Hydrochloric Acid → (S)-2-[4-(3-chloro-2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-N-[1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-propionamide hydrochloride

Temperature

25 °C

A solution of (S)-2-[4-(3-chloro-2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-propionic acid (prepared as in Example 72, 185 mg, 0.46 mmol) in dichloromethane (10 mL) was treated with oxalyl chloride (0.35 mL, 2M in dichloromethane), and N,N-dimethylformamide (1 drop). Effervescence was observed. The reaction mixture was stirred for 2 h at 25° C., under nitrogen. The reaction mixture was concentrated, and dissolved in dichloromethane (5 mL) and treated with (R)-3-(3-amino-pyrazol-1-yl)-propane-1,2-diol (as prepared in Example 38, 87 mg, 0.55 mmol), and triethylamine (102 mg, 1.00 mmol). The reaction mixture was stirred at 25° C., under nitrogen for 18 h. The reaction mixture was diluted with dichloromethane, washed with water, 2N aqueous hydrochloric acid, saturated sodium bicarbonate solution, a saturated sodium chloride solution and dried over magnesium sulfate. The organic layer was concentrated, and the crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g, 50% to 100% ethyl acetate/hexanes) to afford, (S)-2-[4-(3-chloro-2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-N-[1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-propionamide as a fluffy solid. This solid 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 and filtered to give (S)-2-[4-(3-chloro-2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-N-[1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-propionamide hydrochloride (20 mg, 8%) as a solid: LR-ES-MS m/z calculated for C25H29ClF2N4O5 [M]+ 538.18, observed [M+H]+ 539.1; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.58-1.41 (m, 6H) 1.38-1.89 (m, 7H) 3.18-3.41 (m, 2H) 3.80-3.92 (m, 2H) 4.09 (dd, J=13.9, 3.9 Hz, 1H) 4.29 (d, J=18.7 Hz, 1H) 4.64 (d, J=18.7 Hz, 1H) 4.82-4.96 (m, 1H) 5.24 (s, 1H) 6.41 (d, J=2.1 Hz, 1H) 7.40-7.50 (m, 1H) 7.53 (d, J=2.1 Hz, 1H) 7.60-7.74 (m, 1H) 10.78 (s, 1H).

1. concentrationThe reaction mixture was concentrated
2. dissolutiondissolved in dichloromethane (5 mL)
3. stirringThe reaction mixture was stirred at 25° C., under nitrogen for 18 h
4. washwashed with water, 2N aqueous hydrochloric acid, saturated sodium bicarbonate solution
5. dry with materiala saturated sodium chloride solution and dried over magnesium sulfate
6. concentrationThe organic layer was concentrated
7. customthe crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g, 50% to 100% ethyl acetate/hexanes)
8. customto afford
9. customSolvents were evaporated
10. customthe residue was triturated with diethyl ether
11. filtrationfiltered

ORD record

ord-55be4f7534e94fd9817a001d8cc883de

Source dataset

uspto-grants-2010_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07741327B2