PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of actaeInternational Union of Crystallographysearchopen accessarticle submissionjournal home pagethis article
 
Acta Crystallogr Sect E Struct Rep Online. 2009 June 1; 65(Pt 6): o1325–o1326.
Published online 2009 May 20. doi:  10.1107/S1600536809017905
PMCID: PMC2969674

Capecitabine from X-ray powder synchrotron data

Abstract

In the title compound [systematic name 5-de­oxy-5-fluoro-N-(pent­yloxycarbon­yl)cytidine], C15H22FN3O6, the pentyl chain is disordered over two positions with refined occupancies of 0.53 (5) and 0.47 (5). The furan ring assumes an envelope conformation. In the crystal, inter­molecular N—H(...)O hydrogen bonds link the mol­ecules into chains propagating along the b axis. The crystal packing exhibits electrostatic inter­actions between the 5-fluoro­pyrimidin-2(1H)-one fragments of neighbouring mol­ecules as indicated by short O(...)C [2.875 (3) and 2.961 (3) Å] and F(...)C [2.886 (3) Å] contacts.

Related literature

Capecitabine is the first FDA-approved oral chemotherapy for the treatment for some types of cancer, including advanced bowel cancer or breast cancer, see: Wagstaff et al. (2003 [triangle]); Jones et al. (2004 [triangle]).

An external file that holds a picture, illustration, etc.
Object name is e-65-o1325-scheme1.jpg

Experimental

Crystal data

  • C15H22FN3O6
  • M r = 359.35
  • Orthorhombic, An external file that holds a picture, illustration, etc.
Object name is e-65-o1325-efi1.jpg
  • a = 5.20527 (2) Å
  • b = 9.52235 (4) Å
  • c = 34.77985 (13) Å
  • V = 1723.91 (1) Å3
  • Z = 4
  • Synchrotron radiation
  • λ = 0.79483 (4) Å
  • μ = 0.15 mm−1
  • T = 293 K
  • Specimen shape: cylinder
  • 40 × 1 × 1 mm
  • Specimen prepared at 101 kPa
  • Specimen prepared at 293 K
  • Particle morphology: no specific habit, white

Data collection

  • ID31 ESRF Grenoble diffractometer
  • Specimen mounting: 1.0 mm borosilicate glass capillary
  • Specimen mounted in transmission mode
  • Scan method: step
  • Absorption correction: none
  • min = 1.0, 2θmax = 35.0°
  • Increment in 2θ = 0.003°

Refinement

  • R p = 0.055
  • R wp = 0.074
  • R exp = 0.036
  • R B = 0.102
  • S = 2.11
  • Wavelength of incident radiation: 0.79483(4) Å
  • Excluded region(s): no
  • Profile function: Pseudo-Voigt profile coefficients as parameterized in Thompson et al. (1987 [triangle]), asymmetry correction according to Finger et al. (1994 [triangle])
  • 499 reflections
  • 91 parameters
  • 77 restraints
  • H-atom parameters not refined
  • Preferred orientation correction: March–Dollase (Dollase, 1986 [triangle]); direction of preferred orientation 001, texture parameter r = 1.03 (1)

Data collection: ESRF SPEC package; cell refinement: GSAS (Larson & Von Dreele, 1994 [triangle]); data reduction: CRYSFIRE2004 (Shirley, 2000 [triangle]) and MOPAC (Dewar et al., 1985 [triangle]); program(s) used to solve structure: FOX (Favre-Nicolin & Černý, 2002 [triangle]); program(s) used to refine structure: GSAS; molecular graphics: Mercury (Macrae et al., 2006 [triangle]) and PLATON (Spek, 2009 [triangle]); software used to prepare material for publication: enCIFer (Allen et al., 2004 [triangle]).

Table 1
Hydrogen-bond geometry (Å, °)

Supplementary Material

Crystal structure: contains datablocks global, I. DOI: 10.1107/S1600536809017905/cv2544sup1.cif

Rietveld powder data: contains datablocks I. DOI: 10.1107/S1600536809017905/cv2544Isup2.rtv

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

Acknowledgments

This study was supported by the Czech Grant Agency (grant No. GAČR 203/07/0040), the Institute of Chemical Technology in Prague (grant No. 108–08–0017) and the research program MSM 2B08021 of the Ministry of Education, Youth and Sports of the Czech Republic.

supplementary crystallographic information

Comment

Capecitabine is the first FDA-approved oral chemotherapy for the treatment for some types of cancer, including advanced bowel cancer or breast cancer (Wagstaff et al., 2003; Jones et al., 2004). Capecitabine is 5-deoxy-5-fluoro-N-[(pentyloxy)carbonyl]-cytidine and in vivo is enzymatically converted to the active drug 5-fluorouracil. Crystal structure determination of capecitabine was not reported yet. In this paper we report crystal structure determination of the title compound from the powder diffraction data by using synchrotron radiation.

The asymmetric unit consists of one molecule of capecitabine (Fig 1). The crystal packing is stabilized by intermolecular interactions - electrostatic interactions proved by short O···C and F···C contacts (Table 1) and N—H···O hydrogen bonds (Table 2).

Experimental

Samples of crystalline capecitabine were prepared by two methods, a and b, respectively. Method a: capecitabine (10 g) was dissolved in EtOH (80 g). The solution was concentrated under reduced pressure to a residual volume of 25 ml and kept under stirring overnight. The solid was filtered off and dried at room temperature furnishing capecitabine (6 g). Method b: capecitabine (18 g) was dissolved in DCM (200 g) and the solution was evaporated to dryness under reduced pressure. The residue was taken up with toluene (400 g) and about 150 g of solvent were distilled off. The solution was heated up to 50°C and then allowed to 3 spontaneously cool to 25°C. After cooling to 0°C, the solid was filtered off, washed with toluene and dried at 60°C under vacuum to constant weight furnishing capecitabine (16.5 g).

Refinement

Both crystallization procedures lead to one polycrystalline form of capecitabine. It was confirmed by measuring on X-Ray powder diffractometer PANalytical Xpert Pro, Cu Kα radiation (λ = 1.541874 Å). Attempts to determine the structure from these data were unsuccessful probably due to flexible molecule of capecitabine and low resolution of these data. The powder obtained by the first "a" procedure was used for structure determination. X-Ray diffraction data were collected on the high resolution diffractometer ID31 of the European Synchrotron Radiation Facility. The monochromatic wavelength was fixed at 0.79483 (4) Å. Si (111) crystal multi-analyser combined with Si (111) monochromator was used (beam offset angle α = 2°). A rotating 1-mm-diameter borosilicate glass capillary with capecitabine powder was used for the experiment. Data were measured from 1.002°2θ to 34.998°2θ at the room temperature, steps scans was set to 0.003°2θ.

First 20 peaks were used by CRYSFIRE 2004 package (Shirley, 2000) to get a list of possible lattice parameters. The most probable result was selected (a = 5.21 Å, b = 9.52 Å, c = 34.79 Å, V = 1724 Å3, FOM (20) = 330). If 15 Å3 are used as an atomic volume for C, N, O and F and 5 Å3 as a volume for hydrogen atom, the approximate molecular volume is 485 Å3. The found volume of 1724 Å3 suggests that there are four molecules in the unit cell (Z = 4). P212121 space group was selected on the basic of peaks extinction and on the basic of agreement of the Le-bail fit. The structure was solved in program FOX (Favre-Nicolin & Černý, 2002) using parallel tempering algorithm. The initial model was generated by AM1 computing method implemented in program MOPAC (Dewar et al., 1985). For the solution process hydrogen atoms were removed. This model was restrained with bonds and angles restraints, automatically generated by program FOX. The refinement was carried out in GSAS (Larson & Von Dreele, 1994). Hydrogen atoms were added in positions based on geometry and structure was restrained by bonds and angles restraints. Five planar restraints for sp2 hybridization were used (O20/C18/O19/N17, N17/C13/N14/C12, C13/C12/F16/C11, N14/C10/O15/N9 and C4/N9/C10/C11). Due to relatively high Uiso thermal parameters of alkyl chain (C21—C25) the structure was refined with two disordered chains (C21—C25 and C21a—C25a) with occupancy factors 0.53 (5) and 0.47 (5). Uiso thermal parameters were constrained just for atoms in disordered chains by this way (C21/C21a, C22/C22a, C23/C23a, C24/C24a, C25/C25a). At the final stage atomic coordinates of non-hydrogen atoms were refined to the final agreement factors: Rp=0.055 and Rwp=0.0743. The diffraction profiles and the differences between the measured and calculated profiles are shown in Fig. 2.

Figures

Fig. 1.
The molecular structure of capecitabine showing the atomic numbering. Displacement spheres are drawn at the 20% probability level. Only major part of the disordered pentyl chain is shown.
Fig. 2.
The final Rietveld plot showing the measured data (black thin-plus), calculated data (red line) and difference curve (blue line). Calculated positions of the reflections are shown by verical bars.

Crystal data

C15H22FN3O6Dx = 1.385 Mg m3
Mr = 359.35Synchrotron radiation, λ = 0.79483(4) Å
Orthorhombic, P212121µ = 0.14 mm1
a = 5.20527 (2) ÅT = 293 K
b = 9.52235 (4) ÅParticle morphology: no specific habit
c = 34.77985 (13) Åwhite
V = 1723.91 (1) Å3cylinder, 40 × 1 mm
Z = 4Specimen preparation: Prepared at 293 K and 101 kPa
F(000) = 760

Data collection

ID31 ESRF Grenoble diffractometerData collection mode: transmission
Radiation source: X-RayScan method: step
Si(111)min = 1.00°, 2θmax = 35.00°, 2θstep = 0.003°
Specimen mounting: 1.0 mm borosilicate glass capillary

Refinement

Least-squares matrix: full91 parameters
Rp = 0.05577 restraints
Rwp = 0.0746 constraints
Rexp = 0.036H-atom parameters not refined
RBragg = 0.102Weighting scheme based on measured s.u.'s w = 1/σ(Yobs)2
χ2 = 4.452(Δ/σ)max = 0.05
11333 data pointsBackground function: Shifted Chebyschev
Excluded region(s): noPreferred orientation correction: March–Dollase (Dollase, 1986); direction of preferred orientation 001, texture parameter r = 1.03(1)
Profile function: Pseudo-Voigt profile coefficients as parameterized in Thompson et al. (1987), asymmetry correction according to Finger et al. (1994)

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2)

xyzUiso*/UeqOcc. (<1)
C1−0.0205 (8)0.8964 (3)0.86415 (10)0.087 (5)*
C20.0063 (7)0.7423 (4)0.87424 (8)0.048 (5)*
C30.0924 (6)0.6753 (3)0.83655 (8)0.049 (4)*
C4−0.0166 (5)0.7766 (2)0.80775 (7)0.081 (5)*
O5−0.0717 (9)0.9090 (3)0.82416 (10)0.093 (3)*
C60.2118 (13)0.9888 (6)0.87530 (18)0.079 (4)*
O7−0.2355 (9)0.6775 (5)0.88107 (14)0.088 (3)*
O80.0594 (11)0.5279 (3)0.83793 (13)0.109 (3)*
N90.1175 (4)0.79531 (18)0.77283 (7)0.036 (4)*
C100.0276 (4)0.73076 (17)0.73805 (7)0.030 (4)*
C110.3307 (5)0.87392 (18)0.77201 (7)0.023 (4)*
C120.4772 (3)0.90315 (14)0.73950 (6)0.031 (4)*
C130.3691 (3)0.83732 (13)0.70512 (6)0.010 (4)*
N140.1675 (4)0.75150 (16)0.70410 (6)0.028 (4)*
O15−0.1690 (5)0.6596 (2)0.73930 (11)0.046 (3)*
F160.6861 (5)0.98180 (17)0.74183 (10)0.072 (2)*
N170.4922 (3)0.86898 (14)0.67035 (6)0.030 (3)*
C180.4009 (4)0.8094 (2)0.63692 (7)0.063 (5)*
O190.2448 (4)0.7158 (3)0.63482 (12)0.108 (3)*
O200.5359 (5)0.8859 (3)0.60977 (10)0.087 (4)*
C210.491 (4)0.8346 (15)0.57240 (14)0.146 (6)*0.53 (5)
C220.524 (3)0.957 (2)0.5449 (2)0.169 (8)*0.53 (5)
C230.801 (3)0.9940 (19)0.5361 (5)0.174 (9)*0.53 (5)
C240.817 (4)1.1183 (13)0.5087 (4)0.174 (10)*0.53 (5)
C250.700 (5)1.082 (2)0.4695 (5)0.143 (9)*0.53 (5)
C21a0.518 (5)0.8251 (19)0.57299 (18)0.146 (6)*0.47 (5)
C22a0.680 (3)0.9142 (19)0.54603 (17)0.169 (8)*0.47 (5)
C23a0.560 (3)0.939 (2)0.5068 (4)0.174 (9)*0.47 (5)
C24a0.764 (5)0.9452 (15)0.4756 (2)0.174 (10)*0.47 (5)
C25a0.925 (4)1.079 (2)0.4786 (7)0.143 (9)*0.47 (5)
H2510.71231.16170.4530.25*0.53 (5)
H2520.52451.05760.47270.25*0.53 (5)
H2530.79061.00570.45850.25*0.53 (5)
H2410.72611.19530.51950.25*0.53 (5)
H2420.99211.14350.50530.25*0.53 (5)
H2310.88661.01730.55940.25*0.53 (5)
H2320.88310.91520.52460.25*0.53 (5)
H2210.44331.03710.55590.25*0.53 (5)
H2220.44060.93380.52140.25*0.53 (5)
H2110.32160.79810.57060.25*0.53 (5)
H2120.61110.76270.56640.25*0.53 (5)
H610.17941.08330.8680.1*
H620.23780.98420.90230.1*
H630.3610.95570.86240.1*
H210.12490.72670.89460.075*
H310.2730.68940.83560.075*
H11−0.1660.93150.87750.12*
H41−0.17860.73860.80070.12*
H1110.38690.91320.79570.03*
H1710.62240.92460.66990.04*
H82−0.07530.50660.82720.1*
H72−0.2160.5920.8830.12*
H25111.05051.08020.45880.25*0.47 (5)
H25121.0081.0820.50290.25*0.47 (5)
H25130.81641.15890.4760.25*0.47 (5)
H24110.8740.86610.4780.25*0.47 (5)
H24120.68240.9430.45110.25*0.47 (5)
H23110.46821.02520.50720.25*0.47 (5)
H23120.44420.86430.50130.25*0.47 (5)
H22110.70751.00290.55780.25*0.47 (5)
H22120.84020.86840.54240.25*0.47 (5)
H21110.58170.73160.57360.25*0.47 (5)
H21120.34420.82450.56470.25*0.47 (5)

Geometric parameters (Å, °)

C1—C21.515 (5)O20—C211.4080 (21)
C1—O51.421 (5)O20—C21a1.4073 (21)
C1—C61.545 (7)C21—C221.5177 (21)
C1—H110.950C21—H2110.949 (16)
C2—C31.525 (4)C21—H2120.951 (24)
C2—O71.422 (6)C22—C231.5196 (21)
C2—H210.950C22—H2210.950 (22)
C3—C41.502 (4)C22—H2220.950 (9)
C3—O81.413 (4)C23—C241.5219 (21)
C3—H310.950C23—H2310.950 (19)
C4—O51.413 (4)C23—H2320.951 (22)
C4—N91.4123 (19)C24—H2410.949 (19)
C4—H410.950C24—H2420.951 (20)
C6—H610.950C25—C241.5304 (21)
C6—H620.950C25—H2510.951 (19)
C6—H630.950C25—H2520.952 (26)
O7—H720.820C25—H2530.950 (23)
O8—H820.820C21a—C22a1.5189 (21)
N9—C101.4352 (18)C21a—H21110.950 (25)
N9—C111.3389 (19)C21a—H21120.951 (26)
C10—N141.4015 (19)C22a—C23a1.5195 (21)
C10—O151.2282 (19)C22a—H22110.950 (15)
C11—C121.3919 (19)C22a—H22120.950 (21)
C11—H1110.950C23a—C24a1.5233 (21)
C12—C131.4625 (19)C23a—H23110.950 (20)
C12—F161.3228 (19)C23a—H23120.950 (18)
C13—N141.3305 (18)C24a—C25a1.5298 (21)
C13—N171.4013 (19)C24a—H24110.949 (21)
N17—C181.3783 (19)C24a—H24120.952 (18)
N17—H1710.860C25a—H25110.950 (19)
C18—O191.2084 (20)C25a—H25120.950 (27)
C18—O201.3839 (20)C25a—H25130.950 (26)
O15···C12i2.961 (3)O15···C11iii2.875 (3)
F16···C10ii2.886 (3)
C2—C1—O5109.0 (3)O20—C21—H212110.1 (17)
C2—C1—C6114.90 (20)C22—C21—H211110.1 (16)
C2—C1—H11107.52C22—C21—H212109.9 (6)
O5—C1—C6110.16 (20)H211—C21—H212109.4 (9)
O5—C1—H11107.4C21—C22—C23114.26 (21)
C6—C1—H11107.5C21—C22—H221108.2 (6)
C1—C2—C3103.46 (14)C21—C22—H222108.2 (14)
C1—C2—O7112.16 (19)C23—C22—H221108.3 (14)
C1—C2—H21112.53C23—C22—H222108.3 (12)
C3—C2—O7102.85 (18)H221—C22—H222109.5 (16)
C3—C2—H21112.59C22—C23—C24110.85 (21)
O7—C2—H21112.5C22—C23—H231109.1 (13)
C2—C3—C4101.19 (13)C22—C23—H232109.1 (15)
C2—C3—O8110.48 (18)C24—C23—H231109.1 (15)
C2—C3—H31105.17C24—C23—H232109.1 (12)
C4—C3—O8127.86 (19)H231—C23—H232109.5 (16)
C4—C3—H31105.07C23—C24—C25111.26 (21)
O8—C3—H31105.13C23—C24—H241109.1 (12)
C3—C4—O5112.34 (14)C23—C24—H242109.0 (16)
C3—C4—N9117.90 (12)C25—C24—H241109.1 (24)
C3—C4—H41105.26C25—C24—H242109.0 (17)
O5—C4—N9109.57 (17)H241—C24—H242109.4 (11)
O5—C4—H41105.29C24—C25—H251109.6 (20)
N9—C4—H41105.37C24—C25—H252109.5 (21)
C1—O5—C4106.4 (3)C24—C25—H253109.6 (17)
C1—C6—H61109.5H251—C25—H252109.3 (19)
C1—C6—H62109.5H251—C25—H253109.5 (22)
C1—C6—H63109.4H252—C25—H253109.4 (24)
H61—C6—H62109.4O20—C21a—C22a107.18 (20)
H61—C6—H63109.4O20—C21a—H2111110.1 (16)
H62—C6—H63109.6O20—C21a—H2112109.9 (18)
C2—O7—H72109.5C22a—C21a—H2111110.2 (17)
C3—O8—H82109.47C22a—C21a—H2112110.1 (13)
C4—N9—C10120.62 (14)H2111—C21a—H2112109.4 (6)
C4—N9—C11119.91 (14)C21a—C22a—C23a114.36 (21)
C10—N9—C11119.47 (12)C21a—C22a—H2211108.3 (6)
N9—C10—N14118.71 (13)C21a—C22a—H2212108.2 (15)
N9—C10—O15118.59 (15)C23a—C22a—H2211108.2 (19)
N14—C10—O15122.71 (15)C23a—C22a—H2212108.3 (10)
N9—C11—C12125.65 (14)H2211—C22a—H2212109.4 (10)
N9—C11—H111117.16C22a—C23a—C24a110.99 (21)
C12—C11—H111117.19C22a—C23a—H2311109.1 (20)
C11—C12—C13111.59 (12)C22a—C23a—H2312109.0 (11)
C11—C12—F16120.89 (15)C24a—C23a—H2311109.1 (12)
C13—C12—F16127.52 (14)C24a—C23a—H2312109.2 (19)
C12—C13—N14126.04 (12)H2311—C23a—H2312109.5 (16)
C12—C13—N17115.94 (14)C23a—C24a—C25a111.43 (21)
N14—C13—N17118.02 (18)C23a—C24a—H2411109.0 (10)
C10—N14—C13118.29 (13)C23a—C24a—H2412108.9 (21)
C13—N17—C18118.81 (13)C25a—C24a—H2411109.1 (26)
C13—N17—H171120.56C25a—C24a—H2412109.0 (16)
C18—N17—H171120.63H2411—C24a—H2412109.4 (11)
N17—C18—O19125.88 (16)C24a—C25a—H2511109.5 (21)
N17—C18—O20100.60 (15)C24a—C25a—H2512109.5 (21)
O19—C18—O20133.52 (16)C24a—C25a—H2513109.6 (17)
C18—O20—C21111.26 (20)H2511—C25a—H2512109.4 (21)
C18—O20—C21a111.74 (20)H2511—C25a—H2513109.4 (23)
O20—C21—C22107.29 (21)H2512—C25a—H2513109.5 (24)
O20—C21—H211110.0 (9)

Symmetry codes: (i) x−1, y, z; (ii) −x+1, y+1/2, −z+3/2; (iii) −x, y−1/2, −z+3/2.

Hydrogen-bond geometry (Å, °)

D—H···AD—HH···AD···AD—H···A
N17—H171···O8ii0.8601.9562.797 (5)170

Symmetry codes: (ii) −x+1, y+1/2, −z+3/2.

Footnotes

Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: CV2544).

References

  • Allen, F. H., Johnson, O., Shields, G. P., Smith, B. R. & Towler, M. (2004). J. Appl. Cryst.37, 335–338.
  • Dewar, M. J. S., Zoebisch, E. G., Healy, E. F. & Stewart, J. J. P. (1985). J. Am. Chem. Soc.107, 3902–3909.
  • Dollase, W. A. (1986). J. Appl. Cryst.19, 267–272.
  • Favre-Nicolin, V. & Černý, R. (2002). J. Appl. Cryst.35, 734–743.
  • Finger, L. W., Cox, D. E. & Jephcoat, A. P. (1994). J. Appl. Cryst.27, 892–900.
  • Jones, L., Hawkins, N., Westwood, M., Wright, K., Richardson, G. & Riemsma, R. (2004). Health Technol. Assess.8, 1–156. [PubMed]
  • Larson, A. C. & Von Dreele, R. B. (1994). GSAS Report LAUR 86-748. Los Alamos National Laboratory, New Mexico, USA.
  • Macrae, C. F., Edgington, P. R., McCabe, P., Pidcock, E., Shields, G. P., Taylor, R., Towler, M. & van de Streek, J. (2006). J. Appl. Cryst.39, 453–457.
  • Shirley, R. (2000). CRYSFIRE User’s Manual Guildford, England: The Lattice Press.
  • Spek, A. L. (2009). Acta Cryst. D65, 148–155. [PMC free article] [PubMed]
  • Thompson, P., Cox, D. E. & Hastings, J. B. (1987). J. Appl. Cryst.20, 79–83.
  • Wagstaff, A. J., Ibbotson, T. & Goa, K. L. (2003). Drugs, 63, 217–236. [PubMed]

Articles from Acta Crystallographica Section E: Structure Reports Online are provided here courtesy of International Union of Crystallography