Benjamin Podányi

Determination of protonation macro- and microconstants and octanol/water partition coefficient of the antiinflammatory drug niflumic acid

The drug niflumic acid is an amphoteric substance with overlapping pKa values. The acid-base chemistry of the molecule has been characterized in terms of protonation macroconstants (with reference to stoichiometric ionizations) and microconstants (with reference to ionizations of individual species). The proton-binding sites were assigned using 1H and 13C NMR spectroscopy. Due to the very poor water solubility of niflumic acid, the aqueous pKa values were determined from the apparent ionization constants in methanol-water solutions of various proportions by extrapolation to zero co-solvent using the Yasuda-Shedlovsky procedure. The kz tautomerization microconstant of the equilibrium unionized form<-->zwitterionic form was determined from mixtures of organic solvent (dioxane or methanol) with aqueous buffer (at the pH of isoelectric point) by UV spectroscopy, and used for calculation of the other protonation microconstants. The zwitterionic form of the molecule predominates over the uncharged form, the concentration being maximal at the isoelectric pH. The apparent partition coefficients (Papp) of niflumic acid were measured in octanol/water solution by the shake-flask method over a wide pH range. The lipophilicity profile (logPapp vs pH) shows a parabolic shape near its maximum at the isoelectric point. A relationship derived between Papp, PXH0(micropartition coefficient of the uncharged microspecies) and PX-(partition coefficient of the anion) is valid for amphoteric drugs, in cases where the partition of the unionized form and the ion-pair partition of anion can be confirmed. The logP values of microspecies indicate the high lipophilicity of niflumic acid, which is consistent with its good skin penetration and absorption.

Kinetic and theoretic aspects of regiochemistry in the reaction of 4,5-dihalo-3(2H)-pyridazinones with benzylamines

Regioselectivity of nucleophilic substitution reactions of 4,5-dihalo-3(2H)-pyridazinones (1a-d) with benzylamines was studied under different conditions. Second-order kinetics were obtained for reactions of 1a with benzylamine in ethanol-d 6 and toluene-d 8 as well. Experimental results obtained were interpreted on the bases of Klopman-Salem equation and analyses of the reaction paths

Asymmetric reduction of a carbon–nitrogen double bond: enantioselective synthesis of 4,5-dihydro-3H-2,3-benzodiazepines

A highly specific enantioselective reduction, elaborated for the reduction of the 3,4-carbon–nitrogen double bond of 4-methyl-7,8-methylenedioxy-1-(4-nitrophenyl)-4,5-dihydro-3H-2,3-benzodiazepine 4 made possible the synthesis of the enantiomers of the potent non-competitive AMPA/kamate antagonists 2a, b. NMR Investigations of the reducing complex show that there is no formation of an 1,3,2-oxazaborolidine ring as may have been presumed on the basis of literature data.

Syntheses of indolyl-4(3H)-quinazolinones

2-(1H-Indol-2-yl)-4(3H)-quinazolinones (10, 11) and 2-(2-ethoxy-carbo- nyl-1H-indol-3-yl)-4(3H)-quinazolin-4-one (15) are prepared by the Fis- cher indolization of 2-(1-phenylhydrazonoalkyl)- (8, 9) and 2-(2-phenyl- hydrazono-2-ethoxycarbonylethyl)-4(3H)-quinazolinones (14), respecti- vely, by heating in PPA. When 2-phenylhydrazone derivative (14) is hea- ted in 85% phosphoric acid at 180°C, besides indolization ester hydro lysis and decarboxylation also occurred to yield 2-(1H-indol-3-yl)-4(3H) -quinazolinone (16). The 3-(1H-indol-3-yl)-4(3H)-quinazolinone (24) is prepared either from the isomeric 3-indolyl derivatives of anthranila- mide (21, 23) by heating in 98% formic acid, or in «one pot» procedure from 2-[1-(N-methyl-N-phenylamino)ethyl]-4(3H)-quinazolinone (17) by heating in 98% formic acid in the presence of a few drops of conc. hy- drochloric acid. The reaction mechanism is discussed

Structural studies on optical resolution via diasteroisomeric salt formation. Enantiomer separation for cis-permethrinic acid [cis-2,2-dimethyl-3-(2,2-dichlorovinyl)cyclopropanecarboxylic acid]

The pH dependence of enantiomer separation by optical resolution of cis-2,2-dimethyl-3-(2,2-dichlorovinyl)cyclopropanecarboxylic acid (I) with (S)-2-benzylaminobutanol (II) has been investigated. Thermodynamic constants, thermal behaviour, and the molecular and crystal structure were determined in order to evaluate and interpret the results of optical resolution.

Nitrogen bridgehead compounds. Part 45 [1]. Synthesis of 6-arylhydrazono-6,7,8,9-tetrahydro-11H-pyrido-[2,1-b]quinazolin-11-ones

Die Herstellung zahlreicher 6-Arylhydrazono-6,7,8,9-tetrahydro-11H-pyrido[2,1-b]chinazolin-11-one der allgemeinen Formel (III) erfolgt nach verschiedenen Wegen.

Nitrogen bridgehead compounds. Part 82. An unexpected ring transformation of 6-hydrazono-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a]pyrimidine-3-carboxylates

Treatment of 9-hydrazono-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylates with the Vilsmeier-Haack reagent gave unsaturated 7-substituted 9-amino-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylates in a degenerate ring transformation, probably through ring opening via the N(5)-C(6) bond

Novel intermediates of microbial side chain degradation of sitosterol

Abstract We describe the structure and stereochemistry of some new 26-oxygenated steroid derivatives obtained by microbial transformation of sitosterol.

Nitrogen bridgehead compounds. Part 29. Tautomerism and Z–E isomerism of ethyl 9-aminomethylene-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylates and their homologues

1 n H and 13C n.m.r. studies have proved that ethyl 9-dimethylaminomethylene-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylates (2)–(5) and the corresponding pyrrolo homologue (6) exist in the form of E-isomers whereas the azepino[1,2-a]pyrimidine derivative (7) appears as an equilibrium mixture of Z-and E-isomers. On the basis of 15N chemical shifts an analogous tautomeric structure has been established for the 9-dimethylaminomethylene derivatives (2)–(7) and the ethyl 9-arylaminomethylene-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylates (8)–(12) as well. 15N Shifts were sensitively affected by the Z–E isomerism and structural changes in remote parts of the molecule, too. Protonation of compounds (2)–(12) takes place on the N(1) atom, forming a 1,6,7,8-tetrahydro structure.

Isomerism of 9-arylaminomethylene-6,7,8,9-tetrahydro-4-oxo-4H-pyrido[1,2-a]pyrimidines

Several 9-arylaminomethylnene-6,7,8,9-tetrahydro-4-oxo-4H-pyrido[1,2-a]pyrimidines have been synthesized and studied by 1H and 13C n.m.r. spectroscopy. The dominant tautomeric form has been established. Fast Z–E isomerisation has been found around the enamino CC double bond. The effect of the solvent, temperature, and various structural modifications on the equilibrium Z : E isomeric ratios has been measured.