Crystal structure of (±)-2-[4-(4-chlorophenoxymethyl)phenoxy]propionic acid

Abstract

The crystal structure of (�)-2-[4-(4-chlorophenoxymethyl)phenoxy]propionic acid has been determined by direct methods using three-dimensional X-ray diffraction data. The crystals are triclinic, P1, Z 2, a 9.345(2), b 12,602(2), c 6.741(1) �, α 101.37(1), β 97.42(1), γ 101.75(1)�. The structure refined to give a final R 0.084 for 2172 observed reflections. The acid molecules form centrosymmetric hydrogen bonded cyclic dimers [O. . .O,2.619(4) �] about a centre of symmetry in the cell. The oxopropionic acid side chain has a synplanar-synplanar (carbonyl) conformation while the planar p-chlorophenoxymethyl substituent in the p-position has a synclinal orientation relative to the primary phenoxy residue.

A Novel Mechanism of Preferential Enrichment Phenomenon Observed for the Cocrystal of (RS)‐2‐{4‐[(4‐Chlorophenoxy)methyl]phenoxy}propionic Acid and Isonicotinamide

“…(a) Simulated pattern from the single‐crystal X‐ray diffraction data of ( RS )‐CPPPA (black line, data cited from ref. ). Experimental patterns of (b) the as‐synthesized racemic sample (red line) and (c) the slightly R ‐rich crystals of 1.3 % ee obtained at the end of PE crystallization (blue line).…”

“…(RS)-CPPPAc rystallized in the triclinic space group P1 ¯with cell parameters, a = 9.345(2), b = 12.602(2), c = 6.741(1) , a = 101.37(1), b = 97.65(2), g = 101.75(1)8, V = 749.9 3 , Z = 2. [24] In the crystal structure( Figure 1a), homochiral 1D chains were formed alongt he c-axis by two CH/p interactions between a hydrogen atom of the methyl group (C9) and the centroid of the neighbouring phenyl group (A-ring) (CgA) (C9•••CgA, 3.84 )a nd between the C15-H atom of the phenylg roup (Bring) and the centroid of another neighbouring phenyl group (A-ring)( C15•••CgA, 3.96 ). Furthermore,h eterochiral cyclic dimer chains were formed by the hydrogen bonds between two carboxy groups (O2•••O3, 2.62 ,g raph set:R 2 2 (8)) 25,26 along the c-axis (Figure 1a).…”

“…Next, to find a new chiral drug that can show PE by cocrystallization, we have focused on crystalline drugs with a space group of P by the Cambridge Structural Database (CSD) search, because a centrosymmetric molecular arrangement and a homochiral 1D chain structure are very often seen in triclinic crystals. Here we report a new entry of chiral anti‐hyperlipoproteinemia drug [EMD 31 647], ( RS )‐2‐{4‐[(4‐chlorophenoxy)methyl]phenoxy}propionic acid (CPPPA), which has a space group of P and showed a PE phenomenon. Although free CPPPA showed a modest PE result (enrichment up to 26 % ee in the mother liquor) in 2‐PrOH, a 1:1 cocrystal (CPPPA ⋅ INA) composed of CPPPA and isonicotinamide exhibited an excellent PE phenomenon (enrichment up to 93 % ee in the mother liquor).…”

“…(a) Homochiral 1D chains were formedb yt wo CH/p interactions (green broken lines) and heterochiral cyclicdimer chains wereformed by the hydrogen bonds(black broken lines) between adjacent R and S chains alongt he c-axis. (b) Atomic numbering Scheme of CPPPAinr ef [24]…”

“…Comparison of X-ray diffraction patterns of CPPPA. (a) Simulated pattern from the single-crystalX-ray diffraction data of (RS)-CPPPA(black line, data cited from ref [24]…”