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Method for preparing high-yield and high-purity Iguratimod intermediate

An intermediate, methanesulfonamide technology, applied in the field of pharmaceutical preparation, can solve the problems of volatile, incomplete reaction, no purification steps, etc., and achieve the effects of easy industrial production, reduced environmental hazards, and good sample stability.

Active Publication Date: 2018-09-28
YANGTZE RIVER PHARM GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] In summary, although the above three methods can obtain brominated products, they all have defects: 1, chloroform that is more toxic is used; 2, methods (1) and (2) use liquid bromine, which is volatile and toxic Big, and reaction by-product is many, is unfavorable for large-scale production; 3, the copper bromide that method (3) uses is not easy to dissolve, and the short reaction time is incomplete, and the time is long and easily produces dibromo; 4, three kinds of methods all do not have refinement step , dibromo compounds and their derivative products are difficult to remove, increasing quality research work

Method used

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  • Method for preparing high-yield and high-purity Iguratimod intermediate
  • Method for preparing high-yield and high-purity Iguratimod intermediate
  • Method for preparing high-yield and high-purity Iguratimod intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1a

[0037] Example 1a (preparation of 3-bromo-7-methanesulfonamide-6-phenoxy-4H-1-benzo-2,3-dihydropyran-4-one crude product)

[0038]To a 50L dry reactor, add 4.5kg ethyl acetate, 3.15kg methanol, 2.1kg copper bromide, stir for 30 minutes, then add 1kg 7-methanesulfonamide-6-phenoxy-4H-1-benzo - The mixture of 2,3-dihydropyran-4-one and 20kg dichloromethane, after the addition is completed, heat up to 25-35°C and stir for 3-4 hours, filter, and the filtrate uses the mass percentage of sodium thiosulfate Wash three times with 2% sodium thiosulfate aqueous solution, 10kg each time, collect the organic phase; then concentrate the organic phase under reduced pressure at 30-60°C to obtain 1.13kg of 3-bromo-7-methanesulfonamide-6-phenoxy The crude product of yl-4H-1-benzo-2,3-dihydropyran-4-one has a yield of 91%, and a purity of 93.8% by HPLC.

Embodiment 1

[0039] Example 1b (preparation of 3-bromo-7-methanesulfonamide-6-phenoxy-4H-1-benzo-2,3-dihydropyran-4-one crude product)

[0040] To a 50L dry reactor, add 4.5kg ethyl acetate, 3.15kg ethanol, 2.1kg copper bromide, stir for 30 minutes, then add 1kg 7-methanesulfonamide-6-phenoxy-4H-1-benzo - The mixture of 2,3-dihydropyran-4-one and 20kg dichloromethane, after the addition is completed, heat up to 25-35°C and stir for 3-4 hours, filter, and the filtrate uses the mass percentage of sodium thiosulfate Wash three times with 2% sodium thiosulfate aqueous solution, 10kg each time, collect the organic phase; then concentrate the organic phase under reduced pressure at 30-60°C to obtain 1.06kg of 3-bromo-7-methanesulfonamide-6-phenoxy The crude product of -4H-1-benzo-2,3-dihydropyran-4-one has a yield of 86%, and a purity of 92.6% by HPLC.

[0041] Example 1c (preparation of 3-bromo-7-methanesulfonamide-6-phenoxy-4H-1-benzo-2,3-dihydropyran-4-one crude product)

[0042] To a 50L d...

Embodiment 2

[0043] Example 2a (purification of 3-bromo-7-methanesulfonamide-6-phenoxy-4H-1-benzo-2,3-dihydropyran-4-one crude product)

[0044] Into a 100L dry reaction kettle, add 40kg of petroleum ether, lower the temperature to 0-10°C, and then dropwise add the 3-bromo-7-methanesulfonamide-6-phenoxy-4H-1-benzene prepared in Example 1a The mixed solution of crude and-2,3-dihydropyran-4-one and 6kg of dichloromethane, after dropping, keep stirring for 4h, filter, wash the filter cake with 1kg of petroleum ether, collect the filter cake, and heat it at 30~40℃ Dry under vacuum, weigh and check the purity to obtain a total of 1.07kg of 3-bromo-7-methanesulfonamide-6-phenoxy-4H-1-benzo-2,3-dihydropyran-4-one , the yield was 95%, and the HPLC detection purity was 96.4%.

[0045] Example 2b (purification of 3-bromo-7-methanesulfonamide-6-phenoxy-4H-1-benzo-2,3-dihydropyran-4-one crude product)

[0046] Into a 100L dry reactor, add 40kg of petroleum ether, lower the temperature to 0-10°C, and...

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Abstract

The invention discloses a method for preparing an Iguratimod intermediate, i.e., 3-bromo-7-methsulfonamido-6-phenoxy-4H-1-benzo-2,3-dihydropyran-4-one. The method comprises the following steps: (1) dissolving cupric bromide in ethyl acetate and C1-C4 lower alkanol, and carrying out stirring for at least 30 minutes; (2) adding a dichloromethane solution of 7-sulfonamido-6-phenoxy-4H-1-benzo-2,3-dihydropyran-4-one into the solution obtained in the step (1), heating the temperature of the mixture to 20 DEG C to 50 DEG C with stirring, and performing a reaction for 2 to 6 hours; (3) carrying out filtering, washing filter liquor with an aqueous solution of sodium thiosulfate, and concentrating an organic phase, so as to obtain a crude product of the intermediate; and (4) carrying out refining with dichloromethane and petroleum ether, thereby obtaining a refined intermediate. The method is convenient in operation, high in conversion ratio and high in product purity, and the purity can reach96% or more.

Description

technical field [0001] The invention belongs to the field of medicine preparation, in particular, the invention relates to a high-yield and high-purity intermediate of iguratimod, namely 3-bromo-7-methanesulfonamide-6-phenoxy-4H-1-benzene The preparation method of -2,3-dihydropyran-4-one. Background technique [0002] Iguratimod's generic name: Iguratimod, chemical name: N-[3-(formamido)-4-oxo-6-phenoxy-4H-1-benzopyran-7-yl]- Methanesulfonamide, English name: N-[3-(formylamino)-4-oxo-6-phenoxy-4H-1-benzopyran-7-yl]-methanesulfona mide, is a therapeutic class developed by Japan Toyama Company Drugs for rheumatoid arthritis and osteoarthritis. [0003] In the published materials, there are few reports on the preparation process of iguratimod. Basically, 4-chloro-3-nitroanisole is used as the starting material to prepare iguratimod through multi-step reactions. Wherein there are 3 routes using bromination reaction to prepare 3-bromo-7-methanesulfonamide-6-phenoxy-4H-1-benzo-...

Claims

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Application Information

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IPC IPC(8): C07D311/22
CPCC07D311/22
Inventor 赵佳徐浩宇蔡伟罗宏军韩林韩冬李旦尹必喜
Owner YANGTZE RIVER PHARM GRP CO LTD
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