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Synthesis 2001; 2001(4): 0559-0564
DOI: 10.1055/s-2001-12352
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Three Routes for the Synthesis of 6-Benzyl-1-ethoxymethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde

Lene Petersen* , Erik B. Pedersen, Claus Nielsen
  • *Department of Chemistry, University of Southern Denmark, Odense University, Campusvej 55, 5230 Odense M, Denmark; Fax + 45 66 15 87 80; E-mail: ebp@chem.sdu.dk
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Publication Date:
31 December 2001 (online)

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6-Benzyl-1-ethoxymethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde (1) is an analog of MKC-442, a very potent inhibitor of HIV-1 reverse transcriptase. 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 alkylation, 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 alkylated 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 compound 7 as a precursor for 6-benzyl-1-ethoxymethyl-5-oxiranyl-1H-pyrimidine-2,4-dione (11) by reacting 7 with MCPBA, but compound 11 was too reactive and was ring-opened by the m-chlorobenzoate present in the solution. Two intermediates were N-1 alkylated to give new MKC-442 analogs containing a hydroxymethyl group (13) or a cyano group (14) in the C-5 position. None of the compounds showed activity against the mutated HIV-1 virus (Tyr181Cys) but good activities were observed against wild-type HIV-1 for the intermediates 4 and 7 containing iodine or a vinyl group in the C-5 position, respectively.

HIV-1 - non-nucleoside reverse transcriptase inhibitors - MKC-442 analogs - uracil-5-carbaldehydes - 5-vinyluracils

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