A kind of preparation method of leflunomide

A technology of leflunomide and trifluoromethylaniline, which is applied in the field of new preparation technology of pharmaceutical raw material leflunomide, can solve the problems of equipment corrosion, waste of raw materials, a large amount of industrial waste gas and acid waste water, etc., and achieves waste generation. Less liquid and less process pollution

Active Publication Date: 2021-08-20
煌途医药(无锡)有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The use of thionyl chloride in this method not only causes a large amount of industrial waste gas and acidic wastewater, serious industrial pollution, but also serious equipment corrosion
In addition, some documents use more than 2 times the molar amount of 4-trifluoromethylaniline to condense with acid chloride. This method not only brings waste of raw materials, but also increases production costs, and makes 4-trifluoromethylaniline in the final leflunomide product The excessive content of methylaniline affects the quality of leflunomide products

Method used

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  • A kind of preparation method of leflunomide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] 5-Methylisoxazole-4-carboxylic acid

[0034] Dissolve 50 g of ethyl acetoacetate in DMF-DMA, cool to -20°C, slowly add 10.1 g of sodium hydrogen, rise to room temperature and react for 3 hours, add water to precipitate a solid, stir, filter and dry to obtain a dimethylenamine structure. Ethyl N, N-dimethylaminomethylene acetoacetate was cooled to -5°C in ethanol, and 26.7 g of hydroxylamine hydrochloride was added in an equiproportional molar amount, and reacted at room temperature until the raw materials disappeared. After the reaction was completed, the solvent was spin-dried, and 30 % hydrochloric acid aqueous solution was heated to reflux, evaporated to dryness, and recrystallized from toluene to obtain 48 g of 5-methylisoxazole-4-carboxylic acid, with a yield of 98.3%.

[0035] Leflunomide

[0036] Put 20g of 5-methylisoxazole-4-carboxylic acid in dichloromethane, cool to 0°C, add triethylamine and CDI25.5g, stir for half an hour, then add 25.3g of 4-trifluorometh...

Embodiment 2

[0038] 5-Methylisoxazole-4-carboxylic acid

[0039] Dissolve 50 g of ethyl acetoacetate in DMF-DMA, cool to -20°C, slowly add 10.1 g of sodium hydrogen, rise to room temperature and react for 3 hours, add water to precipitate a solid, stir, filter and dry to obtain a dimethylenamine structure. Ethyl N, N-dimethylaminomethylene acetoacetate was cooled to -5°C in ethanol, and 26.7 g of hydroxylamine hydrochloride was added in an equiproportional molar amount, and reacted at room temperature until the raw materials disappeared. After the reaction was completed, the solvent was spin-dried, and 30 % hydrochloric acid aqueous solution was heated to reflux, evaporated to dryness, and recrystallized from toluene to obtain 48 g of 5-methylisoxazole-4-carboxylic acid, with a yield of 98.3%.

[0040] Leflunomide

[0041]Put 20g of 5-methylisoxazole-4-carboxylic acid in dichloromethane, cool to 0°C, add triethylamine and CDI38.3g, stir for half an hour, add 25.3g of 4-trifluoromethylanil...

Embodiment 3

[0043] 5-Methylisoxazole-4-carboxylic acid

[0044] Dissolve 50 g of ethyl acetoacetate in DMF-DMA, cool to -20°C, slowly add 10.1 g of sodium hydrogen, rise to room temperature and react for 3 hours, add water to precipitate a solid, stir, filter and dry to obtain a dimethylenamine structure. Ethyl N, N-dimethylaminomethylene acetoacetate was cooled to -5°C in ethanol, and 26.7 g of hydroxylamine hydrochloride was added in an equiproportional molar amount, and reacted at room temperature until the raw materials disappeared. After the reaction was completed, the solvent was spin-dried, and 30 % hydrochloric acid aqueous solution was heated to reflux, evaporated to dryness, and recrystallized from toluene to obtain 48 g of 5-methylisoxazole-4-carboxylic acid, with a yield of 98.3%.

[0045] Leflunomide

[0046] Put 20g of 5-methylisoxazole-4-carboxylic acid in dichloromethane, cool to 0°C, add triethylamine and CDI25.5g, stir for half an hour, add 38g of 4-trifluoromethylanili...

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Abstract

The invention relates to a new preparation process of leflunomide, a medical raw material drug, which uses ethyl acetoacetate as a raw material to cyclize with hydroxylamine hydrochloride to obtain leflunomide. This process can not only better control the content of 3-methyl isomer and 4-trifluoromethylaniline in the leflunomide product, but also has a higher yield and is more concise. The process produces less industrial waste water and waste gas, is more environmentally friendly, and can effectively reduce production costs and corrosion of equipment.

Description

technical field [0001] The invention relates to a preparation process of a pharmaceutical raw material drug, in particular to a new preparation process of a medical raw material drug leflunomide. Background technique [0002] Leflunomide is the first new drug approved specifically for the treatment of rheumatoid arthritis in more than a decade. This product has immunosuppressive and anti-inflammatory effects, and its mechanism of action is novel. It inhibits cell adhesion and the activity of acid kinase, affects the information transmission of cytokines, and inhibits the activity of dihydroorotate dehydrogenase, thereby inhibiting the relationship between rheumatoid arthritis and rheumatoid arthritis. Proliferation of activated lymphocytes associated with the pathogenesis of arthritis. Animal experiments and clinical results show that leflunomide inhibits local inflammation and connective tissue hyperplasia as well as the systemic response of arthritis. Various signs and s...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D261/18
CPCC07D261/18
Inventor 廖文英
Owner 煌途医药(无锡)有限公司
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