Alogliptin salt and its crystal form, their preparation method and pharmaceutical composition

Abstract

The invention relates to novel omarigliptin salt and crystal form products of the omarigliptin salt, and belongs to the technical field of pharmaceutical chemicrystallization. Compared with existing omarigliptin crystal form products, the omarigliptin salt and the crystal form products of the omarigliptin salt have the advantages of being better in crystal form product stability and solubility, higher in dissolving rate and the like, the bioavailability of medicine can be improved, and the omarigliptin salt and the crystal form products of the omarigliptin salt are better suitable for an application of a solid preparation. The invention also relates to the omarigliptin salt, a preparing method of the crystal form products of the omarigliptin salt, a pharmaceutical composition of the omarigliptin salt and applications of the omarigliptin salt to medicine for treating type 2 diabetes mellitus.

Description

technical field

[0001] The invention relates to the technical field of medicinal chemical crystallization. Specifically, it relates to a novel alogliptin salt and its crystal form, and also relates to the preparation method, pharmaceutical composition and application of the alogliptin salt and its crystal form. Background technique

[0002] Omarigliptin (English name omarigliptin) is an ultra-long-acting dipeptidyl peptidase-IV inhibitor developed by Merck, which is used for the treatment of type 2 diabetes and is administered orally once a week. In December 2014, Merck submitted a new drug application for the experimental hypoglycemic drug omarigliptin to Japan's Pharmaceuticals and Medical Devices Agency (PMDA), marking the world's first regulatory application.

[0003] The chemical name of alogliptin is (2R,3S,5R)-2-(2,5-difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3 ,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-amine, its chemical structure is as follows: ...

Examples

preparation example 1

[0120] Preparation Example 1 Preparation of alogliptin

[0121] Prepared with reference to the preparation method of Patent Document CN103702562A Example 7, the specific operations are as follows:

[0122]

[0123] 1) 8.25g of ketone, 9.8g of pyrazole salt and 124mL of DMAc were charged into a 500mL three-necked flask (equipped with overhead stirring, N 2 inlet and thermocouple), and the resulting homogeneous solution was cooled to Ti = -10 °C. 6.94 g NaBH(OAc) was added portionwise as solid 3 . The reaction is aged at Ti=-10°C until the ketone consumption meets the requirement of ≥98%. NH via slow addition 4 OH (8.3ml) and H 2 Compound O (16.5ml) quenched the reaction slurry. The resulting slurry was heated to Ti = 50°C and then cooled to Ti = 22°C. Filter the slurry. Filter cake with 5:1 DMAc:H 2 O (65 mL) was used for washing, followed by water 65 mL displacement washing. The filter cake was dried until the amount of residual water was ≤ 10%. 10.6 g of the r...

Embodiment 1

[0127] Example 1 Preparation of alogliptin maleate

[0128] At room temperature, dissolve 500 mg of alogliptin in 20 mL of methanol, dissolve 146 mg of maleic acid in 5 mL of methanol, mix the methanol solution of maleic acid and the methanol solution of alogliptin, stir to form a slurry, filter, and filter cake at room temperature Drying under reduced pressure for 4 hours gave 452 mg of alogliptin maleate.

Embodiment 2

[0129] Example 2 Preparation of alogliptin maleate crystal form 1

[0130] At room temperature, 100 mg of augliptin maleate in Example 1 was added to 2 mL of isopropanol to form a suspension, stirred and crystallized for 16 hours, filtered, and the filter cake was dried under reduced pressure at room temperature for 16 hours to obtain 78.6 mg of augliptin Tine maleate crystal form 1, yield 78.6%.

[0131] XRPD patterns such as figure 1 As shown, it shows a crystalline state, indicating that alogliptin maleate crystal form 1 has a good crystalline state.

technical field

[0001] The invention relates to the technical field of medicinal chemical crystallization. Specifically, it relates to a novel alogliptin salt and its crystal form, and also relates to the preparation method, pharmaceutical composition and application of the alogliptin salt and its crystal form. Background technique

[0002] Omarigliptin (English name omarigliptin) is an ultra-long-acting dipeptidyl peptidase-IV inhibitor developed by Merck, which is used for the treatment of type 2 diabetes and is administered orally once a week. In December 2014, Merck submitted a new drug application for the experimental hypoglycemic drug omarigliptin to Japan's Pharmaceuticals and Medical Devices Agency (PMDA), marking the world's first regulatory application.

[0003] The chemical name of alogliptin is (2R,3S,5R)-2-(2,5-difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3 ,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-amine, its chemical structure is as follows: ...

Examples

preparation example 1

[0120] Preparation Example 1 Preparation of alogliptin

[0121] Prepared with reference to the preparation method of Patent Document CN103702562A Example 7, the specific operations are as follows:

[0122]

[0123] 1) 8.25g of ketone, 9.8g of pyrazole salt and 124mL of DMAc were charged into a 500mL three-necked flask (equipped with overhead stirring, N 2 inlet and thermocouple), and the resulting homogeneous solution was cooled to Ti = -10 °C. 6.94 g NaBH(OAc) was added portionwise as solid 3 . The reaction is aged at Ti=-10°C until the ketone consumption meets the requirement of ≥98%. NH via slow addition 4 OH (8.3ml) and H 2 Compound O (16.5ml) quenched the reaction slurry. The resulting slurry was heated to Ti = 50°C and then cooled to Ti = 22°C. Filter the slurry. Filter cake with 5:1 DMAc:H 2 O (65 mL) was used for washing, followed by water 65 mL displacement washing. The filter cake was dried until the amount of residual water was ≤ 10%. 10.6 g of the r...

Embodiment 1

[0127] Example 1 Preparation of alogliptin maleate

[0128] At room temperature, dissolve 500 mg of alogliptin in 20 mL of methanol, dissolve 146 mg of maleic acid in 5 mL of methanol, mix the methanol solution of maleic acid and the methanol solution of alogliptin, stir to form a slurry, filter, and filter cake at room temperature Drying under reduced pressure for 4 hours gave 452 mg of alogliptin maleate.

Embodiment 2

[0129] Example 2 Preparation of alogliptin maleate crystal form 1

[0130] At room temperature, 100 mg of augliptin maleate in Example 1 was added to 2 mL of isopropanol to form a suspension, stirred and crystallized for 16 hours, filtered, and the filter cake was dried under reduced pressure at room temperature for 16 hours to obtain 78.6 mg of augliptin Tine maleate crystal form 1, yield 78.6%.

[0131] XRPD patterns such as figure 1 As shown, it shows a crystalline state, indicating that alogliptin maleate crystal form 1 has a good crystalline state.

Images