Preparation method of key intermediate of chlorantraniliprole

Abstract

The invention provides a preparation method of a chlorantraniliprole key intermediate 2-amino-5-cyano-N, 3-dimethyl benzamide, which comprises the following steps: taking cheap and easily available o-methylaniline as a raw material, acylating an aniline substrate through Boc anhydride, carrying out ortho-lithiation on n-butyllithium, introducing carbon dioxide gas, and carrying out acid hydrolysis to obtain 2-amino-3-methyl benzoic acid, thereby obtaining the chlorantraniliprole key intermediate 2-amino-5-cyano-N, 3-dimethyl benzamide. The preparation method comprises the following steps: firstly, preparing an isatoic anhydride intermediate, then carrying out triphosgene ring closing to obtain an isatoic anhydride intermediate, carrying out bromine para-position halogenation, carrying out cuprous cyanide high-temperature Rosenmn-von Braun reaction, and finally carrying out methylamine ring opening to obtain the target product 2-amino-5-cyano-N, 3-dimethylbenzamide, and although the route is long, the yield is high, the continuity is good, few industrial three wastes are generated, and the cost is lower, so that the preparation method has great industrial production value.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a compound of a key intermediate of chlorantraniliprole and a preparation method thereof. Background Art

[0002] Chlorantraniliprole, whose chemical formula is C 18 H 14 BrCl2N5O2 is a new type of insecticide. The chemical structure of chlorantraniliprole has a new insecticidal principle that no other insecticide has. It can efficiently activate the insect Ryanodine receptor and paralyze and kill the insect by excessively releasing calcium ions in its intracellular calcium store. Chlorantraniliprole has high activity against the larvae of lepidopteran pests, a wide insecticidal spectrum, and good persistence. According to some existing test results, it is also found that its activity against target pests is 10-100 times higher than that of other products, and it can cause disorders in the mating process of some lepidopteran insects. Studies have shown that it can also reduce the egg-laying rate of a variety of noctuid pests. Due to its good persistence and biological characteristics of resistance to rain erosion, it has a longer and more stable protective effect on crops than most other insecticides in use. In terms of controlling major rice pests, it can quickly protect rice growth, especially for pests that are already resistant to other rice insecticides, such as rice leaf roller, striped stem borer, yellow stem borer, and rice borer, and has a good control effect on rice gall midge, rice weevil, and rice water weevil. The pesticide is slightly toxic, very safe for pesticide applicators, and also very safe for beneficial insects, fish and shrimp in rice fields. The effective period can reach more than 15 days, with no residual effect on agricultural products, and good mixing performance with other pesticides. Therefore, chlorantraniliprole has broad application prospects in the field of pesticides, and the compound 2-amino-5-cyano-N,3-dimethylbenzamide involved in this patent is one of the key intermediates of chlorantraniliprole.

[0003] There are many existing methods for preparing 2-amino-5-cyano-N,3-dimethylbenzamide. Usually, 2-amino-3-methylbenzoic acid is used as a raw material, and NIS is used for para-iodination, and then 2-amino-5-cyano-3-methylbenzoic acid is prepared by high-temperature Rosenmund-von Braun reaction with cuprous cyanide, and then oxalyl chloride is used for ring closure, and finally methylamine aqueous solution is used for ring opening. However, the NIS used in the first step of this route is expensive, and the reaction is violently exothermic, with high safety risks. The oxalyl chloride used in the ring closure step will produce toxic gas carbon monoxide, which requires high professional quality of the operator. And the cost of 2-amino-3-methylbenzoic acid itself is also high, which seriously limits the further development and application of this route. Therefore, a new method for preparing 2-amino-5-cyano-N,3-dimethylbenzamide is proposed to solve some problems existing in the above process.

[0004] Summary of the invention DETAILED DESCRIPTION

[0005] In order to make the technical means, creative features, purpose and efficacy of the present invention easy to understand, the present invention is further explained in conjunction with specific examples below. In the following examples, unless otherwise specified, the operating methods used are conventional operating methods, the equipment used are conventional equipment, and the raw materials used are commercially available. The present invention is further described below in conjunction with examples.

[0006] Example

[0007] Step 1. Preparation of Intermediate 1

[0008]

[0009] 500L of water and 500L of ethyl acetate were pumped into a 2000L reactor in sequence, the stirring device was started, and then 265kg of sodium carbonate and 107kg of o-methylaniline were added. After the addition, hot water circulation was started, the reactor was heated to 40°C, and 240kg of Boc anhydride was slowly pumped in batches. After the pumping was completed, the reaction was kept warm for 8 hours. After the TLC reaction was complete, the temperature was lowered to below 30°C, and the layers were allowed to stand and separate. The upper ethyl acetate layer was separated, and the ethyl acetate layer was washed once with 300kg of saturated sodium chloride aqueous solution, dried with sodium sulfate for 30 minutes, filtered, concentrated to about half the volume of ethyl acetate, and 750L of n-heptane was pumped in. After crystallization and pulping for 2 hours, the intermediate 1 was obtained by centrifugal drying, totaling 203kg, with a yield of 98.05%.

[0010] Step 2. Preparation of Intermediate 2

[0011]

[0012] 1200L of anhydrous tetrahydrofuran was pumped into the 2000L reactor, the stirring device was started, and then a total of 203kg of intermediate 1 was added. After the addition was completed, a liquid nitrogen freezing cycle was started to cool the reactor to -78°C. After the temperature dropped to -78°C, 2.5M n-butyl lithium tetrahydrofuran solution was slowly added from the high-level tank, totaling 470.4L. The temperature was strictly controlled not to exceed -70°C during the addition process. After the addition was completed, the reaction was kept warm for 1h. Then, dry carbon dioxide gas was slowly introduced, and the aeration was maintained for about 1h. After the TLC reaction was complete, the temperature in the reactor slowly rose to about -20°C, and 5kg of water was slowly added to quench the excess n-butyl lithium at low temperature. After the quenching was complete, the heating cycle was started to recover tetrahydrofuran. After the tetrahydrofuran is recovered, 600 kg of 6N hydrochloric acid aqueous solution prepared in advance is pumped in, and the temperature is raised to about 80°C for reaction for 1 hour. After the TLC reaction is complete, the pH in the kettle is adjusted to 6-7 with 30% sodium hydroxide aqueous solution. A large amount of solid will precipitate, and centrifugal drying is performed to obtain a total of 148 kg of intermediate 2, with a yield of 99.69%.

[0013] Step 3. Preparation of Intermediate 3

[0014]

[0015] 1200L dry dichloromethane was pumped into the 2000L reactor, the stirring device was started, and then a total of 148kg of intermediate 2 was added. After the addition was completed, the refrigerated water circulation was started, and the temperature in the reactor was cooled to about 0°C. 363.5kg of triphosgene was slowly added in batches, and the temperature was controlled not to exceed 15°C. After about 1h, the addition was completed, and the temperature was kept at 15°C for 1h. After the TLC reaction was complete, 500kg of cold water was pumped in and kept at about 15°C for 1h. The intermediate 3 was centrifugally dried to obtain a total of 156.26kg, with a yield of 90.54%

[0016] Step 4. Preparation of intermediate 4

[0017]

[0018] 1200L dry dichloromethane was pumped into the 2000L reactor, the stirring device was started, and then a total of 156.26kg of intermediate 3 was added. After the addition was completed, the chilled water circulation was started, and the temperature in the reactor was cooled to about 0°C. 169.1kg of bromine was slowly dripped from the high-level tank, and the temperature was controlled not to exceed 10°C. After about 1.5 hours, the addition was completed, and the temperature was kept at 10°C for 2.5 hours. After the TLC reaction was complete, 500kg of 1% sodium bisulfite aqueous solution prepared in advance was pumped in to quench and pulp for 1 hour. Centrifugal drying gave a total of 196.5kg of intermediate 4, with a yield of 86.89%

[0019] Step 5. Preparation of Intermediate 5

[0020]

[0021] 600L N,N-dimethylformamide was pumped into the 3000L reactor, the stirring device was started, and then 196.5kg of intermediate 4 and 82.5kg of cuprous cyanide were added in sequence. After the addition, vacuum nitrogen replacement was purged, and the steam heat cycle was started. The reactor was heated to about 140°C and kept warm for 5h under micro-reflux. After the TLC reaction was complete, the temperature was cooled to room temperature, and 1800kg of saturated ammonium chloride aqueous solution prepared in advance was pumped in, and the mixture was beaten at room temperature for 2h, and centrifuged and dried to obtain 131.8kg of intermediate 5, with a yield of 86.03%

[0022] Step 6. Preparation of 2-amino-5-cyano-N,3-dimethylbenzamide

[0023]

[0024] 800L of methanol was pumped into a 2000L reactor, the stirring device was started, and a total of 131.8kg of intermediate 5 was added. After the addition was completed, the chilled water circulation was started, and the temperature in the reactor was controlled at about 20°C. 81.0kg of 30% methylamine methanol solution was dripped from the high-level tank. After the addition was completed, the temperature was kept at 20°C for 3h. After the TLC reaction was complete, the heating was turned on to concentrate the methanol to about 50L, 300kg of cold water was pumped in, pulping was carried out at 20°C for 2h, and centrifuged. The crude product was then heated with about 500L of 50% ethanol aqueous solution to dissolve and recrystallize, and centrifuged and dried to obtain the target product 2-amino-5-cyano-N,3-dimethylbenzamide, a total of 120.3kg, with a yield of 97.54%.

[0025] Its NMR data are as follows:

[0026] 'HNMR(400MHz, CDCl3)δ8.40(d,J=3.6Hz,1H),7.80(d,J=1.2Hz,1H),7.41(s,1H),7.15(br s,2H),2.08(s,3H)

[0027]

[0028] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing a key intermediate of chlorantraniliprole, the reaction scheme is as follows: Technical solution: The preparation method of 2-amino-5-cyano-N,3-dimethylbenzamide, a key intermediate of chlorantraniliprole, comprises the following steps:

1. React o-methylaniline with Boc anhydride in a weakly alkaline aqueous solution to prepare intermediate 1; 2. The intermediate 1 obtained in step 1 is subjected to ortho-lithiation with n-butyl lithium under deep cooling conditions, and then carbon dioxide gas is introduced, followed by acid hydrolysis to obtain intermediate 2; 3. The intermediate 2 obtained in step 2 is subjected to ring closure with triphosgene to obtain intermediate 3; 4. The intermediate 3 obtained in step 3 is halogenated with liquid bromine to obtain intermediate 4; 5. The intermediate 4 obtained in step 4 is subjected to a high temperature Rosenmund-von Braun reaction with cuprous cyanide to obtain intermediate 5; 6. The intermediate 5 obtained in step 5 is subjected to ring opening with methylamine to finally obtain the target product 2-amino-5-cyano-N,3-dimethylbenzamide; Preferably, the base in step 1 includes but is not limited to potassium carbonate, sodium carbonate, sodium bicarbonate, and the most Preferably sodium carbonate; Preferably, the reaction time of step 1 can be 6-12 hours, for example, 6, 8, 10, 12 hours or any value between any two of them, and most preferably 8 hours; Preferably, the reaction temperature of step 1 may be 30-60°C, for example, 30°C, 40°C, 50°C, 60°C or any value between them, most preferably 40°C; Preferably, the solvent in step 1 can be acetonitrile, tetrahydrofuran, or ethyl acetate, and most preferably ethyl acetate; More preferably, the molar ratio of Boc anhydride to o-methylaniline in step 1 is 1.5:1-1. 1:1, for example, it can be 1.5:1, 1.3:1, 1.2:1, 1.1:1 or any value between them, and the most preferred value is 1.1:1; Further preferably, the volume of the organic solvent used in step 1 is 5 to 10 times the weight of o-methylaniline, for example, it can be 5, 6, 7, 9, 10 times or any value between them, and most preferably 5 times; Preferably, the organic solvent in step 2 may be tetrahydrofuran, diethyl ether, or methyl tert-butyl ether, and tetrahydrofuran is most preferred; Preferably, the reaction time of step 2 can be 1.5-3.5 h, for example, 1.5, 1.6, 2.0, 3.5 h or any value between them, most preferably 3.0 h; Preferably, the acid in step 2 can be hydrochloric acid, sulfuric acid, or trifluoroacetic acid, and hydrochloric acid is most preferred; Further preferably, the molar ratio of n-butyl lithium to intermediate 1 in step 2 is 1.5:1 to 1.1:1, for example, 1.5:1, 1.3:1, 1.2:1, 1.1:1 or any value between them, most preferably 1.2:1; Further preferably, the volume of the organic solvent used in step 2 is 5 to 10 times the weight of the intermediate 1, for example, it can be 5, 6, 7, 9, 10 times or any value between them, and most preferably 6 times; Preferably, the organic solvent in step 3 may be dichloromethane, ethyl acetate, or tetrahydrofuran, and dichloromethane is most preferred; Preferably, the reaction time of step 3 can be 0.5-1.5 h, for example, 0.5, 0.6, 1.0, 1.5 h or any value between them, most preferably 1.0 h; Preferably, the reaction temperature of step 3 may be 0-20°C, for example, 0°C, 5°C, 15°C, 20°C or any value between them, most preferably 15°C; Further preferably, the molar ratio of triphosgene to intermediate 2 in step 3 is 1.5:1 to 1.1:1, for example, 1.5:1, 1.3:1, 1.2:1, 1.1:1 or any value between them, most preferably 1.25:1; Further preferably, the volume of the organic solvent used in step 3 is 5 to 10 times the weight of the intermediate 2, for example, it can be 5, 6, 7, 9, 10 times or any value between them, and most preferably 8 times; Preferably, the organic solvent in step 4 can be dichloromethane, ethyl acetate, methanol, and dichloromethane is most preferred; Preferably, the reaction time of step 4 can be 1.5-3.0 h, for example, 1.5, 2.0, 2.5, 3.0 h or any value between any two of them, and most preferably 2.5 h; Preferably, the reaction temperature of step 4 can be 0-20°C, for example, 0°C, 5°C, 15°C, 20°C or any value between them, most preferably 10°C; Further preferably, the molar ratio of bromine to intermediate 3 in step 4 is 1.5:1 to 1.1:1, for example, 1.5:1, 1.3:1, 1.2:1, 1.1:1 or any value between them, most preferably 1.2:1; Further preferably, the volume of the organic solvent used in step 4 is 5 to 10 times the weight of the intermediate 3, for example, it can be 5, 6, 7, 9, 10 times or any value between them, and most preferably 8 times; Preferably, the organic solvent in step 5 may be N-methylpyrrolidone, N,N-dimethylformamide, dimethyl sulfoxide, and most preferably N,N-dimethylformamide; Preferably, the reaction time of step 5 can be 3.0-6.0 h, for example, 3.0, 3.5, 4.0, 6.0 h or any value between any two of them, most preferably 5 h; Preferably, the reaction temperature of step 5 may be 120-160°C, for example, 120°C, 130°C, 150°C, 160°C or any value between them, most preferably 140°C; Further preferably, the molar ratio of cuprous cyanide to intermediate 4 in step 5 is 1.5:1 to 1.1:1, for example, 1.5:1, 1.3:1, 1.2:1, 1.1:1 or any value between them, most preferably 1.2:1; Further preferably, the volume of the organic solvent used in step 5 is 2 to 5 times the weight of the intermediate 4, for example, it can be 2, 3, 4, 5 times or any value between them, and most preferably 3 times; Preferably, the organic solvent in step 6 may be acetonitrile, methanol, or N,N-dimethylformamide, most preferably methanol; Preferably, the reaction time of step 6 can be 2.0-4.0 h, for example, 2.0, 3.0, 3.5, 4.0 h or any value between any two of them, and most preferably 3.0 h; Preferably, the reaction temperature of step 6 may be 15-25°C, for example, 15°C, 18°C, 20°C, 25°C or any value between them, most preferably 20°C; Further preferably, the molar ratio of the methanol solution of methylamine to the intermediate 5 in step 6 is 1.5:1 to 1.1:1, for example, 1.5:1, 1.3:1, 1.2:1, 1.1:1 or any value between them, most preferably 1.2:1; Further preferably, the volume of the organic solvent used in step 6 is 5 to 10 times the weight of the intermediate 5, for example, it can be 5, 6, 7, 9, 10 times or any value between them, and most preferably 6 times; The beneficial effects of the present invention are as follows: the synthesis cost is effectively reduced, the generation of three industrial wastes is effectively avoided, the process is simple, the operation is convenient, the continuity is good, the raw materials are cheap and easily available, the yield is high, and it is conducive to large-scale industrial production.

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