Bis[(2,2-dimethyl­propano­yloxy)meth­yl] {[2-(6-amino-9H-purin-9-yl)eth­oxy]meth­yl}phospho­nate–succinic acid (2/1)

Sungyup Jung; Jeong-Myeong Ha; Il Won Kim

doi:10.1107/S1600536812006873

. 2012 Feb 24;68(Pt 3):o809–o810. doi: 10.1107/S1600536812006873

Bis[(2,2-dimethylpropanoyloxy)methyl] {[2-(6-amino-9H-purin-9-yl)ethoxy]methyl}phosphonate–succinic acid (2/1)

Sungyup Jung ^a, Jeong-Myeong Ha ^b, Il Won Kim ^a,^*

PMCID: PMC3297872 PMID: 22412675

Abstract

The title compound, C₂₀H₃₂N₅O₈P·0.5C₄H₆O₄, is composed of two 9-{2-[bis(pivaloyloxymethoxy)phosphinylmethoxy]ethyl}adenine, commonly known as adefovir dipivoxil (AD), molecules linked to the carboxylic acid groups of succinic acid (SA). The asymmetric unit contains one molecule of AD and half a molecule of SA, which sits on an inversion center. Both adenine units in the two AD molecules make AD–SA N—H⋯O and SA–AD O—H⋯N hydrogen bonds to SA. In addition, the intermolecular AD–AD N—H⋯O—P hydrogen bond serves to stabilize the cocrystal. There is also a π–π stacking interaction [interplanar spacing 3.34 (19) Å] between adjacent inversion-related adenine groups.

Related literature

For the synthesis and process optimization of 9-{2-[bis(pivaloyloxymethoxy)phosphinylmethoxy]ethyl}adenine, see: Starrett et al. (1992 ▶); Yu et al. (1999 ▶). For the biological and pharmacological relevance of 9-{2-[bis(pivaloyloxymethoxy)phosphinylmethoxy]ethyl}adenine, see: Qaqish et al. (2003 ▶); Julander et al. (2002 ▶). For the structure of a hydrate of the title compound, see: Chang et al. (2007 ▶).

Experimental

Crystal data

C₂₀H₃₂N₅O₈P·0.5C₄H₆O₄
M _r = 560.52
Triclinic,
a = 7.7122 (12) Å
b = 10.1577 (15) Å
c = 19.185 (3) Å
α = 80.409 (8)°
β = 79.718 (9)°
γ = 80.407 (8)°
V = 1443.5 (4) Å³
Z = 2
Mo Kα radiation
μ = 0.15 mm⁻¹
T = 296 K
0.11 × 0.10 × 0.08 mm

Data collection

Bruker SMART CCD diffractometer
Absorption correction: multi-scan (SADABS; Bruker, 2002 ▶) T _min = 0.982, T _max = 0.987
49737 measured reflections
7222 independent reflections
4593 reflections with I > 2σ(I)
R _int = 0.053

Refinement

R[F ² > 2σ(F ²)] = 0.046
wR(F ²) = 0.143
S = 1.01
7222 reflections
417 parameters
H atoms treated by a mixture of independent and constrained refinement
Δρ_max = 0.38 e Å⁻³
Δρ_min = −0.29 e Å⁻³

Data collection: SMART (Bruker, 2002 ▶); cell refinement: SAINT (Bruker, 2002 ▶); data reduction: SAINT; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: ORTEP-3 for Windows (Farrugia, 1997 ▶); software used to prepare material for publication: WinGX (Farrugia, 1999 ▶).

Supplementary Material

Crystal structure: contains datablock(s) I, global. DOI: 10.1107/S1600536812006873/pk2386sup1.cif

e-68-0o809-sup1.cif^{(32.2KB, cif)}

Structure factors: contains datablock(s) I. DOI: 10.1107/S1600536812006873/pk2386Isup2.hkl

e-68-0o809-Isup2.hkl^{(353.4KB, hkl)}

Supplementary material file. DOI: 10.1107/S1600536812006873/pk2386Isup3.cml

Additional supplementary materials: crystallographic information; 3D view; checkCIF report

Table 1. Hydrogen-bond geometry (Å, °).

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N1—H1C⋯O1ⁱ	0.812 (19)	2.14 (2)	2.941 (2)	170.16 (18)
N1—H1B⋯O9	0.79 (2)	2.05 (2)	2.842 (2)	175 (2)
O10—H10⋯N4	0.84 (2)	1.91 (2)	2.734 (2)	166 (2)

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Symmetry code: (i) Inline graphic .

Acknowledgments

This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (grant No. 2010-0005045). It was also supported by the Advanced Track of Green Production Processing for Reducing Greenhouse Gas Emissions of the Korea Institute of Energy Technology Evaluation and Planning (KETEP) funded by the Korean Government Ministry of Knowledge Economy (grant No. 20114010203140).

supplementary crystallographic information

Comment

9-{2-[Bis(pivaloyloxymethoxy)phosphinylmethoxy]ethyl}adenine, also known as adefovir dipivoxil (AD), is a broad-spectrum antiviral from the class of acyclic nucleoside phosphonates. It is an orally bioavailable prodrug of 9-[2-(phosphonylmethoxy)ethyl] adenine, which acts as a chain terminator nucleotide analogue and is effective against the human immunodeficiency virus, herpes viruses, Epstein–Barr virus, retroviruses, cytomegalovirus, and other DNA viruses (Yu et al., 1999; Julander et al., 2002; Qaqish et al., 2003). In the present study, we report a new cocrystal of AD with succinic acid to later study the physical characteristics, such as thermal stability and in vitro release behavior.

Experimental

The title compound was formed during cocrystallization in a 2:1 molar ratio of 9-{2-[bis(pivaloyloxymethoxy)phosphinylmethoxy]ethyl}adenine, commonly known as adefovir dipivoxil, (0.4 mmol, AMoRe Pacific Co., purity > 99%) and succinic acid (0.2 mmol, Sigma–Aldrich, purity > 99%). The two components were dissolved in ethanol (3 ml, Samchun Chemical, Korea, HPLC grade) and heated at 45–50°C for 1 h. The prepared solution was stored in a 25°C incubator, and the crystals were started to be visible after about 1 d. After 2 more weeks, the crystals were filtered, washed with deionized water (Resistivity > 18.2 MΩ-cm; Direct-Q, Millipore), and dried for 24 h in a 40°C vacuum oven.