Potassium Carbonate → ethyl 3-{3-[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-6-chloropyridin-3-yl]-4-methoxyphenyl}propanoate

Participants

Reaction Steps

A mixture of (4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-[(3-bromo-6-chloropyridin-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one (INTERMEDIATE 32) (500 mg, 0.966 mmol), methyl 3-[4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate (INTERMEDIATE 2) (370 mg, 1.107 mmol), potassium carbonate (1M aqueous) (3 ml, 3.00 mmol), and 1,1′-bis(di-t-butylphosphino)ferrocene palladium dichloride (94 mg, 0.145 mmol) in THF (5 ml) was stirred at RT under nitrogen overnight. The reaction was diluted with water and extracted 3 times with ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting EtOAc in hexanes to afford 582 mg of ethyl 3-{3-[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-6-chloropyridin-3-yl]-4-methoxyphenyl}propanoate. 294 mg (0.456 mmol) of this ester was combined with LiOH (1M aqueous) (1 ml, 1.000 mmol) in THF (2 ml)/EtOH (0.5 ml) and stirred at RT under nitrogen overnight. The mixture was diluted with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic was dried over sodium sulfate and the solvent was evaporated under reduced pressure to afford 267 mg of 3-{3-[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-6-chloropyridin-3-yl]-4-methoxyphenyl}propanoic acid, 30 mg of which were combined with copper (spatula tip) and piperidine (5 ml, 50.5 mmol) and was heated at 150° C. for 5 hours in a sealed tube. The reaction was concentrated and purified by RP HPLC to afford the title compound. Mass spectrum (ESI) 666.2 (M+1). 1H NMR (500 MHz, CD3OD) (atropisomers) δ 7.96 (s, 1H); 7.88 (s, 2H); 7.30 (d, J=8.7 Hz, 1H); 7.20 (dd, J=2.2, 8.4 Hz, 1H); 7.02 (s, 1H); 6.95 (d, J=8.5 Hz, 1H); 6.73 (d, J=8.5 Hz, 1H); 5.76 (br s, 1H); 4.60 (br s, 1H); 3.49-4.34 (m, 9H); 2.87 (t, J=7.1 Hz, 2H); 2.57 (br s, 2H); 1.61-1.73 (m, 6H); 0.56 (br s, 3H).

Provenance & Evidence