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Acta Cryst. (2009). E65, o1325-o1326    [ doi:10.1107/S1600536809017905 ]

Capecitabine from X-ray powder synchrotron data

J. Rohlicek, M. Husak, A. Gavenda, A. Jegorov, B. Kratochvil and A. Fitch

Abstract top

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.

Comment top

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).

Related literature top

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); Jones et al. (2004).

Experimental top

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 top

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.

Computing details top

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

Figures top
[Figure 1] 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.
[Figure 2] 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.
5-deoxy-5-fluoro-N-(pentyloxycarbonyl)cytidine top
Crystal data top
C15H22FN3O6Synchrotron radiation
λ = 0.79483 (4) Å
Mr = 359.35µ = 0.15 mm−1
Orthorhombic, P212121T = 293 K
a = 5.20527 (2) ÅCell measurement pressure: 101 kPa
b = 9.52235 (4) ÅSpecimen shape: cylinder
c = 34.77985 (13) Å40 × 1 × 1 mm
V = 1723.913 (12) Å3Specimen prepared at 101 kPa
Z = 4Specimen prepared at 293 K
F000 = 760Particle morphology: no specific habit, white
Dx = 1.385 Mg m−3
Data collection top
ID31 ESRF Grenoble
diffractometer		T = 293 K
Monochromator: Si(111)P = 101 kPa
Specimen mounting: 1.0 mm borosilicate glass capillary2θmin = 1.00, 2θmax = 35.00º
Specimen mounted in transmission modeIncrement in 2θ = 0.003º
Scan method: step
Refinement top
Least-squares matrix: fullProfile function: Pseudo-Voigt profile coefficients as parameterized in Thompson et al. (1987), asymmetry correction according to Finger et al. (1994)
Rp = 0.05591 parameters
Rwp = 0.07477 restraints
Rexp = 0.0366 constraints
RB = 0.102H-atom parameters not refined
S = 2.11Weighting scheme based on measured s.u.'s w = 1/σ(Yobs)2
Wavelength of incident radiation: 0.79483(4) Å(Δ/σ)max = 0.05
Excluded region(s): noPreferred orientation correction: March–Dollase (Dollase, 1986); direction of preferred orientation 001, texture parameter r = 1.03(1)
Crystal data top
C15H22FN3O6Synchrotron radiation
λ = 0.79483 (4) Å
Mr = 359.35µ = 0.15 mm−1
Orthorhombic, P212121T = 293 K
a = 5.20527 (2) ÅSpecimen shape: cylinder
b = 9.52235 (4) Å40 × 1 × 1 mm
c = 34.77985 (13) ÅSpecimen prepared at 101 kPa
V = 1723.913 (12) Å3Specimen prepared at 293 K
Z = 4Particle morphology: no specific habit, white
Data collection top
ID31 ESRF Grenoble
diffractometer		Scan method: step
Specimen mounting: 1.0 mm borosilicate glass capillary2θmin = 1.00, 2θmax = 35.00º
Specimen mounted in transmission modeIncrement in 2θ = 0.003º
Refinement top
Rp = 0.055Excluded region(s): no
Rwp = 0.074Profile function: Pseudo-Voigt profile coefficients as parameterized in Thompson et al. (1987), asymmetry correction according to Finger et al. (1994)
Rexp = 0.03691 parameters
RB = 0.10277 restraints
S = 2.11H-atom parameters not refined
Wavelength of incident radiation: 0.79483(4) ÅPreferred orientation correction: March–Dollase (Dollase, 1986); direction of preferred orientation 001, texture parameter r = 1.03(1)
Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top
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, °) top
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, °) top
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.
Table 1
Selected geometric parameters (Å) top
O15···C12i2.961 (3)O15···C11iii2.875 (3)
F16···C10ii2.886 (3)
Symmetry codes: (i) x−1, y, z; (ii) −x+1, y+1/2, −z+3/2; (iii) −x, y−1/2, −z+3/2.
Table 2
Hydrogen-bond geometry (Å, °) top
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.
Acknowledgements top

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.

references
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