Method for synthesizing intermediate impurities of igutimod

A technology for intermediates and impurities, applied in the field of chemical drug synthesis, can solve the problems of difficulty in separation, affecting the purity of finished products, unable to obtain products with sufficient purity, etc., and achieve the effect of high yield and good purity

Pending Publication Date: 2019-03-01
CHANGZHOU VOCATIONAL INST OF ENG +1
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

But easily produce a kind of process impurity 3-(N,N-dimethylsulfonyl) amino-4-phenoxyanisole (5) in its preparation process, this impurity can participate in follow-up reaction, finally generates finished product ( 1) impurity, i.e. N-[3-(formamido)-4-oxygen-6-phenoxy-4H-1-benzene well pyran-7-yl] dimethanesulfonamide (6), which affects purity of finished product
In order to study the impurities of Iguratimod intermed

Method used

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  • Method for synthesizing intermediate impurities of igutimod
  • Method for synthesizing intermediate impurities of igutimod
  • Method for synthesizing intermediate impurities of igutimod

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] The first step: the preparation of 3-iodo-4-methoxy-anisole (7):

[0031] Take 4.6mmol 5-methoxy-2-phenoxyaniline and 13.9mmol p-toluenesulfonic acid, add 40mL acetonitrile to dissolve, add dropwise 10mL aqueous solution containing 9.2mmol sodium nitrite and 9.2mmol potassium iodide at room temperature. Stir at room temperature for 5 hours, and TLC monitors that the reaction is complete. Add 50 mL of water, extract with methyl tert-butyl ether (30 mL×2), wash with 10% sodium thiosulfate solution, and dry over anhydrous sodium sulfate. Suction filtration, and the filtrate was concentrated to obtain a crude product. Purified by column chromatography (petroleum ether: ethyl acetate = 10:1 elution) to obtain 0.97 g of a light yellow oily substance with a yield of 65.2%. 1 H-NMR (600MHz, CDCl 3 )δ: 7.38(dd, 1H, J=2.4Hz, Ar-H), 7.15-7.18(m, 1H, Ar-H), 6.87(d, 4H, J=2.7Hz, Ar-H), 6.85( d,1H,J=2.0Hz,Ar-H),6.83(d,1H,J=1.5Hz,Ar-H),3.81(s,3H,-OCH 3 ).

[0032] The second ste...

Embodiment 2

[0035] The first step: the preparation of 3-iodo-4-methoxy-anisole (7) is the same as the first step in Example 1.

[0036] The second step: the preparation of intermediate impurity 3-(N,N-dimethylsulfonyl)amino-4-phenoxyanisole (5):

[0037] Dissolve 2.2 mmol of dimethylsulfonamide in 4 mL of solvent xylene, add 2 mmol of 3-iodo-4-methoxy-anisole, 0.2 mmol of Cu(OAc) 2 , 0.4mmol 1,10-phenanthroline, 4mmol potassium carbonate, nitrogen protection, heated to 120 ° C for 5 hours, TLC monitoring complete reaction. Cool to room temperature, add 20 mL of ethyl acetate, filter, wash the filter cake with ethyl acetate, combine the organic phases, wash with saturated brine, and dry over anhydrous sodium sulfate. Suction filtration, and the filtrate was concentrated to obtain a crude product. Column chromatography (petroleum ether: ethyl acetate = 3:1 elution) gave a white solid with a yield of 68%.

Embodiment 3

[0039] The first step: the preparation of 3-iodo-4-methoxy-anisole (7) is the same as the first step in Example 1.

[0040] The second step: the preparation of intermediate impurity 3-(N,N-dimethylsulfonyl)amino-4-phenoxyanisole (5):

[0041] Dissolve 2.4 mmol of dimethylsulfonamide in 3 mL of solvent DMSO, add 2 mmol of 3-iodo-4-methoxy-anisole, 0.2 mmol of Cu(OAc) 2 ·H 2 O, 0.4mmol 1,10-phenanthroline, 4mmol potassium carbonate, nitrogen protection, heated to 120°C for 5 hours, TLC monitoring complete reaction. Cool to room temperature, add 20 mL of ethyl acetate, filter, wash the filter cake with ethyl acetate, combine the organic phases, wash with saturated brine, and dry over anhydrous sodium sulfate. Suction filtration, and the filtrate was concentrated to obtain a crude product. Column chromatography (petroleum ether: ethyl acetate = 3:1 elution) gave a white solid with a yield of 72%.

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Abstract

The invention discloses a method for synthesizing intermediate impurities of igutimod, and belongs to the field of chemical drug synthesis. The method comprises the steps that 3-iodo-4-phenoxy-anisoleis obtained through Sandmeyer reaction iodination with an intermediate 5-methoxy-2-phenoxyaniline as a starting material, and 3-(N,N-dimethylsulfonyl)amino-4-phenoxyanisole is obtained through catalytic reaction of copper. The method has the advantages of simple steps, high yield, good product purity and the like, and helps the study of the igutimod and the intermediate impurities thereof, and control over final product quality.

Description

technical field [0001] The invention belongs to the technical field of chemical drug synthesis, more specifically, relates to a key intermediate impurity 3-(N,N-dimethylsulfonyl)amino-4-phenoxybenzene of a new antirheumatic drug iguratimod Synthesis of Methyl Ether. Background technique [0002] Iguratimod is a non-steroidal anti-inflammatory drug jointly developed by Japan Toyama and Eisai Pharmaceutical Company, the chemical name is N-[3-(formamido)-4-oxo-6-phenoxy- 4H-1-benzopyran-7-yl]methanesulfonamide (1) is a novel anti-rheumatic small molecule drug. Existing literature reports that the synthesis of iguratimod is obtained by using 4-chloro-3-nitroanisole (2) as a raw material through 7 steps of reaction, as shown in the reaction formula 1. Among them, 3-methanesulfonamido-4-phenoxyanisole (4) is the key intermediate. But easily produce a kind of process impurity 3-(N,N-dimethylsulfonyl) amino-4-phenoxyanisole (5) in its preparation process, this impurity can partic...

Claims

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Application Information

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IPC IPC(8): C07C303/40C07C311/48
CPCC07C41/22C07C303/40C07C311/48C07C43/29
Inventor 刘巧云周海平杨怡李耀中陈文华高雨琼杨小林朱小华陈剑赵金亮
Owner CHANGZHOU VOCATIONAL INST OF ENG
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