Chloroacetyl chloride → 4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-{1-[[(3R)-3-hydroxypyrrolidin-1-yl]acetyl]piperidin-3-yloxy}quinazoline

Participants

Reaction Steps

Chloroacetyl chloride (47 μl) was added to a solution of 4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-(piperidin-3-yloxy)quinazoline dihydrochloride (250 mg) and diisopropylethylamine (373 μl) in methylene chloride (10 ml) and the mixture was stirred at room temperature for 1 hour. (R)-(+)-3-pyrrolidinol (202 mg) was added, and the solution stirred for 1 hour before being washed with saturated aqueous sodium bicarbonate (10 ml) and purified by flash column chromatography eluting with increasingly polar mixtures of methylene chloride/methanol (saturated with ammonia) (100/0 to 95/5) to give a foam. This foam was dissolved in methylene chloride (5 ml) and crystallised by the addition of isohexane (50 ml) to give the title product as a mixture of two diastereoisomers (68 mg); 1H NMR Spectrum: (DMSO d6, 100° C.) 1.52 (m, 2H), 1.87 (m, 3H), 2.09 (m, 1H), 2.38 (m, 1H), 2.61 (m, 1H), 2.77 (m, 1H), 3.18 (m, 1H), 3.36 (d, 1H), 3.53 (m, 2H), 3.68 (m, 1H), 3.89 (m, 1H), 3.94 (s, 3H), 4.15 (m, 1H), 4.23 (m, 1H), 4.53 (m, 1H), 7.27 (m, 2H), 7.41 (m, 1H), 7.59 (m, 1H), 7.89 (s, 1H), 8.38 (s, 1H), 9.24 (br s, 1H); Mass Spectrum: (M+H)+ 530.

Provenance & Evidence