Synthetic process for Vonoprazan fumarate

A technology of fumaric acid and fumarate, which is applied in the field of medicine, can solve the problems of cumbersome refining steps, increased production costs, and low product purity, and achieve high product purity, cost saving, and high removal efficiency

Pending Publication Date: 2018-03-09
四川弘远药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The invention solves the problems of low product purity in the prior synthesis process of vonorazan fumarate, cumbersome refining steps are required to increase the purity, and at the same time, the yield is greatly reduced, resulting in a significant increase in production cost and the like.

Method used

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  • Synthetic process for Vonoprazan fumarate
  • Synthetic process for Vonoprazan fumarate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058]Put 10.00g of 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde, 1.29g of 4-dimethylaminopyridine (DMAP), 7.49g of triethylamine and 1L of dichloromethane into the reactor, stir and cool down, Add 11.26g of pyridine-3-sulfonyl chloride dropwise, stir and react for 2 hours after dropping, add 20ml of water to quench the reaction, wash in turn with 20ml of water, 20ml of 20% sodium chloride solution by mass percentage, distill, add 70ml of 75% ethanol solution Heat to dissolve, cool down to crystallize, filter, wash, and dry to obtain 15.12 g of 1-(3-pyridinesulfonyl)-5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde. Yield 86.60%.

[0059] Put 10.00g 1-(3-pyridinesulfonyl)-5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (0.0303mol) and 50ml methanol into the reactor, stir, add 1.63g methylamine (0.05258 mol), stirred and reacted at 5°C for 1 hour, cooled to 0°C, added 0.77g sodium borohydride (0.02026mol), and continued to keep warm for 60 minutes after adding, quenched the reaction ...

Embodiment 2

[0063] Put 10.00g 1-(3-pyridinesulfonyl)-5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (0.0303mol) and 50ml methanol into the reactor, stir, add 1.80g methylamine (0.05806 mol), stirred and reacted at 10°C for 2 hours, cooled to -5°C, slowly and uniformly added 0.64g sodium borohydride (0.01684mol), continued to keep warm for 60 minutes after the addition was complete, added dropwise 20ml of water to quench the reaction, and stirred for 35 minutes , methanol was distilled off under reduced pressure, 120ml of ethyl acetate and 20ml of water were added to the residue, the liquid was separated, the organic layer was taken for washing, and dilute hydrochloric acid was added dropwise under cooling to pH 4, stirred at room temperature for 30 minutes, and the mass percentage concentration was 10% chloride Sodium solution, stirred and crystallized, filtered, and dried to obtain 10.46 g of vonoprazan hydrochloride. Yield 90.49%, HPLC purity 98.04%, impurity content: impurity A is 0.37%,...

Embodiment 3

[0067] Put 10.00g 1-(3-pyridinesulfonyl)-5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (0.0303mol) and 100ml methanol into the reactor, stir, add 1.51g methylamine, 20 Stir the reaction at ℃ for 1 hour, lower the temperature to -10 ℃, slowly and uniformly add 0.58g sodium borohydride (0.01526mol), continue the heat preservation reaction for 90 minutes after the addition, drop water to quench the reaction, stir the reaction for 40 minutes, and remove methanol by distillation under reduced pressure , add 120ml of ethyl acetate and 20ml of water to the residue, separate the layers, take the organic layer and wash it, add dilute hydrochloric acid dropwise to pH 2 under cooling, stir at room temperature for 30 minutes, add saturated sodium chloride solution, stir and crystallize, filter, and dry. Recrystallization gave 8.69 g of Vonorazan hydrochloride. Yield 75.18%, HPLC purity 99.60%, impurity content: impurity A not detected, impurity B 0.028%, impurity C 0.061%, impurity D not d...

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Abstract

The invention provides a preparation method for preparing high-purity 5-(2-fluorophenyl)-N-methyl-1-(3-pyridine sulfonyl)-1H-pyrrole-3-methylamine fumarate. The method comprises the following steps: taking 5-(2-fluorophenyl)-N-methyl-1-(3-pyridine sulfonyl)-1H-pyrrole-3-methylamine hydrochloride as an intermediate; carrying out alkali treatment, and then salifying the treated intermediate with fumaric acid to obtain a finished product. A final product prepared by adopting the method has high purity and low content of key impurities; in addition, the purification and post treatment steps of fumarate are simplified, and the yield is remarkably improved.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a method for synthesizing and preparing Vonorazan fumarate. Background technique [0002] Vonoprazan Fumarate (TAK-438, chemical name: 5-(2-fluorophenyl)-N-methyl-1-(3-pyridinesulfonyl)-1H-pyrrole-3-methyl Amine fumarate) is a novel potassium ion (K + ) Competitive acid blocker (P-CAB), which can inhibit the K + to H + -K + ―The combined effect of ATPase (proton pump) terminates the secretion of gastric acid in advance, and has a strong and lasting effect of inhibiting gastric acid secretion. The original manufacturer of the drug is Takeda Pharmaceutical Co., Ltd., Japan, and it is mainly used for the treatment of erosive esophagitis, gastric ulcer, duodenal ulcer, and eradication of Helicobacter pylori. Compared with the mainstream gastric acid secretion inhibitors "proton pump inhibitors (PPIs)" currently on the market, because vonoprazan does not have CYP2C19 metabolism,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 柯潇陈书明朱安云黄荣
Owner 四川弘远药业有限公司
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