N [4 Cyano 3 (tri­fluoro­meth­yl)phen­yl] 2 methyl­oxirane 2 carboxamide: a bicalutamide inter­mediate

organic papers

Acta Cryst.(2007). E63, o33–o35 doi:10.1107/S1600536806050574 Butcheret al. _C

12H9F3N2O2

o33

Acta Crystallographica Section E

Structure Reports Online

ISSN 1600-5368

N

-[4-Cyano-3-(trifluoromethyl)phenyl]-2-methyl-oxirane-2-carboxamide: a bicalutamide intermediate

Ray J. Butcher,a* R. S. Narasegowda,b H. S. Yathirajan,b H. G. Anilkumarband B. M. Mohanc

a_{Department of Chemistry, Howard University,}

525 College Street NW, Washington, DC 20059, USA,bDepartment of Studies in Chemistry, University of Mysore,

Manasagangotri, Mysore 570 006, India, and

c

Forensic Science Laboratories, Madivala, Bangalore 560 068, India

Correspondence e-mail: raymond.butcher@nrl.navy.mil

Key indicators

Single-crystal X-ray study T= 298 K

Mean(C–C) = 0.002 A˚ Disorder in main residue Rfactor = 0.038 wRfactor = 0.107

Data-to-parameter ratio = 11.5

For details of how these key indicators were automatically derived from the article, see http://journals.iucr.org/e.

Received 2 November 2006 Accepted 23 November 2006

#2007 International Union of Crystallography

All rights reserved

In the title compound, C12H9F3N2O2, the O atoms participate in hydrogen-bonding interactions with both the NH group and also the CH groups of adjoining molecules.

Comment

The title compound, (I), is a bicalutamide intermediate. Bicalutamide is an oral non-steroidal anti-androgen for pros-tate cancer. It is thought to prevent the growth of prospros-tate cancer by blocking the effects of androgens on the cancer cells (Bohlet al., 2005; Tuckeret al., 1988). It blocks the effect of testosterone which is a male sex hormone. Bicalutamide is often used with another drug that lowers testosterone levels in the body. Bicalutamide is an antineoplastic hormonal agent, which is a pure, non-steroidal anti-androgen with affinity for androgen receptors (but not for progestogen, estrogen, or glucocorticoid receptors). Consequently, bicalutamide blocks the action of androgens of adrenal and testicular origin which stimulate the growth of normal and malignant prostatic tissue. Prostate cancer is mostly androgen-dependent and can be treated with surgical or chemical castration. The mechanism of action of bicalutamide competes with androgen for the binding of androgen receptors, consequently blocking the action of androgens of adrenal and testicular origin which stimulate the growth of normal and malignant prostatic tissue (Masiello et al., 2002; Schellhammer, 2002; Schellhammer & Davis, 2004). The crystal structures of related compounds have been recently reported (Hu & Gu, 2005; Tang & Gu, 2005). In view of the importance of the title compound and to confirm the structure, a crystal structure of (I) is reported (Fig. 1).

forming two C—H O and two N—H O interactions involving the oxirane O atom (Fig. 2). These dimers are also linked to adjoining molecules by weak C—H O interactions involving the carbonyl O atom of the carboxamide group.

Experimental

The title compound was obtained as a gift sample from CIPLA, Mumbai, India. The compound was used without further purification. Recrystallization from ethanol yielded X-ray diffraction quality crystals (m.p. 422 K).

Crystal data

C12H9F3N2O2 Mr= 270.21

Monoclinic,P21=n a= 10.2636 (5) A˚

b= 11.5179 (6) A˚

c= 10.4182 (5) A˚

= 102.944 (1)

V= 1200.29 (10) A˚3

Z= 4

Dx= 1.495 Mg m 3

MoKradiation

= 0.13 mm1 T= 298 (2) K Block, colorless 0.480.370.18 mm

Data collection

Bruker APEX-2 CCD area-detector diffractometer

’and!scans

Absorption correction: multi-scan (SADABS; Sheldrick, 1996)

Tmin= 0.914,Tmax= 0.966

10248 measured reflections 2352 independent reflections 2043 reflections withI> 2(I)

Rint= 0.015

max= 26.0

Refinement

Refinement onF2 R[F2_{> 2(F}2_{)] = 0.038} wR(F2_{) = 0.107} S= 1.05 2352 reflections 205 parameters

H atoms treated by a mixture of independent and constrained refinement

w= 1/[2_(F

o2) + (0.0522P)2

+ 0.266P]

whereP= (Fo2+ 2Fc2)/3

(/)max< 0.001

max= 0.18 e A˚

3

min=0.17 e A˚

3

Table 1

Selected geometric parameters (A˚ ,_).

O1—C11 1.2098 (16) O2—C12 1.4346 (17) O2—C14 1.447 (2) N1—C11 1.3595 (18)

N1—C1 1.3972 (16) C12—C14 1.464 (2) C4—C41 1.4419 (19) C41—N41 1.136 (2) C12—O2—C14 61.07 (10)

O1—C11—N1 124.90 (13) O1—C11—C12 120.86 (12)

[image:2.610.46.295.71.192.2]

N1—C11—C12 114.20 (11) O2—C12—C14 59.89 (10) N41—C41—C4 178.03 (18)

Table 2

Hydrogen-bond geometry (A˚ ,_).

D—H A D—H H A D A D—H A

N1—H1N O2i

0.84 (2) 2.48 (2) 3.243 (2) 151 (1) C2—H2A O2i

0.93 2.46 3.264 (2) 145 C14—H14A O1ii

0.97 2.44 3.375 (2) 161 C6—H6A O1 0.93 2.30 2.889 (2) 121 N1—H1N O2 0.84 (2) 2.20 (2) 2.673 (2) 116 (2)

Symmetry codes: (i)x;yþ2;z; (ii)x1

2;yþ32;z12.

The trifluoromethyl group was disordered over two conformations and occupancy factors refined to 0.540 (17) and 0.460 (17). In the refinement process a common C—F distance was refined to a value of 1.3076 (14) A˚ . All H atoms were initially located in a difference Fourier map. The methyl H atoms were then constrained to an ideal geometry, with C—H distances of 0.98 A˚ andUiso(H) = 1.5Ueq(C),

but each group was allowed to rotate freely about its C—C bond. All other carbon-bound H atoms were placed in geometrically idealized positions and constrained to ride on their parent atoms, with C—H distances in the range 0.95–1.00 A˚ and Uiso(H) = 1.2Ueq(C). The

positional parameters for the amine H atom were refined with

Uiso(H) = 1.2Ueq(N).

Data collection:APEX2(Bruker, 2006); cell refinement:SAINT

(Bruker, 2004); data reduction:SAINT; program(s) used to solve structure:SHELXS97(Sheldrick, 1997); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics:

SHELXTL (Bruker, 2003); software used to prepare material for publication:SHELXTL.

organic papers

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Butcheret al. _C

12H9F3N2O2 Acta Cryst.(2007). E63, o33–o35

Figure 1

[image:2.610.48.293.249.463.2]

The molecular structure of (I), showing the atom-numbering scheme. Displacement ellipsoids are drawn at the 20% probability level. Only the major conformer of the disordered trifluoromethyl group is shown.

Figure 2

[image:2.610.312.565.454.518.2]

One of the authors (RSN) thanks the CIPLA Company, Mumbai, for a gift sample of the bicalutamide intermediate. RJB acknowleges the Laboratory for the Structure of Matter at the Naval Research Laboratory for access to their diffractometers.

References

Allen, F. H. (2002).Acta Cryst.B58, 380–388.

Bohl, C. E., Gao, W.-Q., Miller, D. D., Bell, C. E. & Dalton, J. T. (2005).

Pharmacology,102, 6201–6206.

Bruker (2003). SHELXTL. Version 6.14. Bruker AXS Inc., Madison, Wisconsin, USA.

Bruker (2004).SAINT. Version 7.23A. Bruker AXS Inc., Madison, Wisconsin, USA.

Bruker (2006).APEX2. Version 2.0-2. Bruker AXS Inc., Madison, Wisconsin, USA.

Hu, X.-R. & Gu, J.-M. (2005).Acta Cryst.E61, o3897–o3898.

Masiello, D., Cheng, S., Bubley, G. J., Lu, M. L. & Balk, S. P. (2002).J. Biol. Chem.277, 26321–26326.

Schellhammer, P. F. (2002).Exp. Opin. Pharmacother.3, 1313–1328. Schellhammer, P. F. & Davis, J. W. (2004).Clin. Prostate Cancer,2, 213–

219.

Sheldrick, G. M. (1996).SADABS. University of Go¨ttingen, Germany. Sheldrick, G. M. (1997). SHELXS97 and SHELXL97. University of

Go¨ttingen, Germany.

Tang, G.-P. & Gu, J.-M. (2005).Acta Cryst.E61, o3184–o3186.

Tucker, H., Crook, J. W. & Chesterson, G. J. (1988).J. Med. Chem.31, 954–959.

organic papers

Acta Cryst.(2007). E63, o33–o35 Butcheret al. _C

supporting information

sup-1 Acta Cryst. (2007). E63, o33–o35

supporting information

Acta Cryst. (2007). E63, o33–o35 [https://doi.org/10.1107/S1600536806050574]

N

-[4-Cyano-3-(trifluoromethyl)phenyl]-2-methyloxirane-2-carboxamide: a

bicalutamide intermediate

Ray J. Butcher, R. S. Narasegowda, H. S. Yathirajan, H. G. Anilkumar and B. M. Mohan

N-[4-Cyano-3-(trifluoromethyl)phenyl]-2-methyloxirane-2-carboxamide

Crystal data

C12H9F3N2O2

Mr = 270.21 Monoclinic, P21/n

a = 10.2636 (5) Å b = 11.5179 (6) Å c = 10.4182 (5) Å β = 102.944 (1)° V = 1200.29 (10) Å3

Z = 4 F(000) = 552

Dx = 1.495 Mg m−3

Melting point: 422 K

Mo Kα radiation, λ = 0.71073 Å Cell parameters from 5756 reflections θ = 2.5–26.0°

µ = 0.13 mm−1

T = 298 K Block, colorless 0.48 × 0.37 × 0.18 mm

Data collection

Bruker APEX-2 CCD area-detector diffractometer

Radiation source: fine-focus sealed tube Graphite monochromator

φ and ω scans

Absorption correction: multi-scan (SADABS; Sheldrick, 1996) Tmin = 0.914, Tmax = 0.966

10248 measured reflections 2352 independent reflections 2043 reflections with I > 2σ(I) Rint = 0.015

θmax = 26.0°, θmin = 2.5°

h = −12→12 k = −14→14 l = −12→12

Refinement

Refinement on F2

Least-squares matrix: full R[F2 _{> 2σ(F}2_{)] = 0.038}

wR(F2_{) = 0.107}

S = 1.05 2352 reflections 205 parameters 12 restraints

Primary atom site location: structure-invariant direct methods

Secondary atom site location: difference Fourier map

Hydrogen site location: inferred from neighbouring sites

H atoms treated by a mixture of independent and constrained refinement

w = 1/[σ2_(F

o2) + (0.0522P)2 + 0.266P]

where P = (Fo2 + 2Fc2)/3

(Δ/σ)max < 0.001

Δρmax = 0.18 e Å−3

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sup-2 Acta Cryst. (2007). E63, o33–o35

Special details

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 F}2_,

conventional R-factors R are based on F, with F set to zero for negative F2_{. The threshold expression of F}2 _{> σ(F}2_{) 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₎

x y z Uiso*/Ueq Occ. (<1)

F1A −0.0192 (5) 1.4133 (7) 0.3638 (12) 0.112 (2) 0.460 (17) F2A 0.1096 (12) 1.3882 (7) 0.2348 (4) 0.097 (2) 0.460 (17) F3A 0.1819 (7) 1.4534 (5) 0.4173 (6) 0.0958 (19) 0.460 (17) F1B 0.0144 (10) 1.4194 (6) 0.4202 (12) 0.133 (2) 0.540 (17) F2B 0.2084 (6) 1.4354 (6) 0.3930 (8) 0.117 (2) 0.540 (17) F3B 0.0472 (14) 1.3869 (6) 0.2308 (3) 0.131 (3) 0.540 (17) O1 0.08946 (12) 0.79487 (9) 0.35031 (10) 0.0640 (3)

O2 −0.04035 (14) 0.86410 (10) 0.01087 (10) 0.0732 (4) N1 0.05625 (12) 0.96802 (10) 0.24202 (11) 0.0496 (3) H1N 0.0284 (16) 0.9944 (16) 0.1659 (17) 0.059* C1 0.10289 (13) 1.04821 (11) 0.34244 (12) 0.0423 (3) C11 0.04782 (13) 0.85064 (11) 0.25120 (13) 0.0443 (3) C12 −0.02468 (15) 0.79203 (12) 0.12562 (13) 0.0480 (3) C13 0.01051 (18) 0.66736 (14) 0.11129 (18) 0.0657 (4)

H13A −0.0392 0.6383 0.0284 0.099*

H13B −0.0112 0.6229 0.1816 0.099*

H13C 0.1045 0.6609 0.1147 0.099*

C14 −0.15676 (17) 0.83715 (15) 0.06210 (16) 0.0664 (5)

H14A −0.2216 0.7831 0.0128 0.080*

H14B −0.1941 0.8985 0.1066 0.080*

C2 0.08724 (13) 1.16493 (12) 0.30784 (13) 0.0458 (3)

H2A 0.0503 1.1851 0.2208 0.055*

C3 0.12538 (13) 1.25097 (12) 0.40009 (13) 0.0456 (3) C31 0.09872 (14) 1.37465 (14) 0.35674 (13) 0.0639 (4) C4 0.18292 (13) 1.22119 (13) 0.53101 (12) 0.0463 (3) C41 0.22361 (15) 1.30732 (14) 0.63252 (14) 0.0562 (4) N41 0.25692 (16) 1.37267 (15) 0.71500 (15) 0.0784 (5) C5 0.20025 (14) 1.10469 (13) 0.56393 (13) 0.0501 (3)

H5A 0.2398 1.0844 0.6503 0.060*

C6 0.16050 (14) 1.01818 (12) 0.47226 (13) 0.0476 (3)

H6A 0.1720 0.9406 0.4968 0.057*

Atomic displacement parameters (Å2₎

U11 _U22 _U33 _U12 _U13 _U23

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sup-3 Acta Cryst. (2007). E63, o33–o35

F2A 0.188 (6) 0.0500 (18) 0.0536 (19) 0.006 (3) 0.026 (2) 0.0110 (19) F3A 0.133 (3) 0.0434 (16) 0.083 (2) −0.013 (2) −0.035 (3) −0.0116 (16) F1B 0.177 (5) 0.080 (2) 0.157 (5) 0.068 (4) 0.069 (4) 0.007 (3) F2B 0.135 (3) 0.061 (2) 0.159 (4) −0.039 (2) 0.041 (3) 0.010 (2) F3B 0.224 (6) 0.0482 (17) 0.076 (2) 0.026 (3) −0.058 (3) −0.0016 (16) O1 0.0831 (8) 0.0462 (6) 0.0521 (6) 0.0027 (5) −0.0076 (5) 0.0071 (5) O2 0.1179 (10) 0.0552 (7) 0.0396 (5) −0.0222 (7) 0.0033 (6) 0.0006 (5) N1 0.0686 (8) 0.0392 (6) 0.0347 (6) −0.0027 (5) −0.0014 (5) 0.0001 (5) C1 0.0461 (7) 0.0415 (7) 0.0369 (6) −0.0022 (5) 0.0038 (5) −0.0030 (5) C11 0.0477 (7) 0.0398 (7) 0.0434 (7) 0.0010 (5) 0.0056 (5) 0.0006 (5) C12 0.0617 (8) 0.0393 (7) 0.0419 (7) −0.0065 (6) 0.0090 (6) −0.0020 (5) C13 0.0790 (11) 0.0452 (8) 0.0737 (11) −0.0031 (7) 0.0185 (8) −0.0130 (7) C14 0.0745 (10) 0.0555 (9) 0.0568 (9) −0.0057 (8) −0.0117 (8) −0.0029 (7) C2 0.0538 (7) 0.0429 (7) 0.0366 (6) 0.0002 (6) 0.0014 (5) −0.0005 (5) C3 0.0479 (7) 0.0441 (7) 0.0431 (7) −0.0015 (6) 0.0070 (5) −0.0053 (6) C31 0.0828 (11) 0.0445 (8) 0.0587 (9) −0.0006 (8) 0.0039 (8) −0.0081 (7) C4 0.0449 (7) 0.0532 (8) 0.0396 (7) −0.0046 (6) 0.0070 (5) −0.0098 (6) C41 0.0584 (8) 0.0604 (9) 0.0478 (8) −0.0061 (7) 0.0078 (6) −0.0113 (7) N41 0.0893 (10) 0.0782 (10) 0.0625 (9) −0.0127 (8) 0.0058 (7) −0.0298 (8) C5 0.0549 (8) 0.0570 (9) 0.0345 (6) −0.0022 (6) 0.0017 (5) −0.0012 (6) C6 0.0548 (7) 0.0448 (7) 0.0394 (7) 0.0000 (6) 0.0025 (5) 0.0022 (5)

Geometric parameters (Å, º)

F1A—C31 1.3071 (16) C12—C13 1.496 (2)

F2A—C31 1.3096 (16) C13—H13A 0.9600

F3A—C31 1.3071 (16) C13—H13B 0.9600

F1B—C31 1.3075 (16) C13—H13C 0.9600

F2B—C31 1.3075 (16) C14—H14A 0.9700

F3B—C31 1.3078 (16) C14—H14B 0.9700

O1—C11 1.2098 (16) C2—C3 1.3749 (18)

O2—C12 1.4346 (17) C2—H2A 0.9300

O2—C14 1.447 (2) C3—C4 1.4021 (19)

N1—C11 1.3595 (18) C3—C31 1.501 (2)

N1—C1 1.3972 (16) C4—C5 1.387 (2)

N1—H1N 0.838 (17) C4—C41 1.4419 (19)

C1—C2 1.3918 (19) C41—N41 1.136 (2)

C1—C6 1.3930 (18) C5—C6 1.3773 (19)

C11—C12 1.5116 (18) C5—H5A 0.9300

C12—C14 1.464 (2) C6—H6A 0.9300

C12—O2—C14 61.07 (10) C3—C2—C1 121.12 (12)

C11—N1—C1 128.41 (12) C3—C2—H2A 119.4

C11—N1—H1N 114.4 (12) C1—C2—H2A 119.4

C1—N1—H1N 117.2 (12) C2—C3—C4 119.71 (13)

C2—C1—C6 119.38 (12) C2—C3—C31 118.01 (11)

C2—C1—N1 116.38 (11) C4—C3—C31 122.24 (12)

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sup-4 Acta Cryst. (2007). E63, o33–o35

O1—C11—N1 124.90 (13) F1B—C31—F2B 105.5 (4) O1—C11—C12 120.86 (12) F1B—C31—F3B 107.5 (4) N1—C11—C12 114.20 (11) F2B—C31—F3B 111.1 (5) O2—C12—C14 59.89 (10) F3A—C31—F2A 101.4 (4) O2—C12—C13 117.17 (13) F1A—C31—F2A 107.1 (4) C14—C12—C13 121.01 (13) F3A—C31—C3 117.3 (3) O2—C12—C11 113.86 (11) F1A—C31—C3 114.5 (4) C14—C12—C11 117.33 (12) F1B—C31—C3 108.6 (3) C13—C12—C11 115.59 (13) F2B—C31—C3 109.5 (3)

C12—C13—H13A 109.5 F3B—C31—C3 114.2 (3)

C12—C13—H13B 109.5 F2A—C31—C3 110.9 (4)

H13A—C13—H13B 109.5 C5—C4—C3 118.69 (12)

C12—C13—H13C 109.5 C5—C4—C41 118.97 (12)

H13A—C13—H13C 109.5 C3—C4—C41 122.33 (13)

H13B—C13—H13C 109.5 N41—C41—C4 178.03 (18)

O2—C14—C12 59.04 (10) C6—C5—C4 121.80 (12)

O2—C14—H14A 117.9 C6—C5—H5A 119.1

C12—C14—H14A 117.9 C4—C5—H5A 119.1

O2—C14—H14B 117.9 C5—C6—C1 119.28 (13)

C12—C14—H14B 117.9 C5—C6—H6A 120.4

H14A—C14—H14B 115.0 C1—C6—H6A 120.4

C11—N1—C1—C2 −173.36 (14) C2—C3—C31—F1A 87.7 (6) C11—N1—C1—C6 5.5 (2) C4—C3—C31—F1A −90.1 (6) C1—N1—C11—O1 −5.5 (2) C2—C3—C31—F1B 116.3 (7) C1—N1—C11—C12 172.25 (13) C4—C3—C31—F1B −61.4 (7) C14—O2—C12—C13 111.83 (16) C2—C3—C31—F2B −128.9 (5) C14—O2—C12—C11 −108.90 (14) C4—C3—C31—F2B 53.3 (5) O1—C11—C12—O2 −166.44 (13) C2—C3—C31—F3B −3.6 (7) N1—C11—C12—O2 15.75 (18) C4—C3—C31—F3B 178.7 (7) O1—C11—C12—C14 126.44 (16) C2—C3—C31—F2A −33.7 (6) N1—C11—C12—C14 −51.37 (17) C4—C3—C31—F2A 148.6 (6) O1—C11—C12—C13 −26.5 (2) C2—C3—C4—C5 0.2 (2) N1—C11—C12—C13 155.69 (13) C31—C3—C4—C5 177.90 (13) C13—C12—C14—O2 −105.50 (15) C2—C3—C4—C41 −179.30 (13) C11—C12—C14—O2 103.10 (13) C31—C3—C4—C41 −1.6 (2) C6—C1—C2—C3 −1.2 (2) C3—C4—C5—C6 −1.1 (2) N1—C1—C2—C3 177.70 (12) C41—C4—C5—C6 178.40 (13)

C1—C2—C3—C4 1.0 (2) C4—C5—C6—C1 0.9 (2)

C1—C2—C3—C31 −176.84 (12) C2—C1—C6—C5 0.3 (2) C2—C3—C31—F3A −149.4 (5) N1—C1—C6—C5 −178.52 (13) C4—C3—C31—F3A 32.9 (6)

Hydrogen-bond geometry (Å, º)

D—H···A D—H H···A D···A D—H···A

N1—H1N···O2i _{0.84 (2) 2.48 (2) 3.243 (2) 151 (1)}

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sup-5 Acta Cryst. (2007). E63, o33–o35

C14—H14A···O1ii _{0.97 2.44 3.375 (2) 161}

C6—H6A···O1 0.93 2.30 2.889 (2) 121

N1—H1N···O2 0.84 (2) 2.20 (2) 2.673 (2) 116 (2)