CN115304523A - Synthetic method of 3-methyl-2-chloro-4-methylsulfonylbenzoic acid - Google Patents
Synthetic method of 3-methyl-2-chloro-4-methylsulfonylbenzoic acid Download PDFInfo
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- CN115304523A CN115304523A CN202110497053.9A CN202110497053A CN115304523A CN 115304523 A CN115304523 A CN 115304523A CN 202110497053 A CN202110497053 A CN 202110497053A CN 115304523 A CN115304523 A CN 115304523A
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- RRFGGUXLGOVPOP-UHFFFAOYSA-N 2-chloro-3-methyl-4-methylsulfonylbenzoic acid Chemical compound CC1=C(Cl)C(C(O)=O)=CC=C1S(C)(=O)=O RRFGGUXLGOVPOP-UHFFFAOYSA-N 0.000 title claims abstract description 29
- 238000010189 synthetic method Methods 0.000 title claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims abstract description 73
- NHFKECPTBZZFBC-UHFFFAOYSA-N 4-amino-3-methylbenzoic acid Chemical compound CC1=CC(C(O)=O)=CC=C1N NHFKECPTBZZFBC-UHFFFAOYSA-N 0.000 claims abstract description 27
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims abstract description 24
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 18
- 230000009467 reduction Effects 0.000 claims abstract description 18
- 238000005660 chlorination reaction Methods 0.000 claims abstract description 17
- RMBAVIFYHOYIFM-UHFFFAOYSA-M sodium methanethiolate Chemical compound [Na+].[S-]C RMBAVIFYHOYIFM-UHFFFAOYSA-M 0.000 claims abstract description 17
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 16
- 238000006467 substitution reaction Methods 0.000 claims abstract description 16
- 230000003647 oxidation Effects 0.000 claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 14
- 239000002994 raw material Substances 0.000 claims abstract description 13
- 235000010288 sodium nitrite Nutrition 0.000 claims abstract description 12
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims abstract description 11
- HMDHOFNCICZZPD-UHFFFAOYSA-N 3,4-dimethylbenzenecarbothioic s-acid Chemical compound CC1=CC=C(C(O)=S)C=C1C HMDHOFNCICZZPD-UHFFFAOYSA-N 0.000 claims abstract description 8
- 230000009471 action Effects 0.000 claims abstract description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 21
- 239000003054 catalyst Substances 0.000 claims description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 8
- 230000002194 synthesizing effect Effects 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- 239000006184 cosolvent Substances 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 5
- 230000001590 oxidative effect Effects 0.000 claims description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000007868 Raney catalyst Substances 0.000 claims description 4
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 4
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 4
- DSVGQVZAZSZEEX-UHFFFAOYSA-N [C].[Pt] Chemical compound [C].[Pt] DSVGQVZAZSZEEX-UHFFFAOYSA-N 0.000 claims description 4
- 230000015572 biosynthetic process Effects 0.000 claims description 4
- 239000012320 chlorinating reagent Substances 0.000 claims description 4
- 238000003786 synthesis reaction Methods 0.000 claims description 4
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 3
- XSTXAVWGXDQKEL-UHFFFAOYSA-N Trichloroethylene Chemical group ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 claims description 3
- 239000007800 oxidant agent Substances 0.000 claims description 3
- UBOXGVDOUJQMTN-UHFFFAOYSA-N trichloroethylene Natural products ClCC(Cl)Cl UBOXGVDOUJQMTN-UHFFFAOYSA-N 0.000 claims description 3
- CYTYCFOTNPOANT-UHFFFAOYSA-N Perchloroethylene Chemical group ClC(Cl)=C(Cl)Cl CYTYCFOTNPOANT-UHFFFAOYSA-N 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims description 2
- 229950011008 tetrachloroethylene Drugs 0.000 claims description 2
- JVBNILACPMFONW-UHFFFAOYSA-N 3-methyl-4-methylsulfonylbenzoic acid Chemical compound CC1=CC(C(O)=O)=CC=C1S(C)(=O)=O JVBNILACPMFONW-UHFFFAOYSA-N 0.000 claims 1
- 239000005708 Sodium hypochlorite Substances 0.000 abstract description 6
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 abstract description 6
- 238000001308 synthesis method Methods 0.000 abstract description 4
- 239000002351 wastewater Substances 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 3
- 238000003756 stirring Methods 0.000 description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- -1 3-methyl-2-chloro-4-methylthiobenzoic acid Chemical compound 0.000 description 17
- 238000010438 heat treatment Methods 0.000 description 16
- 238000004321 preservation Methods 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 12
- 238000010791 quenching Methods 0.000 description 12
- 230000000171 quenching effect Effects 0.000 description 12
- 238000001914 filtration Methods 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Natural products OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 9
- 239000007864 aqueous solution Substances 0.000 description 8
- 239000012295 chemical reaction liquid Substances 0.000 description 8
- 238000001816 cooling Methods 0.000 description 8
- 239000007787 solid Substances 0.000 description 7
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 6
- 239000000460 chlorine Substances 0.000 description 6
- 229910052801 chlorine Inorganic materials 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 238000011049 filling Methods 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 6
- 239000005711 Benzoic acid Substances 0.000 description 5
- 235000010233 benzoic acid Nutrition 0.000 description 5
- ZUVPLKVDZNDZCM-UHFFFAOYSA-N 3-chloro-2-methylaniline Chemical compound CC1=C(N)C=CC=C1Cl ZUVPLKVDZNDZCM-UHFFFAOYSA-N 0.000 description 4
- 230000003197 catalytic effect Effects 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 238000000967 suction filtration Methods 0.000 description 4
- 238000009423 ventilation Methods 0.000 description 4
- 229960001701 chloroform Drugs 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- DMEDNTFWIHCBRK-UHFFFAOYSA-N 1,3-dichloro-2-methylbenzene Chemical compound CC1=C(Cl)C=CC=C1Cl DMEDNTFWIHCBRK-UHFFFAOYSA-N 0.000 description 2
- RYMMNSVHOKXTNN-UHFFFAOYSA-N 1,3-dichloro-5-methyl-benzene Natural products CC1=CC(Cl)=CC(Cl)=C1 RYMMNSVHOKXTNN-UHFFFAOYSA-N 0.000 description 2
- 239000005620 Tembotrione Substances 0.000 description 2
- UKRYSJBPFJXBBA-UHFFFAOYSA-N [Ni].[Nb].[Ra] Chemical compound [Ni].[Nb].[Ra] UKRYSJBPFJXBBA-UHFFFAOYSA-N 0.000 description 2
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 2
- 239000012346 acetyl chloride Substances 0.000 description 2
- 230000010933 acylation Effects 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000006053 organic reaction Methods 0.000 description 2
- IUQAXCIUEPFPSF-UHFFFAOYSA-N tembotrione Chemical compound ClC1=C(COCC(F)(F)F)C(S(=O)(=O)C)=CC=C1C(=O)C1C(=O)CCCC1=O IUQAXCIUEPFPSF-UHFFFAOYSA-N 0.000 description 2
- XKLPBDMZJSWRBL-UHFFFAOYSA-N 3-benzoylcyclohexane-1,2-dione Chemical compound C=1C=CC=CC=1C(=O)C1CCCC(=O)C1=O XKLPBDMZJSWRBL-UHFFFAOYSA-N 0.000 description 1
- ACZGCWSMSTYWDQ-UHFFFAOYSA-N 3h-1-benzofuran-2-one Chemical compound C1=CC=C2OC(=O)CC2=C1 ACZGCWSMSTYWDQ-UHFFFAOYSA-N 0.000 description 1
- 102000016680 Dioxygenases Human genes 0.000 description 1
- 108010028143 Dioxygenases Proteins 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 235000013339 cereals Nutrition 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000035784 germination Effects 0.000 description 1
- 239000004009 herbicide Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000004065 wastewater treatment Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
- C07C315/02—Preparation of sulfones; Preparation of sulfoxides by formation of sulfone or sulfoxide groups by oxidation of sulfides, or by formation of sulfone groups by oxidation of sulfoxides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
- C07C315/04—Preparation of sulfones; Preparation of sulfoxides by reactions not involving the formation of sulfone or sulfoxide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
- C07C319/20—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides by reactions not involving the formation of sulfide groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a synthetic method of 3-methyl-2-chloro-4-methylsulfonyl benzoic acid. The synthesis method comprises the steps of taking 3-methyl-4-aminobenzoic acid as a raw material, carrying out nucleophilic substitution on the 3-methyl-4-methylthiobenzoic acid and sodium methyl mercaptide under the action of sodium nitrite to obtain 3-methyl-4-methylthiobenzoic acid, and then carrying out chlorination substitution, hydrogenation reduction and oxidation in sequence to obtain 3-methyl-2-chloro-4-methylsulfonylbenzoic acid; or the prepared 3-methyl-4-methylthiobenzoic acid is subjected to chlorination substitution, oxidation and hydrogenation reduction in sequence to prepare the 3-methyl-2-chloro-4-methylsulfonylbenzoic acid. By adopting the reaction route, the method has the advantages of high product yield, high purity, cheap and easily-obtained raw materials, mild reaction conditions, few steps, simple post-treatment, convenient operation, no need of using a large amount of sodium hypochlorite solution, small amount of waste water, remarkably reduced treatment cost and suitability for industrial production.
Description
Technical Field
The invention relates to the technical field of chemical synthesis, in particular to a synthetic method of 3-methyl-2-chloro-4-methylsulfonyl benzoic acid.
Background
The tembotrione, the benzofuranone, the triazasulamone and the like are benzoyl cyclohexanedione herbicides, are p-hydroxyphenylpyruvate dioxygenase (HPPD) inhibitors, are mainly used for preventing and killing annual and perennial broadleaf weeds in paddy rice and cereal fields, can be used before and after germination, and have the advantages of high activity, long control period, small dosage and the like.
3-methyl-2-chlorine-4-methylsulfonylbenzoic acid is an important fine chemical intermediate for synthesizing tembotrione, fursulcotrione and triazophone, and the following two methods are mainly adopted for preparing 3-methyl-2-chlorine-4-methylsulfonylbenzoic acid at present: 1. 2,6-dichlorotoluene is used as a raw material to react with sodium methyl mercaptide to prepare 2-methyl-3-chloro-thiobenzoxide, then acetyl chloride acylation and hydrogen peroxide oxidation are carried out to obtain 3-methyl-2-chloro-4-methylsulfonyl acetophenone, and finally sodium hypochlorite oxidation is carried out to obtain 3-methyl-2-chloro-4-methylsulfonyl benzoic acid. 2. 3-chloro-2-methylaniline is used as a raw material to react with sodium methyl mercaptide to prepare 2-methyl-3-chloro-thiobenzyl ether, and then the 2-methyl-3-chloro-4-methylsulfonyl acetophenone is obtained by acetyl chloride acylation and hydrogen peroxide oxidation, and finally the 3-methyl-2-chloro-4-methylsulfonyl benzoic acid is obtained by sodium hypochlorite oxidation.
The above two methods have the following disadvantages: 1. a large amount of sodium hypochlorite is used for oxidizing the 3-methyl-2-chloro-4-methylsulfonyl acetophenone into a target product, and hydrochloric acid is needed for acidification after the reaction is finished, so that the wastewater amount is large, and the wastewater treatment cost is high; 2. the 2,6-dichlorotoluene is used as a raw material to react with sodium methyl mercaptide to generate 2-methyl-3-chloro-thiobenzoxide, about 7 percent of isomer is generated, and the yield is reduced; 3. the production cost is very high by using 3-chloro-2-methylaniline as the raw material.
In view of this, the invention is particularly proposed.
Disclosure of Invention
The invention provides a synthesis method of 3-methyl-2-chloro-4-methylsulfonylbenzoic acid, which has the advantages of high product yield, high purity, low raw material cost, mild reaction conditions, few steps, simple post-treatment, convenient operation, no need of using a large amount of sodium hypochlorite solution, small amount of waste water, remarkably reduced treatment cost and suitability for industrial production.
The embodiment of the invention provides a synthesis method of 3-methyl-2-chloro-4-methylsulfonyl benzoic acid, which comprises the steps of taking 3-methyl-4-aminobenzoic acid as a raw material, carrying out nucleophilic substitution on the 3-methyl-4-aminobenzoic acid and sodium methyl mercaptide under the action of sodium nitrite to prepare 3-methyl-4-methylthiobenzoic acid, and then carrying out chlorination substitution, hydrogenation reduction and oxidation in sequence to prepare 3-methyl-2-chloro-4-methylsulfonyl benzoic acid;
or 3-methyl-4-aminobenzoic acid is taken as a raw material, nucleophilic substitution is carried out on the 3-methyl-4-aminobenzoic acid and sodium methyl mercaptide under the action of sodium nitrite to prepare 3-methyl-4-methyl thiobenzoic acid, and chlorination substitution, oxidation and hydrogenation reduction are sequentially carried out to prepare 3-methyl-2-chloro-4-methylsulfonyl benzoic acid.
In particular to two reaction routes, one of the reaction routes is as follows:
the method comprises the following steps:
1) 3-methyl-4-aminobenzoic acid and sodium methyl mercaptide are subjected to nucleophilic substitution under the action of sodium nitrite to generate 3-methyl-4-thiomethyl benzoic acid;
2) The 3-methyl-4-thiomethyl benzoate and a chlorinating reagent are subjected to chlorination substitution to generate 2,5,6-trichloro-3-methyl-4-thiomethyl benzoate;
3) 5363 the 3-methyl-2-chloro-4-methylthiobenzoic acid is generated by hydrogenation reduction of 2,5,6-trichloro-3-methyl-4-methylthiobenzoic acid in a reaction kettle;
4) Oxidizing the 3-methyl-2-chloro-4-methylsulfide benzoic acid with an oxidizing reagent to generate the 3-methyl-2-chloro-4-methylsulfonylbenzoic acid.
The second reaction route is as follows:
the method comprises the following steps:
1) 3-methyl-4-aminobenzoic acid and sodium methyl mercaptide are subjected to nucleophilic substitution under the action of sodium nitrite to generate 3-methyl-4-methylthio benzoic acid;
2) The 3-methyl-4-thiomethyl benzoate and a chlorinating reagent are subjected to chlorination substitution to generate 2,5,6-trichloro-3-methyl-4-thiomethyl benzoate;
3) 2,5,6-trichloro-3-methyl-4-methylsulfide benzoic acid is oxidized with an oxidizing reagent to generate 2,5,6-trichloro-3-methyl-4-methylsulfonylbenzoic acid;
4) 5363 and hydrogenating and reducing 2,5,6-trichloro-3-methyl-4-methylsulfonylbenzoic acid in a reaction kettle to generate 3-methyl-2-chloro-4-methylsulfonylbenzoic acid.
In the above two reaction schemes of the present invention, the organic solvent used for the chlorination substitution, the hydrogenation reduction or the oxidation is selected from any one of chloroform, dichloromethane, dichloroethane, trichloroethylene and tetrachloroethylene, and dichloroethane is preferred.
Further, the amount of the organic solvent is 2 to 5 times, preferably 3 to 4 times, the mass of 3-methyl-4-aminobenzoic acid.
Specifically, in the nucleophilic substitution in one or both of the above-mentioned reaction schemes, the molar ratio of 3-methyl-4-aminobenzoic acid to sodium thiomethoxide is 1 (1.4 to 1.8), preferably 1 (1.6 to 1.7).
Further, the reaction temperature of the nucleophilic substitution is-10 to 5 ℃, preferably-10 to-5 ℃.
In the chlorination substitution in one or two of the above reaction routes, the chlorination reagent used in the chlorination substitution is chlorine or sulfuryl chloride, preferably chlorine, so that the production cost can be reduced, and the operation difficulty can be reduced.
Further, the molar ratio of the chlorinating agent to the 3-methyl-4-aminobenzoic acid is (3-10): 1, preferably (4-6): 1.
Further, the reaction temperature of the chlorination substitution is 0 to 20 ℃, preferably 10 to 15 ℃.
In the hydrogenation reduction in the first or second reaction route, the cosolvent used in the hydrogenation reduction is selected from any one of methanol, ethanol, dichloroethane and dichloromethane, and preferably methanol.
Furthermore, the dosage of the cosolvent is 10-20% of the mass of the organic solvent.
Further, the catalyst used for hydrogenation reduction is selected from palladium carbon, raney nickel or platinum carbon, preferably raney nickel.
Further, the amount of the catalyst is 2 to 5%, preferably 2 to 2.5% by mass of the 3-methyl-4-aminobenzoic acid.
Further, the reaction pressure of the hydrogenation reduction is 2 to 6MPa, preferably 3 to 4MPa.
Further, the reaction temperature of the hydrogenation reduction is 50-70 ℃, preferably 55-65 ℃.
In the oxidation in the first or second reaction route, the oxidizing agent used is hydrogen peroxide or oxygen, preferably hydrogen peroxide.
Further, the molar ratio of the oxidizing agent to the 3-methyl-4-aminobenzoic acid is (3-5): 1, preferably (3-4): 1.
Further, the reaction temperature of the oxidation is 70 to 90 ℃, preferably 70 to 80 ℃.
In some specific embodiments, one of the reaction schemes comprises:
adding 3-methyl-4-aminobenzoic acid, concentrated hydrochloric acid and water into a four-mouth reaction bottle with a thermometer, a reflux condenser tube and a stirring paddle, stirring, heating to 50-55 ℃ for salification, and reacting for 0.5h under heat preservation. Cooling to-5-0 deg.c, dropping 30% concentration sodium nitrite solution in the amount of 1.1 equivalent of 3-methyl-4-aminobenzoic acid slowly, and maintaining the temperature for reaction for 0.5 hr. Dropwise adding the mixture into a four-mouth reaction bottle containing 20% sodium methyl mercaptide aqueous solution, carrying out heat preservation reaction for 2.0 hours after the dropwise adding is finished, and carrying out suction filtration to obtain a gray solid, namely 3-methyl-4-thiomethyl benzoate.
Adding an organic solvent, stirring, controlling the temperature to be 10-15 ℃, slowly introducing chlorine gas, keeping the temperature for reaction for 1.0h after the gas introduction is finished, adding water for quenching, heating to 30-35 ℃, stirring for 0.5h, standing for 0.5h for layering to obtain an intermediate 2,5,6-trichloro-3-methyl-4-thiomethyl benzoate, and carrying out organic successive reaction.
Adding an organic phase containing 2,5,6-trichloro-3-methyl-4-methylthiobenzoic acid, a cosolvent and a catalyst into a 500ml high-pressure reaction kettle, filling hydrogen, slowly heating to 55-60 ℃ for reaction for 6.0h, cooling to room temperature, and slowly removing pressure to obtain an organic phase containing an intermediate 3-methyl-2-chloro-4-methylthiobenzoic acid which is successively reacted in the next step.
Adding acetic acid, sulfuric acid and an organic phase containing 2-chloro-3-methyl-4-methylthiobenzoic acid into a four-mouth reaction bottle with a thermometer, a reflux condenser tube and a stirring paddle, stirring, heating to 70-75 ℃, slowly dropwise adding a 30% hydrogen peroxide solution, keeping the temperature for reacting for 1.0h after the dropwise adding is finished, adding water for quenching, and carrying out suction filtration and drying to obtain a white solid target.
In some embodiments, the second reaction scheme comprises:
the preparation process of the intermediate 3-methyl-4-methyl sulfide benzoic acid and 2,5,6-trichloro-3-methyl-4-methyl sulfide benzoic acid is the same as one of the reaction routes.
Adding acetic acid, sulfuric acid and an organic phase containing 2,5,6-trichloro-3-methyl-4-methylthiobenzoic acid into a four-mouth reaction bottle with a thermometer, a reflux condenser pipe and a stirring paddle, stirring, heating to 70-75 ℃, slowly dropwise adding 30% hydrogen peroxide solution, keeping the temperature for reacting for 1.0 hour after dropwise adding, adding water for quenching, standing and layering to obtain an intermediate 2,5,6-trichloro-3-methyl-4-methylsulfonylbenzoic acid-containing organic phase, and sequentially reacting.
Adding an organic phase containing 2,5,6-trichloro-3-methyl-4-methylsulfonylbenzoic acid, a cosolvent and a catalyst into a high-pressure reaction kettle, filling hydrogen, slowly heating to 55-60 ℃, reacting for 6.0h, cooling to room temperature, removing pressure, adding water, quenching, filtering, and drying to obtain a white solid target compound.
The invention has the following beneficial effects:
according to the invention, two reaction routes for synthesizing the 3-methyl-2-chloro-4-methylsulfonylbenzoic acid by taking the 3-methyl-4-aminobenzoic acid as the raw material are obtained through multiple times of experimental condition screening, and the two reaction routes effectively avoid the defects of the existing synthesis method. The inventor finds that by adopting the reaction route, the product yield is high, the purity is high, the raw material cost is low, the reaction condition is mild, the steps are few, the post-treatment is simple, the operation is convenient, a large amount of sodium hypochlorite solution is not needed, the waste water amount is small, the treatment cost is obviously reduced, and the method is suitable for industrial production.
Detailed Description
The following examples are intended to illustrate the invention, but are not intended to limit the scope of the invention.
Example 1
30.23g (0.2 mol) of 3-methyl-4-aminobenzoic acid, 50.64g (0.5 mol) of concentrated hydrochloric acid and 75.96g of water are added into a four-mouth bottle, stirred and heated to 50-55 ℃ to form salt, and the heat preservation reaction is carried out for 0.5h. And (4) cooling to-5-0 ℃, slowly dripping 51g of 30% sodium nitrite aqueous solution, and keeping the temperature for reaction for 0.5h after dripping is finished. Dropwise adding the solution into 112.14g (0.32 mol) of 20% sodium methyl mercaptide aqueous solution, carrying out heat preservation reaction for 2.0h after dropwise adding, carrying out suction filtration to obtain gray solid 3-methyl-4-methylthio benzoate, adding 150 g of dichloroethane, stirring, controlling the temperature to be between 10 and 15 ℃, slowly introducing 71g (1 mol) of chlorine, carrying out heat preservation reaction for 1.0h after ventilation is finished, adding water for quenching, heating to 30 to 35 ℃, stirring for 0.5h, standing for 0.5h for layering, and collecting the organic substance containing the intermediate 2,5,6-trichloro-3-methyl-4-methylthio benzoate to successively carry out the next reaction. Adding 2,5,6-trichloro-3-methyl-4-methylthioethyl benzoate dichloroethane reaction liquid, 15g of methanol and 0.65g of platinum carbon catalyst into a high-pressure reaction kettle, filling hydrogen, slowly heating to 55-60 ℃, keeping the pressure of the reaction kettle between 3-4 Mpa for reacting for 6.0h, cooling to room temperature, removing pressure, filtering out the catalyst for application, adding water into the reaction liquid for layering, and collecting the organic compound containing the intermediate 3-methyl-2-chloro-4-methylthiobenzoic acid for successive next reaction. Adding a few drops of catalytic acetic acid and sulfuric acid, stirring and heating to 70-75 ℃, slowly dropwise adding 90.7g (0.8 mol) of 30% aqueous hydrogen peroxide, keeping the temperature and reacting for 1.0h after dropwise adding, adding water for quenching, filtering and drying to obtain 37.8 g of target 3-methyl-2-chloro-4-methylsulfonylbenzoic acid with the content of 96% and the total yield of 73.1%.
Example 2
30.23g (0.2 mol) of 3-methyl-4-aminobenzoic acid, 50.64g (0.5 mol) of concentrated hydrochloric acid and 75.96g of water are added into a four-mouth bottle, stirred and heated to 50-55 ℃ for salt formation, and the heat preservation reaction is carried out for 0.5h. And (3) slowly dripping 51g of 30% sodium nitrite aqueous solution when the temperature is reduced to-5-0 ℃, and keeping the temperature for reaction for 0.5h after the dripping is finished. The solution is added into 119g (0.34 mol) of 20 percent sodium methyl mercaptide aqueous solution in a dropwise manner, after the dropwise addition is finished, the reaction is carried out for 2.0h under the condition of heat preservation, filtration is carried out to obtain gray solid 3-methyl-4-thiomethyl benzoate, 150 g of trichloromethane is added, the stirring temperature is controlled to be between 10 and 15 ℃, 56.8g (0.8 mol) of chlorine is slowly introduced, after the ventilation is finished, the reaction is carried out for 1.0h under the condition of heat preservation, water is added for quenching, the temperature is increased to between 30 and 35 ℃, the stirring is carried out for 0.5h, standing is carried out for 0.5h for layering, and the intermediate 2,5,6-trichloro-3-methyl-4-thiomethyl benzoate is collected, and the organic reaction is carried out in the next step. Adding 2,5,6-trichloro-3-methyl-4-methylthiobenzoate and trichloromethane reaction liquid, 15g of methanol and 0.65g of catalyst radium niobium nickel into a high-pressure reaction kettle, filling hydrogen, slowly heating to 55-60 ℃, keeping the pressure of the reaction kettle between 3-4 Mpa for reacting for 6.0h, cooling to room temperature, removing pressure, filtering out the catalyst for using, adding water into the reaction liquid for layering, and collecting the organic phase containing the intermediate 3-methyl-2-chloro-4-methylthiobenzoate for continuous reaction in the next step. Adding a few drops of catalytic acetic acid and sulfuric acid, stirring and heating to 70-75 ℃, slowly dropwise adding 90.7g (0.8 mol) of 30% aqueous hydrogen peroxide, keeping the temperature and reacting for 1.0h after dropwise adding, adding water for quenching, filtering and drying to obtain 38.1 g of target 3-methyl-2-chloro-4-methylsulfonylbenzoic acid with the content of 96.2% and the total yield of 73.9%.
Example 3
30.23g (0.2 mol) of 3-methyl-4-aminobenzoic acid, 50.64g (0.5 mol) of concentrated hydrochloric acid and 75.96g of water are added into a four-mouth bottle, stirred and heated to 50-55 ℃ to form salt, and the heat preservation reaction is carried out for 0.5h. And (3) slowly dripping 51g of 30% sodium nitrite aqueous solution when the temperature is reduced to-5-0 ℃, and keeping the temperature for reaction for 0.5h after the dripping is finished. Dropwise adding the solution into 112.14g (0.32 mol) of 20% sodium methyl mercaptide solution, carrying out heat preservation reaction for 2.0h after dropwise adding is finished, carrying out suction filtration to obtain gray solid 3-methyl-4-methylthio benzoate, adding 150 g of dichloroethane, stirring, controlling the temperature to be between 10 and 15 ℃, slowly introducing 71g (1 mol) of chlorine, carrying out heat preservation reaction for 1.0h after ventilation is finished, adding water for quenching, heating to 30 to 35 ℃, stirring for 0.5h, standing for 0.5h for layering, and collecting the intermediate 2,5,6-trichloro-3-methyl-4-methylthio benzoate to successively carry out the next reaction. Adding several drops of acetic acid and sulfuric acid with catalytic amount, stirring and heating to 70-75 ℃, slowly adding 90.7g (0.8 mol) of 30% aqueous hydrogen peroxide, keeping the temperature for reaction for 1.0h after the addition is finished, standing and layering, and collecting the organic phase containing 2,5,6-trichloro-3-methyl-4-methylsulfonylbenzoic acid for successive next reaction. Adding 2,5,6-trichloro-3-methyl-4-methylsulfonylbenzoic acid dichloroethane reaction liquid, 20g of methanol and 0.7g of catalyst platinum carbon into a high-pressure reaction kettle, filling hydrogen, slowly heating to 55-60 ℃, keeping the pressure of the reaction kettle between 3-4 Mpa for reaction for 6.0h, cooling to room temperature, removing pressure, filtering, using the catalyst, adding water into the reaction liquid for quenching, filtering and drying to obtain 38.3 g of target 3-methyl-2-chloro-4-methylsulfonylbenzoic acid, wherein the content is 96.1%, and the total yield is 74.2%.
Example 4
30.23g (0.2 mol) of 3-methyl-4-aminobenzoic acid, 50.64g (0.5 mol) of concentrated hydrochloric acid and 75.96g of water are added into a four-mouth bottle, stirred and heated to 50-55 ℃ to form salt, and the heat preservation reaction is carried out for 0.5h. And (3) slowly dripping 51g of 30% sodium nitrite aqueous solution when the temperature is reduced to-5-0 ℃, and keeping the temperature for reaction for 0.5h after the dripping is finished. The solution is added into 119g (0.34 mol) of 20 percent sodium methyl mercaptide aqueous solution in a dropwise manner, after the dropwise addition is finished, the reaction is carried out for 2.0h under the condition of heat preservation, filtration is carried out to obtain gray solid 3-methyl-4-thiomethyl benzoate, 150 g of trichloroethylene is added, the stirring temperature is controlled to be between 10 and 15 ℃, 56.8g (0.8 mol) of chlorine is slowly introduced, after the ventilation is finished, the reaction is carried out for 1.0h under the condition of heat preservation, water is added for quenching, the temperature is increased to between 30 and 35 ℃, the stirring is carried out for 0.5h, standing is carried out for 0.5h for layering, and the intermediate 2,5,6-trichloro-3-methyl-4-thiomethyl benzoate is collected, and the organic reaction is carried out in the next step. Adding a few drops of acetic acid and sulfuric acid with catalytic amount, stirring and heating to 75-80 ℃, slowly adding 68g (0.6 mol) of 30% hydrogen peroxide solution dropwise, keeping the temperature for reaction for 1.0h after the dropwise addition is finished, standing and layering to obtain an intermediate 2,5,6-trichloro-3-methyl-4-methylsulfonylbenzoic acid-containing organic phase, and continuously reacting in the next step. Adding 2,5,6-trichloro-3-methyl-4-methylsulfonyl benzoic acid trichloroethylene reaction liquid, 20g of methanol and 0.7 catalyst radium niobium nickel into a high-pressure reaction kettle, filling hydrogen, slowly heating to 55-60 ℃, keeping the pressure of the reaction kettle between 3-4 Mpa for reacting for 6.0h, cooling to room temperature, removing pressure, filtering, using the catalyst, adding water into the reaction liquid for quenching, filtering, and drying to obtain a target 3-methyl-2-chloro-4-methylsulfonyl benzoic acid 37.9 g, with the content of 96.3% and the total yield of 73.6%.
Finally, it should be noted that: the above examples are only intended to illustrate the technical solution of the present invention, but not to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some technical features may be equivalently replaced; and such modifications or substitutions do not depart from the spirit and scope of the corresponding technical solutions of the embodiments of the present invention.
Claims (10)
1. A synthetic method of 3-methyl-2-chlorine-4-methyl sulfonyl benzoic acid is characterized in that 3-methyl-4-aminobenzoic acid is used as a raw material, nucleophilic substitution is carried out on the 3-methyl-4-methyl sulfonyl benzoic acid and sodium methyl mercaptide under the action of sodium nitrite to prepare 3-methyl-4-methyl thiobenzoic acid, and then chlorination substitution, hydrogenation reduction and oxidation are sequentially carried out to prepare 3-methyl-2-chlorine-4-methyl sulfonyl benzoic acid;
or 3-methyl-4-aminobenzoic acid is taken as a raw material, nucleophilic substitution is carried out on the 3-methyl-4-aminobenzoic acid and sodium methyl mercaptide under the action of sodium nitrite to prepare 3-methyl-4-methyl thiobenzoic acid, and chlorination substitution, oxidation and hydrogenation reduction are sequentially carried out to prepare 3-methyl-2-chloro-4-methylsulfonyl benzoic acid.
2. The method for synthesizing 3-methyl-2-chloro-4-methylsulfonylbenzoic acid according to claim 1, wherein the organic solvent used for the chlorination substitution, hydrogenation reduction or oxidation is selected from any one of chloroform, dichloromethane, dichloroethane, trichloroethylene and tetrachloroethylene, preferably dichloroethane;
and/or the dosage of the organic solvent is 2 to 5 times, preferably 3 to 4 times of the mass of the 3-methyl-4-aminobenzoic acid.
3. The method for synthesizing 3-methyl-2-chloro-4-methylsulfonylbenzoic acid according to claim 1 or 2, characterized in that the molar ratio of 3-methyl-4-aminobenzoic acid to sodium thiomethoxide in the nucleophilic substitution is 1 (1.4 to 1.8), preferably 1 (1.6 to 1.7).
4. The method of synthesizing 3-methyl-2-chloro-4-methylsulfonylbenzoic acid according to claim 3, characterized in that the reaction temperature of the nucleophilic substitution is-10 to 5 ℃, preferably-10 to-5 ℃.
5. The method for synthesizing 3-methyl-2-chloro-4-methylsulfonylbenzoic acid according to claim 1 or 2, characterized in that the chlorinating agent used for the chlorination substitution is chlorine gas or sulfuryl chloride, preferably chlorine gas;
and/or the molar ratio of the chlorination reagent to the 3-methyl-4-aminobenzoic acid is (3-10): 1, preferably (4-6) is 1.
6. The synthesis of 3-methyl-2-chloro-4-methylsulfonylbenzoic acid according to claim 5, wherein the reaction temperature of the chlorination substitution is 0 to 20 ℃, preferably 10 to 15 ℃.
7. The method for synthesizing 3-methyl-2-chloro-4-methylsulfonylbenzoic acid according to claim 1 or 2, wherein the cosolvent used in the hydrogenation reduction is selected from any one of methanol, ethanol, dichloroethane and dichloromethane, preferably methanol;
and/or the dosage of the cosolvent accounts for 10-20% of the mass of the organic solvent;
and/or the catalyst used in the hydrogenation reduction is selected from palladium carbon, raney nickel or platinum carbon, preferably Raney nickel;
and/or the amount of the catalyst is 2-5%, preferably 2-2.5% of the mass of the 3-methyl-4-aminobenzoic acid.
8. The method of synthesizing 3-methyl-2-chloro-4-methylsulfonylbenzoic acid according to claim 7, wherein the reaction pressure of the hydrogenation reduction is 2 to 6MPa, preferably 3 to 4MPa;
and/or the reaction temperature of the hydrogenation reduction is 50-70 ℃, preferably 55-65 ℃.
9. The process for the synthesis of 3-methyl-2-chloro-4-methylsulfonylbenzoic acid according to claim 1 or 2, characterized in that the oxidizing agent used for the oxidation is hydrogen peroxide or oxygen, preferably hydrogen peroxide;
and/or the molar ratio of the oxidizing reagent to the 3-methyl-4-aminobenzoic acid is (3-5) to 1, preferably (3-4) to 1.
10. The process for the synthesis of 3-methyl-2-chloro-4-methylsulfonylbenzoic acid according to claim 9, characterized in that the oxidation reaction temperature is from 70 to 90 ℃, preferably from 70 to 80 ℃.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1553891A (en) * | 2001-09-11 | 2004-12-08 | �Ϻ���ͨ��ѧ | Method for producing 3-bromomethylbenzoic acids |
| CN110357797A (en) * | 2018-04-11 | 2019-10-22 | 江西天宇化工有限公司 | A kind of preparation method of 2- (the chloro- 3- chloromethyl -4- methylsulfonylbenzoyl of 2-)-hydroresorcinol |
| CN112409226A (en) * | 2019-08-23 | 2021-02-26 | 东莞市东阳光农药研发有限公司 | Substituted benzoyl compound and application thereof |
| CN112689626A (en) * | 2019-07-04 | 2021-04-20 | 东莞市东阳光农药研发有限公司 | Substituted benzoyl-pyrazole compounds and application thereof in agriculture |
-
2021
- 2021-05-07 CN CN202110497053.9A patent/CN115304523B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1553891A (en) * | 2001-09-11 | 2004-12-08 | �Ϻ���ͨ��ѧ | Method for producing 3-bromomethylbenzoic acids |
| CN110357797A (en) * | 2018-04-11 | 2019-10-22 | 江西天宇化工有限公司 | A kind of preparation method of 2- (the chloro- 3- chloromethyl -4- methylsulfonylbenzoyl of 2-)-hydroresorcinol |
| CN112689626A (en) * | 2019-07-04 | 2021-04-20 | 东莞市东阳光农药研发有限公司 | Substituted benzoyl-pyrazole compounds and application thereof in agriculture |
| CN112409226A (en) * | 2019-08-23 | 2021-02-26 | 东莞市东阳光农药研发有限公司 | Substituted benzoyl compound and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| 温彦鹏;张爽;侯广峰;于颖慧;高金胜;: "新型吡唑基取代的甲磺酰基类化合物的合成及除草活性研究", 有机化学, no. 03, pages 642 - 647 * |
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