5-Bromo-1-methyl-1H-imidazole → (1-Methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanone

Temperatur

5.300000190734863 °C

To a 3 L 4-neck flask equipped with an overhead stirrer, nitrogen bubbler, and thermocouple was added 5-bromo-1-methyl-1H-imidazole (47.96 g, 297.9 mmol), followed by THF (537 mL). To this room temperature solution was added isopropylmagnesium chloride/lithium chloride complex [1.3 M] (246.8 mL, 320.8 mmol) (addition temperature maintained between 16.6 and 25° C.) to afford a milky suspension and the reaction was stirred for 60 minutes and then cooled to 5.3° C. in an ice bath. To this mixture was added a solution of N-methoxy-N-methyl-6-(trifluoromethyl)nicotinamide (53.66 g, 229.14 mmol, Intermediate 15, step b) in THF (268.3 mL) (addition temperature between 5.3 and 5.6° C.) to afford an orange mixture. After addition, the reaction was warmed to room temperature over 2 hours. After stirring at room temperature for 18 hours, THF (200 mL) was added and the reaction was stirred for 2 hours. The reaction was then cooled to 4° C. with an ice bath and carefully quenched with 2N HCl to a pH=7, quenching temperature reached 12° C. The mixture was diluted with ethyl acetate (500 mL), phase split and the organic layer was washed with brine (2×200 mL) and dried over sodium sulfate, filtered, and the solvent was removed. Hot ether was added and then filtered to give the title compound as a solid.

1. customTo a 3 L 4-neck flask equipped with an overhead stirrer
2. additionTo this room temperature solution was added isopropylmagnesium chloride/lithium chloride complex [1.3 M] (246.8 mL, 320.8 mmol) (addition temperature maintained between 16.6 and 25° C.)
3. customto afford a milky suspension
4. customto afford an orange mixture
5. additionAfter addition
6. temperaturethe reaction was warmed to room temperature over 2 hours
7. stirringAfter stirring at room temperature for 18 hours
8. stirringthe reaction was stirred for 2 hours
9. temperatureThe reaction was then cooled to 4° C. with an ice bath
10. customcarefully quenched with 2N HCl to a pH=7
11. customquenching temperature
12. customreached 12° C
13. additionThe mixture was diluted with ethyl acetate (500 mL), phase
14. customsplit
15. washthe organic layer was washed with brine (2×200 mL)
16. dry with materialdried over sodium sulfate
17. filtrationfiltered
18. customthe solvent was removed
19. additionHot ether was added
20. filtrationfiltered

ORD-Eintrag

ord-db790b6364ca4b8f8a1a98ebfa498822

Quelldatensatz

uspto-grants-2016_04

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US09309222B2