Diethyl 4-(biphenyl-4-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate

The title compound, C25H27NO4, has a flattened dihydropyridine ring. The benzene and phenyl rings are synclinal to one another, forming a dihedral angle of 49.82 (8)°; the axis of the biphenyl rings makes an 81.05 (9)° angle to the plane of the dihydropyridine ring. In the crystal, N—H⋯O hydrogen bonds link the molecules into chain motifs running along the a-axis direction. The chains are cross-linked by C—H⋯O interactions, forming sheet motifs running slightly off the (110) plane, together with an intermolecular interaction between head-to tail biphenyl groups, thus making the whole crystal packing a three-dimensional network. Intramolecular C—H⋯O hydrogen bonds are also observed.


Comment
Hantzsch 1,4-dihydropyridines (DHPs) are an extensively studied class of compounds that are known predominantly for their L-type voltage gated calcium channel modulation. (Bossert et al. 1981, Triggle 2003 There have been extensive structure-activity relationship (SAR) studies done on DHPs that have revealed the basic structural requirements for robust binding affinity to calcium channels. (Triggle 2003) Other studies in the field have shown that DHPs bind to multiple receptors, most notably the multiple drug resistant protein 1 (MDR1) (Abe et al. 1995, Cole et al. 1989, Tasaki et al. 1995, Vanhoefer et al. 1999, Tolomero et al. 1994, Cindric et al. 2010. Using established SAR more selective compounds can be designed for greater selectivity resulting in more clinically relevant compounds.

Synthesis and crystallization
An oven-dried 100 mL round bottom flask was charged with 1.90g of biphenyl-4-carbaldehyde, 2.86 g of ethyl acetoacetate, 2.49 mL of 14.8M ammonium hydroxide, and a magenetic stir bar. The mixture was taken up in 50 mL of absolute ethanol, and the round bottom flask was fitted with a dean stark trap and heated to reflux while stirring. Reaction progress was monitored via TLC. Once the reaction was complete, excess solvent was removed via rotary evaporation.
The solution was then purified via a silica column chromatography. The product was re-crystallized into white to yellow crystalline clumps with hexane and dichloromethane (yield = 1.24g , 3.06 mmol, 29.31%).

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 1. The methyl H atoms were constrained to an ideal geometry, with C -H = 0.98 Å and U iso (H) = 1.5U eq (C), and were allowed to rotate freely about the C -C bonds. The rest of the H atoms were placed in calculated positions with C -H = 0.95 ~ 1.00 Å and refined as supporting information riding on their carrier atoms with U iso (H) = 1.2U eq (C). The positions of amine H atoms were determined from difference Fourier maps and refined freely along with their isotropic displacement parameters. One low-angle reflection was omitted from the refinement because its observed intensity was much lower than the calculated value as a result of being partially obscured by the beam stop.

Figure 1
Crystal structure of the title compound with labeling and displacement ellipsoids drawn at the 50% probability level.   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 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 > 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 F 2 are statistically about twice as large as those based on F, and R-factors based on ALL data will be even larger.