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Preparation method of high-purity ((5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1h-pyrrol-3-yl)methyl)(methyl)carbamate tert-butyl ester

A technology of methyl carbamic acid and sulfonyl group, which is applied in the field of medicine, can solve the problems unfavorable to the industrial production of vonoprazan fumarate, and achieve the effects of avoiding post-processing methods, simple process and stable yield

Active Publication Date: 2018-07-24
NANJING GRITPHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] ((5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate tert-butyl The key intermediate of Razan, Y.Arikawa et al. reported in J.Med.Chem.2012,55,4446-4456 that column chromatography is required for separation, which is not conducive to the industrial production of Vonorazan fumarate

Method used

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  • Preparation method of high-purity ((5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1h-pyrrol-3-yl)methyl)(methyl)carbamate tert-butyl ester
  • Preparation method of high-purity ((5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1h-pyrrol-3-yl)methyl)(methyl)carbamate tert-butyl ester
  • Preparation method of high-purity ((5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1h-pyrrol-3-yl)methyl)(methyl)carbamate tert-butyl ester

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] S1: Synthesis of tert-butyl ((5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate

[0024] Take 60g of ((5-(2-fluorophenyl)-1H-pyrrol-3-yl)-N-methyl) methylcarbamate tert-butyl ester dissolved in 240ml of anhydrous tetrahydrofuran, nitrogen protection, slowly under ice bath Add 24g of sodium hydride in batches, stir in an ice bath for 10 minutes, heat up to 50-60°C for 0.2-2h, cool down to 0-5°C, slowly add 53.2g of 3-pyridinesulfonyl chloride anhydrous tetrahydrofuran solution 160ml dropwise, After the dropwise addition was completed, stir and react in an ice bath for 10 minutes, raise the temperature to 25-60° C., and stir and react for 1-3 hours. TLC confirmed the reaction end point. Solution of crude tert-butyl phenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate in THF.

[0025] S2: Purification of tert-butyl ((5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate

[0026] Add 1200m...

Embodiment 2

[0028] S1: Synthesis of tert-butyl ((5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate

[0029] Take 60g of ((5-(2-fluorophenyl)-1H-pyrrol-3-yl)-N-methyl) methylcarbamate tert-butyl ester dissolved in 250ml of anhydrous ether, nitrogen protection, slowly under ice bath Add 28g of sodium hydride in batches, stir in an ice bath for 10 minutes, heat up to 30-35°C and react for 30-45 minutes, cool down to 0-5°C, slowly add 53.2g of 3-pyridinesulfonyl chloride anhydrous ether solution 200ml, After the dropwise addition, stir and react in an ice bath for 10 minutes, rise to 30-50°C, stir and react for 1.5-2 hours, and determine the end point of the reaction by TLC. The developer is: V 石油醚 :V 乙酸乙酯 = 1:1, after the reaction is complete, add diatomaceous earth for suction filtration, wash the filter cake with 100ml of anhydrous ether, combine the filtrate and washings, extract with 500ml of purified water and 20% saline respectively, and dry the organ...

Embodiment 3

[0033] S1: Synthesis of tert-butyl ((5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate

[0034] Get 60g of ((5-(2-fluorophenyl)-1H-pyrrol-3-yl)-N-methyl)methylcarbamate tert-butyl ester dissolved in 240ml of anhydrous methyl tetrahydrofuran, nitrogen protection, ice bath Slowly add 24g of sodium hydride in batches, stir in an ice bath for 15 minutes, heat up to 60-70°C for 15-30 minutes, cool down to 0-5°C, and slowly add 53.2g of 3-pyridinesulfonyl chloride anhydrous methyl 150ml of tetrahydrofuran solution. After the dropwise addition, stir the reaction in an ice bath for 10 minutes, raise the temperature to 50-80°C, and stir the reaction for 1-3 hours. The end point of the reaction is determined by TLC. The filter cake was washed with tetrahydrofuran, the combined filtrate and washings were extracted with 500ml purified water and 20% saline respectively, and the organic phase was dried over anhydrous sodium sulfate to obtain ((5-(2-fluoroph...

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Abstract

The invention discloses a preparation method of high-purity tert-butyl ((5-(2-fluorophenyl)-1-(pyridine-3-yl sulfonyl)-1H-pyrrole-3-yl)methyl)(methyl)carbamate, which comprises the following steps: dissolving tert-butyl ((5-(2-fluorophenyl)-1H-pyrrole-3-yl)-N-methyl)methyl carbamate in an organic solvent, adding sodium hydride, heating for reacting, dropwise adding 3-pyridine sulfonyl chloride at low temperature, reacting under stirring for 1-3h, and filtering to obtain a solution of a tert-butyl ((5-(2-fluorophenyl)-1-(pyridine-3-yl sulfonyl)-1H-pyrrole-3-yl)methyl)(methyl)carbamate crude product; adding purified water to the solution, adjusting the pH to weak acidity, cooling, stirring, separating out crystals, carrying out suction filtration, drying a filter cake, pulping with an isopropyl ether and n-heptane mixed solution, carrying out suction filtration and drying to obtain a high-purity product. The process is simple, safe and reliable; the prepared vonoprazan fumarate intermediate tert-butyl ((5-(2-fluorophenyl)-1-(pyridine-3-yl sulfonyl)-1H-pyrrole-3-yl)methyl)(methyl)carbamate has high yield and purity, and is suitable for industrialized scaled production.

Description

technical field [0001] The invention belongs to the field of medicine, in particular to ((5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamic acid tertiary The preparation method of butyl ester. Background technique [0002] Proton pump inhibitors such as omeprazole and lansoprazole inhibit the secretion of gastric acid to treat peptic ulcer, reflux esophagitis, etc., and are widely used in clinical practice. Vonoprazan fumarate (TAK-438, Vonoprazan fumarate) is a new oral anti-gastric acid drug jointly launched by Takeda Pharmaceutical and Otsuka Pharmaceutical. As a potassium ion (K + ) Competitive acid blocker (P-CAB), vonoprazan plays a role in the last step of gastric acid secretion in parietal cells by inhibiting K + to H + 、K + -ATPase (proton pump) binding to inhibit and prematurely terminate gastric acid secretion. Compared with the currently dominant proton pump inhibitors (PPIs), because vonoprazan does not have CYP2C19 metabol...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 卢翔童巍张元元霍立茹赵卿李战刘二军陆滢炎
Owner NANJING GRITPHARMA CO LTD
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