Method for preparing benzoic acid compound

Abstract

Provided in the present invention is a method for preparing a benzoic acid compound represented by formula (I). The benzoic acid compound is synthesized by means of a reaction carried out in an organic solvent-water liquid-liquid two-phase system in the presence of a catalyst, wherein the organic solvent is immiscible with water. In the formula, R1 is H, halogen, a C1-6 alkyl or a halogenated C1-6 alkyl; R2 is H, or a C1-6 alkyl, a C6-10 aryl or a C5-10 heterocyclyl optionally substituted with one or more than two substituents, wherein the substituents are selected from halogen, a C1-6 alkyl, a C1-6 alkoxy, a halogenated C1-6 alkoxy, or oxo(=O); R3 is methanesulfonyl or a halogenated C1-6 alkyl; R4 is halogen; and R4 is located at the ortho, meta or para position relative to R3.

Description

Process for preparing benzoic acid compounds

[0001] This application claims priority to the Chinese application with the application date of January 5, 2025, the application number of 2025100117899, and the invention title of "Process for preparing benzoic acid compounds", the entire content of which constitutes a part of this application. TECHNICAL FIELD

[0002] The present application relates to a process for preparing benzoic acid compounds. BACKGROUND

[0003] Benzoic acid compounds are important chemical intermediates, especially for preparing HPPD inhibitor herbicides such as benzofluor, metamifop, dicyclomet, pyrazolynate, and metazachlor, the specific structures of which are as follows, respectively:

[0004] Chinese patent application CN116178295A discloses a method for preparing 2-methyl-3-(4,5-dihydroisoxazol-3-yl)-methanesulfonyl benzoic acid, which inserts carbonyl reaction of (3-[3-bromo-2-methyl-6-(methanesulfonyl) phenyl]-4,5-dihydroisoxazole) under the action of a catalyst with carbon monoxide and water. This method uses a homogeneous reaction system of organic solvent and water, and the noble metal catalyst used in the reaction is not recycled and reused, which is high in cost.

[0005] WO2024109718A1 obtains 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-methanesulfonyl benzoic acid by mixing 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methanesulfonyl bromobenzene, water, an acid binding agent, a catalyst, a ligand, and a first solvent and reacting. SUMMARY

[0006] There is no report on the recycling and reuse of noble metal catalysts for benzene ring carbonyl insertion reaction using carbon monoxide. Therefore, the present inventors have further researched the process for preparing benzoic acid compounds, aiming to simplify the reaction and post-treatment process operation and solve the problem of catalyst reuse, and on this basis, obtained the present application.

[0007] Specifically, the present application relates to:

[0008] (1) A process for preparing a benzoic acid compound represented by formula (I), characterized by synthesizing by the following reaction, which is carried out in a liquid-liquid two-phase system of an organic solvent-water in the presence of a catalyst, wherein the organic solvent and water are immiscible,

[0009] In the formula, R1 is H, halogen, C1-6 alkyl or haloC 1-6 alkyl;

[0010] R2 is H, C 1-6 alkyl, C 6-10 aryl or C 5-10 heterocyclyl, said substituents being selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, oxo (=0);

[0011] R3 is methylsulfonyl or haloC 1-6 alkyl, preferably methylsulfonyl or CF3;

[0012] R4 is halogen, preferably Br;

[0013] R4 is located at the ortho, meta or para position of R3.

[0014] (2) The production method according to the above (1), wherein R2 is H, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkyl substituted with C 1-6 alkyl, haloC 1-6 alkyl substituted with C 1-6 alkyl,

[0015] (3) The production method according to the above (1) or (2), wherein R2 is H, methyl, Br-CH2-, CF3-CH2-O-CH2-,

[0016] (4) The production method according to any one of the above (1) to (3), wherein the reaction is as follows:

[0017] in the formula, R1 and R2 are as defined in the above (1).

[0018] (5) The production method according to any one of the above (1) to (3), wherein the reaction is as follows:

[0019] (6) The method according to any one of the above (1) to (5), wherein the organic solvent is toluene or xylene, and the mass ratio of the organic solvent to water is (1-10): 1, preferably (2-4): 1.

[0020] (7) The method according to any one of the above (1) to (6), wherein the catalyst is a noble metal catalyst selected from palladium, rhodium, ruthenium, copper, cobalt, preferably a palladium catalyst; preferably further using a catalyst ligand, more preferably the ligand is a phosphorus ligand or a salt thereof.

[0021] (8) The method according to any one of the above (1) to (7), wherein further using a phase transfer catalyst, preferably one of tetrabutylammonium bromide, benzyltriethylammonium chloride, 18-crown-6, cyclodextrin.

[0022] (9) The method according to any one of the above (1) to (8), further comprising the step of, after the reaction is completed, separating the reaction solution, and directly using the organic solvent containing the catalyst to the next reaction.

[0023] (10) A method for preparing HPPD inhibitor herbicides, comprising preparing the benzoic acid intermediate shown in formula I by the method according to any one of the above (1) to (9).

[0024] (11) The method according to the above (10), wherein the HPPD inhibitor herbicide is preferably selected from benzofluor, pyroxasulfone, sulcotrione, azimsulfone, benzofluor.

[0025] (12) The method according to the above (11), wherein the HPPD inhibitor herbicide is sulcotrione or benzofluor, and the method comprises the following benzoic acid intermediate preparation step:

[0026] (13) The method according to the above (11), wherein the HPPD inhibitor herbicide is benzofluor, and the method comprises the following benzoic acid intermediate preparation step:

[0027] (14) The method according to the above (11), wherein the HPPD inhibitor herbicide is pyroxasulfone, and the method comprises the following benzoic acid intermediate preparation step:

[0028] (15) The method according to the above (11), wherein the HPPD inhibitor herbicide is azimsulfone, and the method comprises the following benzoic acid intermediate preparation step:

[0029] The method of the present application can obtain the following beneficial effects:

[0030] (1) After the completion of the homogeneous reaction, filtering, drying, dissolving, acid adjusting, crystallizing, filtering and drying are needed, especially the slow filtering speed of the product salt and the great operation difficulty, the present application is a liquid-liquid two-phase reaction using organic solvent and water as the reaction solvent, after the reaction, directly performing the liquid separation treatment, the operation difficulty is greatly reduced and the process is simplified.

[0031] (2) The noble metal catalyst is dissolved in the organic solvent, the organic phase can be directly reused, i.e. the catalyst can be recycled for multiple times, so that the cost is greatly reduced.

[0032] (3) The reaction yield is improved. DETAILED DESCRIPTION

[0033] The present application relates to the preparation method of the benzoic acid compound shown in formula (I), which is synthesized by the following reaction, the reaction is carried out in the liquid-liquid two-phase system of organic solvent-water in the presence of catalyst, wherein the organic solvent and water are not mutually soluble,

[0034] In the formula, R1 is H, halogen, C 1-6 alkyl or halogenated C 1-6 alkyl;

[0035] R2 is H, C 1-6 alkyl, C 6-10 aryl or C 5-10 heterocyclyl, the substituent is selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, oxo (=O);

[0036] R3 is methylsulfonyl or halogenated C 1-6 alkyl, preferably methylsulfonyl or CF3;

[0037] R4 is halogen, preferably Br;

[0038] R4 is located at the ortho position, meta position or para position of R3.

[0039] In the specific embodiment, R1 is H, Cl, methyl or trifluoromethyl.

[0040] In the specific embodiment, R2 is H, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy-substituted C 1-6 alkyl, halogenated C 1-6 alkoxy-substituted C 1-6 alkyl,

[0041] In a more specific embodiment, R2 is H, methyl, Br-CH2-, CF3-CH2-O-CH2-, The organic solvent used in the preparation method of this invention is a solvent that is immiscible with water, preferably toluene or xylene. The mass ratio of the organic solvent to water is preferably (1-10):1, more preferably (2-4):1. If too little water is added, salts of the compound of formula I will precipitate, resulting in a liquid-liquid-solid three-phase reaction during post-processing, increasing the difficulty of post-processing; while too much water will reduce the concentration of the reactants and increase the reaction time.

[0042] The catalyst used in the preparation method of the present invention is a noble metal catalyst selected from palladium, rhodium, ruthenium, copper, and cobalt, more preferably a palladium catalyst. Specific examples include, but are not limited to, palladium chloride (PdCl2), palladium carbonate (PdCO3), palladium acetate [Pd(OAc)2], palladium / carbon (Pd / C), palladium trifluoroacetate [Pd(OTFA)2], and bis(dba)2, etc., with palladium chloride (PdCl2) being the most preferred.

[0043] In the preparation method of the present invention, a catalyst ligand is preferably used, and more preferably, the ligand is a phosphorus ligand or its salt, and specific examples include, but are not limited to, 1,3-(bis(diphenylphosphine)propane), 1,4-bis(diphenylphosphine)butane, or bis[(4-N,N-dimethylamino)phenyl]di-tert-butylphosphine, etc.

[0044] In a specific embodiment, the preparation method of the present invention is used in the following reaction:

[0045] In the formula, R1 and R2 are as defined above.

[0046] In specific implementations, the reactions described below are included, but are not limited to:

[0047] In a specific embodiment, the above reaction is performed as follows, but not limited to: adding the raw material compound, acid-binding agent, catalyst, optional ligand, optional phase transfer catalyst, organic solvent, and water to a high-pressure reactor; purging with nitrogen; introducing carbon monoxide; pressurizing; and heating to react. After the reaction is complete, the reaction solution is separated, the organic phase is separated, the aqueous phase is acidified to pH 1-3, cooled, and filtered to obtain the benzoic acid compound.

[0048] In a more specific embodiment, the phase transfer catalyst used in the above reaction is tetrabutylammonium bromide, benzyltriethylammonium chloride, 18-crown ether-6, or cyclodextrin, preferably tetrabutylammonium bromide, and the molar ratio of the phase transfer catalyst to the benzoic acid compound is (0.005-0.05):1, preferably (0.01-0.02):1.

[0049] In a more specific embodiment, the acid-binding agent used in the above reaction is potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, triethylamine, cesium carbonate, or N,N-diisopropylethylamine, preferably potassium carbonate, and the molar ratio of the acid-binding agent to the compound of formula II is (1.05-2):1, preferably (1.1-1.3):1.

[0050] In a more specific embodiment, the reaction temperature is 70-140°C, preferably 80-120°C.

[0051] In a more specific embodiment, the reaction pressure is 0.4–4.0 MPa, preferably 1.2–1.5 MPa. Too low a pressure will prolong the reaction time and result in poor reaction selectivity and low product yield; too high a pressure is unsafe.

[0052] According to the preparation method of this invention, the reaction solution after the reaction is completed is separated, and the organic solvent containing the catalyst is directly reused in the next reaction, thus realizing the reuse of the catalyst. The organic solvent containing the catalyst can be reused more than ten times.

[0053] The benzoic acid intermediate of formula I obtained by the above method can be used to prepare HPPD inhibitor herbicides, including but not limited to benzosulfuron, triazole sulfadiazine, cyclosulfuron, bispyribac-sodium, and benzosulfuron.

[0054] This invention enables the direct use of catalysts, which is environmentally friendly and cost-effective. Furthermore, it simplifies post-processing operations and achieves higher product yields.

[0055] The present invention will be described in more detail below through embodiments, but the present invention is not limited to these specific embodiments and examples. Any modifications and changes that do not depart from the spirit and scope of the present invention shall fall within the scope of the present invention.

[0056] Example

[0057] In the following examples, the high-performance liquid chromatography (HPLC) analysis conditions were as follows: the instrument was an Agilent 1100LC HPLC system with a UV detector; the chromatographic column was a C18 reversed-phase column, 250 mm × 4.6 mm × 5.0 μm; the mobile phase was acetonitrile:water (adjusted to pH 3.7–4.1 with formic acid) = 60:40 (V:V); the column temperature was 30 °C; the flow rate was 1.0 mL / min; the wavelength was 210 nm; and the injection volume was 5 μL.

[0058] Example 1 Synthesis of 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methanesulfonylbenzoic acid

[0059] Add 50.0 g (0.1271 mol) of 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methanesulfonylbromobenzene (97% purity), 200 g of toluene, 100 g of water, 19.32 g (0.1398 mol) of potassium carbonate, 1.0 g (0.0031 mol) of tetrabutylammonium bromide, 0.1 g of palladium chloride, and 0.53 g of 1,3-(bis(diphenylphosphine)propane) to a 1000 ml autoclave.

[0060] After purging with nitrogen three times, carbon monoxide was introduced, the pressure was increased to 1.5 MPa, and the temperature was raised to 90°C, maintaining the temperature and pressure. After holding at this temperature for 4–6 hours, samples were taken, and HPLC analysis confirmed that the content of 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methanesulfonylbromobenzene was less than 1%, indicating the reaction was complete.

[0061] The autoclave was depressurized and purged with gas. The autoclave was then opened, and the reaction solution was separated to obtain the organic phase for reuse. 100.0 g of methanol was added to the aqueous phase and stirred thoroughly. A 40% aqueous solution of hydrogen bromide was added dropwise to adjust the pH to 1–3. The mixture was then cooled to 5–10 °C and filtered to obtain 44.40 g of 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methanesulfonylbenzoic acid, with a purity of 97.3% and a yield of 96.6%.

[0062] Example 2 Synthesis of 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methanesulfonylbenzoic acid

[0063] Replacing toluene with xylene in Example 1, while keeping other conditions unchanged, and maintaining the temperature for 4–6 hours, yielded 41.8 g of 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methanesulfonylbenzoic acid, with a purity of 97.5% and a yield of 92.2%.

[0064] Example 3 Synthesis of 2-methyl-3-(4,5-dihydroisoxazole)-4-methanesulfonylbenzoic acid

[0065] Add 50g (0.1524mol) of 3-[3-bromo-2-methyl-6-(methylsulfonyl)phenyl]-4,5-dihydroisoxazole (97% purity), 200g of toluene, 100g of water, 23.17g (0.1677mol) of potassium carbonate, 1.0g (0.0031mol) of tetrabutylammonium bromide, 0.1g of palladium chloride catalyst, and 0.53g of 1,3-(bis(diphenylphosphine)propane) to a 1000ml autoclave.

[0066] After nitrogen purging three times, carbon monoxide was introduced, the pressure was increased to 1.5 MPa, and the temperature was raised to 90°C and maintained. After holding at this temperature for 21 hours, a sample was taken, and HPLC analysis confirmed that the content of 3-[3-bromo-2-methyl-6-(methanesulfonyl)phenyl]-4,5-dihydroisoxazole was less than 1%, indicating that the reaction was complete.

[0067] The autoclave was depressurized and purged with gas. The autoclave was then opened, and the reaction solution was separated to obtain the organic phase for reuse. 100.0 g of methanol was added to the aqueous phase and stirred thoroughly. A 40% aqueous solution of hydrogen bromide was added dropwise to adjust the pH to 1-3. The mixture was then cooled to 5-10 °C and filtered to obtain 40.85 g of 2-methyl-3-(4,5-dihydroisoxazole)-4-methanesulfonylbenzoic acid, with a purity of 99.24% and a yield of 94.0%.

[0068] Example 4 Synthesis of 2-methyl-3-(4,5-dihydroisoxazole)-4-methanesulfonylbenzoic acid

[0069] In Example 3, the amount of toluene was adjusted to 400g and the amount of water was adjusted to 200g, while the other conditions remained unchanged, yielding 41.4g of 2-methyl-3-(4,5-dihydroisoxazole)-4-methanesulfonylbenzoic acid with a content of 95.5% and a yield of 91.6%.

[0070] Example 5 Catalyst Application

[0071] Add 50.0 g (0.1271 mol) of 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methanesulfonylbromobenzene (97% purity), 100 g of water, 19.32 g (0.1398 mol) of potassium carbonate, 1.0 g (0.0031 mol) of tetrabutylammonium bromide, and the organic phase separated in Example 1 (add an appropriate amount of toluene) to a 1000 ml autoclave.

[0072] After purging with nitrogen three times, carbon monoxide was introduced, the pressure was increased to 1.5 MPa, and the temperature was raised to 90°C, maintaining the temperature and pressure. After holding at this temperature for 4–6 hours, samples were taken, and HPLC analysis confirmed that the content of 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methanesulfonylbromobenzene was less than 1%, indicating the reaction was complete.

[0073] The autoclave was depressurized and purged with gas. The autoclave was then opened, and the reaction solution was separated to obtain the organic phase for reuse. 100.0 g of methanol was added to the aqueous phase and stirred thoroughly. A 40% aqueous solution of hydrogen bromide was added dropwise to adjust the pH to 1-3. The mixture was then cooled to 5-10 °C and filtered to obtain 44.05 g of 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methanesulfonylbenzoic acid, with a purity of 97.2% and a yield of 97.1%.

[0074] According to this method, after the organic phase was used for 11 times (solvent loss, and an appropriate amount of toluene was added each time), 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylsulfonylbenzoic acid 42.1 g was obtained, with a content of 98.9%, a yield of 94.05%.

Claims

1. A method for preparing the benzoic acid compound shown in formula (I), characterized in that, The synthesis is achieved through the following reaction, carried out in a liquid-liquid two-phase system of an organic solvent and water in the presence of a catalyst, wherein the organic solvent and water are immiscible. In the formula, R1 represents H, halogen, and C. 1-6 Alkyl or halogenated C 1-6 alkyl; R2 is H, and C is optionally substituted with one or more substituents. 1-6 Alkyl, C 6-10 Aryl or C 5-10 Heterocyclic group, wherein the substituent is selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy group, oxo group (=O); R3 is a methanesulfonyl group or a halogenated C. 1-6 Alkyl group, preferably methanesulfonyl or CF3; R4 is a halogen, preferably Br; R4 is located adjacent to, between, or opposite to R3.

2. The preparation method according to claim 1, wherein R2 is H or C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 alkoxy-substituted C 1-6 Alkyl, Halogenated C 1-6 alkoxy-substituted C 1-6 alkyl, 3. The preparation method according to claim 1 or 2, wherein R2 is H, methyl, Br-CH2-, CF3-CH2-O-CH2-, 4. The preparation method according to any one of claims 1 to 3, wherein, The reaction is as follows: In the formula, R1 and R2 are as defined in claim 1.

5. The preparation method according to any one of claims 1 to 3, wherein, The reaction is as follows:

6. The method according to any one of claims 1 to 5, wherein the organic solvent is toluene or xylene, and the mass ratio of the organic solvent to water is (1 to 10):1, preferably (2 to 4):

1.

7. The method according to any one of claims 1 to 6, wherein the catalyst is a noble metal catalyst selected from palladium, rhodium, ruthenium, copper, and cobalt, preferably a palladium catalyst; preferably further using a catalyst ligand, more preferably a phosphorus ligand or a salt thereof.

8. The method according to any one of claims 1 to 7, wherein a phase transfer catalyst is further used, preferably one of tetrabutylammonium bromide, benzyltriethylammonium chloride, 18-crown ether-6, and cyclodextrin.

9. The method according to any one of claims 1 to 8, the method further comprising the following steps: after the reaction is completed, the reaction solution is separated, and the organic solvent containing the catalyst is directly reused in the next reaction.

10. A method for preparing an HPPD inhibitor herbicide, the method comprising preparing the benzoic acid intermediate of Formula I by means of any one of claims 1-9.

11. The preparation method according to claim 10, wherein the HPPD inhibitor herbicide is selected from benzoxazole, triazolesulfuron, cyclosulfuron, bispyribac-sodium, and benzoxazole.

12. The preparation method according to claim 11, wherein the HPPD inhibitor herbicide is cyclosulfonyl or benzoylflufenican, the method comprising the following benzoic acid intermediate preparation step:

13. The preparation method according to claim 11, wherein the HPPD inhibitor herbicide is benzoyl permethrin, the method comprising the following steps for preparing a benzoic acid intermediate:

14. The preparation method according to claim 11, wherein the HPPD inhibitor herbicide is triazole sulfadiazine, and the method comprises the following steps for preparing a benzoic acid intermediate:

15. The preparation method according to claim 11, wherein the HPPD inhibitor herbicide is bispyribac-sodium, the method comprising the following steps for preparing a benzoic acid intermediate:

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