Potassium Carbonate → (+)-4-Cyclopropyl-9-(1-(2,6-difluoro-4-(quinolin-7-yl)phenyl)-2-hydroxyethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one

Temperature

80 °C

A solution of crude (80% purity) 2-(4-bromo-2,6-difluorophenyl)-2-(4-cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)ethyl acetate (0.361 mmol) in 1,4-dioxane (2 mL) was treated with 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (0.397 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.018 mmol), and 2M aq potassium carbonate (1.083 mmol). The reaction vessel was purged with nitrogen and sealed, and the mixture irradiated in a Biotage Initiator Microwave at 120° C. for 15 min. The reaction was cooled at which point additional portions of 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (0.08 mmol) and PdCl2(dppf)-CH2Cl2 adduct (0.006 mmol) were added. The reaction vessel was purged with nitrogen and sealed, and the mixture irradiated in a Biotage Initiator Microwave at 120° C. for 5 min. The black reaction mixture was then concentrated to minimal volume (˜0.5 mL) under a stream of nitrogen at which point it was diluted with a mixture of ethanol and water (2 mL, 1:1). This mixture was stirred in an oil bath at 80° C. overnight. The resulting solution was concentrated to dryness under a stream of nitrogen and then diluted with water (50 mL) and brine (20 mL). This aqueous mixture was extracted four times with ethyl acetate. The combined organic layers were treated with Silicycle Si-thiol (50 mg), dried over sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by silica gel chromatography (0-7% methanol/dichloromethane) and chiral HPLC (Chromegachiral CC4, methanol) followed by lyophilization from water (w/25% acetonitrile) afforded the title compound as a white solid in >99% ee (29 mg, 15% yield). MS(ES)+ m/e 494.1 [M+H]+. αD=+4 deg (c=0.06, methanol).

1. customThe reaction vessel was purged with nitrogen
2. customsealed
3. customthe mixture irradiated in a Biotage Initiator Microwave at 120° C. for 15 min
4. additionwere added
5. customThe reaction vessel was purged with nitrogen
6. customsealed
7. customthe mixture irradiated in a Biotage Initiator Microwave at 120° C. for 5 min
8. customThe black reaction mixture
9. concentrationwas then concentrated to minimal volume (˜0.5 mL) under a stream of nitrogen at which point it
10. additionwas diluted with a mixture of ethanol and water (2 mL, 1:1)
11. concentrationThe resulting solution was concentrated to dryness under a stream of nitrogen
12. additiondiluted with water (50 mL) and brine (20 mL)
13. extractionThis aqueous mixture was extracted four times with ethyl acetate
14. additionThe combined organic layers were treated with Silicycle Si-thiol (50 mg)
15. dry with materialdried over sodium sulfate
16. filtrationfiltered
17. concentrationconcentrated in vacuo
18. customPurification of the residue by silica gel chromatography (0-7% methanol/dichloromethane) and chiral HPLC (Chromegachiral CC4, methanol)

ORD record

ord-357cabc7c19547909a77f38c8d74521e

Source dataset

uspto-grants-2015_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09084794B2