An improved synthesis of 9-(3-pyridylmethyl)-[2-14C]-9-deazaguanine

Abstract

Purine nucleoside phosphorylase (PNP) inhibitors may be useful in the treatment of a wide variety of disorders in which activated T-cells are pathogenic, such as rheumatoid arthritis and psoriasis, T-cell leukemia and lymphomas, and in the prevention of host-vs. graft rejection. A PNP inhibitor currently in clinical trials is 9-(3-pyridylmethyl)-9-deazaguanine (2-amino-7-(3-pyridylmethyl)-4-oxo-3H,5H-pyrrolo[3,2-d]pyrimidine or peldesine). We now report an improved route which gives 9-(3-pyridylmethyl)-[2-14C]-9-deazaguanine 1 in high yield and avoids the formation of 2-methylthio-7-(3-pyridylmethyl)-4-oxo-3H,5H-[2-14C]-pyrrolo[3,2-d]pyrimidine 1a, the major byproduct of an earlier reported synthesis of 1. In this new route, the source of the label was N,N′-bismethoxycarbonyl-S-methyl-[14C]-isothiopseudourea 8, prepared from 2-methyl-[14C]-2-thiopseudourea in high yield by a phase transfer catalysis method. Condensation of 8 with methyl 3 amino-4-(3-pyridylmethyl)-1H-pyrrolo-2-carboxylate 4 in acetic acid and methanol gave adduct 9 which was cyclized by treatment with sodium methoxide to 2-amino-protected 10. Deprotection of 10 by hydrolysis with 5% NaOH then gave target compound 1 in 82% yield (from 8). The total yield of product 1 was 2.095 g or 459 mCi, based on a specific activity of 52.9 mCi/ mmol.Copyright © 1998 John Wiley & Sons, Ltd.