Methyl iodide → 121929-46-2

Temperature

35 °C

A solution of 5-chloro-3-[(1H-imidazol-1-yl)methyl]-1,2-benzisoxazole (500 g, 2.14 moles) in dimethylformamide (3.5 L) is cooled to -35° C. (dry ice/isopropanol bath) and is subsequently added, all at once, to a precooled (-35° C.) solution of potassium t-butoxide (266 g, 2.37 moles) in dimethylformamide (3.5 L). A deep red color develops immediately. The mixture is stirred at 35° C. for 5 minutes and is then cooled to -55° C. over a period of 10 minutes. At this point, iodomethane (433 g, 3.05 moles) is added all at once. There is an exotherm to -22° C. and then the temperature begins to decrease. At -26° C. the reaction mixture decolorizes, solid potassium bromide separates and there is a mild exotherm to -22° C. which is maintained for 5 minutes. The mixture subsequently cools quickly to -55° C. and stirring is continued for 30 minutes at this temperature. The cooling bath is then removed and the reaction temperature is allowed to rise to 0° C. over a period of 1.5 hours. The reaction mixture is then poured into water (35 L) and the mixture is extracted with ethyl acetate (20 L). The layers are separated and the organic solution is washed with water (6×6 L), dried over anhydrous sodium sulphate (5 Kg), filtered, and evaporated in vacuo. The residual oil is digested with petroleum ether (b.p 40-60° C.) (2×2 L) at room temperature, and the solvent is then decanted and discarded. The digestion process is repeated with ether (4× 3 L) and the combined ethereal extracts are dried over anhydrous sodium sulfate (500 g) and filtered. The filtrate is acidified with ethereal hydrogen chloride (500 mL, 6 N) and the suspension cake is washed with ether (2×500 mL) and the product is digested in refluxing acetone (2 L) for 1 hour. The suspension is cooled to room temperature and filtered. The filter cake is washed with acetone (2×500 mL) and ether (2×500 mL) and the product is dried for 18 hours at 60° C./9 mm Hg to afford 5-chloro-3-[1-(1H-imidazol-1-yl)ethyl]1,2-benzisoxazole hydrochloride, m.p. 161-166° C., of formula IIa wherein R1 is methyl, R3 is 5-chloro, R2 and R4 -R6 are hydrogen.

1. additionis subsequently added
2. temperatureis then cooled to -55° C. over a period of 10 minutes
3. customto -22° C.
4. customAt -26° C.
5. customto -22° C.
6. temperatureis maintained for 5 minutes
7. customsubsequently cools quickly to -55° C.
8. stirringstirring
9. waitis continued for 30 minutes at this temperature
10. customThe cooling bath is then removed
11. waitto rise to 0° C. over a period of 1.5 hours
12. additionThe reaction mixture is then poured into water (35 L)
13. extractionthe mixture is extracted with ethyl acetate (20 L)
14. customThe layers are separated
15. washthe organic solution is washed with water (6×6 L)
16. dry with materialdried over anhydrous sodium sulphate (5 Kg)
17. filtrationfiltered
18. customevaporated in vacuo
19. customis digested with petroleum ether (b.p 40-60° C.) (2×2 L) at room temperature
20. customthe solvent is then decanted
21. dry with materialthe combined ethereal extracts are dried over anhydrous sodium sulfate (500 g)
22. filtrationfiltered
23. washthe suspension cake is washed with ether (2×500 mL)
24. temperaturein refluxing acetone (2 L) for 1 hour
25. temperatureThe suspension is cooled to room temperature
26. filtrationfiltered
27. washThe filter cake is washed with acetone (2×500 mL) and ether (2×500 mL)
28. customthe product is dried for 18 hours at 60° C./9 mm Hg

ORD record

ord-a1fedb3324ae4770b18d3de4519afb04

Source dataset

uspto-grants-1990_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US04957931