Acetoxyacetyl chloride → 4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-{[(2S)-1-(hydroxyacetyl)pyrrolidin-2-yl]methoxy}quinazoline

Participants

Reaction Conditions

Reaction Steps

4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[(2S)-pyrrolidin-2-ylmethoxy]quinazoline hydrochloride (0.25 g, 0.57 mmole; prepared as described in Example 31-starting materials) was dissolved in a mixture of methylene chloride (5 ml) and diisopropylethylamine (0.3 ml). The solution was cooled in an ice/water bath to 4° C. and acetoxyacetyl chloride (0.064 ml, 0.6 mmol) added. The reaction mixture was stirred cold for two hours and then partitioned between methylene chloride and saturated aqueous NaHCO3. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and evaporated. The residue was dissolved in methanol (5 ml) containing anhydrous powdered potassium carbonate (0.2 g). After stirring overnight the solvent was evaporated and the residue purified by column chromatography eluting with methylene chloride/isopropanol (96/4)(containing 0.5% triethylamine). The fractions containing the expected product were evaporated and the residue was triturated with diethylether to give the title product as a white solid (0.1 g, 38%); 1H NMR Spectrum: (CDCl3) 1.95-2.29 (m, 4H); 3.29 (m, 1H); 3.46 (m, 2H); 4.03 (s, 3H); 4.07-4.18 (m, 3H); 4.55 (d, 1H); 4.69 (t, 1H); 7.13-7.16 (m, 2H); 7.26 (s, 1H); 8.26 (m, 1H); 8.35 (s, 1H); 8.48 (s, 1H); 8.66 (s, 1H); Mass Spectrum: (M+H)+ 461.

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