Bernadette Norberg

A rapid and efficient microwave-assisted synthesis of hydantoins and thiohydantoins

The present paper describes studies on the synthesis of the antiepileptic drug phenytoin, and of structurally related derivatives. First, the influence of the solvent has been investigated in the microwave-assisted synthesis of the drug, resulting in a yield improvement and a cleaner reaction. Second; a two-step reaction is described to synthesize selectively and in high yields phenytoin. The first step consists in microwave activation of the reaction of benzil with thiourea, the second step includes the conversion of the resulting 2-thiohydantoin to phenytoin using hydrogen peroxide. Moreover, microwave activation is a very convenient method for the synthesis of 3-alkylated phenytoin derivatives, resulting in a much more selective method than the previously reported procedure using alkylating agents

Pharmaceutical salts and cocrystals involving amino acids: A brief structural overview of the state-of-art

Salification of new drug substances in order to improve physico-chemical or solid-state properties (e.g. dissolution rate or solubility, appropriate workup process, storage for further industrial and marketing development) is a well-accepted procedure. Amino acids, like aspartic acid, lysine or arginine take a great part in this process and are implicated in several different formulations of therapeutic agent families, including antibiotics (amoxicillin from beta lactam class or cephalexin from cephalosporin class), NSAIDs (ketoprofen, ibuprofen and naproxen from profen family, acetylsalicylic acid) or antiarrhythmic agents (e.g. ajmaline). Even if more than a half of known pharmaceutical molecules possess a salifiable moiety, what can be done for new potential drug entity that cannot be improved by transformation into a salt? In this context, after a brief review of pharmaceutical salts on the market and the implication of amino acids in these formulations, we focus on the advantage of using amino acids even when the target compound is not salifiable by exploiting their zwitterionic potentialities for cocrystal edification. We summarize here a series of new examples coming from literature to support the advantages of broadening the application of amino acids in formulation for new drug substances improvement research for non-salifiable molecules.

Advantages of cocrystallization in the field of solid-state pharmaceutical chemistry: L-Proline and MnCl2

Cocrystallization (formation of a cocrystal) is an emerging method to optimize physico-chemical properties of pharmaceutically active compounds. One elegant technique used to obtain such cocrystals is grinding the components together, either alone or in the presence of a small amount of solvent (so called solvent-drop grinding). Dry grinding has been used here to obtain cocrystals (actually a hydrated salt) of L-Proline and MnCl(2). In that context, a new crystalline structure of a multicomponent molecular complex composed of L-Proline and MnCl(2) is here reported. The complex was characterized by powder and single-crystal X-ray diffraction and differential scanning calorimetry. This study underlines the interest of grinding as a method to synthesize original solid-state complexes. It also emphasizes the advantage of combining calorimetric and X-ray diffraction to characterize the newly formed solids. Finally, our work provides structural basis for the role that L-Proline can play within multicomponent solid-state molecular complexes, in particular as a potential cocrystal former acting by both ionic and H-bond interactions when combined to molecules of pharmaceutical interest.

Bis-tetrahydroisoquinoline derivatives: structure analysis of the three stereoisomers of 1,1'-(propane-1,3-diyl)-bis-(6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline).

Crystal structure of the three stereoisomers of 1,1-(propane-1,3-diyl)-bis-(6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline) hydrochloride after resolution by semi-preparative chiral HPLC establishes the absolute configuration and conformation.

Short, asymmetric synthesis of epi-morphine ACNO analogues

A concise and efficient asymmetric synthesis of ACNO analogues of morphine is reported.

Crystallographic, UV spectroscopic and computational studies of the inclusion complex of α-cyclodextrin with p-aminobenzoic acid

Crystal structure of the cyclomaltohexaose (α-cyclodextrin, α-CD) inclusion complex with p-aminobenzoic acid (pABA) has been determined by X-ray diffraction. The host:guest stoichiometry is 1:1. The pABA molecule is included in the cavity with its axis coincident with the axis of α-CD; the benzoic group is inserted in the cavity, while the amino group sticks out from the cavity. Four water molecules are located near the cavity rims and in interstices between the molecules of α-CD participating in a dense network of intermolecular hydrogen bonds. UV–visible spectroscopy was applied to estimate the stability constant (K c) at different temperatures on the basis of the Benesi–Hildebrand equation. This allowed calculation of complexation and on the basis of the Vant Hoff equation. The results are in good agreement with the values obtained by other methods in the literature. Phase-solubility profiles indicate that the solubility of pABA is significantly increased in the presence of α-CD at different pH values, and it was classified as AL-type, indicating a 1:1 stoichiometric inclusion complex in solution. A theoretical investigation has also been carried out on the α-CD-pABA systems in order to search for other stable complexes. PM6 semi-empirical calculations were made to investigate equilibrium geometries of inclusion complexes formed between α-CD and neutral, anionic, cationic and zwitterionic forms of pABA. Two possible orientations were considered (A, with the carboxylic end inside the cavity and B, with the amino group inside the cavity). Preference between A and B orientations of each α-CD-pABA form results from different H-bond interaction patterns.

Conformation and tautomerism of methoxy-substituted 4-phenyl-4-thiazoline-2-thiones: a combined crystallographic and ab initio investigation.

4-Phenyl-4-thiazoline-2-thiol is an active pharmaceutical compound, one of whose activities is as a human indolenamine dioxygenase inhibitor. It has been shown recently that in both the solid state and the gas phase, the thiazolinethione tautomer should be preferred. As part of both research on this lead compound and a medicinal chemistry program, a series of substituted arylthiazolinethiones have been synthesized. The molecular conformations and tautomerism of 4-(2-methoxyphenyl)-4-thiazoline-2-thione and 4-(4-methoxyphenyl)-4-thiazoline-2-thione, both C10H9NOS2, are reported and compared with the geometry deduced from ab initio calculations [PBE/6-311G(d,p)]. Both the crystal structure analyses and the calculations establish the thione tautomer for the two substituted arylthiazolinethiones. In the crystal structure of the 2-methoxyphenyl regioisomer, the thiazolinethione unit was disordered over two conformations. Both isomers exhibit similar hydrogen-bond patterns [R2(2)(8) motif] and form dimers. The crystal packing is further reinforced by short S...S interactions in the 2-methoxyphenyl isomer. The conformations of the two regioisomers correspond to stable geometries calculated from an ab initio energy-relaxed scan.

Solid-State-Trapped Reactive Ammonium Carbamate Self- Derivative Salts of Prolinamide

Single crystals for two polymorphs of the ammonium carbamate self-derivative salt of prolinamide have been successfully obtained and characterized. Decarbonation of the carbamate salts was monitored by calorimetry, confirming stabilization of the reactive carbonated adducts in the solid state. Sublimation of the salts afforded crystals of prolinamide, leading to the first crystal structure of this otherwise common molecule. Reactivity of the ammonium carbamate self-derivative salt is further illustrated by the observation of a series of derived products, including dehydroprolinamide, a methylene-bridged prolinamide, and a bicyclic derivative. Crystal structures of these products display distinct amidic and/or non-amidic hydrogen bonding. This study emphasizes the reactivity of carbonated amines stabilized in the solid and opens perspectives for a systematic study of (solid-state) reactions involving these trapped reactive species.

4-Nitro-N-phthalyl-l-tryptophan

The crystal structure of the title compound [systematic name: (2R)-3-(1H-indol-3-yl)-2-(4-nitro-1,3-dioxoisoindolin-2-yl)propanoic acid], C19H13N3O6, an analogue of epigenetic modulator RG108, is constrained by strong hydrogen bonds between the indole N—H group and a carbonyl O atom of the phthalimide ring of a symmetry-related molecule, and between the protonated O atom of the carboxyl group and a carbonyl O atom of the phthalimide ring. π–π stacking interactions with centroid–centroid distances of 3.638u2005(1) and 3.610u2005(1)u2005Å are also observed between indole and phthalimide rings.

endo-3,3-Dimethyl-4-oxobicyclo­[3.1.0]hexan-2-yl methane­sulfonate

The relative configuration of the endo isomer of the title compound, C9H14O4S, has been established and the conformation of the diastereoisomer is discussed. The five-membered ring adopts an envelope conformation. The conformation of the methanesulfonate substituent is stabilized by intermolecular C—H⋯O hydrogen bonds. The crystal packing results in alternating layers of polar methanesulfonates and stacked bicyclohexanyl rings parallel to ab.