Structural investigation of methyl 3-(4-fluorobenzoyl)-7-methyl-2-phenylindolizine-1-carboxylate, an inhibitory drug towards Mycobacterium tuberculosis

The structural analysis of a phenylindolizine-based drug, namely methyl 3-(4-flurobenzoyl)-7-methyl-2-phenylindolizine-1-carboxylate (I) was carried out; this drug shows an inhibitory action towards mycobacterium tuberculosis. The intermolecular interactions at play were characterized via Hirshfeld surface analysis and fingerprint plots, highlighting the evident role of C—H⋯O, C—H⋯F and C—H⋯π interactions in the formation of the observed crystal structure.

The title compound, comprising a substituted indolizine unit, displays a modest activity against susceptible H37Rv strains of Mycobacterium tuberculosis (Venugopala et al., 2019). Besides the tremendous scope of the pharmacological studies on indolizine-based compounds, the substitution of fluorine on the benzoyl ring, the presence of flexible moieties and of competitive hydrogen-bond acceptors (namely, oxygen O2 in the ester group at C6 and O3 in the carbonyl group at C8) make the structural study of the title compound of extreme relevance. In addition, it is of importance to observe the cooperative interplay of weak interactions that contribute towards the consolidation of the crystal lattice. In the present paper, we report the molecular and crystal structure of the title compound, highlighting its molecular conformation and analysing the different intermolecular interactions via Hirshfeld surface analysis and fingerprint plots.
In particular, the papers reporting TIGXOX (Liu et al., 2007), FEDQAH (Liu et al., 2005) and ODEFIN (Qian et al., 2006) discuss the structural features of molecules comprising the 2-phenyl indolizine skeleton, showing high fluorescent efficiency. In these reports, the respective dihedral angles between the mean plane of the indolizine skeleton and the plane of the phenyl ring are ca 53, 39 and 49 and 45 , comparable to that reported in the title compound.

Hirshfeld surface analysis and fingerprint plots
The significance of the cumulative effect of the interactions involved in the crystal structure can be visualized qualitatively through Hirshfeld surface analysis (Spackman et al., 2009). The Hirshfeld surfaces and the two-dimensional fingerprint plots were calculated using CrystalExplorer (Version 17.5; Wolff et al., 2012)  Crystal packing of title compound showing the formation of molecular sheets parallel to the bc plane via C-HÁ Á ÁO, C-HÁ Á Á and C-HÁ Á ÁF interactions.

Synthesis and crystallization
All chemicals were obtained from Sigma-Aldrich and used without further purification. A mixture of methyl 3-phenylpropiolate (1) (160 mg, 1 mmol), 4-methylpyridine (2) (93 mg, 1 mmol), 2-bromo-1-(4-fluorophenyl)ethan-1-one (3) (217 mg, 1 mmol), and triethylamine (0.101 mg, 1 mmol) in 4.5 mL of acetonitrile were added to a 10 mL microwave tube under a nitrogen atmosphere (Fig. 7). A microwave initiator was used to irradiate the reaction mixture at 373 K for about 5 min. The reaction was monitored via TLC. The solvent was then removed under reduced pressure, the crude residue was diluted with water and the aqueous layer was extracted twice with ethyl acetate, and the combined organic solvent was washed with a brine solution. The organic layer was removed under reduced pressure and the remaining residue was subjected to column chromatography using 60-120 mesh silica gel with an ethyl acetate and hexane solvent system to afford The Hirshfeld surface of title compound mapped over d norm . Dashed lines indicate hydrogen bonds.

Figure 7
The reaction scheme for the synthesis of the title compound.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 2. The hydrogen atoms were placed in idealized positions and refined using a riding model with U iso (H) =1.2U eq (C) or 1.5U eq (C-methyl).

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