Cesium fluoride → Methyl 4-amino-3-chloro-6-(4-chloro-3-ethoxy-2-fluorophenyl)-5-fluoropicolinate

Participants

Reaction Conditions

Reaction Steps

Methyl 4-amino-3-chloro-6-(4-chloro-3-ethoxy-2-fluorophenyl)-5-fluoropicolinate (Compound A). 2-(4-Chloro-3-ethoxy-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (500 mg, 1.7 mmol, 1.0 equiv) and methyl 4-amino-3,6-dichloro-5-fluoropicolinate (400 mg, 1.7 mmol, 1.0 equiv) were sequentially added to a 5 mL Biotage microwave vessel, followed by 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″-phosphinetriyltribenzene-sulfonate (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 (MgSO4), gravity filtered, and concentrated by rotary evaporation. The residue was purified by silica gel column chromatography (eluting with 33% EtOAc/hexane) to afford the desired product, methyl 4-amino-3-chloro-6-(4-chloro-3-ethoxy-2-fluorophenyl)-5-fluoropicolinate as a tan powder (450 mg, 63%): mp 170-172° C.; IR (thin film) 3485 (m), 3380 (s), 2951 (w), 1739 (s), 1610 (s) cm−1; 1H NMR (300 MHz, CDCl3) δ 7.20-7.30 (m, 2H), 4.95 (br s, 2H), 4.19 (q, J=7 Hz, 2H), 3.98 (s, 3H), 1.43 (t, J=7 Hz, 3H); ESIMS m/z 377 ([M+H]+).

Provenance & Evidence