CN112745271A - Preparation method of nifuratel related substance A hydrochloride - Google Patents
Preparation method of nifuratel related substance A hydrochloride Download PDFInfo
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- CN112745271A CN112745271A CN201911036383.7A CN201911036383A CN112745271A CN 112745271 A CN112745271 A CN 112745271A CN 201911036383 A CN201911036383 A CN 201911036383A CN 112745271 A CN112745271 A CN 112745271A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D263/26—Oxygen atoms attached in position 2 with hetero atoms or acyl radicals directly attached to the ring nitrogen atom
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Abstract
The invention provides a preparation method of nifuratel related substance A hydrochloride, which comprises the following steps: (1) reacting sodium methoxide with epoxy chloropropane to obtain 2- (methoxymethyl) -oxetane; (2) dripping 2- (methoxymethyl) -oxetane into hydrazine hydrate to prepare 3-methoxy-2-hydroxy-propylhydrazine; (3) adding diethyl carbonate into 3-methoxy-2-hydroxy-propylhydrazine to obtain nifuratel related substance A, namely N-amino-5-methoxymethyl-2-oxazolidinone; (4) salifying the obtained N-amino-5-methoxymethyl-2-oxazolidinone and concentrated hydrochloric acid to obtain nifuratel related substance A hydrochloride. The preparation method of nifuratel related substance A hydrochloride disclosed by the invention can be used for conveniently and rapidly obtaining nifuratel related substance A hydrochloride, and the obtained nifuratel related substance A hydrochloride has high yield and good purity.
Description
Technical Field
The invention relates to the field of pharmaceutical chemistry, and in particular relates to a preparation method of nifuratel related substance A hydrochloride.
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 the nifuratel part is reported more, and the related literature on the nifuratel related substance A hydrochloride is less. At present, nifuratel related substance A hydrochloride is mainly obtained by preparing a liquid phase from nifuratel reaction liquid, the yield of the prepared nifuratel related substance A hydrochloride is low, the obtaining difficulty is high, and research work of nifuratel related substances is greatly limited, so that a preparation method of nifuratel related substance A hydrochloride with high yield and easy separation is urgently needed to be found.
Disclosure of Invention
The invention aims to provide a preparation method of nifuratel related substance A hydrochloride, namely 3-amino-5-methoxymethyl oxazoline-2-ketone hydrochloride, and the nifuratel related substance A hydrochloride prepared by the method has high yield and purity and is easy to separate.
The invention relates to a preparation method of nifuratel related substance A hydrochloride, which comprises the following steps:
(1) slowly dropwise adding sodium methoxide into epoxy chloropropane at 0-10 ℃, then adding a catalyst, stirring to react until the reaction is complete after the dropwise addition, slowly dropwise adding purified water, separating liquid, taking an organic layer, and drying to obtain 2- (methoxymethyl) -oxetane;
(2) dropwise adding 2- (methoxymethyl) -oxetane into hydrazine hydrate, stirring for reacting for 3-5 h, cooling to room temperature, and then evaporating water and unreacted hydrazine hydrate to obtain 3-methoxy-2-hydroxy-propylhydrazine;
(3) adding diethyl carbonate into 3-methoxy-2-hydroxy-propylhydrazine, stirring, slowly adding an alkaline catalyst, reacting at 50-85 ℃, completely reacting, cooling, and concentrating under reduced pressure to obtain a nifuratel related substance A, namely N-amino-5-methoxymethyl-2-oxazolidinone;
(4) adding the prepared N-amino-5-methoxymethyl-2-oxazolidinone into a dispersing solvent for uniform dispersion, adding hydrochloric acid for adjusting the pH value to 4-8, filtering, adding concentrated hydrochloric acid into the filtrate for salification, stirring for crystallization, filtering, pulping the filter cake by using a pulping solvent, filtering, and drying to obtain nifuratel related substance A hydrochloride, namely 3-amino-5-methoxymethyl oxazoline-2-one hydrochloride.
The reaction route of the preparation method of nifuratel related substance A hydrochloride is as follows:
in the preparation method of nifuratel related substance A hydrochloride, 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 amount of the sodium methoxide is 1.0-1.2 molar equivalents, and preferably, the amount of the sodium methoxide is 1.05-1.1 molar equivalents.
In the preparation method of nifuratel related substance a hydrochloride, in step (2), the amount of hydrazine hydrate is 1.05 to 1.3 molar equivalents, preferably 1.1 to 1.2 molar equivalents; the temperature of the stirring reaction is 80-100 ℃, and preferably 90-95 ℃.
In the preparation method of nifuratel related substance a hydrochloride, in step (3), the amount of diethyl carbonate is 1.0 to 1.2 molar equivalents, preferably 1.05 to 1.1 molar equivalents; the alkaline catalyst is selected from one of sodium methoxide and sodium ethoxide, and sodium ethoxide is preferred; the amount of the basic catalyst is 0.1-0.4 molar equivalent, preferably 0.2-0.3 molar equivalent.
The preparation method of nifuratel related substance A hydrochloride, wherein in step (4), the dispersion solvent is selected from C1-C3Chlorinated alkane of (C)1-C4Preferably, the dispersing solvent is selected from one of dichloromethane, dichloroethane, ethyl acetate and ethyl formate, and further preferably, the dispersing solvent is selected from ethyl acetate; the pulping solvent is selected from C1-C3Preferably, the pulping solvent is absolute ethyl alcohol; the dosage of the concentrated hydrochloric acid is 1.0-1.4 mol equivalent, preferably, the dosage of the concentrated hydrochloric acid is 1.1-1.3 mol equivalent.
The preferred preparation method of the invention is as follows: slowly dropwise adding 1.0-1.2 molar equivalents of sodium methoxide into epoxy chloropropane at 0-10 ℃, adding 0.05-0.2 molar equivalents of 18-crown ether-6, stirring at room temperature to react for 3-5 h after dropwise addition, slowly dropwise adding purified water, separating, taking an organic layer, and drying to obtain the 2- (methoxymethyl) -oxetane. Dropwise adding the prepared 2- (methoxymethyl) -oxetane into 0.05-0.3 molar equivalent of hydrazine hydrate, stirring at 80-100 ℃ for reacting for 3-5 h, cooling to room temperature, and then evaporating water and unreacted hydrazine hydrate. Adding 1.0-1.2 molar equivalents of diethyl carbonate into the reaction solution, stirring, slowly adding 0.1-0.4 molar equivalents of sodium ethoxide, reacting at 50-85 ℃, cooling, and concentrating under reduced pressure to obtain the N-amino-5-methoxymethyl-2-oxazolidinone. Adding the prepared N-amino-5-methoxymethyl-2-oxazolidinone into dichloromethane for uniform dispersion, adding hydrochloric acid for adjusting the pH value to 4-8, filtering, adding 1.0-1.4 molar equivalent of concentrated hydrochloric acid into the filtrate for salification, stirring for crystallization, filtering, pulping the filter cake with absolute ethyl alcohol, filtering, and drying to obtain the 3-amino-5-methoxymethyl oxazoline-2-one hydrochloride.
The further preferable preparation method of the invention is as follows: slowly dropwise adding 1.05-1.1 molar equivalent of sodium methoxide into epoxy chloropropane at 0-10 ℃, adding 0.1-0.15 molar equivalent of 18-crown ether-6, stirring at room temperature to react for 3-5 h after dropwise adding, slowly dropwise adding purified water, separating, taking an organic layer, and drying to obtain the 2- (methoxymethyl) -oxetane. Dropwise adding the prepared 2- (methoxymethyl) -oxetane into 0.1-0.2 molar equivalent of hydrazine hydrate, stirring at 90-95 ℃ for reacting for 3-5 h, cooling to room temperature, and then evaporating water and unreacted hydrazine hydrate. Adding 1.05-1.1 molar equivalent of diethyl carbonate into the reaction solution, stirring, slowly adding 0.2-0.3 molar equivalent of sodium ethoxide, reacting at 50-85 ℃, cooling, and concentrating under reduced pressure to obtain the N-amino-5-methoxymethyl-2-oxazolidinone. Adding the prepared N-amino-5-methoxymethyl-2-oxazolidinone reaction liquid into ethyl acetate for uniform dispersion, adding hydrochloric acid to adjust the pH value to 4-8, filtering, adding concentrated hydrochloric acid with 1.1-1.3 molar equivalents into the filtrate for salification, stirring for crystallization, filtering, pulping the filter cake with absolute ethyl alcohol, filtering, and drying to obtain the 3-amino-5-methoxymethyl oxazoline-2-ketone hydrochloride.
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 term "C1-C3The chloroalkane of (a) "means a saturated monovalent hydrocarbon group having 1 to 3 carbon atoms substituted with at least one chlorine atom. Monochloromethane, dichloromethane, trichloromethane, carbon tetrachloride, monochloroethane, dichloroethane, 1-chloropropane, etc., are all the terms "C1-C3Specific examples of the chlorinated alkane of (1).
The term "C1-C4The "ester solvent" of (a) means a saturated monovalent ester species having 1 to 4 carbon atoms. Methyl formate, ethyl formate, methyl acetate, ethyl acetate, etc. are all terms "C1-C4Specific examples of the ester solvent of (1) ".
The term "C1-C3The "alcoholic solvent" of (a) means a saturated monovalent alcohol substance having 1 to 3 carbon atoms. Methanol, ethanol, propanol, isopropanol, etc. are all the terms "C1-C3Specific examples of the alcohol solvent of (1) ".
The invention provides a preparation method of nifuratel related substance A hydrochloride, namely 3-amino-5-methoxymethyl oxazoline-2-ketone hydrochloride, and the 3-amino-5-methoxymethyl oxazoline-2-ketone hydrochloride 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 A hydrochloride in one step, and is not limited to preparing a very small amount of nifuratel related substance A hydrochloride from nifuratel reaction liquid only by using a preparation liquid phase. The method can conveniently and quickly obtain the nifuratel related substance A hydrochloride, and the obtained nifuratel related substance A hydrochloride has high yield and good purity, thereby providing a foundation for the impurity research of nifuratel.
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
(1) Preparation of 2- (methoxymethyl) -oxetanes
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 192.9g (with the content of 28 percent and 1mol) of sodium methoxide solution into epoxy chloropropane, adding 18-crown ether-613.2 g (0.05mol), stirring and reacting at room temperature for 3-5 h after dropwise adding is finished, slowly dropwise adding purified water, separating liquid, taking an organic layer, and drying to obtain the 2- (methoxymethyl) -oxa-cyclopropane.
(2) Preparation of 3-methoxy-2-hydroxy-propylhydrazine
Dropwise adding the prepared 2- (methoxymethyl) -oxetane into 75.1g (the content is 70 percent and the mole is 1.05) of hydrazine hydrate solution, stirring and reacting for 3-5 h at the temperature of 80-85 ℃, cooling to room temperature, and then evaporating water and unreacted hydrazine hydrate to obtain the 3-methoxy-2-hydroxy-propylhydrazine.
(3) Preparation of N-amino-5-methoxymethyl-2-oxazolidinone
And then adding 118.1g (1mol) of diethyl carbonate into 3-methoxy-2-hydroxy-propylhydrazine, stirring, slowly adding 6.8g (0.1mol) of sodium ethoxide, reacting at 50-85 ℃, completely reacting, cooling, and concentrating under reduced pressure to obtain a nifuratel related substance A, namely N-amino-5-methoxymethyl-2-oxazolidinone.
(4) Preparation of N-amino-5-methoxymethyl-2-oxazolidinone hydrochloride
Adding the N-amino-5-methoxymethyl-2-oxazolidinone into dichloromethane for uniform dispersion, adding hydrochloric acid for adjusting the pH value to 4-8, filtering, adding 98.6g (the content is 37% and the mol is 1%) of concentrated hydrochloric acid into the filtrate for salification, stirring for crystallization, filtering, pulping filter cake methanol, filtering, and drying to obtain nifuratel related substance A hydrochloride (125.1g, the yield is 68.5%, and the purity is 99.35%).
Example 2
(1) Preparation of 2- (methoxymethyl) -oxetanes
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 202.6g (with the content of 28 percent and 1.05mol) of sodium methoxide solution into epoxy chloropropane, adding 18-crown ether-626.4 g (0.1mol), stirring and reacting at room temperature for 3-5 hours after dropwise adding, slowly dropwise adding a proper amount of purified water, separating, taking an organic layer, and drying to obtain the 2- (methoxymethyl) -oxa-cyclopropane.
(2) Preparation of 3-methoxy-2-hydroxy-propylhydrazine
Dropwise adding the prepared 2- (methoxymethyl) -oxetane into 78.7g (the content is 70 percent and the mole is 1.1) of hydrazine hydrate solution, stirring and reacting for 3-5 h at 85-90 ℃, cooling to room temperature, and then evaporating water and unreacted hydrazine hydrate to obtain the 3-methoxy-2-hydroxy-propylhydrazine.
(3) Preparation of N-amino-5-methoxymethyl-2-oxazolidinone
And then adding 124g (1.05mol) of diethyl carbonate into 3-methoxy-2-hydroxy-propylhydrazine, stirring, slowly adding 38.6g (with the content of 28 percent and the mol of 0.2mol) of sodium methoxide solution, reacting at 50-85 ℃, completely reacting, cooling, and concentrating under reduced pressure to obtain a nifuratel related substance A, namely N-amino-5-methoxymethyl-2-oxazolidinone.
(4) Preparation of N-amino-5-methoxymethyl-2-oxazolidinone hydrochloride
Adding the N-amino-5-methoxymethyl-2-oxazolidinone into dichloroethane for uniform dispersion, adding hydrochloric acid to adjust the pH value to 4-8, filtering, adding 108.4g (the content is 37 percent and the mol is 1.1) of concentrated hydrochloric acid into the filtrate to form salt, stirring for crystallization, filtering, pulping the filter cake by using absolute ethyl alcohol, filtering, and drying to obtain nifuratel related substance A hydrochloride, namely 3-amino-5-methoxymethyl oxazoline-2-ketone hydrochloride (127.5g, the yield is 69.8 percent and the purity is 99.68 percent).
Example 3
(1) Preparation of 2- (methoxymethyl) -oxetanes
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 212.2g (with the content of 28 percent and 1.1mol) of sodium methoxide solution into epoxy chloropropane, adding 18-crown ether-639.6 g (0.15mol), stirring and reacting at room temperature for 3-5 hours after dropwise adding, slowly dropwise adding a proper amount of purified water, separating, taking an organic layer, and drying to obtain the 2- (methoxymethyl) -oxa-cyclopropane.
(2) Preparation of 3-methoxy-2-hydroxy-propylhydrazine
Dropwise adding the prepared 2- (methoxymethyl) -oxetane into 82.2g (the content is 70 percent and the mole is 1.15mol) of hydrazine hydrate solution, stirring and reacting for 3-5 h at 90-95 ℃, cooling to room temperature, and then evaporating water and unreacted hydrazine hydrate to obtain the 3-methoxy-2-hydroxy-propylhydrazine.
(3) Preparation of N-amino-5-methoxymethyl-2-oxazolidinone
And adding 129.9g (1.1mol) of diethyl carbonate into 3-methoxy-2-hydroxy-propylhydrazine, stirring, slowly adding 20.4g (0.3mol) of sodium ethoxide, reacting at 50-85 ℃, completely reacting, cooling, and concentrating under reduced pressure to obtain a nifuratel related substance A, namely N-amino-5-methoxymethyl-2-oxazolidinone.
(4) Preparation of N-amino-5-methoxymethyl-2-oxazolidinone hydrochloride
Adding the N-amino-5-methoxymethyl-2-oxazolidinone into ethyl acetate, uniformly dispersing, adding hydrochloric acid to adjust the pH value to 4-8, filtering, adding 118.2g (the content is 37% and is 1.2mol) of concentrated hydrochloric acid into the filtrate to form salt, stirring for crystallization, filtering, pulping the filter cake with a proper amount of absolute ethyl alcohol, filtering, and drying to obtain nifuratel related substance A hydrochloride, namely 3-amino-5-methoxymethyl oxazoline-2-ketone hydrochloride (145.9g, the yield is 79.9%, and the purity is 99.89%).
Example 4
(1) Preparation of 2- (methoxymethyl) -oxetanes
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 221.9g (with the content of 28 percent and 1.15mol) of sodium methoxide solution into epoxy chloropropane, adding 18-crown ether-652.9 g (0.2mol), stirring and reacting at room temperature for 3-5 h after dropwise adding is finished, slowly dropwise adding a proper amount of purified water, separating, taking an organic layer, and drying to obtain the 2- (methoxymethyl) -oxa-cyclopropane.
(2) Preparation of 3-methoxy-2-hydroxy-propylhydrazine
Dropwise adding the prepared 2- (methoxymethyl) -oxetane into 85.8g (the content is 70 percent and the mole is 1.2mol) of hydrazine hydrate solution, stirring and reacting for 3-5 h at 90-95 ℃, cooling to room temperature, and then evaporating water and unreacted hydrazine hydrate to obtain the 3-methoxy-2-hydroxy-propylhydrazine.
(3) Preparation of N-amino-5-methoxymethyl-2-oxazolidinone
And adding 135.8g (1.15mol) of diethyl carbonate into 3-methoxy-2-hydroxy-propylhydrazine, stirring, slowly adding 27.2g (0.4mol) of sodium ethoxide, reacting at 50-85 ℃, completely reacting, cooling, and concentrating under reduced pressure to obtain a nifuratel related substance A, namely N-amino-5-methoxymethyl-2-oxazolidinone.
(4) Preparation of N-amino-5-methoxymethyl-2-oxazolidinone hydrochloride
Adding the N-amino-5-methoxymethyl-2-oxazolidinone into dichloromethane for uniform dispersion, adding hydrochloric acid for adjusting the pH value to 4-8, filtering, adding 128.1g (the content is 37% and the mole is 1.3%) of concentrated hydrochloric acid into the filtrate for salt formation, stirring for crystallization, filtering, pulping the filter cake with N-propanol, filtering, and drying to obtain nifuratel related substance A hydrochloride, namely 3-amino-5-methoxymethyl oxazoline-2-ketone hydrochloride (142.6g, the yield is 78.1%, and the purity is 99.76%).
Example 5
(1) Preparation of 2- (methoxymethyl) -oxetanes
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 231.5g (with the content of 28 percent and 1.2mol) of sodium methoxide solution into epoxy chloropropane, adding 18-crown ether-626.4 g (0.1mol), stirring and reacting at room temperature for 3-5 h after dropwise adding, slowly dropwise adding purified water, separating liquid, taking an organic layer, and drying to obtain the 2- (methoxymethyl) -oxa-cyclopropane.
(2) Preparation of 3-methoxy-2-hydroxy-propylhydrazine
Dropwise adding the prepared 2- (methoxymethyl) -oxetane into 93.0g (the content is 70 percent and the mole is 1.3) of hydrazine hydrate solution, stirring and reacting for 3-5 h at the temperature of 95-100 ℃, cooling to room temperature, and then evaporating water and unreacted hydrazine hydrate to obtain the 3-methoxy-2-hydroxy-propylhydrazine.
(3) Preparation of N-amino-5-methoxymethyl-2-oxazolidinone
And then adding 141.8g (1.2mol) of diethyl carbonate into 3-methoxy-2-hydroxy-propylhydrazine, stirring, slowly adding 38.6g (with the content of 28 percent and the mol of 0.2mol) of sodium methoxide solution, reacting at 50-85 ℃, completely reacting, cooling, and concentrating under reduced pressure to obtain a nifuratel related substance A, namely N-amino-5-methoxymethyl-2-oxazolidinone.
(4) Preparation of N-amino-5-methoxymethyl-2-oxazolidinone hydrochloride
Adding the N-amino-5-methoxymethyl-2-oxazolidinone into ethyl formate, uniformly dispersing, adding hydrochloric acid to adjust the pH value to 4-8, filtering, adding 138.0g (the content is 37% and the mol is 1.4%) of concentrated hydrochloric acid into the filtrate, stirring, crystallizing, filtering, pulping a filter cake by using a proper amount of isopropanol, filtering, and drying to obtain nifuratel related substance A hydrochloride, namely 3-amino-5-methoxymethyl oxazoline-2-ketone hydrochloride (127.1g, the yield is 69.6%, and the purity is 99.71%).
Example 6
(1) Preparation of 2- (methoxymethyl) -oxetanes
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 212.2g (with the content of 28 percent and 1.1mol) of sodium methoxide solution into epoxy chloropropane, adding 18-crown ether-626.4 g (0.1mol), stirring and reacting at room temperature for 3-5 hours after dropwise adding, slowly dropwise adding a proper amount of purified water, separating, taking an organic layer, and drying to obtain the 2- (methoxymethyl) -oxa-cyclopropane.
(2) Preparation of 3-methoxy-2-hydroxy-propylhydrazine
Dropwise adding the prepared 2- (methoxymethyl) -oxetane into 82.2g (the content is 70 percent and the mole is 1.15mol) of hydrazine hydrate solution, stirring and reacting for 3-5 h at 90-95 ℃, cooling to room temperature, and then evaporating water and unreacted hydrazine hydrate to obtain the 3-methoxy-2-hydroxy-propylhydrazine.
(3) Preparation of N-amino-5-methoxymethyl-2-oxazolidinone
And adding 129.9g (1.1mol) of diethyl carbonate into 3-methoxy-2-hydroxy-propylhydrazine, stirring, slowly adding 13.6g (0.2mol) of sodium ethoxide, reacting at 50-85 ℃, completely reacting, cooling, and concentrating under reduced pressure to obtain a nifuratel related substance A, namely N-amino-5-methoxymethyl-2-oxazolidinone.
(4) Preparation of N-amino-5-methoxymethyl-2-oxazolidinone hydrochloride
Adding the N-amino-5-methoxymethyl-2-oxazolidinone into ethyl acetate, uniformly dispersing, adding hydrochloric acid to adjust the pH value to 4-8, filtering, adding 118.2g (the content is 37% and is 1.2mol) of concentrated hydrochloric acid into the filtrate to form salt, stirring for crystallization, filtering, pulping the filter cake with a proper amount of absolute ethyl alcohol, filtering, and drying to obtain nifuratel related substance A hydrochloride, namely 3-amino-5-methoxymethyl oxazoline-2-ketone hydrochloride (144.8g, the yield is 79.3%, and the purity is 99.82%).
Claims (10)
1. A preparation method of nifuratel related substance A hydrochloride comprises the following steps:
(1) slowly dropwise adding sodium methoxide into epoxy chloropropane at 0-10 ℃, then adding a catalyst, stirring to react until the reaction is complete after the dropwise addition, slowly dropwise adding purified water, separating liquid, taking an organic layer, and drying to obtain 2- (methoxymethyl) -oxetane;
(2) dropwise adding 2- (methoxymethyl) -oxetane into hydrazine hydrate, stirring for reacting for 3-5 h, cooling to room temperature, and then evaporating water and unreacted hydrazine hydrate to obtain 3-methoxy-2-hydroxy-propylhydrazine;
(3) adding diethyl carbonate into 3-methoxy-2-hydroxy-propylhydrazine, stirring, slowly adding an alkaline catalyst, reacting at 50-85 ℃, completely reacting, cooling, and concentrating under reduced pressure to obtain a nifuratel related substance A, namely N-amino-5-methoxymethyl-2-oxazolidinone;
(4) adding the prepared N-amino-5-methoxymethyl-2-oxazolidinone into a dispersing solvent for uniform dispersion, adding hydrochloric acid for adjusting the pH value to 4-8, filtering, adding concentrated hydrochloric acid into the filtrate for salification, stirring for crystallization, filtering, pulping the filter cake by using a pulping solvent, filtering, and drying to obtain nifuratel related substance A hydrochloride, namely 3-amino-5-methoxymethyl oxazoline-2-one hydrochloride.
2. The method according to claim 1, wherein in step (1), the catalyst is 18-crown-6, the amount of the catalyst is 0.05 to 0.2 molar equivalent, the temperature of the stirring reaction is room temperature, and the amount of sodium methoxide is 1.0 to 1.2 molar equivalent.
3. The method according to claim 1, wherein in the step (2), the hydrazine hydrate is used in an amount of 1.05 to 1.3 molar equivalents, and the stirring reaction temperature is 80 to 100 ℃.
4. The method according to claim 1, wherein in the step (3), the diethyl carbonate is used in an amount of 1.0 to 1.2 molar equivalents, the basic catalyst is selected from one of sodium methoxide and sodium ethoxide, and the basic catalyst is used in an amount of 0.1 to 0.4 molar equivalents.
5. The method according to claim 1, wherein in the step (4), the dispersion solvent is selected from C1-C3Chlorinated alkane of (C)1-C4The beating solvent is selected from C1-C3The dosage of the concentrated hydrochloric acid is 1.0-1.4 mol equivalent.
6. The method according to claim 2, wherein in step (1), the catalyst is used in an amount of 0.1 to 0.15 molar equivalents, and the sodium methoxide is used in an amount of 1.05 to 1.1 molar equivalents.
7. The method according to claim 3, wherein in the step (2), the hydrazine hydrate is used in an amount of 1.1 to 1.2 molar equivalents, and the temperature of the stirring reaction is 90 to 95 ℃.
8. The method according to claim 4, wherein in the step (3), the diethyl carbonate is used in an amount of 1.05 to 1.1 molar equivalents, the basic catalyst is sodium ethoxide, and the basic catalyst is used in an amount of 0.2 to 0.3 molar equivalents.
9. The method according to claim 5, wherein in the step (4), the dispersing solvent is one selected from dichloromethane, dichloroethane, ethyl acetate and ethyl formate, the pulping solvent is absolute ethanol, and the dosage of the concentrated hydrochloric acid is 1.1-1.3 molar equivalents.
10. Method according to any of claims 1-9, characterized in that it comprises the following steps: slowly dropwise adding 1.05-1.1 molar equivalent of sodium methoxide into epoxy chloropropane at 0-10 ℃, adding 0.1-0.15 molar equivalent of 18-crown ether-6, stirring at room temperature to react for 3-5 h after dropwise addition is finished, slowly dropwise adding purified water, separating, taking an organic layer, and drying to obtain 2- (methoxymethyl) -oxetane; dropwise adding the prepared 2- (methoxymethyl) -oxetane into hydrazine hydrate with the molar equivalent of 0.1-0.2, stirring at 90-95 ℃ for reaction for 3-5 h, cooling to room temperature, and then evaporating water and unreacted hydrazine hydrate; adding 1.05-1.1 molar equivalent of diethyl carbonate into the reaction solution, stirring, slowly adding 0.2-0.3 molar equivalent of sodium ethoxide, reacting at 50-85 ℃, cooling, and concentrating under reduced pressure to obtain N-amino-5-methoxymethyl-2-oxazolidinone; adding the prepared N-amino-5-methoxymethyl-2-oxazolidinone reaction liquid into ethyl acetate for uniform dispersion, adding hydrochloric acid to adjust the pH value to 4-8, filtering, adding concentrated hydrochloric acid with 1.1-1.3 molar equivalents into the filtrate for salification, stirring for crystallization, filtering, pulping the filter cake with absolute ethyl alcohol, filtering, and drying to obtain the 3-amino-5-methoxymethyl oxazoline-2-ketone hydrochloride.
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