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CN-121974834-A - Synthesis of topramezone Process for the preparation of ester intermediates

CN121974834ACN 121974834 ACN121974834 ACN 121974834ACN-121974834-A

Abstract

The invention discloses a method for synthesizing a carfentrazone-ethyl intermediate, which comprises the following steps of 1) carrying out substitution reaction on 2, 6-dichlorotoluene by glycol monomethyl ether, 2) carrying out substitution reaction on chlorobenzene and magnesium to generate a Grignard reagent, then carrying out reaction on the Grignard reagent and carbon dioxide to obtain benzoic acid, 3) carrying out halogenation or nitration reaction on a substituted benzoic acid derivative to generate a 4-halogenated benzoic acid analogue or a 4-nitrobenzoic acid analogue, 4) carrying out reaction on the analogue and methyl mercaptan to generate 4-methylthiobenzoic acid, and 5) carrying out oxidation reaction on the 4-methylthiobenzoic acid derivative to obtain TP-1. The method has the advantages of simple and easily obtained raw materials, simple and convenient reaction operation, no need of using noble metal catalysts and high-pressure reaction equipment, green and environment-friendly performance, suitability for commercial scale production and huge large-scale production potential.

Inventors

  • MA ZHIHONG
  • LIAN XIONGDONG
  • SUN CHAOCHAO

Assignees

  • 上海沃缨生物科技有限公司

Dates

Publication Date
20260505
Application Date
20250930

Claims (6)

  1. 1. The method for synthesizing the carfentrazone-ethyl intermediate is characterized by comprising the following steps of: Step 1, carrying out substitution reaction on 2, 6-dichlorotoluene by using ethylene glycol monomethyl ether, wherein an acid-binding agent is needed to be added in the substitution reaction, the acid-binding agent is one or more than one mixture of NaH, naOH, na 2 CO 3 , triethylamine and pyridine, the reaction solvent is one or more than one mixture of toluene, xylene, DMF, DMSO, dioxane and sulfolane, the equivalent ratio of the ethylene glycol monomethyl ether to the 2, 6-dichlorotoluene is 1:1-5:1, the reaction temperature is 80-250 ℃, and the reaction time is 2-24 hours; Step 2, the substituted chlorobenzene and magnesium obtained in the step 1 generate a Grignard reagent and then react with carbon dioxide to obtain benzoic acid, wherein the solvent for the reaction is one or more than one mixture of toluene, xylene, THF, 2-methyltetrahydrofuran, dioxane, n-butyl ether and isopropyl ether, the equivalent ratio of chlorobenzene to magnesium is 1:1-1:5, the equivalent ratio of chlorobenzene to CO 2 is 1:1-1:5, the Grignard reaction temperature is 0-80 ℃, the Grignard reaction time is 2-24 hours, the insertion reaction temperature is-50 ℃ and the insertion reaction time is 2-24 hours; step 3, the substituted benzoic acid derivative obtained in the step 2 is subjected to halogenation reaction to generate a 4-halogenated benzoic acid analogue, or is subjected to nitration reaction to generate a 4-nitrobenzoic acid analogue; The halogenation reaction comprises one or more of chlorine, liquid bromine, NCS, NBS, sulfonyl chloride, TCCA, dichloro-hydantoin and dibromo-hydantoin, one or more of hexafluoroisopropanol, trifluoroethanol, dichloromethane, trichloromethane, carbon tetrachloride, dichloroethane, nitromethane and p-chlorotrifluoromethyl benzene as reaction solvent, the equivalent ratio of benzoic acid to the halogenating agent is 1:0.5-1:5, the reaction additive is one or more of DMSO, nitro-substituted benzenesulfonic acid and C 6 -C 20 -substituted alkyl or aryl sulfonic acid, the halogenation reaction time is 2-24 hours, and the halogenation reaction temperature is 0-100 ℃; if the reaction solvent is one or more of acetic acid, sulfuric acid and phosphoric acid, the equivalent ratio of benzoic acid to nitric acid is 1:1-1:2, the nitration time is 2-24 hours, and the nitration temperature is-10-100 ℃; Step 4, reacting halogen or nitro in the substituted benzoic acid derivative obtained in the step 3 with methyl mercaptan to generate 4-methylthiobenzoic acid, wherein an acid binding agent is added in the reaction, the acid binding agent is one or more than one mixture of NaH, naOH, na 2 CO 3 , triethylamine and pyridine, a reaction solvent is one or more than one mixture of water, tertiary butanol, THF, dioxane, DMF and toluene, the equivalent ratio of the benzoic acid derivative to the methyl mercaptan is 1:1-1:5, the methyl thioetherification reaction time is 2-24 hours, and the methyl thioetherification reaction temperature is 0-180 ℃; Step 5, oxidizing the 4-methylthio benzoic acid derivative obtained in the step 4 to generate TP-1, wherein the oxidizing agent is one or more of H 2 O 2 , sodium hypochlorite, peracetic acid, oxygen and air, the reaction solvent is one or more of water, DCM, chloroform, THF and ethyl acetate, the equivalent ratio of the phenylsulfide to the oxidizing agent is 1:0.5-1:8, the oxidizing reaction time is 2-24 hours, and the oxidizing reaction temperature is-10 ℃ to 100 ℃.
  2. 2. A process for the synthesis of carfentrazone-ethyl intermediate according to claim 1, characterised in that the acid binding agent in step 1 is preferably KOH and the solvent is preferably toluene in combination with TBAB.
  3. 3. A process for the synthesis of topramezone intermediates according to claim 1, characterized in that the solvent in step 2 is preferably THF, the grignard reaction temperature is preferably 60 ℃, the carbointercalation reaction temperature is preferably-5 ℃.
  4. 4. A process for the synthesis of carfentrazone-ethyl intermediate according to claim 1, characterised in that in step 3 the halogenating agent is preferably NCS, the solvent is preferably nitromethane in combination with DMSO, and the halogenation temperature is preferably 0-5 ℃.
  5. 5. A process for the synthesis of carfentrazone-ethyl intermediate according to claim 1, characterised in that in step 4 the methyl mercaptan is added as a solution of sodium methyl mercaptan at a concentration of 30%, the solvent preferably toluene is combined with DMSO, and water is removed during the reaction by means of a water separator.
  6. 6. The method for synthesizing carfentrazone-ethyl intermediate according to claim 1, wherein the oxidizing agent in the step 5 is preferably hydrogen peroxide, the hydrogen peroxide is 20% concentration, the solvent is preferably acetonitrile, and the oxidation reaction temperature is preferably 0-5 ℃.

Description

Synthesis of topramezone Process for the preparation of ester intermediates Technical Field The invention relates to the technical field of pesticide intermediate synthesis, in particular to a method for synthesizing topramezone and oxadiazon intermediates. Background Tolpyralate (fenbuconazole) is a benzoyl pyrazole HPPD inhibitor herbicide developed by the japanese stone original industry, is mainly used for weeding after corn field seedlings, and has high activity and crop safety. Is characterized in that 1) the activity is high (recommended dosage is 30-50g/hm 2), the control effect is better than mesotrione, 2) the safety to corn is excellent, the corn is suitable for common corn, sweet corn and burst corn, and 3) broadleaf weeds and grassy weeds can be controlled with low dosage (such as 50 milliliters/acre). Wherein, the carboxylic acid intermediate (TP-1) is a key intermediate of carfentrazone-ethyl. At present, several processes for preparing this carboxylic acid intermediate (TP-1) are mainly protected by the japanese stone raw industry by patent layouts (CN 102036968B, CN101541755B, CN103224460a, CN 1011331119B): 1) The first method is to take 2, 6-dimethylbenzene as a raw material, and sequentially synthesize an intermediate TP-1 in 3 steps through ferrous chloride catalyzed methanesulfonylation, aromatic nucleophilic substitution reaction of alcohol and transition metal palladium catalyzed insertion carbonylation reaction. 2) The second method is to take 2-methoxy-3-methyl-4-chloro-phenylsulfone as a raw material, obtain a benzoic acid derivative through palladium-carbon catalyzed carboinsertion reaction, obtain a methyl benzoate derivative through concentrated sulfuric acid catalytic esterification, obtain phenol through removing methyl ether under the action of Lewis acid, and obtain TP-1 through hydrolysis under alkaline conditions after etherification reaction of methoxybromoethane. 3) The third route is to take 2-methoxy-3-methyl-4-chloro-nitrobenzene as raw material, and to prepare phenyl sulfide derivative through the steps of palladium-carbon catalyzed sugar insertion reaction, concentrated sulfuric acid catalyzed esterification reaction, demethylation reaction under the action of Lewis acid, etherification reaction of methoxybromoethane, nitro substitution reaction in the presence of sodium methyl mercaptan, oxidation and hydrolysis reaction to prepare TP-1. Furthermore, chinese scholars report a 4-step method for synthesizing TP-1 in modern pesticides 2020,19 (2): 5. Combining these methods, both methods 2 and 3 of the stoneware industry are reported as lengthy and starting materials are not easy. Furthermore, these three routes reported in Dan Yuanchan require the use of noble metal palladium-catalyzed insertion reactions, which are not only highly demanding for industrial equipment, but also require autoclaves and CO sources, with loss of noble metal, which is a difficulty in cost control of these processes. Sun Bing in modern agriculture report methods also have 1) raw materials are not easy, 2) diazotization coupling and haloform reaction are involved, and a certain risk and the problem of overlarge three wastes exist. Therefore, the preparation method which is safe and easy to operate, has simple and easily available materials, and can avoid heavy metals is designed, and has great practical significance. Disclosure of Invention The invention aims to provide a method for synthesizing a carfentrazone-ethyl intermediate, which aims to solve the problems in the background technology. In order to achieve the purpose, the invention provides the following technical scheme that the method for synthesizing the topramezone intermediate comprises the following steps: Step 1, carrying out substitution reaction on 2, 6-dichlorotoluene by using ethylene glycol monomethyl ether, wherein an acid-binding agent is needed to be added in the substitution reaction, the acid-binding agent is one or more than one mixture of NaH, naOH, na 2CO3, triethylamine and pyridine, the reaction solvent is one or more than one mixture of toluene, xylene, DMF, DMSO, dioxane and sulfolane, the equivalent ratio of the ethylene glycol monomethyl ether to the 2, 6-dichlorotoluene is 1:1-5:1, the reaction temperature is 80-250 ℃, and the reaction time is 2-24 hours; the reaction formula is: Step 2, the substituted chlorobenzene and magnesium obtained in the step 1 generate a Grignard reagent and react with carbon dioxide to obtain benzoic acid, wherein the solvent for the reaction is one or more than one mixture of toluene, xylene, THF, 2-methyltetrahydrofuran, dioxane, n-butyl ether and isopropyl ether, the equivalent ratio of chlorobenzene to magnesium is 1:1-1:5, the equivalent ratio of chlorobenzene to CO 2 is 1:1-1:5, the Grignard reaction temperature is 0-80 ℃, the Grignard reaction time is 2-24 hours, the carbointercalation reaction (reaction with CO 2) temperature is-50 ℃, and the carbointercalation reaction tim