Preparation method of alpha crystal form of Iguratimod

A crystal form and crystallization technology, applied in organic chemistry methods, organic chemistry, etc., can solve the problems of large ethanol consumption and unfavorable industrialization, and achieve the effect of reducing solvent consumption and facilitating industrial operation

Inactive Publication Date: 2016-10-12
JIANGSU QINGJIANG PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] In order to solve the shortcomings of large amount of ethanol, which is not conducive to industrialization, the present invention uses mixed solvents and other solvents to crystallize, and obtains the α crystal form, which greatly reduces the amount of solvent used and is conducive to industrial operation.

Method used

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  • Preparation method of alpha crystal form of Iguratimod
  • Preparation method of alpha crystal form of Iguratimod
  • Preparation method of alpha crystal form of Iguratimod

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] Embodiment 1: raw material preparation mode

[0020] Add 200g of formamidomethyl-2-hydroxy-4-methanesulfonamido-5-phenoxyphenyl ketone and 300mL of N,N-dimethylformamide (DMF) into a 1L reaction flask. Add 200g of N,N-diformamide dimethyl acetal, 33.2g of glacial acetic acid, and 200mL of DMF successively under stirring. Stir at room temperature and react for 7 hours. After the reaction is over, transfer the material to a 10L glass beaker, stir, add 1L of dichloromethane and 1.5L of purified water to the reactor, and adjust the pH of the system to pH4 with 6N hydrochloric acid; after adjusting the pH, continue stirring to make the flocculent The solid precipitated out completely. After the precipitation is completed, filter until there is no continuous drop, discharge the material, and wash the filter cake successively with dichloromethane, purified water, and absolute ethanol for 3 to 5 minutes each, filter, and dry in vacuo to obtain the crude product of iguratimod....

Embodiment 2

[0023] Take 10g of the refined product of Alamode, put it into a 250mL eggplant-shaped flask; add 90ml of a 1:1 DMF / ethanol mixed solvent, reflux at 90°C for 30 minutes, let it stand for crystallization (room temperature, about 25°C), suction filter, and vacuum dry ( 50°C, vacuum degree Figure 5 shown.

Embodiment 3

[0025] Take 10g of the refined product of Alamode, put it into a 1000mL eggplant-shaped flask; add 350ml of a 1:4 DMF / ethanol mixed solvent, reflux at 90°C for 30 minutes, stand for crystallization (in the refrigerator, about -5°C), suction filter, vacuum Dry (50°C, vacuum degree Figure 6 shown.

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Abstract

The invention discloses a preparation method of an alpha crystal form of Iguratimod. A preparation process is optimized with the method, an ethanol / DMF mixed solvent with better solubility is used, the use quantity of the solvent is reduced, production time is shortened, the cost is reduced, and the method can be applied to industrial production.

Description

technical field [0001] The invention relates to the field of pharmaceutical manufacturing, in particular to a method for preparing crystal form α of antirheumatic drug iguratimod. Background technique [0002] Iguratimod (T-614) is a new type of disease-modifying drug (DMARDs) for the treatment of rheumatoid arthritis jointly developed by Toyama and Eisai Pharmaceuticals. It applied for registration in Japan in September 2003 and was approved for marketing on June 29, 2012. Clinical trials are underway in South Africa, the United Kingdom and South Korea. Iguratimod has been marketed in China for the treatment of rheumatic diseases. [0003] US20070287844 discloses the XRD patterns and manufacturing methods of four iguratimod crystal forms; Japanese patents 5-97840 and 5-125072 disclose crystallization with acetone to obtain the α crystal form, but the solubility of acetone is poor, and 1g of iguratimod The raw material needs about 80ml of solvent, which is not conducive to...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D311/22
CPCC07D311/22C07B2200/13
Inventor 李新辈马玉恒
Owner JIANGSU QINGJIANG PHARMA
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