反应详情

A mixture of 94.82 g (0.5 mole) of 2-chloro-6-fluorobenzthioamide, 50 mL (0.525 mole) of dimethyl sulfate, and 800 mL of 1,2-dichloroethane was heated at reflux temperature for 1 h. LC analysis indicated complete conversion to the thioimidate. The reaction solution was cooled to RT with ice-bath cooling, and the thioimidate salt precipitated from the solution. To the thick slurry was added 100 mL (1.25 mole) of pyridine. The salts instantly dissolved into solution, followed by immediate precipitation of pyridine salts. After further cooling to 10° C., 125 g (0.5 mole) of 3,4,5-trichloro-2-thiophenecarbonyl chloride dissolved in 200 mL of 1,2-dichloroethane was added in three portions. Temperature of the reaction mixture rose to 20° C. during each addition and was allowed to cool back to 10° C. before the next addition. The reaction mixture was allowed to stir at RT for 0.5 h. LC analysis indicated major acylated thioimidate and <2% area of starting thioimidate. To the slurry was added 1.0 L of water and the layers separated. LC internal standard analysis of the organics indicated a 94% in-pot yield of the acylated intermediate. The 1,2-dichloroethane solution was heated to 70° C., and a solution of 40 mL (0.75 mole) of methylhydrazine in 60 mL of water was added via a pump over 20 min. The temperature of the reaction mixture was maintained between 70° and 73° C. The solution was heated an additional 2 h, when GC analysis indicate no remaining acylated intermediate and a 38:1 ratio of desired product/off-isomer. The reaction mixture was cooled to RT, and 500 mL of octane followed by 1 L of 0.5 N LiOH was added. After stirring for 10 min, the layers were separated. The organic solution was then stirred with 750 mL of a 2% bleach solution for 0.25 h to remove remaining mercaptan compounds. The temperature of the mixture rose to 31° C. during this reaction. The layers were separated and upon concentration of the 1,2-dichloroethane on a roto-evaporator, a tan sandy precipitate formed. This solid was filtered and exposed to vacuum oven drying at 40° C. to give 144.8 g (73% wt) of the desired product as a tan crystalline powder. GC analysis indicated <0.2% area of the off-isomer, and LC internal standard analysis indicated a 98% purity, giving an overall isolated 72% yield of 1-methyl-3-(2-chloro-6-fluoro)phenyl-5-(3,4,5-trichloro-2-thienyl)-1H-1,2,4-triazole.

1. temperaturewas heated
2. temperatureat reflux temperature for 1 h
3. temperaturecooling
4. customthe thioimidate salt precipitated from the solution
5. dissolutionThe salts instantly dissolved into solution
6. customfollowed by immediate precipitation of pyridine salts
7. temperatureAfter further cooling to 10° C.
8. additionwas added in three portions
9. additionTemperature of the reaction mixture rose to 20° C. during each addition
10. temperatureto cool back to 10° C. before the next addition
11. customthe layers separated
12. temperatureThe 1,2-dichloroethane solution was heated to 70° C.
13. temperatureThe temperature of the reaction mixture was maintained between 70° and 73° C
14. temperatureThe solution was heated an additional 2 h
15. temperatureThe reaction mixture was cooled to RT
16. additionwas added
17. stirringAfter stirring for 10 min
18. customthe layers were separated
19. stirringThe organic solution was then stirred with 750 mL of a 2% bleach solution for 0.25 h
20. customto remove
21. customThe temperature of the mixture rose to 31° C. during this reaction
22. customThe layers were separated and upon concentration of the 1,2-dichloroethane on a roto-evaporator
23. customa tan sandy precipitate formed
24. filtrationThis solid was filtered
25. customdrying at 40° C.