反应详情

Prepared using General Procedure 8. To a stirred solution of (S)-tert-butyl 1-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)pyrrolidine-2-carboxylate (350 mg, 0.465 mmol) in DCM (5 mL) was added TFA (5 mL) and stirred at room temperature for 2 h. The reaction mixture was diluted with toluene (10 mL) and solvent removed. The residue was dissolved in EA (50 mL), THF (5 mL) and acetone (10 mL) and washed with a mixture of saturated aqueous NaHCO3 (10 mL) and brine (40 mL). The aqueous layer was removed and acetic acid (5 mL) was added. The organic layer was washed with brine (50 mL) and dried over MgSO4. The solvent was removed and residual acetic acid was removed under high vacuum overnight. The material was dissolved in DCM (5 mL) and ACN (5 mL) was added. The material was stirred under a flow of air for 1 hour and the suspension was filtered and the solid washed with additional ACN (5 mL) and iso-hexanes (20 mL) to give 134 mg (41%) of (S)-1-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)-pyrimidin-2-yl)phenyl)propanoyl)pyrrolidine-2-carboxylic acid Compound 328 as a yellow powder. LCMS-ESI (m/z) calculated for C40H48N4O5S: 696.3. found 697.3 [M+H]+, tR=10.59 min (Method 10). The chiral purity was calculated at >93% e.e. (Chiral Method). 1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 9.17 (s, 2H), 8.74 (d, J=8.3 Hz, 1H), 8.38-8.27 (m, 2H), 7.86-7.76 (m, 2H), 7.71 (d, J=3.9 Hz, 1H), 7.57-7.48 (m, 2H), 7.14-7.02 (m, 2H), 6.92 (d, J=3.9 Hz, 1H), 4.94-4.86 (m, 1H), 4.33-4.27 (m, 1H), 4.04 (t, J=6.5 Hz, 2H), 3.86-3.74 (m, 1H), 3.69-3.59 (m, 1H), 3.19-3.01 (m, 2H), 2.24-2.13 (m, 1H), 2.01-1.84 (m, 3H), 1.80-1.68 (m, 2H), 1.52-1.23 (m, 17H), 0.93-0.85 (m, 3H).

1. customPrepared
2. customremoved
3. dissolutionThe residue was dissolved in EA (50 mL)
4. washTHF (5 mL) and acetone (10 mL) and washed with a mixture of saturated aqueous NaHCO3 (10 mL) and brine (40 mL)
5. customThe aqueous layer was removed
6. additionacetic acid (5 mL) was added
7. washThe organic layer was washed with brine (50 mL)
8. dry with materialdried over MgSO4
9. customThe solvent was removed
10. customresidual acetic acid was removed under high vacuum overnight
11. dissolutionThe material was dissolved in DCM (5 mL)
12. additionACN (5 mL) was added
13. stirringThe material was stirred under a flow of air for 1 hour
14. filtrationthe suspension was filtered
15. washthe solid washed with additional ACN (5 mL) and iso-hexanes (20 mL)