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High-purity canagliflozin compound and preparation method thereof

A technology of compounds and complexes, applied in organic chemistry and other fields

Active Publication Date: 2014-04-02
JIANGSU AOSAIKANG PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The α-configuration impurity of canagliflozin and the purification of canagliflozin are not involved in these two patents

Method used

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  • High-purity canagliflozin compound and preparation method thereof
  • High-purity canagliflozin compound and preparation method thereof
  • High-purity canagliflozin compound and preparation method thereof

Examples

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Effect test

preparation example 1

[0066]

[0067] According to the method in Journal of Medicinal Chemistry2010, 53, 6355-60, the trimethylsilyl-protected canagliflozin (Formula 1) was obtained, and then the trimethylsilyl and methoxy groups were removed according to the method published in the document , to obtain canagliflozin (Formula 2). The specific method is as follows:

[0068] Add compound 1 (6.3kg, 13.2mol) into 60L of dichloromethane, add triethylsilane (4.6kg, 39.9mol) and cool with dry ice acetone, add boron trifluoride ether solution (5L, 39.5mmol) dropwise Then, the reaction mixture was heated to 0°C and stirred for 2 hours, and saturated aqueous sodium bicarbonate solution (80 L) was slowly added to the reaction kettle to quench the reaction. Separate the layers, concentrate the organic phase under reduced pressure to dryness, add 100L of water and 70L of ethyl acetate, stir and extract, then extract the water phase with 70L of ethyl acetate, combine the organic phases, wash with 50L of wate...

Embodiment 1

[0081] Dissolve canagliflozin (10.0g, 22.5mmol) in absolute ethanol (200ml), add L-proline (7.8g, 67.7mmol, 3eq), heat to reflux, all solids are dissolved, and then slowly Cool to room temperature, filter the precipitated solid, and wash the filter cake with absolute ethanol to obtain canagliflozin L-proline complex.

[0082] Add the complex to purified water (200ml), adjust the pH to 2 with hydrochloric acid, extract with methyl tert-butyl ether (100ml×3), combine the organic phases, wash with saturated sodium chloride solution, concentrate, there are a lot of solids Precipitated, filtered, and the filter cake was washed with a small amount of cold methyl tert-butyl ether, and vacuum-dried at 50°C to obtain 8.9 g of canagliflozin finished product, with a yield of 89%.

[0083] HPLC detection of α-configuration impurities: 0.017%.

Embodiment 2

[0085] Canagliflozin (17.2g, 38.7mmol) was added to 95% ethanol (250ml), L-proline (11.1g, 96.4mmol, 2.5eq) was added, heated to reflux, all the solids were dissolved, and then slowly Slowly cooled to 10°C, gradually a solid precipitated out. The precipitated solid was filtered, and the filter cake was washed with absolute ethanol to obtain the canagliflozin L-proline complex.

[0086] Add the complex to purified water (200ml), adjust the pH to 1 with hydrochloric acid, extract with ether (150ml×3), combine the organic phases, wash with saturated sodium chloride solution, concentrate, a large amount of solids are precipitated, filter, filter The cake was washed with a small amount of cold diethyl ether and dried under vacuum at 55°C to obtain 15.4 g of canagliflozin finished product with a yield of 90%.

[0087] HPLC detection of α-configuration impurities: 0.026%.

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Abstract

The invention belongs to the field of drug synthesis and relates to a high-purity canagliflozin compound represented by a formula I shown in a drawing and a preparation method thereof. According to the canagliflozin compound provided by the invention, the content of an alpha-configuration impurity represented by a formula II shown in a drawing is lower than 1% and is further lower than 0.5%. The preparation method comprises the steps of preparing a eutectic substance from canagliflozin and amino acid in a solvent, separating the eutectic substance, and then, decomposing the eutectic substance, thereby obtaining the canagliflozin compound.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and relates to a method for preparing high-purity canagliflozin, in particular to a method for purifying canagliflozin by forming a complex with amino acids and canagliflozin. Background technique [0002] Canagliflozin is a sodium-glucose cotransporter 2 (SGLT-2) inhibitor for the treatment of diabetes, which has a structural formula shown in the following formula I: [0003] [0004] Its common synthetic route is: [0005] [0006] Among them, M is lithium or zinc, and Z is a protecting group, commonly used as TMS. [0007] In the above preparation process, the glycosidic bond formed has two configurations of α and β, and canagliflozin is of the β type. Although the β-configuration is advantageous in the preparation process, the generation of α-configuration impurities is unavoidable. [0008] [0009] Patent application CN101801371 (Example 7-9) discloses the method of carrying out ac...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D409/10
CPCC07D409/10
Inventor 赵俊宗在伟杜有国刘子宁于春江刘同根
Owner JIANGSU AOSAIKANG PHARMA CO LTD
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