A practical and chromatography-free multikilogram synthesis of a 3-isoxazolol containing antifibrinolytic agent, AZD6564, has been developed in eight steps and 7% overall yield starting from methyl 2-chloroisonicotinate. Highlights in the synthesis are a Negishi coupling and an enzymatic resolution of a racemic ester. 

The crystal structure of form 4 of the drug 4-[4-(2-adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl]benzoic acid is determined using a protocol for NMR powder crystallography at natural isotopic abundance combining solid-state (1)H NMR spectroscopy, crystal structure prediction, and density functional theory chemical shift calculations. This is the first example of NMR crystal structure determination for a molecular compound of previously unknown structure, and at 422 g/mol this is the largest compound to which this method has been applied so far.

Oxidation of the spirocyclic oxindole derivative, isamic acid 1, led to decarboxylation and ring expansion to quinazolino[4,5-b]quinazoline-6,8-dione 7 rather than, as previously believed, its isomer 6. The structure of 7 was confirmed by X-ray crystallography. Condensation of isatin (indole-2,3-dione) and 2-aminobenzamide led to the spirocyclic molecule, spiro[3H-indole-3,2′(1H)quinazoline]-2,4′(1H,3H)dione 8, which was also identified as an intermediate in the oxidation of isamic acid. Mild hydrolysis of 7 gave the 10-membered molecule 22. Isamic acid could easily be converted to N-nitrosoisamic acid, which when heated in ethanol underwent a ring expansion to a hydroximino derivative, 38, of compound 6. The structure of 38 was confirmed by X-ray crystallography.

The number of antibiotic-resistant bacteria is increasing worldwide, and the demand for novel antimicrobials is constantly growing. Antimicrobial peptides (AMPs) could be an important part of future treatment strategies of various bacterial infection diseases. However, AMPs have relatively low stability, because of proteolytic and chemical degradation. As a consequence, carrier systems protecting the AMPs are greatly needed, to achieve efficient treatments. In addition, the carrier system also must administrate the peptide in a controlled manner to match the therapeutic dose window. In this work, lyotropic liquid crystalline (LC) structures consisting of cubic glycerol monooleate/water and hexagonal glycerol monooleate/oleic acid/water have been examined as carriers for AMPs. These LC structures have the capability of solubilizing both hydrophilic and hydrophobic substances, as well as being biocompatible and biodegradable. Both bulk gels and discrete dispersed structures (i.e., cubosomes and hexosomes) have been studied. Three AMPs have been investigated with respect to phase stability of the LC structures and antimicrobial effect: AP114, DPK-060, and LL-37. Characterization of the LC structures was performed using small-angle X-ray scattering (SAXS), dynamic light scattering, ζ-potential, and cryogenic transmission electron microscopy (Cryo-TEM) and peptide loading efficacy by ultra performance liquid chromatography. The antimicrobial effect of the LCNPs was investigated in vitro using minimum inhibitory concentration (MIC) and time-kill assay. The most hydrophobic peptide (AP114) was shown to induce an increase in negative curvature of the cubic LC system. The most polar peptide (DPK-060) induced a decrease in negative curvature while LL-37 did not change the LC phase at all. The hexagonal LC phase was not affected by any of the AMPs. Moreover, cubosomes loaded with peptides AP114 and DPK-060 showed preserved antimicrobial activity, whereas particles loaded with peptide LL-37 displayed a loss in its broad-spectrum bactericidal properties. AMP-loaded hexosomes showed a reduction in antimicrobial activity.

Solubility is a frequently recurring issue within pharmaceutical industry, and new methods to proactively resolve this are of fundamental importance. Here, a novel methodology is reported for intrinsic solubility improvement, using in silico prediction of crystal structures, by perturbing key interactions in the crystalline solid state. The methodology was evaluated with a set of benzodiazepine molecules, using the two‐dimensional molecular structure as the only a priori input. The overall trend in intrinsic solubility was correctly predicted for the entire set of benzodiazepines molecules. The results also indicate that, in drug compound series where the melting point is relatively high (i.e., “brick dust” compounds), the reported methodology should be very suitable for identifying strategically important molecular substitutions to improve solubility. As such, this approach could be a useful predictive tool for rational compound design in the early stages of drug development.

A new redox couple, [Cu(bpye)2]+/2+, has been synthesized, and applied in dye-sensitized solar cells (DSSCs). Overall efficiencies of 9.0% at 1 sun and 9.9% at 0.5 sun were obtained, which are considerably higher than those obtained for cells containing the reference redox couple, [Co(bpy)3]2+/3+. These results represent a record for copper-based complex redox systems in liquid DSSCs. Fast dye regeneration, sluggish recombination loss processes, faster electron self-exchange reactions and suitable redox potentials are the main reasons for the observed increase in efficiency. In particular, the main disadvantage of cobalt complex-based redox couples, charge-transport problems, appears to be resolved by a change to copper complex redox couples. The results make copper complex-based redox couples very promising for further development of highly efficient DSSCs.

A major drug project in the neuroscience area aimed at designing and developing a viable manufacturing process for AR-A2. This turned out to be a tough challenge that resulted in the use of three different synthetic routes. One step to be included from the very start was a Pd-catalyzed C-N bond formation, and this was retained throughout the later versions of the synthesis. At the time of initiating this project in 1998, the combined Buchwald and Hartwig protocols for effecting the chemistry in question-coupling of a N-containing moiety to an aromatic nucleus had only been known for a few years. Therefore, a lot of experimentation was needed to increase the insight and understanding of the chemistry to optimize the performance to fit for large-scale application. The outcome of the efforts resulted in successfully carrying out the chemical transformation is described in detail in this chapter.

This study focused on the mechanistic interpretation of ex vivo oxidation of a candidate drug in blood plasma samples. An unexpected lipid peroxide-mediated epoxidation followed by a dramatic rearrangement led to production of a five-membered oxazole derivative from the original six-membered pyrazinone-carboxamide core of a human neutrophil elastase inhibitor, 6-(1-(4-cyanophenyl)-1H-pyrazol-5-yl)-N-ethyl-5-methyl-3-oxo-4-(3-(trifluoromethyl)phenyl)-3,4-dihydropyrazine-2-carboxamide (AZD9819). The rearranged oxidation product 2-(1-(4-cyanophenyl)-1H-pyrazol-5-yl)-5-(N-ethylacetamido)-N-(3-(trifluoromethyl)phenyl)oxazole-4-carboxamide was characterized by accurate-mass tandem mass spectrometry fragmentations, by two-dimensional NMR and X-ray crystallography of an authentic standard, and by incorporation of an (18)O atom from molecular (18)O2 to the location predicted by our proposed mechanism. The lipid peroxide-mediated oxidation was demonstrated by using human low-density lipoprotein (LDL) in pH 7.4 phosphate buffer and by inhibiting the oxidation with ascorbic acid or l-glutathione, two antioxidants effective in both plasma and the LDL incubation. A nucleophilic mechanism for the epoxidation of AZD9819 by lipid hydroperoxides explains the prevention of its ex vivo oxidation by acidification of the plasma samples. The discovery of the lipid peroxide-dependent oxidation of an analyte and the means of prevention could provide valuable information for biotransformation and bioanalysis.

The retention of vitamin C and carotenoids was studied in the cv. 'Tommy Atkins' mango as affected by osmotic dehydration prior to hot air drying. Osmotic dehydration (OD) was carried out over 15 h at 25°C using sucrose solutions of 45°BRIX with and without 1% (w/w) calcium chloride or 1% ascorbic acid with a fruit to solution ratio of 1:10 (w/w), and the OD-treated mango samples were then dried in an air convection oven at 50°C or 70°C. An osmotic pretreatment before drying significantly reduced the drying time and prevented colour change in dried mango. Addition of calcium in the OD solution significantly improved vitamin C retention, on average from 44% to 57%. However, the addition of ascorbic acid to the osmotic solution highly increased the retention of vitamin C content in the dried mango. The retention of all-trans-β-carotene was significantly lower in all OD treated mango samples dried at 50°C but remained unchanged in OD-treated mango samples with calcium or vitamin C dried at 70°C. Moreover, osmotic dehydration with and without additives reduced the ratio of 13-cis-β-carotene to all-trans-β-carotene. The results showed that the addition of calcium or vitamin C to the osmotic solution can improve the nutritional value of dried mango.

Glioblastoma remains an incurable brain cancer. Drugs developed in the past 20 years have not improved the prognosis for patients, necessitating the development of new treatments. We have previously reported the therapeutic potential of the quinoline methanol Vacquinol-1 (1) that targets glioblastoma cells and induces cell death by catastrophic vacuolization. Compound 1 is a mixture of four stereoisomers due to the two adjacent stereogenic centers in the molecule, complicating further development in the preclinical setting. This work describes the isolation and characterization of the individual isomers of 1 and shows that these display stereospecific pharmacokinetic and pharmacodynamic features. In addition, we present a stereoselective synthesis of the active isomers, providing a basis for further development of this compound series into a novel experimental therapeutic for glioblastoma.

A classical resolution of a racemic carboxylic acid through salt formation and an asymmetric hydrogenation of an α,β-unsaturated carboxylic acid were investigated in parallel to prepare an enantiomerically pure alkanoic acid used as a key intermediate in the synthesis of an antiplaque candidate drug. After an extensive screening of rhodium- and ruthenium-based catalysts, we developed a rhodium-catalyzed hydrogenation that gave the alkanoic acid with 90% ee, and after a subsequent crystallization with (R)-1-phenylethanamine, the ee was enriched to 97%. The chiral acid was then used in sequential Negishi and Suzuki couplings followed by basic hydrolysis of a nitrile to an amide to give the active pharmaceutical ingredient in 22% overall yield.

2,2′-Biindolyl has been condensed with aromatic and aliphatic aldehydes and products featuring 10-membered rings have been obtained. Thus, benzaldehyde gave compound 24a as the primary product, which readily underwent transannular oxidative coupling to 25a. The structures of both compounds were confirmed by X-ray crystallography. The product from 2,2′-biindolyl and formaldehyde under strongly acidic conditions was slightly different leading to compound 11, whose structure also was confirmed by X-ray crystallography. In this case, two molecules of 2,2′-biindolyl reacted with six molecules of formaldehyde.

We report a Rh-catalyzed, enantioselective silylation of arene C–H bonds directed by a (hydrido)silyl group. (Hydrido)silyl ethers that are formed in situ by hydrosilylation of benzophenone or its derivatives undergo asymmetric C–H silylation in high yield with excellent enantioselectivity in the presence of [Rh(cod)Cl]₂ and a chiral bisphosphine ligand. The stereoselectivity of this process also allows enantioenriched diarylmethanols to react with site selectivity at one aryl group over the other. Enantioenriched benzoxasiloles from the silylation process undergo a range of transformations to form C–C, C–O, C–I, or C–Br bonds.

A method for the preparation of [3'-3H]-4-(2'-chloro-6'- hydroxyphenyl)-2-thioxo-3,4-dihydro-1H-indeno[1,2-d]pyrimidin-5 (2H)-one (1), a TRPA1 inhibitor, was developed for the evaluation of imaging properties of a class of TRPA1 inhibitors. 1 was prepared via tritiation of a protected benzaldehyde followed by a tetrachlorosilane catalyzed multicomponent one-step fusion and was obtained at a specific activity of 0.9 TBq/mmol. A 3H-NMR spectrum on 13.5MBq at 75 μM was recorded.

This paper describes the scale-up of a highly exothermic and fast reaction from a microreactor with an internal volume of less than 1 mL to a mesoreactor with an internal volume of 13.5 mL. The development of a continuous process for manufacturing a ketone from an ester using a Grignard reagent is described. The different steps undertaken and the considerations made to be able to operate in continuous mode and achieve a product output of ca. 0.5 kg are presented.

The synthetic route and properties of three 2D hybrid organic/inorganic lead iodide perovskite materials are reported. The 2D perovskites were synthesized from the reaction between PbI₂and the di-cations of 1,4-diaminobutane, 1,6-diaminohexane, and 1,8-diaminooctane. The resulting products were [NH₃(CH₂)₄NH₃]PbI₄ (BdAPbI₄), [NH₃(CH₂)₆NH₃]PbI₄ (HdAPbI₄), and [NH₃(CH₂)₈NH₃]PbI₄ (OdAPbI₄). Structural characterization shows that two dimensional perovskite structures were formed with inorganic structural planes separated by organic layers. Absorption spectra show band gaps of 2.37 eV (BdAPbI₄), 2.44 eV (HdAPbI₄), and 2.55 eV (OdAPbI₄). The 2D perovskite materials were investigated as light absorbing materials in solid state solar cells. The best performing material under moist, ambient conditions was BdAPbI₄(1.08% efficiency), which was comparable to methylammonium Pb(II) iodide (MAPbI₃) solar cells (2.1% efficiency) manufactured and studied under analogous conditions. When compared to MAPbI₃, the 2D materials have larger band gaps and lower photoconductivity, while BdAPbI₄based solar cells shows a comparable absorbed photon-to-current efficiency as compared toMAPbI₃ based ones.

Agonism of GPR119 is viewed as a potential therapeutic approach for the treatment of type II diabetes and other elements of metabolic syndrome. During progression of a previously disclosed candidate 1 through mice toxicity studies, we observed tonic-clonic convulsions in several mice at high doses. An in vitro hippocampal brain slice assay was used to assess the seizure liability of subsequent compounds, leading to the identification of an aryl sulfone as a replacement for the 3-cyano pyridyl group. Subsequent optimization to improve the overall profile, specifically with regard to hERG activity, led to alkyl sulfone 16. This compound did not cause tonic-clonic convulsions in mice, had a good pharmacokinetic profile, and displayed in vivo efficacy in murine models. Importantly, it was shown to be effective in wild-type (WT) but not GPR119 knockout (KO) animals, consistent with the pharmacology observed being due to agonism of GPR119.

The solid-liquid solubility of the title compound has been measured by a gravimetric method in five pure organic solvents over the temperature range (283 to 323) K. The melting temperature and associated enthalpy of fusion have been determined by differential scanning calorimetry (DSC), and the heat capacity of the solid and the melt have been determined over a range of temperatures by means of temperature-modulated DSC. Melting data and the extrapolated difference in heat capacity between the melt and the solid have been used to calculate the Gibbs energy, enthalpy, and entropy of fusion and the ideal solubility from below ambient temperature to the melting point. On the basis of estimated activity coefficients at equilibrium, solutions in all the five solvents are shown to exhibit positive deviation from Raoult's law. The highest mole fraction solubility is observed in methanol, and all van't Hoff solubility curves are nonlinear. Solubility data is well correlated by a recently proposed semiempirical regression model.