反应详情

To a solution of DIPEA (1.37 ml, 7.68 mmol) and 1-(4-((2-aminopyridin-4-yl)methoxy)naphthalen-1-yl)-3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)urea (Intermediate A) (2.00 g, 3.84 mmol) in DCM (40 mL) and DMF (8.0 mL) was added chloroacetyl chloride (0.61 mL, 7.68 mmol). The reaction mixture was stirred at RT for 1 hr. LC-MS indicated nearly complete consumption of the starting material. A further portion of chloracetyl chloride (100 μl, 1.25 mmol) was added. After stirring for 1 hr at RT, the reaction mixture was partitioned between DCM (40 mL) and saturated aq NaHCO3 solution (40 mL). The organic phase was concentrated in vacuo and purified by column chromatography (80 g, 0-10% MeOH in DCM, gradient elution). Product fractions were concentrated in vacuo and the residue triturated with diethyl ether (20 mL) and iso-hexane (20 mL). The solid was collected by filtration to afford N-(4-((4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)methyl)pyridin-2-yl)-2-chloroacetamide (Intermediate B) as a light purple solid (1.07 g, 42%): m/z 597, 599 (M+H)+ (ES+).

1. customconsumption of the starting material
2. stirringAfter stirring for 1 hr at RT
3. customthe reaction mixture was partitioned between DCM (40 mL) and saturated aq NaHCO3 solution (40 mL)
4. concentrationThe organic phase was concentrated in vacuo
5. custompurified by column chromatography (80 g, 0-10% MeOH in DCM, gradient elution)
6. concentrationProduct fractions were concentrated in vacuo
7. customthe residue triturated with diethyl ether (20 mL) and iso-hexane (20 mL)
8. filtrationThe solid was collected by filtration