CN108727215B - Preparation method of metronidazole - Google Patents

Preparation method of metronidazole Download PDF

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CN108727215B
CN108727215B CN201810241180.0A CN201810241180A CN108727215B CN 108727215 B CN108727215 B CN 108727215B CN 201810241180 A CN201810241180 A CN 201810241180A CN 108727215 B CN108727215 B CN 108727215B
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reaction
metronidazole
solution
dichloromethane
mass concentration
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CN108727215A (en
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陈斌
汪营磊
丁峰
刘卫孝
刘亚静
马玲
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Xian Modern Chemistry Research Institute
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    • 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
    • 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

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention discloses a method for preparing 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 mixed acid consisting of concentrated nitric acid with the mass concentration of 98% and fuming sulfuric acid with the mass concentration of 20% 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; (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, incomplete N, N' -dimethyl urea nitration, harsh hydrolysis conditions, low yield and the like in the preparation process of the methyl nitramine. The method is mainly used for preparing the metronidazole.

Description

Preparation method of metronidazole
Technical Field
The invention relates to N, N' -dimethyl urea nitration and hydrolysis, in particular to a preparation method of 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, incomplete N, N' -dimethylurea nitration, harsh hydrolysis conditions, low yield and the like, and is difficult to realize high-efficiency preparation.
Disclosure of Invention
The invention aims to solve the technical problems of overcoming the defects of complex reaction operation steps, incomplete N, N' -dimethylurea nitration, harsh hydrolysis conditions, low yield and the like in the preparation process of the methyl nitramine in the background technology and providing the preparation method of the methyl nitramine, which has the advantages of complete nitration, simple and convenient post-treatment operation, mild hydrolysis conditions and higher yield.
The invention has the following conception: aiming at the current situations of complicated reaction operation steps, incomplete N, N' -dimethyl urea nitration, harsh hydrolysis conditions and low yield in the synthesis method of the methyl nitramine, the synthesis method with complete nitration, simple and convenient treatment operation after nitration, mild hydrolysis conditions and high yield is sought. The mixed acid system formed by substituting 20% fuming sulfuric acid for sulfuric acid and nitric acid can improve the nitration degree of N, N' -dimethyl urea, and is favorable for improving the yield; the nitrified liquid is diluted by ice water, the temperature is adjusted to be directly hydrolyzed, 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 preparation 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 fuming sulfuric acid with the mass concentration of 20% (the mass fraction of sulfur trioxide is 20% in the mixture of sulfuric acid and sulfur trioxide) to carry out nitration reaction at the reaction temperature of-5-0 ℃, and pouring the reaction mixture into ice water for dilution after the addition is finished; wherein the mass ratio of N, N' -dimethyl urea, concentrated nitric acid with the mass concentration of 98%, fuming sulfuric acid with the mass concentration of 20% 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 preparation 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 fuming sulfuric acid with the mass concentration of 20% 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%, fuming sulfuric acid with the mass concentration of 20% 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:
(1) according to the invention, the mixed acid system is formed by adopting 20% fuming sulfuric acid instead of sulfuric acid and 98% concentrated nitric acid by mass concentration, so that the nitration degree of N, N' -dimethyl urea can be improved, and the yield is improved;
(2) the invention adopts a method of adjusting the temperature and directly hydrolyzing after the nitrifying liquid is diluted by ice water, thereby reducing the steps of extracting the intermediate N, N '-dimethyl-N, N' -dinitrourea by dichloromethane, alkali washing, water washing and the like;
(3) the method changes the hydrolysis of boiling water into the hydrolysis of room temperature, reduces the reaction temperature, improves the hydrolysis effect of N, N '-dimethyl-N, N' -dinitrourea, and improves the yield of the metronidazole from 57.9 percent to 89.2 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 fuming sulfuric acid with the mass concentration of 20% 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 154g of the metronidazole, wherein the yield is 89.2%, and the purity is more than or equal to 99.4%.
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 20% fuming sulfuric acid 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 119g of the metronidazole, wherein the yield is 68.9%, and the purity is more than or equal to 98.7%.
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 98 percent concentrated nitric acid and 218g of 20 percent fuming sulfuric acid to carry out nitration reaction at the reaction temperature of-5 ℃ to 0 ℃, and after the addition is finished, the reaction mixture is poured into 400g of ice water to be diluted.
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 150g of the metronidazole, wherein the yield is 86.9%, and the purity is more than or equal to 99.4%.
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 20% fuming sulfuric acid 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 133g of the methylamine, wherein the yield is 77.1%, and the purity is more than or equal to 99.1%.
Example 5
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 316g of concentrated nitric acid with the mass concentration of 98% and 265g of fuming sulfuric acid with the mass concentration of 20% 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 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 131g with the yield of 75.9% and the purity of more than or equal to 98.6%.
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 fuming sulfuric acid with the mass concentration to carry out 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 to be diluted.
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 142g of the metronidazole, wherein the yield is 82.3%, and the purity is more than or equal to 99.3%.
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 fuming sulfuric acid with the mass concentration of 20% 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 100min, separating the hydrolysate phase after the reaction is ended, drying the dichloromethane phase with anhydrous magnesium sulfate, and concentrating to obtain 153g of the metronidazole, wherein the yield is 88.6%, and the purity is more than or equal to 98.8%.
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 20% fuming sulfuric acid 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 143g of the metronidazole, wherein the yield is 82.9%, and the purity is more than or equal to 98.5%.
Example 9
100g N, N' -dimethyl urea is dissolved in 200mL dichloromethane to prepare 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 20% fuming sulfuric acid 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 137g of the metronidazole, wherein the yield is 79.4%, and the purity is more than or equal to 99.2%.

Claims (5)

1. A preparation method of the 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 fuming sulfuric acid with the mass concentration of 20% to carry out nitration reaction at the reaction temperature of-5-0 ℃, and pouring the reaction mixture into 400g of ice water to dilute 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 154g of the metronidazole, wherein the yield is 89.2%, and the purity is more than or equal to 99.4%.
2. A preparation method of the metronidazole comprises the following steps:
dissolving 100g N, N' -dimethylurea in 200mL of dichloromethane to prepare a solution, slowly adding the solution into a mixed acid consisting of 260g of 98% concentrated nitric acid and 218g of 20% fuming sulfuric acid to carry out nitration reaction at the reaction temperature of-5-0 ℃, and pouring the reaction mixture into 400g of ice water to dilute 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 150g of the metronidazole, wherein the yield is 86.9%, and the purity is more than or equal to 99.4%.
3. A preparation method of the 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 20% fuming sulfuric acid 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 142g of the metronidazole, wherein the yield is 82.3%, and the purity is more than or equal to 99.3%.
4. A preparation method of the 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 fuming sulfuric acid with the mass concentration of 20% to carry out nitration reaction at the reaction temperature of-5-0 ℃, and pouring the reaction mixture into 400g of ice water to dilute after the addition is finished;
heating the diluent to 20 ℃ for hydrolysis reaction for 100min, separating the hydrolysate phase after the reaction is ended, drying the dichloromethane phase with anhydrous magnesium sulfate, and concentrating to obtain 153g of the metronidazole, wherein the yield is 88.6%, and the purity is more than or equal to 98.8%.
5. A preparation method of the 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 20% fuming sulfuric acid to carry out nitration reaction at the reaction temperature of-5-0 ℃, and pouring the reaction mixture into 400g of ice water to dilute 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 143g of the metronidazole, wherein the yield is 82.9%, and the purity is more than or equal to 98.5%.
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Citations (2)

* 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
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

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CZ2003580A3 (en) * 2000-08-30 2006-07-12 Dynamit Nobel Gmbh Explosivstoff-Und Systemtechnik Process for preparing DNDA

Patent Citations (2)

* 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
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

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