Crystal and molecular structure analysis of flutamide. Bifurcated helicoidal C-H ⋯ O hydrogen bonds

Abstract

Crystal structure determination and semiempirical AM 1 and PM3 calculations were performed on flutamide {2-methyl-N[4 nitro-3-(trifluoromethyl) phenyl] propamide}, a powerful nonsteroidal androgen antagonist. The molecule is almost planar apart from CF3, NO2, and CH 3 groups. The NO 2 plane makes an angle of 36.3(4) ~ with the least-square plane of the phenyl ring. The molecules are intermoleculady linked by one N--H-9 9 O and one C--H 9 9 9 O hydrogen bonds. A bifurcated helicoidal hydrogen bond network is formed by the intermolecular C--H 9 9 9 O hydrogen bond together with another intramolecular C--H 9 9 9 O hydrogen bond. The calculated structures are in good agreement with the crystallographic conformations. AM 1 is more accurate for predicting the intramolecular C--H 9 9 9 O hydrogen bond while PM3 gives a better geometry for the crowded nitro group. AMI and PM3 charges of benzenic hydrogens are used to predict the propensity of these atoms to form hydrogen bonds. The noncentrosymmetric space group of the crystal (Pna20, the calculated dipole moment (8.88 D), and the calculated angle between molecular dipoles and the twofold axis (-49 ~ close to the optimal value (54.7 ~ indicate that flutamide might be a possible candidate for nonlinear optical material.

Powder crystallography of pharmaceutical materials by combined crystal structure prediction and solid-state 1H NMR spectroscopy

“…The structure is comprised of 2 symmetry equivalent molecules in the unit cell, and it belongs to the P2 1 monoclinic space group with unit cell dimensions: a = 10.130(1) Å, b = 9.866(2) Å, c = 8.445(1) Å. Powdered flutamide (2-methyl-N(4-nitro-3-(trifluoromethyl)phenyl)propamide) was purchased from Sigma-Aldrich and used without further purification. The reference crystal structure of flutamide, (CSD entry code: WEZCOT) (Scheme 1-II), was previously determined by single crystal XRD 40 at 294 K. The structure is comprised of 4 symmetry equivalent molecules in the unit cell, and it belongs to the Pna2 1 orthorhombic space group with unit cell dimensions: a = 11.856(2) Å, b = 20.477(3) Å, c = 4.9590(9) Å. Powdered flufenamic acid (2-((3-(trifluoromethyl)phenyl)amino)-benzoic acid) was purchased from Fluka and used without further purification. The reference crystal structure of the corresponding flufenamic acid polymorph, (CSD entry code: FPAMCA11) (Scheme 1-III), was previously determined from single crystal XRD data 41 recorded at room temperature, and was confirmed by powder XRD to be the polymorph studied here.…”

Nilutamide

“…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.…”

Contribution of CH· · ·X Hydrogen Bonds to Biomolecular Structure

“…The decade of the 1990s saw what could arguably be termed an explosion of studies of the CHÁ Á ÁX interaction that broadened the sorts of systems that engage in this phenomenon, while better defining it [31,32]. Alkynes and alkenes were found to participate in such bonds [33][34][35][36], as did aryl groups [37][38][39][40][41][42], and even CH groups present in smaller rings [43,44], carboranes [45] and even cubyl arrangements [46]. Organometallic systems were also found to contain such bonds on a regular basis [47][48][49].…”