A synthetic method for cyantraniliprole impurity

Abstract

The invention discloses a method for synthesizing a cyantraniliprole impurity. The chemical name of the impurity is 3-bromo-1-(3-chloro-2-pyridyl)-N-[4-(formamido)-2-methyl-6-[(methylamino)carbonyl]phenyl]-1-hydrogen-pyrazole-5-carboxamide. 2-amino-3-methylbenzoic acid is used as a starting material, and the product is sequentially subjected to triphosgene cyclization, nitration, amine transesterification ring-opening, hydrogenation reduction, and two-step amide condensation reactions to finally obtain a target compound, 3-bromo-1-(3-chloro-2-pyridyl)-N-[4-(formamido)-2-methyl-6-[(methylamino)carbonyl]phenyl]-1-hydrogen-pyrazole-5-carboxamide. The whole reaction route has simple conditions, is easy to operate, and is economical and practical.

Description

Technical Field

[0001] The present invention belongs to the technical field of drug synthesis, and in particular relates to a method for synthesizing a cyantraniliprole impurity. The chemical name of the impurity is 3-bromo-1-(3-chloro-2-pyridyl)-N-[4-(formamido)-2-methyl-6-[(methylamino)carbonyl]phenyl]-1-hydrogen-pyrazole-5-carboxamide. Background Art

[0002] Cyantraniliprole, also known as cyantraniliprole, is a second-generation ryanodine receptor inhibitor insecticide developed by DuPont following chlorantraniliprole. Cyantraniliprole is produced by modifying various polar groups on the benzene ring, resulting in higher efficacy and a wider range of applicability, effectively controlling lepidopteran, hemipteran, and coleopteran pests. 3-Bromo-1-(3-chloro-2-pyridinyl)-N-[4-(formamido)-2-methyl-6-[(methylamino)carbonyl]phenyl]-1-hydro-pyrazole-5-carboxamide is an impurity introduced during cyanantraniliprole production and is considered toxic. EU standards require its content in the technical product to be less than 0.00002% (w / w). Its molecular structure is shown in Formula I below.

[0003]

[0004] my country's pesticide registration system is also beginning to prioritize impurities in technical materials. Registrants are required to provide information on impurities exceeding 0.1% and conduct qualitative analysis. Consequently, extensive research is required on impurities such as 3-bromo-1-(3-chloro-2-pyridinyl)-N-[4-(formamido)-2-methyl-6-[(methylamino)carbonyl]phenyl]-1-hydrogen-pyrazole-5-carboxamide.

[0005] Since the content of 3-bromo-1-(3-chloro-2-pyridyl)-N-[4-(formamido)-2-methyl-6-[(methylamino)carbonyl]phenyl]-1hydro-pyrazole-5-carboxamide produced during the production of cyantraniliprole is very low, it is not feasible to extract it, so it needs to be synthesized. Summary of the Invention

[0006] The object of the present invention is to overcome the defects existing in the prior art and provide a method for synthesizing cyantraniliprole impurity. The chemical name of the impurity is 3-bromo-1-(3-chloro-2-pyridyl)-N-[4-(formamido)-2-methyl-6-[(methylamino)carbonyl]phenyl]-1hydro-pyrazole-5-carboxamide. 2-amino-3-methylbenzoic acid is used as a starting material. The method is sequentially subjected to cyclization with triphosgene, nitration, amine transesterification ring opening, hydrogenation reduction, and two-step amide condensation reaction to finally obtain the target compound 3-bromo-1-(3-chloro-2-pyridyl)-N-[4-(formamido)-2-methyl-6-[(methylamino)carbonyl]phenyl]-1hydro-pyrazole-5-carboxamide. The entire reaction route has simple conditions, the reaction process is easy to operate, and the product is economical and practical.

[0007] To achieve the above objectives, the technical solution of the present invention is to design a method for synthesizing cyantraniliprole impurity, whose chemical name is 3-bromo-1-(3-chloro-2-pyridyl)-N-[4-(formamido)-2-methyl-6-[(methylamino)carbonyl]phenyl]-1-hydrogen-pyrazole-5-carboxamide, comprising the following steps:

[0008] S1: 8-methyl-1H-benzo[d][1,3]oxazine-2,4-dione was prepared by using 2-amino-3-methylbenzoic acid as a raw material and reacting with triphosgene under alkaline reagent conditions to obtain 8-methyl-1H-benzo[d][1,3]oxazine-2,4-dione. The reaction formula is as follows:

[0009]

[0010] S2: Prepare 6-nitro-8-methyl-1H-benzo[d][1,3]oxazine-2,4-dione. Use 8-methyl-1H-benzo[d][1,3]oxazine-2,4-dione prepared in step S1 as a raw material, and perform nitration reaction to obtain 6-nitro-8-methyl-1H-benzo[d][1,3]oxazine-2,4-dione. The reaction formula is as follows:

[0011]

[0012] S3: 2-amino-N,3-dimethyl-5-nitrobenzamide is prepared by using 6-nitro-8-methyl-1H-benzo[d][1,3]oxazine-2,4-dione prepared in step S2 as a raw material and reacting it with methylamine under alkaline reagent conditions to obtain 2-amino-N,3-dimethyl-5-nitrobenzamide through amine ester exchange ring-opening reaction. The reaction formula is as follows:

[0013]

[0014] S4: preparing 2,5-diamino-N,3-dimethylbenzamide, using the 2-amino-N,3-dimethyl-5-nitrobenzamide prepared in step S3 as a raw material, and subjecting it to a hydrogenation reduction reaction to obtain 2,5-diamino-N,3-dimethylbenzamide, the reaction formula of which is the following formula V:

[0015]

[0016] S5: preparing 2-amino-5-formamido-N,3-dimethylbenzamide, using the 2,5-diamino-N,3-dimethylbenzamide prepared in step S4 as a raw material, and subjecting it to an amide condensation reaction with a formic acid solution to obtain 2-amino-5-formamido-N,3-dimethylbenzamide, the reaction formula of which is the following formula VI:

[0017]

[0018] S6: Preparation of 3-bromo-1-(3-chloro-2-pyridyl)-N-[4-(formamido)-2-methyl-6-[(methylamino)carbonyl]phenyl]-1H-pyrazole-5-carboxamide. The 2-amino-5-formamido-N,3-dimethylbenzamide prepared in step S5 is used as a raw material, and subjected to an amide condensation reaction with 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamide to obtain 3-bromo-1-(3-chloro-2-pyridyl)-N-[4-(formamido)-2-methyl-6-[(methylamino)carbonyl]phenyl]-1H-pyrazole-5-carboxamide. The reaction formula is the following formula VII:

[0019]

[0020] A preferred technical solution is that in step S1, the alkaline reagent used is a mixture of triethylamine and ethyl acetate, the molar feed ratio of 2-amino-3-methylbenzoic acid, triphosgene, and triethylamine is 1:0.7-1:1.5-2, the mass feed ratio of 2-amino-3-methylbenzoic acid to ethyl acetate is 1:10-15, the reaction temperature is 20-40°C, and the reaction time is 30-45h.

[0021] Another preferred technical solution is that in step S2, the mass feed ratio of 8-methyl-1H-benzo[d][1,3]oxazine-2,4-dione, concentrated sulfuric acid, and concentrated nitric acid is 1:5-7:0.6-1, the reaction temperature is -5-0°C, and the reaction time is 1-2h.

[0022] Another preferred technical solution is that in step S3, the alkaline reagent used is a mixture of pyridine and acetonitrile, the molar feed ratio of 6-nitro-8-methyl-1H-benzo[d][1,3]oxazine-2,4-dione to pyridine and methylamine is 1:0.5~1:3~4, the mass feed ratio of 6-nitro-8-methyl-1H-benzo[d][1,3]oxazine-2,4-dione to acetonitrile is 1:7~10, the reaction temperature is 60~90°C, and the reaction time is 18~25h.

[0023] Another preferred technical solution is that in step S4, the catalyst used is Pd / C, the solvent used is a mixed solution of dichloromethane and methanol, the mass feed ratio of 2-amino-N,3-dimethyl-5-nitrobenzamide and Pd / C is 1:0.2-0.5, the mass feed ratio of 2-amino-N,3-dimethyl-5-nitrobenzamide, dichloromethane, and methanol is 1:25:37.5, the reaction temperature is 10-30°C, and the reaction time is 3-5h.

[0024] Another preferred technical solution is that in step S5, the solvent used is DMF, the formic acid solution used is a mixture of formic acid and acetic anhydride, the molar feed ratio of 2,5-diamino-N,3-dimethylbenzamide, acetic anhydride, and formic acid is 1:4-6:4-6, the mass feed ratio of 2,5-diamino-N,3-dimethylbenzamide and DMF is 1:6-10, the reaction temperature is 10-30°C, and the reaction time is 3-5h.

[0025] A preferred technical solution is that the specific operation of step S6 is to use the 2-amino-5-formamido-N,3-dimethylbenzamide prepared in step S5 as a raw material, and in a solvent containing 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, diisopropylethylamine, and DMF, at room temperature, react with 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid to obtain 3-bromo-1-(3-chloro-2-pyridyl)-N-[4-(formamido)-2-methyl-6-[( The molar feed ratio of 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamide, 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid, 2-amino-5-formamido-N,3-dimethylbenzamide, diisopropylethylamine, and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate is 1:1.1-2:1-2:1-2, the mass feed ratio of 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid and DMF is 1:20, and the reaction time is 2-5 h.

[0026] The advantages and beneficial effects of the present invention are:

[0027] The invention discloses a method for synthesizing a cyantraniliprole impurity. The method uses 2-amino-3-methylbenzoic acid as a starting material, sequentially undergoes cyclization with triphosgene, nitration, amine transesterification ring-opening, hydrogenation reduction, and a two-step amide condensation reaction to finally obtain the target compound 3-bromo-1-(3-chloro-2-pyridyl)-N-[4-(formamido)-2-methyl-6-[(methylamino)carbonyl]phenyl]-1hydro-pyrazole-5-carboxamide. The entire reaction route has simple conditions, the reaction process is easy to operate, and the product is economical and practical. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 The 3-bromo-1-(3-chloro-2-pyridyl)-N-[4-(formamido)-2-methyl-6-[(methylamino)carbonyl]phenyl]-1-hydrogen-pyrazole-5-carboxamide prepared in Example 1 is 1 H NMR spectrum;

[0029] Figure 2 This is the MS spectrum of 3-bromo-1-(3-chloro-2-pyridinyl)-N-[4-(formamido)-2-methyl-6-[(methylamino)carbonyl]phenyl]-1-hydrogen-pyrazole-5-carboxamide prepared in Example 1. DETAILED DESCRIPTION

[0030] The following embodiments are further described in conjunction with the accompanying drawings and examples. The following embodiments are only used to more clearly illustrate the technical solutions of the present invention and are not intended to limit the scope of protection of the present invention.

[0031] Example 1

[0032] The synthetic method of the present invention is used to prepare 3-bromo-1-(3-chloro-2-pyridyl)-N-[4-(formamido)-2-methyl-6-[(methylamino)carbonyl]phenyl]-1-hydrogen-pyrazole-5-carboxamide, comprising the following steps:

[0033] S1: Take a 500mL three-necked flask, add 2-amino-3-methylbenzoic acid (20g, 132mmol), triethylamine (24g, 237.6mmol) and ethyl acetate (266mL, 240g), control the temperature at 10-15℃ and stir, slowly add triphosgene (31.8g, 107mmol) dissolved in ethyl acetate (100mL) dropwise, and react at 25℃ for 40h; after the reaction is completed, filter and wash the filter cake with water and dry to obtain the intermediate 8-methyl-1H-benzo[d][1,3]oxazine-2,4-dione (17.22g) with a yield of 74%.

[0034] S2: Take a 250mL three-necked flask, add concentrated sulfuric acid (103.2g), control the temperature at 0±5℃ and stir, add 8-methyl-1H-benzo[d][1,3]oxazine-2,4-dione (17.2g, 97.2mmol) in batches, slowly add concentrated nitric acid (13.8g) dropwise under stirring, and react for 1h; after the reaction is completed, add ice water (400mL) to the reaction solution, filter with suction, wash and dry the filter cake to obtain 6-nitro-8-methyl-1H-benzo[d][1,3]oxazine-2,4-dione (20.2g), yield: 93%.

[0035] S3: In a 250 mL three-necked flask, add 6-nitro-8-methyl-1H-benzo[d][1,3]oxazine-2,4-dione (20.2 g, 91 mmol), pyridine (5.8 g, 72.8 mmol), and acetonitrile (172 mL). Add methylamine (9.8 g, 318.5 mmol) dropwise to the reaction mixture under an ice bath. Stir the reaction mixture at 70°C for 20 h. After the reaction is complete, cool the mixture, filter the reaction mixture, wash the filter cake, and dry it to obtain 2-amino-N,3-dimethyl-5-nitrobenzamide (17 g) in an 89% yield.

[0036] S4: In a 250 mL hydrogenation reaction flask, add 2-amino-N,3-dimethyl-5-nitrobenzamide (4.0 g, 19.1 mmol), Pd / C (1.4 g), dichloromethane / methanol (100 / 150 mL), and 0.5 MPa H2. The reaction mixture was reacted at 20°C for 3.5 h. After the reaction, the reaction mixture was filtered and the filtrate was concentrated to dryness to obtain 2,5-diamino-N,3-dimethylbenzamide (3.3 g) in a yield of 97%.

[0037] S5: Add 2,5-diamino-N,3-dimethylbenzamide (3.3 g, 18.6 mmol) and DMF (26 mL) to a 100 mL three-necked flask. Add a mixture of acetic anhydride (9.5 g, 93 mmol), formic acid (4.3 g, 93 mmol), and DMF (20 mL) dropwise under an ice bath. After the addition is complete, the reaction mixture is incubated at 20°C for 3.5 h. After the reaction is complete, the reaction mixture is concentrated, and the residue is slurried with acetonitrile (30 mL) for 0.5 h and filtered. The filter cake is dried to obtain 2-amino-5-formamido-N,3-dimethylbenzamide (1.79 g) in a yield of 46%.

[0038] S6: Take a 100 mL three-necked flask and add 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid (2 g, 6.6 mmol), diisopropylethylamine (1.3 g, 9.9 mmol, 9.9 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 3.8 g), and DMF (40 mL). The reaction solution was reacted at room temperature for 0.5 h, and 2-amino-5-formamido-N,3-dimethylbenzamide (2 g, 9.9 mmol) was added and stirred at room temperature for 3 h. After the reaction, water was added, the mixture was filtered, and the filter cake was dried to obtain a crude product. The crude product was purified by pre-HPLC to obtain 3 g of 3-bromo-1-(3-chloro-2-pyridinyl)-N-[4-(formamido)-2-methyl-6-[(methylamino)carbonyl]phenyl]-1hydro-pyrazole-5-carboxamide as a yellow solid in a yield of 86%.

[0039] The 3-bromo-1-(3-chloro-2-pyridyl)-N-[4-(formamido)-2-methyl-6-[(methylamino)carbonyl]phenyl]-1-hydrogen-pyrazole-5-carboxamide prepared in Example 1 was subjected to nuclear magnetic resonance analysis using a BUUKER AV-400 nuclear magnetic resonance spectrometer. The nuclear magnetic spectrum is shown in the attached FIG. Figure 1 , Its nuclear magnetic data are as follows: 1H-NMR: δppm 10.262(s,1H),10.123(s,1H),8.486to 8.494(d,1H),8.268(s,1H),8.153to 8.169(d,1H),8.073(s,1H),7.588to7.613(m,1H),7.534(s,1H),7.523(s,1H),7.375(s,1H),2.649to 2.657(d,3H),2.123(s,3H), which is consistent with the molecular formula C 19 H 16 The peak positions of hydrogen atoms in BrClN6O3 are consistent.

[0040] The 3-bromo-1-(3-chloro-2-pyridyl)-N-[4-(formamido)-2-methyl-6-[(methylamino)carbonyl]phenyl]-1-hydrogen-pyrazole-5-carboxamide prepared in Example 1 was analyzed by mass spectrometry using a Thermo LTQ-orbitrap XL mass spectrometer. The mass spectrum is shown in the attached Figure 2 , Positive polarity ESI(+) / ESI, mass spectrometry ESI(+) result [M+H]+ m / z is 490.6, it can be inferred that the molecular weight of the sample is 490, which is consistent with C 19 H 16 The theoretical molecular weight of BrClN6O3 is consistent.

[0041] Example 2

[0042] The synthetic method of the present invention is used to prepare 3-bromo-1-(3-chloro-2-pyridyl)-N-[4-(formamido)-2-methyl-6-[(methylamino)carbonyl]phenyl]-1-hydrogen-pyrazole-5-carboxamide, comprising the following steps:

[0043] S1: Take a 500mL three-necked flask, add 2-amino-3-methylbenzoic acid (20g, 132mmol), triethylamine (26.7g, 264mmol) and ethyl acetate (333mL, 300g), control the temperature at 10-15℃ and stir, slowly add triphosgene (39.2g, 132mmol) dissolved in ethyl acetate (110mL) dropwise, and react at 40℃ for 30h; after the reaction is completed, filter and wash the filter cake with water and dry to obtain the intermediate 8-methyl-1H-benzo[d][1,3]oxazine-2,4-dione (17.22g) with a yield of 79%.

[0044] S2: Take a 250mL three-necked flask, add concentrated sulfuric acid (120.4g), control the temperature at 0±5℃ and stir, add 8-methyl-1H-benzo[d][1,3]oxazine-2,4-dione (17.2g, 97.2mmol) in batches, slowly add concentrated nitric acid (17.2g) dropwise under stirring, and react for 1h; after the reaction is completed, add ice water (400mL) to the reaction solution, filter with suction, wash and dry the filter cake to obtain 6-nitro-8-methyl-1H-benzo[d][1,3]oxazine-2,4-dione (20.2g), yield: 95%.

[0045] S3: In a 250 mL three-necked flask, add 6-nitro-8-methyl-1H-benzo[d][1,3]oxazine-2,4-dione (20.2 g, 91 mmol), pyridine (7.2 g, 91 mmol), and acetonitrile (202 mL). Add methylamine (11.3 g, 364 mmol) dropwise to the reaction mixture under an ice bath. Stir the mixture at 70°C for 20 h. After the reaction is complete, cool the mixture, filter the mixture, and wash and dry the filter cake to obtain 2-amino-N,3-dimethyl-5-nitrobenzamide (17 g) in an 89% yield.

[0046] S4: In a 250 mL hydrogenation reaction flask, add 2-amino-N,3-dimethyl-5-nitrobenzamide (4.0 g, 19.1 mmol), Pd / C (2 g), dichloromethane / methanol (100 / 150 mL), and 0.5 MPa H2. The reaction mixture was reacted at 20°C for 3.5 h. After the reaction, the reaction mixture was filtered and the filtrate was concentrated to dryness to obtain 2,5-diamino-N,3-dimethylbenzamide (3.3 g) in a yield of 97%.

[0047] S5: Add 2,5-diamino-N,3-dimethylbenzamide (3.3 g, 18.6 mmol) and DMF (33 mL) to a 100 mL three-necked flask. Add a mixture of acetic anhydride (11.4 g, 111.6 mmol), formic acid (5.1 g, 111.6 mmol), and DMF (20 mL) dropwise under an ice bath. After the addition is complete, the reaction mixture is incubated at 20°C for 3.5 h. After the reaction is complete, the reaction mixture is concentrated, and the residue is slurried with acetonitrile (30 mL) for 0.5 h and filtered. The filter cake is dried to obtain 2-amino-5-formamido-N,3-dimethylbenzamide (1.79 g) in a yield of 46%.

[0048] S6: Take a 100 mL three-necked flask and add 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid (2 g, 6.6 mmol), diisopropylethylamine (1.7 g, 13.2 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 5 g, 13.2 mmol), and DMF (40 mL). The reaction solution was reacted at room temperature for 0.5 h, and 2-amino-5-formamido-N,3-dimethylbenzamide (2.7 g, 13.2 mmol) was added and stirred at room temperature for 3 h. After the reaction, water was added, the mixture was filtered, and the filter cake was dried to obtain a crude product. The crude product was purified by pre-HPLC to obtain 3 g of 3-bromo-1-(3-chloro-2-pyridinyl)-N-[4-(formamido)-2-methyl-6-[(methylamino)carbonyl]phenyl]-1hydro-pyrazole-5-carboxamide as a yellow solid in a yield of 85%.

[0049] Example 3

[0050] The synthetic method of the present invention is used to prepare 3-bromo-1-(3-chloro-2-pyridyl)-N-[4-(formamido)-2-methyl-6-[(methylamino)carbonyl]phenyl]-1-hydrogen-pyrazole-5-carboxamide, comprising the following steps:

[0051] S1: Take a 500mL three-necked flask, add 2-amino-3-methylbenzoic acid (20g, 132mmol), triethylamine (20g, 198mmol) and ethyl acetate (220mL, 198.4g), control the temperature at 10-15℃ and stir, slowly add triphosgene (17.3g, 92.5mmol) dissolved in ethyl acetate (100mL) dropwise, and react at 20℃ for 45h; after the reaction is completed, filter and wash the filter cake with water and dry to obtain the intermediate 8-methyl-1H-benzo[d][1,3]oxazine-2,4-dione (17.22g) with a yield of 75%.

[0052] S2: Take a 250mL three-necked flask, add concentrated sulfuric acid (86g), control the temperature at 0±5℃ and stir, add 8-methyl-1H-benzo[d][1,3]oxazine-2,4-dione (17.2g, 97.2mmol) in batches, slowly add concentrated nitric acid (10.3g) dropwise under stirring, and react for 1h; after the reaction is completed, add ice water (400mL) to the reaction solution, filter with suction, wash and dry the filter cake to obtain 6-nitro-8-methyl-1H-benzo[d][1,3]oxazine-2,4-dione (20.2g), yield: 90%.

[0053] S3: In a 250 mL three-necked flask, add 6-nitro-8-methyl-1H-benzo[d][1,3]oxazine-2,4-dione (20.2 g, 91 mmol), pyridine (3.6 g, 45.5 mmol), and acetonitrile (141 mL). Add methylamine (8.5 g, 273 mmol) dropwise to the reaction mixture under an ice bath. Stir the mixture at 70°C for 20 h. After the reaction is complete, cool the mixture, filter the mixture, and wash and dry the filter cake to obtain 2-amino-N,3-dimethyl-5-nitrobenzamide (16.8 g) in an 88% yield.

[0054] S4: In a 250 mL hydrogenation reaction flask, add 2-amino-N,3-dimethyl-5-nitrobenzamide (4.0 g, 19.1 mmol), Pd / C (0.8 g), dichloromethane / methanol (100 / 150 mL), and 0.5 MPa H2. The reaction mixture was reacted at 20°C for 3.5 h. After the reaction, the reaction mixture was filtered and the filtrate was concentrated to dryness to obtain 2,5-diamino-N,3-dimethylbenzamide (3.3 g) in a yield of 97%.

[0055] S5: Take a 100mL three-necked flask, add 2,5-diamino-N,3-dimethylbenzamide (3.3g, 18.6mmol) and DMF (19.8mL), and add a mixture of acetic anhydride (7.6g, 74.4mmol) and formic acid (3.4g, 74.4mmol) and DMF (20mL) dropwise under ice bath. After the addition is complete, the reaction solution is reacted at 20°C for 3.5h. After the reaction is completed, the reaction solution is concentrated, and the residue is slurried with acetonitrile (30mL) for 0.5h and filtered. The filter cake is dried to obtain 2-amino-5-formamido-N,3-dimethylbenzamide (1.79g), with a yield of 46%.

[0056] S6: Take a 100 mL three-necked flask and add 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid (2 g, 6.6 mmol), diisopropylethylamine (0.94 g, 7.3 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 2.8 g, 7.3 mmol), and DMF (40 mL). The reaction solution was reacted at room temperature for 0.5 h, and 2-amino-5-formamido-N,3-dimethylbenzamide (1.5 g, 7.3 mmol) was added and stirred at room temperature for 3 h. After the reaction, water was added, the mixture was filtered, and the filter cake was dried to obtain a crude product. The crude product was purified by pre-HPLC to obtain 3 g of 3-bromo-1-(3-chloro-2-pyridinyl)-N-[4-(formamido)-2-methyl-6-[(methylamino)carbonyl]phenyl]-1hydro-pyrazole-5-carboxamide as a yellow solid in a yield of 87%.

[0057] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the technical principles of the present invention. These improvements and modifications should also be regarded as within the scope of protection of the present invention.

Claims

1. A method for synthesizing cyantraniliprole impurities, characterized in that: Its chemical name is 3-bromo-1-(3-chloro-2-pyridyl)-N-[4-(formamido)-2-methyl-6-[(methylamino)carbonyl]phenyl]-1-hydrogen-pyrazole-5-carboxamide, and it comprises the following steps: S1: 8-methyl-1H-benzo[d][1,3]oxazine-2,4-dione was prepared by using 2-amino-3-methylbenzoic acid as a raw material and reacting it with triphosgene under alkaline reagent conditions to obtain 8-methyl-1H-benzo[d][1,3]oxazine-2,4-dione. The reaction formula is as follows: Formula II. The alkaline reagent used is a mixture of triethylamine and ethyl acetate. The reaction temperature is 20-40°C and the reaction time is 30-45h: S2: Prepare 6-nitro-8-methyl-1H-benzo[d][1,3]oxazine-2,4-dione. Use 8-methyl-1H-benzo[d][1,3]oxazine-2,4-dione prepared in step S1 as a raw material, and perform nitration reaction to obtain 6-nitro-8-methyl-1H-benzo[d][1,3]oxazine-2,4-dione. The reaction formula is as follows: S3: 2-amino-N,3-dimethyl-5-nitrobenzamide is prepared by using 6-nitro-8-methyl-1H-benzo[d][1,3]oxazine-2,4-dione prepared in step S2 as a raw material, and reacting it with methylamine under alkaline reagent conditions to obtain 2-amino-N,3-dimethyl-5-nitrobenzamide through amine ester exchange ring-opening reaction. The reaction formula is the following formula IV. The alkaline reagent used is a mixture of pyridine and acetonitrile. The reaction temperature is 60-90°C and the reaction time is 18-25 hours: S4: preparing 2,5-diamino-N,3-dimethylbenzamide, using the 2-amino-N,3-dimethyl-5-nitrobenzamide prepared in step S3 as a raw material, and subjecting it to a hydrogenation reduction reaction to obtain 2,5-diamino-N,3-dimethylbenzamide, the reaction formula of which is the following formula V: S5: preparing 2-amino-5-formamido-N,3-dimethylbenzamide, using the 2,5-diamino-N,3-dimethylbenzamide prepared in step S4 as a raw material, and subjecting it to an amide condensation reaction with a formic acid solution to obtain 2-amino-5-formamido-N,3-dimethylbenzamide, the reaction formula is the following formula VI, the formic acid solution used is a mixture of formic acid and acetic anhydride, the reaction temperature is 10-30° C., and the reaction time is 3-5 hours: S6: Preparation of 3-bromo-1-(3-chloro-2-pyridyl)-N-[4-(formamido)-2-methyl-6-[(methylamino)carbonyl]phenyl]-1H-pyrazole-5-carboxamide. The 2-amino-5-formamido-N,3-dimethylbenzamide prepared in step S5 is used as a raw material, and subjected to an amide condensation reaction with 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamide to obtain 3-bromo-1-(3-chloro-2-pyridyl)-N-[4-(formamido)-2-methyl-6-[(methylamino)carbonyl]phenyl]-1H-pyrazole-5-carboxamide. The reaction formula is the following formula VII:

2. The method for synthesizing cyantraniliprole impurities according to claim 1, wherein: In step S1, the molar feed ratio of 2-amino-3-methylbenzoic acid, triphosgene, and triethylamine is 1:0.7 to 1:1.5 to 2, and the mass feed ratio of 2-amino-3-methylbenzoic acid to ethyl acetate is 1:10 to 15.

3. The method for synthesizing cyantraniliprole impurities according to claim 1, wherein: In the step S2, the mass feed ratio of 8-methyl-1H-benzo[d][1,3]oxazine-2,4-dione, concentrated sulfuric acid, and concentrated nitric acid is 1:5-7:0.6-1, the reaction temperature is -5-0°C, and the reaction time is 1-2h.

4. The method for synthesizing cyantraniliprole impurities according to claim 1, wherein: In the step S3, the molar feed ratio of 6-nitro-8-methyl-1H-benzo[d][1,3]oxazine-2,4-dione to pyridine and methylamine is 1:0.5 to 1:3 to 4, and the mass feed ratio of 6-nitro-8-methyl-1H-benzo[d][1,3]oxazine-2,4-dione to acetonitrile is 1:7 to 10.

5. The method for synthesizing cyantraniliprole impurities according to claim 1, wherein: In the step S4, the catalyst used is Pd / C, the solvent used is a mixed solution of dichloromethane and methanol, the mass feed ratio of 2-amino-N,3-dimethyl-5-nitrobenzamide and Pd / C is 1:0.2-0.5, the mass feed ratio of 2-amino-N,3-dimethyl-5-nitrobenzamide, dichloromethane, and methanol is 1:25:37.5, the reaction temperature is 10-30°C, and the reaction time is 3-5h.

6. The method for synthesizing cyantraniliprole impurities according to claim 1, wherein: In the step S5, the solvent used is DMF, the molar feed ratio of 2,5-diamino-N,3-dimethylbenzamide, acetic anhydride, and formic acid is 1:4-6:4-6, and the mass feed ratio of 2,5-diamino-N,3-dimethylbenzamide to DMF is 1:6-10.

7. The method for synthesizing cyantraniliprole impurities according to claim 1, wherein: The specific operation of step S6 is to use the 2-amino-5-formamido-N,3-dimethylbenzamide prepared in step S5 as a raw material, and in a solvent containing 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, diisopropylethylamine, and DMF, at room temperature, react with 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid to obtain 3-bromo-1-(3-chloro-2-pyridyl)-N-[4-(formamido)-2-methyl-6-[(methylamino)carbonyl]-4 ... The molar feed ratio of 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamide, 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid, 2-amino-5-carboxamido-N,3-dimethylbenzamide, diisopropylethylamine, and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate is 1:1.1-2:1-2:1-2, the mass feed ratio of 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamide and DMF is 1:20, and the reaction time is 2-5 h.

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