CN114149375A - Intermediate for synthesizing sulfentrazone and synthesis method thereof - Google Patents

Intermediate for synthesizing sulfentrazone and synthesis method thereof Download PDF

Info

Publication number
CN114149375A
CN114149375A CN202111287333.3A CN202111287333A CN114149375A CN 114149375 A CN114149375 A CN 114149375A CN 202111287333 A CN202111287333 A CN 202111287333A CN 114149375 A CN114149375 A CN 114149375A
Authority
CN
China
Prior art keywords
reaction
sulfentrazone
acetamide
synthesis
acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202111287333.3A
Other languages
Chinese (zh)
Inventor
骆成才
李玉麒
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Zhejiang University of Science and Technology ZUST
Original Assignee
Zhejiang University of Science and Technology ZUST
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Zhejiang University of Science and Technology ZUST filed Critical Zhejiang University of Science and Technology ZUST
Priority to CN202111287333.3A priority Critical patent/CN114149375A/en
Publication of CN114149375A publication Critical patent/CN114149375A/en
Pending legal-status Critical Current

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles 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
    • C07D249/12—Oxygen or sulfur atoms

Landscapes

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

Abstract

An intermediate for synthesizing sulfentrazone and its synthetic method, the first step is in the structure that does not have N-difluoro methyl to substitute triazolinone ring, on 5 th place of benzene ring nitrify and react with nitryl reduction directly, because before not forming N-difluoro methyl to substitute triazolinone ring, carry on nitrify and nitro reduction on benzene ring first, needn't consider the instability problem of N-difluoro methyl to substitute triazolinone ring, so can choose more methods and need not consider adopting the influence of these methods on N-difluoro methyl to substitute triazolinone ring, thus help the lasting improvement of the synthetic technology of sulfentrazone, synthesize the yield higher than already disclosed technical scheme with this intermediate to synthesize sulfentrazone; the specific structural formula is as follows:
Figure DDA0003333600050000011

Description

Intermediate for synthesizing sulfentrazone and synthesis method thereof
Technical Field
The invention relates to the technical field of synthesizing an intermediate of sulfentrazone, in particular to an intermediate for synthesizing sulfentrazone and a synthesis method thereof.
Background
A herbicide of difluoromethyl triazolinone, sulfentrazone, its chemical structural formula is as follows:
Figure BDA0003333600030000011
the chemical name of the herbicide is N- (2, 4-dichloro-5- (4-difluoromethyl-4, 5-dihydro-3-methyl-5-oxo-1H-1, 2, 4-triazol-1-yl) phenyl) methanesulfonamide, and the current synthetic method of the herbicide generally adopts the following basic method:
Figure BDA0003333600030000012
(Zhang Yuan, Sun Yonghui, Shi Jie Ping, pesticide, 2013, 52(4), 260-Bian 262.), the total yield of the reaction is 26.8 percent.
The analysis of the basic method shows that: the method takes 2, 4-dichloroaniline as a raw material, and the final sulfentrazone is obtained through the steps of diazotization, hydrazone formation, cyclization, N-difluoromethylation, nitration, reduction, mesylation and the like. In addition, Liqian et al also reported a method for synthesizing sulfentrazone by the same route (Liqian, Xugang, Yanglirong, Wujian, chemical reaction engineering and technology, 2012, 28(5), 412-. In addition, the patent document CN103951627B and other patents also disclose the preparation of sulfentrazone, but the disclosure of the patent document is an improvement on the individual steps in the basic method for synthesizing sulfentrazone. Moreover, these prior art schemes have low overall yield and are all based on N-difluoromethyl substituted triazolinone ring- (R) -methyl
Figure BDA0003333600030000022
After the formation, the nitration reaction and the nitro reduction reaction are carried out under the condition of mixed acid on the 5-position benzene ring on the left side, and the total yield of the two steps of reactions (nitration reaction and nitro reduction reaction) is only about 70 percent, so that the sulfentrazone produced by adopting the technical scheme has high cost; in addition, since the N-difluoromethyl-substituted triazolinone ring is unstable under certain conditions (e.g., under mild reaction conditions such as strong acid nitration and reduction, the N-difluoromethyl-substituted triazolinone ring may be decomposed and damaged), the method adopted for benzene ring nitration and reduction in the presence of the N-difluoromethyl-substituted triazolinone ring is limited by the stability of the group, which is not favorable for continuous improvement of the technical scheme.
Disclosure of Invention
The invention aims at the defects of the prior art and provides an intermediate for synthesizing sulfentrazone, namely N- (2, 4-dichloro-5- (3-methyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazole-1-yl) phenyl) acetamide, the structure of the intermediate does not need to place an N-difluoromethyl substituted triazolinone ring in strong reaction conditions of mixed acid nitration, reduction and the like, the risk of instability of the structure of the N-difluoromethyl substituted triazolinone ring is reduced, and in addition, the yield of the sulfentrazone synthesized by using the intermediate can be higher than that of the disclosed technical scheme.
In order to solve the technical problems, the invention adopts the technical scheme that: an intermediate for synthesizing sulfentrazone, the chemical name of the intermediate is N- (2, 4-dichloro-5- (3-methyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazole-1-yl) phenyl) acetamide, and the structural formula is as follows:
Figure BDA0003333600030000021
further, the synthesis method of the intermediate for synthesizing sulfentrazone comprises the following specific synthesis route:
Figure BDA0003333600030000031
preferably, the synthesis method of the intermediate for synthesizing sulfentrazone comprises the following specific synthesis steps:
(1) adding 2, 4-dichloroaniline and concentrated sulfuric acid into a reaction container, and cooling in an ice water bath; then, a mixture consisting of concentrated sulfuric acid and concentrated nitric acid is dripped at the temperature of 0 ℃ or below, and the reaction is continued at the same temperature after the dripping is finished; after the reaction is finished, adding the reaction mixture into an ice water mixture, filtering out precipitates, and crystallizing in an isopropanol/water mixed solvent to obtain 2, 4-dichloro-5-nitroaniline;
(2) adding the 2, 4-dichloro-5-nitroaniline prepared in the step (1) and alkali into a reaction vessel containing a solvent, and uniformly stirring; dropwise adding acetyl chloride into the reaction container at room temperature, and continuing to react at room temperature after dropwise adding; after the reaction is finished, adding the reaction mixture into ice water, separating liquid, washing a solvent layer with saturated saline solution for 2-4 times respectively, then washing with water for 1-2 times, drying with anhydrous sodium sulfate, filtering, removing the solvent, and crystallizing the obtained crude product in ethanol/water to obtain N- (2, 4-dichloro-5-nitrophenyl) acetamide;
(3) adding the N- (2, 4-dichloro-5-nitrophenyl) acetamide prepared in the step (2) and a material for nitro reduction into a reaction vessel, uniformly stirring, and slowly heating to 80-90 ℃ for reaction; after the reaction is finished, neutralizing the reaction mixture to pH 7.5-8.5, respectively extracting with ethyl acetate for 2-5 times, combining ethyl acetate, drying with anhydrous sodium sulfate, filtering, removing ethyl acetate, and crystallizing the obtained crude product in ethanol/water to obtain N- (5-amino-2, 4-dichlorophenyl) acetamide;
(4) adding N- (5-amino-2, 4-dichlorophenyl) acetamide and concentrated hydrochloric acid prepared by the method in the step (3) into a reaction vessel, stirring for 0.5-1.5 hours, cooling to below-10 ℃, dropwise adding a solution formed by dissolving sodium nitrite in water under the protection of nitrogen, and continuing to react for 1.5-2.5 hours at the same temperature after dropwise adding; adding stannous chloride into the reaction mixture in batches at the temperature of minus 10 ℃ or below, stirring for reaction for 0.5 to 2 hours after adding, then heating to room temperature and continuing to react for 2 to 4 hours; adding saturated sodium hydroxide solution, adjusting pH to 8-9, extracting, drying, filtering, and removing the extraction solvent to obtain N- (2, 4-dichloro-5-hydrazinophenyl) acetamide;
(5) adding the N- (2, 4-dichloro-5-hydrazinophenyl) acetamide prepared by the method in the step (4) and hydrochloric acid into a reaction vessel, and uniformly stirring at room temperature; dripping solution formed by dissolving pyruvic acid in water; continuously stirring and reacting for 20-40min after the dropwise adding is finished, then filtering to obtain a precipitate, then leaching the precipitate for 2-5 times by using ice water, and drying the obtained solid in a vacuum environment to obtain 2- (2- (5-acetamido-2, 4-dichlorophenyl) hydrazono) propionic acid;
(6) adding the 2- (2- (5-acetamido-2, 4-dichlorophenyl) hydrazono) propionic acid synthesized in the step (5), triethylamine, azido diphenyl phosphate and toluene into a reaction vessel, and uniformly stirring; slowly heating the reaction mixture to reflux; stopping the reaction after refluxing for 4-6 hours, adding the cooled reaction mixture into a sodium hydroxide solution, and separating the solution; and then adding concentrated hydrochloric acid into the lower layer solution to adjust the pH value to be 5-6.5, filtering, washing filter cakes for 2-5 times by using clear water respectively, and drying the obtained solid to obtain the target product N- (2, 4-dichloro-5- (3-methyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazole-1-yl) phenyl) acetamide.
Preferably, the ratio of the addition amount of the 2, 4-dichloroaniline to the concentrated sulfuric acid (the concentrated sulfuric acid added for the first time) in the step (1) is 0.1-0.2 mol: 100ml (namely, 0.1 to 0.2mol of 2, 4-dichloroaniline is added into every 100ml of concentrated sulfuric acid); the volume ratio of the concentrated sulfuric acid to the concentrated nitric acid in the mixture of the concentrated sulfuric acid and the concentrated nitric acid is 9-12: 1.
Preferably, the ratio of the addition amount of the 2, 4-dichloroaniline to the mixture of concentrated sulfuric acid and concentrated nitric acid in the step (1) is 0.2-0.25 mol: 100ml (i.e. 0.2-0.25mol of 2, 4-dichloroaniline per 100ml of a mixture of concentrated sulphuric acid and concentrated nitric acid).
Preferably, the molar ratio of the 2, 4-dichloro-5-nitroaniline to the base in step (2) is: 1:2-3.
Preferably, the molar ratio of acetyl chloride to base in step (2) is: 1:1.8-2.2.
Preferably, the solvent in step (2) is at least one organic solvent selected from dichloromethane, chloroform and dichloroethane, and the base is one selected from triethylamine, pyridine and diisopropylethylamine.
Preferably, the nitro-group reducing material in step (3) is one of concentrated hydrochloric acid and stannous chloride, or Fe and acetic acid, or sodium sulfide or catalytic hydrogenation.
Further preferably, the nitro-reduced material in step (3) is concentrated hydrochloric acid and stannous chloride, wherein the molar ratio of the stannous chloride to the N- (5-nitro-2, 4-dichlorophenyl) acetamide is: 2.5-3.5:1.
Preferably, the molar ratio of the N- (5-amino-2, 4-dichlorophenyl) acetamide to the sodium nitrite and the stannous chloride in the step (4) is: 1:1:2.5-3.5.
Preferably, the concentration of the hydrochloric acid in the step (5) is 4-6 mol/l.
Preferably, the reaction ratio of the N- (2, 4-dichloro-5-hydrazinophenyl) acetamide and 4-6mol/l hydrochloric acid in the step (5) is as follows: 0.15-0.3 mol: 100 ml.
Preferably, in the solution formed by pyruvic acid and water in the step (5), the ratio of pyruvic acid to water is as follows: 0.15-0.3 mol: 100 ml.
Preferably, the molar ratio of the 2- (2- (5-acetamido-2, 4-dichlorophenyl) hydrazono) propionic acid, the triethylamine and the diphenyl phosphorazidate in the step (6) is 1: 0.8-1.2: 0.8-1.2.
Preferably, the concentration of the sodium hydroxide solution in the step (6) is 0.8-1.2 mol/l.
The invention has the advantages and beneficial effects that:
1. the application still uses the prior art 2, 4-dichloroaniline as the starting material, and is different from the prior art in that the application synthesizes the final intermediate N- (2, 4-dichloro-5- (3-methyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazole-1-yl) phenyl) acetamide by directly nitrating 5-position of the benzene ring of the 2, 4-dichloroaniline through mixed acid in the first step, and then carrying out the subsequent cyclization reaction of acetyl protected amino, stannous reducing nitryl, diazotization reduction diazo, hydrazone formation, triazolinone ring and the like, the synthesis steps of the intermediate are easy to implement, the raw materials are cheap and easy to obtain, the reaction conditions are mild, the starting material is the same as the prior art, and the reaction yield is high, can efficiently and economically synthesize the N- (2, 4-dichloro-5- (3-methyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazole-1-yl) phenyl) acetamide intermediate.
2. The application provides an intermediate of the following structure for the first time:
Figure BDA0003333600030000051
as a brand new intermediate for synthesizing sulfentrazone, the intermediate is introduced into the step of synthesizing the sulfentrazone, and avoids the instability of the traditional N-difluoromethyl substituted triazolinone ring under certain conditions.
3. N- (2, 4-dichloro-5- (3-)Methyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazole-1-yl) phenyl) acetamide, the intermediate contains a triazolinone ring structure, and then the compound is synthesized with sulfentrazone, wherein the structural formula of the sulfentrazone is as follows:
Figure BDA0003333600030000052
it can be seen from this that the structure of the triazolinone ring of the compounds described above in the present application is subsequently introduced into CHF2A group, and NHCOCH3Conversion of groups to NHSO2CH3The final synthesis of the sulfentrazone can be completed by the groups, the subsequent two groups do not directly occur on a benzene ring on the left side, the introduction of the groups does not need a concentrated acid reaction environment (the mixture of concentrated nitric acid and concentrated sulfuric acid) or a nitro reduction reaction, the intermediate is obtained by adjusting the concentrated acid reaction to the first step of starting the reaction of the raw material 2, 4-dichloroaniline, and the 2, 4-dichloroaniline reacts with the concentrated acid to introduce nitro on the benzene ring; thereby eliminating the technical problem that the ring structure of the N-difluoromethyl substituted triazolinone is unstable (the ring-forming macromolecule is unstable relative to the micromolecule) under the concentrated acid environment and the nitro reduction reaction condition; therefore, the synthesis method effectively avoids the instability of the traditional N-difluoromethyl substituted triazolinone ring under certain conditions, and can reduce the generation of byproducts, thereby improving the synthesis yield of sulfentrazone.
4. The intermediate for synthesizing the sulfentrazone is used as an intermediate for synthesizing the sulfentrazone, is a brand-new intermediate for preparing the sulfentrazone, can select various methods and conditions for benzene ring nitration and nitro reduction due to the absence of an N-difluoromethyl substituted triazolinone ring during nitration and nitro reduction reaction on a benzene ring, does not need to consider the stability problem of the N-difluoromethyl substituted triazolinone ring under the methods and conditions, enlarges the adaptable range of reaction conditions, can provide more choices for developing more advanced sulfentrazone synthesis processes, and has important significance for the synthesis of the sulfentrazone.
Drawings
FIG. 1 NMR spectrum of N- (2, 4-dichloro-5-hydrazinophenyl) acetamide prepared in example 1.
FIG. 2 NMR carbon spectrum of N- (2, 4-dichloro-5-hydrazinophenyl) acetamide prepared in example 1.
FIG. 3 mass spectrum of N- (2, 4-dichloro-5-hydrazinophenyl) acetamide prepared in example 1.
FIG. 4 NMR spectrum of 2- (2- (5-acetamido-2, 4-dichlorophenyl) hydrazono) propionic acid prepared in example 1.
FIG. 5 NMR carbon spectrum of 2- (2- (5-acetamido-2, 4-dichlorophenyl) hydrazono) propionic acid prepared in example 1.
FIG. 6 NMR carbon spectrum of 2- (2- (5-acetamido-2, 4-dichlorophenyl) hydrazono) propionic acid prepared in example 1.
FIG. 7 NMR spectrum of N- (2, 4-dichloro-5- (3-methyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) phenyl) acetamide prepared in example 1.
FIG. 8 NMR carbon spectrum of N- (2, 4-dichloro-5- (3-methyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) phenyl) acetamide prepared in example 1.
FIG. 9 Mass spectrum of N- (2, 4-dichloro-5- (3-methyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) phenyl) acetamide prepared in example 1.
Detailed Description
The present invention will be described in further detail below by way of examples, but the present invention is not limited to only the following examples.
The specific dosage of each material related to the embodiment of the application is quantified by a rounding mode; the intermediate structures referred to in the following examples of the present application are all materials synthesized in the previous step and used as starting materials in the next step; other adopted raw materials are all conventional raw materials in the industry or products sold in the market without special description.
Example 1
1. Adding 64.80 g (0.40mol) of 2, 4-dichloroaniline and 300ml of concentrated sulfuric acid into a 500ml round-bottom flask, and cooling in an ice-water bath; a mixture of 160ml of concentrated sulfuric acid and 16ml of concentrated nitric acid was added dropwise at 0 ℃ and the reaction was continued at the same temperature for 2 hours after the addition. The reaction mixture was then added to 1500ml of an ice-water mixture, the precipitate was filtered off and crystallized in an isopropanol/water mixed solvent (isopropanol/water mixed solvent: 3:1 by volume, same as in example 2) to give 66.24 g (0.32mol) of 2, 4-dichloro-5-nitroaniline in 80% yield.
2. A500 ml round bottom flask was charged with 200ml of methylene chloride, 62.10 g (0.30mol) of 2, 4-dichloro-5-nitroaniline and 66.79 g (0.66mol) of triethylamine and stirred well. 86.35 g (0.33mol) of acetyl chloride was added dropwise to the flask at room temperature, and after the addition was completed, the reaction was continued at room temperature for 5 hours. After the reaction, the reaction mixture was added to 200ml of ice water, and the resulting mixture was separated, and the dichloromethane layer was washed twice with 100ml of saturated brine, once with 100ml of water, dried over anhydrous sodium sulfate, filtered, and the dichloromethane was removed, and the crude product obtained was crystallized from ethanol/water (ethanol/water ratio 2:1, same as in example 2) to obtain 70.97 g (0.285mol) of N- (2, 4-dichloro-5-nitrophenyl) acetamide (N- (5-nitro-2, 4-dichlorophenyl) acetamide), which was a product, with a yield of 95%.
3. 200ml of concentrated hydrochloric acid, 113.77 g (0.6mol) of stannous chloride and 49.80 g (0.20mol) of N- (5-nitro-2, 4-dichlorophenyl) acetamide were put into a 500ml round bottom flask, stirred uniformly and slowly heated to 85 ℃ for reaction for 8 hours. After the reaction was completed, the reaction mixture was neutralized to pH 8 with sodium hydroxide solution, extracted three times with 300ml of ethyl acetate, respectively, the ethyl acetate was combined, dried over anhydrous sodium sulfate, filtered to remove the ethyl acetate, and the resulting crude product was crystallized in ethanol/water (the volume ratio of ethanol to water was 3:1, the same as in example 2) to obtain 42.05 g (0.192mol) of N- (5-amino-2, 4-dichlorophenyl) acetamide as a product, with a yield of 96%.
4. A1000 ml round bottom flask was charged with 65.72 g (0.30mol) of N- (5-amino-2, 4-dichlorophenyl) acetamide and 200ml of concentrated hydrochloric acid, stirred for 1 hour, cooled to-10 ℃ and added dropwise with a solution of 20.7 g (0.30mol) of sodium nitrite in 120ml of water under nitrogen protection, and the reaction was continued at the same temperature for 2 hours after completion of the addition. 170.65 g (0.90mol) of stannous chloride was added in portions to the above reaction mixture at-10 ℃ and after the addition was completed, the reaction was stirred for 1 hour, and then the reaction was continued for 3 hours while warming to room temperature. Saturated sodium hydroxide solution was added, pH was adjusted to 9, dichloromethane was extracted (dichloromethane was used as an extraction solvent), dried over anhydrous sodium sulfate, filtered, and dichloromethane was removed to obtain 56.16 g (0.24mol) of the product N- (2, 4-dichloro-5-hydrazinophenyl) acetamide, which was a product with a yield of 80%.
The obtained product N- (2, 4-dichloro-5-hydrazinophenyl) acetamide is subjected to detection of hydrogen spectrum and carbon spectrum:1H NMR(500MHz，CDCl3)δ8.45(1H，s，-NH-CO-)，7.95(1H，s，-NH-NH2)，7.50(1H，s，-C6H-)，7.23(1H，s，-C6H-)，4.12(2H，s，-NH2-)，2.23(3H，s，-CH3CO-) (see FIG. 1 in particular).
13C NMR(500MHz，CD3OD)δ170.60(-CO-)，108.10～142.71(-C6H2-)，22.08(-CH3- (see in particular FIG. 2).
ESI-MS C8H9Cl2N3O[M+HCOOH]+Calculating the value: 279.02, found 279.10 (see fig. 3).
5. N- (2, 4-dichloro-5-hydrazinophenyl) acetamide 46.82 g (0.20mol) and 100ml hydrochloric acid at 5.0mol/l were added to a 250ml round bottom flask and stirred well at room temperature. A solution of 17.61 g (0.20mol) of pyruvic acid in 100ml of water was added dropwise, during which the reaction mixture gradually became cloudy. After the dropwise addition, the reaction was continued for half an hour with stirring, the precipitate was filtered, and the precipitate was rinsed with 70ml of ice water three times, respectively, and the resulting solid was dried under vacuum at 50 ℃ to obtain 54.72 g of 2- (2- (5-acetylamino-2, 4-dichlorophenyl) hydrazono) propionic acid in 90% yield.
The obtained product 2- (2- (5-acetamido-2, 4-dichlorophenyl) hydrazono) propionic acid is subjected to spectrogram detection as shown in attached figures 4-6:
1H NMR(500MHz，CDCl3) δ 8.03(s, 1H), 7.42(s, 1H), 2.19(s, 3H), 2.15(s, 3H) (fig. 4, hydrogen spectrum).
13C NMR(500MHz，CD3OD)δ170.66，154.09, 145.69, 139.50, 134.27, 128.92, 118.00, 114.26, 110.12, 21.98, 18.91 (fig. 5 carbon spectrum).
ESI-MS C11H11Cl2N3O3[M-H]-Calculating the value: 303.0177, 305.0148, found: 302.0185, 304.0141 (FIG. 6 Mass Spectrum).
6. 60.83 g (0.20mol) of 2- (2- (5-acetamido-2, 4-dichlorophenyl) hydrazono) propionic acid, 20.24 g (0.20mol) of triethylamine, 55.04 g (0.20mol) of DPPA (diphenylphosphoryl azide) and 120ml of toluene were added to a 250ml round-bottomed flask and stirred uniformly. The reaction mixture was slowly heated to 80 ℃ with evolution of gas, at 110 ℃ under reflux, and the solution gradually separated. After refluxing for 5 hours, the reaction was stopped, and the cooled reaction mixture was added to 150ml of a 1.0mol/l sodium hydroxide solution and separated. Concentrated hydrochloric acid is added into the lower layer solution to adjust the pH value to 6, and a large amount of brown yellow solid is separated out. Filtering, leaching filter cakes with 50ml of clean water for three times respectively, and drying the obtained solid in vacuum at 50 ℃ to obtain 54.36 g (0.18mol) of the product N- (2, 4-dichloro-5- (3-methyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazole-1-yl) phenyl) acetamide, the yield of which is 90 percent.
The obtained product N- (2, 4-dichloro-5- (3-methyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) phenyl) acetamide was subjected to spectrum detection as shown in the attached FIGS. 7 to 9:
1H NMR(500MHz，CD3OD) δ 8.09(s, 1H), 7.70(s, 1H), 2.24(s, 3H), 2.19(s, 3H) (fig. 7 hydrogen spectrum).
13C NMR(500MHz，CD3OD) δ 170.57, 154.09, 145.69, 132.75, 130.11, 128.79, 127.88, 126.83, 124.90, 22.14, 10.65 (fig. 8 carbon spectrum).
ESI-MS C11H10Cl2N4O2[M+H]+Calculating the value: 300.0181, 302.0151, found: 301.0278, 303.0243 (FIG. 9 Mass Spectrum).
The embodiment shows that the method of the application indeed obtains a brand-new intermediate for preparing sulfentrazone, the yield of the intermediate is high (yield is 90%), and the risk that triazolinone rings are unstable in a reaction environment in a subsequent process of preparing the sulfentrazone is avoided, so that the generation of byproducts can be reduced, and the synthesis yield of the sulfentrazone is improved.
Example 2
1. To a 500ml round bottom flask, 81.00 g (0.50mol) of 2, 4-dichloroaniline and 330ml of concentrated sulfuric acid were added, and the mixture was cooled in an ice-water bath. A mixture of 180ml of concentrated sulfuric acid and 18ml of concentrated nitric acid was added dropwise at 0 ℃ and the reaction was continued at the same temperature for 2 hours after the addition. The reaction mixture was added to 1600ml of an ice-water mixture, and the precipitate was filtered off and crystallized from an isopropanol/water mixed solvent to give 80.73 g (0.39mol) of 2, 4-dichloro-5-nitroaniline in 78% yield.
2. 220ml of chloroform, 62.10 g (0.30mol) of 2, 4-dichloro-5-nitroaniline and 54.51 g (0.69mol) of pyridine were charged into a 250ml round-bottomed flask and stirred at room temperature. 94.2 g (0.36mol) of acetyl chloride was added dropwise to the flask at room temperature, and the reaction was continued at room temperature for 5 hours after the completion of the addition. After the reaction is finished, adding the reaction mixture into 220ml of ice water, separating liquid, washing a chloroform layer with 120ml of saturated saline solution twice respectively, washing with 120ml of water once again, drying with anhydrous sodium sulfate, filtering, removing chloroform, and crystallizing the obtained crude product in ethanol/water to obtain 70.22 g (0.282mol) of product N- (2, 4-dichloro-5-nitrophenyl) acetamide (N- (5-nitro-2, 4-dichlorophenyl) acetamide), wherein the yield is 94%;
3. 230ml of concentrated hydrochloric acid, 132.73 g (0.7mol) of stannous chloride and 56.03 g (0.225mol) of N- (5-nitro-2, 4-dichlorophenyl) acetamide were put into a 500ml round-bottomed flask, and after stirring uniformly, the temperature was slowly raised to 85 ℃ to react for 8.5 hours. After the reaction was completed, the reaction mixture was neutralized to pH 8 with sodium hydroxide solution, extracted three times with 320ml of ethyl acetate, respectively, and the ethyl acetate was combined, dried over anhydrous sodium sulfate, filtered to remove the ethyl acetate, and the resulting crude product was crystallized from ethanol/water to obtain 46.87 g (0.214mol) of N- (5-amino-2, 4-dichlorophenyl) acetamide as a product in 95% yield.
4. 76.65 g (0.35mol) of N- (5-amino-2, 4-dichlorophenyl) acetamide and 210ml of concentrated hydrochloric acid are added into a 1000ml round bottom flask, the temperature is reduced to-10 ℃ after stirring for 1 hour, a solution of 24.15 g (0.35mol) of sodium nitrite in 125ml of water is added dropwise under the protection of nitrogen, and the reaction is continued for 2 hours at the same temperature after the dropwise addition. 205.73 g of stannous chloride (1.085mol) were added in portions to the above reaction mixture at-10 ℃ and after the addition was complete, the reaction was stirred for 1 hour, then warmed to room temperature and continued for 3 hours. Adding saturated sodium hydroxide solution, adjusting the pH value to 9, extracting with dichloromethane, drying with anhydrous sodium sulfate, filtering, and removing dichloromethane to obtain 66.46 g (0.284mol) of N- (2, 4-dichloro-5-hydrazinophenyl) acetamide product with the yield of 81%;
5. 42.13 g (0.18mol) of N- (2, 4-dichloro-5-hydrazinophenyl) acetamide and 120ml of hydrochloric acid with a concentration of 4.8mol/l were added to a 250ml round-bottom flask and stirred well at room temperature. A solution of 15.85 g (0.18mol) of pyruvic acid in 90 ml of water is added dropwise, during which the reaction mixture gradually becomes cloudy. After the dropwise addition, the reaction is continued for 25min by stirring, the precipitate is filtered, the precipitate is rinsed with 65ml of ice water for three times, and the obtained solid is dried in vacuum at 50 ℃ to obtain 48.97 g of the product 2- (2- (5-acetamido-2, 4-dichlorophenyl) hydrazono) propionic acid with the yield of 89.5 percent;
6. 60.82 g (0.20mol) of 2- (2- (5-acetamido-2, 4-dichlorophenyl) hydrazono) propionic acid, 18.22 g (0.18mol) of triethylamine, 49.54 g (0.18mol) of DPPA (diphenylphosphoryl azide) and 110ml of toluene were added to a 250ml round-bottomed flask and stirred well. The reaction mixture was slowly heated to 80 ℃ with evolution of gas, at 110 ℃ under reflux, and the solution gradually separated. After refluxing for 5.5 hours, the reaction was stopped, and the cooled reaction mixture was added to 145ml of a 1.0mol/l sodium hydroxide solution and separated. Concentrated hydrochloric acid is added into the lower layer solution to adjust the pH value to 6, and a large amount of brown yellow solid is separated out. The filtrate was washed with 50ml of clear water three times, and the obtained solid was dried under vacuum at 50 ℃ to obtain 52.85 g (0.175mol) of the product N- (2, 4-dichloro-5- (3-methyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) phenyl) acetamide with 87.5% yield.
The above examples show that, as an important intermediate for synthesizing sulfentrazone, N- (2, 4-dichloro-5- (3-methyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) phenyl) acetamide in the application can effectively avoid the existence of a triazolinone ring structure in a strong acid environment of mixed acid nitration and avoid the risk of structural instability of the triazolinone ring structure under such reaction conditions; and the synthesis method of the intermediate enables the finally obtained sulfentrazone to have high yield.
The intermediate for synthesizing the sulfentrazone is a brand new compound, does not appear in the existing synthesis of the sulfentrazone, other intermediate structures before and after the intermediate related to the application are all brand new intermediates for synthesizing the sulfentrazone, and each intermediate can be used as an important raw material for synthesizing the sulfentrazone, so that the intermediate has very important protective significance for an applicant and provides more choices for a synthetic route of the sulfentrazone; more importantly, the intermediate of the application and other intermediates for synthesizing sulfentrazone before and after the intermediate can realize that: during the nitration and the nitro reduction reaction on the benzene ring, because the N-difluoromethyl substituted triazolinone ring does not exist, various methods and conditions for nitration of the benzene ring and nitro reduction can be selected without considering the stability problem of the N-difluoromethyl substituted triazolinone ring under the methods and conditions, so that more choices and development ideas can be provided for developing more advanced synthesis processes of sulfentrazone, and the method has important significance for the synthesis of the sulfentrazone; the application or the subsequent intermediate structure is used for synthesizing sulfentrazone, so that the yield of the final target product and the yield and purity of other intermediates are effectively improved; therefore, the applicant has separately filed patent applications for various intermediates involved in this particular process for synthesizing sulfentrazone.

Claims (10)

1. An intermediate for synthesizing sulfentrazone, which is characterized in that: the structure of the intermediate is as follows:
Figure FDA0003333600020000011
2. the synthesis process of an intermediate for the synthesis of sulfentrazone according to claim 1, characterized in that: the specific synthetic route of the method is as follows:
Figure FDA0003333600020000012
3. the synthesis process of an intermediate for the synthesis of sulfentrazone according to claim 2, characterized in that: the specific synthesis steps comprise:
(1) adding 2, 4-dichloroaniline and concentrated sulfuric acid into a reaction container, and cooling in an ice water bath; then, a mixture consisting of concentrated sulfuric acid and concentrated nitric acid is dripped at the temperature of 0 ℃ or below, and the reaction is continued at the same temperature after the dripping is finished; after the reaction is finished, adding the reaction mixture into an ice water mixture, filtering out precipitates, and crystallizing in an isopropanol/water mixed solvent to obtain 2, 4-dichloro-5-nitroaniline;
(2) adding the 2, 4-dichloro-5-nitroaniline prepared in the step (1) and alkali into a reaction vessel containing a solvent, and uniformly stirring; dropwise adding acetyl chloride into the reaction container at room temperature, and continuing to react at room temperature after dropwise adding; after the reaction is finished, adding the reaction mixture into ice water, separating liquid, washing a solvent layer with saturated saline solution for 2-4 times respectively, then washing with water for 1-2 times, drying with anhydrous sodium sulfate, filtering, removing the solvent, and crystallizing the obtained crude product in ethanol/water to obtain N- (2, 4-dichloro-5-nitrophenyl) acetamide;
(3) adding the N- (2, 4-dichloro-5-nitrophenyl) acetamide prepared in the step (2) and a material for nitro reduction into a reaction vessel, uniformly stirring, and slowly heating to 80-90 ℃ for reaction; after the reaction is finished, neutralizing the reaction mixture to pH 7.5-8.5, respectively extracting with ethyl acetate for 2-5 times, combining ethyl acetate, drying with anhydrous sodium sulfate, filtering, removing ethyl acetate, and crystallizing the obtained crude product in ethanol/water to obtain N- (5-amino-2, 4-dichlorophenyl) acetamide;
(4) adding N- (5-amino-2, 4-dichlorophenyl) acetamide and concentrated hydrochloric acid prepared by the method in the step (3) into a reaction vessel, stirring for 0.5-1.5 hours, cooling to below-10 ℃, dropwise adding a solution formed by dissolving sodium nitrite in water under the protection of nitrogen, and continuing to react for 1.5-2.5 hours at the same temperature after dropwise adding; adding stannous chloride into the reaction mixture in batches at the temperature of minus 10 ℃ or below, stirring for reaction for 0.5 to 2 hours after adding, then heating to room temperature and continuing to react for 2 to 4 hours; adding saturated sodium hydroxide solution, adjusting pH to 8-9, extracting, drying, filtering, and removing the extraction solvent to obtain N- (2, 4-dichloro-5-hydrazinophenyl) acetamide;
(5) adding the N- (2, 4-dichloro-5-hydrazinophenyl) acetamide prepared by the method in the step (4) and hydrochloric acid into a reaction vessel, and uniformly stirring at room temperature; dropwise adding a solution formed by dissolving pyruvic acid in water, continuing to stir for reaction for 20-40min after dropwise adding is finished, then filtering to obtain a precipitate, then leaching the precipitate for 2-5 times by using ice water, and drying the obtained solid in a vacuum environment to obtain 2- (2- (5-acetamido-2, 4-dichlorophenyl) hydrazono) propionic acid;
(6) adding the 2- (2- (5-acetamido-2, 4-dichlorophenyl) hydrazono) propionic acid synthesized in the step (5), triethylamine, azido diphenyl phosphate and toluene into a reaction vessel, and uniformly stirring; slowly heating the reaction mixture to reflux; stopping the reaction after refluxing for 4-6 hours, adding the cooled reaction mixture into a sodium hydroxide solution, and separating the solution; and then adding concentrated hydrochloric acid into the lower layer solution to adjust the pH value to be 5-6.5, filtering, washing filter cakes for 2-5 times by using clear water respectively, and drying the obtained solid to obtain the target product N- (2, 4-dichloro-5- (3-methyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazole-1-yl) phenyl) acetamide.
4. A synthesis process of an intermediate for the synthesis of sulfentrazone according to claim 3, characterized in that: the adding amount ratio of the 2, 4-dichloroaniline to the concentrated sulfuric acid in the step (1) is 0.1-0.2 mol: 100 ml; the volume ratio of the concentrated sulfuric acid to the concentrated nitric acid in the mixture of the concentrated sulfuric acid and the concentrated nitric acid is 9-12: 1.
5. A synthesis process of an intermediate for the synthesis of sulfentrazone according to claim 3, characterized in that: the adding amount ratio of the mixture consisting of the 2, 4-dichloroaniline, the concentrated sulfuric acid and the concentrated nitric acid in the step (1) is 0.2-0.25 mol: 100 ml.
6. A synthesis process of an intermediate for the synthesis of sulfentrazone according to claim 3, characterized in that: the molar ratio of the 2, 4-dichloro-5-nitroaniline to the alkali in the step (2) is as follows: 1: 2-3; the molar ratio of acetyl chloride to alkali in the step (2) is as follows: 1:1.8-2.2.
7. A synthesis process of an intermediate for the synthesis of sulfentrazone according to claim 3, characterized in that: the solvent in the step (2) is at least one organic solvent of dichloromethane, trichloromethane and dichloroethane, and the base is one of triethylamine, pyridine or diisopropylethylamine.
8. A synthesis process of an intermediate for the synthesis of sulfentrazone according to claim 3, characterized in that: the nitro-group reducing material in the step (3) is one of concentrated hydrochloric acid and stannous chloride, or Fe and acetic acid, or sodium sulfide or catalytic hydrogenation.
9. The synthesis process of an intermediate for the synthesis of sulfentrazone according to claim 8, characterized in that: the nitro-reduced material in the step (3) is concentrated hydrochloric acid and stannous chloride, wherein the molar ratio of the stannous chloride to the N- (5-nitro-2, 4-dichlorophenyl) acetamide is as follows: 2.5-3.5: 1; the molar ratio of the N- (5-amino-2, 4-dichlorophenyl) acetamide to the sodium nitrite and the stannous chloride in the step (4) is as follows: 1:1:2.5-3.5.
10. A synthesis process of an intermediate for the synthesis of sulfentrazone according to claim 3, characterized in that: the concentration of the hydrochloric acid in the step (5) is 4-6mol/l, and the reaction ratio of the N- (2, 4-dichloro-5-hydrazinophenyl) acetamide to the hydrochloric acid of 4-6mol/l in the step (5) is as follows: 0.15-0.3 mol: 100 ml; in the solution formed by pyruvic acid and water in the step (5), the ratio of pyruvic acid to water is as follows: 0.15-0.3 mol: 100 ml; the molar use ratio of the 2- (2- (5-acetamido-2, 4-dichlorophenyl) hydrazono) propionic acid, the triethylamine and the azido diphenyl phosphate in the step (6) is 1: 0.8-1.2: 0.8-1.2; the concentration of the sodium hydroxide solution in the step (6) is 0.8-1.2 mol/l.
CN202111287333.3A 2021-11-02 2021-11-02 Intermediate for synthesizing sulfentrazone and synthesis method thereof Pending CN114149375A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202111287333.3A CN114149375A (en) 2021-11-02 2021-11-02 Intermediate for synthesizing sulfentrazone and synthesis method thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202111287333.3A CN114149375A (en) 2021-11-02 2021-11-02 Intermediate for synthesizing sulfentrazone and synthesis method thereof

Publications (1)

Publication Number Publication Date
CN114149375A true CN114149375A (en) 2022-03-08

Family

ID=80459495

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202111287333.3A Pending CN114149375A (en) 2021-11-02 2021-11-02 Intermediate for synthesizing sulfentrazone and synthesis method thereof

Country Status (1)

Country Link
CN (1) CN114149375A (en)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4743291A (en) * 1984-10-31 1988-05-10 Fmc Corporation Herbicidal aryl triazolinones
JPH02229157A (en) * 1989-03-02 1990-09-11 Nissan Chem Ind Ltd Tetrahydrophthalimide derivative and herbicide
CN106478532A (en) * 2016-08-27 2017-03-08 江苏瑞邦农药厂有限公司 A kind of method of synthesis sulfentrazone

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4743291A (en) * 1984-10-31 1988-05-10 Fmc Corporation Herbicidal aryl triazolinones
JPH02229157A (en) * 1989-03-02 1990-09-11 Nissan Chem Ind Ltd Tetrahydrophthalimide derivative and herbicide
CN106478532A (en) * 2016-08-27 2017-03-08 江苏瑞邦农药厂有限公司 A kind of method of synthesis sulfentrazone

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
李勤耕 等: "有机化学", vol. 1, 西安：第四军医大学出版社, pages: 226 - 228 *
梁凯 ，等: "磺酰三唑酮的合成及工艺研究", 化学反应工程与工艺, vol. 28, no. 5, pages 413 *

Similar Documents

Publication Publication Date Title
AU2009245791B2 (en) Method for manufacturing aryl carboxamides
EP2230234A1 (en) Process for the preparation of rufinamide
EP3812366B1 (en) A preparation method for m-diamide compounds
CN104968649B (en) Method for preparing amicarbazone, intermediate compound and method for preparing hydrazine carboxylic acid
EA011555B1 (en) A process for the preparation of [1,4,5]-oxadiazepine derivatives
CN114149375A (en) Intermediate for synthesizing sulfentrazone and synthesis method thereof
CN114057659B (en) Intermediate for synthesizing sulfenamide and synthesis method thereof
CN108610290B (en) Preparation method of fluxapyroxad
CN114031520A (en) 2- (2- (5-acetamido-2, 4-dichlorophenyl) hydrazono) propionic acid compound and synthetic method thereof
CN114181162B (en) Preparation method of sulfonyl carfentrazone-ethyl
CN114044758B (en) Synthetic method of intermediate for preparing triazolinone herbicide sulfenamide
CN114149342A (en) N- (2, 4-dichloro-5-hydrazinophenyl) acetamide compound and synthesis method thereof
JP4641795B2 (en) Process for producing 1,2,4-triazolylmethyloxiranes
AU737994B2 (en) Process for preparing o-(3-amino-2-hydroxy-propyl)-hydroxymic acid halides
US5200551A (en) Method of preparing an intermediate for the manufacture of bambuterol
JP2002519409A (en) Method for producing 2-nitro-5- (phenylthio) -aniline
JP2023537236A (en) An improved chlorantraniliprole process using a crystalline intermediate
CN114276306A (en) Synthetic method of sulfentrazone
CN106866560B (en) Lesinurad synthesis method
CN114315744A (en) Synthetic method of sulfentrazone intermediate
CA1119179A (en) Process for preparing n-tritylimidazole compounds
CN115536643A (en) Preparation method of key intermediate of isavuconazole medicine
EP1000939B1 (en) Producing z-isomer of hydrogen bromide salt of 2-aminothiazole derivative
JPS5944359A (en) Manufacture of 1-azolyl-3,3-dimethyl-1- phenoxybutane-2-ol
JPS5940387B2 (en) Method for stereospecifically producing cis-imidazolyl-oxime ether derivatives

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination