Crystal form of dapagliflozin, preparation method, and applications thereof

A technology of dapagliflozin and crystal form, which is applied in the field of compound crystal form, can solve problems such as difficulty in stirring, large particles, large particle size and hardness, etc., and achieve the effect of easy crystallization process and stable crystallization rate

Active Publication Date: 2019-05-03
JIANGSU SUZHONG PHARM GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] However, in the current preparation process of (S)-propanediol structure (Ia), instant crystallization is extremely prone to occur, that is, after adding (S)-1,2-propanediol to a solution containing dapagliflozin, solids and solvents are precipitated in a short period of time. Enclosed together, a large amount of thick sauce is produced, and the obtained dapagliflozin-(s)-1,2-propanediol monohydrate (Ia) has larger particles and greater hardness
During the preparation process, during instant crystallization, the crystallized product contains a large amount of organic solvent, which is difficult to stir, and after the crystallized product is dried, the particle size and hardness are large, which is not conducive to pharmaceuticals

Method used

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  • Crystal form of dapagliflozin, preparation method, and applications thereof
  • Crystal form of dapagliflozin, preparation method, and applications thereof
  • Crystal form of dapagliflozin, preparation method, and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Take 4.06g (9.94mmol) of Daxigliflozin and add it to 40ml of isopropyl acetate, stir at 29°C, add 0.80g (10.51mmol) of 1,2-propanediol, stir at a speed of 100 rpm, after 1h, Add 40ml of cyclohexane. After the addition of cyclohexane, the solvent system becomes turbid, and the solid crystallizes. Continue to stir for 30 minutes, filter with suction, wash the filter cake with a small amount of cyclohexane, and dry it in vacuum at 30°C for 24 hours to obtain 4.00g of white solid powder. (7.95 mmol), which is the crystal form compound Ic of dapagliflozin; the yield is 80.0% (molar yield, calculated based on the amount of dapagliflozin added, the same below), the purity is 99.9%, and the melting point is 76°C.

[0040] The detection method of purity is HPLC method, inertsil ODS-SP 5um 4.6×250mm column, flow rate 1.0ml / min, detection at 220nm, methanol-water (75:25) as mobile phase, area normalization method calculation, the same below .

[0041] Using a thermogravimetric an...

Embodiment 2

[0048] Take 4.05g (9.91mmol) of Daxigliflozin and add it to 40ml of isopropyl acetate, stir at 0°C, add 0.81g (10.60mmol) of 1,2-propanediol, stir at a speed of 100 rpm, after 1h, Add 40ml of cyclohexane. After the addition of cyclohexane, the solvent system becomes turbid, and the solid crystallizes. Continue to stir for 3h, filter with suction, wash the filter cake with a small amount of cyclohexane, and vacuum dry at 30°C for 24h to obtain 4.28g of white solid powder (8.51mmol), yield 87.0%, purity 99.9%, melting point 76 ° C, because the preparation method is similar to Example 1, and the melting point is consistent, indicating that the same crystal form of dapagliflozin compound was obtained as in Example 1, the same below.

Embodiment 3

[0050] Add 4.03g (9.86mmol) of Daxigliflozin into 40ml of methyl tert-butyl ether, stir at 0°C, add 0.78g (9.86mmol) of 1,2-propanediol, stir at 100 rpm, 1h Finally, add 40ml of n-heptane. After the addition of n-heptane is completed, the solvent system becomes turbid, and the solid crystallizes. Continue to stir for 60 minutes, filter with suction, wash the filter cake with a small amount of n-heptane, and dry it in vacuum at 30°C for 24 hours to obtain a white solid powder 4.48g (8.91mmol), yield 90.4%, purity 99.9%, melting point 76°C.

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Abstract

The invention discloses a crystal form of dapagliflozin and preparation method thereof. The dapagliflozin is stirred and dissolved with 1,2-propylene glycol in an organic solvent; then a low-polar solvent is added, and cooling crystallization is carried out at certain temperature; the mixture then is filtered to obtain a solid; the solid is subjected to pressure-reduced vacuum drying to prepare acrystal form compound of dapagliflozin, which has high purity and has obvious structural features of the crystal. The crystal form compound of dapagliflozin has good thermal stability and allows large-scale production. The crystal form compound and a composition thereof are mainly used for treatment on diabetes type II.

Description

technical field [0001] The invention relates to the field of compound crystal forms, in particular to a dapagliflozin crystal form and a preparation method thereof, and the application of the crystal form compound and its composition in the field of type II diabetes treatment. Background of the invention [0002] Dapagliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor jointly developed by Bristol-Myers Squibb and AstraZeneca for the treatment of type II diabetes. Its structural formula is: [0003] [0004] Darpagliflozin has a low melting point and is an oily liquid at room temperature (25°C). It is usually prepared in the crystalline form of solvates and complexes for drug preparation. [0005] Chinese patent CN101479287B reports various crystal forms of dapagliflozin. These include: [0006] (S)-propylene glycol structure Ia; its structural formula Ia: [0007] [0008] (R)-Propanediol structure Ib; Its structural formula Ib: [0009] [0010] Com...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D309/10A61K31/351A61P3/10
Inventor 岳永力唐海涛葛海涛王正俊何爱见孙健马永刚黄杰
Owner JIANGSU SUZHONG PHARM GRP CO LTD
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