CN116375614A - Synthesis method of cyclosulfamide intermediate - Google Patents
Synthesis method of cyclosulfamide intermediate Download PDFInfo
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- CN116375614A CN116375614A CN202310368467.0A CN202310368467A CN116375614A CN 116375614 A CN116375614 A CN 116375614A CN 202310368467 A CN202310368467 A CN 202310368467A CN 116375614 A CN116375614 A CN 116375614A
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- methyl
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- benzoate
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- methylsulfonyl
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- 238000001308 synthesis method Methods 0.000 title claims abstract description 8
- 238000000034 method Methods 0.000 claims abstract description 21
- LTVRGAWOEOKGJZ-UHFFFAOYSA-N 1-chloro-3-methoxy-2-methylbenzene Chemical compound COC1=CC=CC(Cl)=C1C LTVRGAWOEOKGJZ-UHFFFAOYSA-N 0.000 claims abstract description 15
- QPJVMBTYPHYUOC-UHFFFAOYSA-N Methyl benzoate Natural products COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 claims abstract description 12
- 229940095102 methyl benzoate Drugs 0.000 claims abstract description 12
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000002994 raw material Substances 0.000 claims abstract description 8
- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 claims abstract description 6
- 230000001590 oxidative effect Effects 0.000 claims abstract description 3
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 42
- 238000006243 chemical reaction Methods 0.000 claims description 35
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 33
- -1 3-methyl-2-chloro-4-methylthiobenzoic acid methyl ester Chemical compound 0.000 claims description 29
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- 239000002904 solvent Substances 0.000 claims description 27
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 21
- 239000003054 catalyst Substances 0.000 claims description 18
- 238000010791 quenching Methods 0.000 claims description 18
- 230000000171 quenching effect Effects 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- 230000015572 biosynthetic process Effects 0.000 claims description 13
- 238000003786 synthesis reaction Methods 0.000 claims description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 230000002194 synthesizing effect Effects 0.000 claims description 10
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 7
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 6
- 239000012295 chemical reaction liquid Substances 0.000 claims description 5
- XMVONEAAOPAGAO-UHFFFAOYSA-N sodium tungstate Chemical compound [Na+].[Na+].[O-][W]([O-])(=O)=O XMVONEAAOPAGAO-UHFFFAOYSA-N 0.000 claims description 5
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 4
- 235000005074 zinc chloride Nutrition 0.000 claims description 3
- 239000011592 zinc chloride Substances 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 2
- 239000003999 initiator Substances 0.000 claims description 2
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 2
- 238000004321 preservation Methods 0.000 claims description 2
- 150000003254 radicals Chemical class 0.000 claims description 2
- 238000001953 recrystallisation Methods 0.000 claims description 2
- 238000010992 reflux Methods 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- 239000000126 substance Substances 0.000 abstract description 2
- 239000012074 organic phase Substances 0.000 description 18
- YQYVOGFWLVVXMM-UHFFFAOYSA-N methyl 3-(bromomethyl)-2-chloro-4-methylsulfonylbenzoate Chemical compound COC(=O)C1=CC=C(S(C)(=O)=O)C(CBr)=C1Cl YQYVOGFWLVVXMM-UHFFFAOYSA-N 0.000 description 16
- 239000000543 intermediate Substances 0.000 description 13
- 238000010907 mechanical stirring Methods 0.000 description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 229960000583 acetic acid Drugs 0.000 description 4
- 238000010189 synthetic method Methods 0.000 description 4
- 241000196324 Embryophyta Species 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 230000031709 bromination Effects 0.000 description 3
- 238000005893 bromination reaction Methods 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 239000012362 glacial acetic acid Substances 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 238000005911 haloform reaction Methods 0.000 description 2
- 230000002147 killing effect Effects 0.000 description 2
- BBWCBPYXCNCYAT-UHFFFAOYSA-N methyl 2-chloro-3-methyl-4-methylsulfonylbenzoate Chemical compound COC(=O)C1=CC=C(S(C)(=O)=O)C(C)=C1Cl BBWCBPYXCNCYAT-UHFFFAOYSA-N 0.000 description 2
- 230000003405 preventing effect Effects 0.000 description 2
- VOYADQIFGGIKAT-UHFFFAOYSA-N 1,3-dibutyl-4-hydroxy-2,6-dioxopyrimidine-5-carboximidamide Chemical compound CCCCn1c(O)c(C(N)=N)c(=O)n(CCCC)c1=O VOYADQIFGGIKAT-UHFFFAOYSA-N 0.000 description 1
- 239000005620 Tembotrione Substances 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 101100339555 Zymoseptoria tritici HPPD gene Proteins 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000002363 herbicidal effect Effects 0.000 description 1
- 239000004009 herbicide Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 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 1
- 239000002912 waste gas Substances 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
- C07C315/04—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
- 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
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
Abstract
The invention belongs to the field of chemical industry, and discloses a synthesis method of a cyclosulfamide intermediate, which comprises the following steps: 1) 2-methyl-3-chloranisole is used as a raw material to carry out Friedel-crafts acylation reaction with methyl chloroformate to obtain 3-methyl-2-chloro-4-methylthio methyl benzoate; 2) Oxidizing 3-methyl-2-chloro-4-methylthio methyl benzoate to obtain 3-methyl-2-chloro-4-methylsulfonyl methyl benzoate; 3) And brominating the 3-methyl-2-chloro-4-methylsulfonyl benzoate to obtain the target product, namely the 2-chloro-3-bromomethyl-4-methylsulfonyl benzoate. The invention has the technical advantages of simple process, high yield and the like.
Description
Technical Field
The invention belongs to the field of chemical industry, and in particular relates to a synthesis method of a cyclosulfamide intermediate.
Background
The Tembotrione is a trione herbicide developed by Bayer in Germany, belongs to an HPPD inhibitor, is mainly used for preventing and killing broadleaf weeds and grassy weeds in corn fields and paddy fields, and has good preventing and killing effect on part of resistant weeds.
The key intermediate methyl 3-bromomethyl-2-chloro-4-methylsulfonyl benzoate (methyl 2-chloro-3-bromomethyl-4-methylsulfonyl benzoate, namely, 2-chloro-3-bromomethyl-4-methylsulfonyl benzoate) is synthesized by mainly taking 2-methyl-3-chloroanisole as a raw material, and 3-bromomethyl-2-chloro-4-methylsulfonyl benzoate is obtained through Friedel-crafts acylation reaction, hydrogen peroxide oxidation, haloform reaction, methanol esterification and 5 steps of bromination, wherein the reaction formula is as follows:
the reaction has the defects of long route and more three wastes.
Disclosure of Invention
The invention aims to provide a synthesis method of a cyclosulfamide intermediate with simple process and high yield.
In order to solve the technical problems, the invention provides a synthesis method of a cyclosulfamide intermediate, which comprises the following steps:
1) 2-methyl-3-chloranisole (I) is used as a raw material to carry out Friedel-crafts acylation reaction with methyl chloroformate to obtain 3-methyl-2-chloro-4-methylthio methyl benzoate (II);
2) Oxidizing 3-methyl-2-chloro-4-methylthiobenzoic acid methyl ester (II) to obtain 3-methyl-2-chloro-4-methylsulfonyl benzoic acid methyl ester (III);
3) The 3-methyl-2-chloro-4-methylsulfonyl benzoate (III) is brominated to obtain the target product, namely the 2-chloro-3-bromomethyl-4-methylsulfonyl benzoate (IV).
Improvement of the synthesis method of the cyclosulfamide intermediate:
step 1), synthesis of 3-methyl-2-chloro-4-methylthiobenzoic acid methyl ester (II):
adding (adding in batches) a catalyst I into an organic solvent I at 20-30 ℃, adding (dripping) methyl chloroformate, adding (dripping) 2-methyl-3-chloroanisole (I), carrying out heat preservation reaction at 20-30 ℃ until the reaction is finished, quenching the reaction liquid, separating the liquid, and recovering the solvent to obtain 3-methyl-2-chloro-4-methylthio methyl benzoate (II);
the 2-methyl-3-chloroanisole: methyl chloroformate: the mol ratio of the catalyst I is 1:1.05-1.2: 1.05 to 1.2;
step 2), synthesis of 3-methyl-2-chloro-4-methylsulfonyl benzoate (III):
mixing a solvent II, a catalyst II and 3-methyl-2-chloro-4-methylthio methyl benzoate (II), dropwise adding hydrogen peroxide at the temperature of 35-80 ℃, keeping the temperature of 35-80 ℃ for reaction until the reaction is finished, quenching the reaction liquid (adding water and solvent into the reaction liquid for quenching), separating the liquid, and recovering the solvent to obtain 3-methyl-2-chloro-4-methylsulfonyl methyl benzoate (III);
3-methyl-2-chloro-4-methylsulfanyl benzoic acid methyl ester (II): hydrogen peroxide: the mol ratio of the catalyst II is 1:2-4: 0.005-0.01;
the mass concentration of the hydrogen peroxide is 10-35%;
step 3), synthesis of 2-chloro-3-bromomethyl-4-methylsulfonylbenzoic acid methyl ester (IV):
mixing a solvent III, 3-methyl-2-chloro-4-methylsulfonyl methyl benzoate (III), hydrobromic acid (aqueous solution of hydrogen bromide) and a catalyst III, dropwise adding hydrogen peroxide, reacting at the temperature of about 35-85 ℃ until the reaction is finished, cooling to 25-35 ℃, separating liquid, washing with water, recovering the solvent, and recrystallizing with the solvent to obtain 2-chloro-3-bromomethyl-4-methylsulfonyl methyl benzoate (IV);
3-methyl-2-chloro-4-methylsulfonyl benzoate (III): hydrogen bromide: hydrogen peroxide: the molar ratio of the catalyst III is 1:1.0 to 1.5:1.5 to 2:0.02 to 0.05;
the mass concentration of the hydrogen bromide in the hydrobromic acid (hydrogen bromide aqueous solution) is 10-48%; the mass concentration of the hydrogen peroxide is 10-35%.
Further improvements in the synthetic methods of the present cyclosulfamide intermediates:
in the step 1):
the catalyst I is at least any one of the following: aluminum trichloride, zinc chloride, ferric trichloride (i.e., one or more);
in the step 2):
the catalyst II is sodium tungstate;
in the step 3):
catalyst III is Azobisisobutyronitrile (AIBN) or other free radical initiator.
Further improvements in the synthetic methods of the present cyclosulfamide intermediates:
in the step 1):
the organic solvent I is chloroform, dichloromethane and dichloroethane;
the dosage of the organic solvent I is 1 to 5 times of the mass of the 2-methyl-3-chloroanisole;
the quenching method comprises the following steps: controlling the temperature below 25 ℃, pouring the reaction solution into water, and quenching; the quenching water dosage is 1-4 times of the reactant mass;
the temperature of the dropwise adding of the 2-methyl-3-chloranisole (I) is 20-30 ℃.
Further improvements in the synthetic methods of the present cyclosulfamide intermediates:
in the step 2):
solvent II is at least any one of the following: methanol, ethanol, isopropanol, dichloroethane, dichloromethane, toluene, acetic acid (i.e., one or more);
the quenching water consumption of the 3-methyl-2-chloro-4-methylthio methyl benzoate (II) is 1-2 times of the mass of the solvent II, the quenching solvent is one of dichloroethane and toluene, and the consumption is 1-1.5 times of the mass of the solvent II.
Further improvements in the synthetic methods of the present cyclosulfamide intermediates:
in the step 3), the solvent III is carbon tetrachloride, chloroform, methylene dichloride or dichloroethane; dropwise adding hydrogen peroxide at room temperature to reflux the solvent; the solvent used for recrystallization is alcohols such as methanol, ethanol, isopropanol, etc.
The synthetic route of the invention is as follows: 2-methyl-3-chloranisole (I) is used as a raw material, friedel-crafts acylation reaction is carried out on the raw material and methyl chloroformate to obtain 3-methyl-2-chloro-4-methylthio benzoic acid methyl ester (II), oxidation is carried out to obtain 3-methyl-2-chloro-4-methylsulfonyl benzoic acid methyl ester (III), and finally bromination is carried out to obtain a target product, namely 2-chloro-3-bromomethyl-4-methylsulfonyl benzoic acid methyl ester (IV).
The beneficial effects of the invention are mainly as follows:
1. 2-methyl-3-chloranisole (I) is adopted as a raw material, friedel-crafts acylation reaction is carried out on the raw material and methyl chloroformate to obtain 3-methyl-2-chloro-4-methylthio methyl benzoate (II), then the 3-methyl-2-chloro-4-methylsulfonyl methyl benzoate (III) is obtained through oxidation, and finally the process of obtaining the target product 2-chloro-3-bromomethyl-4-methylsulfonyl methyl benzoate (IV) through bromination is carried out, so that two steps of reactions are reduced compared with the prior process, the cost is low, the operation is easy, and the total yield is obviously improved.
2. The haloform reaction and the esterification reaction are avoided, pollution sources such as waste water, waste gas and the like are greatly reduced, and the method is suitable for large-scale industrial production.
Detailed Description
The invention will be further described with reference to the following specific examples, but the scope of the invention is not limited thereto:
example 1, method for synthesizing a cyclosulfamide intermediate, the following steps are sequentially performed:
step 1), synthesis of 3-methyl-2-chloro-4-methylthiobenzoic acid methyl ester (II):
520g of dichloroethane is added into a 2L four-mouth bottle, mechanical stirring is started, the temperature is controlled to be 25+/-5 ℃, 146.7g (1.1 mol) of aluminum trichloride is added in batches, 104g (1.1 mol) of methyl chloroformate is added dropwise, and the temperature is kept for 1h after the dropwise addition; 172.7g (1 mol) of 2-methyl-3-chloroanisole (I) is added dropwise at the temperature of 25+/-5 ℃, the temperature is kept for 3 hours after the dripping, the reaction is finished, the temperature is controlled below 25 ℃, the reaction solution is poured into 690g of water for quenching, and the solution is separated. The organic phase was recovered under reduced pressure and the dichloroethane was stripped off to give 219.2g of methyl 3-methyl-2-chloro-4-methylthiobenzoate (II), 99% GC content and 95% yield.
Step 2), synthesis of methyl 3-methyl-2-chloro-4-methylsulfonyl benzoate (III)
219.2g of glacial acetic acid is added into a 2L four-mouth bottle, mechanical stirring is started, 0.95g (0.007 mol) of sodium tungstate and 219.2g (0.95 mol) of 3-methyl-2-chloro-4-methylthiobenzoic acid methyl ester (II) are added, the temperature is raised to 75 ℃, 230.7g (2.38 mol) of 35% hydrogen peroxide is started to be added dropwise, and the system temperature is controlled to be 75+/-5 ℃ in the dropwise adding process; and (5) after the dripping is finished, preserving heat and reacting for 3 hours. After the reaction, adding 438g of water and 219.2g of dichloroethane into the reaction system to quench, separating out an organic phase, extracting the aqueous phase with 219.2g of dichloroethane twice respectively, combining the organic phases obtained by extraction, recovering the dichloroethane under reduced pressure from the combined organic phases, and obtaining 244.6g of methyl 3-methyl-2-chloro-4-methylsulfonyl benzoate (III) with GC content of 99% and yield of 98%.
Step 3), synthesis of methyl 2-chloro-3-bromomethyl-4-methylsulfonylbenzoate (IV)
489.2g of dichloroethane are added into a 3L four-necked flask, mechanical stirring is started, 244.6g (0.93 mol) of 3-methyl-2-chloro-4-methylsulfonyl benzoate (III), 172.6g (1.02 mol) of 48% hydrobromic acid and 3.95g (0.024 mol) of azodiisobutyronitrile are added, and the temperature is raised to 80+/-3 ℃; 135.7g (1.40 mol) of 35 percent hydrogen peroxide is dripped, and the temperature of the system is controlled to be 80+/-3 ℃ in the dripping process; after the completion of the dropwise addition, the reaction is carried out for 2 hours at a temperature of between 30 and 5 ℃ after the completion of the reaction, the reaction solution is cooled to be separated, and the organic phase is washed with 244.6g of water. The dichloroethane is removed from the organic phase to dryness under normal pressure, the temperature is reduced to about 80 ℃, 244.6g of isopropanol is dripped, the temperature is reduced to 0 ℃ for crystallization, suction filtration is carried out, the filter cake is leached by the isopropanol, 302.1g of 2-chloro-3-bromomethyl-4-methylsulfonyl methyl benzoate (IV) is obtained after drying, the content is 99 percent, and the yield is 95 percent. The total yield of the reaction was 88%.
Example 2, method for synthesizing a cyclosulfamide intermediate, the following steps are sequentially performed:
step 1), synthesis of 3-methyl-2-chloro-4-methylthiobenzoic acid methyl ester (II):
the aluminum trichloride in step 1) of example 1 was changed to zinc chloride, the amount remaining unchanged at 1.1mol; the remainder being identical to example 1, step 1); 214.6g of methyl 3-methyl-2-chloro-4-methylthiobenzoate (II) was obtained, the GC content was 99%, and the yield was 93%.
Step 2), synthesis of methyl 3-methyl-2-chloro-4-methylsulfonyl benzoate (III)
214.5g of glacial acetic acid is added into a 2L four-mouth bottle, mechanical stirring is started, 0.93g (about 0.007 mol) of sodium tungstate and 214.5g (0.93 mol) of 3-methyl-2-chloro-4-methylthiobenzoic acid methyl ester (II) are added, the temperature is raised to 75 ℃, 225.9g (2.33 mol) of 35% hydrogen peroxide is started to be added dropwise, and the system temperature is controlled to be 75+/-5 ℃ in the dropwise adding process; and (5) after the dripping is finished, preserving heat and reacting for 3 hours. After the reaction, adding 429g of water and 214g of dichloroethane into the reaction system to quench, separating out an organic phase, extracting the aqueous phase with 214g of dichloroethane twice respectively, combining the extracted organic phases, recovering the dichloroethane under reduced pressure from the combined organic phases, and obtaining 239.4g of 3-methyl-2-chloro-4-methylsulfonyl methyl benzoate (III) with GC content of 99% and yield of 98%.
Step 3), synthesis of methyl 2-chloro-3-bromomethyl-4-methylsulfonylbenzoate (IV)
478.8g of dichloroethane was added to a 3L four-necked flask, mechanical stirring was started, 239.4g (0.91 mol) of methyl 3-methyl-2-chloro-4-methylsulfonyl benzoate (III), 169g (1.00 mol) of 48% hydrobromic acid, 3.87g (0.0236 mol) of azobisisobutyronitrile were added, and the temperature was raised to 80.+ -. 3 ℃; 132.8g (1.37 mol) of 35 percent hydrogen peroxide is dripped, and the temperature of the system is controlled to be 80+/-3 ℃ in the dripping process; after the completion of the dropwise addition, the reaction was carried out for 2 hours at a constant temperature, the reaction solution was cooled to 30.+ -. 5 ℃ and separated, and the organic phase was washed with 239.4g of water. The organic phase is subjected to normal pressure dichloroethane removal until the organic phase is dried, the temperature is reduced to about 80 ℃, 239.4g of methanol is dripped, the temperature is reduced to 0 ℃, crystallization is carried out, suction filtration is carried out, a filter cake is leached by methanol, 295.8g of 2-chloro-3-bromomethyl-4-methylsulfonyl methyl benzoate (IV) is obtained after drying, the content is 99%, and the yield is 96%. The total yield of the reaction was 87.5%.
Example 3, method for synthesizing a cyclosulfamide intermediate, the following steps are performed in order:
step 1), synthesis of 3-methyl-2-chloro-4-methylthiobenzoic acid methyl ester (II):
the "dichloroethane" in step 1) of example 1 was changed to "dichloromethane" and the amount was still 520g, the remainder being identical to step 1) of example 1; 221.5g of methyl 3-methyl-2-chloro-4-methylthiobenzoate (II) was obtained, the GC content was 99%, and the yield was 96%.
Step 2), synthesis of methyl 3-methyl-2-chloro-4-methylsulfonyl benzoate (III)
221.5g of glacial acetic acid is added into a 2L four-mouth bottle, mechanical stirring is started, 0.96g (about 0.0072 mol) of sodium tungstate and 221.5g (0.96 mol) of 3-methyl-2-chloro-4-methylthiobenzoic acid methyl ester (II) are added, the temperature is raised to 75 ℃, 233.1g (2.4 mol) of 35% hydrogen peroxide is dripped, and the system temperature is controlled to be 75+/-5 ℃ in the dripping process; and (5) after the dripping is finished, preserving heat and reacting for 3 hours. After the reaction, 442g of water and 221.5g of methylene dichloride are added into the reaction system to quench, an organic phase is separated, the aqueous phase is extracted twice with 221.5g of methylene dichloride, the extracted organic phases are combined, the methylene dichloride is recovered under reduced pressure from the combined organic phases, and the methylene dichloride is stripped to obtain 249.7g of methyl 3-methyl-2-chloro-4-methylsulfonyl benzoate (III), the GC content of which is 98.5%, and the yield is 99%.
Step 3), synthesis of methyl 2-chloro-3-bromomethyl-4-methylsulfonylbenzoate (IV)
500g of methylene chloride is added into a 3L four-mouth bottle, mechanical stirring is started, 249.7g (0.95 mol) of 3-methyl-2-chloro-4-methylsulfonyl methyl benzoate (III), 192.2g (1.14 mol) of 48% hydrobromic acid and 4.4g (0.027 mol) of azodiisobutyronitrile are added, and the temperature is raised to 37+/-2 ℃; 157g (1.62 mol) of 35% hydrogen peroxide is added dropwise, and the temperature of the system is controlled at 36+/-2 ℃ in the dropping process; after the completion of the dropwise addition, the reaction is carried out for 4 hours at a temperature of between 30 and 2 ℃ after the completion of the reaction, the reaction solution is cooled to be separated, and the organic phase is washed with 250g of water. The organic phase is subjected to normal pressure methylene chloride removal until the organic phase is dried, the temperature is reduced to about 35 ℃, 250g of methanol is dripped, the temperature is reduced to 0 ℃, crystallization is carried out, suction filtration is carried out, a filter cake is leached by methanol, 285.4g of 2-chloro-3-bromomethyl-4-methylsulfonyl methyl benzoate (IV) is obtained after drying, the content is 99%, and the yield is 91%. The total yield of the reaction was 86%.
Finally, it should also be noted that the above list is merely a few specific embodiments of the present invention. Obviously, the invention is not limited to the above embodiments, but many variations are possible. All modifications directly derived or suggested to one skilled in the art from the present disclosure should be considered as being within the scope of the present invention.
Claims (6)
1. The synthesis method of the cyclosulfamide intermediate is characterized by comprising the following steps of:
1) 2-methyl-3-chloranisole is used as a raw material to carry out Friedel-crafts acylation reaction with methyl chloroformate to obtain 3-methyl-2-chloro-4-methylthio methyl benzoate;
2) Oxidizing 3-methyl-2-chloro-4-methylthio methyl benzoate to obtain 3-methyl-2-chloro-4-methylsulfonyl methyl benzoate;
3) And brominating the 3-methyl-2-chloro-4-methylsulfonyl benzoate to obtain the target product, namely the 2-chloro-3-bromomethyl-4-methylsulfonyl benzoate.
2. The method for synthesizing a cyclosulfamide intermediate according to claim 1, wherein:
step 1), synthesis of 3-methyl-2-chloro-4-methylthiobenzoic acid methyl ester:
adding a catalyst I into an organic solvent I at 20-30 ℃, adding methyl chloroformate, adding 2-methyl-3-chloroanisole, keeping the temperature at 20-30 ℃ for reaction until the reaction is finished, quenching the reaction liquid, separating the liquid, and recovering the solvent to obtain 3-methyl-2-chloro-4-methylthio methyl benzoate;
the 2-methyl-3-chloroanisole: methyl chloroformate: the mol ratio of the catalyst I is 1:1.05-1.2: 1.05 to 1.2;
step 2), synthesizing 3-methyl-2-chloro-4-methylsulfonyl methyl benzoate:
mixing a solvent II, a catalyst II and 3-methyl-2-chloro-4-methylthio methyl benzoate, dropwise adding hydrogen peroxide at the temperature of 35-80 ℃, keeping the temperature of 35-80 ℃ for reaction until the reaction is finished, quenching the reaction liquid, separating the liquid, and recovering the solvent to obtain 3-methyl-2-chloro-4-methylsulfonyl methyl benzoate;
3-methyl-2-chloro-4-methylsulfanyl benzoic acid methyl ester: hydrogen peroxide: the mol ratio of the catalyst II is 1:2-4: 0.005-0.01;
the mass concentration of the hydrogen peroxide is 10-35%;
step 3), synthesizing 2-chloro-3-bromomethyl-4-methylsulfonyl benzoate:
mixing a solvent III, 3-methyl-2-chloro-4-methylsulfonyl methyl benzoate, hydrobromic acid and a catalyst III, dropwise adding hydrogen peroxide, carrying out heat preservation reaction until the reaction is finished, cooling to 25-35 ℃, separating liquid, washing with water, recovering the solvent, and recrystallizing with the solvent to obtain 3-bromomethyl-2-chloro-4-methylsulfonyl methyl benzoate;
3-methyl-2-chloro-4-methylsulfonyl benzoate: hydrogen bromide: hydrogen peroxide: the molar ratio of the catalyst III is 1:1.0 to 1.5:1.5 to 2:0.02 to 0.05;
the mass concentration of hydrogen bromide in hydrobromic acid is 10-48%; the mass concentration of the hydrogen peroxide is 10-35%.
3. A method of synthesizing a cyclosulfamide intermediate according to claim 2, wherein:
in the step 1):
the catalyst I is at least any one of the following: aluminum trichloride, zinc chloride and ferric trichloride;
in the step 2):
the catalyst II is sodium tungstate;
in the step 3):
the catalyst III is azodiisobutyronitrile or other free radical initiator.
4. A method of synthesizing a cyclosulfamide intermediate according to claim 3, wherein:
in the step 1):
the organic solvent I is chloroform, dichloromethane and dichloroethane;
the dosage of the organic solvent I is 1 to 5 times of the mass of the 2-methyl-3-chloroanisole;
the quenching method comprises the following steps: controlling the temperature below 25 ℃, pouring the reaction solution into water, and quenching;
the temperature of the dropwise adding of the 2-methyl-3-chloranisole is 20-30 ℃.
5. The method for synthesizing a cyclosulfamide intermediate according to claim 4, wherein:
in the step 2):
solvent II is at least any one of the following: methanol, ethanol, isopropanol, dichloroethane, dichloromethane, toluene, acetic acid;
the quenching water consumption of the 3-methyl-2-chloro-4-methylthio methyl benzoate is 1-2 times of the mass of the solvent II, the quenching solvent is one of dichloroethane and toluene, and the consumption is 1-1.5 times of the mass of the solvent II.
6. The method for synthesizing a cyclosulfamide intermediate according to claim 5, wherein:
in the step 3), the solvent III is carbon tetrachloride, chloroform, methylene dichloride or dichloroethane; dropwise adding hydrogen peroxide at room temperature to reflux the solvent; the solvent used for recrystallization is methanol, ethanol, isopropanol.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2011079766A (en) * | 2009-10-06 | 2011-04-21 | Sumitomo Seika Chem Co Ltd | Method for preparing 4-halophenyl alkyl sulfone |
| CN109678767A (en) * | 2018-12-27 | 2019-04-26 | 浙江中山化工集团股份有限公司 | A kind of synthesis technology of herbicide tembotrions |
| CN114787122A (en) * | 2019-08-13 | 2022-07-22 | 威娜德国有限责任公司 | Novel polycondensation synthesis of 2-methoxymethyl-p-phenylenediamine |
-
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2011079766A (en) * | 2009-10-06 | 2011-04-21 | Sumitomo Seika Chem Co Ltd | Method for preparing 4-halophenyl alkyl sulfone |
| CN109678767A (en) * | 2018-12-27 | 2019-04-26 | 浙江中山化工集团股份有限公司 | A kind of synthesis technology of herbicide tembotrions |
| CN114787122A (en) * | 2019-08-13 | 2022-07-22 | 威娜德国有限责任公司 | Novel polycondensation synthesis of 2-methoxymethyl-p-phenylenediamine |
Non-Patent Citations (1)
| Title |
|---|
| 余玉，等: "玉米田除草剂环磺酮的合成", 农药, vol. 56, no. 5, pages 326 - 327 * |
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