阅读说明：本技术 一种硝呋太尔有关物质b的制备方法 (Preparation method of nifuratel related substance B ) 是由 胡子豪 景瑞 李凤 于 2019-10-29 设计创作，主要内容包括：本发明提供一种硝呋太尔有关物质B的制备方法,包括以下步骤：(1)在0～10℃下,将甲硫醇钠缓慢滴加至环氧氯丙烷中,然后加入催化剂,滴加完毕,搅拌反应至反应完全；(2)将ZnCl-2加入到上述反应液中,升温,搅拌反应3～5h；冷却到室温,减压蒸馏得1,3-双(甲硫基)丙-2-醇。本发明公开的硝呋太尔有关物质B制备方法可以方便、快速的获取硝呋太尔有关物质B,所得到的硝呋太尔有关物质B收率高、纯度好。(The invention provides a preparation method of a nifuratel related substance B, which comprises the following steps: (1) slowly dropwise adding sodium methyl mercaptide into epoxy chloropropane at 0-10 ℃, then adding a catalyst, and stirring to react until the reaction is complete after the dropwise addition is finished; (2) reacting ZnCl 2 Adding the mixture into the reaction solution, heating, and stirring for reaction for 3-5 hours; cooling to room temperature, and distilling under reduced pressure to obtain the 1, 3-bis (methylthio) propan-2-ol. The preparation method of the nifuratel related substance B disclosed by the invention can be used for conveniently and rapidly obtaining the nifuratel related substance B, and the obtained nifuratel related substance B is high in yield and good in purity.)

1. A preparation method of a nifuratel related substance B comprises the following steps:

(1) slowly dropwise adding sodium methyl mercaptide into epoxy chloropropane at 0-10 ℃, then adding a catalyst, and stirring to react until the reaction is complete after the dropwise addition is finished;

(2) reacting ZnCl₂Adding the mixture into the reaction solution, heating, and stirring for reaction for 3-5 hours; cooling to room temperature, and distilling under reduced pressure to obtain nifuratel related substance B, namely 1, 3-bis (methylthio) propan-2-ol.

2. The method according to claim 1, wherein in the step (1), the catalyst is 18-crown-6, the amount of the catalyst is 0.05-0.2 molar equivalent, the temperature of the stirring reaction is room temperature, and the amount of the sodium methyl mercaptide is 2.2-3.0 molar equivalent.

3. The method according to claim 1, wherein in step (2), the ZnCl is₂The dosage of the catalyst is 0.01-0.05 molar equivalent, and the reaction temperature is 50-90 ℃.

4. The method according to claim 2, wherein in the step (1), the catalyst is used in an amount of 0.1 to 0.15 molar equivalents, and the sodium methyl mercaptide is used in an amount of 2.4 to 2.7 molar equivalents.

5. The method according to claim 3, wherein in step (2), the ZnCl is₂The dosage of the catalyst is 0.01-0.03 molar equivalent, and the reaction temperature is 70-80 ℃.

6. The method of claim 1, comprising the steps of: slowly dropwise adding 2.2-3.0 molar equivalent of sodium methoxide into epoxy chloropropane at 0-10 ℃, adding 0.05-0.2 molar equivalent of 18-crown ether-6, and stirring at room temperature to react for 3-5 h after dropwise addition; adding 0.01-0.05 molar equivalent of ZnCl2 into the reaction solution, heating to 50-90 ℃, and stirring for reaction for 3-5 hours; cooling to room temperature, and distilling under reduced pressure to obtain the 1, 3-bis (methylthio) propan-2-ol.

7. The method of claim 6, comprising the steps of: slowly dropwise adding 2.4-2.7 molar equivalent of sodium methyl mercaptide into epoxy chloropropane at 0-10 ℃, adding 0.1-0.15 molar equivalent of 18-crown ether-6, and stirring at room temperature for reaction for 3-5 after dropwise addition; adding 0.01-0.03 molar equivalent of ZnCl2 into the reaction solution, heating to 70-80 ℃, and stirring for reaction for 3-5 hours; cooling to room temperature, and distilling under reduced pressure to obtain the 1, 3-bis (methylthio) propan-2-ol.

Technical Field

The invention relates to the field of pharmaceutical chemistry, in particular to a preparation method of a nifuratel related substance B.

Background

Nifuratel (Nifuratel), chemical name: 5- [ (methylthio) methyl group]-3- [ (5-nitrofurfurylidene) amino]-2-oxazolidinone (5-methylothyl-3- (5-nitrofurylideneamino) -2-oxazolidinone) of formula: c₁₀H₁₁N₃O₅S, molecular weight: 285.28, the structural formula is as follows:

nifuratel is developed, researched and marketed in 60 s by Poli Industria Chimica S.p.A company of Italy, has an obvious effect of treating vaginal mixed infection, has the same trichomonacidal activity as metronidazole, has an antibacterial effect, can effectively kill chlamydia trachomatis and mycoplasma, and has a certain activity on candida. The nifuratel oral administration and the vaginal administration show that the tolerance is good, the drug resistance phenomenon does not exist, the cure rate of the nifuratel oral administration and the vaginal administration to the bacterial vaginitis is equivalent to that of ampicillin and carbenicillin, and the incidence rate of adverse reactions is obviously lower than that of the ampicillin and the carbenicillin. Nifuratel is a broad-spectrum antibiotic, has strong killing effect on common pathogens of gynecological infection, such as gram-positive and gram-negative bacteria, trichomonas, mould, chlamydia and mycoplasma, and has good treatment effect on vulva and vaginal infection and leukorrhagia caused by bacteria, trichomonas, mould and candida, urinary system infection, alimentary canal amoeba disease and Giardia disease. At present, tablets, suppositories and ointments containing these compounds as the main ingredient are on the market in many countries at home and abroad.

The content of the effective components of the medicine is an important mark for reflecting the purity of the medicine, and impurities in the medicine directly influence the curative effect of the medicine and can cause toxic and side effects. The impurities of the medicine are other chemical substances except the medicine introduced or generated in the production and storage processes, and the existence of the impurities not only affects the purity of the medicine, but also brings non-therapeutic active toxic and side effects and must be controlled. For safe and effective use of drugs, the quality standards of drugs have strict requirements on the purity of active ingredients of drugs and the limits of impurities, and generally, more than 0.1% of drug impurities should be identified and quantified by a selective method.

Due to human drug safety concerns, both domestic and international drug regulatory agencies established very low limits for quality control of unknown impurities before commercialization of products of pharmaceutical active ingredients. The quality control limit for known impurities is typically 0.15%, but the quality control limit for unknown impurities will typically be less than 0.10%, so the purity of the product is very important in the preparation of the drug substance.

Nifuratel is reported in the literature to be unstable chemically and to produce harmful impurities during the synthesis. The research on related substances of nifuratel is reported more, and the related literature on nifuratel related substance B is less. At present, the nifuratel related substance B is mainly obtained by preparing a liquid phase from a nifuratel reaction solution, the yield of the prepared nifuratel related substance B is low, the obtaining difficulty is high, and research work of nifuratel related substances is greatly limited, so that a preparation method of the nifuratel related substance B which is high in yield and easy to separate is urgently needed to be found.

Disclosure of Invention

The invention aims to provide a preparation method of nifuratel related substance B, namely 1, 3-bis (methylthio) propan-2-ol, which is used for synthesizing the nifuratel related substance B by a one-pot method, is simple to operate and is suitable for industrial production. The nifuratel related substance B prepared by the method is high in yield, high in purity and easy to separate.

The invention relates to a preparation method of a nifuratel related substance B, which comprises the following steps:

(1) slowly dropwise adding sodium methyl mercaptide into epoxy chloropropane at 0-10 ℃, then adding a catalyst, and stirring to react until the reaction is complete after the dropwise addition is finished;

(2) reacting ZnCl₂And adding the mixture into the reaction solution, heating, and stirring for reaction for 3-5 hours. Cooling to room temperature, and distilling under reduced pressure to obtain the 1, 3-bis (methylthio) propan-2-ol.

The reaction route of the preparation method of the nifuratel related substance B is as follows:

in the preparation method of nifuratel related substance B, in step (1), the catalyst is 18-crown-6, and the amount of the catalyst is 0.05 to 0.2 molar equivalent, preferably 0.1 to 0.15 molar equivalent; the temperature of the stirring reaction is room temperature; the dosage of the sodium methyl mercaptide is 2.2-3.0 molar equivalent, and preferably, the dosage of the sodium methyl mercaptide is 2.4-2.7 molar equivalent.

The preparation method of nifuratel related substance B, wherein in step (2), the ZnCl is₂Is used in an amount of 0.01 to 0.05 molar equivalents, preferably, the ZnCl is used in₂The amount of the compound is 0.01-0.03 molar equivalent; the reaction temperature is 50-90 ℃, preferably 70-80 ℃.

The preferred preparation method of the invention is as follows: slowly dropwise adding 2.2-3.0 molar equivalents of sodium methoxide into epoxy chloropropane at 0-10 ℃, adding 0.05-0.2 molar equivalents of 18-crown ether-6, and stirring and reacting at room temperature for 3-5 h after dropwise addition. And (3) adding 0.01-0.05 molar equivalent of ZnCl2 into the reaction solution, heating to 50-90 ℃, and stirring for reaction for 3-5 hours. Cooling to room temperature, and distilling under reduced pressure to obtain the 1, 3-bis (methylthio) propan-2-ol.

The further preferable preparation method of the invention is as follows: slowly dropwise adding 2.4-2.7 molar equivalent of sodium methyl mercaptide into epoxy chloropropane at 0-10 ℃, adding 0.1-0.15 molar equivalent of 18-crown ether-6, stirring and reacting at room temperature for 3-5 h after dropwise adding. 0.01 to 0.03 mole equivalent of ZnCl₂Adding the mixture into the reaction solution, heating to 70-80 ℃, and stirring for reaction for 3-5 hours. Cooling to room temperature, and distilling under reduced pressure to obtain the 1, 3-bis (methylthio) propan-2-ol.

In the present invention, the term "molar equivalent" is calculated based on the amount of the substance of the initial reactant epichlorohydrin, and the molar equivalent value of the relevant reactant is calculated by the formula: molar equivalents are the amount of material of the reactants per amount of material of epichlorohydrin.

The invention provides a preparation method of a nifuratel related substance B, namely 1, 3-bis (methylthio) propan-2-ol, and the 1, 3-bis (methylthio) propan-2-ol prepared by the method has high yield and high purity, and can be well applied to the synthesis and analysis processes of nifuratel raw material medicines.

The invention firstly uses a synthetic method to prepare the nifuratel related substance B at one time, and is not limited to preparing a very small amount of nifuratel related substance B from nifuratel reaction liquid only by using a preparation liquid phase. The method synthesizes the nifuratel related substance B through a one-pot method, the nifuratel related substance B can be conveniently and rapidly obtained, the obtained nifuratel related substance B is high in yield and good in purity, and a foundation is provided for the research of nifuratel impurities.

Detailed Description

The present application is further illustrated with reference to specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present application.

The test methods in the following examples, in which specific conditions are not specified, may be carried out according to conventional conditions or according to conditions recommended by the manufacturers. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is familiar to those skilled in the art.

Example 1

Adding 92.5g (1mol) of epoxy chloropropane into a reaction bottle, carrying out ice bath, stirring and controlling the temperature to be 0-10 ℃, slowly dropwise adding 771.1g (with the content of 20 percent and 2.2mol) of sodium methyl mercaptide solution into epoxy chloropropane, adding 18-crown ether-613.2 g (0.05mol), and stirring and reacting at room temperature for 3-5 h after dropwise adding. Reacting ZnCl₂Adding 1.4g (0.01mol) of the mixture into the reaction solution, heating to 50-60 ℃, and stirring for reaction for 3-5 h. Cooled to room temperature, and distilled under reduced pressure to give 1, 3-bis (methylthio) propan-2-ol (131.7g, yield 86.5%).

Example 2

Adding 92.5g (1mol) of epoxy chloropropane into a reaction bottle, carrying out ice bath, stirring and controlling the temperature to be 0-10 ℃, slowly dropwise adding 806.2g (with the content of 20 percent and 2.3mol) of sodium methyl mercaptide solution into epoxy chloropropane, adding 18-crown ether-626.4 g (0.1mol), and stirring and reacting at room temperature for 3-5 h after dropwise adding. Reacting ZnCl₂2.7g (0.02mol) of the reaction solution is added into the reaction solution, the temperature is raised to 60 to 70 ℃, and the reaction is stirred for 3 to 5 hours. Cooled to room temperature, and distilled under reduced pressure to give 1, 3-bis (methylthio) propan-2-ol (134.5g, yield 88.3%).

Example 3

Adding 92.5g (1mol) of epoxy chloropropane into a reaction bottle, carrying out ice bath, stirring and controlling the temperature to be 0-10 ℃, slowly dropwise adding 841.2g (with the content being 20 percent and 2.4mol) of sodium methyl mercaptide solution into epoxy chloropropane, adding 18-crown ether-631.7 g (0.12mol), and stirring and reacting at room temperature for 3-5 h after dropwise adding. Reacting ZnCl₂4.1g (0.03mol) of the reaction solution is added into the reaction solution, the temperature is raised to 70 to 80 ℃, and the reaction is stirred for 3And about 5 h. Cooled to room temperature, and distilled under reduced pressure to give 1, 3-bis (methylthio) propan-2-ol (136.3g, yield 89.5%).

Example 4

Adding 92.5g (1mol) of epoxy chloropropane into a reaction bottle, carrying out ice bath, stirring and controlling the temperature to be 0-10 ℃, slowly dropwise adding 876.3g (with the content of 20 percent and 2.5mol) of sodium methyl mercaptide solution into epoxy chloropropane, adding 18-crown ether-639.6 g (0.15mol), and stirring and reacting at room temperature after dropwise adding. Reacting ZnCl₂5.5g (0.04mol) of the reaction solution is added into the reaction solution, the temperature is raised to 80 ℃ to 90 ℃, and the reaction is stirred for 3 to 5 hours. Cooled to room temperature, and distilled under reduced pressure to give 1, 3-bis (methylthio) propan-2-ol (129.7g, yield 85.2%).

Example 5

Adding 92.5g (1mol) of epoxy chloropropane into a reaction bottle, carrying out ice bath, stirring and controlling the temperature to be 0-10 ℃, slowly dropwise adding 911.3g (with the content being 20 percent and 2.6mol) of sodium methyl mercaptide solution into epoxy chloropropane, adding 18-crown ether-652.9 g (0.2mol), and stirring and reacting at room temperature for 3-5 h after dropwise adding. Reacting ZnCl₂6.8g (0.05mol) of the reaction solution is added into the reaction solution, the temperature is raised to 70 ℃ to 80 ℃, and the reaction is stirred for 3 to 5 hours. Cooled to room temperature, and distilled under reduced pressure to give 1, 3-bis (methylthio) propan-2-ol (135.1g, yield 88.7%).

Example 6

Adding 92.5g (1mol) of epoxy chloropropane into a reaction bottle, carrying out ice bath, stirring and controlling the temperature to be 0-10 ℃, slowly dropwise adding 946.4g (with the content being 20 percent and 2.7mol) of sodium methyl mercaptide solution into epoxy chloropropane, adding 18-crown ether-626.4 g (0.1mol), and stirring and reacting at room temperature for 3-5 h after dropwise adding. Reacting ZnCl₂Adding 1.4g (0.01mol) of the mixture into the reaction solution, heating to 60-70 ℃, and stirring for reaction for 3-5 h. Cooled to room temperature, and distilled under reduced pressure to give 1, 3-bis (methylthio) propan-2-ol (133.2g, yield 87.5%).

Example 7

Adding 92.5g (1mol) of epoxy chloropropane into a reaction bottle, carrying out ice bath, stirring and controlling the temperature to be 0-10 ℃, slowly dropwise adding 1016.5g (with the content being 20 percent and 2.9mol) of sodium methyl mercaptide solution into epoxy chloropropane, adding 18-crown ether-631.7 g (0.12mol), and stirring and reacting at room temperature for 3-5 h after dropwise adding. Reacting ZnCl₂ 2.7g(0.02mol) of the mixture is added into the reaction solution, the temperature is raised to 70-80 ℃, and the mixture is stirred and reacted for 3-5 hours. Cooled to room temperature, and distilled under reduced pressure to give 1, 3-bis (methylthio) propan-2-ol (135.8g, yield 89.2%).

Example 8

Adding 92.5g (1mol) of epoxy chloropropane into a reaction bottle, carrying out ice bath, stirring and controlling the temperature to be 0-10 ℃, slowly dropwise adding 1051.5g (with the content of 20 percent and the content of 3.0mol) of sodium methyl mercaptide solution into epoxy chloropropane, adding 18-crown ether-639.6 g (0.15mol), and stirring and reacting at room temperature for 3-5 h after dropwise adding. Reacting ZnCl₂4.1g (0.03mol) of the reaction solution is added into the reaction solution, the temperature is raised to 70 ℃ to 80 ℃, and the reaction is stirred for 3 to 5 hours. Cooled to room temperature, and distilled under reduced pressure to give 1, 3-bis (methylthio) propan-2-ol (133.4g, yield 87.6%).