Acetic Acid → HCID 135974981, compound

Participants

Reaction Steps

A solution of 2-[4-(4-Amino-phenylethynyl)-1-(2-hydroxy-ethyl)-1H-pyrazol-3-yl]-4-chloro-phenol (2A) (7.08 g, 20.0 mmol), N-Boc-2(R)-piperidinecarboxylic acid (3A) (18.35 g, 80.0 mmol) and 4-dimethylaminopyridine (DMAP, 0.978 g, 8.0 mmol) in anhydrous THF (100 mL) was cooled to 0° C. with and ice-water bath. N,N′-Diisopropylcarbodiimide (DIPC, 12.39 mL, 80.0 mmol) was added slowly to the above solution. The ice-water bath was removed and the reaction mixture was stirred at rt overnight. Water (˜5 mL) and methanol (100 mL) were added. The mixture was cooled to 0° C. A solution of LiOH.H2O (17.0 g, 405 mmol) in water (60 mL) were added slowly. The mixture was stirred at 0° C. for 2 h. It was then neutralized with acetic acid (23 mL, 402 mmol). The mixture was diluted with ethyl acetate (˜200 mL), and washed with brine, and dried over sodium sulfate. It was filtered, concentrated and filtered again to remove diisopropylurea. The filtrate was purified with silica column chromatography eluting with hexanes-ethyl acetate (v/v 1/1, 2/3) to provide the title compound (4A, 8.2 g) as a yellowish solid in 72.6% yield. 1H NMR (CDCl3, 500 MHz) δ 10.59 (s, 1H), 8.67 (d, 1H, J=1.5 Hz), 8.40 (br s, 1H), 7.77 (s, 1H), 7.54 (s, 4H), 7.20 (dd, 1H, J=9.0, 1.5 Hz), 6.96 (d, 1H, J=9.0 Hz), 4.88 (s, 1H), 4.31 (t, 2H, J=4.5 Hz), 4.06 (t, 3H, J=4.5 Hz), 3.75 (br s, 1H), 2.87 (t, 1H, J=12.0 Hz), 2.34 (m, 3H), 1.90-1.20 (m, 15H). LCMS (ESI) m/z 587.15 (MNa+), 565.16 (MH+), 465.19 (100), 354.09; HPLC: tR=5.22 min.

Provenance & Evidence