Three routes for the synthesis of 6-benzyl-1-ethoxymethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde

6-Benzyl-1-ethoxymethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbaldehy de (1) is an analog of MKC-442, a very potent inhibitor of HIV-1 reverse tr anscriptase. Compound 1 was synthesized by three different routes. 6-Benzyl -1-ethoxymethyl-5-vinyl-1H-pyrimidine-2,4-dione (7) was synthesized in five steps from 6-benzyl-1H-pyrimidine-2,4-dione (2) by iodination; N-1 alkylat ion, N-3 protection, Pd(0) catalyzed coupling with tetravinyltin and then N -3 deprotection. Compound 7 was then cleaved with ozone to give compound 1. In another route compound 2 was hydroxymethylated, oxidized and N-1 alkyla ted to give compound 1. Finally, compound 1 was synthesized from 6-benzyl-2 ,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (10) by reduction with Raney Nickel followed by N-1 alkylation. An attempt was made to use compou nd 7 as a precursor for 6-benzyl-1-ethoxymethyl-5-oxiranyl-1H-pyrimidine-2, 4-dione (11) by reacting 7 with MCPRA, but compound 11 was too reactive and was ring-opened by the m-chlorobenzoate present in the solution. Two inter mediates were N-1 alkylated to give new MKC-442 analogs containing a hydrox ymethyl group (13) or a cyano group (14) in the C-5 position. None of the c ompounds showed activity against the mutated HIV-1 virus (Tyr181Cys) but go od activities were observed against wildtype HIV-1 for the intermediates 4 and 7 containing iodine or a vinyl group in the C-5 position, respectively.