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Preparation method of 5-methyl isoxazole-4-ethyl formate

A technology of methylisoxazole and ethyl formate, applied in the field of medicinal chemistry, can solve the problems of high regioselectivity, reduced product purity, low isomer content, etc. high rate effect

Inactive Publication Date: 2012-11-21
DALIAN UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

3-Methylisoxazole-4-carboxylic acid ethyl ester introduces the related substance Leflunomide-3-methyl isomerization (II) into the final leflunomide product through hydrolysis, chlorination and acylation, which reduces the product Purity, Affects Quality
The advantage of this method is that the regioselectivity of the reaction is high and the isomer content is low; the disadvantage is that the reaction yield is low

Method used

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  • Preparation method of 5-methyl isoxazole-4-ethyl formate

Examples

Experimental program
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Effect test

Embodiment 1

[0039] Embodiment 1: the preparation of ethyl 2-ethoxymethylene acetoacetate (III)

[0040] Add 133.1 g (1.02 mol) of ethyl acetoacetate, 184.6 g (1.24 mol) of triethyl orthoformate, and 256.2 g (2.01 mol) of ethyl orthoformate in a 1000 ml four-neck flask equipped with a rectifying column, heat and stir to 115-125°C, during the reaction process, by-products with low boiling points (≤100°C) are simultaneously fractionated. After 2 hours of reaction, TLC detection (ethyl acetate:petroleum ether=1:2 as developer) stopped the reaction without raw material, and collected 106-1 10°C / 0.69kPa fraction by vacuum distillation to obtain light yellow liquid 2-ethoxymethylene 156 g of ethyl acetoacetate, the yield was 84.7%, and the content of ethyl 2-ethoxymethyleneacetoacetate was 99.10% (detected by gas chromatography).

Embodiment 2

[0041] Embodiment 2: Preparation of ethyl 2-ethoxymethylene acetoacetate (III)

[0042] Add 260.5g (2.00mol) of ethyl acetoacetate, 362.6g (2.44mol) of triethyl orthoformate, and 521.1g (4.09mol) of acetic anhydride in a 2000ml four-necked bottle equipped with a rectifying column, heat and stir to 113-121°C, low boiling point (≤100°C) by-products are distilled out during the reaction. After 2 hours of reaction, TLC detection (ethyl acetate:petroleum ether=1:2 as developing solvent) stopped the reaction without raw materials, and collected fractions at 106-108°C / 0.67kPa by distillation under reduced pressure to obtain light yellow liquid 2-ethoxymethyleneacetyl Ethyl acetate was 309.5g, the yield was 83.1%, and the content of ethyl 2-ethoxymethyleneacetoacetate was 99.2% (detected by gas chromatography).

Embodiment 3

[0043] Example 3: Preparation of ethyl 5-methylisoxazole-4-carboxylate (IV) Hydroxylamine hydrochloride 2.52g (0.036mol) and 9ml of water were stirred and dissolved at 5°C, and sodium hydroxide was slowly added under stirring to adjust the pH of the solution to 12.1. Prepare 6.14 g (0.033 mol) of ethyl 2-ethoxymethylene acetoacetate mixed with 7 ml of absolute ethanol solution, add dropwise the aqueous solution of hydroxylamine hydrochloride and sodium hydroxide prepared above at room temperature, and keep stirring at 25 ° C for 4 h ( The progress of the reaction was tracked by TLC, ethyl acetate:petroleum ether=1:4 as the developing solvent). After the reaction was completed, the reaction solution was divided into two layers, and the upper organic phase solution was separated; the lower aqueous phase solution was extracted with dichloromethane (2×50ml), and the organic phases were combined. The organic phase was washed with water (4 × 50ml) until the aqueous layer was neutra...

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Abstract

The invention relates to a preparation method of 5-methyl isoxazole-4-ethyl formate, characterized by using cheap and easily available ethyl acetoacetate and triethyl orthoformate as raw materials and condensing the raw materials to prepare 2-ethoxymethylene ethyl acetoacetate, then reacting 2-ethoxymethylene ethyl acetoacetate with an aqueous solution of hydroxylamine hydrochloride and inorganic base in an organic solvent to prepare 5-methyl isoxazole-4-ethyl formate, wherein the total yield of the two steps is higher than 78.0%, the content is higher than 99.0%, and the content of the isomer 3-methyl isoxazole-4-ethyl formate is less than 1.0%. The preparation method has the advantages of low production cost, low content of the isomer 3-methyl isoxazole-4-ethyl formate, simple process, and mild reaction conditions, and is suitable for industrial production.

Description

technical field [0001] The invention relates to a preparation method of ethyl 5-methylisoxazole-4-carboxylate, a key intermediate of leflunomide, which belongs to the field of medicinal chemistry and can be used for preparing high-purity leflunomide. Background technique [0002] Leflunomide (I) is a new type of immunomodulator with multiple physiological activities, which belongs to isoxazole derivatives, and its chemical name is N-(4-trifluoromethylbenzene)-5-methylisoxan Azole-4-carboxamide is mainly used in the treatment of rheumatoid arthritis. Leflunomide can not only relieve the symptoms of rheumatoid arthritis, but also effectively inhibit the development of the disease, and has low toxic and side effects. [0003] [0004] Ethyl 5-methylisoxazole-4-carboxylate is an essential raw material for the synthesis of leflunomide. It undergoes three steps of hydrolysis, chlorination and acylation to obtain leflunomide. The route is shown in the figure below: [0005] ...

Claims

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Application Information

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IPC IPC(8): C07D261/18
Inventor 孟庆伟余志勇李智刘召鹏
Owner DALIAN UNIV OF TECH
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