Reaction Steps
A mixture containing 3.48 g (9 mm) of 2-pivaloylamino-4-hydroxy-6-(3-tetrahydropyr-2-yloxyprop-1-en-1-yl)-pyrido[2,3-d]pyrimidine, 3.12 g, (1.2 equiv.) of diethyl N-(4-iodobenzoyl)glutamate, 546 mg (20%) of tris(2-methylphenyl)phosphine, 201 mg (10%) of palladium acetate and 85.5 mg (5%) of cuprous iodide in 15 ml of triethylamine and 240 ml of acetonitrile was heated at reflux under nitrogen. After 12 hours., 1.17 g of diethyl N-(4-iodobenzoyl)glutamate was added and the reaction mixture was heated at reflux under nitrogen for an additional 12 hours. The reaction mixture then was concentrated under reduced pressure and the residue was chromatographed on silica gel, eluting with 20:1 ethyl acetate:hexane. (Recovered starting material can be recycled through the foregoing procedure.) The concentrated material was dissolved in 1:5 ethyl acetate:ether and this solution was refrigerated for 15 hours. The solid which formed was collected by filtration, washed with cold ethyl acetate and dried to yield diethyl N-[4-{1-(tetrahydropyr-2-yloxy)-3-(2-pivaloylamino-4-hydroxypyrido[2,3-d]pyrimidin-6-yl)prop-2-en-2-yl}benzoyl]glutamate. mp. 273°-275° C. Analysis calculated for C36H45N4O9 ; C, 62.50; H, 6.56; N, 10.12. Found: C, 62.21; H, 6.34; N, 9.83. NMR (CDCL3), delta, 1.24 (t, 3H, J=7 Hz), 1.32 (t 3H, J=7 Hz), 1.32 (s, 9H), 1.53-1.87 (m, 6H), 2.11-2.22 (m, 1H), 2.29-2.41 (m 1H), 2.42-2.58 (m, 2H), 3.53-3.59 (m, 1H), 3.80-3.88 (m, 1H), 4.13 (q, 2H, J=7 Hz), 4.25 (q, 2H, J=7 Hz), 4.33 (d, 1H, J=14 Hz), 4.62 (d, 1H, J=14 Hz), 4.75-4.83 (m, 2H), 6.84 (s, 1H), 7.12 (brs, 1H, NH, J =7 Hz), 7.31 (d, 2H, J=8.1 Hz), 7.79 (d, 2H, J=8.1 Hz), 8.13 (d, 1H, J=1.6 Hz), 8.34 (brs, NH), 8.42 (d, 1H, J=1.6 Hz), 11.99 (brs, NH).
