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Crystal structures of four organic salts of trihexyphenidyl at 90 K.

ABSTRACT: The syntheses and crystal structure studies of four organic salts of trihexyphenidyl, viz., trihexyphenidylium [1-(3-cyclo-hexyl-3-hy-droxy-3-phenyl-prop-yl)piperidin-1-ium] 4-nitro-benzoate, C₂₀H₃₂NO⁺·C₇H₄NO₄ ^- (I), trihexyphenidylium 4-hy-droxy-benzoate, C₂₀H₃₂NO⁺·C₇H₅O^- (II), trihexyphenidylium 4-bromo-benzoate, C₂₀H₃₂NO⁺·C₇H₄BrO₂ ^- (III), and trihexyphenidylium thio-phene-2-carboxyl-ate hemihydrate, 2C₂₀H₃₂NO⁺·2C₅H₃O₂S^-·H₂O (IV), con-ducted at 90 K are described. Structures I, II, and III are solvent free with one cation-anion pair per asymmetric unit, while IV crystallizes as a hemihydrate, having two cation-anion pairs and one water of crystallization in its asymmetric unit. Structures I and III exhibit configurational disorder of the cation. Structure IV also exhibits disorder, but only of the thio-phene-2-carboxyl-ate anions. Structure II is a non-merohedric twin by a twofold rotation about [403]. The main supra-molecular motifs in I, II, and III are similar R ² ₂(10) rings between cation-anion pairs, although their packing within the crystals is distinct. As a consequence of having two cation-anion pairs and a water mol-ecule in its asymmetric unit, the packing in IV is by far the most complex of the four structures, its hydrogen-bonding patterns being quite different from I, II, or III. In all the crystals studied, N-H⋯O, O-H⋯O, and C-H⋯O inter-actions are observed, plus C-H⋯Br close contacts for III.

SUBMITTER: Vinaya

PROVIDER: S-EPMC10439416 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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Crystal structures of four organic salts of trihexyphenidyl at 90 K.

Vinaya Basavaraju Yeriyur B YB Yathirajan Hemmige S HS Parkin Sean S

Acta crystallographica. Section E, Crystallographic communications 20230714 Pt 8

The syntheses and crystal structure studies of four organic salts of trihexyphenidyl, viz., trihexyphenidylium [1-(3-cyclo-hexyl-3-hy-droxy-3-phenyl-prop-yl)piperidin-1-ium] 4-nitro-benzoate, C20H32NO+·C7H4NO4 - (I), trihexyphenidylium 4-hy-droxy-benzoate, C20H32NO+·C7H5O- (II), trihexyphenidylium 4-bromo-benzoate, C20H<sub ...[more]

PMID: 37601391

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Project description:Bedaquiline [systematic name: 1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol, C32H31BrN2O2] is one of two important new drugs for the treatment of drug-resistant tuberculosis (TB). It is marketed in the US as its fumarate salt {systematic name: [4-(6-bromo-2-methoxyquinolin-3-yl)-3-hydroxy-3-(naphthalen-1-yl)-4-phenylbutyl]dimethylazanium 3-carboxyprop-2-enoate, C32H32BrN2O2+·C4H3O4-}, and about a dozen other salts of bedaquiline have been described in patent literature, but none have so far been structurally described. In a first communication, we present the crystal structure of bedaquilinium fumarate and of two new benzoate salts, as well as that of a degradation product of the reaction of bedaquilinium fumarate with sodium ethoxide, 3-benzyl-6-bromo-2-methoxyquinoline, C17H14BrNO. The fumarate and benzoate salts both feature cations monoprotonated at the dimethylamino group. The much less basic quinoline N atom remains unprotonated. Both salts feature a 1:1 cation-to-anion ratio, with the fumarate being present as monoanionic hydrofumarate. The conformations of the cations are compared to that of free base bedaquiline and with each other. The flexible backbone of the bedaquiline structure leads to a landscape of conformations with little commonalities between the bedaquiline entities in the various structures. The conformations are distinctively different for the two independent molecules of the free base, the two independent molecules of the hydrofumarate salt, and the one unique cation of the benzoate salt. Packing of the salts is dominated by hydrogen bonding. Hydrogen-bonding motifs, as well as the larger hydrogen-bonded entities within the salts, are quite similar for the salts, despite the vastly differing conformations of the cations, and both the hydrofumarate and the benzoate structure feature chains of hydrogen-bonded anions that are surrounded by and hydrogen bonded to the larger bedaquilinium cations, leading to infinite broad ribbons of anions, cations, and (for the benzoate salt) water molecules. The benzoate salt was isolated in two forms: as a 1.17-hydrate (C32H32BrN2O2+·C7H5O2-·1.166H2O), obtained from acetone or propanol solution, with one fully occupied water molecule tightly integrated into the hydrogen-bonding network of anions and cations, and one partially occupied water molecule [refined occupancy 16.6 (7)%], only loosely hydrogen bonded to the quinoline N atom. The second form is an acetonitrile solvate (C32H32BrN2O2+·C7H5O2-·0.742CH3CN·H2O), in which the partially occupied water molecule is replaced by a 74.2 (7)%-occupied acetonitrile molecule. The partial occupancy induces disorder for the benzoate phenyl ring. The acetonitrile solvate is unstable in atmosphere and converts into a form not distinguishable by powder XRD from the 1.17-hydrate.

Project description:Eleven (4-phen-yl)piperazinium salts containing organic anions have been prepared and structurally characterized, namely, 4-phenyl-piperazin-1-ium 4-fluoro-benzoate monohydrate, C10H15N2 +·C7H4FO2 -·H2O, 1; 4-phenyl-piperazin-1-ium 4-bromo-benzoate monohydrate, C10H15N2 +·C7H4BrO2 -·H2O, 3; 4-phenyl-piperazin-1-ium 4-iodo-benzoate, C10H15N2 +·C7H4IO2 -, 4; 4-phenyl-piperazin-1-ium 4-nitro-benzoate, C10H15N2 +·C7H4NO4 -, 5; 4-phenyl-piperazin-1-ium 3,5-di-nitro-salicylate, C10H15N2 +·C7H3N2O7 -, 6; 4-phenyl-piperazin-1-ium 3,5-di-nitro-benzoate, C10H15N2 +·C7H3N2O6 -, 7; 4-phenyl-piperazin-1-ium picrate, C10H15N2 +·C6H2N3O7 -, 8; 4-phenyl-piperazin-1-ium benzoate monohydrate, C10H15N2 +·C7H5O2 -·H2O, 9; 4-phenyl-piperazin-1-ium p-toluene-sulfonate, C10H15N2 +·C7H7O3S-, 10; 4-phenyl-piperazin-1-ium tartarate monohydrate, C10H15N2 +·C4H5O6 -·H2O, 11; and 4-phenyl-piperazin-1-ium fumarate, C10H15N2 +·C4H3O4 -, 12. Compounds 1 and 3-12 are all 1:1 salts with the acid proton transferred to the phenyl-piperaizine basic N atom (the secondary amine) with the exception of 3 where there is disorder in the proton position with it being 68% attached to the base and 32% attached to the acid. Of the structures with similar stoichiometries only 3 and 9 are isomorphous. The 4-phenyl substituent in all cases occupies an equatorial position except for 12 where it is in an axial position. The crystal chosen for structure 7 was refined as a non-merohedral twin. There is disorder in 5, 6, 10 and 11. For both 5 and 6, a nitro group is disordered and was modeled with two equivalent orientations with occupancies of 0.62 (3)/0.38 (3) and 0.690 (11)/0.310 (11), respectively. For 6, 10 and 11, this disorder is associated with the phenyl ring of the phenyl-piperazinium cation with occupancies of 0.687 (10)/0.313 (10), 0.51 (7)/0.49 (7) and 0.611 (13)/389 (13), respectively. For all salts, the packing is dominated by the N-H⋯O hydrogen bonds formed by the cation and anion. In addition, several structures contain C-H⋯π (1, 3, 4, 8, 9, 10, and 12) and aromatic π-π stacking inter-actions (6 and 8) and one structure (5) contains a -NO2⋯π inter-action. For all structures, the Hirshfeld surface fingerprint plots show the expected prominent spikes as a result of the N-H⋯O and O-H⋯O hydrogen bonds.

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Crystal structures of four organic salts of trihexyphenidyl at 90 K.

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Crystal structures of four organic salts of trihexyphenidyl at 90 K.

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