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Preparation method of vonoprazan fumarate and intermediate thereof

A technology of vonoprazan fumarate and intermediates, which is applied in the field of medicinal chemistry and can solve the problems of many operation steps, cumbersome synthesis steps, and many impurities

Inactive Publication Date: 2018-12-21
珠海润都制药股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0017] The synthesis steps of this route are cumbersome, and liquid bromine with strong toxicity and corrosiveness is used in the synthesis process, and hydrogen chloride gas strongly corrodes the device; after the ester is reduced to alcohol and then oxidized to aldehyde, this reaction has many operating steps, and the reaction process There are many impurities generated, and the yield of the product obtained is low

Method used

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  • Preparation method of vonoprazan fumarate and intermediate thereof
  • Preparation method of vonoprazan fumarate and intermediate thereof
  • Preparation method of vonoprazan fumarate and intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Preparation of Compound IV:

[0043] In the reaction flask, dissolve 100 g of the compound of formula II obtained by reacting formula I with sulfuric acid in nitrobenzene, add 120 g of 4-chlorobutane-2,3-dienoyl chloride, and under the action of catalyst aluminum tribromide, The compound of formula II and 4-chlorobutane-2,3-dienoyl chloride undergoes acylation reaction, and the molar ratio of the catalyst aluminum tribromide in the 4-chlorobutane-2,3-dienoyl chloride and the acylation reaction is 1:1.8, that is, add 126g of catalyst aluminum tribromide; the mass volume ratio of compound II and the solvent carbon disulfide in the acylation reaction is: 1g:6ml, that is, the solvent carbon disulfide is 600ml. 93.22 g of the compound of formula III was prepared by the sulfohydrolysis reaction, and the yield of the compound of formula III under this condition was 83.53%.

[0044] Dissolve 93.22 g of the prepared compound of formula III in toluene, put it into a reactor, add...

Embodiment 2

[0049] Preparation of Compound IV:

[0050] In the reaction flask, dissolve 100 g of the compound of formula II obtained by reacting formula I with sulfuric acid in nitrobenzene, add 120 g of 4-chlorobutane-2,3-dienoyl chloride, and under the action of catalyst aluminum tribromide, Formula II compound and 4-chlorobutane-2,3-dienoyl chloride undergo acylation reaction, the molar ratio of 4-chlorobutane-2,3-dienoyl chloride and the catalyst in the acylation reaction is 1:2.4, That is, 168g of aluminum tribromide is added as a catalyst; the mass volume ratio of compound II and the solvent in the acylation reaction is: 1g:8ml, that is, the solvent nitrobenzene is 800ml, and after reacting for 5 hours at a temperature of 28°C, the reaction is carried out by desulfonation and hydrolysis. 106.4 g of the compound of formula III was prepared, and the yield of the compound of formula III under the conditions was 92.38%.

[0051] Dissolve 106.4 g of the prepared compound of formula III ...

Embodiment 3

[0056] Preparation of compound VII:

[0057] Place 88.04 g of the prepared compound of formula IV in an inert gas steam, and at the reaction temperature, first pass a certain amount of ammonia water for 35 minutes, and pretreat the catalyst before the reaction to ensure that the water vapor and ammonia gas can be evenly distributed. Distributed in the catalyst aluminum silicate; then, furan is fed through another peristaltic pump, and ammonia water continues to be added dropwise at this time. The molar ratio of the compound of formula IV to ammonia and water was 1: (1:35), and 65.11 g of the compound of formula V was prepared, with a conversion rate of 82.99%.

[0058] Dissolve 65.11 g of the prepared compound of formula V in toluene, carry out sulfonamidation reaction with pyridine-3-sulfonyl chloride in a reactor, and prepare the compound of formula VI; dissolve the prepared compound of formula VI in ethanol, and undergo bromination After the reaction, the obtained substanc...

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Abstract

The invention discloses a preparation method of vonoprazan fumarate. The method comprises the steps that R1) a compound of formula I is subjected to sulfonation to obtain a compound of formula II; R2)the compound of the formula II is dissolved in a solvent, and is acylated with 4-chlorobutane-2,3-dienoyl chloride, and a compound of the formula III is obtained by desulfuration hydrolysis reaction;R3) the compound of formula III is dissolved in an organic solvent and a compound of formula IV is obtained by halogen transfer; R4) the compound of the formula IV is placed in an inert gas water vapor, and an excess of aqueous ammonia and a catalyst are added to carry out a reaction to prepare a compound of formula V; R5) the compound of formula V is subjected to amidation with pyridine-3-sulfonyl chloride to prepare a compound of formula VI; R6) the compound of the formula VI is dissolved in an organic solvent, after bromination reaction, amination reaction, and salt formation with fumaricacid, a compound of formula VII is obtained. The preparation method of the vonoprazan fumarate has the advantages of simple operation, easy availability of raw materials, less side reactions, less waste, and low production cost.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a preparation method of vonoprazan fumarate, a drug for treating hypersecretion of gastric acid, and an intermediate. Background technique [0002] Vonoprazan fumarate (TAK-438) has better efficacy than lansoprazole in the treatment of gastric ulcer / duodenal ulcer, reflux esophagitis, and eradication of Helicobacter pylorus, and is more tolerable and safe Sex is also good. Omeprazole and Lansoprazole are traditional irreversible proton pump inhibitors that inhibit the secretion of gastric acid to treat peptic ulcer, reflux esophagitis and other related diseases. [0003] Omeprazole is a proton pump inhibitor that specifically acts on the proton pump of gastric parietal cells (H + , K + -ATPase), irreversibly binds to the sulfhydryl group of the proton pump through a disulfide bond, thereby inhibiting H + , K + -ATPase activity, making H in parietal cells + It cannot be tr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12C07D307/56
CPCC07D307/56C07D401/12
Inventor 覃志俊王晴晴董雪林祁红林黄肖艳
Owner 珠海润都制药股份有限公司
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