تفاعل #47413

معادلة التفاعل

N,N-diisopropylethylamine

(S)-2-[4-(2-fluoro-3-hydroxy-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-(2-fluoro-3-hydroxy-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 67.9%

المذيبات

dichloromethane

ظروف التفاعل

المعالجة

1. 1
   workup.STIRRINGThe mixture was stirred at room temperature for 4 h
2. 2
   أخرىthe solvents were evaporated
3. 3
   استخلاصThe residue was extracted with ethyl acetate
4. 4
   غسيلwashed with a citric acid solution
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 reverse phase HPLC (C18, 20% to 100% acetonitrile/water) which

الإجراء التجريبي

To a solution of (S)-2-[4-(2-fluoro-3-hydroxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (0.100 g, 0.31 mmol) in dichloromethane (3 mL) was added 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 0.100 g, 0.64 mmol) and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (0.137 g, 0.31 mmol). The mixture was stirred at 0° C. and N,N-diisopropylethylamine (0.04 g, 0.31 mmol) was added. The mixture was stirred at room temperature for 4 h and the solvents were evaporated. The residue was extracted with ethyl acetate and washed with a citric acid solution. The organic layer was washed with brine and dried over sodium sulfate. The solvents were evaporated and the residue was purified by reverse phase HPLC (C18, 20% to 100% acetonitrile/water) which afforded (S)-2-[4-(2-fluoro-3-hydroxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide (0.097 g, 57%) as an off-white solid: HR-ES-MS m/z calculated for C23H29FN4O5 [M+H]+ 461.2195, observed 461.2194, 1H NMR (400 MHz, DMSO-d6) δ ppm 1.00 0.90 (d, J=6.4 Hz, 3H), 0.94 (d, J=6.4 Hz, 3H), 1.05 (s, 3H), 1.07 (s, 3H), 1.37-1.51 (m, 1H), 1.57 (ddd, J=13.6, 9.1, 4.8 Hz, 1H), 1.68-1.84 (m, 1H), 3.90 (s, 2H), 4.20 (d, J=18.5 Hz, 1H), 4.59 (d, J=18.5 Hz, 1H), 4.67 (s, 1H), 4.85-4.92 (m, 1H), 4.88 (s, 1H), 6.45 (d, J=1.9 Hz, 1H), 6.85 (t, J=7.4 Hz, 1H), 6.91 (t, J=7.9 Hz, 1H), 6.98-7.10 (m, 1H), 7.54 (d, J=1.9 Hz, 1H), 10.36 (br. s., 1H), 10.79 (s, 1H).

المصدر