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Preparation method of Iguratimod formylation intermediates

A technology of Aylamod formyl and intermediates, which is applied in the field of chemical drug synthesis, can solve the problems of slow reaction rate, many impurities, and low yield, and achieve the effects of fast reaction speed, high yield, and improved purity

Active Publication Date: 2018-11-02
康美(北京)药物研究院有限公司 +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The purpose of the present invention is to provide a preparation method of iguratimod formylation intermediate to solve the technical problems of slow reaction rate, many impurities and low yield in the prior art

Method used

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  • Preparation method of Iguratimod formylation intermediates
  • Preparation method of Iguratimod formylation intermediates
  • Preparation method of Iguratimod formylation intermediates

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preparation example Construction

[0041] The invention provides a method for preparing an iguratimod formylation intermediate, comprising the steps of:

[0042] Reaction of formic acid, sodium formate and pivaloyl chloride to obtain a mixed anhydride, adding compound I for carbamoylation reaction to obtain the formylation intermediate of iguratimod;

[0043] Wherein, the structural formula of the compound I is The structural formula of the iguratimod formylation intermediate is

[0044] The invention adopts formic acid and pivaloyl chloride to prepare mixed acid anhydride, because the formic acid is dissolved in acetone, the reaction with pivaloyl chloride is a homogeneous reaction, the reaction speed is fast, and the conversion rate is high. Moreover, formic acid maintains the relatively acidic environment of the system, avoids the side reaction of the self-condensation reaction of the α-aminoketone compound in the raw material under alkaline conditions to generate piperazine compounds, improves the yield...

Embodiment 1

[0068] A preparation method for an iguratimod formylation intermediate, comprising the steps of:

[0069] (A) Add 1.43kg of formic acid and 2.64kg of sodium formate into 30L of acetone, stir at 18-20°C, and after the dispersion is uniform, add 3.74kg of pivaloyl chloride, stir and react for 1 hour to obtain a system containing mixed anhydrides;

[0070] (B) Add 12.02 kg of 2-amino-1-(2-methoxy-4-methanesulfonamido-5-phenoxy)phenylethanone hydrochloride to the reaction system obtained in step (A) (Compound I) and 2.64kg of sodium formate, the temperature is controlled at 10-20°C, stirred for 3 hours, and the reaction is terminated;

[0071] (C) Reduce the temperature of the system obtained in step (B) by 10±5°C, and slowly add water under stirring conditions, keeping the temperature during the water addition process not exceeding 20°C, after adding water, control the temperature to 15±5°C, and stir After 1h, filter, wash the filter cake with water, and collect the filter cake;...

Embodiment 2

[0073] A preparation method for an iguratimod formylation intermediate, comprising the steps of:

[0074] (A) Add 2.30kg of formic acid and 5.10kg of sodium formate into 48L of acetone, stir at 18-20°C, after the dispersion is uniform, add 9.04kg of pivaloyl chloride, stir for 1 hour, and obtain a system containing mixed anhydride;

[0075] (B) Add 12.02 kg of 2-amino-1-(2-methoxy-4-methanesulfonamido-5-phenoxy)phenylethanone hydrochloride to the reaction system obtained in step (A) (Compound I) and 5.10kg of sodium formate, the temperature is controlled at 10-20°C, stirred and reacted for 3h, and the reaction is terminated;

[0076] (C) Reduce the temperature of the system obtained in step (B) by 10±5°C, and slowly add water under stirring conditions, keeping the temperature during the water addition process not exceeding 20°C, after adding water, control the temperature to 15±5°C, and stir After 1h, filter, wash the filter cake with water, and collect the filter cake; heat ...

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Abstract

The invention relates to the technical field of synthesis of chemical drugs, in particular to a preparation method of Iguratimod formylation intermediates. The preparation method comprises the following steps: mixed acid anhydride is prepared from formic acid, sodium formate and pivaloyl chloride, a compound I is added for carbamylation, and the Iguratimod formylation intermediates are obtained. Mixed acid anhydride is prepared from formic acid and pivaloyl chloride, the reaction with pivaloyl chloride is a homogeneous reaction, reaction speed is high, and conversion rate is high; the relatively acidic environment of the system is kept by formic acid, side reactions in which piperazine compounds are generated from alpha-aminoketone compounds in raw materials through own condensation reaction under alkaline conditions are avoided, yield is increased, impurities are reduced, and purity is improved. The Iguratimod formylation intermediates prepared with the method are high in purity and can be used for preparing Iguratimod.

Description

technical field [0001] The invention relates to the technical field of chemical drug synthesis, in particular to a preparation method of an iguratimod formylation intermediate. Background technique [0002] Iguratimod (T-614) is a non-steroidal anti-inflammatory drug (NSAIDs) whose chemical name is 3-formamido-7-methanesulfonyl-6-phenoxy-4H-benzene Pyran-4-one is a disease-modifying drug for the treatment of rheumatoid arthritis and osteoarthritis jointly developed by Japan Toyama and Eisai Pharmaceutical Company. Compared with previous disease-modifying drugs, it is characterized by rapid effect, and its curative effect is equal to that of high-efficiency antirheumatic drugs (SAP, MTX), but its toxicity is low. Its mechanism of action is related to inhibiting the release of arachidonic acid, bradykinin, IL-1 and IL-6. Studies have shown that in vitro, T-614 can affect the expression of pro-inflammatory response factors (Preinflammatory Response Cytokines, PIRC) in synovio...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C303/40C07C311/08
CPCC07C303/40C07C311/08
Inventor 廖凯俊陶泽东董婧婧许冬瑾马兴田
Owner 康美(北京)药物研究院有限公司
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