The preparation of 3H-labeled acyclic nucleoside phosphonates and study of their stability

Abstract

9-(2-Phosphonomethoxyethyl)-2,6-diamino-[8-3 H]purine (4), 9-(2-phosphonomethoxyethyl)-[8-3 H]guanine (6) and (R)-9-(2-phosphonomethoxypropyl)-[8-3 H]adenine (11) with specific activities of 10.9, 7.9 and 16 Ci/mmol, respectively, were prepared by a catalytic dehalogenation of the corresponding 8-bromo derivatives 1, 2 and 9. The rate of the exchange of the tritium label on C-8 of the purine ring in title compounds with the hydrogen of water under physiological pH at 20°C was studied using 3 H NMR. The loss of 3 H-label attained 7% in [8-3 H]tenofovir (11), 10% in [8-3 H]PMEDAP (4) and 12% in [8-3 H]PMEG (6) after the period of 3 weeks. Storage at a temperature of -196°C in liquid nitrogen ensured a better than 97% radiochemical purity of the prepared labeled compounds even after a six-month period.

The Di-Tert-Butyl Oxymethylphosphonate Route to the Antiviral Drug Tenofovir

“…A new practical two-step sequence for the synthesis of tenofovir was developed using the hitherto unknown (di-tert-butoxyphosphoryl)methyl 4-methylbenzenesulfonate (13) and (di-tertbutoxyphosphoryl)methyl methanesulfonate (14). These crystalline key intermediates could be synthesized in gram amounts using straightforward chemistry and avoiding any chromatography step.…”

“…Furthermore, no recrystallization was necessary as excessive mesyl chloride completely hydrolyzed during the aqueous work-up and no byproducts formed. Crystalline (di-tertbutoxyphosphoryl)methyl methanesulfonate(14) could be obtained in 97% yield even on multigram scale (Scheme 6).Scheme 6: Mesylation of di-tert-butyl (hydroxymethyl)phosphonate.2.4 Synthesis of PMPA using tert-butyl oxymethyl phosphonates 13 and 14.For screening the alkylation of HPA, the focus was laid on using mesylate 14 due to its more efficient preparation. Performing the reaction in DMF and using other bases than Mg(O t Bu)2 such as KOtBu, NaOtBu or NaH led to product mixtures containing both N-and O-alkylated HPA, bis-alkylated HPA and both isomers of 9-propenyladenine which probably had formed due to transesterification and subsequent elimination.…”

Di-tert-butyl Phosphonate Route to the Antiviral Drug Tenofovir

“…There is no variation in the alkyl group of oyxmethyl phosphonates reported in the literature other than the use of diisopropyl ester, which requires similar conditions for the deprotection as the diethyl ester 6. 14,15 Tert-butyl phosphonates 16,17 are also known for being deprotected under aqueous acidic conditions. In this report, the synthesis of di-tert-butyl oxymethyl phosphonates and their suitability for preparing PMPA was investigated.…”

The Di-Tert-Butyl Oxymethylphosphonate Route to the Antiviral Drug Tenofovir

“…There is no variation of the alkyl group of oyxmethyl phosphonates reported in literature than the use of diisopropyl ester which requires similar conditions for the deprotection as the diethyl ester 6. 14,15 Tert-butyl phosphonates 16,17 are also known for being deprotected under aqueous acidic conditions. In this report, the synthesis of di-tert-butyl oxymethyl phosphonates and their suitability for preparing PMPA (1) was investigated.…”

“…An oven-dried Schlenk flask was charged with HPA (4, >98%, 5.00 g, 25.9 mmol 1.0 eq.) and magnesium tert-butoxide (93%,14.24. g, 77.64 mmol, 3.0 eq.)…”