Vonoprazan fumarate preparation method

A technology for vornorazan fumarate and a compound is applied in the field of preparation of vornorazan fumarate, which can solve the problems of difficult operation, high equipment requirements, and high cost, and achieves reduction in the burden of post-reaction treatment and the reduction of The effect of operation difficulty and low equipment requirements

Active Publication Date: 2017-02-01
SHANDONG JINCHENG PHARMACEUTICAL GROUP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] This process route is similar to the route of the patent CN201080018114, the difference is that ethyl cyanoacetate is used instead of malononitrile, the ester group is first reduced to a hydroxyl group, and then the hydroxyl group is reduced to an aldehyde group, and the synthesis steps are more complicated. Strong corrosive bromine and hydrogen chloride, as well as flammable palladium carbon and diisobutyl aluminum hydride, the cost is high, the operation is difficult, and it is not suitable for industrial production
[0014] The main disadvantages of the existing synthetic route of vornorazan fumarate (TAK438) are: (1) use materials such as highly corrosive bromine and hydrogen chloride, which have high requirements for equipment; (2) use palladium Extremely flammable reducing reagents such as carbon, Raney nickel, diisobutyl aluminum hydride, etc., are difficult to operate and pose a great safety hazard; (3) the synthesis route is cumbersome, the reaction is not easy to control, there are many impurities, and post-treatment is often used Purification by column chromatography is difficult to operate and is not suitable for industrial production

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Preparation of Compound IV:

[0039] In a 2000ml reaction bottle, add 138g of 2-fluoroacetophenone, 114g of allylamine, 966ml of absolute ethanol, and 10ml of glacial acetic acid, heat the reaction system to 50°C, keep it warm for 6h, and cool to At room temperature, a large amount of solids precipitated, stirred for 1 hour, then cooled to 0-10°C, kept warm for 1 hour, filtered with suction, rinsed the filter cake with cold ethanol, and dried to obtain 165 g of white solid, compound IV, with a yield of 93%.

Embodiment 2

[0041] Preparation method 1 of compound V:

[0042] In a 3000ml reaction flask, add 160g of compound IV, 8.5g of cuprous iodide, 285g of triphenylphosphine, and 640ml of dioxane. Under nitrogen protection, stir at 40°C for 16h. TLC detects the progress of the reaction. After the reaction is completed, cool Bring to room temperature, add 1280ml of water, then add 320ml of ethyl acetate to extract three times, combine the organic phase, add 240ml of 1% dilute hydrochloric acid to the organic phase, stir for 15min, separate the liquid, then wash the organic phase with 360ml*3 water for three times, and separate the liquid , the organic phase was concentrated to dryness to obtain a dark brown oil, which was dissolved by adding 240ml of ethanol, and 800ml of water was added dropwise with stirring at room temperature, and a solid precipitated out. The temperature was lowered to 5-10°C, kept for 1h, and suction filtered to obtain 135g of a light yellow solid. That is compound V, the ...

Embodiment 3

[0044] Preparation method 2 of compound V:

[0045]In a 3000ml reaction flask, add 160g of compound IV, 1.7g of cuprous iodide, 474g of triphenylphosphine, and 1600ml of dioxane, under the protection of nitrogen, stir at 60°C for 24h, check the progress of the reaction by TLC, after the completion of the reaction, cool Bring to room temperature, add 1280ml of water, then add 320ml of ethyl acetate to extract three times, combine the organic phase, add 240ml of 1% dilute hydrochloric acid to the organic phase, stir for 15min, separate the liquid, then wash the organic phase with 360ml*3 water for three times, and separate the liquid , the organic phase was concentrated to dryness to obtain a dark brown oil, which was dissolved by adding 240ml of ethanol, and 800ml of water was added dropwise with stirring at room temperature, and a solid precipitated out. The temperature was lowered to 5-10°C, kept for 1h, and suction filtered to obtain 127g of a light yellow solid. That is com...

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PUM

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Abstract

The invention concretely relates to a vonoprazan fumarate preparation method, and belongs to the field of medicines and chemical engineering. The method comprises the following steps: 1, carrying out condensation on 2-fluoroacetophenone used as an initial raw material and allylamine to obtain a compound IV; 2, carrying out a ring closing reaction on the compound IV under the catalysis of a copper catalyst in the presence of a ligand in order to obtain a compound V; 3, carrying out a sulfoamidation reaction on the compound V and pyridine-3-sulfonyl chloride to generate a compound VII; 4, carrying out a bromination reaction on the compound VII by using N-bromosuccimide in order to generate a compound VIII; 5, carrying out an amination reaction on the compound VIII and methylamine hydrochloride under the action of a catalyst and an alkali in order to obtain vonoprazan alkali; and 6, carrying out salt formation on the vonoprazan alkali and fumaric acid in order to obtain vonoprazan fumarate. The preparation method has the advantages of simplicity in operation, mild reaction conditions, high yield and high purity of the product, and easiness in industrial production.

Description

technical field [0001] The invention relates to a preparation method of vonoprazan fumarate, which belongs to the technical field of medicine and chemical industry. Background technique [0002] 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethylamine fumarate, Chinese name: Fuma Vonoprazan acid, English name: Vonoprazan Fumarate, trade name: Takecab, is a potassium ion competitive acid blocker developed by Takeda Pharmaceutical Company in Japan, used for the treatment of erosive esophagitis, gastric ulcer, duodenal ulcer , Helicobacter pylori eradication, etc. It was launched in Japan on December 26, 2014. The chemical structure of vonorazan fumarate is as follows: [0003] [0004] The publicly reported synthetic routes of vonorazan fumarate mainly include the following: [0005] In the patent CN200680040789 applied by Japan's Takeda Pharmaceutical Company in China, the synthetic route method of vonoprazan fumarate is reported. Using ethyl ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12C07C51/41C07C57/15
CPCC07D401/12
Inventor 南红燕孙滨伊茂聪马庆双王晓光
Owner SHANDONG JINCHENG PHARMACEUTICAL GROUP CO LTD
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