Diisopropylethylamine → HCID 57920129, compound

Participants

Reaction Conditions

Reaction Steps

A solution of (S)-2-[4-(2,3-dichloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methy-1-pentanoic acid (130 mg, 0.36 mmol) in N,N-dimethylformamide (4 mL) was treated with 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 80 mg, 0.51 mmol), benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (340 mg, 0.76 mmol) and N,N-diisopropylethylamine (120 mg, 0.93 mmol). The reaction mixture was stirred for 4 h at 25° C., under nitrogen. The reaction mixture was diluted with ethyl acetate, washed with saturated ammonium chloride, water, a saturated sodium chloride solution and dried over sodium sulfate. The organic layer was concentrated, and the crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g, 40% to 100% ethyl acetate/hexanes) to afford (S)-2-[4-(2,3-dichloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide as a fluffy material. This material was dissolved in dichloromethane (4 mL) and treated with 1M hydrogen chloride in diethyl ether (4 mL). Solvents were evaporated and the residue was triturated with diethyl ether. Solid was filtered to give (S)-2-[4-(2,3-dichloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide hydrochloride (60 mg, 31%): HR-ES-MS m/z calculated for C23H28Cl2N4O4 [M+H]+ 495.1561, observed 495.1564; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.90 (d, J=6.3 Hz, 3H) 0.94 (d, J=6.3 Hz, 3H) 1.04 (s, 3H) 1.06 (s, 3H) 1.35-1.65 (m, 2H) 1.67-1.86 (m, 1H) 3.89 (s, 2H) 4.22 (d, J=18.5 Hz, 1H) 4.63 (d, J=18.5 Hz, 1H) 4.86-4.91 (m, 1H) 4.92 (s, 1H) 6.44 (d, J=2.1 Hz, 1H) 7.44-7.59 (m, 3H) 7.64 (dd, J=7.5, 1.8 Hz, 1H) 10.82 (s, 1H).

Provenance & Evidence