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A kind of preparation method of Alamod intermediate

A technology of intermediates and equations, applied in the preparation of sulfonic acid amides, organic chemistry, etc., can solve the problems of sodium azide being prone to explosion, unfavorable for industrialized production, prone to side reactions, etc. The effect of low reaction and operation difficulty

Active Publication Date: 2022-04-12
江苏润安制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] The bromine used in this route has high activity, is difficult to operate, and is prone to side reactions; sodium azide is prone to explosion and is dangerous, which is not conducive to industrial production

Method used

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  • A kind of preparation method of Alamod intermediate
  • A kind of preparation method of Alamod intermediate
  • A kind of preparation method of Alamod intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Dissolve 1.02g of formic acid in 50ml of dichloromethane, add it to a 250ml three-necked flask and stir, control the temperature at 15-25°C, add 5.28g (1.5eq) N,N-carbonyldiimidazole (CDI) in batches, and complete the addition Stir for 1 hour, the system dissolves, and add 8.40 g (1.0 eq) of 2-amino-1-(2-methoxy-4-methanesulfonamido-5-phenoxybenzene in batches at 15-25 °C Base) ethyl ketone hydrochloride (4), react for 1-2h, TLC monitors the complete reaction of the raw materials, add 50ml of purified water and 50ml of dichloromethane to the reaction system, stir for 30min, separate layers, and concentrate the organic phase to dryness under reduced pressure. Add 50ml of isopropanol to make slurry for 30min, and filter with suction to obtain compound 1 (7.54g, 91.7%) with a purity of 99.95%. 1 H-NMR (400 MHz, DMSO-d6) δ (ppm): 3.14(s, 3H), 3.95(s,3H), 4.47~4.48(d, 2H), 6.98~7.00(m, 2H), 7.11~ 7.15(m, 1H), 7.29~7.32(d,2H), 7.37~7.41(m, 2H), 8.11~8.12(d, 1H), 8.27~8.29(t,...

Embodiment 2

[0034] Dissolve 1.02g of formic acid in 50ml of dichloromethane, add it into a 250ml three-necked flask and stir, control the temperature at 15-25°C, add 3.52g (1.0eq) N,N-carbonyldiimidazole (CDI) in batches, and finish adding Stir for 1 hour, the system dissolves, and add 8.40 g (1.0 eq) of 2-amino-1-(2-methoxy-4-methanesulfonamido-5-phenoxybenzene in batches at 15-25 °C Base) ethyl ketone hydrochloride (4), react for 1-2h, TLC monitors the complete reaction of the raw materials, add 50ml of purified water and 50ml of dichloromethane to the reaction system, stir for 30min, separate layers, and concentrate the organic phase to dryness under reduced pressure. Add 50ml of isopropanol to make slurry for 30min, and filter with suction to obtain compound 1 (6.44g, 78.3%).

Embodiment 3

[0036] Dissolve 1.02g of formic acid in 50ml of dichloromethane, add it into a 250ml three-necked flask and stir, control the temperature at 15-25°C, add 7.05g (2.0eq) N,N-carbonyldiimidazole (CDI) in batches, and finish adding Stir for 1 hour, the system dissolves, and add 8.40 g (1.0 eq) of 2-amino-1-(2-methoxy-4-methanesulfonamido-5-phenoxybenzene in batches at 15-25 °C Base) ethyl ketone hydrochloride (4), react for 1-2h, TLC monitors the complete reaction of the raw materials, add 50ml of purified water and 50ml of dichloromethane to the reaction system, stir for 30min, separate layers, and concentrate the organic phase to dryness under reduced pressure. Add 50ml of isopropanol to make slurry for 30min, and filter with suction to obtain compound 1 (7.02g, 85.4%).

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Abstract

The invention discloses a method for preparing an iguratimod intermediate. The synthesis route uses formic acid as a starting material, and reacts with N,N-carbonyldiimidazole (CDI) to obtain formyl with high activity through the active ester method. Imidazole, and then react with 2-amino-1-(2-methoxy-4-methanesulfonamido-5-phenoxyphenyl) ethanone hydrochloride to prepare the important intermediate compound of iguratimod . This method has the advantages of safety, environmental protection, simple operation, high yield, good product purity, suitable for industrial production, etc., and is suitable for the preparation of iguratimod intermediates.

Description

technical field [0001] The invention belongs to the technical field of medicine and chemical industry, and in particular relates to a preparation method of formamidomethyl-2-methoxy-4-methanesulfonamido-5-phenoxyphenyl ketone, an important intermediate of Airamod. Background technique [0002] Iguratimod, chemical name N-[3-(formamido)-4-oxo-6-phenoxy-4H-1-benzopyran-7-yl]-methanesulfonamide, is a new A non-steroidal anti-inflammatory drug that selectively inhibits cyclooxygenase-2 (COX-2), and has antipyretic, analgesic, anti-arthritis, and immunomodulatory effects. [0003] In 2012, Simcere Pharmaceuticals was the first to be approved for marketing in China under the product name Edexin; in June of the same year, Japan’s PMDA approved Toyama and Eisai Pharmaceuticals to market the drug under the product names Kolbet Tablets and Careram. [0004] At present, there are relatively few synthetic routes of Alamod. According to literature review and summary, there are mainly th...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C311/08C07C303/40
CPCC07C303/40C07D233/60C07C311/08
Inventor 王栋龙玺国钟健王崇益胡凯徐琳寓胡刚乔文吴廷照
Owner 江苏润安制药有限公司