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Preparation method of leflunomide

The technology of leflunomide and methylisoxazole is applied in the field of new technology for the preparation of pharmaceutical raw material leflunomide, which can solve the problems of increased production cost, waste of raw materials, exceeding the standard and the like, and achieves reduction of production cost and process pollution. The effect of small size and less waste liquid

Active Publication Date: 2020-06-05
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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  • Preparation method of leflunomide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] 5-Methylisoxazole-4-carboxylic acid

[0035] 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%.

[0036] Leflunomide

[0037] 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-trifluoromethy...

Embodiment 2

[0039] 5-Methylisoxazole-4-carboxylic acid

[0040] 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%.

[0041] Leflunomide

[0042]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-trifluoromethylanili...

Embodiment 3

[0044] 5-Methylisoxazole-4-carboxylic acid

[0045] 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%.

[0046] Leflunomide

[0047] 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-trifluoromethylanilin...

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Abstract

The invention relates to a novel preparation process of a medicine bulk drug leflunomide. Ethyl acetoacetate is used as a raw material to be cyclized with hydroxylamine hydrochloride to obtain leflunomide. According to the process, the content of 3-methyl isomer and the content of4-trifluoromethylaniline in the leflunomide product can be better controlled, the yield is higher, and the process is simpler. The process generates less industrial wastewater and waste gas, is more environment-friendly, and can effectively reduce the production cost and corrosion to 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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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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