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

Abstract

ester-(1) and 3-carboxylic acid-isoxazole (2) derivatives of an antiviral drug analogue WIN 61893 were synthesized and characterized by X-ray crystallography and NMR spectroscopy. Crystallization experiments afforded two polymorphic structures for the ethyl ester derivative and two solvate structures for the carboxylic acid derivative based on their ability to form intermolecular hydrogen bonding interactions with the solvent molecules. The conformations of the derivatives depended greatly on the orientation of the planar isoxazole and phenyl-oxadiazole ring systems with respect to one another and were found to take up perpendicular, linear or tilted conformations. The carboxylic acid derivative was furthermore observed to undergo isoxazole ring cleavage by decarboxylation in DMSO solution and transforming into a β-keto nitrile ring-opening product over several days, whereas, the isoxazole ring of the ethyl ester derivative was not affected.

Hydrophobic pocket targeting probes for enteroviruses

“…The synthesis of the probe (2) was accomplished by an amide coupling reaction of the carboxylic acid derivative 30 (1) with 11-amino-1-undecanol in dichloromethane in the pres-ence of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDC) coupling reagent and a catalytic amount of 1-hydroxybenzotriazole (HOBt) in good yield (Scheme 2). Subsequent Steglich esterification reaction with a p-mercaptobenzoic acid ( pMBA) protected Au 102 ( pMBA) 44 cluster 31,32 or an azadioxatriangulenium dye molecule 33,34 in DCM in the presence of dicyclohexylcarbodiimide (DCC) and a catalytic amount of N,N-dimethylaminopyridine (DMAP) afforded the gold (3) and fluorescent dye (4) labeled probes (see the ESI † for details).…”

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

“…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 . In all of the structures, the propyloxy unit is in a gauche conformation, with torsion angles in the range 62.4-69.2 .…”

“…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 .…”

Study on Typical Diarylurea Drugs or Derivatives in Cocrystallizing with Strong H-Bond Acceptor DMSO

“…The solvation of active pharmaceutical ingredients (APIs) could offer benefits on physicochemical properties, so it has gradually become an attractive strategy in drug design and polymorph screening. 26,27 So far, several drugs as solvates covering ethanolate, acetone, and DMSO complexes have been approved. 28−30 Cumulative research on the complexation of diarylureas with strong acceptors suggest that the solvation of urea-containing drugs is a feasible direction.…”