Methanol → (1S)-1-(3,5-difluorophenyl)-1-[1-(diphenylmethyl)azetidin-3-yl]-2-methylpropan-2-ol

A suspension of 67.03 g (272 mmole) of CeCl3 in 500 mL dry THF was stirred in a 2 L three-necked flask under N, at rt. After 30 minutes, the mixture was cooled to −78° C. in a dry ice-acetone bath and 155 mL of a 1.6M solution of methyllithium in ether was added dropwise with vigorous stirring. The yellow-green mixture was stirred at −78° C. for an additional 30 minutes and then a solution of 28.75 g (70.6 mmole) of methyl (3,5-difluorophenyl)[1-(diphenylmethyl)azetidin-3-yl]acetate in 100 mL of dry THF was added over 30 minutes, at such a rate as to keep the temperature below −60° C. The mixture was left stirring at −78° C. for 1 h, then excess carbanion was decomposed by the dropwise addition of 20 mL of methanol and 1000 mL of ether while the solution warmed to −40° C. The reaction was quenched by addition of saturated aqueous NH4Cl until the most of the solids had precipitated to the bottom surface of the flash. The liquid layer was decanted into a 2 L separatory funnel and the solids were triturated with three 200 mL portions of dichloromethane. The combined organic layers were washed with two 400 mL portions of aqueous NH4Cl solution and brine, then dried over Na2SO4 and concentrated to a white solid. The residue was purified on ChiralPak AD resin using 5% isopropanol-heptane. Fractions containing the faster enantiomer were pooled and concentrated to afford the title compound, which is the (+) enantiomer; 1H NMR(CDCl3) δ 1.07 (s, 3H), 1.14 (S, 3H), 2.28 (t, 1H, J=7.5 Hz), 2.74 (d, 1H, J=10.7 Hz), 2.82 (t, 1H, J=7.5 Hz), 3.10-3.16 (m, 2M), 3.62 (m, 1H), 4.20 (s, 1H), 6.67-6.73 (m, 3H), 7.21-7.45 (m, 10); Mass Spectrum: m/e=408.

1. temperaturethe mixture was cooled to −78° C. in a dry ice-acetone bath
2. stirringThe yellow-green mixture was stirred at −78° C. for an additional 30 minutes
3. customthe temperature below −60° C
4. waitThe mixture was left
5. stirringstirring at −78° C. for 1 h
6. temperaturewarmed to −40° C
7. customThe reaction was quenched by addition of saturated aqueous NH4Cl until the most of the solids
8. customhad precipitated to the bottom surface of the flash
9. customThe liquid layer was decanted into a 2 L separatory funnel
10. customthe solids were triturated with three 200 mL portions of dichloromethane
11. washThe combined organic layers were washed with two 400 mL portions of aqueous NH4Cl solution and brine
12. dry with materialdried over Na2SO4
13. concentrationconcentrated to a white solid
14. customThe residue was purified on ChiralPak AD resin
15. additionFractions containing the faster enantiomer
16. concentrationconcentrated

ORD record

ord-28b7f2db8545490eaedc6917e84d32c3

Source dataset

uspto-grants-2011_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07906503B2