Pyridine → HCID 22921552, compound

Temperature

0 °C

Under a nitrogen atmosphere, a stirred solution of 0.4 gram (0.0009 mole) of 2-[2-trifluoromethyl-5-fluoro-6-(1-methyl-6-trifluoromethyluracil-3-yl)benzimidazol-1-yl]propan-1-ol (Compound 7--prepared as in Step A of Example 8) in 10 mL of diethyl ether was cooled in an ice-water bath, and 0.07 mL (0.0009 mole) of pyridine was added at a rate to maintain the reaction mixture temperature below 5° C. Upon completion of the addition, 0.1 mL (0.0013 mole) of thionyl chloride was added dropwise from a syringe. Upon completion of the addition, the reaction mixture stirred at about 0° C. for 30 minutes. After this time, the reaction mixture was allowed to warm to ambient temperature, where it stirred for about 18 hours. Analysis of the reaction mixture by thin layer chromatography (TLC) indicated the reaction was not complete. The reaction mixture was concentrated under reduced pressure to a residue. The residue was dissolved in methylene chloride, and 0.1 mL of thionyl chloride and 0.07 mL of pyridine were added. The mixture was warmed to reflux, where it stirred for about 24 hours. Analysis of the reaction mixture using TLC indicated the reaction was still not complete. Additional equivalents of thionyl chloride and pyridine were were added to the reaction mixture each day for a period of five days, as the reaction mixture stirred at reflux. At the end of five days the reaction mixture was allowed to cool to ambient temperature, where it stirred for two days. The reaction mixture was then poured into water and extracted with ethyl acetate. The extract was washed with an aqueous solution saturated with sodium chloride and dried with sodium sulfate. The mixture was filtered, and the filtrate concentrated under reduced pressure, yielding about 0.3 gram of 1-methyl-3-[1-(1-methyl-2-chloroethyl)-2-trifluoromethyl-5-fluorobenzimidazol-6-yl]-6-trifluoromethyluracil, mp 93°-95° C. The NMR spectrum was consistent with the proposed structure.

1. temperatureto maintain the reaction mixture temperature below 5° C
2. additionwas added dropwise from a syringe
3. additionUpon completion of the addition
4. temperatureto warm to ambient temperature
5. stirringwhere it stirred for about 18 hours
6. concentrationThe reaction mixture was concentrated under reduced pressure to a residue
7. dissolutionThe residue was dissolved in methylene chloride
8. addition0.1 mL of thionyl chloride and 0.07 mL of pyridine were added
9. temperatureThe mixture was warmed
10. temperatureto reflux
11. stirringwhere it stirred for about 24 hours
12. additionAdditional equivalents of thionyl chloride and pyridine were were added to the reaction mixture each day for a period of five days, as the reaction mixture
13. stirringstirred
14. temperatureat reflux
15. customAt the end of five days
16. temperatureto cool to ambient temperature
17. stirringwhere it stirred for two days
18. additionThe reaction mixture was then poured into water
19. extractionextracted with ethyl acetate
20. washThe extract was washed with an aqueous solution saturated with sodium chloride
21. dry with materialdried with sodium sulfate
22. filtrationThe mixture was filtered
23. concentrationthe filtrate concentrated under reduced pressure

ORD record

ord-272d15f4dbd44f36b2a8e5ed808d357d

Source dataset

uspto-grants-1997_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US05661108