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Method for preparing crystals and application of crystals

A technology of crystal form and crystal seed, applied in the field of crystal preparation and its use, can solve the problems of undocumented preparation method, difficult control of product crystal form, difficult crystal form B, etc., and achieve the effect of repeatable production

Active Publication Date: 2014-12-24
王军
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Among them, crystal forms B and C are slowly volatilized at room temperature in an aqueous system, but the preparation method of slow volatilization is difficult to be used for industrialized mass production of crystal form B; control, it is easy to obtain hemihydrate crystal form A (US 2008 / 0146515A1 crystal form) in an aqueous system
As mentioned above, only 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene crystal was proposed in CN103588762A The preparation conditions for Form B to slowly volatilize in a solvent at room temperature, there is neither record nor inspiration for the preparation methods of other types of Form B

Method used

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  • Method for preparing crystals and application of crystals
  • Method for preparing crystals and application of crystals
  • Method for preparing crystals and application of crystals

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] Preparation of Form B Seed Crystals

[0055] Suspend 50 mg of Canagliflozin hemihydrate (form A) in 5 mL of water, then heat to 85° C., add 20 mg of mannitol, and stir. The temperature of the above heated solution was lowered to 5 degrees Celsius at a cooling rate of 10 degrees Celsius per hour. During the cooling process, obvious white solids were produced, and these white solids were collected by filtration. Use after natural drying 1 H-NMR characterizes the white solid, and NMR data show that the white solid only contains Canagliflozin and water. NMR data are shown as follows: 1H NMR (d6-DMSO, 400 MHZ): 2.26 (3H, s), 3.13-3.28 (4H, m), 3.44 (1H, m), 3.69 (1H, m), 3.96 (1H, d, J=9.2HZ), 4.10, 4.15(each 1H, d, J=16.0HZ), 4.44(1H, t, J=5.6HZ), 4.73(1H, d, J=6.0HZ), 4.92(2H , d, J=4.8HZ), 6.80(1H, d, J=3.6HZ), 7.11-7.16(2H, m), 7.18-7.25(3H, m), 7.28(1H, d, J=3.6HZ) , 7.59 (2H, dd, J=8.8, 5.4HZ). Then XRPD was used to characterize the sample, and the result showed ...

Embodiment 2

[0062] Preparation of Form B

[0063] 156mg of Canagliflozin hemihydrate (crystal form A), suspended in 22mL of water, then heated to 85°C, cooled to 75°C at a rate of 10°C / hour, and added 10mg of crystal form B seed crystals (in Example 1 prepared), continue to cool down to 5°C at a rate of 10°C / hour, and all the above operations are completed under stirring. After cooling down, a white solid was produced, and stirring was continued overnight. The white solid was collected by filtration and dried under vacuum at room temperature for 1 hour. dry solid 1 H-NMR and XRPD analysis and characterization showed that the obtained crystal form was Form B.

Embodiment 3

[0065] 200mg of Canagliflozin hemihydrate (crystal form A), suspended in 20mL of water / ethanol mixed solvent (ethanol content 10%, v / v), then heated to 70 ° C, at a rate of 10 ° C / hour, cooled to At 65°C, add 10mg of Form B seed crystals (prepared in Implementation 1), and continue to cool down to 5°C at a rate of 10°C / hour, and all the above operations are completed under stirring. After cooling down, a white solid was produced, and stirring was continued overnight. The white solid was collected by filtration and dried under vacuum at room temperature for 1 hour. dry solid 1 H-NMR and XRPD analysis and characterization showed that the obtained crystal form was Form B.

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Abstract

The invention discloses novel crystal form III and crystal form IV of 1-(beta-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl, a preparation method of the crystal form III and the crystal form IV and a medicinal application of the crystal form III and the crystal form IV in treatment of diabetes mellitus. The crystal form III serving as an octanol compound has a more remarkable action effect on treatment of diabetes mellitus, and is prepared by carrying out supersaturated precipitation or re-crystallization in octanol or a solution containing octanol. The octanol serving as a gap junction blocker has an effect of reducing diabetic complications, such as a pharmacological action for resisting cardiomyocyte edema and hypertrophy and a neuroprotective effect, so that compared with other crystal forms, the crystal form III has a more remarkable action effect on diabetes mellitus treatment, especially prevention of cardiovascular complications of patients with early diabetes mellitus.

Description

technical field [0001] The present invention relates to a new crystal form B of 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene and its Preparation method and use. Background technique [0002] Diabetes mellitus is an endocrine-metabolic disease with hyperglycemia as its common hallmark. Disorders of sugar, protein, fat and secondary water and electrolyte metabolism caused by absolute or relative insufficient secretion of insulin. It can involve chronic damage and dysfunction of various systems of the whole body, especially the eyes, kidneys, heart, blood vessels, and nerves, and even induce many fatal complications. With the aging of the world population, diabetes has become a common and frequently-occurring disease, and it is a disease that seriously endangers human health. Research data show that the number of diabetic patients worldwide has increased from 150 million in 2000 to 280 million, and it is estimated that nearly 500 million peop...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D409/10A61K31/381A61P3/10A61P27/02A61P25/28A61P13/12A61P17/02A61P5/50A61P3/06A61P3/04A61P3/00A61P9/00A61P9/12A61P19/06
CPCC07D409/10
Inventor 王军
Owner 王军
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