The preparation method of nifuratel

A technology of nifuratel and molar ratio, applied in the field of preparation of pharmaceutical compounds

Active Publication Date: 2016-05-11
HUNAN FANGSHENG PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0016] The technical problem to be solved by the present invention is to overcome the above disadvantages, research and design a simple and high-yield method for preparing high-purity nifuratel, so that the method is simple, easy, low-pollution, and suitable for industrial production

Method used

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  • The preparation method of nifuratel
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  • The preparation method of nifuratel

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preparation example Construction

[0041] (5) Preparation of Nifuratel (Target Compound 1)

[0042] In an ice-water bath, add the mixture obtained in step (3) dropwise to the reaction system obtained in step (4), and stir at 0-40°C for 1-4 hours, typically at room temperature for about 1 hour, then let it stand 2 hours. During this period, the target product 1 was produced as a yellow precipitate, which could be obtained by filtration. The crude product was purified by recrystallization. In this step, after the two reaction systems are mixed, sodium ethoxide and phosphoric acid are neutralized, and the operation of removing acid and alkali respectively is omitted.

[0043] Different from the prior art using acetic acid for recrystallization, the present invention uses N,N-dimethylformamide or 1,4-dioxane for recrystallization. This is beneficial to the stability of nifuratel. Nifuratel is a Schiff base, which will be partially decomposed under high temperature and acidic conditions. The mass ratio of nifur...

Embodiment 1

[0046] Add 297.9 grams (3.22mol) of epichlorohydrin and 35.5 grams (0.161mol) of 15-crown-5 into the reaction flask, stir mechanically, add dropwise 1127 grams (content: 20%, 3.22mol) of sodium methyl mercaptide, React at 20°C for 4 hours, a white solid is produced in the reaction bottle, add water to dissolve the solid, separate the liquids, wash the organic phase with water, dry over anhydrous magnesium sulfate, and filter with suction to obtain 330 g (3.17 mol) of intermediate 3 with a purity of 98.5% , yield 98.4%.

[0047] Take 990 g (15.85 mol) of hydrazine hydrate and add it to the reaction flask, raise the temperature to 95°C, and add the compound intermediate intermediate 3 dropwise under stirring. After the dropwise addition, continue to react at this temperature for 3 hours, cool to room temperature, and then evaporate Water and unreacted hydrazine hydrate yielded 418 g (3.07 mol) of hydrazinolyzed intermediate 4.

[0048] Add 362 grams (3.07 mol) of diethyl carbon...

Embodiment 2

[0054] Add 297.9 grams (3.22mol) of epichlorohydrin and 35.5 grams (0.161mol) of 15-crown-5 into the reaction flask, stir mechanically, add dropwise 1127 grams (content: 20%, 3.22mol) of sodium methyl mercaptide, After reacting at 20°C for 4 hours, a white solid was produced in the reaction bottle. Water was added to dissolve the solid, and the liquid was separated. The organic phase was washed with water, dried with anhydrous magnesium sulfate, and filtered with suction to obtain 330 g (3.17 mol) of intermediate 3.

[0055] Take 990 g (15.85 mol) of hydrazine hydrate and add it to the reaction flask, raise the temperature to 95°C, and add the compound intermediate intermediate 3 dropwise under stirring. After the dropwise addition, continue to react at this temperature for 3 hours, cool to room temperature, and then evaporate Water and unreacted hydrazine hydrate yielded 418 g (3.07 mol) of hydrazinolyzed intermediate 4.

[0056] Add 362 grams (3.07 mol) of diethyl carbonate ...

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Abstract

The invention relates to a method for preparing nifuratel. The method comprises the steps of (1) synthesizing 2-(methylmercapto-methyl)-oxacyclopropane through epoxy chloropropane and sodium methyl mercaptide; (2) generating reaction between hydrazine hydrate and the 2-(methylmercapto-methyl)-oxacyclopropane to synthesize 3-methylmercapto-2-hydroxy-propyl hydrazine; (3) generating reaction between diethyl carbonate and 3-methylmercapto-2-hydroxy-propyl hydrazine to prepare N-amino-5-methylmercapto-methyl-2-oxazolidinone; (4) hydrolyzing 5-nitrofuran formaldehyde diacetate ester under an acidic condition to prepare 5-nitro-2-furaldehyde; (5) generating reaction between the 5-nitro-2-furaldehyde and the N-amino-5-methylmercapto-methyl-2-oxazolidinone obtained in the step (3) to obtain the nifuratel, wherein in the step (1), 15-crown ether-5 is used as a catalyst, so that the conversion rate is high; no organic solvent is used during posttreatment of a product, and the posttreatment is simple.

Description

technical field [0001] The invention belongs to the field of medicine synthesis, and in particular relates to a preparation method of a medicine compound. Background technique [0002] Nifuratel, chemical name 5-[(methylthio)methyl]-3-[(5-nitrofurfurylidene)amino]-2-oxazolidinone, molecular formula: C 10 h 11 N 3 o 5 S, molecular weight: 285.28, its structural formula is as follows: [0003] [0004] Nifuratel has a good curative effect on the treatment of common gynecological vaginal infections caused by trichomonas, Candida albicans, bacteria, etc., especially in the treatment of mixed vaginal infections, which is better than the existing clinical commonly used drugs. At present, tablets, suppositories, and ointments with its main ingredients have been listed in my country and many countries. [0005] In patents US3288787, BE635608, FR1588152, and GB969126, methyl (2-hydroxy-3-chloropropyl) sulfide is used as a raw material, and 3-methylmercapto-2 is obtained throu...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D413/12
CPCC07D413/12
Inventor 张庆华陈波刘丰良
Owner HUNAN FANGSHENG PHARMACEUTICAL CO LTD
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