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Cetagliptin salt crystal form and amorphism and preparation method and application thereof

An amorphous, crystal form technology, applied in the field of Shengglitin salt and its preparation, can solve the problems of lack of Shengglitin salt, crystal form, poor drugability and the like

Active Publication Date: 2018-08-10
CGENETECH (SUZHOU CHINA) CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] At present, shengagliptin in free base form is a viscous oil with poor druggability and there is no report on the salt and crystal form of shengagliptin

Method used

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  • Cetagliptin salt crystal form and amorphism and preparation method and application thereof
  • Cetagliptin salt crystal form and amorphism and preparation method and application thereof
  • Cetagliptin salt crystal form and amorphism and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0115] Embodiment 1, the preparation method of the phosphate amorphous form of the compound of formula (I):

[0116] Dissolve 20 mg of the compound of formula (I) in 0.5 mL of methyl tert-butyl ether, then add phosphoric acid in an equimolar ratio to the compound of formula (I), stir and react at room temperature (25±2°C) for 12 hours, and collect the solid available.

[0117] After testing, the resulting solid is an amorphous form of phosphate, and its XRPD pattern is as follows figure 1 , TGA diagram and DSC diagram such as figure 2 , 1H NMR as shown in image 3 . XRPD results indicated that the solid was amorphous. figure 2The middle TGA result showed that the sample had a weight loss of 7.0% when heated to 150°C, and the mDSC result showed that the glass transition temperature of the sample was 47.6°C (midpoint temperature). image 3 The 1H NMR (DMSO-d6) spectrum and the KF results (4.3%) in Table 7 below showed that the solid contained residual solvents diethyl eth...

Embodiment 2

[0127] Embodiment 2, the preparation method of the phosphate crystal form A of the compound of formula (I):

[0128] Dissolve the phosphate salt of the amorphous compound of formula (I) prepared in Example 1 in a mixed solvent of isoamyl alcohol and water with a volume ratio of 19:1, slowly volatilize the solution, and collect the solid to obtain it.

[0129] After testing, the obtained solid is crystal form A of phosphate, and its XRPD data is shown in Table 9 below, and its XRPD pattern is shown in Figure 4 , TGA diagram and DSC diagram as shown in Figure 5 . XRPD showed high crystallinity, TGA results showed that the sample had a weight loss of 6.4% when heated to 150°C, and DSC results showed that the sample had two endothermic peaks at 100.9°C and 132.7°C (peak temperature) before decomposition. Figure 6 XRPD characterization showed that phosphate form A transformed into phosphate form B after heating at 50 °C for 48 h.

[0130] Table 9

[0131]

Embodiment 3

[0132] Embodiment 3, the preparation method of the phosphate crystal form B of the compound of formula (I):

[0133] 15 mg of the phosphate salt of the amorphous compound of formula (I) prepared in Example 1 was dissolved in 1 ml of ethanol, and then evaporated slowly at room temperature (25±2° C.) to obtain a solid.

[0134] After testing, the obtained solid is crystal form B of phosphate, and its XRPD data is shown in Table 10, and its XRPD pattern is as follows Figure 7 , TGA graph and DSC graph such as Figure 8 , 1H NMR characterization results as Figure 9 shown. XRPD shows that the crystalline form has high crystallinity. The TGA results showed a 6.1% weight loss when the sample was heated to 150°C. DSC results showed that the sample had two endothermic peaks at 103.2°C and 133.5°C (peak temperature) before decomposition. The 1H NMR (DMSO-d6) spectrum shows that there is no signal peak of isopropanol, and combined with the weight loss of the crystal form B sample ...

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Abstract

The invention relates to a salt of a compound in a formula (I) as shown in the specification. The salt is crystal or amorphous phosphate or crystal or amorphous oxalate. By salification screening andresearching on the compound in the formula (I), a novel salt form suitable for medicine development is discovered, and medicine solubility is improved. Especially, a phosphate crystal form B is high in crystallinity and stability, low in hygroscopicity, great in oral bioavailability, high in tolerance in long-term administration, less prone to causing hypoglycemia and great in serum DPPIV inhibition effect, and accordingly better options are provided for medicine subsequent development.

Description

technical field [0001] The invention relates to the field of chemistry and medicine, in particular to a salt of senagliptin and a preparation method thereof. Background technique [0002] Shengagliptin, the chemical name is (8R)-7-[(3R)-3-amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7 ,8-tetrahydro-8-methyl-3-(trifluoromethyl)imidazo[1,5-a]pyrazine, the structural formula is as shown in formula (I): [0003] [0004] For the preparation method of senagliptin, refer to Example 1 of CN103351391B. Senagliptin is a therapeutic drug for the treatment or prevention of dipeptidyl peptidase-related diseases, such as diabetes, especially type 2 diabetes. [0005] Currently, shengagliptin in the free base form is a viscous oil with poor druggability and there is no report on the salt and crystal form of shengagliptin. Therefore, it is of great significance to develop the salt of senagliptin and study its crystal form. Contents of the invention [0006] Through systematic s...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/4985A61P3/10
CPCA61P3/10C07D487/04C07B2200/13A61K31/5383
Inventor 郝岩张仁延潘慧平张福治殷时杰丁炬平余强
Owner CGENETECH (SUZHOU CHINA) CO LTD
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