Reaktion #47287

Reaktionsgleichung

hydrogen chloride

(S)-2-[4-(2-chloro-6-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-propionic acid

pyrazin-2-ylamine

bromotripyrrolidinophosphonium hexafluorophosphate

N,N-diisopropylethylamine

→

(S)-2-[4-(2-chloro-6-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-N-pyrazin-2-yl-propionamide hydrochloride

Ausbeute 33.0%

Lösungsmittel

ethyl acetate

dichloromethane

diethyl ether

dichloromethane

Reaktionsbedingungen

Aufarbeitung

1. 1
   Waschenwashed with saturated ammonium chloride, water
2. 2
   Trocknena saturated sodium chloride solution and dried over sodium sulfate
3. 3
   EinengenThe organic layer was concentrated
4. 4
   Sonstigethe crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g, 0% to 100% ethyl acetate/hexanes)
5. 5
   Sonstigeto give a waxy material
6. 6
   Sonstigewere evaporated
7. 7
   SonstigeThe residue was triturated with diethyl ether
8. 8
   Filtrationfiltered

Vorschrift

A solution of (S)-2-[4-(2-chloro-6-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-propionic acid (prepared as in Example 67, 200 mg, 0.52 mmol) in dichloromethane (5 mL) was treated with pyrazin-2-ylamine (65 mg, 0.68 mmol), bromotripyrrolidinophosphonium hexafluorophosphate (503 mg, 1.1 mmol) and N,N-diisopropylethylamine (110 mg, 0.85 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, 0% to 100% ethyl acetate/hexanes) to give a waxy material. This material was dissolved in dichloromethane (2 mL). The clear solution was treated with hydrogen chloride in diethyl ether (1M, 4 mL) and solvents were evaporated. The residue was triturated with diethyl ether and filtered to afford (S)-2-[4-(2-chloro-6-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-N-pyrazin-2-yl-propionamide hydrochloride (28 mg, 33%) as a orange solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 0.77-1.37 (m, 6H) 1.43-1.95 (m, 7H) 4.29 (d, J=18.7 Hz, 1H) 4.64 (d, J=18.7 Hz, 1H) 5.00 (s, 1H) 5.02-5.12 (m, 1H) 7.36-7.57 (m, 3H) 8.38 (d, J=2.4 Hz, 1H) 8.40-8.47 (m, 1H) 9.27 (d, J=1.2 Hz, 1H) 11.20 (s, 1H). HR-ES-MS m/z calculated for C23H24ClFN4O3 459.1594, observed 459.1593 [M+H]+.

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