Reaction Steps
A slurry of (E)-3-[1,3-bis(cyclohexylmethyl)-1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl]cinnamic acid (from step (a), 0.50 g) in anhydrous N,N-dimethylformamide (10 mL) was heated briefly to near reflux under nitrogen. N,N′-carbonyldiimidazole (Aldrich, 0.202 g, 1.22 mmol) was then added to the pale yellow slurry, which thinned and turned orange as a gas evolved. Within minutes the slurry turned a bright yellow and thickened as a yellow solid formed. The mixture was stirred for 18 h, diluted with dichloromethane (30 mL), and filtered. The bright yellow solid was washed with dichloromethane (30 mL), and dried at 40° C. to provide (E)-1,3-bis(cyclohexylmethyl)-8-(3-(2-(1H-imidazol-1-ylcarbonyl)vinyl)phenyl)-9H-purin-2,6(1H,3H)-dione as a yellow powder (0.403 g). To a mixture of this compound (0.40 g, 0.74 mmol) and nonaethylene glycol monomethyl ether, (part (a) of example 10, 0.350 g) in N,N-dimethyl fornamide (10 ml) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (Aldrich, 0.112 g). The resulting solution was stirred at 55° C. for 20 h. The solution was cooled to room temperature and adjusted to pH 7 by addition of 1N HCl. Chloroform (50 mL) was added and the solution was washed with water (2×20 mL). The combined organic layers were washed with brine, dried (magnesium sulfate) and concentrated under reduced pressure. The residual waxy solid was chromatrographed on silica gel eluted with 10% methanol/chloroform to give (E)-3-[1,3-bis(cyclohexylmethyl)-1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl]cinnamic acid nonaethylene glycol methyl ether ester as a white waxy solid (0.421 g, 63%); 1H-NMR (DMSO-d6) δ: 8.53 (s, 1, aryl CH), 8.13 (d, J=7.7, 1, aryl CH), and 7.80 (d, J=8.5, 1, aryl CH), 7.71 (d, J=16, 1, CH═) 7.58, (m, 1, aryl CH), 6.78, (d, J=15.9, 1, CH═) 4.28 (m,2, CH2O), 3.91, (d, J=7.2, 2, CH2N), 3.77 (d, J=7.2, CH2N), 3.68 (m, 2, CH2O), 3.70-3.40 (m, 32, 16 CH2), 3.21 (s, 3, CH3), 2.1-1.6 and 1.4-1.0 (m, 22, cyclohexyl CH2 and CH).
