Cesium fluoride → Methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-(1-fluoroethyl)phenyl)-5-fluoropicolinate

Participants

Reaction Conditions

Reaction Steps

Methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-(1-fluoroethyl)phenyl)-5-fluoropicolinate (Compound H). 2-(4-Chloro-2-fluoro-3-(1-fluoroethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (510 mg, 1.7 mmol, 1.0 equivalent (equiv)) and methyl 4-amino-3,6-dichloro-5-fluoropicolinate (prepared by the methods described in U.S. Pat. No. 6,784,137 B2; 400 mg, 1.7 mmol, 1.0 equiv) were sequentially added to a 5 mL Biotage microwave vessel, followed by cesium fluoride (CsF; 510 mg, 3.3 mmol, 2.0 equiv), palladium(II) acetate (19 mg, 0.084 mmol, 0.05 equiv), and sodium 3,3′,3″-phosphinetriyltribenzenesulfonate (95 mg, 0.17 mmol, 0.10 equiv). A 3:1 mixture of water-acetonitrile (3.2 mL) was added and the resulting brown mixture was heated in a benchtop microwave at 150° C. for 5 min. The cooled reaction mixture was diluted with water (150 mL) and extracted with CH2Cl2 (4×50 mL). The combined organic extracts were dried with magnesium sulfate (MgSO4), gravity filtered, and concentrated by rotary evaporation. The residue was purified by reverse phase column chromatography (eluting with a 5% acetonitrile to 100% acetonitrile gradient) to afford the desired product, methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-(1-fluoroethyl)phenyl)-5-fluoropicolinate as a tan semisolid (220 mg, 35%): IR (thin film) 3475 (w), 3353 (m), 3204 (w), 3001 (w), 2955 (w), 1738 (s), 1711 (s), 1624 (s) cm−1; 1H NMR (300 MHz, CDCl3) δ 7.50 (m, 1H), 7.30 (m, 1H), 7.21 (d, J=2 Hz, 1H), 6.16 (dq, J=46, 7 Hz, 1H), 4.96 (br s, 2H), 3.97 (s, 3H), 1.75 (dd, J=23, 7 Hz, 3H); ESIMS m/z 379 ([M+H]+).

Provenance & Evidence