Scaleable processes for the synthesis of (-)-β-D-2,6-diaminopurine dioxolane (Amdoxovir, DAPD) and (-)-β-D-2-aminopurine dioxolane (APD)

Abstract

An efficient and scalable synthesis of (-)-DAPD and (-)-APD has been developed. We discovered that t-butyl cyanoacetate can be used as a new additive for the sugar nucleoside base coupling step en route to DAPD with improved β-selectivity and an isolated yield four fold greater than the original process scale method. Using this new process, (-)-DAPD has been prepared on greater than 20 g scale. In the synthesis of (-)-APD, a key enzyme-catalyzed hydrolysis reaction afforded the water-soluble deprotected α-anomer while leaving the β-anomer completely untouched.

Fig. 1

(−)-β-D-2,6-Diaminopurine dioxolane (DAPD) and (−)-β-D-2-Aminopurine dioxolane (APD).

Scheme 1

Early synthesis of (−)-DAPD.

Scheme 2

Reagents and conditions: (a) (i) LiAl(Ot-Bu)₃H, THF, −20 °C, 2 h; (ii) Ac₂O, DMAP, −10 °C, 2 h, rt, overnight, 60%; (b) (i) 2,6-dichloropurine, 5, HMDS, (NH₄)₂SO₄, reflux, 2 h; (ii) TMSI, CH₂Cl₂, −10 °C to rt, 6 h, 9–18%; (c) (i) NaN₃, DMF, rt, 1 h; (ii) n-BuBr, rt, 0.5 h; (d) H₂, 5% Pd/C, DMF, rt; (e) (i) n-butyl amine, MeOH, reflux, 4h; (ii) recrystallization denatured ethanol:water 52:48 w/w 61–91% (four steps).

Scheme 3

Reagents and conditions: (a) CNCH₂COO^tBu, TMSI, CH₂Cl₂, −10 to −15 °C; 1 h; 4 °C, 15 h, rt for 3h, 45%; (b) HMDS, (NH₄)₂SO₄, reflux, 4 h; (c) NH₃/MeOH, rt, 25 h, 83%

Scheme 4

Reagents and conditions: (a) TMSI, CHCl₃, silylated 2-amino-6-chloropurine −10 ~ −15 °C, 2 h; rt, 15h; reflux, 5 h; (b) silica gel chromatography (hexane:ethyl acetate 100:0 to 0:100) 46% from 4; (c) H₂/Pd-C, NH₄OH/MeOH, rt, 20 h, 84%.