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Preparation method of Iguratimod intermediate

A technology for intermediates and compounds, which is applied in the field of chemical drug synthesis, can solve the problems of difficult handling of iron sludge, large environmental pollution, and difficulty in obtaining raw materials, and achieves the effects of high environmental protection, high safety and less difficulty in reaction operation.

Pending Publication Date: 2022-05-27
常州佳德医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Wherein, N-(5-methoxy-2-phenoxyphenyl)methanesulfonamide is a key intermediate in the synthetic technique of iguratimod, while in the prior art, N-(5-methoxy- In the preparation process of 2-phenoxyphenyl)methanesulfonamide, there are raw materials that are not easy to obtain, and the iron sludge produced in the process of reducing nitro by iron powder is difficult to deal with, and the environmental pollution is large.

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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Effect test

Embodiment 1

[0027] N-(5-methoxy-2-phenoxyphenyl)methanesulfonamide (compound IV) is prepared by the preparation method of an Iguratimod intermediate of the present invention, and the specific operation is as follows:

[0028] Step S1: add 4g p-nitroanisole (compound I), 0.26g cuprous chloride, 2.2g methoxyamine hydrochloride and 60mL DMF into a 100mL reaction flask, add 16g potassium tert-butoxide below 30°C The temperature was raised to 60-65 °C for 2 hours, and then cooled to room temperature; the reaction solution was poured into 150 mL of ice water, extracted 3 times with 50 mL of ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 3.0 g of compound II crude product ; Add 600 mL of n-hexane to the crude compound II, heat under reflux for 1 hour, filter while hot, and dry the filter cake to obtain 2.1 g of pure compound II, yield: 47.8%. as attached Figures 1 to 2 Shown: the mass spectrum data of compound II is MS(ESI) m / z: 1...

Embodiment 2

[0032] N-(5-methoxy-2-phenoxyphenyl)methanesulfonamide (compound IV) is prepared by the preparation method of an Iguratimod intermediate of the present invention, and the specific operation is as follows:

[0033]Step S1: add 4g p-nitroanisole (compound I), 0.52g copper acetate, 6.6g methoxyamine hydrochloride and 60mL DMF to the 100mL reaction flask, add 7.7g sodium methoxide below 30°C; The reaction was carried out at 70-75 °C for 2 hours, and then cooled to room temperature; the reaction solution was poured into 150 mL of ice water, extracted three times with 50 mL of ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 3.6 g of compound II crude product; 600 mL of n-hexane was added to the crude product II, heated to reflux for 1 hour, filtered while hot, and the filter cake was suctioned to dryness to obtain 2.6 g of pure compound II, yield: 59%. The mass spectrum data of pure compound II is MS(ESI) m / z: 169 (M+H)+...

Embodiment 3

[0037] N-(5-methoxy-2-phenoxyphenyl)methanesulfonamide (compound IV) is prepared by the preparation method of an Iguratimod intermediate of the present invention, and the specific operation is as follows:

[0038] Step S1: add 4g p-nitroanisole (compound I), 0.26g cuprous chloride, 3.32g methoxyamine salt and 60mL DMF to the 100mL reaction flask, add 9.7g sodium ethoxide below 30°C; The reaction was carried out at 75-80°C for 2 hours, and then cooled to room temperature; the reaction solution was poured into 150 mL of ice water, extracted three times with 50 mL of ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 3.4 g of compound II crude product; 600 mL of n-hexane was added to the crude product II, heated under reflux for 1 hour, filtered while hot, and the filter cake was suction-dried to obtain 2.5 g of pure compound II, yield: 57%. The mass spectrum data of pure compound II is MS(ESI) m / z: 169 (M+H)+, which is ...

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Abstract

The invention discloses a preparation method of an Iguratimod intermediate, which comprises the following steps: by taking p-nitroanisole as a raw material, carrying out substitution nucleophilic substitution (VNS) on p-nitroanisole and methoxyamine hydrochloride in the presence of a copper salt catalyst and an acid-binding agent to generate 5-methoxy-2-nitroaniline (compound II); the synthesis method comprises the following steps: carrying out a nucleophilic substitution reaction on 5-methoxy-2-nitroaniline (compound II) and methanesulfonyl chloride to generate a compound III, etherifying the compound III and phenol under the catalysis of a copper salt to generate N-(5-methoxy-2-phenoxy phenyl) methane sulfonamide (compound IV), and reagents used in the synthesis process are non-highly toxic products and are easy to obtain; no iron powder is used in the reaction process, so that iron mud which is harmful to the environment is not generated, and the environmental protection property is high; the reaction operation difficulty is small, the safety is high, and a foundation is laid for industrial preparation of Iguratimod drugs.

Description

technical field [0001] The invention relates to the technical field of chemical drug synthesis, in particular to a preparation method of an Ilarmod intermediate. Background technique [0002] Rheumatoid arthritis (RA) is a chronic, inflammatory synovitis-based systemic disease of unknown etiology. It is characterized by polyarticular, symmetrical, and aggressive joint inflammation of the facet joints of the hands and feet, often accompanied by extra-articular organ involvement and positive serum rheumatoid factor, which can lead to joint deformity and loss of function. iguratimod is a novel drug for the treatment of rheumatoid arthritis (RA) and osteoarthritis (OA), which can significantly reduce the inflammatory response, not only selectively inhibit cyclooxygenase COX-2, but also inhibit inflammation The production of cytokines, tumor necrosis factor, lymphocytes and immunoglobulins has autoimmune regulatory effects, and the onset of action is rapid. It has better efficac...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C303/38C07C303/40C07C311/08C07C213/02C07C217/84
CPCC07C303/38C07C303/40C07C213/02C07C217/84C07C311/08
Inventor 张超吕列超邵翀
Owner 常州佳德医药科技有限公司
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