5-Fluoro-1-(penta­noyl)pyrimidine-2,4(1H,3H)-dione

Lehmler, H.-J.; Parkin, S.

doi:10.1107/S1600536808004418

organic compounds

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Volume 64| Part 3| March 2008| Page o617

doi:10.1107/S1600536808004418

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5-Fluoro-1-(pentanoyl)pyrimidine-2,4(1H,3H)-dione

Hans-Joachim Lehmler ^a ^* and Sean Parkin ^b

^aDepartment of Occupational and Environmental Health, University of Iowa, 100 Oakdale Campus, 124 IREH, Iowa City, IA 52242-5000, USA, and ^bDepartment of Chemistry, University of Kentucky, Lexington, KY 40506-0055, USA
^*Correspondence e-mail: hans-joachim-lehmler@uiowa.edu

(Received 11 February 2008; accepted 13 February 2008; online 22 February 2008)

The pentanoyl group and the 5-fluorouracil moiety of the title compound, C₉H₁₁FN₂O₃, are essentially coplanar, with the pentanoyl carbonyl group oriented towards the ring CH group and away from the nearer ring carbonyl group. In the crystal structure, two inversion-related molecules form a dimer structure, in which two N—H⋯O hydrogen bonds generate an intermolecular R₂²(8) ring. In addition, there are intra- and intermolecular C—H⋯O interactions.

Related literature

For similar 5-fluoropyrimidine-2,4(1H,3H)-dione structures with N1-acyl substituents, see: Beall et al. (1997 ); Jiang et al. (1988 ); Lehmler & Parkin (2000 ). For related literature, see: Roberts & Sloan (1999 ).

Experimental

Crystal data

C₉H₁₁FN₂O₃
M_r = 214.20
Triclinic, $[P \overline 1]$
a = 5.3165 (2) Å
b = 9.3986 (4) Å
c = 10.1895 (5) Å
α = 96.000 (3)°
β = 100.957 (3)°
γ = 105.539 (3)°
V = 475.04 (4) Å³
Z = 2
Mo Kα radiation
μ = 0.13 mm⁻¹
T = 87.8 (2) K
0.30 × 0.30 × 0.03 mm

Data collection

Nonius KappaCCD diffractometer
Absorption correction: multi-scan (SCALEPACK; Otwinowski & Minor, 1997 ) T_min = 0.963, T_max = 0.996
12409 measured reflections
2167 independent reflections
1727 reflections with I > 2σ(I)
R_int = 0.037

Refinement

R[F² > 2σ(F²)] = 0.047
wR(F²) = 0.092
S = 1.02
2167 reflections
137 parameters
H-atom parameters constrained
Δρ_max = 0.23 e Å⁻³
Δρ_min = −0.24 e Å⁻³

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N3—H3⋯O4ⁱ	0.88	1.99	2.8588 (16)	170
C6—H6⋯O7	0.95	2.28	2.6102 (17)	100
C6—H6⋯O7ⁱⁱ	0.95	2.34	3.2266 (19)	154
Symmetry codes: (i) -x+2, -y+1, -z+2; (ii) -x, -y+1, -z+1.

Data collection: COLLECT (Nonius, 1998 ); cell refinement: SCALEPACK (Otwinowski & Minor, 1997); data reduction: DENZO-SMN (Otwinowski & Minor, 1997); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: XP in SHELXTL (Sheldrick, 2008); software used to prepare material for publication: SHELXL97 and local procedures.

Supporting information

Crystal structure: contains datablocks I, global. DOI: 10.1107/S1600536808004418/at2544sup1.cif

Structure factors: contains datablock I. DOI: 10.1107/S1600536808004418/at2544Isup2.hkl

checkCIF report

Comment top

Despite the potential pharmaceutical application of acyl-5-fluorouracil prodrugs, the crystal structures of only three acyl derivatives have been reported (Beall et al., 1997; Jiang et al., 1988; Lehmler & Parkin, 2000). We herein describe the crystal structures of another acyl-5-fluorouracil prodrug, 5-fluoro-1-(1-oxopentyl)-2,4(1H,3H)-pyrimidinedione.

The molecular structures of the title compound and the other 1-acyl-5-fluorouracil derivatives are very similar. Specifically, the 1-acyl group and the 5-fluorouracil moiety are almost coplanar, with the C7?O7 carbonyl group oriented towards the C6—H group and away from the C2?O2 group in all four crystal structures. The C6—N1—C7—O7 dihedral angle of all 1-acyl-5-fluorouracil derivatives is comparable and ranges from 1.6 to 17.3° (Beall et al., 1997; Jiang et al., 1988; Lehmler & Parkin, 2000). In the crystal structure, two inversion-related molecules form a dimer structure, in which two N—H···O hydrogen bonds generate an intermolecular R₂²(8) ring. In addition, there are C—H···O type-intra and intermolecular interactions.

Related literature top

For similar 5-fluoropyrimidine-2,4(1H,3H)-dione structures with N1-acyl substituents, see: Beall et al. (1997); Jiang et al. (1988); Lehmler & Parkin (2000). For related literature, see: Roberts & Sloan (1999).

Experimental top

5-Fluoro-1-(1-oxopentyl)-2,4(1H,3H)-pyrimidinedione was synthesized by acylation of 5-fluorouracil with pentanoyl chloride and recrystallized from diethylether at 253 K (Beall et al., 1997; Lehmler & Parkin, 2000; Roberts & Sloan, 1999).

Computing details top

Data collection: COLLECT (Nonius, 1998); cell refinement: SCALEPACK (Otwinowski & Minor, 1997); data reduction: DENZO-SMN (Otwinowski & Minor, 1997); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: XP in SHELXTL (Sheldrick, 2008); software used to prepare material for publication: SHELXL97 (Sheldrick, 2008) and local procedures.

Figures top

Fig. 1. View of the title compound showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 50% probability level.

5-Fluoro-1-(pentanoyl)pyrimidine-2,4(1H,3H)-dione top

Crystal data top

C₉H₁₁FN₂O₃	Z = 2
M_r = 214.20	F(000) = 224
Triclinic, P1	D_x = 1.497 Mg m⁻³
Hall symbol: -P 1	Mo Kα radiation, λ = 0.71073 Å
a = 5.3165 (2) Å	Cell parameters from 6994 reflections
b = 9.3986 (4) Å	θ = 1.0–27.5°
c = 10.1895 (5) Å	µ = 0.13 mm⁻¹
α = 96.000 (3)°	T = 88 K
β = 100.957 (3)°	Irregular plate, colourless
γ = 105.539 (3)°	0.30 × 0.30 × 0.03 mm
V = 475.04 (4) Å³

Data collection top

Nonius KappaCCD diffractometer	2167 independent reflections
Radiation source: fine-focus sealed tube	1727 reflections with I > 2σ(I)
Graphite monochromator	R_int = 0.037
Detector resolution: 18 pixels mm^-1	θ_max = 27.5°, θ_min = 2.1°
ω scans at fixed χ = 55°	h = −6→6
Absorption correction: multi-scan (SCALEPACK; Otwinowski & Minor, 1997)	k = −12→12
T_min = 0.963, T_max = 0.996	l = −13→13
12409 measured reflections

Refinement top

Refinement on F²	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F² > 2σ(F²)] = 0.047	Hydrogen site location: inferred from neighbouring sites
wR(F²) = 0.092	H-atom parameters constrained
S = 1.02	w = 1/[σ²(F_o²) + (0.0269P)² + 0.2309P] where P = (F_o² + 2F_c²)/3
2167 reflections	(Δ/σ)_max < 0.001
137 parameters	Δρ_max = 0.23 e Å⁻³
0 restraints	Δρ_min = −0.24 e Å⁻³

Crystal data top

C₉H₁₁FN₂O₃	γ = 105.539 (3)°
M_r = 214.20	V = 475.04 (4) Å³
Triclinic, P1	Z = 2
a = 5.3165 (2) Å	Mo Kα radiation
b = 9.3986 (4) Å	µ = 0.13 mm⁻¹
c = 10.1895 (5) Å	T = 88 K
α = 96.000 (3)°	0.30 × 0.30 × 0.03 mm
β = 100.957 (3)°

Data collection top

Nonius KappaCCD diffractometer	2167 independent reflections
Absorption correction: multi-scan (SCALEPACK; Otwinowski & Minor, 1997)	1727 reflections with I > 2σ(I)
T_min = 0.963, T_max = 0.996	R_int = 0.037
12409 measured reflections

Refinement top

R[F² > 2σ(F²)] = 0.047	0 restraints
wR(F²) = 0.092	H-atom parameters constrained
S = 1.02	Δρ_max = 0.23 e Å⁻³
2167 reflections	Δρ_min = −0.24 e Å⁻³
137 parameters

Special details top

Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes.

Refinement. Refinement of F² against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F², conventional R-factors R are based on F, with F set to zero for negative F². The threshold expression of F² > 2σ(F²) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F² are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger.

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

	x	y	z	U_iso*/U_eq
N1	0.4196 (2)	0.37039 (13)	0.62262 (12)	0.0131 (3)
O2	0.7435 (2)	0.24634 (12)	0.65488 (10)	0.0208 (3)
C2	0.6455 (3)	0.33911 (17)	0.69638 (15)	0.0146 (3)
N3	0.7532 (2)	0.42493 (13)	0.82378 (12)	0.0149 (3)
H3	0.8913	0.4049	0.8723	0.018*
O4	0.7890 (2)	0.60838 (12)	0.99779 (10)	0.0176 (3)
C4	0.6725 (3)	0.53737 (16)	0.88432 (15)	0.0148 (3)
F5	0.34305 (17)	0.66618 (10)	0.85412 (8)	0.0198 (2)
C5	0.4391 (3)	0.56025 (16)	0.80080 (15)	0.0142 (3)
C6	0.3224 (3)	0.48168 (16)	0.67833 (14)	0.0135 (3)
H6	0.1698	0.5013	0.6273	0.016*
O7	0.1183 (2)	0.35259 (12)	0.42664 (10)	0.0189 (3)
C7	0.2850 (3)	0.30070 (16)	0.48388 (15)	0.0139 (3)
C8	0.3615 (3)	0.17280 (17)	0.41877 (15)	0.0162 (3)
H8A	0.3494	0.0949	0.4775	0.019*
H8B	0.5500	0.2088	0.4108	0.019*
C9	0.1823 (3)	0.10375 (17)	0.27854 (15)	0.0170 (3)
H9A	0.1644	0.1853	0.2267	0.020*
H9B	0.2710	0.0418	0.2302	0.020*
C10	−0.0962 (3)	0.00735 (17)	0.28048 (16)	0.0192 (4)
H10A	−0.1828	0.0668	0.3330	0.023*
H10B	−0.0809	−0.0788	0.3262	0.023*
C11	−0.2706 (3)	−0.0500 (2)	0.13778 (17)	0.0266 (4)
H11A	−0.2890	0.0351	0.0929	0.040*
H11B	−0.4482	−0.1117	0.1427	0.040*
H11C	−0.1868	−0.1103	0.0860	0.040*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
N1	0.0116 (6)	0.0140 (6)	0.0139 (6)	0.0054 (5)	0.0013 (5)	0.0013 (5)
O2	0.0197 (6)	0.0233 (6)	0.0206 (6)	0.0133 (5)	−0.0006 (5)	−0.0007 (5)
C2	0.0119 (7)	0.0156 (8)	0.0167 (8)	0.0044 (6)	0.0029 (6)	0.0047 (6)
N3	0.0117 (6)	0.0165 (7)	0.0155 (7)	0.0060 (5)	−0.0016 (5)	0.0023 (5)
O4	0.0164 (6)	0.0196 (6)	0.0153 (6)	0.0061 (5)	0.0002 (4)	0.0007 (5)
C4	0.0141 (8)	0.0139 (8)	0.0170 (8)	0.0031 (6)	0.0050 (6)	0.0047 (6)
F5	0.0199 (5)	0.0208 (5)	0.0193 (5)	0.0116 (4)	0.0009 (4)	−0.0027 (4)
C5	0.0142 (7)	0.0139 (8)	0.0170 (8)	0.0069 (6)	0.0049 (6)	0.0033 (6)
C6	0.0106 (7)	0.0152 (8)	0.0166 (8)	0.0062 (6)	0.0037 (6)	0.0043 (6)
O7	0.0197 (6)	0.0210 (6)	0.0163 (6)	0.0108 (5)	−0.0009 (5)	0.0011 (5)
C7	0.0115 (7)	0.0153 (8)	0.0149 (7)	0.0030 (6)	0.0035 (6)	0.0036 (6)
C8	0.0159 (8)	0.0166 (8)	0.0172 (8)	0.0066 (6)	0.0035 (6)	0.0037 (6)
C9	0.0175 (8)	0.0176 (8)	0.0156 (8)	0.0064 (7)	0.0026 (6)	−0.0006 (6)
C10	0.0189 (8)	0.0175 (8)	0.0219 (8)	0.0066 (7)	0.0051 (7)	0.0029 (7)
C11	0.0242 (9)	0.0236 (9)	0.0270 (9)	0.0045 (7)	0.0013 (7)	−0.0024 (7)

Geometric parameters (Å, º) top

N1—C6	1.3999 (18)	C7—C8	1.499 (2)
N1—C2	1.4093 (19)	C8—C9	1.526 (2)
N1—C7	1.4526 (18)	C8—H8A	0.9900
O2—C2	1.2084 (17)	C8—H8B	0.9900
C2—N3	1.3837 (18)	C9—C10	1.520 (2)
N3—C4	1.3743 (19)	C9—H9A	0.9900
N3—H3	0.8800	C9—H9B	0.9900
O4—C4	1.2291 (17)	C10—C11	1.523 (2)
C4—C5	1.446 (2)	C10—H10A	0.9900
F5—C5	1.3462 (16)	C10—H10B	0.9900
C5—C6	1.325 (2)	C11—H11A	0.9800
C6—H6	0.9500	C11—H11B	0.9800
O7—C7	1.2077 (17)	C11—H11C	0.9800

C6—N1—C2	120.42 (12)	C9—C8—H8A	109.1
C6—N1—C7	115.53 (12)	C7—C8—H8B	109.1
C2—N1—C7	123.89 (12)	C9—C8—H8B	109.1
O2—C2—N3	121.00 (13)	H8A—C8—H8B	107.9
O2—C2—N1	124.45 (13)	C10—C9—C8	114.16 (12)
N3—C2—N1	114.55 (13)	C10—C9—H9A	108.7
C4—N3—C2	128.41 (13)	C8—C9—H9A	108.7
C4—N3—H3	115.8	C10—C9—H9B	108.7
C2—N3—H3	115.8	C8—C9—H9B	108.7
O4—C4—N3	122.41 (13)	H9A—C9—H9B	107.6
O4—C4—C5	124.89 (14)	C9—C10—C11	111.57 (13)
N3—C4—C5	112.70 (13)	C9—C10—H10A	109.3
C6—C5—F5	120.95 (13)	C11—C10—H10A	109.3
C6—C5—C4	122.57 (14)	C9—C10—H10B	109.3
F5—C5—C4	116.48 (13)	C11—C10—H10B	109.3
C5—C6—N1	121.32 (13)	H10A—C10—H10B	108.0
C5—C6—H6	119.3	C10—C11—H11A	109.5
N1—C6—H6	119.3	C10—C11—H11B	109.5
O7—C7—N1	116.83 (13)	H11A—C11—H11B	109.5
O7—C7—C8	123.69 (13)	C10—C11—H11C	109.5
N1—C7—C8	119.47 (12)	H11A—C11—H11C	109.5
C7—C8—C9	112.37 (12)	H11B—C11—H11C	109.5
C7—C8—H8A	109.1

C6—N1—C2—O2	−179.04 (14)	F5—C5—C6—N1	−179.41 (12)
C7—N1—C2—O2	−3.7 (2)	C4—C5—C6—N1	0.2 (2)
C6—N1—C2—N3	0.63 (19)	C2—N1—C6—C5	0.1 (2)
C7—N1—C2—N3	175.95 (12)	C7—N1—C6—C5	−175.62 (13)
O2—C2—N3—C4	177.79 (14)	C6—N1—C7—O7	5.59 (19)
N1—C2—N3—C4	−1.9 (2)	C2—N1—C7—O7	−169.94 (13)
C2—N3—C4—O4	−178.30 (14)	C6—N1—C7—C8	−175.64 (12)
C2—N3—C4—C5	2.1 (2)	C2—N1—C7—C8	8.8 (2)
O4—C4—C5—C6	179.25 (14)	O7—C7—C8—C9	−6.9 (2)
N3—C4—C5—C6	−1.2 (2)	N1—C7—C8—C9	174.46 (12)
O4—C4—C5—F5	−1.1 (2)	C7—C8—C9—C10	−74.69 (17)
N3—C4—C5—F5	178.46 (12)	C8—C9—C10—C11	176.35 (13)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
N3—H3···O4ⁱ	0.88	1.99	2.8588 (16)	170
C6—H6···O7	0.95	2.28	2.6102 (17)	100
C6—H6···O7ⁱⁱ	0.95	2.34	3.2266 (19)	154

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

Experimental details

Crystal data
Chemical formula	C₉H₁₁FN₂O₃
M_r	214.20
Crystal system, space group	Triclinic, P1
Temperature (K)	88
a, b, c (Å)	5.3165 (2), 9.3986 (4), 10.1895 (5)
α, β, γ (°)	96.000 (3), 100.957 (3), 105.539 (3)
V (Å³)	475.04 (4)
Z	2
Radiation type	Mo Kα
µ (mm⁻¹)	0.13
Crystal size (mm)	0.30 × 0.30 × 0.03

Data collection
Diffractometer	Nonius KappaCCD diffractometer
Absorption correction	Multi-scan (SCALEPACK; Otwinowski & Minor, 1997)
T_min, T_max	0.963, 0.996
No. of measured, independent and observed [I > 2σ(I)] reflections	12409, 2167, 1727
R_int	0.037
(sin θ/λ)_max (Å⁻¹)	0.649

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.047, 0.092, 1.02
No. of reflections	2167
No. of parameters	137
H-atom treatment	H-atom parameters constrained
Δρ_max, Δρ_min (e Å⁻³)	0.23, −0.24

Computer programs: COLLECT (Nonius, 1998), SCALEPACK (Otwinowski & Minor, 1997), DENZO-SMN (Otwinowski & Minor, 1997), SHELXS97 (Sheldrick, 2008), XP in SHELXTL (Sheldrick, 2008), SHELXL97 (Sheldrick, 2008) and local procedures.

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
N3—H3···O4ⁱ	0.88	1.99	2.8588 (16)	170
C6—H6···O7	0.95	2.28	2.6102 (17)	100
C6—H6···O7ⁱⁱ	0.95	2.34	3.2266 (19)	154

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

References

Beall, H. D., Prankerd, R. J. & Sloan, K. B. (1997). Drug Dev. Ind. Pharm. 23, 517–525. CrossRef CAS Google Scholar
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Lehmler, H.-J. & Parkin, S. (2000). Acta Cryst. C56, e518–e519. Web of Science CSD CrossRef CAS IUCr Journals Google Scholar
Nonius (1998). COLLECT. Nonius BV, Delft, The Netherlands. Google Scholar
Otwinowski, Z. & Minor, W. (1997). Methods in Enzymology, Vol. 276, Macromolecular Crystallography, Part A, edited by C. W. Carter Jr & R. M. Sweet, pp. 307–326. New York: Academic Press. Google Scholar
Roberts, W. J. & Sloan, K. B. (1999). J. Pharm. Sci. 88, 515–522. Web of Science CrossRef PubMed CAS Google Scholar
Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122. Web of Science CrossRef CAS IUCr Journals Google Scholar

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doi:10.1107/S1600536808004418

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