organic compounds\(\def\hfill{\hskip 5em}\def\hfil{\hskip 3em}\def\eqno#1{\hfil {#1}}\)

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ISSN: 2056-9890

Nilutamide

aDepartment of Industrial and Physical Pharmacy, Purdue University, West Lafayette, IN 47907, USA, and bDepartment of Chemistry, Purdue University, West Lafayette, IN 47907, USA
*Correspondence e-mail: lstaylor@purdue.edu

(Received 20 January 2012; accepted 27 January 2012; online 4 February 2012)

The crystal structure of nilutamide [systematic name: 5,5-dimethyl-3-[4-nitro-3-(trifluoro­meth­yl)phen­yl]imidazolidine-2,4-dione], C12H10F3N3O4, was determined at 150 K. The dihedral angle between the mean planes through the imidazoline [maximum deviation = 0.0396 (14) Å] and benzene rings is 51.49 (5)°. The mol­ecule exhibits inter­molecular hydrogen bonding via N—H⋯O inter­actions, resulting in the formation of chains parallel to the c axis.

Related literature

For the structure of a related compound, see: Cense et al. (1994[Cense, J. M., Agafanov, V., Ceolin, R., Ladure, P. & Rodier, N. (1994). Struct. Chem. 5, 79-84.]).

[Scheme 1]

Experimental

Crystal data
  • C12H10F3N3O4

  • Mr = 317.23

  • Monoclinic, P 21 /c

  • a = 12.3304 (9) Å

  • b = 9.8875 (2) Å

  • c = 12.2118 (3) Å

  • β = 117.322 (8)°

  • V = 1322.74 (14) Å3

  • Z = 4

  • Cu Kα radiation

  • μ = 1.31 mm−1

  • T = 150 K

  • 0.20 × 0.12 × 0.05 mm

Data collection
  • Rigaku Rapid II diffractometer

  • Absorption correction: multi-scan (CrystalClear; Rigaku, 2001[Rigaku (2001). CrystalClear. Rigaku Corporation, Tokyo, Japan.]) Tmin = 0.733, Tmax = 0.937

  • 13145 measured reflections

  • 2324 independent reflections

  • 2019 reflections with I > 2σ(I)

  • Rint = 0.028

Refinement
  • R[F2 > 2σ(F2)] = 0.032

  • wR(F2) = 0.085

  • S = 1.12

  • 2324 reflections

  • 206 parameters

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

  • Δρmax = 0.31 e Å−3

  • Δρmin = −0.22 e Å−3

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A D—H H⋯A DA D—H⋯A
N14—H14⋯O12i 0.84 (2) 2.06 (2) 2.894 (2) 172.3 (15)
Symmetry code: (i) [x, -y+{\script{1\over 2}}, z+{\script{1\over 2}}].

Data collection: CrystalClear (Rigaku, 2001[Rigaku (2001). CrystalClear. Rigaku Corporation, Tokyo, Japan.]); cell refinement: CrystalClear; data reduction: CrystalClear; program(s) used to solve structure: SIR2004 (Burla et al., 2005[Burla, M. C., Caliandro, R., Camalli, M., Carrozzini, B., Cascarano, G. L., De Caro, L., Giacovazzo, C., Polidori, G. & Spagna, R. (2005). J. Appl. Cryst. 38, 381-388.]); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008[Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.]) and a local program based on the method of Prince & Nicholson (1983[Prince, E. & Nicholson, W. L. (1983). Acta Cryst. A39, 407-410.]); molecular graphics: ORTEPII (Johnson, 1976[Johnson, C. K. (1976). ORTEPII. Report ORNL-5138. Oak Ridge National Laboratory, Tennessee, USA.]) and PLATON (Spek, 2009[Spek, A. L. (2009). Acta Cryst. D65, 148-155.]); software used to prepare material for publication: SHELXL97 and local programs.

Supporting information


Comment top

The title compound is a potent antiandrogen used primarily in the treatment of advanced stage prostrate cancer. While no single-crystal structure has been reported for this compound before, there have been reported structures for structurally related compounds like flutamide by Cense et al. (1994). However, the molecular arrangement of nilutamide is different from flutamide since flutamide does not exhibit any hydrogen bonding between the NH and the CO.

The imidazoline ring of the title compound (Fig. 1) is roughly planar [maximum deviation 0.0396 (14) Å for atom C15] and forms a dihedral angle of 51.49 (5)° with the benzene ring. The nitro group is tilted by 56.35 (7)° with respect to the benzene ring. In the crystal, molecules are linked by intermolecular N—H···O hydrogen interactions (Table 1) forming chains parallel to the c axis.

Related literature top

For the structure of a related compound, see: Cense et al. (1994).

Experimental top

Nilutamide powder was obtained from Sigma-Aldrich Company and used without further purification.A solution of the compound (20 mg ml-1) was prepared in acetonitrile in a 3 ml glass vial. The solution was allowed to evaporate slowly by sealing the vial with parafilm and making a few small holes in the parafilm using a fine needle.

Refinement top

The imidazoline H atom was located in a difference Fourier map and refined freely [N–H = 0.841 (19) Å]. All other H atoms were positioned geometrically [C–H = 0.95–0.98 Å] and refined using a riding model, with Uiso(H) = 1.2 Ueq(C) or 1.5 Ueq(C) for methyl H atoms. A rotating group model was applied to the methyl groups. Seven outliers (-2 0 2, -8 7 8, -8 2 13, -6 2 13, -9 1 14, -7 1 14, -6 1 14), were removed from the final refinement using a local program based on the method of Prince & Nicholson (1983).

Computing details top

Data collection: CrystalClear (Rigaku, 2001); cell refinement: CrystalClear (Rigaku, 2001); data reduction: CrystalClear (Rigaku, 2001); program(s) used to solve structure: SIR2004 (Burla et al., 2005); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008) and a local program based on the method of Prince & Nicholson (1983); molecular graphics: ORTEPII (Johnson, 1976) and PLATON (Spek, 2009); software used to prepare material for publication: SHELXL97 (Sheldrick, 2008) and local programs.

Figures top
[Figure 1] Fig. 1. The molecular structure of the title compound indicating the 50% probability displacement ellipsoids and the atomic numbering for the non-H atoms.
5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]imidazolidine-2,4-dione top
Crystal data top
C12H10F3N3O4F(000) = 648
Mr = 317.23Dx = 1.593 Mg m3
Monoclinic, P21/cCu Kα radiation, λ = 1.54184 Å
Hall symbol: -P 2ybcCell parameters from 13145 reflections
a = 12.3304 (9) Åθ = 4–66°
b = 9.8875 (2) ŵ = 1.31 mm1
c = 12.2118 (3) ÅT = 150 K
β = 117.322 (8)°Needle, colorless
V = 1322.74 (14) Å30.20 × 0.12 × 0.05 mm
Z = 4
Data collection top
Rigaku Rapid II
diffractometer
2019 reflections with I > 2σ(I)
Confocal optics monochromatorRint = 0.028
ω scansθmax = 66.6°, θmin = 4.0°
Absorption correction: multi-scan
(CrystalClear; Rigaku, 2001)
h = 1414
Tmin = 0.733, Tmax = 0.937k = 1111
13145 measured reflectionsl = 1314
2324 independent reflections
Refinement top
Refinement on F2H atoms treated by a mixture of independent and constrained refinement
Least-squares matrix: full w = 1/[σ2(Fo2) + (0.0389P)2 + 0.5381P]
where P = (Fo2 + 2Fc2)/3
R[F2 > 2σ(F2)] = 0.032(Δ/σ)max < 0.001
wR(F2) = 0.085Δρmax = 0.31 e Å3
S = 1.12Δρmin = 0.22 e Å3
2324 reflectionsExtinction correction: SHELXL97 (Sheldrick 2008)
206 parametersExtinction coefficient: 0.72E-02
0 restraints
Crystal data top
C12H10F3N3O4V = 1322.74 (14) Å3
Mr = 317.23Z = 4
Monoclinic, P21/cCu Kα radiation
a = 12.3304 (9) ŵ = 1.31 mm1
b = 9.8875 (2) ÅT = 150 K
c = 12.2118 (3) Å0.20 × 0.12 × 0.05 mm
β = 117.322 (8)°
Data collection top
Rigaku Rapid II
diffractometer
2324 independent reflections
Absorption correction: multi-scan
(CrystalClear; Rigaku, 2001)
2019 reflections with I > 2σ(I)
Tmin = 0.733, Tmax = 0.937Rint = 0.028
13145 measured reflections
Refinement top
R[F2 > 2σ(F2)] = 0.0320 restraints
wR(F2) = 0.085H atoms treated by a mixture of independent and constrained refinement
S = 1.12Δρmax = 0.31 e Å3
2324 reflectionsΔρmin = 0.22 e Å3
206 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. Outlier data were removed using a local program based on the method of Prince and Nicholson.

Refinement on F2 for ALL reflections except for 0 with very negative F2 or flagged by the user for potential systematic errors. Weighted R-factors wR and all goodnesses of fit S are based on F2, conventional R-factors R are based on F, with F set to zero for negative F2. The observed criterion of F2 > σ(F2) is used only for calculating R_factor_obs 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
xyzUiso*/Ueq
F10.23075 (8)0.18106 (10)0.90252 (9)0.0335 (3)
F20.15392 (8)0.06052 (10)0.99582 (10)0.0362 (3)
F30.26813 (8)0.22939 (11)1.08854 (9)0.0414 (3)
O120.39601 (9)0.28832 (12)0.72787 (9)0.0254 (3)
O150.12113 (9)0.25489 (11)1.13651 (9)0.0236 (3)
O410.14267 (12)0.47236 (14)0.74335 (12)0.0419 (3)
O420.26114 (10)0.46290 (12)0.94084 (12)0.0350 (3)
N40.16293 (12)0.44744 (13)0.84896 (13)0.0264 (3)
N110.23339 (10)0.27413 (13)0.92377 (11)0.0189 (3)
N140.32753 (11)0.20473 (13)1.03076 (12)0.0212 (3)
C10.13395 (12)0.31698 (15)0.90267 (13)0.0189 (3)
C20.03031 (13)0.23688 (15)0.94671 (13)0.0196 (3)
C30.06962 (13)0.27696 (15)0.93109 (13)0.0199 (3)
C40.06014 (13)0.39789 (15)0.86842 (13)0.0208 (3)
C50.04267 (13)0.47766 (16)0.82365 (13)0.0214 (3)
C60.14103 (13)0.43759 (15)0.84249 (13)0.0198 (3)
C120.35389 (13)0.26571 (15)0.83743 (13)0.0187 (3)
C130.42547 (13)0.22238 (15)0.90554 (13)0.0197 (3)
C150.21768 (13)0.24400 (14)1.04444 (13)0.0187 (3)
C310.18088 (13)0.18783 (16)0.98009 (15)0.0261 (4)
C1310.51338 (13)0.33459 (17)0.89947 (15)0.0259 (4)
C1320.49281 (15)0.08983 (17)0.85113 (15)0.0289 (4)
H20.02760.15430.98770.023*
H50.04650.55890.78050.026*
H60.21210.49240.81440.024*
H140.3407 (15)0.2040 (18)1.0925 (17)0.025 (5)*
H13A0.55180.31030.95140.039*
H13B0.57650.34590.81410.039*
H13C0.46820.41950.92900.039*
H13D0.43340.01880.86150.043*
H13E0.54790.10230.76320.043*
H13F0.54020.06350.89380.043*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
F10.0288 (5)0.0330 (6)0.0494 (6)0.0026 (4)0.0270 (5)0.0030 (4)
F20.0316 (5)0.0277 (5)0.0541 (7)0.0076 (4)0.0239 (5)0.0092 (5)
F30.0242 (5)0.0495 (7)0.0348 (6)0.0072 (4)0.0000 (4)0.0041 (5)
O120.0208 (5)0.0387 (7)0.0175 (6)0.0017 (5)0.0096 (5)0.0017 (5)
O150.0213 (5)0.0300 (6)0.0169 (6)0.0000 (4)0.0065 (5)0.0026 (4)
O410.0498 (8)0.0485 (8)0.0436 (8)0.0091 (6)0.0354 (7)0.0007 (6)
O420.0190 (6)0.0307 (7)0.0522 (8)0.0037 (5)0.0138 (6)0.0056 (6)
N40.0255 (7)0.0240 (7)0.0356 (8)0.0028 (5)0.0190 (6)0.0046 (6)
N110.0165 (6)0.0242 (7)0.0173 (6)0.0004 (5)0.0088 (5)0.0011 (5)
N140.0209 (6)0.0295 (7)0.0163 (6)0.0012 (5)0.0111 (5)0.0011 (5)
C10.0176 (7)0.0244 (8)0.0165 (7)0.0024 (6)0.0093 (6)0.0028 (6)
C20.0214 (7)0.0198 (8)0.0180 (7)0.0003 (6)0.0095 (6)0.0001 (6)
C30.0177 (7)0.0238 (8)0.0172 (7)0.0000 (6)0.0072 (6)0.0041 (6)
C40.0184 (7)0.0261 (8)0.0198 (7)0.0050 (6)0.0104 (6)0.0053 (6)
C50.0240 (7)0.0217 (8)0.0186 (7)0.0026 (6)0.0098 (6)0.0003 (6)
C60.0186 (7)0.0230 (8)0.0177 (7)0.0014 (6)0.0081 (6)0.0009 (6)
C120.0197 (7)0.0196 (8)0.0182 (7)0.0016 (6)0.0099 (6)0.0006 (6)
C130.0187 (7)0.0254 (8)0.0166 (7)0.0011 (6)0.0093 (6)0.0002 (6)
C150.0225 (8)0.0169 (7)0.0187 (7)0.0021 (6)0.0112 (6)0.0013 (6)
C310.0211 (8)0.0273 (9)0.0298 (9)0.0004 (6)0.0118 (7)0.0022 (7)
C1310.0213 (8)0.0336 (9)0.0264 (8)0.0016 (7)0.0142 (7)0.0022 (7)
C1320.0291 (8)0.0289 (9)0.0289 (9)0.0069 (7)0.0135 (7)0.0027 (7)
Geometric parameters (Å, º) top
F1—C311.3470 (18)C2—H20.9500
F2—C311.3381 (19)C3—C41.395 (2)
F3—C311.3313 (19)C3—C311.504 (2)
O12—C121.2133 (18)C4—C51.375 (2)
O15—C151.2101 (18)C5—C61.392 (2)
O41—N41.2210 (18)C5—H50.9500
O42—N41.2254 (18)C6—H60.9500
N4—C41.4762 (18)C12—C131.5258 (19)
N11—C121.3740 (18)C13—C1311.529 (2)
N11—C151.4268 (18)C13—C1321.530 (2)
N11—C11.4281 (17)C131—H13A0.9800
N14—C151.3437 (18)C131—H13B0.9800
N14—C131.4602 (19)C131—H13C0.9800
N14—H140.841 (19)C132—H13D0.9800
C1—C61.382 (2)C132—H13E0.9800
C1—C21.385 (2)C132—H13F0.9800
C2—C31.388 (2)
O41—N4—O42125.39 (13)N11—C12—C13106.92 (12)
O41—N4—C4117.55 (13)N14—C13—C12101.37 (11)
O42—N4—C4117.04 (13)N14—C13—C131111.39 (12)
C12—N11—C15111.48 (11)C12—C13—C131110.15 (12)
C12—N11—C1126.52 (12)N14—C13—C132112.05 (13)
C15—N11—C1121.83 (12)C12—C13—C132109.76 (12)
C15—N14—C13113.43 (12)C131—C13—C132111.66 (12)
C15—N14—H14119.3 (12)O15—C15—N14130.31 (14)
C13—N14—H14122.2 (12)O15—C15—N11123.39 (13)
C6—C1—C2121.44 (13)N14—C15—N11106.30 (12)
C6—C1—N11120.12 (13)F3—C31—F2106.75 (13)
C2—C1—N11118.41 (13)F3—C31—F1107.08 (12)
C1—C2—C3120.15 (14)F2—C31—F1106.13 (12)
C1—C2—H2119.90F3—C31—C3112.82 (13)
C3—C2—H2119.90F2—C31—C3111.52 (12)
C2—C3—C4117.63 (13)F1—C31—C3112.13 (13)
C2—C3—C31118.88 (14)C13—C131—H13A109.50
C4—C3—C31123.48 (13)C13—C131—H13B109.50
C5—C4—C3122.64 (13)H13A—C131—H13B109.50
C5—C4—N4116.64 (13)C13—C131—H13C109.50
C3—C4—N4120.71 (13)H13A—C131—H13C109.50
C4—C5—C6119.02 (14)H13B—C131—H13C109.50
C4—C5—H5120.50C13—C132—H13D109.50
C6—C5—H5120.50C13—C132—H13E109.50
C1—C6—C5119.09 (13)H13D—C132—H13E109.50
C1—C6—H6120.50C13—C132—H13F109.50
C5—C6—H6120.50H13D—C132—H13F109.50
O12—C12—N11126.85 (13)H13E—C132—H13F109.50
O12—C12—C13126.22 (13)
C12—N11—C1—C651.1 (2)C15—N11—C12—C131.60 (16)
C15—N11—C1—C6123.91 (15)C1—N11—C12—C13177.03 (13)
C12—N11—C1—C2130.60 (15)C15—N14—C13—C126.36 (16)
C15—N11—C1—C254.39 (19)C15—N14—C13—C131110.78 (14)
C6—C1—C2—C30.1 (2)C15—N14—C13—C132123.33 (14)
N11—C1—C2—C3178.20 (13)O12—C12—C13—N14177.45 (14)
C1—C2—C3—C41.1 (2)N11—C12—C13—N142.59 (15)
C1—C2—C3—C31179.93 (13)O12—C12—C13—C13164.52 (19)
C2—C3—C4—C50.7 (2)N11—C12—C13—C131115.44 (13)
C31—C3—C4—C5179.61 (14)O12—C12—C13—C13258.8 (2)
C2—C3—C4—N4179.62 (13)N11—C12—C13—C132121.22 (13)
C31—C3—C4—N41.4 (2)C13—N14—C15—O15172.23 (15)
O41—N4—C4—C555.63 (19)C13—N14—C15—N117.49 (16)
O42—N4—C4—C5122.84 (15)C12—N11—C15—O15174.20 (14)
O41—N4—C4—C3125.35 (16)C1—N11—C15—O151.5 (2)
O42—N4—C4—C356.18 (19)C12—N11—C15—N145.55 (16)
C3—C4—C5—C60.8 (2)C1—N11—C15—N14178.77 (13)
N4—C4—C5—C6178.24 (13)C2—C3—C31—F399.05 (16)
C2—C1—C6—C51.4 (2)C4—C3—C31—F382.01 (18)
N11—C1—C6—C5179.61 (13)C2—C3—C31—F221.1 (2)
C4—C5—C6—C11.8 (2)C4—C3—C31—F2157.86 (14)
C15—N11—C12—O12178.37 (15)C2—C3—C31—F1139.95 (14)
C1—N11—C12—O122.9 (2)C4—C3—C31—F139.0 (2)
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
N14—H14···O12i0.84 (2)2.06 (2)2.894 (2)172.3 (15)
Symmetry code: (i) x, y+1/2, z+1/2.

Experimental details

Crystal data
Chemical formulaC12H10F3N3O4
Mr317.23
Crystal system, space groupMonoclinic, P21/c
Temperature (K)150
a, b, c (Å)12.3304 (9), 9.8875 (2), 12.2118 (3)
β (°) 117.322 (8)
V3)1322.74 (14)
Z4
Radiation typeCu Kα
µ (mm1)1.31
Crystal size (mm)0.20 × 0.12 × 0.05
Data collection
DiffractometerRigaku Rapid II
diffractometer
Absorption correctionMulti-scan
(CrystalClear; Rigaku, 2001)
Tmin, Tmax0.733, 0.937
No. of measured, independent and
observed [I > 2σ(I)] reflections
13145, 2324, 2019
Rint0.028
(sin θ/λ)max1)0.595
Refinement
R[F2 > 2σ(F2)], wR(F2), S 0.032, 0.085, 1.12
No. of reflections2324
No. of parameters206
H-atom treatmentH atoms treated by a mixture of independent and constrained refinement
Δρmax, Δρmin (e Å3)0.31, 0.22

Computer programs: CrystalClear (Rigaku, 2001), SIR2004 (Burla et al., 2005), SHELXL97 (Sheldrick, 2008) and a local program based on the method of Prince & Nicholson (1983), ORTEPII (Johnson, 1976) and PLATON (Spek, 2009), SHELXL97 (Sheldrick, 2008) and local programs.

Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
N14—H14···O12i0.84 (2)2.06 (2)2.894 (2)172.3 (15)
Symmetry code: (i) x, y+1/2, z+1/2.
 

Acknowledgements

The authors thank the National Science Foundation Engineering Research Center for Structured Organic Particulate Systems for financial support (NSF ERCSOPS; EEC-0540855).

References

First citationBurla, M. C., Caliandro, R., Camalli, M., Carrozzini, B., Cascarano, G. L., De Caro, L., Giacovazzo, C., Polidori, G. & Spagna, R. (2005). J. Appl. Cryst. 38, 381–388.  Web of Science CrossRef CAS IUCr Journals
First citationCense, J. M., Agafanov, V., Ceolin, R., Ladure, P. & Rodier, N. (1994). Struct. Chem. 5, 79–84.  CSD CrossRef CAS Web of Science
First citationJohnson, C. K. (1976). ORTEPII. Report ORNL-5138. Oak Ridge National Laboratory, Tennessee, USA.
First citationPrince, E. & Nicholson, W. L. (1983). Acta Cryst. A39, 407–410.  CrossRef CAS Web of Science IUCr Journals
First citationRigaku (2001). CrystalClear. Rigaku Corporation, Tokyo, Japan.
First citationSheldrick, G. M. (2008). Acta Cryst. A64, 112–122.  Web of Science CrossRef CAS IUCr Journals
First citationSpek, A. L. (2009). Acta Cryst. D65, 148–155.  Web of Science CrossRef CAS IUCr Journals

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