(S)-6-Chloro-4-cyclopropylethynyl-4-trifluoromethyl-1H-3,1-benzoxazin-2(4H)-one

Two independent molecules comprise the crystallographic asymmetric unit in the title antiretroviral agent Efavirenz, C14H9ClF3NO2, and these have noteworthy differences in conformation. The major difference relates to the orientation of the 2-cyclopropylethynyl residue relative to the six-membered heterocycle: this approaches an orthogonal disposition in molecule a compared to a more flattened conformation in molecule b, the difference being reflected in the Oring—C—C—Cethyne torsion angles of 65 (4) and 159 (5)°, respectively. The independent molecules are connected via the eight-membered {⋯HNC (O)}2 amide synthon. Disorder is noted in the cyclopropane ring of molecule b in that two orientations of equal weight were discerned.

Two independent molecules comprise the crystallographic asymmetric unit in the title antiretroviral agent Efavirenz, C 14 H 9 ClF 3 NO 2 , and these have noteworthy differences in conformation. The major difference relates to the orientation of the 2-cyclopropylethynyl residue relative to the sixmembered heterocycle: this approaches an orthogonal disposition in molecule a compared to a more flattened conformation in molecule b, the difference being reflected in the O ring -C-C-C ethyne torsion angles of 65 (4) and 159 (5) , respectively. The independent molecules are connected via the eightmembered {Á Á ÁHNC (O)} 2 amide synthon. Disorder is noted in the cyclopropane ring of molecule b in that two orientations of equal weight were discerned.
The use of the EPSRC X-ray crystallographic service at the University of Southampton, England and the valuable assistance of the staff there is gratefully acknowledged. JLW acknowledges support from CAPES (Brazil).

S1. Comment
The title anti-retroviral agent, Efavirenz, is a second-generation non-nucleoside inhibitor of HIV-1 reverse transcriptase (RT) that has been approved for use against HIV-1 infection. It is also called Sustiva or Stocrin and is manufactured by Bristol-Myers Squibb. Compared with first-generation drugs such as nevirapine, Efavirenz shows greater resilience to drug resistance mutations within HIV-1 RT. Effective treatment through inhibition of HIV reverse transcriptase has been shown for both nucleoside based inhibitors, such as azidothymidine, and non-nucleoside based inhibitors, such as Efavirenz. Efavirenz is also used in combination with other anti-retroviral agents as part of an expanded post-exposure prophylaxis regimen to reduce the risk of HIV infection in people exposed to a significant risk (Adkins & Noble, 1998;Gazzard, 1999;de Clercq et al., 2009;Markowitz et al., 2009;Young et al., 2009).
Two independent molecules comprise the asymmetric unit in (I), labelled a and b, Fig. 1. There are significant differences in conformation between the molecules and these relate primarily to the disposition of the 2-cyclopropylethynyl residue to the six-membered hetero-ring. As seen from Fig. 1, each hetero ring adopts a flattened half-chain conformation with the C4a and C4b atoms being the pivotal atoms. In molecule a, the C4a atom is orientated towards the same side of the six-membered ring as the 2-cyclopropylethynyl residue which occupies a position orthogonal to the sixmembered ring as seen in the O3a/C4a/C10a/C11a torsion angle of 65 (4) °. In molecule b, the C4b atom and 2-cyclopropylethynyl residue lie to opposite sides of the six-membered ring and the comparable torsion angle is 159 (5) °. The independent molecules associate via the eight-membered {···HNC(O)} 2 amide synthon, Table 1 and Fig. 1.

S2. Experimental
Crystals used in the crystallographic study were grown from aqueous methanol solution of (I).
The amide-N H atoms were refined freely, see Table 1 for distances. Disorder was resolved for the cyclopropane ring of molecule b in that two positions, of equal weight (from refinement), were discerned for one of wing C atoms, C14b, so that each component of the disordered ring shared two atoms, C12b and C13b.  Molecular structure (I) showing the hydrogen bonding (orange dashed lines) between the two molecules comprising the crystallographic asymmetric unit, the atom-labelling scheme, and displacement ellipsoids at the 50% probability level.
Only one component of the disordered C12b-C14b cyclohexane ring is shown for reasons of clarity.

Special details
Geometry. All s.u.'s (except the s.u. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell s.u.'s are taken into account individually in the estimation of s.u.'s in distances, angles and torsion angles; correlations between s.u.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell s.u.'s is used for estimating s.u.'s involving l.s. planes. Refinement. Refinement of F 2 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 F 2 . The threshold expression of F 2 > 2σ(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 F 2 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 (Å 2 )
x y z U iso */U eq Occ.