Cesium fluoride → (1,1-dimethylethyl) 3-[[5-methyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alaninate

Participants

Reaction Steps

A mixture of 620 mg (1.6 mmoles) of 4-bromo-5-methyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-piperidinyl]-pyrimidine, 565 mg (1.92 mmoles) of (1,1-dimethylethyl) 3-amino-N-[(phenylmethoxy)carbonyl]alaninate (prepared according to J. Med. Chem. (2001), 44(8), 1158-1176), 340 mg (2.25 mmoles) of caesium fluoride, 73 mg (0.08 mmoles) of tris(dibenzylideneacetone) dipalladium(0), 100 mg (0.16 mmoles) of S(−)2,2′-bis(diphenyl-phosphino)-1,1′-binaphthyl in 50 ml of dioxane is heated under reflux for 5 hours. After cooling down another 280 mg (0.96 mmoles) of (1,1-dimethylethyl)-3-amino-N-[(phenylmethoxy)carbonyl]alaninate, 340 mg (2.25 mmoles) of caesium fluoride, 73 mg (0.08 mmoles) of tris(dibenzylideneacetone) dipalladium(0), and 100 mg (0.16 mmoles) of S(−)2,2′-bis(diphenyl-phosphino)-1,1′-binaphthyl are then added and the reaction mixture is heated under reflux for 5 hours. The reaction mixture is evaporated to dryness under reduced pressure (2 kPa) and the residue is taken up in ethyl acetate, water and a saturated solution of sodium bicarbonate. The organic phase is separated, dried over magnesium sulphate and the solvent is evaporated off under reduced pressure (2 kPa). The residue is chromatographed a first time on silicagel eluting with a gradient of ethyl acetate-methylene chloride-triethylamine-methanol from 50-50-0-0 to 50-50-2-2. The product obtained is chromatographed a second time on alumina eluting with a mixture of heptane-methylene chloride 50-50 then with ethyl acetate-diisopropyl ether 50-50. 360 mg (Yield=37%) of expected product is obtained in the form of an amorphous white solid.

Provenance & Evidence