Synthesis of (−)‐DAPD

Abstract

A new synthesis of (-)-DAPD, suitable for large scale development, is described.

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

“…The crude product was crystallized from isopropanol and 690 mg (45% yield) of colorless β-isomer crystals were obtained. NMR analysis revealed one mol equivalent of isopropanol in addition to (2 R , 4 R )-2-isobutyryloxymethyl-4-(2,6-diaminopurin-9-yl)-1,3-dioxolane, 8 13 . 1 H-NMR (400 MHz, DMSO- d 6 ) δ: 0.95–1.04 (m, 12H, 4 × CH 3 ); 2.44–2.40 (m, 1H, CH); 3.71–3.75 (m, 1H, CH), 4.17–4.52 (m, 5H, CH, 2 × CH 2 ); 5.20 (t, 1H, J =3.2 Hz, CH); 5.80 (brs, 2H, NH 2 ) 6.17 (dd, 1H, J =1.6 Hz, J =5.6 Hz, CH); 6.71 (brs, 2H, NH 2 ); 7.74 (s, 1H, ArH).…”

“…13 The resolution relies on a simple two-step synthesis of racemic, ester protected, dioxolane lactone from commercially available 2,2-dimethoxy or 2,2-diethoxy ethanol in an isolated 79% yield. An enzyme resolution of the racemic dioxolane lactone completes the three-step sequence to the key intermediate ( R )-lactone B, 3 (Scheme 2).…”

“…13 As shown in Scheme 2, this process started with the selective reduction of ( R )-lactone B, 3 with lithium tri- tert -butoxyaluminum hydride followed by acylation with acetic anhydride to provide (2 R -4 R / S )-4-acetoxy-2-isobutyryloxymethyl-1,3-dioxolane, 4 . In the key coupling step, 2,6-dichloropurine, 5 and dioxolane acetate, 4 were used under Vobrüggen conditions to afforded a crude mixture of nucleoside analogs as a 1:1 mixture of α- and β-anomers.…”

Adenosine Dioxolane Nucleoside Phosphoramidates As Antiviral Agents for Human Immunodeficiency and Hepatitis B Viruses

“…Reagents and conditions: (a) Reference 20; i) HMDS, NH 4 SO 4 , nucleoside base; ii) TMSI, CHCl 3 , −10 °C; (b) (i) nucleophile, THF, reflux; (ii) NH 3 /CH 3 OH, CH 3 OH, rt, 12 h; (c) Pd/C, H 2 , NaOH, 20 h.…”

“…The (−)-β-D-(2 R ,4 R )-1,3-dioxolane purine modified nucleosides were synthesized from key intermediate (−)-β-D-1,3-dioxolanyl-2,6-dichloropurine, 2 , which was obtained by the glycosylation reaction of silylated 2,6-dichloropurine with acetoxy dioxolane derivative 1 . 20 …”