Method for preparing topramezone intermediate 3-(4, 5-dihydro-3-isoxazolyl)-2-methyl-4-(methylsulfonyl) benzoic acid
By using formate esters instead of carbon monoxide in the carbonyl insertion reaction during the synthesis of benzoxazine intermediates, the synthetic steps were simplified and the yield was improved. This solved the problems of long reaction steps and low yield in the prior art, and made industrial production feasible.
Patent Information
- Application Number
- CN202511415762.2
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-09-30
- Publication Date
- 2025-12-26
AI Technical Summary
Existing synthetic routes for benzoxazine intermediates suffer from problems such as long reaction steps, low yield, complex raw materials, and difficulty in industrialization. In particular, the synthesis method of intermediate INT2 has problems such as the need for protection reaction due to premature carboxyl group formation and low carbon monoxide utilization.
Using 3-(3-halo-2-methyl-6-(methanesulfonyl)phenyl)-4,5-dihydroisoxazole as the starting material, the target compound was obtained by esterification via carbonylation reaction of formate under a metal catalyst, followed by hydrolysis. This simplified the reaction steps and improved the yield. Using formate instead of carbon monoxide as the starting material reduced losses and transportation difficulties.
The two-step reaction synthesis of the target product was achieved, which improved the yield and simplified the process flow, reduced carbon monoxide loss and transportation difficulties, and the raw materials were widely available and suitable for industrial production.
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Abstract
Description
TECHNICAL FIELD
[0001] The present application relates to the technical field of organic synthesis, in particular to a method for preparing 3-(4,5-dihydro-3-isoxazolyl)-2-methyl-4-(methylsulfonyl)benzoic acid, an intermediate of topramezone. BACKGROUND
[0002] Topramezone, trade name "Campus R" or "Braun", is a benzoyl pyrazolone herbicide with high selectivity and safety developed by BASF, Germany, which belongs to the class of hydroxyphenylpyruvate dioxygenase (HPPD) inhibitors. It is safer than mesotrione and nicosulfuron, and is the safest herbicide for corn field, and is also one of the herbicides with the least mammalian toxicity. Topramezone can effectively control annual grasses and broadleaf weeds in corn fields, and is safe to corn. Its use range has gradually expanded to crops such as rice and sugarcane, and it can be safely used in combination with other pesticides.
[0003] The currently reported preparation processes of topramezone mainly include the following two routes.
[0004] Route 1:
[0005] Route 2:
[0006] The two routes contain two key intermediates: INT1 (bromide: 3-(3-bromo-2-methyl-6-(methylsulfonyl)phenyl)-4,5-dihydroisoxazole) and INT2 (carboxylic acid: 3-(4,5-dihydro-3-isoxazolyl)-2-methyl-4-(methylsulfonyl)benzoic acid).
[0007] The key intermediate INT1 in route 1, BASF reported five synthesis methods in patents WO1999058509 and CN1757634.
[0008]
[0009] The above synthesis route is one of the methods, in which INT1 is prepared from 2,3-dimethylaniline through 5 steps with a total yield of 26%. This method has fewer reaction steps, and if the intermediate synthesis method can be further improved to increase the yield, this method can realize industrial production.
[0010] Another method is to prepare INT1 from 2-methyl-3-nitrotoluene through 6 steps with a total yield of 31%, which is also an industrialized route method.
[0011] The key intermediate INT2 in route 2 is disclosed by BASF in patent WO1998031681. The reaction route for preparing INT2 is as follows: 2,3-dimethylthioanisole is used as the starting material, an acetyl group is introduced, a methylsulfonyl group is prepared by oxidation, a carboxyl group is prepared by oxidation and esterification, an isoxazole ring is prepared by multi-step reaction, and finally hydrolysis is performed. This method has a long route and low total yield due to the premature generation of the carboxyl group, which needs to be protected in subsequent reactions. The synthesis method disclosed by Hailier Pharmaceutical in patent CN108203415 is to introduce an acetyl group and oxidize to obtain INT2, but the reaction conditions and examples are not given. Li Lin of Hebei Medical University discloses in patent CN110183392 that 2-cyano-3-nitrotoluene is used as the starting material, a carboxyl group is prepared by Grignard reaction or butyllithium and carbon dioxide, a methylsulfonyl group is prepared by oxidation, an isoxazole ring is prepared, and different reaction sequences are adjusted to obtain INT2 by multiple routes. The starting material of this method is higher in price than dimethylaniline or 2-methyl-3-nitrotoluene, and the intermediates are separated by chromatography column, which is difficult to be industrialized.
[0012] Jiangsu Zhongqi discloses in patent CN110922367 that 2,3-dimethylthioanisole is used as the starting material, and a carboxylic acid INT2 is prepared by 6-step reaction with a total yield of 39.1%. This method synthesizes an intermediate chloride INT3, substitutes a cyano group for the chlorine, and then hydrolyzes to obtain INT2. A toxic cyanide is used in the reaction.
[0013] With the gradual maturity and industrialization of route 1 process, the synthesis of carboxylic acid from INT1 or INT3 is also a good choice. Jiangsu Qizhou discloses in patent CN112125898 that INT2 carboxylic acid is prepared from INT3 by Grignard reaction with a yield of 80%. Shandong Yisheng discloses in patent CN116178295 that INT2 carboxylic acid is prepared from INT1 by reaction with CO in the presence of a palladium catalyst with a yield of 88.4%. However, CO is used in the reaction, and after the reaction is completed, more CO is burned and discharged, the utilization rate of CO is low, and CO is inconvenient to transport and has few sources. SUMMARY
[0014] To solve the above technical problems, the purpose of the present application is to provide a method for preparing 3-(4,5-dihydro-3-isoxazolyl)-2-methyl-4-(methylsulfonyl)benzoic acid, an intermediate of benzofluorazole, which has fewer reaction steps, simple raw materials and high yield.
[0015] To achieve the above purpose, the present application provides the following technical scheme: the method comprises the following steps: S1. 3-(3-halo-2-methyl-6-(methylsulfonyl)phenyl)-4,5-dihydroisoxazole as starting material, with formate ester in the presence of metal catalyst, carbonyl insertion reaction, the acid generated in the reaction is neutralized with base to produce intermediate carboxylate ester; S2. The carboxylate ester is hydrolyzed to produce the target compound I (i.e. INT2): 3-(4,5-dihydro-3-isoxazolyl)-2-methyl-4-(methylsulfonyl)benzoic acid.
[0016] Preferably, the 3-(3-halo-2-methyl-6-(methylsulfonyl)phenyl)-4,5-dihydroisoxazole in S1 is 3-(3-bromo-2-methyl-6-(methylsulfonyl)phenyl)-4,5-dihydroisoxazole or 3-(3-chloro-2-methyl-6-(methylsulfonyl)phenyl)-4,5-dihydroisoxazole.
[0017] Preferably, the formate ester in S1 is methyl formate, ethyl formate, propyl formate, isopropyl formate or butyl formate.
[0018] Preferably, the metal catalyst in S1 is a chloride of Pd, Ni, Ru, Co, Mo or a combination of acetate and ligand thereof.
[0019] Preferably, the organic solvent used in the carbonyl insertion reaction in S1 is DMF, DMSO, dioxane, toluene, xylene or THF.
[0020] Preferably, the reaction temperature of the carbonyl insertion reaction in S1 is 80-130°C.
[0021] Preferably, the base in S1 is triethylamine, N,N-diisopropyl ethylamine, tripropylamine, pyridine, sodium bicarbonate, potassium bicarbonate, sodium carbonate or potassium carbonate.
[0022] Preferably, the ligand includes tpp, dppp or dppf.
[0023] Compared with the prior art, the present application has the following advantages: The present application starts from 3-(3-bromo-2-methyl-6-(methylsulfonyl)phenyl)-4,5-dihydroisoxazole or 3-(3-chloro-2-methyl-6-(methylsulfonyl)phenyl)-4,5-dihydroisoxazole, formate ester as a substitute for carbon monoxide, in the presence of a metal catalyst, carbonyl insertion reaction to generate ester, ester hydrolysis to produce the target product carboxylic acid, which is synthesized by carbonyl insertion reaction through two steps, and the reaction steps are short. Compared with using carbon monoxide, using formate ester instead of carbon monoxide reduces the loss of carbon monoxide, the source of raw materials is easy to obtain, the transportation and supply are convenient, and the reaction yield is also good. BRIEF DESCRIPTION OF DRAWINGS
[0024] Figure 1 Synthetic route of the present application.
[0025] Figure 2 Compound I 1 H-NMR (400MHz, DMSO-D6).
[0026] Figure 3 Mass spectrum of Compound I (LC-MS-ESI). DETAILED DESCRIPTION
[0027] The technical solutions in the embodiments of the present application will be clearly and completely described below with reference to the drawings in the embodiments of the present application. Obviously, the described embodiments are only part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor fall within the scope of protection of the present application.
[0028] Example 1: In a 200ml pressure tank, 3-(3-bromo-2-methyl-6-(methylsulfonyl) phenyl)-4, 5-dihydroisoxazole 31.8g, DMF 64g, ethyl formate 14.8g, dichlorobis(triphenylphosphine)palladium 0.3g, and triethylamine 11g were put in. The tank was closed and replaced with nitrogen. The stirring was started and the temperature was raised to 100-110℃ for reaction. After 8h of reaction, the sample was detected and qualified. The temperature was lowered and the product was discharged. Water 200g was added to the residue, and 32% liquid alkali 12.5g was slowly added dropwise. After the dropwise addition was completed, activated carbon was added. After stirring at room temperature for 2h, the product was filtered. 31% hydrochloric acid was added dropwise to the filtrate until the pH was 2-3. Solid was precipitated, which was filtered, washed with water and dried to obtain the product 25.1g with a yield of 88.6% and a purity of >98%.
[0029] Example 2: In a 200ml pressure tank, 3-(3-bromo-2-methyl-6-(methylsulfonyl) phenyl)-4, 5-dihydroisoxazole 31.8g, DMF 64g, ethyl formate 11.2g, dichlorobis(triphenylphosphine)palladium 0.3g, and potassium bicarbonate 16.8g were put in. The tank was closed and replaced with nitrogen. The stirring was started and the temperature was raised to 110-120℃ for reaction. After 12h of reaction, the sample was detected and qualified. The temperature was lowered and the product was discharged. Water 200g was added to the residue, and 32% liquid alkali 12.5g was slowly added dropwise. After the dropwise addition was completed, activated carbon was added. After stirring at room temperature for 2h, the product was filtered. 31% hydrochloric acid was added dropwise to the filtrate until the pH was 2-3. Solid was precipitated, which was filtered, washed with water and dried to obtain the product 24.8g with a yield of 87.5% and a purity of >98%.
[0030] Example 3: In a 200ml pressure tank, put 3-(3-bromo-2-methyl-6- (methylsulfonyl) phenyl)-4, 5-dihydroisoxazole 31.8g, dioxane 64g, ethyl formate 11.2g, Pd(dppf)Cl2 0.2g, and triethylamine 11g. Close the tank and replace with nitrogen. Turn on the stirring and heat to 110~120℃ for reaction. After 10h, take a sample for testing. When the sample is qualified, cool down and discharge. Add water 200g to the residue, slowly add 32% liquid alkali 12.5g, add activated carbon after dropping, stir for 2h at room temperature, and then filter. Add 31% hydrochloric acid to the filtrate until pH 2~3, and then filter, wash with water, and dry to obtain the product 25.8g, with a yield of 91.1% and a purity of >98%.
[0031] While the embodiments of the application have been shown and described, it is to be understood that the embodiments proposed are only by way of example and are not to be construed in a limiting sense, but the scope of the present application should be gauged in terms of the appended claims and their equivalents.
Claims
1. A method for preparing benzoxazolone intermediate 3-(4,5-dihydro-3-isoxazolyl)-2-methyl-4-(methylsulfonyl)benzoic acid, characterized in that: The method includes the following steps: S1. An intermediate carboxylic acid ester is prepared by reacting 3-(3-halo-2-methyl-6-(methanesulfonyl)phenyl)-4,5-dihydroisoxazole as a starting material with a formate ester under the catalysis of a metal catalyst, and neutralizing the acid produced by the reaction with a base; wherein the formate ester is methyl formate, ethyl formate, propyl formate, isopropyl formate, or butyl formate. S2. The target compound I, 3-(4,5-dihydro-3-isoxazolyl)-2-methyl-4-(methylsulfonyl)benzoic acid, was prepared by hydrolysis of the carboxylic acid ester.
2. The method for preparing benzoxazolone intermediate 3-(4,5-dihydro-3-isoxazolyl)-2-methyl-4-(methylsulfonyl)benzoic acid according to claim 1, characterized in that: The 3-(3-halo-2-methyl-6-(methylsulfonyl)phenyl)-4,5-dihydroisoxazole described in S1 is 3-(3-bromo-2-methyl-6-(methylsulfonyl)phenyl)-4,5-dihydroisoxazole or 3-(3-chloro-2-methyl-6-(methylsulfonyl)phenyl)-4,5-dihydroisoxazole.
3. The method for preparing benzoxazolone intermediate 3-(4,5-dihydro-3-isoxazolyl)-2-methyl-4-(methylsulfonyl)benzoic acid according to claim 1, characterized in that: The metal catalyst described in S1 is a combination of chlorides of Pd, Ni, Ru, Co, and Mo or their acetates and ligands.
4. The method for preparing benzoxazolone intermediate 3-(4,5-dihydro-3-isoxazolyl)-2-methyl-4-(methylsulfonyl)benzoic acid according to claim 1, characterized in that: The organic solvent used in the carbonyl insertion reaction described in S1 is DMF, DMSO, dioxane, toluene, xylene, or THF.
5. The method for preparing benzoxazolone intermediate 3-(4,5-dihydro-3-isoxazolyl)-2-methyl-4-(methylsulfonyl)benzoic acid according to claim 1, characterized in that: The reaction temperature for the carbonyl insertion reaction described in S1 is 80℃~130℃.
6. The method for preparing benzoxazolone intermediate 3-(4,5-dihydro-3-isoxazolyl)-2-methyl-4-(methylsulfonyl)benzoic acid according to claim 1, characterized in that: The base mentioned in S1 is triethylamine, N,N-diisopropylethylamine, tripropylamine, pyridine, sodium bicarbonate, potassium bicarbonate, sodium carbonate, or potassium carbonate.
7. The method for preparing benzoxazolone intermediate 3-(4,5-dihydro-3-isoxazolyl)-2-methyl-4-(methylsulfonyl)benzoic acid according to claim 3, characterized in that: The ligands include tpp, dppp, or dppf.
Citation Information
Patent Citations
3-heterocyclyl-substituted benzoyl derivatives
WO1998031681A1
Method for producing isoxazoline-3-yl-acyl benzene
WO1999058509A1