تفاعل #47681

معادلة التفاعل

(S)-2-amino-4-methyl-pentanoic acid pyrazin-2-ylamide

(E)-4-bromo-3-[3-(2-hydroxy-2-methyl-propyl)-phenoxy]-but-2-enoic acid ethyl ester

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

N,N-diisopropylethylamine

→

(S)-2-{4-[3-(2-hydroxy-2-methyl-propyl)-phenoxy]-2-oxo-2,5-dihydro-pyrrol-1-yl}-4-methyl-pentanoic acid pyrazin-2-ylamide

المردود 22.5%

المذيبات

acetonitrile

ظروف التفاعل

المعالجة

1. 1
   أخرىwere sealed in a tube
2. 2
   درجة الحرارةThe mixture was cooled
3. 3
   تركيزconcentrated in vacuo
4. 4
   أخرىThe residue was partitioned between ethyl acetate (20 mL) and water (20 mL)
5. 5
   أخرىthe phases separated
6. 6
   تجفيفThe organic phase was dried over sodium sulfate
7. 7
   ترشيحfiltered
8. 8
   تركيزconcentrated in vacuo
9. 9
   workup.DISSOLUTIONThe residue was dissolved in tetrahydrofuran (5 mL)
10. 10
    أخرىsealed in an Emry Optimizer microwave tube
11. 11
    أخرىmicrowaved at 160° C. for 4 h
12. 12
    درجة الحرارةThe mixture was cooled
13. 13
    تركيزconcentrated in vacuo
14. 14
    أخرىThe residue was purified by flash column chromatography (silica gel, 5% to 35% ethyl acetate/hexanes)

الإجراء التجريبي

A mixture of (S)-2-amino-4-methyl-pentanoic acid pyrazin-2-ylamide (prepared as in Example 245, 0.400 g, 1.92 mmol), (E)-4-bromo-3-[3-(2-hydroxy-2-methyl-propyl)-phenoxy]-but-2-enoic acid ethyl ester (prepared as in Example 235, 0.462 g, 1.29 mmol) and N,N-diisopropylethylamine (0.734 g, 5.69 mmol) in acetonitrile (16.6 mL) were sealed in a tube and heated at 100° C. for 12 h. The mixture was cooled and concentrated in vacuo. The residue was partitioned between ethyl acetate (20 mL) and water (20 mL) and the phases separated. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in tetrahydrofuran (5 mL), sealed in an Emry Optimizer microwave tube and microwaved at 160° C. for 4 h. The mixture was cooled and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 5% to 35% ethyl acetate/hexanes) to afford (S)-2-{4-[3-(2-hydroxy-2-methyl-propyl)-phenoxy]-2-oxo-2,5-dihydro-pyrrol-1-yl}-4-methyl-pentanoic acid pyrazin-2-ylamide (127 mg, 22%) as a tan solid: HR-ES-MS m/z calculated for C24H30N4O4 [M+H]+ 439.234, observed 439.2341; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.91 (d, J=6.9 Hz, 3H), 0.93 (d, J=6.9 Hz, 3H), 1.04 (s, 6H), 1.39-1.70 (m, 2H), 1.72-1.87 (m, 1H), 2.66 (s, 2H), 4.21 (d, J=18.4 Hz, 1H), 4.36 (s, 1H), 4.55 (d, J=18.4 Hz, 1H), 4.83 (s, 1H), 5.02 (dd, J=10.9, 4.5 Hz, 1H), 6.94-7.19 (m, 3H), 7.34 (t, J=7.5 Hz, 1H), 8.36 (d, J=2.7 Hz, 1H), 8.41 (d, J=1.5 Hz, 1H), 9.26 (s, 1H), 11.16 (s, 1H).

المصدر