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Volume 68 
Part 11 
Pages o472-o474  
November 2012  

Received 5 September 2012
Accepted 19 October 2012
Online 27 October 2012

{5'-O-[Bis(4-methoxyphenyl)(phenyl)methyl]-2'-deoxy-[beta]-D-threopentofuranosyl}thymine ethyl acetate 0.25-solvate

aJiangsu Institute of Nuclear Medicine, Wuxi 214063, People's Republic of China
Correspondence e-mail: wy_why007@163.com

The title compound, C31H32N2O7·0.25C4H8O2, is a key intermediate in the synthesis of [18F]fluorine-labelled thymidine (18F-FLT), which is the most widely used molecular imaging probe for positron emission tomography (PET). The crystallographic asymmetric unit contains two independent thymine molecules plus one partially occupied site for an ethyl acetate molecule. The two independent thymine molecules show similar geometrical features, except that the dimethoxytrityl groups adopt different orientations with respect to the remainder of the molecule. Each thymine base adopts an anti conformation with respect to the attached deoxyribose ring, and the deoxyribose rings show C3-endo puckering. The conformation of the side chain at the C1 position of the deoxyribose ring is gauche+. Intermolecular N-H...O and O-H...O hydrogen bonds link the molecules into one-dimensional chains.

Comment

[18F]Fluorine-labeled thymidine (FLT) appears to be the most promising radiopharmaceutical because of its lack of in vivo degradation, metabolic trapping in proliferating cells and the favourable half life for PET imaging (Troost et al., 2010[Troost, E. C. C., Bussink, J., Hoffmann, A. L., Boerman, O. C., Oyen, W. J. G. & Kaanders, J. H. (2010). J. Nucl. Med. 51, 866-874.]; Agool et al., 2011[Agool, A., Slart, R. H., Thorp, K. K., Glaudemans, A., Cobben, D., Been, L. B., Burlage, F. R., Elsinga, P. H., Dierckx, R., Vellenga, E. & Holter, J. (2011). Nucl. Med. Commun. 32, 17-22.]). The title compound, (I)[link], is one of the key intermediates in the chemical synthesis of 18F-FLT. It comprises thymidine protected at the 5'-O-position by reaction with dimethoxytrityl chloride in pyridine (Martin et al., 2002[Martin, S. J., Eisenbarth, J. A., Wagner-Utermann, U., Mier, W., Henze, M. & Pritzkow, H. (2002). Nucl. Med. Biol. 29, 253-273.]; Yun et al., 2003[Yun, M., Oh, S. J., Ha, H. J., Ryu, J. S. & Moon, D. H. (2003). Nucl. Med. Biol. 30, 151-157.]).

[Scheme 1]

The crystal structure of (I)[link] has two independent thymine molecules in the asymmetric unit (molecules A and B; Fig. 1[link]) and one ethyl acetate molecule with a site-occupation factor of 0.50. The bond lengths and angles (Table 1[link]) are similar to those reported for other deoxythymidine analogs (Young & Wilson, 1975[Young, D. W. & Wilson, H. R. (1975). Acta Cryst. B31, 961-965.]; Sato, 1988[Sato, T. (1988). Acta Cryst. C44, 870-872.]; Jia et al., 1990a[Jia, Z., Tourigny, G., Delbaere, L. T. J., Stuart, A. L. & Gupta, S. V. (1990a). Can. J. Chem. 68, 836-841.],b[Jia, Z., Tourigny, G., Stuart, A. L., Delbaere, L. T. J. & Gupta, S. V. (1990b). Acta Cryst. C46, 2182-2185.]). The two molecules exhibit similar geometrical features, except that the dimethoxytrityl group adopts a different orientation with respect to the remainder of the molecule (Fig. 2[link]). The conformation of the thymine ring with respect to the deoxyribose ring is anti, as inferred from the torsion angles about the glycosyl bond (C8-N1-C4-O1). The thymine ring (O3/O4/N1/N2/C5-C9) is essentially planar (average deviations from the mean plane of 0.019 and 0.015 Å for molecules A and B, respectively) and makes dihedral angles of 81.3 (1) and 80.1 (1)° with the mean plane through the attached deoxyribose ring (O1/C1-C4).

The C-C bonds within the deoxyribose rings (Table 1[link]) have bond lengths in the range 1.514 (5)-1.543 (5) Å. The conformations of the rings are C3-endo, with atoms C3 and C3' displaced by 0.52 and 0.51 Å, respectively, from the mean plane constituted by the remaining four atoms of each deoxyribose ring. The puckering mode is described by the pseudorotation phase angle, P (Altona & Sundaralingam, 1972[Altona, C. & Sundaralingam, M. (1972). J. Am. Chem. Soc. 94, 8205-8212.]; Saenger, 1984[Saenger, W. (1984). Principles of Nucleic Acid Structure, pp. 21-25 and 69-71. New York: Springer-Verlag.]); here, P = 164.5 (3) and 158.2 (3)° for molecules A and B, respectively. The ring puckering amplitude [tau]m= 34.7 (2) and 34.0 (2)°, which is in agreement with [tau]m = 38±3° observed for nucleosides. Further insight into the distortions is obtained from the Cremer-Pople puckering parameters (Cremer & Pople, 1975[Cremer, D. & Pople, J. A. (1975). J. Am. Chem. Soc. 97, 1354-1358.]): for molecule A, Q = 0.334 (4) Å and [varphi] = 76.1 (6)°; for molecule B, Q = 0.326 (4) Å and [varphi] = 70.3 (6)°.

The conformation about the C1-C10 and C1'-C10' bonds is gauche+ (g+), as seen from the torsion angles (Table 1[link]). Although the g+ conformation is the most common for the side chain at C1 for cytidine and 2'-deoxycytidine nucleosides (Young & Wilson, 1975[Young, D. W. & Wilson, H. R. (1975). Acta Cryst. B31, 961-965.]; Jia et al., 1990a[Jia, Z., Tourigny, G., Delbaere, L. T. J., Stuart, A. L. & Gupta, S. V. (1990a). Can. J. Chem. 68, 836-841.]; Audette et al., 1997[Audette, G. F., Zoghaib, W. M., Tourigny, G., Gupta, S. V. & Delbaere, L. T. J. (1997). Acta Cryst. C53, 1099-1101.], 1998[Audette, G. F., Kumar, S. V. P., Gupta, S. V. & Quail, J. W. (1998). Acta Cryst. C54, 1987-1990.]), some 2'-deoxycytidine analogues display a trans conformation (Sato, 1988[Sato, T. (1988). Acta Cryst. C44, 870-872.]; Jia et al., 1990b[Jia, Z., Tourigny, G., Stuart, A. L., Delbaere, L. T. J. & Gupta, S. V. (1990b). Acta Cryst. C46, 2182-2185.]; Napper et al., 1995[Napper, S., Stuart, A. L., Kumar, S. V. P., Gupta, V. S. & Delbaere, L. T. J. (1995). Acta Cryst. C51, 96-98.]). The torsion angles about the O5-C10 and O5'-C10' bonds (Table 1[link]) show that the dimethoxytrityl group is in a staggered orientation, as in other trityl nucleoside structures (Capron et al., 1994[Capron, M. A., McEldoon, W. L., Baenziger, N. C. & Wiemer, D. F. (1994). Acta Cryst. C50, 291-294.]). As shown in Fig. 2[link], the dimethyloxytrityl groups adopt different orientations in molecules A and B, related by rotation of the group around the C11-O5 or C11'-O5' bonds.

In the crystal structure, molecules A and B are linked into one-dimensional chains running parallel to the a axis by several intermolecular hydrogen bonds (Table 2[link] and Fig. 3[link]). The thymine rings in two approximately centrosymmetrically arranged molecules interact through pairs of N2'-H2'N...O4 and N2-H2N...O4' hydrogen bonds. Neighbouring pairs of molecules are then linked by O-H...O hydrogen bonds from the exocyclic hydroxy group of the deoxyfuranose ring to the O atoms of the thymine groups. These interactions are bifurcated, viz. O2-H2O...O3i and O2'-H2'O...O3'ii, and O2-H2O...O4'i and O2'-H2'O...O4ii (symmetry codes are as in Table 2[link]).

[Figure 1]
Figure 1
The asymmetric unit of (I)[link], showing displacement ellipsoids at the 30% probability level. H atoms have been omitted.
[Figure 2]
Figure 2
Overlay of molecules A (dark spheres; blue in the electronic version of the paper) and B (light spheres; red), showing the different orientations adopted by the dimethoxytrityl group. H atoms have been omitted.
[Figure 3]
Figure 3
The molecular packing of (I)[link], showing the intermolecular hydrogen-bond network. H atoms not involved in hydrogen bonding have been omitted. Symmetry codes as in Table 2[link].

Experimental

The title compound was synthesized according to the literature procedure of Yun et al. (2003[Yun, M., Oh, S. J., Ha, H. J., Ryu, J. S. & Moon, D. H. (2003). Nucl. Med. Biol. 30, 151-157.]). The crude product was recrystallized from ethyl acetate (m.p. 349.8-350.3 K; literature 350 K). 1H NMR (400 MHz; DMSO-d6): [delta] 7.29-6.84 (m, 14H, Ar-H and H-6), 3.85 (m, 1H, H-4'), 3.73 (s, 6H, OCH3), 3.42 (m, 2H, H-5), 2.51 (m, 2H, H-2), 1.79 (s, 3H, 5-CH3). 13C NMR (100 MHz, DMSO-d6): [delta] 85.2 (C-1'), 83.7 (CPh3), 80.3 (C-4'), 69.0 (C-3'), 60.1 (C-5'), 55.3 (OCH3), 41.4 (C-2'), 12.8 (CH3).

Crystal data
  • C31H32N2O7·0.25C4H8O2

  • Mr = 566.61

  • Monoclinic, P 21

  • a = 10.542 (2) Å

  • b = 17.931 (4) Å

  • c = 17.136 (3) Å

  • [beta] = 107.51 (3)°

  • V = 3089.1 (11) Å3

  • Z = 4

  • Mo K[alpha] radiation

  • [mu] = 0.09 mm-1

  • T = 153 K

  • 0.54 × 0.32 × 0.25 mm

Data collection
  • Rigaku AFC10/Saturn724+ diffractometer

  • 24617 measured reflections

  • 7094 independent reflections

  • 6327 reflections with I > 2[sigma](I)

  • Rint = 0.038

Refinement
  • R[F2 > 2[sigma](F2)] = 0.056

  • wR(F2) = 0.151

  • S = 1.00

  • 7094 reflections

  • 790 parameters

  • 5 restraints

  • H atoms treated by a mixture of independent and constrained refinement

  • [Delta][rho]max = 0.79 e Å-3

  • [Delta][rho]min = -0.32 e Å-3

Table 1
Selected geometric parameters (Å, °)

O1-C1 1.452 (4)
O1-C4 1.422 (4)
C1-C2 1.531 (4)
C2-C3 1.515 (4)
C3-C4 1.518 (5)
O1'-C1' 1.442 (4)
O1'-C4' 1.423 (4)
C1'-C2' 1.543 (5)
C2'-C3' 1.514 (5)
C3'-C4' 1.520 (5)
C8-N1-C4-O1 -120.7 (3)
C11-O5-C10-C1 -175.7 (3)
O1-C1-C10-O5 -66.4 (3)
C8'-N1'-C4'-O1' -121.5 (3)
C11'-O5'-C10'-C1' 175.5 (3)
O1'-C1'-C10'-O5' -63.3 (4)

Table 2
Hydrogen-bond geometry (Å, °)

D-H...A D-H H...A D...A D-H...A
N2-H2N...O4' 0.96 (4) 1.81 (4) 2.774 (4) 180 (5)
O2-H2O...O3i 0.84 2.28 3.000 (4) 144
O2-H2O...O4'i 0.84 2.54 3.029 (4) 119
N2'-H2'N...O4 0.77 (4) 2.02 (4) 2.778 (4) 172 (4)
O2'-H2'O...O3'ii 0.95 (5) 2.27 (5) 3.060 (4) 141 (4)
O2'-H2'O...O4ii 0.95 (5) 2.33 (5) 2.873 (4) 116 (4)
Symmetry codes: (i) x-1, y, z; (ii) x+1, y, z.

H atoms bound to C atoms were placed geometrically and refined using a riding model, with C-H = 0.95 (aromatic), 0.98 (methyl), 0.99 (methylene) or 1.00 Å (methine) and Uiso(H) = 1.2Ueq(C). The methyl groups were allowed to rotate around their local threefold axes. H atoms bound to N2, N2' and O2' were located in difference Fourier maps and refined without restraint. Atom H2O could not be treated in this way and so was placed geometrically and refined as riding, with O-H = 0.84 Å and Uiso(H) = 1.2Ueq(O). The site occupancy of the ethyl acetate molecule was constrained to 0.5 in order to produce reasonable displacement parameters. The geometry of this molecule was also restrained with bond-length restraints and the atomic displacement parameters of solvent atoms O16 and C63 were constrained to be identical. The maxima in the final difference Fourier map are located around the solvent molecule. In the absence of significant anomalous scattering effects, Friedel pairs were merged as equivalent data. The absolute structure was assigned on the basis of the known chirality of thymidine used in the chemical synthesis.

Data collection: CrystalClear (Rigaku, 2008[Rigaku (2008). CrystalClear. Rigaku Corporation, Tokyo, Japan.]); cell refinement: CrystalClear; data reduction: CrystalClear; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008[Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.]); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008[Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.]); molecular graphics: DIAMOND (Brandenburg, 2004[Brandenburg, K. (2004). DIAMOND. Crystal Impact GbR, Bonn, Germany.]); software used to prepare material for publication: SHELXL97.


Supplementary data for this paper are available from the IUCr electronic archives (Reference: BI3048 ). Services for accessing these data are described at the back of the journal.


Acknowledgements

This research was supported by Jiangsu Province Science and Technology Support Program for Social Development (grant No. BE2010623).

References

Agool, A., Slart, R. H., Thorp, K. K., Glaudemans, A., Cobben, D., Been, L. B., Burlage, F. R., Elsinga, P. H., Dierckx, R., Vellenga, E. & Holter, J. (2011). Nucl. Med. Commun. 32, 17-22.  [CrossRef] [ChemPort] [PubMed]
Altona, C. & Sundaralingam, M. (1972). J. Am. Chem. Soc. 94, 8205-8212.  [CrossRef] [ChemPort] [PubMed] [ISI]
Audette, G. F., Kumar, S. V. P., Gupta, S. V. & Quail, J. W. (1998). Acta Cryst. C54, 1987-1990.  [CrossRef] [details]
Audette, G. F., Zoghaib, W. M., Tourigny, G., Gupta, S. V. & Delbaere, L. T. J. (1997). Acta Cryst. C53, 1099-1101.  [CrossRef] [details]
Brandenburg, K. (2004). DIAMOND. Crystal Impact GbR, Bonn, Germany.
Capron, M. A., McEldoon, W. L., Baenziger, N. C. & Wiemer, D. F. (1994). Acta Cryst. C50, 291-294.  [CrossRef] [details]
Cremer, D. & Pople, J. A. (1975). J. Am. Chem. Soc. 97, 1354-1358.  [CrossRef] [ChemPort] [ISI]
Jia, Z., Tourigny, G., Delbaere, L. T. J., Stuart, A. L. & Gupta, S. V. (1990a). Can. J. Chem. 68, 836-841.  [CrossRef] [ChemPort]
Jia, Z., Tourigny, G., Stuart, A. L., Delbaere, L. T. J. & Gupta, S. V. (1990b). Acta Cryst. C46, 2182-2185.  [CrossRef] [details]
Martin, S. J., Eisenbarth, J. A., Wagner-Utermann, U., Mier, W., Henze, M. & Pritzkow, H. (2002). Nucl. Med. Biol. 29, 253-273.  [CrossRef]
Napper, S., Stuart, A. L., Kumar, S. V. P., Gupta, V. S. & Delbaere, L. T. J. (1995). Acta Cryst. C51, 96-98.  [CrossRef] [details]
Rigaku (2008). CrystalClear. Rigaku Corporation, Tokyo, Japan.
Saenger, W. (1984). Principles of Nucleic Acid Structure, pp. 21-25 and 69-71. New York: Springer-Verlag.
Sato, T. (1988). Acta Cryst. C44, 870-872.  [CrossRef] [details]
Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.  [CrossRef] [details]
Troost, E. C. C., Bussink, J., Hoffmann, A. L., Boerman, O. C., Oyen, W. J. G. & Kaanders, J. H. (2010). J. Nucl. Med. 51, 866-874.  [CrossRef] [PubMed]
Young, D. W. & Wilson, H. R. (1975). Acta Cryst. B31, 961-965.
Yun, M., Oh, S. J., Ha, H. J., Ryu, J. S. & Moon, D. H. (2003). Nucl. Med. Biol. 30, 151-157.  [CrossRef] [PubMed] [ChemPort]


Acta Cryst (2012). C68, o472-o474   [ doi:10.1107/S010827011204351X ]