Cyclobutanone → HCID 58513750, compound

Temperature

0 °C

To a cold (−10° C.) solution of 5-bromo-2-iodopyridine (3.0 g, 10.57 mmol) in tetrahydrofuran (35 mL) was added isopropylmagnesium chloride (5.55 ml, 11.10 mmol, 2 M solution in tetrahydrofuran) dropwise over 10 minutes. The reaction was allowed to warm to 0° C. over 1 hour and then cooled to −10° C. Cyclobutanone (0.792 ml, 10.57 mmol) was added dropwise, and the reaction was warmed to 15° C. over 1 hour to give a homogenous solution. The reaction was cooled to −78° C. (precipitate formed). The reaction was warmed to ˜0° C. and diluted with an additional 50 mL tetrahydrofuran to dissolve the precipitate. The reaction was cooled to −78° C., and n-butyllithium (4.23 ml, 10.57 mmol, 2.5 M in hexane) was added dropwise. The reaction was stirred for 0.5 hours, and tributyltin chloride (2.87 mL, 10.57 mmol) was added dropwise. The reaction was stirred at −78° C. for 15 minutes, and was then quenched by the dropwise addition of saturated aqueous sodium bicarbonate solution. The layers were separated, and the aqueous layer was extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with water, brine, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with a gradient of 0 to 10% ethyl acetate in hexane, to give the title compound. MS ESI(+) m/z 440.2 [M+H]+.

1. temperaturecooled to −10° C
2. temperaturethe reaction was warmed to 15° C. over 1 hour
3. customto give a homogenous solution
4. temperatureThe reaction was cooled to −78° C.
5. custom(precipitate formed)
6. temperatureThe reaction was warmed to ˜0° C.
7. dissolutionto dissolve the precipitate
8. temperatureThe reaction was cooled to −78° C.
9. stirringThe reaction was stirred at −78° C. for 15 minutes
10. customwas then quenched by the dropwise addition of saturated aqueous sodium bicarbonate solution
11. customThe layers were separated
12. extractionthe aqueous layer was extracted with ethyl acetate (3×30 mL)
13. washThe combined organic layers were washed with water, brine
14. dry with materialdried with anhydrous sodium sulfate
15. filtrationfiltered
16. concentrationconcentrated under reduced pressure
17. customThe residue was purified by chromatography on silica gel
18. washeluting with a gradient of 0 to 10% ethyl acetate in hexane

ORD record

ord-29516a9ac83740bc8d4a54511b42d05b

Source dataset

uspto-grants-2014_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08691810B2