阅读说明：本技术 一种2-氨基-5-氯-n,3-二甲基苯甲酰胺的制备方法 (Preparation method of 2-amino-5-chloro-N, 3-dimethylbenzamide ) 是由 张虎 周炜 徐秋龙 周志豪 褚小静 于 2020-05-27 设计创作，主要内容包括：本发明涉及一种2-氨基-5-氯-N,3-二甲基苯甲酰胺的制备方法。该制备方法包含了以下步骤：以2-硝基-3-甲基苯甲酸为起始原料,依次经还原反应、氯代反应、酯化反应和氨解反应,得到2-氨基-5-氯-N,3-二甲基苯甲酰胺。本发明的制备方法为2-氨基-5-氯-N,3-二甲基苯甲酰胺的合成提供了一条新的路径,整条路线收率可达80％以上,成本显著降低,各步骤反应条件温和,三废数量少,适合工业化生产。(The invention relates to a preparation method of 2-amino-5-chloro-N, 3-dimethylbenzamide. The preparation method comprises the following steps: 2-nitro-3-methyl benzoic acid is taken as an initial raw material, and the 2-amino-5-chloro-N, 3-dimethyl benzamide is obtained by reduction reaction, chlorination reaction, esterification reaction and ammonolysis reaction in sequence. The preparation method provides a new path for synthesizing the 2-amino-5-chloro-N, 3-dimethylbenzamide, the yield of the whole route can reach more than 80%, the cost is obviously reduced, the reaction conditions of each step are mild, the quantity of three wastes is small, and the preparation method is suitable for industrial production.)

1. A preparation method of 2-amino-5-chloro-N, 3-dimethyl benzamide is characterized in that: the method comprises the following steps:

K1. 2-nitro-3-methylbenzoic acid is used as an initial raw material to carry out reduction reaction to obtain 2-amino-3-methylbenzoic acid;

K2. performing chlorination reaction on 2-amino-3-methylbenzoic acid to obtain 2-amino-5-chloro-3-methylbenzoic acid;

K3. carrying out esterification reaction on 2-amino-5-chloro-3-methylbenzoic acid to obtain 2-amino-5-chloro-3-methylbenzoate;

K4. 2-amino-5-chloro-3-methylbenzoate is subjected to ammonolysis reaction to obtain 2-amino-5-chloro-N, 3-dimethylbenzamide.

2. The method of claim 1, wherein: the 2-nitro-3-methyl benzoic acid in K1 and hydrogen are subjected to reduction reaction in ethanol under the condition of a catalyst, and the catalyst is Raney nickel.

3. The method of claim 2, wherein: the feeding mass ratio of the 2-nitro-3-methylbenzoic acid to the Raney nickel is 1: 0.01-0.05; the hydrogen pressure is 0.1MPa to 1.5 MPa; the reaction temperature of the reduction reaction is 20-80 ℃; the reaction time of the reduction reaction is 3-8 h.

4. The method of claim 1, wherein: the chlorination is carried out with 2-amino-3-methylbenzoic acid as described in K2 and chlorine in an organic solvent.

5. The method of claim 4, wherein: the organic solvent is one or more of chloroform, dichloroethane, acetonitrile and tetrahydrofuran; the feeding molar ratio of the 2-amino-3-methylbenzoic acid to the chlorine gas is 1:1 to 1.5; the reaction temperature of the chlorination reaction is 20-80 ℃; the reaction time of the chlorination reaction is 2-4 h.

6. The method of claim 1, wherein: the esterification of 2-amino-5-chloro-3-methylbenzoic acid described in K3 with alcohols is carried out under the action of concentrated sulfuric acid.

7. The method of claim 6, wherein: the alcohol is one or more of methanol, ethanol, isopropanol and n-butanol; the feeding molar ratio of the 2-amino-5-chloro-3-methylbenzoic acid to the concentrated sulfuric acid is 1: 0.1 to 0.5; the reaction time of the chlorination reaction is 4-10 h.

8. The method of claim 1, wherein: the 2-amino-5-chloro-3-methylbenzoate described in K4 was subjected to the aminolysis reaction with methylamine in an alcohol.

9. The method of claim 8, wherein: the alcohol is one or more of methanol, ethanol, isopropanol and n-butanol; the feeding molar ratio of the 2-amino-5-chloro-3-methylbenzoate to the methylamine is 1: 1-1.5; the reaction temperature of the ammonolysis reaction is 20-60 ℃; the reaction time of the ammonolysis reaction is 2-8 h.

Technical Field

The invention relates to a preparation method of 2-amino-5-chloro-N, 3-dimethylbenzamide.

Background

Chlorantraniliprole, the common name of which is Chlorantranilprole, is an anthranilamide pesticide successfully developed by DuPont in 2000, the trade names of which are Altaco, Coragen, Rynaxypyr, KANGWI and KK technical products, and the chemical name of which is: 3-bromo-N- { 4-chloro-2-methyl-6- [ (methylamino) carbonyl]Phenyl } -1- (3-chloro-2-pyridines)Pyridyl) -1H-pyrazole-5-amide with CAS registry number of 500008-45-7 and molecular formula of C₁₈H₁₄BrCl₂N₅O₂The chemical structural formula is as follows:

2-amino-5-chloro-N, 3-dimethyl benzamide is an important intermediate for synthesizing chlorantraniliprole, and the existing 2-amino-5-chloro-N, 3-dimethyl benzamide synthesis methods mainly comprise two methods. The first method comprises the following steps: o-toluidine is used as a raw material, the o-toluidine is condensed with chloral hydrate and hydroxylamine hydrochloride to generate oxime, the oxime is dehydrated and subjected to ring closing under the action of concentrated sulfuric acid to obtain isatin, then the isatin anhydride is oxidized by hydrogen peroxide to generate isatoic anhydride, the isatoic anhydride is subjected to ring opening by methylamine gas to obtain 2-amino-N, 3-dimethylbenzamide, and finally the 2-amino-5-chloro-N, 3-dimethylbenzamide is obtained by chlorination of sulfuryl chloride. The whole route has the advantages that the starting material o-toluidine is cheaper, and the disadvantages that the total yield is lower and is only about 30 percent, and the total raw material cost is higher. And a large amount of Na is used in the reaction process₂SO₄And concentrated sulfuric acid, the three wastes are large. A specific synthetic route of the method is as follows:

the second method comprises the following steps: 2-amino-3-methylbenzoic acid is taken as a raw material, NCS chlorination is firstly carried out to obtain 2-amino-5-chloro-3-methylbenzoic acid, then solid phosgene cyclization is carried out to obtain a compound 11, and finally ring opening is carried out by methylamine gas to obtain an intermediate 2-amino-5-chloro-N, 3-dimethylbenzamide. The whole route has the advantage of high total yield of about 70%. Disadvantages are that the starting material 2-amino-3-methylbenzoic acid is expensive, the chlorination reaction uses expensive and atom-uneconomical NCS, the cyclization uses solid phosgene, the atom is uneconomical, and a large amount of HCl is generated and needs to be neutralized by adding alkali, so that a large amount of solid waste is generated. The specific synthetic route of the second method is as follows:

the method I is used for preparing the 2-amino-5-chloro-N, 3-dimethylbenzamide, and has the advantages of lower total yield, higher total raw material cost and more three wastes; the preparation of 2-amino-5-chloro-N, 3-dimethylbenzamide by the second method has higher total cost and more solid wastes due to the more expensive starting materials and used reagents. Therefore, the development of a synthetic method which has high yield, low cost, high atom economy and environmental friendliness is of great significance for the industrialization of the 2-amino-5-chloro-N, 3-dimethylbenzamide.

Disclosure of Invention

The invention aims to provide a novel preparation method of 2-amino-5-chloro-N, 3-dimethylbenzamide, which has high yield, low cost, high atom economy and less three wastes.

In order to achieve the purpose, the invention adopts the following technical scheme:

the invention provides a preparation method of 2-amino-5-chloro-N, 3-dimethylbenzamide, which comprises the following steps:

K1. 2-nitro-3-methylbenzoic acid is used as an initial raw material to carry out reduction reaction to obtain 2-amino-3-methylbenzoic acid;

K2. performing chlorination reaction on 2-amino-3-methylbenzoic acid to obtain 2-amino-5-chloro-3-methylbenzoic acid;

K3. carrying out esterification reaction on 2-amino-5-chloro-3-methylbenzoic acid to obtain 2-amino-5-chloro-3-methylbenzoate;

K4. 2-amino-5-chloro-3-methylbenzoate is subjected to ammonolysis reaction to obtain 2-amino-5-chloro-N, 3-dimethylbenzoyl.

Preferably, the 2-nitro-3-methylbenzoic acid described in K1 is subjected to the reduction reaction with hydrogen in ethanol under the presence of a catalyst.

In the invention, the specific operation steps of the reduction reaction are as follows: dissolving 2-nitro-3-methylbenzoic acid in ethanol, placing the solution in a hydrogenation kettle, adding a catalyst, closing the hydrogenation kettle, introducing hydrogen, heating for reaction, filtering while the solution is hot after the reaction is finished, recovering the catalyst, and distilling the filtrate under reduced pressure to remove the solvent to obtain the 2-amino-3-methylbenzoic acid.

Preferably, the feeding mass ratio of the 2-nitro-3-methylbenzoic acid to the ethanol in the reduction reaction is 1: 4-6, preferably 1: 5.

Preferably, nitrogen is used for 1 to 3 times before the introduction of hydrogen.

Preferably, the catalyst is raney nickel.

Further preferably, the feeding mass ratio of the 2-nitro-3-methylbenzoic acid to the raney nickel is 1: 0.01-0.05.

More preferably, the hydrogen pressure is 0.1 to 1.5 MPa.

Further preferably, the reaction temperature of the reduction reaction is 20 ℃ to 80 ℃.

More preferably, the reaction temperature of the reduction reaction is 50 ℃ to 70 ℃.

More preferably, the reaction time of the reduction reaction is 3 to 8 hours.

More preferably, the reaction time of the reduction reaction is 4 to 6 hours.

Preferably, the 2-amino-3-methylbenzoic acid described in K2 is subjected to the chlorination reaction with chlorine in an organic solvent.

In the invention, the specific operation steps of the chlorination reaction are as follows: placing 2-amino-3-methylbenzoic acid into a reaction container, adding an organic solvent, stirring and heating, introducing chlorine gas for reaction, cooling to room temperature after the reaction is finished, and filtering to obtain 2-amino-5-chloro-3-methylbenzoic acid.

The feeding mass ratio of the 2-amino-3-methylbenzoic acid to the organic solvent in the chlorination reaction is 1: 4-6, and preferably 1: 5.

Further preferably, the organic solvent includes but is not limited to one or more of chloroform, dichloroethane, acetonitrile, tetrahydrofuran.

More preferably, the solvent is dichloroethane.

Further preferably, the feeding molar ratio of the 2-amino-3-methylbenzoic acid to the chlorine gas is 1: 1-1.5.

Further preferably, the reaction temperature of the chlorination reaction is 20-80 ℃.

More preferably, the reaction temperature of the chlorination reaction is 50 ℃ to 60 ℃.

More preferably, the reaction time of the chlorination reaction is 2 to 4 hours.

Preferably, the esterification of 2-amino-5-chloro-3-methylbenzoic acid described in K3 with an alcohol is carried out in the presence of concentrated sulfuric acid.

In the invention, the esterification reaction comprises the following specific operation steps: placing 2-amino-5-chloro-3-methylbenzoic acid into a reaction container, adding alcohol, cooling in an ice water bath, dropwise adding concentrated sulfuric acid, heating for reflux reaction after dropwise adding, distilling to remove alcohol after reaction, adding water, pulping at room temperature, and filtering to obtain 2-amino-5-chloro-3-methylbenzoic acid methyl ester.

The feeding mass ratio of the 2-amino-5-chloro-3-methylbenzoic acid to the alcohol in the esterification reaction is 1: 4-6, and preferably 1: 5.

Further preferably, the alcohol includes but is not limited to one or more of methanol, ethanol, isopropanol and n-butanol.

Further preferably, the feeding molar ratio of the 2-amino-5-chloro-3-methylbenzoic acid to the concentrated sulfuric acid is 1: 0.1-0.5.

Further preferably, the reaction time of the chlorination reaction is 4 to 10 hours.

Preferably, the 2-amino-5-chloro-3-methylbenzoate described in K4 is subjected to the aminolysis reaction with methylamine in an alcohol.

In the invention, the specific operation steps of the ammonolysis reaction are as follows: adding 2-amino-5-chloro-3-methyl benzoate and alcohol into a reaction container, stirring and heating, introducing methylamine gas for reaction, and distilling to remove the alcohol after the reaction is finished to obtain the 2-amino-5-chloro-N, 3-dimethyl benzamide.

The feeding mass ratio of the methyl 2-amino-5-chloro-3-methylbenzoate to the alcohol in the ammonolysis reaction is 1: 3-5, and preferably 1: 4.

Further preferably, the alcohol is one or more of methanol, ethanol, isopropanol and n-butanol.

Further preferably, the feeding molar ratio of the 2-amino-5-chloro-3-methylbenzoate to the methylamine is 1: 1-1.5.

Further preferably, the reaction temperature of the ammonolysis reaction is 20 ℃ to 60 ℃.

More preferably, the reaction temperature of the ammonolysis reaction is 45-60 ℃.

Further preferably, the reaction time of the ammonolysis reaction is 2 to 8 hours.

The reaction formula of the invention is as follows:

the preparation method provides a new path for the synthesis of the 2-amino-5-chloro-N, 3-dimethylbenzamide, the reaction conditions of the steps in the preparation method are mild, the yield is high, the total yield is more than 80%, the quantity of three wastes is small, no solid waste is generated, the preparation method is environment-friendly and suitable for industrial production, the problems of low reaction yield, high cost, poor atom economy and more three wastes in the prior art are solved, and the production cost of the intermediate 2-amino-5-chloro-N, 3-dimethylbenzamide is greatly reduced, so that the production cost of the chlorantraniliprole is reduced, and convenience is provided for the industrial production of the chlorantraniliprole.

Due to the adoption of the technical scheme, compared with the prior art, the invention has the following advantages:

the new preparation method of the 2-amino-5-chloro-N, 3-dimethylbenzamide has the advantages of high yield, low cost, high atom economy and less three wastes, and is suitable for industrial production.

Detailed Description

The technical solution of the present invention is further described below with reference to specific embodiments, but the present invention is not limited to the following embodiments. The implementation conditions used in the examples can be further adjusted according to specific requirements, and the implementation conditions not indicated are generally the conditions in routine experiments.