Preparation method of iguratimod intermediate

A technology of intermediates and equations, applied in the preparation of sulfonic acid amide, organic chemistry, etc., can solve the problems that sodium azide is prone to explosion, unfavorable to industrial production, and prone to side reactions, etc. Response and operation are less difficult

Active Publication Date: 2021-01-12
江苏润安制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0013] The bromine used in this route has high activity, is difficult to operate, and is prone to side r...

Method used

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  • Preparation method of iguratimod intermediate
  • Preparation method of iguratimod intermediate
  • Preparation method of iguratimod intermediate

Examples

Experimental program
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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 preparation method of an iguratimod intermediate. The preparation method comprises the following steps: by using formic acid as a starting raw material, subjecting formic acid to reacting with N,N-carbonyldiimidazole (CDI) via an active ester method to obtain formylimidazole with higher activity, and subjecting the formylimidazole to reacting with 2-amino-1-(2-methoxy-4-methanesulfonamido-5-phenoxyphenyl)ethanone hydrochloride to obtain an important intermediate compound of iguratimod. The method has the advantages of being safe, environmentally friendly, easy to operate, high in yield, good in product purity, suitable for industrial production and the like, and is suitable for preparing the iguratimod intermediate.

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 Airamode. 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 t...

Claims

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Application Information

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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
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