反应详情

A solution of (S)-methyl 2-(2-((2-(allyloxy)benzyl)carbamoyl)-5-(4-(but-3-en-1-yl)-4-methylpiperidin-1-yl)-7-methylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate (0.023 g, 0.037 mmol, 1 equiv) and TsOH (7 mg, 0.037 mmol, 1 equiv) in DCE (19 mL) was heated to 80° C. The Hoveyda Grubbs 2nd generation catalyst (5 mg, 0.007 mmol, 0.2 equiv) was added. The pale green brown solution was stirred for 2 h. Upon cooling to ambient temperature, the reaction was washed with saturated aqueous NaHCO3, dried (Na2SO4), and concentrated in vacuo. The dark residue was then taken up in MeOH (2 mL) and NaBH4 (2 mg, 0.052 mmol, 1.4 equiv) was added. After stirring 1 h, the reaction was added to saturated aqueous NaHCO3 and extracted with DCM (×3). The combined DCM extracts were dried (Na2SO4) and concentrated in vacuo. The crude product was taken up in 9:1 MeOH:water (2 mL) and LiOH.H2O (78 mg, 1.684 mmol, 50 equiv) was added. The reaction was heated to 60° C. for 6 h. Upon cooling to ambient temperature, the reaction was filtered and purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19×mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 30-70% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to provide the product (7.1 mg, 31%). 1H NMR (500 MHz, DMSO-d6) δ 8.71-8.61 (m, 1H), 8.08 (s, 1H), 7.36 (d, J=7.0 Hz, 1H), 7.27-7.18 (m, 2H), 7.07 (d, J=8.2 Hz, 1H), 6.85 (t, J=7.3 Hz, 1H), 5.90 (s, 1H), 4.44-4.28 (m, 2H), 4.14 (td, J=10.6, 6.0 Hz, 2H), 3.68 (br. s., 2H), 3.06 (d, J=7.9 Hz, 1H), 2.57 (br. s., 1H), 2.37 (s, 3H), 2.09-1.93 (m, 3H), 1.68-1.25 (m, 9H), 1.17 (s, 9H), 0.98 (s, 3H); LCMS (ESI, M+1): 577.5.

1. washthe reaction was washed with saturated aqueous NaHCO3
2. dry with materialdried (Na2SO4)
3. concentrationconcentrated in vacuo
4. stirringAfter stirring 1 h
5. extractionextracted with DCM (×3)
6. dry with materialThe combined DCM extracts were dried (Na2SO4)
7. concentrationconcentrated in vacuo
8. temperatureThe reaction was heated to 60° C. for 6 h
9. temperatureUpon cooling to ambient temperature
10. filtrationthe reaction was filtered
11. custompurified via preparative LC/MS with the following conditions
12. waitGradient: 30-70% B over 20 minutes
13. customa 5-minute hold