تفاعل #47391

معادلة التفاعل

N,N-diisopropylethylamine

(S)-2-[4-(3-ethoxy-2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid

1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol

(S)-2-[4-(2,3-dichloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-amide hydrochloride

benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate

→

(S)-2-[4-(3-ethoxy-2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide

المردود 55.0%

المذيبات

N,N-dimethylformamide

ظروف التفاعل

المعالجة

1. 1
   workup.STIRRINGThe mixture was stirred at room temperature for 7 h
2. 2
   أخرىthe solvents were evaporated
3. 3
   workup.ADDITIONThe residue was treated with ethyl acetate and ammonium chloride solution
4. 4
   أخرىthe organic layer separated
5. 5
   غسيلThe organic layer was washed with brine
6. 6
   تجفيفdried over sodium sulfate
7. 7
   أخرىThe solvents were evaporated
8. 8
   أخرىthe residue was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 25 g, 30% to 100% ethyl acetate/hexanes) which

الإجراء التجريبي

To a solution of (S)-2-[4-(3-ethoxy-2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (0.460 g, 1.31 mmol) in N,N-dimethylformamide (10 mL) was added 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032, Example 80, 0.264 g, 1.70 mmol), and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (1.22 g, 2.76 mmol). The mixture was stirred at 0° C. and N,N-diisopropylethylamine (0.340 g, 2.63 mmol) was added. The mixture was stirred at room temperature for 7 h and the solvents were evaporated. The residue was treated with ethyl acetate and ammonium chloride solution, and the organic layer separated. The organic layer was washed with brine and dried over sodium sulfate. The solvents were evaporated and the residue was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 25 g, 30% to 100% ethyl acetate/hexanes) which afforded (S)-2-[4-(3-ethoxy-2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide (0.350 g, 55%) as a yellow solid: HR-ES-MS m/z calculated for C25H33FN4O5 [M+H]+ 489.2508, observed 489.2508, 1H NMR (300 MHz, DMSO-d6) δ ppm 1.00 0.90 (d, J=6.3 Hz, 3H), 0.93 (d, J=6.3 Hz, 3H), 1.05 (br. s., 3H), 1.06 (br. s., 3H), 1.36 (t, J=6.8 Hz, 3H), 1.47 (br. s., 1H), 1.50-1.64 (m, 1H), 1.63-1.86 (m, 1H), 3.89 (s, 2H), 4.15 (q, J=6.8 Hz, 2H), 4.21 (d, J=18.7 Hz, 1H), 4.60 (d, J=18.7 Hz, 1H), 4.68 (s, 1H), 4.83-4.93 (m, 1H), 4.89 (s, 1H), 6.44 (d, J=2.1 Hz, 1H), 6.96-7.07 (m, 1H), 7.07-7.26 (m, 2H), 7.53 (d, J=2.1 Hz, 1H), 10.80 (s, 1H).

المصدر