Varying degrees of homostructurality in a series of cocrystals of antimalarial drug 11-azaartemisinin with salicylic acids.

The X-ray structures of three new 1:1 pharmaceutical cocrystals of 11-azaartemisinin (11-Aza; systematic name: 1,5,9-trimethyl-14,15,16-trioxa-11-azatetracyclo[10.3.1.04,13.08,13]hexadecan-10-one, C15H23NO4) with bromo-substituted salicylic acids [namely, 5-bromo- (5-BrSalA, C7H5BrO3), 4-bromo- (4-BrSalA, C7H5BrO3) and 3,5-dibromosalicylic acid (3,5-Br2SalA, C7H4Br2O3)] are reported. All the structures are related to the parent 11-Aza:SalA cocrystal (monoclinic P21) reported previously. The 5-BrSalA analogue is isostructural with the parent, with lattice expansion along the c axis. The 4-BrSalA and 3,5-Br2SalA cocrystals retain the highly preserved 21 stacks of the molecular pairs, but these pack with a varying degree of slippage with respect to neighbouring stacks, altering the close contacts between them, and represent two potential alternative homostructural arrangements for the parent compound. Structure redeterminations of the bromosalicylic acids 5-BrSalA, 4-BrSalA and 3,5-Br2SalA at 100 K show that the packing efficiency of the cocrystals need not be higher than the parent coformers, based on specific-volume calculations, attributable to the strong O-H...O=C hydrogen bonds of 2.54 Šin the cocrystals.

Chiral anionic layers in tartramide spiroborate salts and variable solvation for [NR4][B(TarNH2)2] (R = Et, Pr or Bu).

The spiroborate anion, namely, 2,3,7,8-tetracarboxamido-1,4,6,9-tetraoxa-5λ4-boraspiro[4.4]nonane, [B(TarNH2)2]-, derived from the diol L-tartramide TarNH2, [CH(O)(CONH2)]2, shows a novel self-assembly into two-dimensional (2D) layer structures in its salts with alkylammonium cations, [NR4]+ (R = Et, Pr and Bu), and sparteinium, [HSpa]+, in which the cations and anions are segregated. The structures of four such salts are reported, namely, the tetrapropylazanium salt, C12H28N+·C8H12BN4O8-, the tetraethylazanium salt hydrate, C8H20N+·C8H12BN4O8-·6.375H2O, the tetrabutylazanium salt as the ethanol monosolvate hemihydrate, C16H36N+·C8H12BN4O8-·C2H5OH·0.5H2O, and the sparteinium (7-aza-15-azoniatetracyclo[7.7.1.02,7.010,15]heptadecane) salt as the ethanol monosolvate, C15H27N2+·C8H12BN4O8-·C2H5OH. The 2D anion layers have preserved intermolecular hydrogen bonding between the amide groups and a typical metric repeat of around 10 × 15 Å. The constraint of matching the interfacial area organizes the cations into quite different solvated arrangements, i.e. the [NEt4] salt is highly hydrated with around 6.5H2O per cation, the [NPr4] salt apparently has a good metric match to the anion layer and is unsolvated, whilst the [NBu4] salt is intermediate and has EtOH and H2O in its cation layer, which is similar to the arrangement for the chiral [HSpa]+ cation. This family of salts shows highly organized chiral space and offers potential for the resolution of both chiral cations and neutral chiral solvent molecules.

Tandem crystallization strategies for resolution of 3,3,3-trifluorolactic acid [CF3 CH(OH)COOH] by chiral benzylamines.

Resolution of rac-3,3,3-trifluorolactic acid by diastereomeric salt formation was reinvestigated. The use of (S)-1-phenylethylamine gives coprecipitation of two diastereomeric phases, 1 (S)-[NH3 CH(CH3 )Ph](S)-[CF3 CH(OH)COO] and 2 (S)-[NH3 CH(CH3 )Ph](R)-[CF3 CH(OH)COO]·H2 O. Pure phase 1 may be obtained using molecular sieves as desiccants. Resolution by (S,S)-2-amino-1-phenylpropan-1,3-diol gives monoclinic (S,S)-[NH3 CH(CH2 OH)CHOHPh] (R)-[CF3 CH(OH)-COO] 3 with minor (S)-3,3,3-trifluorolactate contamination, which is precluded in the recrystallized orthorhombic form 4. A new resolution using inexpensive phenylglycinol gives pure phase 5 (S)-[NH3 CH(CH2 OH)Ph] (S)-[CF3 CH(OH)COO] in 76% yield, 94% ee in a single step, in preference to its (S)-(R) diastereomer 6. Overall efficient resolution for both enantiomers of the trifluorolactic acid (each ca. 70% yield, 99% ee) may be achieved by various two-step "tandem" crystallizations, involving direct addition of either water or a second base to the filtrate from the initial reaction.

Cocrystals of the antimalarial drug 11-azaartemisinin with three alkenoic acids of 1:1 or 2:1 stoichiometry.

The stoichiometry, X-ray structures and stability of four pharmaceutical cocrystals previously identified from liquid-assisted grinding (LAG) of 11-azaartemisinin (11-Aza; systematic name: 1,5,9-trimethyl-14,15,16-trioxa-11-azatetracyclo[10.3.1.04,13.08,13]hexadecan-10-one) with trans-cinnamic (Cin), maleic (Mal) and fumaric (Fum) acids are herein reported. trans-Cinnamic acid, a mono acid, forms 1:1 cocrystal 11-Aza:Cin (1, C15H23NO4·C9H8O2). Maleic acid forms both 1:1 cocrystal 11-Aza:Mal (2, C15H23NO4·C4H4O4), in which one COOH group is involved in self-catenation, and 2:1 cocrystal 11-Aza2:Mal (3, 2C15H23NO4·C4H4O4). Its isomer, fumaric acid, only affords 2:1 cocrystal 11-Aza2:Fum (4). All cocrystal formation appears driven by acid-lactam R22(8) heterosynthons with short O-H...O=C hydrogen bonds [O...O = 2.56 (2) Å], augmented by weaker C=O...H-N contacts. Despite a better packing efficiency, cocrystal 3 is metastable with respect to 2, probably due to a higher conformational energy for the maleic acid molecule in its structure. In each case, the microcrystalline powders from LAG were useful in providing seeding for the single-crystal growth.

Isolation and enantiostability of the B-chiral bis(salicylato)borate anions [B R (Sal)2] and [B S (Sal)2].

The chiral spiroborate anions [B S (Sal)2] and [B R (Sal)2], (R and S subscripts indicate boron stereochemistry) have been isolated as 1 : 1 quininium and 1 : 2 sparteinium salts, [HQuin][B S (Sal)2] and [H2Spa][B R (Sal)2]2 respectively, by either cation metathesis or a simple one-pot synthesis involving reaction of boric and salicylic acids with the alkaloid base. Circular dichroism (CD) spectroscopy shows that the B-based chirality is stable in polar aprotic media, such as DMF or DMSO, though labile in protic solutions. Enantiopure salts with achiral counter-cations such as [NBu4][B R (Sal)2] may then be prepared by exchange, so these B-chiral anions may have use in metathesis-based resolutions. Due to a site disorder the anion in [H2Spa][B R (Sal)2]2 is limited to 70% ee, however an enantiopure analogue [H2Spa][B R (5-Cl-Sal)2]2 is readily formed using 5-chlorosalicylic acid. This also indicates a wide family of stable enantiopure B-chiral anions may be isolated by this approach.

Chiral bis(mandelato)borate salts for resolution via metathesis crystallization.

Spiroborate anions have potential for crystallization or resolution and chiral bis(mandelato)borate anions can be used for the efficient resolution of a diverse range of racemic cations via diastereomeric salt formation. The syntheses, X-ray crystal structures and solubilities of three chiral bis(mandelato)borate salts, namely poly[[aqua-µ3-bis[(R)-mandelato]borato-lithium(I)] monohydrate], [Li(C16H12BO6)(H2O)]n or Li[B(R-Man)2]·H2O, (1), ammonium bis[(R)-mandelato]borate, NH4+·C16H12BO6- or NH4[B(R-Man)2], (2), and tetra-n-butylammonium bis[(R)-mandelato]borate, C16H36N+·C16H12BO6- or NBu4[B(R-Man)2], (3), are reported. They all have a BS configuration and show a reasonably well-conserved anion geometry. The main conformational variation is the orientation of the two phenyl groups, supporting the idea that [B(Man)2]- is a semi-rigid anion. The salts are differentially soluble in a range of solvents, meaning they could be useful as reagents for resolution via a metathesis crystallization approach.

Bis(mandelato)borate: an effective, inexpensive spiroborate anion for chiral resolution.

Bis(mandelato)borate [B(Man)2](-) (R- or S-) anions are simply prepared and appear widely effective for resolution of racemic cations. Three examples demonstrate their scope; the alkaloid tetrahydropalmatine (THP), 1,2-diaminopropane (1,2-dap) and the metal-organic complex [Co(phen)3](3+) are readily resolved, either by a facile one-pot procedure, or via counter-ion metathesis.