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Trelagliptin succinate crystal form A preparation method

A technology of troagliptin succinate and succinic acid, which is applied in the chemical field, can solve problems such as carcinogenicity, unfavorable environmental protection, and unsatisfactory product purity, and achieve the effect of low price

Inactive Publication Date: 2017-12-05
WEIHAI DISU PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Chinese patent 200780049086.5 discloses crystal forms A, B, C, D, E, F, G and their preparation methods. The patent disclosed acetonitrile, dichloromethane, 1,4-dioxane, dimethylformamide , hexane, tetrahydrofuran, toluene, trifluoroethanol and other solvents, most of which are the second-class solvents in ICH Q3c. Animal experiments have proved that the second-class solvents in ICH Q3c are more toxic and some are carcinogenic, so they are not suitable for use in raw materials. final process
In actual work, these mixed solvents are not conducive to solvent recovery, not conducive to environmental protection, and the purity of the obtained products is not ideal

Method used

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  • Trelagliptin succinate crystal form A preparation method
  • Trelagliptin succinate crystal form A preparation method

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Embodiment 1, prepare trexagliptin high-quality goods:

[0027] Add 16.4kg of absolute ethanol and 1.49kg of succinic acid into the reaction kettle, stir and heat (40-50°C) until completely dissolved, cool down to 20-30°C; set aside. Add 41.4kg of absolute ethanol and 4.14kg of trexagliptin crude product to the reaction kettle and stir to completely dissolve; add the ethanol solution of succinic acid to the trexagliptin crude product solution, stir at 10°C for 2.0h, and centrifuge to obtain succinic acid Trexagliptin crude product.

[0028] Add 41.4kg of drinking water and the crude product of trexagliptin succinate obtained by centrifugation in the reactor, stir and dissolve, add 55.1kg of dichloromethane, stir for 15min, let stand for 15min, and separate the liquid; add sodium chloride to the aqueous phase in the reactor 14kg, adjust the pH value to 9 with 1mol / l sodium hydroxide solution, stir for 0.5h, centrifuge, rinse with 10kg of drinking water, and dry to obtai...

Embodiment 2

[0029] Embodiment 2, prepare trexagliptin fine-quality goods:

[0030] Add 16.4kg of absolute ethanol and 1.49kg of succinic acid into the reaction kettle, stir and heat (40-50°C) until completely dissolved, cool down to 20-30°C; set aside. Add 41.4kg of absolute ethanol and 4.14kg of trexagliptin crude product to the reaction kettle and stir to completely dissolve; add the ethanol solution of succinic acid into the trexagliptin crude product solution, stir at 40°C for 2.0h, and centrifuge to obtain succinic acid Trexagliptin crude product.

[0031] Add 41.4kg of drinking water and the crude product of trexagliptin succinate obtained by centrifugation in the reactor, stir and dissolve, add 55.1kg of dichloromethane, stir for 15min, let stand for 15min, and separate the liquid; add sodium chloride to the aqueous phase in the reactor 14kg, add ammonia water to adjust the PH value to 10, stir for 0.5h, centrifuge, rinse with 10kg of drinking water, and dry to obtain the fine pro...

Embodiment 3

[0032] Embodiment 3, prepare trexagliptin high-quality goods:

[0033] Add 16.4kg of absolute ethanol and 1.49kg of succinic acid into the reaction kettle, stir and heat (40-50°C) until completely dissolved, cool down to 20-30°C; set aside. Add 41.4kg of absolute ethanol and 4.14kg of trexagliptin crude product to the reaction kettle and stir to completely dissolve; add the ethanol solution of succinic acid to the trexagliptin crude product solution, stir at 20°C for 2.0h, and centrifuge to obtain succinic acid Trexagliptin crude product.

[0034] Add 41.4kg of drinking water and the crude product of trexagliptin succinate obtained by centrifugation in the reactor, stir and dissolve, add 55.1kg of dichloromethane, stir for 15min, let stand for 15min, and separate the liquid; add sodium chloride to the aqueous phase in the reactor 14kg, add ammonia water to adjust the pH value to 9.5, stir for 0.5h, centrifuge, rinse with 10kg of drinking water, and dry to obtain trexagliptin ...

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Abstract

The present invention relates to a trelagliptin succinate crystal form A preparation method, and belongs to the technical field of the chemistry. The technical scheme comprises: preparing a trelagliptin fine product, and preparing a trelagliptin succinate bulk drug. The invention provides the trelagliptin succinate crystal form A preparation method suitable for industrial production, wherein the purity of the product prepared through the method is more than 99.95%; and the used single solvent anhydrous ethanol can be recovered and applied, is the optimal solvent for preparing the trelagliptin succinate crystal form A, is the bulk drug refining solvent recommended in ICH, and has characteristics of low prices and environmental protection.

Description

technical field [0001] The invention relates to a preparation method of trexagliptin succinate A crystal form, which belongs to the field of chemical technology. Background technique [0002] Trelagliptin succinate is a dipeptidyl peptidase IV (DPP-4) inhibitor that controls blood sugar levels through selective and sustained inhibition of DPP-4. DPP-4 is an enzyme that triggers the inactivation of incretins (glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which are It plays an important role in regulation.Inhibition of DPP-4 can increase blood glucose level-dependent insulin secretion, thereby controlling blood glucose levels. [0003] Trexagliptin succinate was launched in Japan on March 26, 2015 by Takeda Corporation for controlling blood sugar, once a week. It is one of the only two varieties of chemical medicine that is currently taken once a week. Trexagliptin succinate A crystal form has the characteristics of stable propertie...

Claims

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Application Information

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IPC IPC(8): C07D401/04
CPCC07D401/04C07B2200/13
Inventor 刘江丛日刚夏克波刘春姜晓军王海波李西贺
Owner WEIHAI DISU PHARMA CO LTD
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