A kind of method for preparing potassium ion competitive blocker intermediate

A technology of reagents and condensing agents, applied in the field of organic chemical synthesis of pharmaceutical intermediates, can solve the problems of difficulty in meeting the needs of the pharmaceutical industry, expensive starting materials, low yields, etc., and achieves a novel process route, low cost, and mild reaction conditions. Effect

Active Publication Date: 2022-08-05
RAFFLES PHAMRMATECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The starting material of this route is relatively expensive; although the route is short, the yield in the pyrrole ring and methylation steps is low, which is difficult to meet the needs of the pharmaceutical industry

Method used

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  • A kind of method for preparing potassium ion competitive blocker intermediate
  • A kind of method for preparing potassium ion competitive blocker intermediate
  • A kind of method for preparing potassium ion competitive blocker intermediate

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043]

[0044] 1. Synthesis of compound 2

[0045] Add 66.7 g of dimethyl malonate and 60.1 g of N,N-dimethylformamide dimethyl acetal to a 500-ml reaction flask, warm up to 70 ° C for 2 hours, cool to room temperature, add 65 g of 2 , 4-difluorobenzylamine, the temperature was raised to 70°C and the reaction was continued for 2 hours. After cooling to room temperature, 500 ml of water and 500 ml of ethyl acetate were added, stirred for 10 minutes, left to separate layers, the organic phase was washed with saturated brine, dried with anhydrous sulfuric acid, concentrated under reduced pressure to remove the solvent, and the residue was added with n-heptane Slurried, filtered, and dried to give 111.1 g of compound 2, 85.8% yield, as a white solid.

[0046] 1 H-NMR (400MHz, d 6 -DMSO): 9.40(br,1H), 8.14-8.18-(m,1H), 7.42-7.49(m,1H), 7.27-7.32(m,1H), 7.12-7.17(m,1H), 4.64( d, 2H), 3.64(d, 3H), 3.60(d, 3H); ESI-MS: m / z 286.14[M+1]

[0047] 2. Synthesis of compound 3A

[...

Embodiment 2

[0060]

[0061] 1. Synthesis of compound 2

[0062] In a 500mL reaction flask, add 50.8 g of dimethyl malonate, 74.1 g of trimethyl orthoformate, and 71.3 g of acetic anhydride, heat to 100 °C for 2 hours, then drop to room temperature, add 50 g of 2,4-dimethy Fluorobenzylamine, the temperature was raised to 90°C and the reaction was continued for 2 hours. The temperature was lowered to room temperature, 500 ml of water and 500 ml of ethyl acetate were added, stirred for 10 minutes, and the layers were separated. The residue was added with n-heptane to be slurried, filtered, and dried to obtain 83.9 g of compound 2 with a yield of 84.2% and a white solid.

[0063] 2. Synthesis of compound 3B

[0064] 20 g of compound 2, 45.7 g of cesium carbonate powder, 200 ml of N,N-dimethylformamide, and 11.5 g of 4-methoxybenzyl chloride were added to a 500-ml reaction flask, and heated to 80 °C under nitrogen protection for the reaction. 2 hours. After cooling to room temperature, ...

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Abstract

A method for synthesizing a key intermediate compound 1 of a novel potassium ion competitive blocker fexuprazan belongs to the field of pharmaceutical intermediate synthesis. The purpose of the present invention is to solve the problems of high preparation cost and low yield of compound 1, further increase the production capacity, and reduce the production cost. The method of the invention takes 2,4-difluorobenzylamine as a raw material, and sequentially undergoes condensation reaction, benzyl protection, cyclization under basic conditions, methylation, deprotection, etc. to obtain the target product. The method for synthesizing compound 1 of the present invention adopts a novel process route, the yield is greater than 50%, and has the characteristics of novel route, mild reaction conditions, low cost and the like.

Description

technical field [0001] The invention belongs to the field of organic chemical synthesis of pharmaceutical intermediates, in particular to a method for synthesizing a key intermediate of a novel potassium ion competitive blocker fexuprazan. Background technique [0002] Erosive esophagitis is a common disease of the digestive system, most of which are caused by acid reflux or bile reflux. At present, the main drugs on the market for this disease are pantoprazole, ranitidine, famotidine, omeprazole, esomeprazole, etc. Among them, esomeprazole has the best therapeutic effect. [0003] South Korea's Daewoong Pharmaceutical Company recently announced the first phase III clinical data of the new gastroesophageal reflux disease drug fexuprazan, a novel potassium ion-competitive blocker, at Digestive Disease Week (DDW) 2020, confirming that fexuprazan has significant The efficacy of inhibiting gastric acid secretion is even better than esomeprazole in relieving heartburn and other...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D207/36C07C229/30C07C227/18
CPCC07D207/36C07C229/30C07C227/18
Inventor 黄志宁周章涛叶伟平费安杰米成根杨曼欣
Owner RAFFLES PHAMRMATECH CO LTD
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