Morpholine → Isopropyl 4-chloro-6-(morpholin-4-ylcarbonyl)pyridine-2-carboxylate

Beteiligte Stoffe

Reaktionsschritte

n-butyllithium (1.92 mL, 2.5M in hexanes) was added dropwise to a −78° C. solution of morpholine (0.42 mL, 4.8 mmol) in anhydrous THF followed by slow warming to room temperature. The solution was transferred to an addition funnel via cannulation and then added dropwise to a solution of dimethyl 4-chloropyridine-2,6-dicarboxylate (1.0 g, 4.4 mmol, Intermediate 251) in anhydrous THF. A slight precipitate was observed during the addition. After stirring two hrs at room temperature an additional 0.5 equivalence of the morpholino-lithium reagent was added to the reaction and after an additional two hrs of stirring another 0.5 equivalence was added followed by stirring one hour to reach completion. The solvent was removed under reduced pressure and the residue was suspended in methylene chloride and the product was extracted with a sat. sodium bicarbonate solution (×3). The sodium bicarbonate portion was acidified with conc. HCl to pH 3 and then extracted with EtOAc (×10), followed by drying with MgSO4 and concentrating to a solid (0.8 g, 70%). MS (ES) MH+: 271 for C11H11ClN2O4. The solid was suspended in anhydrous toluene (75 mL) and to this was added triisopropylorthoformate (1.97 mL, 8.9 mmol) slowly followed by heating to reflux for 12 hours. After cooling to room temperature the solvent was removed under reduced pressure and the residue was suspended in 1N HCl. Basification to pH8 with saturated sodium bicarbonate followed by extraction with EtOAc (×3), drying with MgSO4 and removal of solvent yielded a tan solid. Purification by silica gel flash column (gradient elution to 3:1 EtOAc:CH2Cl2) yielded a white solid (0.23 g) MS (ES) MH+: 313 for C14H17ClN2O4; NMR: 1.33 (s, 3 H) 1.35 (s, 3 H) 3.41 (s, 2 H) 3.44 (d, 2 H) 3.58 (d, 2 H) 3.68 (s, 4 H) 5.17 (dt, 1 H) 8.01 (d, 1H) 8.13 (d, 1 H).

Herkunft & Nachweise