5-Fluoro-1-[(4S,5R)-5-(2-hydroxy­ethyl)-2,2-dimethyl-1,3-dioxolan-4-yl]pyrimidine-2,4(1H,3H)-dione

Angel Mendoza; Martha Sosa-Rivadeneyra; Fernando Sartillo-Piscil; Leticia Quintero; Marcos Flores-Alamo

doi:10.1107/S1600536810016065

. 2010 May 12;66(Pt 6):o1317. doi: 10.1107/S1600536810016065

5-Fluoro-1-[(4S,5R)-5-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxolan-4-yl]pyrimidine-2,4(1H,3H)-dione

Angel Mendoza ^a,^*, Martha Sosa-Rivadeneyra ^b, Fernando Sartillo-Piscil ^b, Leticia Quintero ^b, Marcos Flores-Alamo ^c

PMCID: PMC2979416 PMID: 21579410

Abstract

In the title compound, C₁₁H₁₅FN₂O₅, the five-membered ring has an envelope conformation, while the six-membered ring is essentially planar, with a maximum deviation of 0.032 (2) Å from the mean plane. The crystal packing is stabilized by intermolecular N—H⋯O and O—H⋯O hydrogen bonds, generating a layer structure parallel to (001).

Related literature

For applications of modified nucleosides in medical chemistry, see: Huryn & Okabe (1992 ▶); Minuk et al. (1992 ▶); Luscombe et al. (1996 ▶); Korba & Boyd (1996 ▶). For the synthesis, see: Valdivia et al. (2005 ▶); Xie et al. (1996 ▶). For ring conformation analysis, see: Cremer & Pople (1975 ▶).

Experimental

Crystal data

C₁₁H₁₅FN₂O₅
M _r = 274.25
Monoclinic,
a = 20.8905 (8) Å
b = 5.5751 (1) Å
c = 13.5639 (5) Å
β = 126.297 (6)°
V = 1273.21 (12) Å³
Z = 4
Cu Kα radiation
μ = 1.06 mm⁻¹
T = 298 K
0.40 × 0.12 × 0.08 mm

Data collection

Oxford Diffraction Gemini Atlas CCD diffractometer
Absorption correction: analytical (CrysAlis RED; Oxford Diffraction, 2009 ▶) T _min = 0.885, T _max = 0.964
4606 measured reflections
1786 independent reflections
1732 reflections with I > 2σ(I)
R _int = 0.013

Refinement

R[F ² > 2σ(F ²)] = 0.027
wR(F ²) = 0.071
S = 1.04
1786 reflections
181 parameters
1 restraint
H atoms treated by a mixture of independent and constrained refinement
Δρ_max = 0.23 e Å⁻³
Δρ_min = −0.20 e Å⁻³
Absolute structure: Flack (1983 ▶), 498 Friedel pairs
Flack parameter: 0.0 (2)

Data collection: CrysAlis CCD (Oxford Diffraction, 2009 ▶); cell refinement: CrysAlis RED (Oxford Diffraction, 2009 ▶); data reduction: CrysAlis RED; 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 datablocks I, global. DOI: 10.1107/S1600536810016065/is2543sup1.cif

e-66-o1317-sup1.cif^{(18.7KB, cif)}

Structure factors: contains datablocks I. DOI: 10.1107/S1600536810016065/is2543Isup2.hkl

e-66-o1317-Isup2.hkl^{(86.1KB, hkl)}

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
N2—H1N⋯O5ⁱ	0.83 (2)	2.01 (2)	2.828 (2)	167 (3)
O5—H1O⋯O2ⁱⁱ	0.75 (3)	2.16 (3)	2.876 (2)	160 (3)

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Symmetry codes: (i) Inline graphic ; (ii) .

Acknowledgments

Special thanks to BUAP for financial support.

supplementary crystallographic information

Comment

For many years, design of modified nucleosides has been a focal point of research in medicinal chemistry (Huryn & Okabe, 1992). Modified nucleosides have acquired an important role as therapeutic agents for the treatment of patients with devastating infections with viruses such as human immunodeficiency virus (HIV), hepatitis B virus (HBV), and herpes viruses. A class of nucleoside analogues for antiviral chemotherapy is that where cyclic carbohydrate moiety is replaced with open-chain "acyclic" sugar moieties. Among purine acyclic nucleosides, are Acyclovir, Ganciclovir and Penciclovir (Minuk et al., 1992; Luscombe et al., 1996; Korba & Boyd, 1996).

In this context and as result of our continuing investigations on the synthesis of nucleoside analogues, we report a new compound 1 (Scheme 1). This new analogue might present a similarity with a number of acyclic nucleosides, which showed remarkable antiviral properties.

In the present paper, we report the structure of title compound 1. In the [(1'S, 2'R)-(1', 2'-O-isopropylidene-4'-hydroxy-1-butyl)], the five member ring (C5/C6/O3/O4/C9) shows an envelope conformation on atom C6 with puckering parameters (Cremer & Pople, 1975) q₂ = 0.238 (2) Å and φ₂ = 69.8 (6)°. For the six member ring uracil, shows a planar configuration with torsion angle (N1—C4—N2—C3) of 4.8 (3)°, and C1—C2 = 1.325 (3) Å and N2—C4 = 1.384 (2) Å (double bond). The crystal packing is stabilized by two intermolecular hydrogen bonds [O5···O2 = 2.828 (2) Å and N2···O5 = 2.876 (2) Å], generating a layer parallel to the (001) plane.

Experimental

Deshomologation of previos nucleoside analogue, 1-[(1'S,2'R,4'S)-(1',2'-O-isopropylidene-4',5'-dihydroxy-1'-pentyl)]-5-fluorouracil, was achieved following non-aqueous protocol (Valdivia et al., 2005; Xie et al., 1996). Reaction was carried out by two steps: a) periodic acid/ethyl acetate, 30 min, b) EtOH/H2O/ NaBH4, 20 min, rt. Final purification of compound 1 was achieved by crystallization from hexane. Yield 80%, white solid, m.p. 184 °C; [α]_D -18.51 (c 1.0, CH₃OH). ¹H NMR (300 MHz, CDCl₃/TMS) 1.53 (s, 3H), 1.57 (s, 3H), 1.95 (m, 1H), 2.11 (m, 1H), 3.80 (m, 2H), 4.21 (m, 1H), 5.90 (d, 1H, J = 5.1 Hz), 7.3 (s, 1H). ¹³C MNR (75 MHz, CDCl₃/TMS) 26.9, 27.9, 34.9, 55.8, 58.9, 79.4, 86.8, 111.6, 142.2, 149.5, 157.5.