CN108440335B - Synthetic method of metronidazole - Google Patents

Synthetic method of metronidazole Download PDF

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CN108440335B
CN108440335B CN201810239920.7A CN201810239920A CN108440335B CN 108440335 B CN108440335 B CN 108440335B CN 201810239920 A CN201810239920 A CN 201810239920A CN 108440335 B CN108440335 B CN 108440335B
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reaction
metronidazole
solution
dichloromethane
mass concentration
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CN108440335A (en
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陈斌
汪营磊
刘亚静
陆婷婷
闫峥峰
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Xian Modern Chemistry Research Institute
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Xian Modern Chemistry Research Institute
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C243/00—Compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
    • C07C243/02—N-nitro compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C273/00—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C273/18—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas
    • C07C273/1854—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas by reactions not involving the formation of the N-C(O)-N- moiety
    • C07C273/1863—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas by reactions not involving the formation of the N-C(O)-N- moiety from urea

Abstract

The invention discloses a method for synthesizing metronidazole, which takes N, N' -dimethylurea as a raw material and comprises the following steps: (1) dissolving N, N' -dimethyl urea in dichloromethane to prepare a solution, slowly adding the solution into nitric-sulfuric mixed acid for nitration reaction at the reaction temperature of-5-0 ℃, and pouring the reaction mixture into ice water for dilution after the addition is finished; (2) heating the diluent obtained in the step (1) to 5-30 ℃ for hydrolysis reaction for 30-120 min, separating the hydrolysate phase after the reaction is ended, drying the dichloromethane phase with anhydrous magnesium sulfate, and concentrating to obtain the metronidazole. The invention aims to solve the problems of complex reaction operation steps, harsh hydrolysis conditions, low yield and the like in the preparation process of the metronidazole. The method is mainly used for preparing the metronidazole.

Description

Synthetic method of metronidazole
Technical Field
The invention relates to N, N' -dimethyl urea nitration and hydrolysis, in particular to a method for synthesizing methyl nitramine, belonging to organic synthesis.
Background
The methyl nitramine is an important organic compound, not only can be used as an elementary substance explosive, but also can be used as an intermediate for synthesizing nitramine energetic materials.
The synthesis method of the methyl nitramine mainly takes N, N ' -dimethyl urea as a raw material, firstly synthesizes the N, N ' -dimethyl-N, N ' -dinitrourea, and then carries out hydrolysis reaction to obtain a target product. US4418212A and US4476322A disclose a method for synthesizing metronidazole, comprising dissolving N, N ' -dimethylurea in dichloromethane to prepare a solution, adding mixed nitric-sulfuric acid to carry out nitration, pouring ice water after the reaction is finished and extracting with dichloromethane, carrying out alkali washing and water washing to obtain a dichloromethane solution of N, N ' -dimethyl-N, N ' -dinitrourea, and then hydrolyzing the solution in boiling water to prepare the metronidazole with a yield of 57.9%. The method has the problems of complex reaction operation steps, harsh hydrolysis conditions, low yield and the like, and is difficult to realize high-efficiency preparation.
Disclosure of Invention
The invention aims to overcome the defects of complex reaction operation steps, harsh hydrolysis conditions, low yield and the like in the preparation process of the metronidazole in the background technology, and provides a synthetic method of the metronidazole, which has the advantages of simple and convenient post-treatment operation, mild hydrolysis conditions and higher yield.
The invention has the following conception: aiming at the current situations of complex reaction operation steps, harsh hydrolysis conditions and low yield in the synthesis method of the metronidazole, the synthesis method which is simple and convenient in treatment operation after nitration, mild in hydrolysis conditions and high in yield is sought. The nitration liquid is diluted by ice water, the temperature is adjusted for direct hydrolysis, the steps of extraction separation, washing and the like of the intermediate N, N '-dimethyl-N, N' -dinitrourea can be reduced, the hydrolysis temperature is close to room temperature, the yield can be improved, the energy consumption can be reduced, and the cost can be reduced. The research of the inventor finds that the nitration liquid is directly diluted and hydrolyzed, so that the steps of extracting and washing the intermediate are reduced, the hydrolysis of the intermediate can be carried out at room temperature, the loss of the intermediate can be effectively reduced, the energy consumption of hydrolysis by boiling water is reduced, and the yield of the metronidazole is improved, thereby reducing the preparation cost.
The invention provides a synthetic method of metronidazole, comprising the following steps:
(1) dissolving N, N' -dimethyl urea in dichloromethane to prepare a solution, slowly adding the solution into mixed acid consisting of concentrated nitric acid with the mass concentration of 98% and concentrated sulfuric acid with the mass concentration of 98% to carry out nitration reaction at the reaction temperature of-5-0 ℃, and pouring the reaction mixture into ice water to dilute after the addition of the materials is finished; wherein the mass ratio of N, N' -dimethyl urea, concentrated nitric acid with the mass concentration of 98%, concentrated sulfuric acid with the mass concentration of 98% and ice water is 1: 1.72-4.31: 1.69-3.41: 4;
(2) heating the diluent obtained in the step (1) to 5-30 ℃ for hydrolysis reaction for 30-120 min, separating the hydrolysate phase after the reaction is ended, drying the dichloromethane phase with anhydrous magnesium sulfate, and concentrating to obtain the metronidazole.
The preferred synthetic method of the metronidazole comprises the following steps:
(1) dissolving N, N' -dimethyl urea in dichloromethane to prepare a solution, slowly adding the solution into mixed acid consisting of concentrated nitric acid with the mass concentration of 98% and concentrated sulfuric acid with the mass concentration of 98% to carry out nitration reaction at the reaction temperature of-5-0 ℃, and pouring the reaction mixture into ice water to dilute after the addition of the materials is finished; wherein the mass ratio of N, N' -dimethyl urea, concentrated nitric acid with the mass concentration of 98%, concentrated sulfuric acid with the mass concentration of 98% and ice water is 1: 2.78: 2.33: 4;
(2) heating the diluent obtained in the step (1) to 20 ℃ for hydrolysis reaction, wherein the hydrolysis time is 60min, separating hydrolysate phases after the reaction is ended, drying a dichloromethane phase by using anhydrous magnesium sulfate, and concentrating to obtain the metronidazole.
The invention has the beneficial effects that:
the invention adopts the method of adjusting the temperature for direct hydrolysis after the nitration liquid is diluted by ice water, reduces the steps of extracting the intermediate N, N '-dimethyl-N, N' -dinitrourea by dichloromethane, washing with alkali, washing with water and the like, changes the hydrolysis by boiling water into the hydrolysis at room temperature, reduces the reaction temperature, improves the hydrolysis effect of the N, N '-dimethyl-N, N' -dinitrourea, and improves the yield of the metronidazole from 57.9 percent to 86.9 percent.
Detailed Description
Example 1
100g N, N' -dimethyl urea is dissolved in 200mL of dichloromethane to prepare a solution, the solution is slowly added into mixed acid consisting of 278g of concentrated nitric acid with the mass concentration of 98% and 233g of concentrated sulfuric acid with the mass concentration of 98% for nitration reaction, the reaction temperature is-5 ℃ to 0 ℃, and after the addition is finished, the reaction mixture is poured into 400g of ice water for dilution.
Heating the diluent to 20 ℃ for hydrolysis reaction for 60min, separating the hydrolysate phase after the reaction is ended, drying the dichloromethane phase with anhydrous magnesium sulfate, and concentrating to obtain 150g of the metronidazole, wherein the yield is 86.9%, and the purity is more than or equal to 99.3%.
Structural identification of the metronidazole:
elemental analysis CH4N2O2Calculating the value: c15.79, H5.263, N36.84;
measured value: c16.16, H5.312, N37.28.
IR(KBr),υ/cm-1:2950，2898，1574，1336，775，738。
1H NMR(CDCl3,δ,ppm):3.28(s,3H,-CH3)。
The product obtained by the invention is confirmed to be the metronidazole by analysis and detection.
Example 2
100g N, N' -dimethyl urea is dissolved in 200mL of dichloromethane to prepare a solution, the solution is slowly added into mixed acid consisting of 201g of concentrated nitric acid with the mass concentration of 98% and 169g of concentrated sulfuric acid with the mass concentration of 98% for nitration reaction, the reaction temperature is-5 ℃ to 0 ℃, and after the addition is finished, the reaction mixture is poured into 400g of ice water for dilution.
Heating the diluent to 5 ℃ for hydrolysis reaction for 30min, separating the hydrolysate phase after the reaction is ended, drying the dichloromethane phase with anhydrous magnesium sulfate, and concentrating to obtain 115g of the metronidazole, wherein the yield is 66.6%, and the purity is more than or equal to 98.9%.
Example 3
100g N, N' -dimethyl urea is dissolved in 200mL of dichloromethane to prepare a solution, the solution is slowly added into mixed acid consisting of 260g of concentrated nitric acid with the mass concentration of 98% and 218g of concentrated sulfuric acid with the mass concentration of 98% for nitration reaction, the reaction temperature is-5 ℃ to 0 ℃, and after the addition is finished, the reaction mixture is poured into 400g of ice water for dilution.
Heating the diluent to 25 ℃ for hydrolysis reaction for 80min, separating the hydrolysate phase after the reaction is ended, drying the dichloromethane phase with anhydrous magnesium sulfate, and concentrating to obtain 146g of the methylamine, wherein the yield is 84.5%, and the purity is more than or equal to 98.6%.
Example 4
100g N, N' -dimethyl urea is dissolved in 200mL of dichloromethane to prepare a solution, the solution is slowly added into mixed acid consisting of 250g of concentrated nitric acid with the mass concentration of 98% and 210g of concentrated sulfuric acid with the mass concentration of 98% for nitration reaction, the reaction temperature is-5 ℃ to 0 ℃, and after the addition is finished, the reaction mixture is poured into 400g of ice water for dilution.
Heating the diluent to 30 ℃ for hydrolysis reaction for 120min, separating the hydrolysate phase after the reaction is ended, drying the dichloromethane phase with anhydrous magnesium sulfate, and concentrating to obtain 129g of the methylamine, wherein the yield is 74.7%, and the purity is more than or equal to 99.4%.
Example 5
Dissolving 100g N, N' -dimethyl urea in 200mL of dichloromethane to prepare a solution, slowly adding the solution into mixed acid consisting of 316g of concentrated nitric acid with the mass concentration of 98% and 265g of concentrated sulfuric acid with the mass concentration of 98% for nitration reaction at the reaction temperature of-5-0 ℃, and pouring the reaction mixture into 400g of ice water for dilution after the addition.
Heating the diluent to 10 ℃ for hydrolysis reaction for 50min, separating the hydrolysate phase after the reaction is ended, drying the dichloromethane phase with anhydrous magnesium sulfate, and concentrating to obtain the nitrosamine 127g with the yield of 73.5 percent and the purity of more than or equal to 98.8 percent.
Example 6
100g N, N' -dimethyl urea is dissolved in 200mL of dichloromethane to prepare a solution, the solution is slowly added into mixed acid consisting of 338g of concentrated nitric acid with the mass concentration of 98% and 284g of concentrated sulfuric acid with the mass concentration of 98% for nitration reaction, the reaction temperature is-5 ℃ to 0 ℃, and after the addition is finished, the reaction mixture is poured into 400g of ice water for dilution.
Heating the diluent to 15 ℃ for hydrolysis reaction for 70min, separating the hydrolysate phase after the reaction is ended, drying the dichloromethane phase with anhydrous magnesium sulfate, and concentrating to obtain 138g of the metronidazole, wherein the yield is 79.9%, and the purity is more than or equal to 99.2%.
Example 7
100g N, N' -dimethyl urea is dissolved in 200mL of dichloromethane to prepare a solution, the solution is slowly added into mixed acid consisting of 278g of concentrated nitric acid with the mass concentration of 98% and 233g of concentrated sulfuric acid with the mass concentration of 98% for nitration reaction, the reaction temperature is-5 ℃ to 0 ℃, and after the addition is finished, the reaction mixture is poured into 400g of ice water for dilution.
Heating the diluent to 20 ℃ for hydrolysis reaction, wherein the hydrolysis time is 100min, separating the hydrolysate phase after the reaction is ended, drying the dichloromethane phase by using anhydrous magnesium sulfate, and concentrating to obtain 149g of the metronidazole, wherein the yield is 86.3%, and the purity is more than or equal to 98.6%.
Example 8
100g N, N' -dimethyl urea is dissolved in 200mL of dichloromethane to prepare a solution, the solution is slowly added into mixed acid consisting of 273g of concentrated nitric acid with the mass concentration of 98% and 229g of concentrated sulfuric acid with the mass concentration of 98% for nitration reaction, the reaction temperature is-5 ℃ to 0 ℃, and after the addition is finished, the reaction mixture is poured into 400g of ice water for dilution.
Heating the diluent to 25 ℃ for hydrolysis reaction for 40min, separating the hydrolysate phase after the reaction is ended, drying the dichloromethane phase with anhydrous magnesium sulfate, and concentrating to obtain 139g of the metronidazole, wherein the yield is 80.5%, and the purity is more than or equal to 99.3%.
Example 9
100g N, N' -dimethyl urea is dissolved in 200mL of dichloromethane to prepare a solution, the solution is slowly added into mixed acid consisting of 230g of concentrated nitric acid with the mass concentration of 98% and 193g of concentrated sulfuric acid with the mass concentration of 98% for nitration reaction, the reaction temperature is-5 ℃ to 0 ℃, and after the addition is finished, the reaction mixture is poured into 400g of ice water for dilution.
Heating the diluent to 30 ℃ for hydrolysis reaction for 60min, separating the hydrolysate phase after the reaction is ended, drying the dichloromethane phase with anhydrous magnesium sulfate, and concentrating to obtain 133g of the methylamine, wherein the yield is 77%, and the purity is more than or equal to 98.7%.

Claims (5)

1. A synthetic method of metronidazole comprises the following steps:
dissolving 100g N, N' -dimethyl urea in 200mL of dichloromethane to prepare a solution, slowly adding the solution into mixed acid consisting of 278g of concentrated nitric acid with the mass concentration of 98% and 233g of concentrated sulfuric acid with the mass concentration of 98% for nitration reaction at the reaction temperature of-5-0 ℃, and pouring the reaction mixture into 400g of ice water for dilution after the addition is finished;
heating the diluent to 20 ℃ for hydrolysis reaction for 60min, separating the hydrolysate phase after the reaction is ended, drying the dichloromethane phase with anhydrous magnesium sulfate, and concentrating to obtain 150g of the metronidazole, wherein the yield is 86.9%, and the purity is more than or equal to 99.3%.
2. A synthetic method of metronidazole comprises the following steps:
dissolving 100g N, N' -dimethyl urea in 200mL of dichloromethane to prepare a solution, slowly adding the solution into mixed acid consisting of 260g of concentrated nitric acid with the mass concentration of 98% and 218g of concentrated sulfuric acid with the mass concentration of 98% for nitration reaction at the reaction temperature of-5-0 ℃, and pouring the reaction mixture into 400g of ice water for dilution after the addition is finished;
heating the diluent to 25 ℃ for hydrolysis reaction for 80min, separating the hydrolysate phase after the reaction is ended, drying the dichloromethane phase with anhydrous magnesium sulfate, and concentrating to obtain 146g of the methylamine, wherein the yield is 84.5%, and the purity is more than or equal to 98.6%.
3. A synthetic method of metronidazole comprises the following steps:
dissolving 100g N, N' -dimethyl urea in 200mL of dichloromethane to prepare a solution, slowly adding the solution into a mixed acid consisting of 338g of concentrated nitric acid with the mass concentration of 98% and 284g of concentrated sulfuric acid with the mass concentration of 98% for nitration reaction at the reaction temperature of-5-0 ℃, and pouring the reaction mixture into 400g of ice water for dilution after the addition is finished;
heating the diluent to 15 ℃ for hydrolysis reaction for 70min, separating the hydrolysate phase after the reaction is ended, drying the dichloromethane phase with anhydrous magnesium sulfate, and concentrating to obtain 138g of the metronidazole, wherein the yield is 79.9%, and the purity is more than or equal to 99.2%.
4. A synthetic method of metronidazole comprises the following steps:
dissolving 100g N, N' -dimethyl urea in 200mL of dichloromethane to prepare a solution, slowly adding the solution into mixed acid consisting of 278g of concentrated nitric acid with the mass concentration of 98% and 233g of concentrated sulfuric acid with the mass concentration of 98% for nitration reaction at the reaction temperature of-5-0 ℃, and pouring the reaction mixture into 400g of ice water for dilution after the addition is finished;
heating the diluent to 20 ℃ for hydrolysis reaction, wherein the hydrolysis time is 100min, separating the hydrolysate phase after the reaction is ended, drying the dichloromethane phase by using anhydrous magnesium sulfate, and concentrating to obtain 149g of the metronidazole, wherein the yield is 86.3%, and the purity is more than or equal to 98.6%.
5. A synthetic method of metronidazole comprises the following steps:
dissolving 100g N, N' -dimethyl urea in 200mL of dichloromethane to prepare a solution, slowly adding the solution into mixed acid consisting of 273g of concentrated nitric acid with the mass concentration of 98% and 229g of concentrated sulfuric acid with the mass concentration of 98% for nitration reaction at the reaction temperature of-5-0 ℃, and pouring the reaction mixture into 400g of ice water for dilution after the addition is finished;
heating the diluent to 25 ℃ for hydrolysis reaction for 40min, separating the hydrolysate phase after the reaction is ended, drying the dichloromethane phase with anhydrous magnesium sulfate, and concentrating to obtain 139g of the metronidazole, wherein the yield is 80.5%, and the purity is more than or equal to 99.3%.
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4476322A (en) * 1982-07-01 1984-10-09 The United States Of America As Represented By The Secretary Of The Navy Synthesis of dimethylmethylene dinitramine

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2997501A (en) * 1958-08-04 1961-08-22 Shiino Kazuo 1, 3-dinitro-1, 3-dimethyl urea
AU2002226308A1 (en) * 2000-08-30 2002-04-08 Dynitec Gmbh Method for producing dnda
DE10142126A1 (en) * 2001-08-30 2003-03-27 Dynamit Nobel Ag Production of a mixture of N,N'-dimethylbisnitramine and N,N'-diethylbisnitramine, useful as a plasticizer in propellant charges, comprises nitration using highly concentrated nitric acid

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4476322A (en) * 1982-07-01 1984-10-09 The United States Of America As Represented By The Secretary Of The Navy Synthesis of dimethylmethylene dinitramine

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