Pleconaril Polymorphs:  Crystal Structures of Form I and Form III, Evidence of the Enantiotropy, and Assessment of the Structural Purity

Abstract

Form I (HT) and form III (LT) of pleconaril are enantiotropically related with a calculated temperature of transition Tτ ) 35.7 °C (supposing an ideal behavior). Structural data obtained from single crystal X-ray diffraction at 100 K and room temperature show that (i) form I (HT) can be described as a network of dimers and form III can be described as a three-dimensional weakly H-bonded network of monomers. (ii) These two varieties contradict the density rule. (iii) The solid-solid transition (not observed) could only occur via a destructive-reconstructive mechanism. Investigations on the pleconaril-ethanol binary system show that the conversion form I S form III at Tτ ) 31 ( 2 °C is only possible when mediated by a solvent. A favorable set of thermodynamical and kinetic conditions allows quantification of form I in form III down to 0.1% by using differential scanning calorimetry. To assess the structural purity, this method could be applied to other compounds fulfilling five restrictive conditions.

Crystal structure of 5-{3-[2,6-dimethyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]propyl}-N-(11-hydroxyundecyl)isoxazole-3-carboxamide hemihydrate

“…A search of the Cambridge Structural Database (CSD; Version 5.36, November 2014; Groom & Allen, 2014) revealed the presence of nine structures (CSD refcode VOGDAY contains two independent molecules; Salorinne et al, 2014) with the substructure 3-{3,5-dimethyl-4-[3-(3-methylisoxazol-5-yl)propoxy]phenyl}-5-methyl-1,2,4-oxadiazole. These nine structures belong to three similar compounds of 5-{3-[2,6dimethyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]propyl}isoxazole-3-carboxylic acid (Salorinne et al, 2014), ethyl 5-{3-[2,6dimethyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]propyl}isoxazole-3-carboxylate (Salorinne et al, 2014) and 3-{3,5-dimethyl-4-[3-(3-methylisoxazol-5-yl)propoxy]phenyl}-5-trifluoromethyl-1,2,4-oxadiazole (Coste et al, 2004). In six of the nine structures (CSD refcodes VOGCOL01, VOGDAY, HAJYUN, HAJYUN01, HAJYUN02 and HAJYUN03; Salorinne et al, 2014;Coste et al, 2004), the isoxazole and phenyloxadiazole heterocyclic rings of the WIN framework are almost coplanar, similar to the title compound.…”

“…These nine structures belong to three similar compounds of 5-{3-[2,6dimethyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]propyl}isoxazole-3-carboxylic acid (Salorinne et al, 2014), ethyl 5-{3-[2,6dimethyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]propyl}isoxazole-3-carboxylate (Salorinne et al, 2014) and 3-{3,5-dimethyl-4-[3-(3-methylisoxazol-5-yl)propoxy]phenyl}-5-trifluoromethyl-1,2,4-oxadiazole (Coste et al, 2004). In six of the nine structures (CSD refcodes VOGCOL01, VOGDAY, HAJYUN, HAJYUN01, HAJYUN02 and HAJYUN03; Salorinne et al, 2014;Coste et al, 2004), the isoxazole and phenyloxadiazole heterocyclic rings of the WIN framework are almost coplanar, similar to the title compound. However, in two of the structures (CSD refcodes VOGCOL and VOGDEL; Salorinne et al, 2014), the heterocyclic ring systems are tilted slightly with angles of 34-38 between the ring planes, whereas in one of the structures (CSD refcode VOGCOL; Salorinne et al, 2014), the heterocyclic ring systems are closer to a perpendicular orientation, with an angle of ca 60.8 .…”

Polymorphic and solvate structures of ethyl ester and carboxylic acid derivatives of WIN 61893 analogue and their stability in solution

“…13 Likewise, the propyloxy unit is found in a gauche conformation in both of the Pleconaril forms I and III (63.6-67.9°) structures. However, only linear conformation between planes A and B is observed for both of the Pleconaril polymorphs (form I: ϕ = 17.2°and form III: ϕ = 9.9°).…”

“…However, only linear conformation between planes A and B is observed for both of the Pleconaril polymorphs (form I: ϕ = 17.2°and form III: ϕ = 9.9°). 13 …”

“…12,13 In these two polymorphic structures the Pleconaril molecules were described to pack either as a network of dimers (form I) or as a threedimensional weakly hydrogen-bonded network of monomers (form III). 13 In comparison to the structure of the prior WIN 61893 analogue, the oxadiazole ring methyl group was substituted with a trifluoromethyl group in the Pleconaril derivative (Scheme 1). 14 Our aim was to functionalize the isoxazole ring 3-position with an anchoring carboxylate group in order to produce a potentially better analogue to the inherent palmitic acid that is commonly found in the hydrophobic pocket of enterovirus capsid.…”