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CN119775254A - Preparation method of o-formamidobenzamide compounds and intermediates thereof - Google Patents

Preparation method of o-formamidobenzamide compounds and intermediates thereof Download PDF

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CN119775254A
CN119775254A CN202311283346.2A CN202311283346A CN119775254A CN 119775254 A CN119775254 A CN 119775254A CN 202311283346 A CN202311283346 A CN 202311283346A CN 119775254 A CN119775254 A CN 119775254A
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acid
reaction
formula
compound
halogen
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Inventor
郝树林
包如胜
徐坚勇
金晓东
陈兆利
蔡海涛
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Shunyi Yichang Chemical Co ltd
Shunyi Co ltd
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Shunyi Yichang Chemical Co ltd
Shunyi Co ltd
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Abstract

The present application relates to a process for the preparation of anthranilamide compounds having the formula (I) and intermediates thereof, wherein the process comprises reacting an aniline compound, a pyridine compound and a sulfonyl chloride R 8S(O)2 Cl in salt form. The preparation method provided by the application is simple to operate, can directly obtain the final product, avoids unnecessary side reactions, simplifies the resolution procedure of intermediates, can greatly improve the reaction yield and improves the atom utilization rate.

Description

Preparation method of o-carboxamido benzamide compound and intermediate thereof
Technical Field
The application relates to the field of organic synthesis, in particular to a preparation method of an o-formamido benzamide compound and an intermediate thereof.
Background
The prior art WO2006062978A1 discloses anthranilamide compounds of the formula and intermediates thereof.
However, the chlorination reaction in the process of preparing the intermediate 3-substituted 2-amino-5-halogenated benzamide has side reaction, the raw material reaction is incomplete, unnecessary byproducts and tar are generated, separation is difficult, the reaction yield is reduced, in addition, the post-treatment alkali adjustment operation brings water, partial products are hydrolyzed, impurities are generated, and the reaction yield and the product purity are further reduced.
Therefore, there is an urgent need in the art for an improved method for preparing anthranilamide compounds with simple operation, few by-products and high yield.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a preparation method of an o-carboxamido benzamide compound and an intermediate thereof, which is simple to operate, can directly obtain a final product, avoids unnecessary side reactions, simplifies the resolution procedure of the intermediate, improves the atomic utilization rate, and can greatly improve the reaction yield.
In a first aspect, the present invention provides a process for preparing an anthranilamide compound having the formula (I), comprising:
Reacting an aniline compound having the formula (II)
Pyridine compounds of formula (III)
The reaction is carried out and the reaction is carried out,
Wherein,
R 1 is selected from H, halogen or C 1-C4 alkyl;
r 2 is selected from H, halogen or cyano;
R 3 is selected from H, C 1-C4 alkyl, C 3-C10 cycloalkyl, or C 4-C10 cycloalkylalkyl, wherein the C 1-C4 alkyl, C 3-C10 cycloalkyl, or C 4-C10 cycloalkylalkyl is optionally substituted with halogen or cyano;
R 4 is selected from halogen, C 1-C4 alkyl, or C 1-C4 alkoxy, wherein the C 1-C4 alkyl or C 1-C4 alkoxy is optionally substituted with halogen;
R 5 is selected from halogen;
R 6 is selected from hydrogen or halogen;
Q is selected from halogen, hydroxy, -O-SO 2-R7, wherein R 7 is C 1-C4 alkyl or halogenated C 1-C4 alkyl, and
X is an inorganic acid or an organic acid.
In one embodiment of the invention, when Q is selected from hydroxy, the method may further comprise adding sulfonyl chloride R 8S(O)2 Cl to the mixture of the compound of formula (II) and the compound of formula (III), R 8 is selected from C 1-C4 alkyl or substituted phenyl, optionally substituted with halogen, C 1-C4 alkyl or nitro.
In a preferred embodiment of the present invention, the reaction may be carried out in the presence of a base, preferably the base may be selected from pyridine or triethylamine, preferably 3-methylpyridine.
In a preferred embodiment of the present invention, the reaction may be carried out at a temperature of-10 ℃ to 30 ℃ (e.g., 0 ℃,10 ℃, 20 ℃, etc.) when a base is present.
In another preferred embodiment of the invention, the ratio of the compound of formula (II), the compound of formula (III), the sulfonyl chloride and the base may be 1-1.3:1:0.2-2:2-4, or any ratio therebetween, e.g. 1:1:1:3, 1.2:1:0.5:2 or 1.3:1:1.5:4, etc., on a molar basis.
In one embodiment of the invention, when Q is selected from halogen, the reaction may be performed in the absence of a base. In this case, the released acid gas can be absorbed and used as a byproduct or the acid gas is used for replacing aniline to form salt in the previous step, so that the method is simple and the three wastes are less. In a preferred embodiment of the invention, the reaction may be carried out at a higher temperature, for example at a temperature of 80 ℃ to 160 ℃ (e.g. 100 ℃, 120 ℃ or 140 ℃ etc.), when the base is not present.
In one embodiment of the invention, when Q is selected from-O-SO 2-R7, the reaction may be carried out in the presence of a base, preferably the base may be selected from pyridine or triethylamine, preferably 3-methylpyridine, more preferably the reaction may be carried out at a temperature of-10 ℃ to 30 ℃. For the ratio of the amounts of the respective reactants, reference may be made to the case where Q is selected from hydroxyl groups as described above, and the description thereof will be omitted.
In one embodiment of the present invention, the reaction may be carried out in an organic solvent, preferably the organic solvent may be selected from nitriles (e.g. acetonitrile, propionitrile), esters (e.g. methyl acetate, ethyl acetate, butyl acetate), ketones (e.g. acetone, methyl ethyl ketone, methyl butyl ketone), haloalkanes (e.g. dichloromethane, trichloromethane, tetrachloroethylene), ethers (e.g. diethyl ether, methyl tert-butyl ether, tetrahydrofuran, p-dioxane), aromatic hydrocarbons (e.g. benzene, toluene, chlorobenzene, dichlorobenzene) or tertiary amines (e.g. trialkylamines, dialkylanilines, optionally substituted pyridines) solvents and any combination thereof, preferably dichloromethane, dichloroethane, dichlorobutane, acetonitrile, propionitrile, chlorobenzene, toluene, xylene or tetrachloroethylene.
In one embodiment of the present invention, the inorganic acid may be selected from hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, carbonic acid, phosphoric acid or boric acid, and/or the organic acid may be selected from formic acid, acetic acid, maleic acid, citric acid, malic acid, oxalic acid, tartaric acid, succinic acid, benzoic acid, salicylic acid or caffeic acid.
Unless otherwise indicated, references herein to "a compound having formula (N)" or "a compound of formula (N) (e.g., a compound of formula (I)) also encompass isotopically-labeled compounds wherein any one of the atoms of the compound is replaced by an isotopic atom thereof. The present invention includes all pharmaceutically acceptable isotopically-labeled compounds of formula (N) wherein one or more atoms are replaced by an atom having the same atomic number as, but a different atomic mass or mass number than, the atoms typically found in nature.
Examples of isotopes suitable for inclusion in compounds of the invention include isotopes of hydrogen, such as 2 H (D) and 3 H (T), isotopes of carbon, such as 11C、13 C and 14 C, isotopes of chlorine, such as 37 Cl, isotopes of fluorine, such as 18 F, isotopes of iodine, such as 123 I and 125 I, isotopes of nitrogen, such as 13 N and 15 N, isotopes of oxygen, such as 15O、17 O and 18 O, and isotopes of sulfur, such as 35 S.
Isotopically-labeled compounds of formula (N) can generally be prepared by conventional techniques known to those skilled in the art or by using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously used in a manner analogous to those described in the examples and preparations attached herein.
As used herein, the term "substituted" means that one or more (preferably 1 to 5, more preferably 1 to 3) hydrogen atoms in the group are independently replaced by a corresponding number of substituents.
As used herein, the term "optionally" means that the event described may or may not occur. For example, a group "optionally substituted" means that the group may be unsubstituted or substituted.
As used herein, the term "alkyl" refers to saturated aliphatic hydrocarbons, including straight and branched chains. For example, the term "C 1-C12 alkyl" refers to a straight or branched chain radical having 1 to 12 carbon atoms. The term "C 1-C12 alkyl" includes the terms "C 1-C3 alkyl", "C 1-C4 alkyl" and "C 1-C6 alkyl" in its definition. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, isopentyl, neopentyl, 3-methylbutyl, 2, 3-dimethylpropyl, 2, 3-dimethylbutyl, hexyl, and the like.
As used herein, the term "C 4-C10 cycloalkylalkyl" refers to an interconnected cycloalkyl and alkyl group having a total of 4 to 10 carbon atoms, such as cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, and the like.
The compounds of the present application may be prepared in a variety of ways known to those skilled in the art of organic synthesis. Those skilled in the art can refer to the synthetic routes of the specific compounds of the specific examples of the present application, and appropriately adjust the reaction raw materials and reaction conditions to obtain synthetic methods of other compounds.
In a second aspect, the present invention also provides an aniline compound in the form of a salt having the formula (II),
Wherein R 1、R2、R3 and X are as previously defined.
In a third aspect, the present invention also provides a pyridine compound having the formula (III-3),
Wherein R 1、R2、R3 and R 7 are as defined previously.
In a fourth aspect, the present invention also provides a process for preparing a salt form of an aniline compound having formula (II-1), comprising:
the compound of formula (IV)
With an acidic reagent and a halogenating reagent to obtain the aniline compound in the form of a salt having the formula (II-1),
Wherein R 1 and R 3 are as defined previously, and R 2 is halogen.
In one embodiment of the invention, the acidic reagent may be selected from hydrogen chloride, acetic acid, hydrogen bromide, phosphoric acid or sulfuric acid.
In one embodiment of the present invention, the halogenating agent may be selected from chlorine, sulfonyl chloride, N-chlorosuccinimide, dichlorohydantoin, liquid bromine, dibromohydantoin, perbrominated pyridine hydrobromide, or N-bromosuccinimide.
In one embodiment of the present invention, the reaction solvent may be selected from methylene chloride, ethylene dichloride, ethylene dibromide, ethylene dichloride or propionitrile. In one embodiment of the present invention, the ratio of the compound of formula (IV), the acidic reagent and the halogenating reagent may be 1:1 to 1.5:1.1 to 1.5 on a molar basis.
In one embodiment of the invention, the reaction may be carried out at a temperature of 30-50 ℃, preferably 35-45 ℃.
The inventor finds that side reactions exist in the chlorination reaction in the process of preparing the anthranilamide intermediate, unnecessary byproducts and tar are generated, separation is difficult, the reaction yield is reduced, in addition, the post-treatment alkali-adjusting operation brings water, partial products are hydrolyzed, impurities are generated, and the reaction yield and the product purity are further reduced.
According to the invention, the amino group is protected firstly, then the anthranilamide salt compound is prepared, the byproduct generation can be effectively reduced, the consumption of the chlorinating agent is reduced, the operation requirement is low, the influence of introducing unnecessary moisture on a reaction system is avoided, the post-treatment operation steps are reduced, the process stability is good, the reaction yield is high, and the method is suitable for industrial production.
In addition, the anthranilamide salt compound prepared by the method can be directly used for the next reaction, the reaction can be carried out in the absence of alkali, in this case, the released acid gas can be absorbed as a raw material to be directly used for the next batch of intermediate body to form salt, thereby achieving the purposes of recycling, simple method and less three wastes.
Compared with the prior art, the preparation method provided by the invention has the technical advantages that the preparation method is simple to operate, the final product can be directly obtained, unnecessary side reactions are avoided, the resolution procedure of intermediates is simplified, the reaction yield can be greatly improved, and the atom utilization rate is improved.
Those skilled in the art will appreciate that the definitions and preferences described in one aspect of the application apply equally to other aspects. It will be apparent to those skilled in the art that embodiments of the various aspects of the application may be combined in various ways without departing from the subject matter and concepts of the application, and such combinations are included within the scope of the application.
Detailed Description
The compounds of the present application may be synthesized by a variety of methods familiar to those skilled in the art of organic synthesis. The following specific examples illustrate methods for synthesizing certain exemplary compounds, which are well known in the art of synthetic chemistry.
The invention is further illustrated below in conjunction with examples, which do not limit the scope of the invention. Unless otherwise indicated, all reagents used in the examples were obtained from commercial sources, and the instrumentation used in the synthesis experiments and product analysis assays, and the like, were conventional instrumentation commonly used in organic syntheses.
EXAMPLE 1 preparation of 2-amino-5-chloro-3, N-dimethylbenzamide hydrochloride
2000G of dichloroethane and 295.2g of 2-amino-3, N-dimethylbenzamide (1.8 mol,1 eq.) were introduced into the flask, the temperature was controlled at 35℃throughout, and 65.7g of hydrogen chloride (1.8 mol,1 eq.) gas was slowly introduced over 1 h. After the completion of the reaction, the mixture was discharged, 279.4g (2.07 mol,1.15 eq) of a sulfonyl chloride solution was added dropwise, the mixture was reacted for 2 hours at a temperature of 2 hours after the completion of the dropwise addition within 30 minutes, and the mixture was sampled and detected, and the temperature was lowered to 10 ℃.
After sampling is qualified, the feed liquid is filtered, and the feed liquid is leached with dichloroethane for 2 times to obtain 396.4g of 2-amino-5-chloro-3, N-dimethylbenzamide hydrochloride (1.687 mol), the moisture content is less than 0.1%, the byproduct content is less than 0.1%, and the reaction yield is 93.7%, and can be directly used for the next reaction without purification.
EXAMPLE 2 preparation of 2-amino-5-chloro-3, N-dimethylbenzamide hydrochloride
2000G of dichloroethane and 295.2g of 2-amino-3, N-dimethylbenzamide (1.8 mol,1 eq.) were introduced into the flask, the temperature was controlled at 40℃throughout, and 65.7g of hydrogen chloride (1.8 mol,1 eq.) gas was slowly introduced over 1h. After the completion of the reaction, the mixture was discharged, 315.8g (2.34 mol,1.3 eq) of a sulfonyl chloride solution was added dropwise, the mixture was reacted for 2 hours at a temperature of 30 minutes, and the mixture was sampled and detected, and the temperature was lowered to 10 ℃.
After sampling, the feed liquid was filtered and rinsed 2 times with dichloroethane to give 398.0g of 2-amino-5-chloro-3, N-dimethylaniline hydrochloride (1.694 mol), moisture content <0.1%, by-product content <0.1%, reaction yield 94.1%, which could be used directly in the next reaction without purification.
EXAMPLE 3 preparation of 2-amino-5-chloro-3, N-dimethylbenzamide hydrochloride
2000G of dichloroethane and 295.2g of 2-amino-3, N-dimethylbenzamide (1.8 mol,1 eq.) were introduced into the flask, the temperature was 45℃throughout, and 65.7g of hydrogen chloride (1.8 mol,1 eq.) gas was slowly introduced over 1 h. After the completion of the reaction, the reaction was carried out for 2 hours with heat preservation after the completion of the dropwise addition of 267.3g (1.98 mol,1.1 equivalent) of a sulfonyl chloride solution, followed by sampling and detection, and then the temperature was lowered to 10 ℃.
After sampling is qualified, the feed liquid is filtered, and is leached with dichloroethane for 2 times, so as to obtain 392.5g of 2-amino-5-chloro-3, N-dimethylbenzamide hydrochloride (1.670 mol), the moisture content is less than 0.1%, the byproduct content is less than 0.1%, and the reaction yield is 92.8%, and can be directly used for the next reaction without purification.
EXAMPLE 4 preparation of 2-amino-5-bromo-3, N-dimethylbenzamide bromate
2000G of dibromoethane and 295.2g of 2-amino-3, N-dimethylbenzamide (1.8 mol,1 eq.) were introduced into the reaction flask, the temperature was controlled at 45℃throughout, and hydrogen bromide (0.18 mol,0.10 eq.) gas was slowly introduced. Discharging after passing, controlling the temperature at 40 ℃ in the whole process, slowly dropwise adding 316.4g (1.98 mol,1.1 equivalent) of bromine, after dropwise adding in 60-90 minutes, carrying out heat preservation reaction for 2h, sampling and detecting, and cooling to 10 ℃ after the reaction is finished.
After the sample was taken out, the feed solution was filtered and rinsed 2 times with dibromoethane to obtain 536.9g of 2-amino-5-bromo-3, N-dimethylbenzamide bromate (1.652 mol), the water content was <0.1%, and the reaction yield was 91.8%.
EXAMPLE 5 preparation of 2-amino-5-bromo-3, N-dimethylbenzamide bromate
2000G of dibromoethane and 295.2g of 2-amino-3, N-dimethylbenzamide (1.8 mol,1 eq.) were introduced into the reaction flask, the temperature was controlled at 40℃throughout, and hydrogen bromide (0.09 mol,0.05 eq.) gas was slowly introduced. And (3) exhausting after passing through, slowly dropwise adding 345.2g (2.16 mol,1.2 equivalent) of bromine, finishing dropwise adding within 60-90 minutes, preserving heat for reaction for 2 hours, sampling and detecting, and cooling to 10 ℃ after the reaction is finished.
After the sample was taken out, the feed liquid was filtered and rinsed 2 times with dibromoethane to obtain 537.6g of 2-amino-5-bromo-3, N-dimethylbenzamide bromate (1.654 mol), the moisture content was <0.1%, and the reaction yield was 91.9%.
EXAMPLE 6 preparation of chlorantraniliprole from 2-amino-5-chloro-3, N-dimethylbenzamide hydrochloride and 3-bromo-1- (3-chloropyridin-2-yl) -1H-pyrazole-5-carboxylic acid
396.4G of 2-amino-5-chloro-3, N-dimethylbenzamide hydrochloride (1.687 mol,1.03 eq) prepared in example 1 was charged into a reaction flask, 1300g of dichloroethane solvent was charged, 496.1g of 3-bromo-1- (3-chloropyridin-2-yl) -1H-pyrazole-5-carboxylic acid (1.640 mol,1.0 eq), 395.7g of 3-methylpyridine (4.255 mol,2.6 eq) were added dropwise, the temperature was controlled at 10℃and the reaction was continued at 10℃for 2 hours after completion of the dropwise addition of 280.8g of methanesulfonyl chloride (2.45 mol,1.5 eq).
After the reaction is finished and the sample is detected to be qualified, carrying out suction filtration, water washing and drying on the feed liquid to obtain 757.7g of chlorantraniliprole finished product, wherein the yield of the chlorantraniliprole finished product is 94.6 percent based on the 3-bromo-1- (3-chloropyridin-2-yl) -1H-pyrazole-5-formic acid, and the HPLC area normalized purity is 99.0 percent.
EXAMPLE 7 preparation of chlorantraniliprole from 2-amino-5-chloro-3, N-dimethylbenzamide hydrochloride and 3-bromo-1- (3-chloropyridin-2-yl) -1H-pyrazole-5-carboxamide
To a reaction flask were charged 390 g of 2-amino-5-chloro-3, N-dimethylbenzamide hydrochloride (1.694 mol,1.03 eq) prepared in example 2, 1300g of dichloroethane solvent, 526.5g of 3-bromo-1- (3-chloropyridin-2-yl) -1H-pyrazole-5-carbonyl chloride (1.640 mol,1.0 eq), 335.2g of 3-methylpyridine (3.6 mol,2.20 eq), and the reaction was continued at 5℃for 2 hours.
After the reaction is finished and the sample is detected to be qualified, the feed liquid is filtered, washed and dried to obtain 755.2g of chlorantraniliprole finished product, the yield of the 3-bromo-1- (3-chloropyridin-2-yl) -1H-pyrazole-5-formyl chloride is 94.5%, and the HPLC area is normalized to the purity of 99.1%.
EXAMPLE 8 preparation of Chlorantraniliprole from 2-amino-5-chloro-3, N-dimethylbenzamide hydrochloride and 3-bromo-1- (3-chloropyridin-2-yl) -1H-pyrazole-5-methanesulfonic anhydride
392.5G of 2-amino-5-chloro-3, N-dimethylbenzamide hydrochloride (1.67 mol,1.02 eq) prepared in example 3 was charged into a reaction flask, 1300g of dichloroethane solvent was charged, 627.3g of 3-bromo-1- (3-chloropyridin-2-yl) -1H-pyrazole-5-methanesulfonic anhydride (1.64 mol,1.0 eq), 335.2g of 3-methylpyridine (3.5 mol,2.13 eq) at a controlled temperature of 0℃and the reaction was continued for 2 hours.
After the reaction is finished and the sample is detected to be qualified, the feed liquid is filtered, washed and dried to obtain 751.3g of chlorantraniliprole finished product, the yield is 93.7 percent by 3-bromo-1- (3-chloropyridin-2-yl) -1H-pyrazole-5-methanesulfonic anhydride, and the HPLC area normalized purity is 98.8 percent.
EXAMPLE 9 preparation of Chlorantraniliprole with 2-amino-5-chloro-3, N-dimethylbenzamide bisulfate and 3-bromo-1- (3-chloropyridin-2-yl) -1H-pyrazole-5-carboxylic acid
501.1G of 2-amino-5-chloro-3, N-dimethylbenzamide hydrogen sulfate (1.69mol, 1.03 eq) are charged into a reaction flask, 1300g of dichloroethane solvent is charged, 496.1g of 3-bromo-1- (3-chloropyridin-2-yl) -1H-pyrazole-5-carboxylic acid (1.64 mol,1.0 eq), 395.7g of 3-methylpyridine (4.25 mol,2.6 eq) are charged, the temperature is controlled at 10℃and 280.8g of methylsulfonyl chloride (2.45 mol,1.5 eq) are added dropwise, and the reaction is continued at 10℃for 2 hours after the completion of the dropwise addition.
After the reaction is finished and the sample is detected to be qualified, carrying out suction filtration, water washing and drying on the feed liquid to obtain 755.6g of chlorantraniliprole finished product, wherein the yield of the chlorantraniliprole finished product is 94.4 percent based on 3-bromo-1- (3-chloropyridin-2-yl) -1H-pyrazole-5-formic acid, and the HPLC area normalized purity is 99.0 percent.
EXAMPLE 10 preparation of Chlorantraniliprole with 2-amino-5-chloro-3, N-dimethylbenzamide bisulfate and 3-bromo-1- (3-chloropyridin-2-yl) -1H-pyrazole-5-carboxamide
Into the reaction flask were charged 501.1g of 2-amino-5-chloro-3, N-dimethylbenzamide hydrogensulfate (1.690 mol,1.03 eq.) and 1300g of dichloroethane solvent, 526.4g of 3-bromo-1- (3-chloropyridin-2-yl) -1H-pyrazole-5-carbonyl chloride (1.64 mol,1.0 eq.) and 335.2g of 3-methylpyridine (3.5 mol,2.13 eq.) at a temperature of 10℃and the reaction was continued for 2 hours.
After the reaction is finished and the sample is detected to be qualified, carrying out suction filtration, water washing and drying on the feed liquid to obtain 748.4g of chlorantraniliprole finished product, wherein the yield of the 3-bromo-1- (3-chloropyridin-2-yl) -1H-pyrazole-5-formyl chloride is 92.8%, and the HPLC area normalized purity is 98.2%.
EXAMPLE 11 preparation of Chlorantraniliprole with 2-amino-5-chloro-3, N-dimethylbenzamide bisulfate and 3-bromo-1- (3-chloropyridin-2-yl) -1H-pyrazole-5-methanesulfonic anhydride
501.1G of 2-amino-5-chloro-3, N-dimethylbenzamide hydrogensulfate (1.69 mol,1.03 eq.) are charged into the reaction flask, 1300g of dichloroethane solvent, 627.3g of 3-bromo-1- (3-chloropyridin-2-yl) -1H-pyrazole-5-methanesulfonic anhydride (1.64 mol,1.0 eq.) and 344.5g of 3-methylpyridine (3.7 mol,2.26 eq.) are charged, the temperature is controlled at 10℃and the reaction is continued for 2 hours.
After the reaction is finished and the sample is detected to be qualified, 740.6g of chlorantraniliprole finished product is obtained by suction filtration, water washing and drying of the feed liquid, and the yield of the 3-bromo-1- (3-chloropyridin-2-yl) -1H-pyrazole-5-methanesulfonic anhydride is 91.8 percent and the HPLC area normalized purity is 98.2 percent.
EXAMPLE 12 preparation of Chlorantraniliprole from 2-amino-5-chloro-3, N-dimethylbenzamide dihydrogen phosphate and 3-bromo-1- (3-chloropyridin-2-yl) -1H-pyrazole-5-carboxylic acid
501.1G of 2-amino-5-chloro-3, N-dimethylbenzamide dihydrogen phosphate (1.69 mol,1.03 eq) are introduced into a reaction flask, 1300g of dichloroethane solvent are introduced, 496.1g of 3-bromo-1- (3-chloropyridin-2-yl) -1H-pyrazole-5-carboxylic acid (1.64 mol,1.0 eq) and 316.5g of 3-methylpyridine (3.4 mol,2.07 eq) are introduced, the temperature is controlled at 10℃and 280.8g of methylsulfonyl chloride (2.45 mol,1.5 eq) are added dropwise, and the reaction is continued at 10℃for 2 hours after the completion of the dropwise addition.
After the reaction is finished and the sample is detected to be qualified, carrying out suction filtration, water washing and drying on the feed liquid to obtain 750.5g of chlorantraniliprole finished product, wherein the yield of the chlorantraniliprole finished product is 93.3 percent based on 3-bromo-1- (3-chloropyridin-2-yl) -1H-pyrazole-5-formic acid, and the HPLC area normalized purity is 98.5 percent.
EXAMPLE 13 preparation of Chlorantraniliprole from 2-amino-5-chloro-3, N-dimethylbenzamide dihydrogen phosphate and 3-bromo-1- (3-chloropyridin-2-yl) -1H-pyrazole-5-carbonyl chloride
Into the reaction flask was charged 501.1g of 2-amino-5-chloro-3, N-dimethylbenzamide dihydrogen phosphate (1.69 mol,1.03 eq), 1300g of dichloroethane solvent, 526.4g of 3-bromo-1- (3-chloropyridin-2-yl) -1H-pyrazole-5-carbonyl chloride (1.64 mol,1.0 eq) and 353.8g of 3-methylpyridine (3.8 mol,2.32 eq), and the reaction was continued at 10℃for 2 hours under thermal insulation.
After the reaction is finished and the sampling and detection are qualified, carrying out suction filtration and water washing on the feed liquid, and drying to obtain 750.7g of chlorantraniliprole finished product, wherein the yield is 93.7%, and the HPLC area normalization purity is 98.9%.
EXAMPLE 14 preparation of Chlorantraniliprole from 2-amino-5-chloro-3, N-dimethylbenzamide dihydrogen phosphate and 3-bromo-1- (3-chloropyridin-2-yl) -1H-pyrazole-5-methanesulfonic anhydride
Into the reaction flask were charged 501.1g of 2-amino-5-chloro-3, N-dimethylbenzamide dihydrogen phosphate (1.69 mol,1.03 equivalent), 1300g of a dichloroethane solvent, 627.3g of 3-bromo-1- (3-chloropyridin-2-yl) -1H-pyrazole-5-methanesulfonic anhydride (1.64 mol,1.0 equivalent), 344.5g of 3-methylpyridine (3.7 mol,2.26 equivalent), the temperature was controlled at 10℃and the reaction was continued at 10℃for 2 hours.
After the reaction is finished and the sampling and detection are qualified, carrying out suction filtration and water washing on the feed liquid, and drying to obtain 741.2g of chlorantraniliprole finished product, wherein the yield is 91.7%, and the HPLC area normalization purity is 98.0%.
EXAMPLE 15 preparation of chlorantraniliprole from 2-amino-5-chloro-3, N-dimethylbenzamide hydrochloride and 3-bromo-1- (3-chloropyridin-2-yl) -1H-pyrazole-5-carboxamide
To a reaction flask was charged 390 g of 2-amino-5-chloro-3, N-dimethylbenzamide hydrochloride (1.694 mol,1.03 eq) prepared in example 2, 1300g of a chlorobenzene solvent, 526.5g of 3-bromo-1- (3-chloropyridin-2-yl) -1H-pyrazole-5-carboxamide chloride (1.640 mol,1.0 eq), and the resultant hydrogen chloride gas was used for 2-amino-3, N-dimethylbenzamide hydrochloride in example 1 by heating to 130℃and reacting for 2 hours under thermal insulation.
After the reaction is finished and the sample is detected to be qualified, carrying out suction filtration, water washing and drying on the feed liquid to obtain 752.9g of chlorantraniliprole finished product, wherein the yield of 3-bromo-1- (3-chloropyridin-2-yl) -1H-pyrazole-5-formyl chloride is 93.9%, and the HPLC area normalized purity is 97.8%.
Comparative example 1 preparation of 2-amino-5-chloro-3, N-dimethylbenzamide (see CN 101492387A)
17.5G (107 mmol) of 3-methyl-2-aminobenzoylmethylamine and 100mL of acetonitrile were placed in a reaction flask equipped with a condensation thermometer, 17.0g (126 mmol) of sulfonyl chloride diluted with 50mL of acetonitrile was added dropwise to the flask in an ice bath, the dropwise addition time was kept at about 2 hours, and after the dropwise addition was completed, the flask was heated to 55.+ -. 1 ℃ for further reaction for 0.5 hour. Sampling and detecting, wherein the content of the residual raw material is 38%, and continuously dropwise adding 7.5g (55.5 mmol) of sulfonyl chloride until the content of the raw material is less than 0.1%.
After the reaction, regulating the pH to 11 by using a NaOH solution with the mass concentration of 10 percent, stirring for 10 minutes, separating liquid, washing an organic phase with water for 2 times, concentrating to obtain a solid product crude product, and recrystallizing to obtain 16.5g of light red needle crystals, namely 2-amino-5-chloro-N, 3-dimethylbenzamide, wherein the reaction yield is 77.7 percent. The water content is 0.7% and the by-product content in the system is 8.4% by sampling detection analysis.
According to analysis, the method needs to add an alkaline reagent, then concentrate and recrystallize to obtain a product, the actual operation process is complex, acetonitrile is adopted as a solvent, acetonitrile and water are mutually soluble and difficult to separate, and the water content of the product exceeds the standard. Due to the influence of side reactions, a large amount of byproducts exist, and the reaction yield is low.
Comparative example 2 preparation of 2-amino-5-chloro-3, N-dimethylbenzamide (see CN 115181031A)
10G (61.0 mmol) of methyl 2-amino-3-methylbenzoate are placed in a flask, 20g of chloroform is added, the temperature is raised to 30 ℃, 8.59g of a solution of sulfonyl chloride (63.6 mmol) in chloroform (10 g) is slowly added dropwise, the dropwise addition time is 1h, and after the completion, the temperature is kept for 1h. Sampling and detecting, wherein the content of the residual raw material is 45%, and continuously dropwise adding 6.1g (45 mmol) of sulfonyl chloride until the content of the raw material is less than 0.1%.
After the reaction, desolventizing, adding 30g of toluene and 20g of water, dropwise adding 10% sodium hydroxide solution, adjusting the pH to about 8, extracting with toluene, washing the organic phase with water to neutrality, desolventizing under negative pressure to obtain 9.6g of methyl 2-amino-5-chloro-3-methylbenzoate, and the yield is 79.3%. The water content is 0.5% and the by-product content in the system is 7.2% by sampling detection analysis.
According to analysis, the method needs to add an alkaline reagent, and then extracts and desolventizes to obtain a product, so that the actual operation process is complex, and meanwhile, a large amount of byproducts exist under the influence of side reactions, so that the reaction yield is low.
Comparative example 3 preparation of 2-amino-5-chloro-3, N-dimethylbenzamide (without Hydrogen chloride gas)
2000G of dichloroethane and 295.2g of 2-amino-3, N-dimethylbenzamide (1.8 mol,1 equivalent) are put into a reaction bottle, the whole temperature is controlled at 40 ℃, 279.4g (2.07 mol,1.15 equivalent) of sulfonyl chloride solution is dripped, the dripping is completed within 30 minutes, the reaction is carried out for 2 hours under heat preservation, sampling and detection are carried out, and 109.4g (0.81 mol) of sulfonyl chloride is continuously added to the rest of raw materials till the content of the raw materials is less than 0.1 percent. And cooling to 10 ℃ after the reaction is finished.
After sampling, removing the solvent, adding 10% sodium hydroxide solution, adjusting the pH to about 8, extracting with toluene, washing the organic phase with water to neutrality, desolventizing under negative pressure to obtain 281.0g of 2-amino-3, N-dimethylbenzamide, wherein the water content is 0.5%, the by-product content is 6.5%, and the reaction yield is 78.6%.
According to analysis, the method needs to add an alkaline reagent, and then extracts and desolventizes to obtain a product, so that the actual operation process is complex, and meanwhile, a large amount of byproducts exist under the influence of side reactions, so that the reaction yield is low.
Comparative example 4 preparation of Chlorantraniliprole (see CN 102285899A)
To a mixture of 3-bromo-1- (3-chloro-2-pyridinyl) -1H-pyrazole-5-carboxylic acid (6.05 g,20.0 mmol) and 2-amino-5-chloro-N, 3-dimethylbenzamide (4.17 g,21.0 mmol) in dichloromethane (18 mL) was added 3-methylpyridine (4.84 g,52 mmol). The mixture was cooled to-5 ℃, then methanesulfonyl chloride (2.75 g,24 mmol) was added dropwise at-5 to 0 ℃, and the mixture was stirred at 0-5 ℃ for 3h.
Then, water (9 mL) was added dropwise, and methylene chloride (18 mL) was added to the thick suspension, and the mixture was stirred at 0 ℃ for 1h. The mixture was filtered and the solid washed with ice-cold 2:1 dichloromethane-water (2X 4.5 mL) and dried under nitrogen to give 8.05g of the title compound as an off-white powder in about 83.0% yield based on 3-bromo-1- (3-chloro-2-pyridinyl) -1H-pyrazole-5-carboxylic acid.
Comparative example 5
298.9G of 2-amino-5-chloro-3, N-dimethylbenzamide (1.50 mol,1.03 eq) obtained in comparative example 3 was charged into a reaction flask, 1300g of dichloroethane solvent, 441.7g of 3-bromo-1- (3-chloropyridin-2-yl) -1H-pyrazole-5-carboxylic acid (1.46 mol,1.0 eq), 353.5g of 3-methylpyridine (3.80 mol,2.6 eq), the temperature was controlled at 10℃and 250.8g of methylsulfonyl chloride (2.19 mol,1.5 eq) was added dropwise, and the reaction was continued at 10℃for 2 hours after completion of the dropwise addition.
After the reaction is finished and the sample is detected to be qualified, carrying out suction filtration, water washing and drying on the feed liquid to obtain 622.5g of chlorantraniliprole finished product, wherein the yield of the chlorantraniliprole finished product is 85.6 percent based on 3-bromo-1- (3-chloro-2-pyridyl) -1H-pyrazole-5-carboxylic acid, and the HPLC area normalized purity is 97.0 percent.
For convenience of comparison, the data of the reactants and the amounts thereof in the examples and comparative examples, and the yields in each step are shown in tables 1 and 2 below.
TABLE 1
TABLE 2
From the results shown in tables 1 and 2, the method of the invention can effectively reduce the byproduct generation, reduce the consumption of chlorinating agent (sulfonyl chloride), has low operation requirement, avoids the influence of introducing unnecessary moisture on a reaction system, reduces the post-treatment operation steps, has good process stability and high reaction yield by protecting amino and then preparing the anthranilamide salt compound, and is suitable for industrial production.
In the prior art, an alkaline reagent is required to be added, and then the product is obtained through multi-step operation, the actual operation process is complex, and is influenced by side reaction, a large amount of byproducts exist, the reaction yield is low, and the actual production is not facilitated. The post-treatment of the anthranilamide salt compound can be carried out by filtering or centrifuging to obtain a high-purity product, and the product can be directly used for the next reaction.
The preferred embodiments of the present invention have been described in detail above, but the present invention is not limited to the specific details of the above embodiments, and various simple modifications can be made to the technical solution of the present invention within the scope of the technical concept of the present invention, and all the simple modifications belong to the protection scope of the present invention.
In addition, the specific features described in the above embodiments may be combined in any suitable manner, and in order to avoid unnecessary repetition, various possible combinations are not described further.
Moreover, any combination of the various embodiments of the invention can be made without departing from the spirit of the invention, which should also be considered as disclosed herein.

Claims (15)

1.一种制备具有式(I)的邻甲酰胺基苯甲酰胺类化合物的方法，其包括：1. A method for preparing an o-formamidobenzamide compound of formula (I), comprising: 使具有式(II)的盐形式的苯胺化合物The aniline compound having the salt form of formula (II) 具有式(III)的吡啶化合物A pyridine compound having formula (III) 进行反应，其中，Reaction, wherein R1选自H、卤素或C1-C4烷基；R 1 is selected from H, halogen or C 1 -C 4 alkyl; R2选自H、卤素或氰基； R2 is selected from H, halogen or cyano; R3选自H、C1-C4烷基、C3-C10环烷基或C4-C10环烷基烷基，其中所述C1-C4烷基、C3-C10环烷基或C4-C10环烷基烷基任选地被卤素或氰基取代；R 3 is selected from H, C 1 -C 4 alkyl, C 3 -C 10 cycloalkyl or C 4 -C 10 cycloalkylalkyl, wherein the C 1 -C 4 alkyl, C 3 -C 10 cycloalkyl or C 4 -C 10 cycloalkylalkyl is optionally substituted with halogen or cyano; R4选自卤素、C1-C4烷基或C1-C4烷氧基，其中所述C1-C4烷基或C1-C4烷氧基任选地被卤素取代；R 4 is selected from halogen, C 1 -C 4 alkyl or C 1 -C 4 alkoxy, wherein the C 1 -C 4 alkyl or C 1 -C 4 alkoxy is optionally substituted with halogen; R5选自卤素； R5 is selected from halogen; R6选自氢或卤素； R6 is selected from hydrogen or halogen; Q选自卤素、羟基、-O-SO2-R7，其中，R7为C1-C4烷基或者卤代C1-C4烷基；以及Q is selected from halogen, hydroxyl, -O-SO 2 -R 7 , wherein R 7 is C 1 -C 4 alkyl or halogenated C 1 -C 4 alkyl; and X为无机酸或有机酸。X is an inorganic acid or an organic acid. 2.根据权利要求1所述的方法，其中，当Q选自羟基时，所述方法进一步包括将磺酰氯R8S(O)2Cl加入式(II)化合物和式(III)化合物的混合物中，2. The method according to claim 1, wherein when Q is selected from hydroxyl, the method further comprises adding sulfonyl chloride R 8 S(O) 2 Cl to the mixture of the compound of formula (II) and the compound of formula (III), R8选自C1-C4烷基或取代苯基，其任选地被卤素、C1-C4烷基或硝基取代。R 8 is selected from C 1 -C 4 alkyl or substituted phenyl, which is optionally substituted by halogen, C 1 -C 4 alkyl or nitro. 3.根据权利要求2所述的方法，其中，所述反应在碱的存在下进行，优选地，所述碱选自吡啶或三乙胺，优选3-甲基吡啶，更优选地，所述反应在-10℃-30℃的温度下进行。3. The method according to claim 2, wherein the reaction is carried out in the presence of a base, preferably, the base is selected from pyridine or triethylamine, preferably 3-methylpyridine, more preferably, the reaction is carried out at a temperature of -10°C to 30°C. 4.根据权利要求3所述的方法，其中，以摩尔量计，式(II)化合物、式(III)化合物、磺酰氯和碱的比例为1-1.3：1：0.2-2：2-4。4. The method according to claim 3, wherein the ratio of the compound of formula (II), the compound of formula (III), the sulfonyl chloride and the base is 1-1.3:1:0.2-2:2-4 in molar amount. 5.根据权利要求1所述的方法，其中，当Q选自卤素时，所述反应在不存在碱的情况下进行，优选地，所述反应在80℃-160℃的温度下进行。5. The method according to claim 1, wherein when Q is selected from halogen, the reaction is carried out in the absence of a base, preferably, the reaction is carried out at a temperature of 80°C-160°C. 6.根据权利要求1所述的方法，其中，当Q选自-O-SO2-R7时，所述反应在碱的存在下进行，优选地，所述碱选自吡啶或三乙胺，优选3-甲基吡啶，更优选地，所述反应在-10℃-30℃的温度下进行。The method according to claim 1, wherein when Q is selected from -O-SO2-R7 , the reaction is carried out in the presence of a base, preferably, the base is selected from pyridine or triethylamine, preferably 3-methylpyridine, more preferably, the reaction is carried out at a temperature of -10°C to 30°C. 7.根据权利要求1-6中任一项所述的方法，其中，所述反应在有机溶剂中进行，优选地，所述有机溶剂选自腈类、酯类、酮类、卤代烷类、醚类、芳族烃类或叔胺类溶剂及其任意组合，优选为二氯甲烷、二氯乙烷、二氯丁烷、乙腈、丙腈、氯苯、甲苯、二甲苯或四氯乙烯。7. The method according to any one of claims 1 to 6, wherein the reaction is carried out in an organic solvent, preferably, the organic solvent is selected from nitriles, esters, ketones, halogenated alkanes, ethers, aromatic hydrocarbons or tertiary amine solvents and any combination thereof, preferably dichloromethane, dichloroethane, dichlorobutane, acetonitrile, propionitrile, chlorobenzene, toluene, xylene or tetrachloroethylene. 8.根据权利要求1-6中任一项所述的方法，其中，所述无机酸选自氢氟酸、盐酸、氢溴酸、氢碘酸、硝酸、硫酸、碳酸、磷酸或硼酸；和/或所述有机酸选自甲酸、乙酸、马来酸、柠檬酸、苹果酸、草酸、酒石酸、琥珀酸、苯甲酸、水杨酸或咖啡酸。8. The method according to any one of claims 1 to 6, wherein the inorganic acid is selected from hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, carbonic acid, phosphoric acid or boric acid; and/or the organic acid is selected from formic acid, acetic acid, maleic acid, citric acid, malic acid, oxalic acid, tartaric acid, succinic acid, benzoic acid, salicylic acid or caffeic acid. 9.一种具有式(II)的盐形式的苯胺化合物，9. An aniline compound in the form of a salt of formula (II), 其中，R1、R2、R3和X如权利要求1中所定义。wherein R 1 , R 2 , R 3 and X are as defined in claim 1. 10.一种具有式(III-3)的吡啶化合物，10. A pyridine compound having formula (III-3), 其中，R1、R2、R3和R7如权利要求1中所定义。wherein R 1 , R 2 , R 3 and R 7 are as defined in claim 1. 11.一种制备具有式(II-1)的盐形式的苯胺化合物的方法，其包括：11. A method for preparing an aniline compound in the form of a salt of formula (II-1), comprising: 将式(IV)化合物The compound of formula (IV) 与酸性试剂和卤化试剂反应，以得到所述具有式(II-1)的盐形式的苯胺化合物，reacting with an acidic reagent and a halogenating reagent to obtain the aniline compound in the form of a salt of formula (II-1), 其中，R1和R3如权利要求1中所定义，并且R2为卤素。wherein R1 and R3 are as defined in claim 1, and R2 is halogen. 12.根据权利要求11所述的方法，其中，所述酸性试剂选自氯化氢、乙酸、溴化氢、磷酸或硫酸。12. The method according to claim 11, wherein the acidic reagent is selected from hydrogen chloride, acetic acid, hydrogen bromide, phosphoric acid or sulfuric acid. 13.根据权利要求11所述的方法，其中，所述卤化试剂选自氯气、磺酰氯、N-氯代丁二酰亚胺、二氯海因、液溴、二溴海因、过溴化吡啶氢溴酸盐或N-溴代丁二酰亚胺。13. The method according to claim 11, wherein the halogenating agent is selected from chlorine, sulfonyl chloride, N-chlorosuccinimide, dichlorohydantoin, liquid bromine, dibromohydantoin, perbrominated pyridine hydrobromide or N-bromosuccinimide. 14.根据权利要求11所述的方法，其中，以摩尔量计，式(IV)化合物、酸性试剂和卤化试剂的比例为1：1-1.5：1.1-1.5。14. The method according to claim 11, wherein the ratio of the compound of formula (IV), the acidic reagent and the halogenating reagent is 1:1-1.5:1.1-1.5 in molar amount. 15.根据权利要求11所述的方法，其中，所述反应在30-50℃、优选35-45℃的温度下进行。15. The method according to claim 11, wherein the reaction is carried out at a temperature of 30-50°C, preferably 35-45°C.
CN202311283346.2A 2023-10-07 2023-10-07 Preparation method of o-formamidobenzamide compounds and intermediates thereof Pending CN119775254A (en)

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