Crystal structures of salts of bedaquiline

The single-crystal structures of three salts of bedaquiline, a drug used for the treatment of drug-resistant tuberculosis (TB), are described.
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.