Preparation method of vonorazan fumarate

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 Japan's Takeda Pharmaceutical Company, 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 Co., Ltd. in China, the synthetic route method of vonoprazan fumarate is reported. Using ethyl...

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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

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