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Preparation method of vonoprazan fumarate

A technology of vonoprazan fumarate and methyl carbamic acid, which is applied in the field of medicine, can solve the problems of unfavorable industrial production of vonoprazan fumarate, a total yield of less than 40%, and cumbersome post-processing operations, and achieve The synthesis process is safe and reliable, the equipment is simple, and the effect of post-processing is simple

Active Publication Date: 2015-11-25
NANJING GRITPHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] In 2010, Takeda disclosed an improved synthetic route in CN201080018114: in the synthesis of the intermediate 5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde, use Acetonitrile is used as a solvent, DIEA is used as an acid-binding agent, and DMAP is used as a catalyst, but there are many side reactions, cumbersome post-treatment operations, low yield, and the total yield is less than 40%.
On the other hand, the post-synthetic treatment in the above-mentioned literature uses column chromatography, which is not conducive to the industrial production of Vonorazan fumarate

Method used

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  • Preparation method of vonoprazan fumarate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0067] S1: Synthesis of 1-(5-(2-fluorophenyl)-1H-pyrrol-3-yl)-N-methylmethylamine (II):

[0068]

[0069] 37.8g of 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (I) was dissolved in 160ml of methanol at room temperature, and 51.2g of 40% methylamino alcohol solution was added dropwise, and stirred at 25-35°C for 6-8 hours , add 15.1g sodium borohydride in batches under ice bath, react at 20-30°C for 1-2 hours, add 58g of acetone under ice bath to quench, add 200ml ethyl acetate and purified water, extract, add 5% dilute organic phase Adjust the pH to 2-3 with hydrochloric acid, add 20% potassium carbonate to the water phase to adjust the pH to 9-10, add 200ml of ethyl acetate for extraction, wash the organic phase with purified water until neutral, extract once with saturated sodium chloride solution, anhydrous sulfuric acid After drying over sodium, the solvent was removed to obtain 38.0 g of 1-(5-(2-fluorophenyl)-1H-pyrrol-3-yl)-N-methylmethylamine as a white solid crude p...

Embodiment 2

[0085] S1: Synthesis of 1-(5-(2-fluorophenyl)-1H-pyrrol-3-yl)-N-methylmethylamine (II):

[0086] 47.2g of 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (I) was dissolved in 200ml of methanol at room temperature, 64g of 40% methylamino alcohol solution was added dropwise, stirred at 25-35°C for 6-8 hours, Add 33.7g potassium borohydride in batches under ice bath, react at 20-30°C for 1-2 hours, add 72.5g acetone under ice bath to quench, add 200ml ethyl acetate and purified water, extract, add 5% dilute organic phase Adjust the pH to 2-3 with hydrochloric acid, add 20% potassium carbonate to the water phase to adjust the pH to 9-10, add 200ml of ethyl acetate for extraction, wash the organic phase with purified water until neutral, extract once with saturated sodium chloride solution, anhydrous sulfuric acid After drying over sodium, the solvent was removed to obtain 46.5 g of crude 1-(5-(2-fluorophenyl)-1H-pyrrol-3-yl)-N-methylmethylamine (II) as a white solid, with a yield of ...

Embodiment 3

[0096] S1: Synthesis of 1-(5-(2-fluorophenyl)-1H-pyrrol-3-yl)-N-methylmethylamine (II):

[0097] 47.25g of 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (I) was dissolved in 200ml of methanol at room temperature, 64g of 40% methylamino alcohol solution was added dropwise, stirred at 25-35°C for 6-8 hours, Add 13.6g of lithium borohydride in batches under ice bath, react at 20-30°C for 1-2 hours, add 72.5g of acetone under ice bath to quench, add 200ml of ethyl acetate and purified water, extract, add 5% dilute organic phase Adjust the pH to 2-3 with hydrochloric acid, add 20% potassium carbonate to the water phase to adjust the pH to 9-10, add 200ml of ethyl acetate for extraction, wash the organic phase with purified water until neutral, extract once with saturated sodium chloride solution, anhydrous sulfuric acid After sodium drying, the solvent was removed to obtain 45.45 g of 1-(5-(2-fluorophenyl)-1H-pyrrol-3-yl)-N-methylmethylamine (II) as a white solid crude product, with...

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Abstract

The invention discloses a preparation method of vonoprazan fumarate. The preparation method includes: S1, dissolving 5-(2-fluorophenyl)-1H-pyrrole-3-carboxaldehyde (I) in organic solvent, mixing with methylamine alcohol solution for 6-8h to generate imine, reducing with metal borohydride for 1-2h, and performing post-treatment to obtain a compound according to a formula II; S2, dissolving the compound prepared in the step S1 according to the formula II, in organic solvent, performing ice bathing and mixing with Boc anhydride to allow reaction for 1-2h, and performing post-treatment to obtain a compound according to a formula III; S3, dissolving the compound prepared in the step S2 according to the formula III, in organic solvent, adding sodium hydride and crown ether, adding 3-pyridine sulfuryl chloride, mixing for reaction for 1-2h, and performing post-treatment to obtain a compound according to a formula IV; S4, reacting the compound prepared in the step S3 according to the formula IV, in trifluoroacetic acid and methylene dichloride solution to obtain a compound according to a formula V; and S5, dissolving the compound prepared in the step S4 according to the formula V, in organic solvent to be salified with fumaric acid, thereby obtaining the vonoprazan fumarate (VI). The preparation method has few side reactions and high intermediate purity and allows simple post-treatment.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to a preparation method of vonoprazan fumarate, an inhibitor of gastric acid secretion. Background technique [0002] Proton pump inhibitors such as omeprazole and lansoprazole inhibit the secretion of gastric acid to treat peptic ulcer, reflux esophagitis, etc., and are widely used in clinical practice. Vonoprazan fumarate (TAK-438, Vonoprazanfumarate) is a new oral anti-gastric acid drug jointly launched by Takeda Pharmaceutical and Otsuka Pharmaceutical. As a potassium ion (K + ) Competitive acid blocker (P-CAB), vonoprazan plays a role in the last step of gastric acid secretion in parietal cells by inhibiting K + to H + 、K + -ATPase (proton pump) binding to inhibit and prematurely terminate gastric acid secretion. Compared with the currently dominant proton pump inhibitors (PPIs), because vonoprazan does not have CYP2C19 metabolism, it has shown better efficacy in clinic...

Claims

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Application Information

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IPC IPC(8): C07D401/12
CPCY02P20/55C07D401/12
Inventor 卢翔张元元霍立茹李战赵卿周静张慧陆滢炎
Owner NANJING GRITPHARMA CO LTD
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