反应详情

温度

65 °C

Weighed polymer supported Triphenylphosphine (181 mg, 271 μmol, 3 eq; 1.5 mmol/gm) into a 20 mL scintillation vial; capped and flushed with nitrogen. The resin was then suspended in 2.0 mL dry THF and mixed in a rotary shaker for 2 minutes. N-(3-(4-chloro-1-methyl-1H-pyrazol-5-yl)-4-hydroxyphenyl)-5-methylisoxazole-3-carboxamide (30.00 mg, 90.20 μmol) was added. The suspension was mixed briefly then DIAD (diisopropyl azodicarboxylate, 27.94 μL, 144.3 μmol) was added. After 30 minutes in a rotary shaker a solution of (S)-tert-butyl 1-hydroxypropan-2-ylcarbamate (19.75 mg. 112.7 μmol) in 0.5 mL of dry THF was added. The resulting suspension was heated to 65° C. and mixed overnight. LCMS showed that the reaction did not go to completion. A fresh batch of DIAD (27.94 μl, 144.3 μmol) and (S)-tert-butyl 1-hydroxypropan-2-ylcarbamate (19.75 mg. 112.7 μmol) were added to the reaction mixture and the suspension was heated to 65° C. and mixed overnight. The suspension was filtered and the resin washed with THF (3×3 mL). The filtrate and washings were combined and concentrated under vacuum. The resulting residue was dissolved in 20% TFA in DCM (2.0 mL), heated to 65° C. and mixed in a rotary shaker for 1.0 hour. The organic solvent was removed under vacuum and the crude residue was dissolved in acetonitrile (0.8 mL), neutralized with saturated NaHCO3 and subjected to purification by preparative LCMS. The desired fractions were pooled, frozen and lyophilized to afford the title compound as an off-white solid (21.34% yield). LCMS m/z=390.3 (M+H); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.16 (d, J=6.82 Hz, 3 H), 2.54 (s, 3 H), 3.46-3.57 (m, 1 H), 3.66 (bs, 3 H), 3.95-4.16 (m, 2 H), 6.66 (s, 1 H), 7.35 (dd, J=9.09, 2.53 Hz, 1 H), 7.66 (s, 1 H), 7.74 (d, J=2.53 Hz, 1 H), 7.95 (dd, J=9.09, 2.53 Hz, 1 H), 7.97-8.04 (bs, 2H), 10.76 (s, 1 H).

1. customcapped
2. customflushed with nitrogen
3. additionmixed in a rotary shaker for 2 minutes
4. additionThe suspension was mixed briefly
5. additionmixed overnight
6. temperaturethe suspension was heated to 65° C.
7. additionmixed overnight
8. filtrationThe suspension was filtered
9. washthe resin washed with THF (3×3 mL)
10. concentrationconcentrated under vacuum
11. dissolutionThe resulting residue was dissolved in 20% TFA in DCM (2.0 mL)
12. temperatureheated to 65° C.
13. additionmixed in a rotary shaker for 1.0 hour
14. customThe organic solvent was removed under vacuum
15. dissolutionthe crude residue was dissolved in acetonitrile (0.8 mL)
16. customsubjected to purification by preparative LCMS
17. temperaturefrozen