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EXAMPLE 172; 4-[7-(2-Morpholin-4-yl-2-oxo-ethoxy)-quinazolin-4-yl]-piperidine-1-carboxylic acid (4-pyrrolidin-1-yl-phenyl)-amide; a. 4-[7-(2-Morpholin-4-yl-2-oxo-ethoxy)-quinazolin-4-yl]-piperidine-1-carboxylic acid tert-butyl ester; A mixture of morpholine (107.4 mg, 1.23 mmol) and methyl glycolate (77.5 mg, 860 mumol) was stirred at 150° C. for 3 hr. The resulting homogeneous clear amber oil was taken up in toluene (2.x.2 mL) with repeated rotary evaporation to remove methanol. The residue was taken up in dry THF (860 muL) and KOtBu was added (113 mg, 1.01 mmol). The mixture was stirred at 100° C. for 5-10 min until a brown slurry formed with no visible chunks. The mixture was then allowed to cool to rt, 4-(7-fluoro-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (302 mg, 912 mumol), as prepared in Example 65b, was added, and the resulting nearly homogeneous reddish-brown solution was stirred at rt for 1 hr, at which point the reaction solidified into a paste. The reaction was taken up in DCM (4 mL) and washed with 1M NaHCO3 (1.x.2 mL) and 1M NaH2PO4 (1.x.2 mL), and the organic layer was dried (Na2SO4) and concentrated. The residue was purified by silica flash chromatography (9:1 DCM/acetone-->8:2-->8:2 DCM/acetone/3percent DMEA eluent) to provide the title compound as a pale yellow oil (94.8 mg, 24percent over two steps). LC/MS (ESI): calcd mass 456.2, found 457.3 (MH)+.
With sodium hydride; In 1,4-dioxane; at 25℃; for 24h;
To a solution of methyl beta-chloro-delta-nitro-S-pyridinecarboxylate (2 g, 9.3 mmol) in dioxane (40 mL) were added NaH (0.4 g, 10.2 mmol, 60percent in mineral oil) and methyl EPO <DP n="43"/>hydroxyacetate (0.78 g, 9.3 mmol). After stirring at 25°C for 24 hr, the solution was partitioned between ethyl acetate and water. The aqueous solution was extracted several times with ethyl acetate. The organic fractions were combined, concentrated and purified with column chromatography (silica, 5 -30percent ehtyl acetate in hexane) to provide the title compound as a white solid (1.3 g, 56percent): LC/MS (ES) m/e 271 (M+H)+
b) Preparation of NaH (60percent) (0.022 mol) was stirred in petroleum ether and then decanted (2*). THF (40 ml) was added. A solution of methyl glycolate 98percent (0.022 mol) in THF (40 ml) was added dropwise (exothermic temperature rise to 26° C.). The reaction mixture was stirred at room temperature for 2 hours. A solution of intermediate (41) (0.02 mol) in THF (40 ml) was added dropwise at 20° C./25° C. The reaction mixture was stirred and refluxed for 20 hours, giving reaction mixture (I). NaH (60percent) was stirred twice in petroleum ether and decanted twice. THF (40 ml) was added. Methyl glycolate 98percent in THF (40 ml) was added and the reaction mixture was stirred and refluxed for one hour, giving reaction mixture (II). Reaction mixture (I) was added and the whole was stirred and refluxed for another 24 hours. The mixture was cooled and the solvent was evaporated. The residue was partitioned between water and CH2Cl2. The layers were separated. The aqueous layer was extracted with CH2Cl2. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated, yielding 6.2 g of intermediate (42).
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