Tert-butyl 3-formylazetidine-1-carboxylate → tert-Butyl-3-((4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(hydroxy)methyl)azetidine-1-carboxylate

온도

-70 °C

To a flask containing 6-bromo-4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinoline (1.0 g, 2.32 mmol, Intermediate 47: step d) was added THF (30 mL) resulting in a colorless homogeneous mixture. The solution was cooled to −70° C. and then n-BuLi (2.5M in hexanes, 1.08 mL, 2.69 mmol)) was added drop wise. The color of the solution became a dark opaque reddish-brown color. After 2 min, tert-butyl 3-formylazetidine-1-carboxylate (545 mg, 2.94 mmol, in 3 mL THF) was introduced. After 5 min, the reaction mixture was placed in an ice-water bath and allowed to stir for 30 min at which time the mixture was quenched with NH4Cl solution. The contents were diluted further with water and extracted with EtOAc (5×40 mL). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to provide a yellow foam. The crude material was chromatographed on silica gel (20% EtOAc-Hexanes increasing to 50% EtoAc) to give the title compound (950 mg) as a white solid. 1H NMR (500 MHz, CDCl3) δ 8.06 (d, J=1.7 Hz, 1H), 7.84 (d, J=8.6 Hz, 1H), 7.63 (dd, J=8.6, 1.9 Hz, 1H), 7.50 (d, J=8.2 Hz, 2H), 7.38 (d, J=8.1 Hz, 2H), 4.99 (dd, J=8.0, 3.3 Hz, 1H), 4.35 (s, 2H), 4.05 (bs, 2H), 3.82 (t, J=8.7 Hz, 1H), 3.74-3.67 (m, 1H), 2.99-2.90 (m, 1H), 2.20-2.15 (m, 1H), 1.41 (s, 9H). MS (ESI): mass calcd. for C27H28ClF3N2O4: 536.98, m/z found 537.2 [M+H]+.

1. customresulting in a colorless homogeneous mixture
2. waitAfter 5 min
3. customthe reaction mixture was placed in an ice-water bath
4. customwas quenched with NH4Cl solution
5. additionThe contents were diluted further with water
6. extractionextracted with EtOAc (5×40 mL)
7. washThe combined organics were washed with brine
8. dry with materialdried over MgSO4
9. filtrationfiltered
10. concentrationconcentrated
11. customto provide a yellow foam
12. customThe crude material was chromatographed on silica gel (20% EtOAc-Hexanes increasing to 50% EtoAc)

ORD 기록

ord-9a84162d3027463f8895e2658ada77bb

출처 데이터셋

uspto-grants-2016_03

DOI

10.6084/m9.figshare.5104873.v1

특허 번호

US09290476B2