Method for the synthesis of uric acid derivatives

A general procedure to obtain tetra-substituted uric acid by stepwise N-alk ylation is described. 2,6-Dichloropurine (1) was condensed with 1-propanol by Mitsunobu reaction to give 9-propyl congener (2). Treatment of 2 with am monia gave adenine derivative (4a), which was converted to the 8-oxoadenine (5b) in 3 steps. Methylation of 5b proceeded site-specifically to give 6-a mino-2-chloro-7,8-dihydro-7-methyl-9-propylpurin-8-one (6) as a sole produc t. Compound 6 was successively treated with NaNO2 and iodomethane to give 2 -chloro-1,6,7,8-tetrahydro-1,7-dimethyl-9-propylpurin-6,8-dione (9) accompa nied by the O-6-methyl product (8) in 75% and 6.9%, respectively. After nuc leophilic substitution of 9 with NaOAc, the product (11) was reacted with i odomethane to give the uric acid (12) and the 2-methoxy product (13) in 46% and 15.5%, respectively. However, the reaction of 11. with the benzylating agents gave only O-benzyl products (14a,b).