Novel environment-friendly process for preparing leflunomide

A technology for leflunomide and trifluoromethylaniline is applied in the field of green technology for preparing leflunomide, and can solve the problems of a large amount of industrial waste gas and acidic waste water, affecting the quality of leflunomide products, serious industrial pollution and the like, Achieve stable product quality, high yield and high regioselectivity

Active Publication Date: 2014-04-16
CHANGZHOU YABANG PHARMA
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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, increases production costs, but also 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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  • Novel environment-friendly process for preparing leflunomide
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Examples

Experimental program
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Effect test

Embodiment 1

[0024] Example 1: Ethyl 5-methylisoxazole-4-carboxylate (III)

[0025] Take ethyl N,N-dimethylaminomethyleneacetoacetate (185g, 1.0mol) and add it to 600ml of methanol, start stirring, start freezing, cool the reaction system to -5°C, and slowly add 50% An aqueous solution of hydroxylamine (66 g, 1.0 mol) was added dropwise to keep the reaction system stable at -5°C to 0°C. After the dropwise addition, raise the temperature to 10°C to 15°C to continue the reaction until the raw materials disappear. After the reaction was completed, the reaction solution (200ml×3) was extracted with dichloromethane, and the organic phases were combined. The organic phase was washed once each with saturated aqueous sodium bicarbonate solution (300ml) and water (300ml), dried over anhydrous sodium sulfate, and concentrated to obtain 143g of milky white liquid with a yield of 92.2%.

Embodiment 2

[0026] Example 2: 5-Methylisoxazole-4-carboxylic acid (IV)

[0027] Add ethyl 5-methylisoxazole-4-carboxylate (155g, 1.0mol) into a mixed solvent of 36% hydrochloric acid (300ml) and glacial acetic acid (150ml), start stirring, and heat to reflux until the raw material disappears . After the reaction was completed, the solvent was evaporated to obtain a taupe solid, which was added to toluene (150ml), heated to 90°C to 100°C to dissolve, and after cooling to room temperature, solid crystals were precipitated, filtered, the filter cake was washed with toluene and water, and dried to obtain White solid 82g, yield 64.6%.

Embodiment 3

[0028] Embodiment 3: Leflunomide (I)

[0029]5-Methylisoxazole-4-carboxylic acid (127g, 1.0mol) was dissolved in dichloromethane (600ml), and after cooling to -5°C in an ice-water bath, triethylamine (106g, 1.05mol) was slowly added, Keep the temperature not exceeding 0°C. After the addition is complete, slowly add a solution of methyl chloroformate (94.5g, 1.0mol) in dichloromethane (200ml) dropwise, and keep the temperature not exceeding 0°C during the dropwise addition. After the dropwise addition was continued at 0°C for half an hour, a solution of 4-trifluoromethylaniline (169g, 1.05mol) in dichloromethane (200ml) was added dropwise, keeping the temperature below 0°C during the dropwise addition. After the dropwise addition, continue to react at -5°C to 0°C until the raw materials disappear. After the reaction was completed, the reaction solution was washed with aqueous sodium bicarbonate solution (300ml×2), water (300ml×2), and saturated brine (300ml×2), and the organic...

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Abstract

The invention relates to a novel environment-friendly process for preparing leflunomide, which can better control the content of 3-methylisomer and 4-trifluoromethylaniline in the leflunomide, has higher yield and is simpler. The process generates little industrial effluent and exhaust gas, is more environment-friendly and can effectively reduce 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 (leflunomide) is the first new drug approved specifically for the treatment of rheumatoid arthritis in the past ten years. 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. Vario...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D261/18A61P29/00A61P19/02
Inventor 陈再新夏正君蒋龙林送荆小燕史惠忠马堰启于鸿飞王汉元
Owner CHANGZHOU YABANG PHARMA
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