The mainstream industrial synthesis route for tsulfuron (Tembotrione)

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The main industrial synthesis route for tembotrione is as follows: 3-chloro-2-methylaniline → diazotization → methanethiolation → Fuchs acylation → oxidation → halohydrin formation → esterification → bromination → etherification → hydrolysis → acyl chloridation → condensation and transposition → purification. This involves 10 steps in total, with an overall yield of approximately 7.6% and a purity of ≥99%. I. Core synthesis route (industrial mainstream) 1. Diazotization-methanethiolation (intermediate 1) – Raw materials: 3-chloro-2-methylaniline, sodium nitrite, sodium methanethiolate – Conditions: 0–5°C, acidic (HCl) ； After diazotization, sodium methanethiolate is added dropwise – Product: 2-chloro-6-methanethiolotoluene (purity ≥95%) 2. Friedel-Crafts acylation (Intermediate 2) – Raw materials: Intermediate 1, acetyl chloride, anhydrous AlCl3 – Conditions: dichloroethane, 25–40°C – Product: 2-chloro-3-methyl-4-methanethiophenone 3. Oxidation (Intermediate 3) – Raw materials: Intermediate 2, hydrogen peroxide (30%), sodium tungstate as catalyst – Conditions: methanol/water, 40–60℃ ； Sulfur oxide ether → Sulfone – Product: 2-chloro-3-methyl-4-methanesulfonylphenylacetone 4. Chloroform reaction (Intermediate 4) – Raw materials: Intermediate 3, sodium hypochlorite (10%), NaOH – Conditions: Chloroform/water, 50–70℃ ； Deacetylation to carboxylic acid – Product: 2-chloro-3-methyl-4-methanesulfonylbenzoic acid 5. Esterification (Intermediate 5) – Raw materials: Intermediate 4, methanol, concentrated sulfuric acid – Conditions: Reflux for 6–8 hours ； Distillation under reduced pressure to remove methanol – Product: Methyl 2-chloro-3-methyl-4-methanesulfonylbenzoate 6. Radical bromination (Intermediate 6) – Raw materials: Intermediate 5, NBS, BPO (initiator) – Conditions: Carbon tetrachloride, reflux ； Methyl → Bromomethyl – Product: Methyl 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate 7. Esterification (Intermediate 7) – Raw materials: Intermediate 6, sodium trifluoroethoxide (prepared in-house) – Conditions: DMF, 60–80℃ ； Williamson ether synthesis – Product: Methyl 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-mesylbenzoate 8. Hydrolysis (Intermediate 8, key benzoic acid) – Raw materials: Intermediate 7, aqueous NaOH solution – Conditions: Methanol/water, reflux ； Ester hydrolysis → Carboxylic acid – Product: 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-mesylbenzoic acid (purity ≥98%) 9. Acyl chlorination (intermediate 9) – Raw materials: Intermediate 8, thionyl chloride (in excess) – Conditions: Dichloroethane, reflux ； Depressurization to remove excess SOCl₂ – Product: corresponding benzoyl chloride (used directly in the next step, without isolation). 10. Condensation–transposition (crude cyclosulfone) – Raw materials: intermediate 9, 1,3-cyclohexanedione, acid scavenger, transposition agent – Traditional method: transposition catalyzed by **acetone cyanohydrin (highly toxic)** – New process: composite bases (such as DBN/phosphazine bases) are used as alternatives, offering greater safety – Conditions: dichloroethane, 20–40℃ ； Condensation first, then transposition – Product: crude cyclic sulfone. 11. Purification (active ingredient) – Acidification → washing → concentration → recrystallization (methanol/water or toluene) – Purity: ≥99% (HPLC) ； Overall yield: 7–8%. II. Key process parameters – Bromination: NBS/BPO is used as a substitute for liquid bromine, offering higher safety and better selectivity. - Translocation: Highly toxic to traditional acetone cyanohydrin ； The new process uses a composite organic base, resulting in fewer waste streams and ease of industrialization. - Waste treatment: Fluorine/chlorine-containing wastewater requires neutralization + extraction + biological treatment ； Waste incineration treatment. III. Alternative route (patent optimization) – Route A: Starting from 2,6-dichlorotoluene, proceed with methanethiolation → acylation → oxidation → halocarbonyl formation → esterification → bromination → etherification → hydrolysis → acyl chlorination → condensation. - Route B: Sodium trifluoroethanolate is used in place of potassium tert-butoxide, resulting in a yield of 10–12% and being more environmentally friendly. IV. Industrialization costs and safety – Raw material costs: trifluoroethanol, NBS, and 1,3-cyclohexanedione account for a large proportion. - Safety risk: Bromination and acyl chlorination are highly exothermic ； Trifluoroethanol is flammable ； Traditional transposition agents are highly toxic. - Environmental pressure: Fluorine-containing organic wastewater, salt residues, and VOCs require strict treatment. V. Quality standards (active ingredient) – Appearance: White to off-white crystalline powder. - Purity: ≥99.0% (HPLC). - Moisture: ≤0.5% ； Melting point: about 125°C.