Vonoprazan fumarate single crystal, preparation method and uses thereof

Abstract

The present invention relates to a vonoprazan fumarate single crystal, a preparation method and uses thereof. According to the present invention, the X-ray powder diffraction results show that the characteristic peaks are showed at the 2[theta] of 11.4, 12.3, 13.5, 15.1, 15.3, 16.9, 18.6, 20.4, 20.7, 22.4 and 25.1, the obtained single crystal is not reported, and other determination results show that the crystal structure belongs to a monoclinic system, the space group is P2(1) / c, the intracellular molecular number Z is 4m the single crystal is a colorless orthorhombic crystal at a room temperature, the morphology is good, and the HPLC purity is up to more than 99.5%; and with the preparation method, the vonoprazan fumarate and other impurities are well separated, and the good reproducibility is good.

Description

technical field

[0001] The invention belongs to the field of chemical synthesis. Specifically, the invention relates to a single crystal of vonoprazan fumarate and its preparation method and application. Background technique

[0002] Oral anti-gastric acid new drug developed by Takeda Pharmaceutical Co., Ltd.—Vonoprazan fumarate (compound shown in formula I) belongs to potassium ion (K + ) A new class of gastric acid secretion inhibitors, competitive acid blockers (P-CAB), can inhibit the last step of gastric acid secretion in parietal cells by inhibiting K + to H + -K + - The combination of ATPase (proton pump) terminates the secretion of gastric acid in advance, and has a strong and long-lasting inhibitory effect on gastric acid secretion.

[0003]

[0004] Takeda Pharmaceutical has submitted a new drug application (NDA) for vonoprazan fumarate to the Japanese Ministry of Labor, Health and Welfare (MHLW) on February 28, 2014, and obtained vonoprazan fumarate in Japan...

Examples

Embodiment 1

[0029] Example 1 Synthesis of Crude Vonorazan Fumarate

[0030] According to the following two steps to synthesize the crude product of vonoprazan fumarate, the specific synthesis method is as follows:

[0031] Step 1 Synthesis of 5-(2-fluorophenyl)-1-[(pyridin-3-yl)sulfonyl]-1H-pyrrole-3-carbaldehyde, the specific method is as follows:

[0032] Add acetonitrile (50ml), 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (10g), 4-dimethylaminopyridine (1.3g) and N,N-diisopropyl to the reaction flask at room temperature Ethylamine (13 g), stirred at 40° C. to 50° C. for 2 hours, followed by TLC to complete the reaction. Add 1 mol / L hydrochloric acid solution to the reaction system to adjust the pH=4-5, then add water (60ml) and stir. Filtration and drying gave 5-(2-fluorophenyl)-1-[(pyridin-3-yl)sulfonyl]-1H-pyrrole-3-carbaldehyde (15.5 g, yellow solid).

[0033] Step 2 Synthesize the crude product of vonoprazan fumarate, the specific method is as follows:

[0034] Methanol (40ml)...

Embodiment 2

[0036] Example 2 Preparation of Vonoprazan Fumarate Single Crystal

[0037] Weigh 1.0 g of the vonoprazan fumaric acid crude product obtained in Example 1, add the crystallization solvent methanol / water (5 ml / 5 ml) mixed solution, raise the temperature to 60 ° C ~ 70 ° C, and wait until the product is completely dissolved. In the evaporation method, the temperature was set at 25° C., and cultured for 5 days, colorless crystals were precipitated, and observed under a microscope, the crystals were vonoprazan fumaric acid single crystals, and the HPLC purity was 99.5%.

Embodiment 3

[0038] Example 3 Preparation of Vonoprazan Fumarate Single Crystal

[0039] Weigh 1.0 g of the vonoprazan fumaric acid crude product obtained in Example 1, add the crystallization solvent methanol / water (4 ml / 16 ml) mixed solution, raise the temperature to 60° C. to 70° C., and wait until the product is completely dissolved. In the evaporation method, the temperature was set at 30° C., and cultured for 10 days, a colorless crystal was precipitated, and observed under a microscope, the crystal was vonoprazan fumaric acid single crystal, and the HPLC purity was 99.6%.

technical field

[0001] The invention belongs to the field of chemical synthesis. Specifically, the invention relates to a single crystal of vonoprazan fumarate and its preparation method and application. Background technique

[0002] Oral anti-gastric acid new drug developed by Takeda Pharmaceutical Co., Ltd.—Vonoprazan fumarate (compound shown in formula I) belongs to potassium ion (K + ) A new class of gastric acid secretion inhibitors, competitive acid blockers (P-CAB), can inhibit the last step of gastric acid secretion in parietal cells by inhibiting K + to H + -K + - The combination of ATPase (proton pump) terminates the secretion of gastric acid in advance, and has a strong and long-lasting inhibitory effect on gastric acid secretion.

[0003]

[0004] Takeda Pharmaceutical has submitted a new drug application (NDA) for vonoprazan fumarate to the Japanese Ministry of Labor, Health and Welfare (MHLW) on February 28, 2014, and obtained vonoprazan fumarate in Japan...

Examples

Embodiment 1

[0029] Example 1 Synthesis of Crude Vonorazan Fumarate

[0030] According to the following two steps to synthesize the crude product of vonoprazan fumarate, the specific synthesis method is as follows:

[0031] Step 1 Synthesis of 5-(2-fluorophenyl)-1-[(pyridin-3-yl)sulfonyl]-1H-pyrrole-3-carbaldehyde, the specific method is as follows:

[0032] Add acetonitrile (50ml), 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (10g), 4-dimethylaminopyridine (1.3g) and N,N-diisopropyl to the reaction flask at room temperature Ethylamine (13 g), stirred at 40° C. to 50° C. for 2 hours, followed by TLC to complete the reaction. Add 1 mol / L hydrochloric acid solution to the reaction system to adjust the pH=4-5, then add water (60ml) and stir. Filtration and drying gave 5-(2-fluorophenyl)-1-[(pyridin-3-yl)sulfonyl]-1H-pyrrole-3-carbaldehyde (15.5 g, yellow solid).

[0033] Step 2 Synthesize the crude product of vonoprazan fumarate, the specific method is as follows:

[0034] Methanol (40ml)...

Embodiment 2

[0036] Example 2 Preparation of Vonoprazan Fumarate Single Crystal

[0037] Weigh 1.0 g of the vonoprazan fumaric acid crude product obtained in Example 1, add the crystallization solvent methanol / water (5 ml / 5 ml) mixed solution, raise the temperature to 60 ° C ~ 70 ° C, and wait until the product is completely dissolved. In the evaporation method, the temperature was set at 25° C., and cultured for 5 days, colorless crystals were precipitated, and observed under a microscope, the crystals were vonoprazan fumaric acid single crystals, and the HPLC purity was 99.5%.

Embodiment 3

[0038] Example 3 Preparation of Vonoprazan Fumarate Single Crystal

[0039] Weigh 1.0 g of the vonoprazan fumaric acid crude product obtained in Example 1, add the crystallization solvent methanol / water (4 ml / 16 ml) mixed solution, raise the temperature to 60° C. to 70° C., and wait until the product is completely dissolved. In the evaporation method, the temperature was set at 30° C., and cultured for 10 days, a colorless crystal was precipitated, and observed under a microscope, the crystal was vonoprazan fumaric acid single crystal, and the HPLC purity was 99.6%.

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