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Vonoprazan fumarate key intermediate and preparation method thereof

A technology of vonorazan fumarate and its intermediates, which is applied in the field of organic synthesis, can solve the problems of complex preparation reaction routes, many post-processing procedures, and increased product costs, and achieve simple processes, reduced difficulty, risk, and cost low effect

Inactive Publication Date: 2017-09-15
BEIJING THTD PHARMA TECH JOINT CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the prior art, the preparation reaction route of 5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile is complicated, and there are many post-treatment procedures, toxic and unstable reactants need to be used, and the industrial operation is difficult. Dangerous, high amount of catalyst, increased product cost

Method used

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  • Vonoprazan fumarate key intermediate and preparation method thereof
  • Vonoprazan fumarate key intermediate and preparation method thereof
  • Vonoprazan fumarate key intermediate and preparation method thereof

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preparation example Construction

[0079] The preparation method of the key intermediate of vonoprazan fumarate of the present invention mainly includes 3-step procedures, the process is simple, the post-treatment is simple, no toxic reactants and unstable reactants are used, and the difficulty and danger of industrial operation are reduced. The use of catalyst is small, the cost is low, the yield is high, and it is suitable for large-scale production.

[0080] Optionally, the preparation method of the compound 2 comprises:

[0081] Part of the solvent, HBr and hydrogen peroxide are prepared into solution A for subsequent use;

[0082] Add the solution A to the mixed solution of o-fluoroacetophenone and the rest of the solvents to carry out the reaction. After the reaction, add water, then add the reducing agent, stir and separate the layers, and the obtained organic phase is washed and set aside;

[0083] Add malononitrile to the organic phase, stir to dissolve completely, then add alkali to react;

[0084] ...

Embodiment 1

[0167] A preparation method for the key intermediate of vornorazan fumarate, comprising the steps of:

[0168] 1. Preparation of malononitrile condensate:

[0169] First, 3.5 kg of ethyl acetate was added to the reaction bottle; at room temperature, under magnetic stirring, 1.8 kg of HBr aqueous solution with a mass fraction of 47% and 750 g of hydrogen peroxide were added to form solution A, which was sealed for later use;

[0170]Add 1.4 kg of o-fluoroacetophenone and 5.5 kg of ethyl acetate into the reaction flask, seal and stir at room temperature until clear; add the above solution A dropwise at 20°C, and react within this temperature range for 4 hours after the dropwise addition; determine the reaction After completion, lower the temperature to 15°C, control the temperature below 25°C, add 7 kg of water dropwise, then add 250 grams of sodium sulfite, stir for 20 minutes, and separate layers; the organic phase is washed with saturated sodium bicarbonate and saturated sodi...

Embodiment 2

[0178] A preparation method for the key intermediate of vornorazan fumarate, comprising the steps of:

[0179] 1. Preparation of malononitrile condensate:

[0180] First, add 4 kg of ethyl acetate to the reaction bottle; at room temperature, under magnetic stirring, add 2 kg of HBr aqueous solution with a mass fraction of 47% and 900 g of hydrogen peroxide to configure solution A, and seal it for later use;

[0181] Add 1.4 kg of o-fluoroacetophenone and 6 kg of ethyl acetate into the reaction bottle, seal and stir at room temperature until clear; add the above solution A dropwise at 30°C, and react within this temperature range for 3 hours after the dropwise addition; determine the reaction After completion, lower the temperature to 15°C, control the temperature below 35°C, add 8 kg of water dropwise, then add 300 grams of sodium sulfite, stir for 30 minutes, and separate layers; the organic phase is washed with saturated sodium bicarbonate and saturated sodium chloride solut...

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Abstract

The invention provides a vonoprazan fumarate key intermediate and a preparation method thereof. The preparation method of the vonoprazan fumarate key intermediate mainly comprises three procedures, and is simple in process and simple in aftertreatment; toxic reactants and unstable reactants are not required, difficulty and dangerousness of industrial operation are reduced, the use amount of a catalyst is small, the cost is low, the yield is high, and the vonoprazan fumarate key intermediate is suitable for large-scale production. The vonoprazan fumarate key intermediate is high in purity, and can be used for preparing vonoprazan fumarate.

Description

technical field [0001] The invention relates to the technical field of organic synthesis, in particular to a key intermediate of vonoprazan fumarate and a preparation method thereof. Background technique [0002] Vonoprazan Fumarate (TAK-438) was developed by Takeda, Japan, and was approved for marketing in Japan on December 26, 2014. The drug belongs to the potassium-competitive acid blocker (Potassium-competitive acid blocker, A new class of inhibitors of P-CAB). P-CABs have the characteristics of lipophilicity, weak alkalinity, high dissociation constant and stability at low pH value, so Vonorazan has fast-acting, strong and long-lasting inhibitory effect on gastric acid secretion. In the last step, by inhibiting the binding of K to H,K-ATPase (proton pump), it also has an early termination effect on gastric acid secretion. [0003] Takeda has conducted several clinical trials in Japan investigating the efficacy of vonoprazan Fumarate for indications of erosive esophagi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/34
CPCC07D207/34
Inventor 王红平
Owner BEIJING THTD PHARMA TECH JOINT CO LTD
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