反应详情

1-Chloro-N,N-2-trimethyl-1-propenylamine (78 μl, 0.588 mmol, 1.2 eq) was added dropwise to a stirred solution of 3-[4-(tert-butoxycarbonyl)piperazin-1-yl]benzoic acid (150 mg, 0.588 mmol, 1.2 eq) in THF (10 ml) under nitrogen. The mixture was stirred at room temperature overnight. tert-Butyl 5-amino-3-[(3,5-dimethoxyphenyl)methoxy]pyrazole-1-carboxylate (172 mg, 0.490 mmol, 1 eq) and pyridine (48 μl, 0.588 mol, 1.2 eq) were added and the mixture was heated at 65° C. overnight. The mixture was allowed to cool to room temperature and 4M HCl in dioxane (2 ml) was added. Stirring was continued at room temperature overnight. The precipitated yellow solid was collected by filtration and washed with THF. The solid was triturated with aq NaHCO3 (4 ml) and DCM (2 ml). A small amount of a brown gum remained out of solution. The gum was collected by filtration and washed with water and ether. The aqueous filtrate was extracted with ethyl acetate (3×10 ml) and the combined extracts were dried over MgSO4, filtered and evaporated. The extracted product was combined with the gum from filtration and purified by silica column chromatography, eluting with a gradient of 10-12% MeOH in DCM. Product fractions were evaporated to give the title compound as a white solid (27 mg, 10% yield); 1H NMR (399.902 MHz, DMSO+d4-AcOD) δ 3.13-3.21 (m, 4H), 3.33-3.40 (m, 4H), 3.68 (s, 6H), 5.02 (s, 2H), 5.71 (s, 1H), 6.38 (t, 1H), 6.52 (d, 2H), 7.12-7.17 (m, 1H), 7.33 (t, 1H), 7.37-7.41 (m, 1H), 7.46-7.49 (m, 1H). MS: m/z 438 (MH+)

1. temperaturethe mixture was heated at 65° C. overnight
2. temperatureto cool to room temperature
3. stirringStirring
4. waitwas continued at room temperature overnight
5. filtrationThe precipitated yellow solid was collected by filtration
6. washwashed with THF
7. customThe solid was triturated with aq NaHCO3 (4 ml) and DCM (2 ml)
8. filtrationThe gum was collected by filtration
9. washwashed with water and ether
10. extractionThe aqueous filtrate was extracted with ethyl acetate (3×10 ml)
11. dry with materialthe combined extracts were dried over MgSO4
12. filtrationfiltered
13. customevaporated
14. filtrationThe extracted product was combined with the gum from filtration
15. custompurified by silica column chromatography
16. washeluting with a gradient of 10-12% MeOH in DCM
17. customProduct fractions were evaporated