-60° C. for 1 h.

[0047]Cool the reaction solution with ice-salt water to 0-5°C, stir and crystallize for 4 hours, filter, remove tartaric acid through subsequent operations, and then salt and crystallize with benzoic acid, filter, and dry the filter cake under reduced pressure to constant weight to obtain benzoic acid Alogliptin 8.98g.

[0048] The refined alogliptin benzoate is detected by HPLC, and the purity is 99.98%, and the impurity content of the alogliptin benzoate enantiomer is 0.02%.

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Abstract

The invention relates to the field of pharmaceutical chemistry, and discloses a method for refining alogliptin benzoate. The method comprises the following steps: S1. A alogliptin benzoate crude product is added into an organic solvent for dissolving according to a proportion, wherein the proportion of alogliptin benzoate crude product to the organic solvent is 1g:2-10mL, the crude product is heated at 40-60 DEG C with stirring for dissolved clarification, wherein the organic solvent is selected from any one of acetone, tetrahydrofuran, alcohols and acetonitrile; S2. an aqueous solution of tartrate is added into liquid with dissolved clarification in the step S1, the aqueous solution of tartrate is added according to a proportion, wherein the proportion of the alogliptin benzoate crude product and the aqueous solution of tartrate is 1g:2-6mL, and heating is carried out at 40-60 DEG C with stirring for 1 hour; S2. cooling, crystallization and filtering are carried out in order to obtain solid without tartrate, the solid and benzoic acid form salt, crystallization and filtering are carried out, pressure reduction and drying are carried out for filter cakes, and a refined product of alogliptin benzoate is obtained. The refining method can reduce the content of enantiomer to 0.05% or below, refining yield reaches 89% or above, and safety and effectiveness of clinic application are guaranteed.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, more specifically, to a method for refining alogliptin benzoate. Background technique [0002] Alogliptin benzoate, molecular formula is C 25 h 27 N 5 o 4 , chemical name: 2-[6-[3(R)-Aminopiperidin-1-yl]-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-ylmethyl]benzonitrolebenzoate, for serine Protease dipeptidyl peptidase IV (DPP-IV) inhibitor, can maintain the level of glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) in the body, promote the secretion of insulin, thus exert Hypoglycemic efficacy. Peptidyl peptidase IV (Dipeptidyl peptidase IV, DPP-IV) inhibitors have high oral bioavailability, which greatly improves patient compliance compared with injections, reduces blood sugar and can avoid complications such as hypoglycemia and obesity. Therefore, this Drugs like these are very suitable for the early treatment of type 2 diabetes. [0003] A sta...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04
CPCC07D401/04
Inventor 文峰球姚亮元袁红波朱婧王琼瑶钟爱军
Owner 湖南千金湘江药业股份有限公司
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