Cesium fluoride → Methyl 2'-chloro-3'-fluoro-2-(methoxymethyl)biphenyl-4-carboxylate

Temperature

90 °C

A mixture of methyl 4-bromo-3-(methoxymethyl)benzoate (Intermediate 1, Step 2, 3.00 g, 11.6 mmol), 2-chloro-3-fluorophenylboronic acid (2.42 g, 13.9 mmol), cesium fluoride (5.27 g, 34.7 mmol), palladium acetate (52 mg, 0.23 mmol) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (285 mg, 0.69 mmol) was prepared in dioxane (30 mL) and water (15 mL), and then heated at 90° C. for 1 hour. Additional amounts of 2-chloro-3-fluorophenylboronic acid (2.42 g, 13.9 mmol), palladium acetate (52 mg, 0.23 mmol) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (285 mg, 0.69 mmol) were added, and then the resulting mixture was maintained at 90° C. for 1 additional hour. The reaction mixture was diluted with MTBE (200 mL) and washed with water (2×100 mL) and brine (100 mL). The aqueous layers were extracted with MTBE (100 mL). The organic layers were combined, dried (MgSO4) and treated with activated charcoal. After filtration through a Celite pad, the solution was concentrated under vacuum. After purification by flash chromatography (silica, heptane/EtOAc), the title compound was obtained as a pale yellow oil. HPLC (Method A) Rt 4.9 min (Purity: 99.6%). LC/MS (Method B): 309.0 (M+H)+.

1. washwashed with water (2×100 mL) and brine (100 mL)
2. extractionThe aqueous layers were extracted with MTBE (100 mL)
3. dry with materialdried (MgSO4)
4. additiontreated with activated charcoal
5. filtrationAfter filtration through a Celite pad
6. concentrationthe solution was concentrated under vacuum
7. customAfter purification by flash chromatography (silica, heptane/EtOAc)

ORD record

ord-bc8a4de914f646e4ba2d4cc81c7cbb91

Source dataset

uspto-grants-2014_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08815919B2