Cesium carbonate → Methyl 3-[6-(azetidine-1-carbonyl)pyridin-3-yl]oxy-5-[(3S)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-benzoate

Participants

Reaction Steps

A mixture of methyl 3-hydroxy-5-[(3S)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-benzoate (Intermediate 8) (530 mg, 2 mmol), azetidin-1-yl-(5-bromopyridin-2-yl)methanone (CAS no. 845306-16-3) (531 mg, 2.2 mmol), caesium carbonate (1.956 g, 6 mmol) and tris(triphenylphosphine)copper bromide (CAS no. 15709-74-7) (373 mg, 0.4 mmol) in DMA (5 mL) was stirred at 160° C. for 6 hours. The DMA was evaporated under reduced pressure and the residue was dissolved in water (520 mL) washed with ethyl acetate (3×20 mL). The aqueous fraction was acidified with 2N hydrochloric acid and extracted with ethyl acetate (3×100 mL), the combined organic layers were washed with water (2×20 mL) and brine (20 mL), dried (MgSO4) and the solvent removed under reduced pressure. The residue was dissolved in THF (6 mL) and methanol (3 mL) and was treated dropwise with 2M (trimethylsilyl)diazomethane in hexane (1.1 mL). The reaction was stirred for 30 min then treated with 1 drop of acetic acid, stirred for another 15 minutes and evaporated to dryness under reduced pressure. The residue was purified by chromatography eluting with 0-100% ethyl acetate/hexane to give afford the product (439 mg, 52%). 1H NMR δ (300 MHz, CDCl3) 2.10-2.24 (m, 1H), 2.35 (quintet, 2H), 2.52-2.67 (m, 1H), 2.93 (s, 3H), 3.34-3.56 (m, 2H), 3.89 (s, 3H), 4.25 (t, 2H), 4.70 (t, 2H), 4.91 (t, 1H), 6.99 (s, 1H), 7.32 (s, 1H), 7.35 (d, 1H), 7.53 (s, 1H), 8.10 (d, 1H), 8.31 (s, 1H); m/z 426 (M+H)+.

Provenance & Evidence