Sodium borohydride → Tert-butyl 3-hydroxycycloheptylcarbamate

To a solution of tert-butyl 3-oxocycloheptylcarbamate (31.09 g, 137 mmol) in methanol (454 mL) was added sodium borohydride (15.52 g, 410 mmol) portion-wise over ˜10 minutes with mixing. The resulting solution was stirred for 2 h at room temperature and then diluted with water (200 mL). The methanol was removed in-vacuo and the resulting aqueous mixture was diluted further with 500 mL ethyl acetate and 100 mL saturated aqueous sodium bicarbonate. The layers were separated and the aqueous layer back-extracted with 2×1000 mL ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated to an oil that was purified by silica gel chromatography (0-50% ethyl acetate in hexanes). Product containing fractions were concentrated to afford tert-butyl 3-hydroxycycloheptylcarbamate (21.1 g, 92 mmol, 67.3% yield). MS (ESI) m/z 230.3 [M+H]+. The above two reactions were repeated starting with 9.52 g cyclohept-2-enone and yielding 9.27 g of tert-butyl 3-hydroxycycloheptylcarbamate. The two batches of tert-butyl 3-hydroxycycloheptylcarbamate were then combined. 29.2 g of the combined material was separated into the 4 constituent stereoisomers (two diastereomers and their corresponding enantiomers) by preparative chiral SFC utilizing multiple injections over a series of 3 separate columns. First column: ChiralPak IC-H, 250×30 mm I.D., isocratic 15% ethanol in CO2, 38° C. Second column: ChiralCel OJ-H, 250×30 mm I.D., isocratic 10% isopropanol in CO2, 38° C. Third column: ChiralPak AD-H, 250×50 mm I.D., isocratic 20% isopropanol in CO2, 38° C. The separated isomers were characterized on an analytical scale Phenomenex Lux Amylose-2 column, 250×4.6 mm I.D., isocratic 15% ethanol in CO, (10 min run time) and labeled as Intermediate 1 to Intermediate 4.

1. additionwith mixing
2. customThe methanol was removed in-vacuo
3. additionthe resulting aqueous mixture was diluted further with 500 mL ethyl acetate and 100 mL saturated aqueous sodium bicarbonate
4. customThe layers were separated
5. extractionthe aqueous layer back-extracted with 2×1000 mL ethyl acetate
6. dry with materialThe combined organic layers were dried over anhydrous magnesium sulfate
7. filtrationfiltered
8. concentrationconcentrated to an oil that
9. customwas purified by silica gel chromatography (0-50% ethyl acetate in hexanes)
10. additionProduct containing fractions
11. concentrationwere concentrated

ORD record

ord-31aa18df1bd24d1e872a39599678182d

Source dataset

uspto-grants-2015_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09139534B2