Nitrogen → Methyl 1-(4-bromo-2-iodobenzyl)-4-(difluoromethyl)cyclohexanecarboxylate

Temperatur

-78 °C

Methyl 4-(difluoromethyl)cyclohexanecarboxylate (Intermediate 89, 2.46 g, 12.8 mmol) was dissolved in THF (25 mL). The atmosphere was exchanged to N2 (g), and the solution was cooled to −78° C. Lithium diisopropylamide (1.8M in THF/heptane/ethylbenzene) (8.51 mL, 15.3 mmol) was added, while the temperature was kept at −78° C. The solution was stirred for 60 min at −78° C. A solution of 4-bromo-1-(bromomethyl)-2-iodobenzene (see Caruso, A.; Tovar, J., D. J. Org. Chem. 2011, 76, 2227-2239., 4.8 g, 12.8 mmol) in THF (5.0 mL) was added via syringe. The reaction was removed from the cooling bath, and allowed to reach r.t., while stirred for 2.5 h. Water (30 mL) was added, followed by DCM (30 mL). The organic layer was collected and dried over MgSO4, filtered and evaporated in vacuo. The residue was purified by flash chromatography, (0-100% EtOAc in heptanes, 220 g SiO2) to give the title compound (3.29 g, 53% yield): 1H NMR (500 MHz, CDCl3) δ ppm 1.11-1.20 (m, 2 H), 1.39 (td, 2 H), 1.67-1.80 (m, 3 H), 2.30 (d, 2 H), 3.01 (s, 2 H), 3.70 (s, 3 H), 5.49 (d, 1 H), 6.89 (d, 1 H), 7.38 (dd, 1 H), 7.99 (d, 1 H), MS (CI) m/z 487 [M+H]1.

1. customwas kept at −78° C
2. customThe reaction was removed from the cooling bath
3. customto reach r.t.
4. stirringwhile stirred for 2.5 h
5. additionWater (30 mL) was added
6. customThe organic layer was collected
7. dry with materialdried over MgSO4
8. filtrationfiltered
9. customevaporated in vacuo
10. customThe residue was purified by flash chromatography, (0-100% EtOAc in heptanes, 220 g SiO2)

ORD-Eintrag

ord-bd928621aa24497bba475906ef74801e

Quelldatensatz

uspto-grants-2013_04

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US08415483B2