Preparation method of o-formamidobenzamide compounds and intermediates thereof

Abstract

The present application relates to a method for preparing an o-formamidobenzamide compound having formula (I) and an intermediate thereof, wherein the method comprises reacting an aniline compound in the form of a salt, a pyridine compound and a sulfonyl chloride R 8 S(O) 2 The preparation method provided by the present invention is simple to operate, can directly obtain the final product, avoids unnecessary side reactions and simplifies the separation process of the intermediate, can greatly improve the reaction yield, and improve the atomic utilization rate.

Description

Technical Field

[0001] The present application relates to the field of organic synthesis, and in particular to a method for preparing an o-formamidobenzamide compound and an intermediate thereof. Background Art

[0002] The prior art WO2006062978A1 discloses o-formamidobenzamide compounds and intermediates thereof represented by the following formula.

[0003]

[0004] However, the chlorination reaction in the process of preparing the intermediate 3-substituted 2-amino-5-halogenated benzamide has side reactions, the raw materials react incompletely, and unnecessary by-products and tar are generated, which are difficult to separate, reducing the reaction yield. In addition, the post-treatment alkali adjustment operation brings in moisture, which will also hydrolyze part of the product and produce impurities, further reducing the reaction yield and product purity.

[0005] Therefore, the present invention is in urgent need of an improved method for preparing o-formamidobenzamide compounds with simple operation, few by-products and high yield. Summary of the invention

[0006] The object of the present invention is to provide a method for preparing an o-formamidobenzamide compound and an intermediate thereof in view of the deficiencies in the prior art. The method is simple to operate, can directly obtain the final product, avoids unnecessary side reactions, simplifies the separation process of the intermediate, improves the atomic utilization rate, and can greatly improve the reaction yield.

[0007] In a first aspect, the present invention provides a method for preparing an o-formamidobenzamide compound having formula (I), comprising:

[0008]

[0009] The aniline compound having the salt form of formula (II)

[0010]

[0011] A pyridine compound having formula (III)

[0012]

[0013] To react,

[0014] in,

[0015] R1 is selected from H, halogen or C1-C4 alkyl;

[0016] R2 is selected from H, halogen or cyano;

[0017] R3 is selected from H, C1-C4 alkyl, C3-C 10 Cycloalkyl or C4-C 10 Cycloalkylalkyl, wherein the C1-C4 alkyl, C3-C 10 Cycloalkyl or C4-C 10 Cycloalkylalkyl is optionally substituted with halogen or cyano;

[0018] R4 is selected from halogen, C1-C4 alkyl or C1-C4 alkoxy, wherein the C1-C4 alkyl or C1-C4 alkoxy is optionally substituted with halogen;

[0019] R5 is selected from halogen;

[0020] R6 is selected from hydrogen or halogen;

[0021] Q is selected from halogen, hydroxyl, -O-SO2-R7, wherein R7 is C1-C4 alkyl or halogenated C1-C4 alkyl; and

[0022] X is an inorganic acid or an organic acid.

[0023] In one embodiment of the present invention, when Q is selected from hydroxyl, the method may further comprise reacting sulfonyl chloride R 8 S(O)2Cl is added to a mixture of a compound of formula (II) and a compound of formula (III), wherein R8 is selected from C1-C4 alkyl or substituted phenyl, which is optionally substituted by halogen, C1-C4 alkyl or nitro.

[0024] 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.

[0025] In a preferred embodiment of the present invention, when a base is present, the reaction can be carried out at a temperature of -10°C to 30°C (eg, 0°C, 10°C or 20°C, etc.).

[0026] In another preferred embodiment of the present invention, the molar ratio of the compound of formula (II), the compound of formula (III), the sulfonyl chloride and the base can be 1-1.3:1:0.2-2:2-4, or any ratio therebetween, for example, 1:1:1:3, 1.2:1:0.5:2 or 1.3:1:1.5:4, etc.

[0027] In one embodiment of the present invention, when Q is selected from halogen, the reaction can be carried out in the absence of a base. In this case, the released acidic gas can be absorbed and used as a by-product or used in the previous step of using the acidic gas to replace the aniline salt formation step, the method is simple, and the three wastes are less. In a preferred embodiment of the present invention, when a base is not present, the reaction can be carried out at a higher temperature, such as 80°C-160°C (such as 100°C, 120°C or 140°C, etc.).

[0028] In one embodiment of the present invention, when Q is selected from -O-SO2-R7, the reaction can be carried out in the presence of a base, preferably, the base can be selected from pyridine or triethylamine, preferably 3-methylpyridine, more preferably, the reaction can be carried out at a temperature of -10°C-30°C. For the amount ratio of each reactant, the above-mentioned case where Q is selected from hydroxyl can be referred to, and no further details are given here.

[0029] In one embodiment of the present invention, the reaction can be carried out in an organic solvent. Preferably, the organic solvent can 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), halogenated alkanes (e.g., dichloromethane, chloroform, tetrachloroethylene), ethers (e.g., ethyl 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.

[0030] In one embodiment of the present invention, the inorganic acid can 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 can 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.

[0031] Unless otherwise indicated, references herein to "a compound of formula (N)" or "a compound of formula (N)" (e.g., a compound of formula (I)) also encompass isotope-labeled compounds in which any atom in the compound is replaced by an isotope atom thereof. The present invention includes all pharmaceutically acceptable isotope-labeled compounds of the compound of formula (N), wherein one or more atoms are replaced by atoms having the same atomic number as the atoms commonly found in nature but a different atomic mass or mass number.

[0032] Examples of suitable isotopes for inclusion in the compounds of the present invention include isotopes of hydrogen such as 2 H(D) and 3H(T), isotopes of carbon, such as 11 C. 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 15 O. 17 O and 18 O, and isotopes of sulfur such as 35 S.

[0033] 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 an analogous manner to those described in the Examples and Preparations appended herein.

[0034] 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.

[0035] As used herein, the term "optionally" means that the event it describes may or may not occur. For example, a group "optionally substituted" means that the group may be unsubstituted or substituted.

[0036] As used herein, the term "alkyl" refers to a saturated aliphatic hydrocarbon, including straight and branched chains. For example, the term "C1-C 12 "Alkyl" refers to a straight or branched chain radical having 1 to 12 carbon atoms. 12 "Alkyl" includes within its definition the terms "C1-C3 alkyl", "C1-C4 alkyl", and "C1-C6 alkyl". Examples of alkyl 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.

[0037] As used herein, the term “C4-C 10 "Cycloalkylalkyl" refers to cycloalkyl and alkyl groups having a total of 4 to 10 carbon atoms connected to each other, for example, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, etc.

[0038] The compounds of the present application can 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 embodiments of the present application and make appropriate adjustments to the reaction raw materials and reaction conditions to obtain synthetic methods for other compounds.

[0039] In a second aspect, the present invention also provides an aniline compound in the form of a salt having formula (II),

[0040]

[0041] wherein R1, R2, R3 and X are as defined above.

[0042] In a third aspect, the present invention also provides a pyridine compound having formula (III-3),

[0043]

[0044] wherein R1, R2, R3 and R7 are as defined above.

[0045] In a fourth aspect, the present invention also provides a method for preparing an aniline compound in the form of a salt of formula (II-1), comprising:

[0046]

[0047] The compound of formula (IV)

[0048]

[0049] reacting with an acidic reagent and a halogenating reagent to obtain the aniline compound in the form of a salt of formula (II-1),

[0050] Among them, R 1 and R 3 As defined above, and R 2 It is a halogen.

[0051] In one embodiment of the present invention, the acidic reagent may be selected from hydrogen chloride, acetic acid, hydrogen bromide, phosphoric acid or sulfuric acid.

[0052] In one embodiment of the present invention, the halogenating agent may be selected from chlorine, sulfonyl chloride, N-chlorosuccinimide, dichlorohydantoin, liquid bromine, dibromohydantoin, perbrominated pyridinium hydrobromide or N-bromosuccinimide.

[0053] In one embodiment of the present invention, the reaction solvent may be selected from dichloromethane, dichloroethane, dibromoethane, dichlorobutane 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 1:1-1.5:1.1-1.5 in terms of molar amount.

[0054] In one embodiment of the present invention, the reaction may be carried out at a temperature of 30-50°C, preferably 35-45°C.

[0055] The inventors have found that the chlorination reaction in the process of preparing the o-aminobenzamide intermediate has side reactions, generating unnecessary by-products and tar, which are difficult to separate and reduce the reaction yield. In addition, the post-treatment alkali adjustment operation introduces moisture, which will also hydrolyze part of the product and generate impurities, further reducing the reaction yield and product purity.

[0056] The invention protects the amino group first and then prepares the o-aminobenzamide salt compound, thereby effectively reducing the generation of by-products, reducing the amount of the chlorinating agent, having low operation requirements, avoiding the influence of unnecessary moisture on the reaction system and reducing the post-processing operation steps, having good process stability, high reaction yield and being suitable for industrial production.

[0057] In addition, the o-aminobenzamide salt compound prepared by the present invention can be directly used in the next reaction, and the reaction can be carried out in the absence of a base. In this case, the released acidic gas can be absorbed as a raw material and directly used in the next batch of intermediate salt formation, thereby achieving recycling, a simple method, and less three wastes.

[0058] Compared with the prior art, the technical solution of the present invention includes at least the following technical advantages: the preparation method provided by the present invention is simple to operate, can directly obtain the final product, avoids unnecessary side reactions and simplifies the splitting process of the intermediates, can greatly improve the reaction yield, and improve the atomic utilization rate.

[0059] Those skilled in the art will appreciate that the definitions and preferences described in one aspect of the present application are equally applicable to other aspects. Those skilled in the art will appreciate that the embodiments of various aspects of the present application can be combined in various ways without departing from the subject matter and ideas of the present application, and these combinations are also included in the scope of the present application. DETAILED DESCRIPTION

[0060] The compounds of the present application can be synthesized by various methods familiar to those skilled in the art of organic synthesis. The following specific examples provide methods for synthesizing some exemplary compounds, which are well known in the field of synthetic chemistry.

[0061] The present invention is further described below with reference to examples; however, these examples do not limit the scope of the present invention. Unless otherwise stated, all reactants used in the examples are obtained from commercial sources; the instruments and equipment used in the synthesis experiments and product analysis and detection are conventional instruments and equipment commonly used in organic synthesis.

[0062] Example 1: Preparation of 2-amino-5-chloro-3, N-dimethylbenzamide hydrochloride

[0063] 2000g of ethylene dichloride and 295.2g of 2-amino-3, N-dimethylbenzamide (1.8mol, 1 equivalent) were added to the reaction bottle, and the temperature was controlled at 35°C throughout the process. 65.7g of hydrogen chloride (1.8mol, 1 equivalent) gas was slowly introduced within 1 hour. After the gas was exhausted, 279.4g (2.07mol, 1.15 equivalent) of sulfonyl chloride solution was added dropwise within 30 minutes. The reaction was kept warm for 2 hours, and samples were taken for testing. After the reaction was completed, the temperature was lowered to 10°C.

[0064] After the sampling was qualified, the feed liquid was filtered and rinsed with dichloroethane twice to obtain 396.4g of 2-amino-5-chloro-3,N-dimethylbenzamide hydrochloride (1.687mol), with a moisture content of <0.1%, a by-product content of <0.1%, a reaction yield of 93.7%, and it can be directly used in the next step without purification.

[0065] Example 2: Preparation of 2-amino-5-chloro-3, N-dimethylbenzamide hydrochloride

[0066] 2000g of ethylene dichloride and 295.2g of 2-amino-3, N-dimethylbenzamide (1.8mol, 1 equivalent) were added to the reaction bottle, and the temperature was controlled at 40°C throughout the process. 65.7g of hydrogen chloride (1.8mol, 1 equivalent) gas was slowly introduced within 1 hour. After the gas was exhausted, 315.8g (2.34mol, 1.3 equivalent) of sulfonyl chloride solution was added dropwise within 30 minutes. The reaction was kept warm for 2 hours, and samples were taken for testing. After the reaction was completed, the temperature was lowered to 10°C.

[0067] After the sampling is qualified, the feed liquid is filtered and rinsed with dichloroethane twice to obtain 398.0g of 2-amino-5-chloro-3,N-dimethylbenzamide hydrochloride (1.694mol), with a moisture content of <0.1%, a by-product content of <0.1%, a reaction yield of 94.1%, and can be directly used in the next step without purification.

[0068] Example 3: Preparation of 2-amino-5-chloro-3, N-dimethylbenzamide hydrochloride

[0069] 2000g of ethylene dichloride and 295.2g of 2-amino-3, N-dimethylbenzamide (1.8mol, 1 equivalent) were added to the reaction bottle, and the temperature was controlled at 45°C throughout the process. 65.7g of hydrogen chloride (1.8mol, 1 equivalent) gas was slowly introduced within 1 hour. After the gas was exhausted, 267.3g (1.98mol, 1.1 equivalent) of sulfonyl chloride solution was added dropwise within 30 minutes. The reaction was kept warm for 2 hours, and samples were taken for testing. After the reaction was completed, the temperature was lowered to 10°C.

[0070] After the sampling was qualified, the feed liquid was filtered and rinsed with dichloroethane twice to obtain 392.5g of 2-amino-5-chloro-3,N-dimethylbenzamide hydrochloride (1.670mol), with a moisture content of <0.1%, a by-product content of <0.1%, a reaction yield of 92.8%, and it can be directly used in the next step without purification.

[0071] Example 4: Preparation of 2-amino-5-bromo-3, N-dimethylbenzamide bromate

[0072] 2000g of dibromoethane and 295.2g of 2-amino-3, N-dimethylbenzamide (1.8mol, 1 equivalent) were added to the reaction bottle, and the temperature was controlled at 45°C throughout the process. Hydrogen bromide (0.18mol, 0.10 equivalent) gas was slowly introduced. After the gas was exhausted, the temperature was controlled at 40°C throughout the process, and 316.4g (1.98mol, 1.1 equivalent) of bromine was slowly added dropwise. The addition was completed within 60-90 minutes. The reaction was kept warm for 2h, and samples were taken for testing. After the reaction was completed, the temperature was lowered to 10°C.

[0073] After the sampling was qualified, the feed liquid was filtered and rinsed twice with dibromoethane to obtain 536.9 g of 2-amino-5-bromo-3, N-dimethylbenzamide bromate (1.652 mol), with a moisture content of <0.1% and a reaction yield of 91.8%.

[0074] Example 5: Preparation of 2-amino-5-bromo-3, N-dimethylbenzamide bromate

[0075] Put 2000g of dibromoethane and 295.2g of 2-amino-3, N-dimethylbenzamide (1.8mol, 1 equivalent) into the reaction bottle, control the temperature at 40°C throughout the process, and slowly pass hydrogen bromide (0.09mol, 0.05 equivalent) gas. After the gas is exhausted, slowly add 345.2g (2.16mol, 1.2 equivalent) of bromine dropwise, and the addition is completed within 60-90 minutes. Keep the temperature for 2h, take samples for testing, and cool to 10°C after the reaction is completed.

[0076] After the sampling was qualified, the feed liquid was filtered and rinsed twice with dibromoethane to obtain 537.6 g of 2-amino-5-bromo-3, N-dimethylbenzamide bromate (1.654 mol), with a moisture content of <0.1% and a reaction yield of 91.9%.

[0077] 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

[0078] Into the reaction flask, 396.4 g of 2-amino-5-chloro-3, N-dimethylbenzamide hydrochloride (1.687 mol, 1.03 equivalents) prepared in Example 1, 1300 g of dichloroethane solvent, 496.1 g of 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid (1.640 mol, 1.0 equivalents), 395.7 g of 3-methylpyridine (4.255 mol, 2.6 equivalents) were added, the temperature was controlled at 10°C, 280.8 g of methylsulfonyl chloride (2.45 mol, 1.5 equivalents) was added dropwise, and the reaction was continued at 10°C for 2 hours after the addition was completed.

[0079] After the reaction was completed and the sampling test was qualified, the feed liquid was filtered, washed with water, and dried to obtain 757.7 g of chlorantraniliprole finished product, with a yield of 94.6% based on 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid and a HPLC area-normalized purity of 99.0%.

[0080] 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-carbonyl chloride

[0081] Into the reaction flask, 398 g of 2-amino-5-chloro-3, N-dimethylbenzamide hydrochloride (1.694 mol, 1.03 equivalents) prepared in Example 2, 1300 g of dichloroethane solvent, 526.5 g of 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carbonyl chloride (1.640 mol, 1.0 equivalents) and 335.2 g of 3-methylpyridine (3.6 mol, 2.20 equivalents) were added, the temperature was controlled at 5°C, and the reaction was continued for 2 hours.

[0082] After the reaction was completed and the sampling test was qualified, the feed liquid was filtered, washed with water, and dried to obtain 755.2 g of chlorantraniliprole finished product, with a yield of 94.5% based on 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carbonyl chloride and an HPLC area normalized purity of 99.1%.

[0083] 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

[0084] Into the reaction flask, 392.5 g of 2-amino-5-chloro-3, N-dimethylbenzamide hydrochloride (1.67 mol, 1.02 equivalents) prepared in Example 3, 1300 g of dichloroethane solvent, 627.3 g of 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-methanesulfonic anhydride (1.64 mol, 1.0 equivalents), and 335.2 g of 3-methylpyridine (3.5 mol, 2.13 equivalents) were added, the temperature was controlled at 0°C, and the reaction was continued for 2 hours.

[0085] After the reaction was completed and the sampling test was qualified, the feed liquid was filtered, washed with water, and dried to obtain 751.3 g of chlorantraniliprole finished product, with a yield of 93.7% based on 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-methanesulfonic anhydride and an HPLC area normalized purity of 98.8%.

[0086] Example 9: Preparation of chlorantraniliprole from 2-amino-5-chloro-3, N-dimethylbenzamide hydrogen sulfate and 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid

[0087] 501.1 g 2-amino-5-chloro-3, N-dimethylbenzamide hydrogen sulfate (1.690 mol, 1.03 equivalents) was added into the reaction flask, along with 1300 g dichloroethane solvent, 496.1 g 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid (1.64 mol, 1.0 equivalents) and 395.7 g 3-methylpyridine (4.25 mol, 2.6 equivalents). The temperature was controlled at 10°C, and 280.8 g methylsulfonyl chloride (2.45 mol, 1.5 equivalents) was added dropwise. After the addition was completed, the reaction was continued at 10°C for 2 hours.

[0088] After the reaction was completed and the sampling test was qualified, the feed liquid was filtered, washed with water, and dried to obtain 755.6 g of chlorantraniliprole finished product, with a yield of 94.4% based on 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid and a HPLC area normalized purity of 99.0%.

[0089] Example 10: Preparation of chlorantraniliprole from 2-amino-5-chloro-3, N-dimethylbenzamide hydrogen sulfate and 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carbonyl chloride

[0090] 501.1 g of 2-amino-5-chloro-3, N-dimethylbenzamide hydrogen sulfate (1.690 mol, 1.03 equivalents), 1300 g of dichloroethane solvent, 526.4 g of 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carbonyl chloride (1.64 mol, 1.0 equivalents), and 335.2 g of 3-methylpyridine (3.5 mol, 2.13 equivalents) were added to the reaction flask. The temperature was controlled at 10°C and the reaction was continued for 2 hours.

[0091] After the reaction was completed and the sampling test was qualified, the feed liquid was filtered, washed with water, and dried to obtain 748.4 g of chlorantraniliprole finished product, with a yield of 92.8% based on 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carbonyl chloride and an HPLC area normalized purity of 98.2%.

[0092] Example 11: Preparation of chlorantraniliprole from 2-amino-5-chloro-3, N-dimethylbenzamide hydrogen sulfate and 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-methanesulfonic anhydride

[0093] 501.1 g of 2-amino-5-chloro-3, N-dimethylbenzamide hydrogen sulfate (1.69 mol, 1.03 equivalents), 1300 g of dichloroethane solvent, 627.3 g of 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-methanesulfonic anhydride (1.64 mol, 1.0 equivalents), and 344.5 g of 3-methylpyridine (3.7 mol, 2.26 equivalents) were added to the reaction flask, the temperature was controlled at 10°C, and the reaction was continued for 2 hours.

[0094] After the reaction was completed and the sampling test was qualified, the feed liquid was filtered, washed with water, and dried to obtain 740.6 g of chlorantraniliprole finished product, with a yield of 91.8% based on 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-methanesulfonic anhydride and an HPLC area normalized purity of 98.2%.

[0095] 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

[0096] Into the reaction flask, add 501.1 g of 2-amino-5-chloro-3, N-dimethylbenzamide dihydrogen phosphate (1.69 mol, 1.03 equivalents), 1300 g of dichloroethane solvent, 496.1 g of 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid (1.64 mol, 1.0 equivalents), 316.5 g of 3-methylpyridine (3.4 mol, 2.07 equivalents), control the temperature at 10°C, add 280.8 g of methylsulfonyl chloride (2.45 mol, 1.5 equivalents), and continue to react at 10°C for 2 hours after the addition is complete.

[0097] After the reaction was completed and the sampling test was qualified, the feed liquid was filtered, washed with water, and dried to obtain 750.5 g of chlorantraniliprole finished product, with a yield of 93.3% based on 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid and an HPLC area normalized purity of 98.5%.

[0098] 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

[0099] 501.1 g of 2-amino-5-chloro-3, N-dimethylbenzamide dihydrogen phosphate (1.69 mol, 1.03 equivalents), 1300 g of dichloroethane solvent, 526.4 g of 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carbonyl chloride (1.64 mol, 1.0 equivalents), and 353.8 g of 3-methylpyridine (3.8 mol, 2.32 equivalents) were added to the reaction bottle, the temperature was controlled at 10°C, and the reaction was continued for 2 hours.

[0100] After the reaction was completed and the samples were tested to be qualified, the feed liquid was filtered, washed with water, and dried to obtain 750.7 g of chlorfenapyr finished product with a yield of 93.7% and an HPLC area-normalized purity of 98.9%.

[0101] 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

[0102] 501.1 g of 2-amino-5-chloro-3, N-dimethylbenzamide dihydrogen phosphate (1.69 mol, 1.03 equivalents), 1300 g of dichloroethane solvent, 627.3 g of 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-methanesulfonic anhydride (1.64 mol, 1.0 equivalents), and 344.5 g of 3-methylpyridine (3.7 mol, 2.26 equivalents) were added to the reaction bottle, the temperature was controlled at 10°C, and the reaction was continued at 10°C for 2 hours.

[0103] After the reaction was completed and the sampling test was qualified, the feed liquid was filtered, washed with water, and dried to obtain 741.2 g of chlorantraniliprole finished product with a yield of 91.7% and an HPLC area normalized purity of 98.0%.

[0104] 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-carbonyl chloride

[0105] Into the reaction flask, 398 g of 2-amino-5-chloro-3, N-dimethylbenzamide hydrochloride (1.694 mol, 1.03 equivalents) prepared in Example 2, 1300 g of chlorobenzene solvent, 526.5 g of 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carbonyl chloride (1.640 mol, 1.0 equivalents) were added, and the temperature was raised to 130° C. and kept warm for 2 hours. The generated hydrogen chloride gas was used for 2-amino-3, N-dimethylbenzamide hydrochloride in Example 1.

[0106] After the reaction was completed and the sampling test was qualified, the feed liquid was filtered, washed with water, and dried to obtain 752.9 g of chlorantraniliprole finished product, with a yield of 93.9% based on 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carbonyl chloride and an HPLC area normalized purity of 97.8%.

[0107] Comparative Example 1: Preparation of 2-amino-5-chloro-3, N-dimethylbenzamide (see CN101492387A)

[0108] Add 17.5g (107mmol) 3-methyl-2-aminobenzamide and 100mL acetonitrile to a reaction bottle with a condenser and a thermometer, and add 17.0g (126mmol) of sulfonyl chloride diluted with 50mL acetonitrile dropwise in an ice bath, and keep the addition time for about 2h. After the addition is completed, heat to 55±1°C and continue the reaction for 0.5h. Sampling and testing, the remaining raw material content is 38%, and continue to add 7.5g (55.5mmol) of sulfonyl chloride until the raw material content is <0.1%.

[0109] After the reaction, the pH was adjusted to 11 with a 10% NaOH solution, stirred for 10 minutes, separated, and the organic phase was washed twice with water, concentrated to obtain a crude solid product, and recrystallized to obtain 16.5 g of light red needle-shaped crystals, namely 2-amino-5-chloro-N,3-dimethylbenzamide, with a reaction yield of 77.7%. After sampling and analysis, the water content was 0.7%, and the by-product content in the system was 8.4%.

[0110] After analysis, it is found that the method needs to add an alkaline reagent, and then concentrate and recrystallize to obtain the product. The actual operation process is complicated. Acetonitrile is used as a solvent. Acetonitrile and water are miscible and difficult to separate. The moisture content of the product exceeds the standard. Affected by side reactions, there are a large number of by-products and the reaction yield is low.

[0111] Comparative Example 2: Preparation of 2-amino-5-chloro-3, N-dimethylbenzamide (see CN115181031A)

[0112] 10g (61.0mmol) of methyl 2-amino-3-methylbenzoate was placed in a flask, 20g of chloroform was added, the temperature was raised to 30°C, and a solution of 8.59g of sulfonyl chloride (63.6mmol) in chloroform (10g) was slowly added dropwise for 1h, and the temperature was kept for 1h after the addition. Samples were taken for testing, and the remaining raw material content was 45%, and 6.1g (45mmol) of sulfonyl chloride was continued to be added dropwise until the raw material content was <0.1%.

[0113] After the reaction is completed, the solvent is removed, 30 g of toluene and 20 g of water are added, 10% sodium hydroxide solution is added dropwise, the pH is adjusted to about 8, toluene is used for extraction, the organic phase is washed with water until neutral, and the solvent is removed under negative pressure to obtain 9.6 g of methyl 2-amino-5-chloro-3-methylbenzoate with a yield of 79.3%. After sampling and analysis, the water content is 0.5%, and the by-product content in the system is 7.2%.

[0114] After analysis, it is found that this method requires the addition of an alkaline reagent, followed by extraction and desolventization to obtain the product. The actual operation process is complicated, and at the same time, affected by side reactions, a large amount of by-products are present, and the reaction yield is low.

[0115] Comparative Example 3: Preparation of 2-amino-5-chloro-3, N-dimethylbenzamide (without hydrogen chloride gas)

[0116] 2000g of dichloroethane and 295.2g of 2-amino-3, N-dimethylbenzamide (1.8mol, 1 equivalent) were added to the reaction flask, and the temperature was controlled at 40°C throughout the process. 279.4g (2.07mol, 1.15 equivalent) of sulfonyl chloride solution was added dropwise within 30 minutes. The reaction was kept warm for 2h, and samples were taken for testing. If most of the raw materials remained unreacted, 109.4g (0.81mol) of sulfonyl chloride was added until the raw material content was <0.1%. After the reaction was completed, the temperature was lowered to 10°C.

[0117] After the sampling is qualified, the solvent is removed, 10% sodium hydroxide solution is added, the pH is adjusted to about 8, extracted with toluene, the organic phase is washed with water until neutral, and desolventized under negative pressure to obtain 281.0g 2-amino-3,N-dimethylbenzamide, with a moisture content of 0.5%, a by-product content of 6.5%, and a reaction yield of 78.6%.

[0118] After analysis, it is found that this method requires the addition of an alkaline reagent, followed by extraction and desolventization to obtain the product. The actual operation process is complicated, and at the same time, affected by side reactions, a large amount of by-products are present, and the reaction yield is low.

[0119] Comparative Example 4: Existing preparation method of chlorantraniliprole (see CN102285899A)

[0120] To a mixture of 3-bromo-1-(3-chloro-2-pyridyl)-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°C, then, methanesulfonyl chloride (2.75 g, 24 mmol) was added dropwise at -5 to 0°C, and the mixture was stirred at 0-5°C for 3 h.

[0121] Then, water (9 mL) was added dropwise, and dichloromethane (18 mL) was added to the thick suspension, and the mixture was stirred at 0° C. for 1 h. The mixture was filtered, and the solid was washed with ice-cold 2:1 dichloromethane-water (2×4.5 mL), and dried under nitrogen to obtain 8.05 g of the title compound as a nearly white powder, with a yield of about 83.0% based on 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylic acid.

[0122] Comparative Example 5

[0123] Into the reaction flask, 298.9 g of 2-amino-5-chloro-3, N-dimethylbenzamide (1.50 mol, 1.03 equivalents) prepared in Comparative Example 3, 1300 g of dichloroethane solvent, 441.7 g of 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid (1.46 mol, 1.0 equivalents), 353.5 g of 3-methylpyridine (3.80 mol, 2.6 equivalents) were added, the temperature was controlled at 10 ° C, 250.8 g of methylsulfonyl chloride (2.19 mol, 1.5 equivalents) was added dropwise, and the reaction was continued at 10 ° C for 2 hours after the addition was completed.

[0124] After the reaction was completed and the sampling test was qualified, the feed liquid was filtered, washed with water, and dried to obtain 622.5 g of chlorantraniliprole finished product, with a yield of 85.6% based on 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylic acid and an HPLC area-normalized purity of 97.0%.

[0125] For the convenience of comparison, the reactants and their amounts in the examples and comparative examples, as well as the yield of each step and other data are listed in the following Tables 1 and 2.

[0126] Table 1

[0127]

[0128]

[0129] Table 2

[0130]

[0131] It can be seen from the results in Table 1 and Table 2 that the method of the present invention can effectively reduce the generation of by-products and the amount of the chlorinating agent (sulfonyl chloride) by first protecting the amino group and then preparing the o-aminobenzamide salt compound, has low operating requirements, avoids the introduction of unnecessary moisture to affect the reaction system and reduces the post-processing operation steps, has good process stability, high reaction yield, and is suitable for industrial production.

[0132] The prior art requires the addition of an alkaline reagent and then a multi-step operation to obtain the product, which is complicated in the actual operation process, and is affected by side reactions, resulting in a large amount of by-products, a low reaction yield, and is not conducive to actual production. The post-treatment of the preparation of the anthranilamide salt compound of the present invention is only performed by filtering or centrifugation to separate a high-purity product, which can be directly used in the next step reaction.

[0133] The preferred embodiments of the present invention are described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the technical concept of the present invention, a variety of simple modifications can be made to the technical solution of the present invention, and these simple modifications all belong to the protection scope of the present invention.

[0134] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any suitable manner without contradiction. In order to avoid unnecessary repetition, the present invention will not further describe various possible combinations.

[0135] In addition, various embodiments of the present invention may be arbitrarily combined, and as long as they do not violate the concept of the present invention, they should also be regarded as the contents disclosed by the present invention.

Claims

1. A method for preparing an o-formamidobenzamide compound of formula (I), comprising: The aniline compound having the salt form of formula (II) A pyridine compound having formula (III) Reaction, wherein R1 is selected from H, halogen or C1-C4 alkyl; R2 is selected from H, halogen or cyano; R3 is selected from H, C1-C4 alkyl, C3-C 10 Cycloalkyl or C4-C 10 Cycloalkylalkyl, wherein the C1-C4 alkyl, C3-C 10 Cycloalkyl or C4-C 10 Cycloalkylalkyl is optionally substituted with halogen or cyano; R4 is selected from halogen, C1-C4 alkyl or C1-C4 alkoxy, wherein the C1-C4 alkyl or C1-C4 alkoxy is optionally substituted with halogen; R5 is selected from halogen; R6 is selected from hydrogen or halogen; Q is selected from halogen, hydroxyl, -O-SO2-R7, wherein R7 is C1-C4 alkyl or halogenated C1-C4 alkyl; and X is an inorganic acid or an organic acid.

2. The method according to claim 1, wherein: When Q is selected from hydroxyl, the method further comprises reacting a sulfonyl chloride R 8 S(O)2Cl is added to a mixture of the compound of formula (II) and the compound of formula (III), R8 is selected from C1-C4 alkyl or substituted phenyl, which is optionally substituted by halogen, C1-C4 alkyl or nitro.

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. The method according to claim 3, wherein: In terms of molar amount, 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.

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 to 160°C.

6. 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. 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. 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. An aniline compound in the form of a salt of formula (II), in, R1, R2, R3 and X are as defined in claim 1.

10. A pyridine compound having formula (III-3), in, R1, R2, R3 and R7 are as defined in claim 1.

11. A method for preparing an aniline compound in the form of a salt of formula (II-1), comprising: The compound of formula (IV) reacting with an acidic reagent and a halogenating reagent to obtain the aniline compound in the form of a salt of formula (II-1), Among them, R 1 and R 3 As defined in claim 1, and R 2 It is a halogen.

12. The method according to claim 11, wherein: The acidic agent is selected from hydrogen chloride, acetic acid, hydrogen bromide, phosphoric acid or sulfuric acid.

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. The method according to claim 11, wherein: In terms of molar amount, the ratio of the compound of formula (IV), the acidic reagent and the halogenating reagent is 1:1-1.5:1.1-1.

5.

15. The method according to claim 11, wherein: The reaction is carried out at a temperature of 30-50°C, preferably 35-45°C.

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