Ethyl chloroformate → Ethyl 4-cyano-1-((2-(trimethylsilyl)ethoxy)-methyl)-1H-imidazole-2-carboxylate

Temperature

-50 °C

A 12-L, four-neck, round-bottom flask equipped with a mechanical stirrer, a temperature probe, and an addition funnel with a nitrogen inlet was charged with 2-bromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-4-carbonitrile [390 g, 1.29 mol, as prepared in the previous step) and anhydrous tetrahydrofuran (4.0 L). Agitation was initiated and the reaction mixture was cooled to −50° C. using a dry ice/acetone bath. Isopropylmagnesium chloride (2.0 M in THF, 760 mL, 1.52 mol) was added through the addition funnel over 30 min to maintain the internal temperature below −40° C. The reaction was stirred for a further 30 min at −43° C., after which time it was cooled to −78° C. Ethyl chloroformate (210 mL, 2.20 mol) was added through the addition funnel over 10 min to maintain the internal temperature below −60° C. The reaction was stirred for a further 40 min at −70° C., at which point the dry ice/acetone bath was removed and the reaction was allowed to warm to ambient temperature over 1.5 h. The reaction mixture was cooled in an ice bath to 0° C. and quenched by the slow addition of satd ammonium chloride solution (1.8 L) at such a rate that the internal temperature was maintained below 10° C. The reaction mixture was transferred into a 12-L separatory funnel, diluted with ethyl acetate (4.0 L), and the layers were separated. The organic layer was washed with brine (2×2.0 L) and concentrated under reduced pressure at 35° C. to give a brown oil. The crude oil was dissolved in dichloromethane (300 mL) and purified by chromatography (15×22 cm, 1.5 kg of silica gel, 10:1 to 4:1 heptane/ethyl acetate) to give a yellow oil, which was dissolved in EtOAc (100 mL), diluted with heptane (2.0 L), and stored in a refrigerator for 5 h. The resulting slurry was filtered to give the title compound as a crystalline white solid (141 g, 37%). The 1H and 13C NMR spectra were consistent with the assigned structure.

1. temperatureto maintain the internal temperature below −40° C
2. temperatureafter which time it was cooled to −78° C
3. temperatureto maintain the internal temperature below −60° C
4. customwas removed
5. temperatureto warm to ambient temperature over 1.5 h
6. temperatureThe reaction mixture was cooled in an ice bath to 0° C.
7. customquenched by the slow addition of satd ammonium chloride solution (1.8 L) at such a rate that the internal temperature
8. temperaturewas maintained below 10° C
9. customThe reaction mixture was transferred into a 12-L separatory funnel
10. additiondiluted with ethyl acetate (4.0 L)
11. customthe layers were separated
12. washThe organic layer was washed with brine (2×2.0 L)
13. concentrationconcentrated under reduced pressure at 35° C.
14. customto give a brown oil
15. custompurified by chromatography (15×22 cm, 1.5 kg of silica gel, 10:1 to 4:1 heptane/ethyl acetate)
16. customto give a yellow oil, which
17. waitstored in a refrigerator for 5 h
18. filtrationThe resulting slurry was filtered

ORD record

ord-611e202de3ab48a89bbf603c37318434

Source dataset

uspto-grants-2010_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07645755B2