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Preparation method of vonoprazan intermediate

A compound and reaction technology, applied in the field of preparation of vonolazan intermediates, can solve the problems of harsh reaction conditions and cumbersome operations

Active Publication Date: 2021-02-02
SHANGHAI TIANCI INT PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] The above three reported routes have more than 4 steps and involve reactions such as pressurized hydrogenation and low-temperature reduction. The reaction conditions are harsh, there is a certain risk, and the operation is cumbersome.

Method used

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  • Preparation method of vonoprazan intermediate
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  • Preparation method of vonoprazan intermediate

Examples

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preparation example Construction

[0065] The preparation method of Weissmeier reagent:

[0066] Add N,N-dimethylformamide into dichloromethane, cool down to 0°C, add phosphorus oxychloride dropwise, stir for 30

[0067] The solution obtained in minutes.

[0068] The preparation method of formula V compound

[0069] Aiming at the defects of the existing preparation methods of the compound of formula V, the present invention provides a novel preparation method of the compound of formula V, which uses pyrrole as a raw material and prepares the compound of formula V, an intermediate of vonorazan, under mild reaction conditions. Described method specifically comprises the steps:

[0070]

[0071] (1) In the first solvent, in the presence of a brominating reagent, the compound of formula I undergoes a bromination reaction to obtain the compound of formula II;

[0072] (2) In the second solvent, in the presence of a base, a sulfonylation reaction occurs between the compound of formula II and pyridine-3-sulfonyl...

Embodiment 1

[0105] Synthesis of embodiment 1 2-bromopyrrole

[0106]

[0107] Add tetrahydrofuran (100mL) to pyrrole (20g), cool down to -15°C, add N-bromosuccinimide (63.4g) in batches, keep warm until the reaction is complete, add ice-water solution, and extract the aqueous phase with ethyl acetate , the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain the target compound (39.4 g), yield: 91%. MS (ESI): [M+1] + = 145.94.

Embodiment 2

[0108] Example 2 Synthesis of 3-(2-bromo-pyrrole-1-sulfonyl)-pyridine

[0109]

[0110] Add 2-bromopyrrole (20g) into acetonitrile (100mL), add triethylamine (20.9g), add pyridine-3-sulfonyl chloride (29.3g) dropwise at room temperature, after the addition is complete, react at 40°C until the reaction is complete, add dilute Adjust the pH to 4-5 with hydrochloric acid, add water (200 mL) dropwise, add ethyl acetate for extraction, wash the organic phase with saturated brine, and concentrate to dryness to obtain 35.5 g of the target compound, yield: 90%. MS (ESI): [M+1] + = 286.95.

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Abstract

The invention provides a preparation method of a vonoprazan intermediate. Specifically, the vonoprazan intermediate is obtained through a bromination reaction, a sulfonylation reaction, a Vilsmeier reaction and a Suzuki reaction. According to the preparation method, dangerous hydrogenation reaction and low-temperature reaction are avoided, and the reaction has the advantages of mild conditions, easiness in operation, cheap raw materials, low production cost and high total yield.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method of a Wonorazan intermediate. Background technique [0002] Vonoprazan fumarate (TAK-438or Vonoprazan Fumarate, Takecab) is a potassium ion competitive acid blocker (P-CAB) developed by Takeda Pharmaceutical Company, which was first approved for marketing in Japan in December 2014. It is used to treat gastric acid-related diseases such as Helicobacter pylori infection, gastroesophageal reflux, peptic ulcer, duodenal ulcer, esophagitis, gastric ulcer, etc., but its poor solubility greatly affects its oral absorption and bioavailability degree, which limits its clinical application. [0003] The structure of vonorazan fumarate is shown below: [0004] [0005] The compound of the present invention is an important intermediate of vonoprazan fumarate, and its structure is as follows: [0006] [0007] The synthesis method of the Wonorazan in...

Claims

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Application Information

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IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 李函璞李勇刚王卓沙飞
Owner SHANGHAI TIANCI INT PHARMA
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