Kálmán Simon

Synthesis, absolute configuration and intermediates of 9-fluoro- 6,7- dihydro-5-methyl-1-oxo-1H,5H-benzo[i.j]quinolizine-2-carboxylic acid (flumequine)

Abstract The antibacterial agent 9-fluoro-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid (flumequine) was synthesized in optically active form from 6-fluoro-2-methyl-1,2,3,4-tetrahydroquinoline (FTHQ). Racemic FTHQ was resolved with the enantiomers of 3-bromocamphor-8-sulfonic acid. The configurations were established by X-ray structures of the two diastereoisomeric salts. Enantiomeric excesses were determined by 1H NMR analysis.

Pseudosymmetry and chiral discrimination in optical resolution via diastereoisomeric salt formation. The crystal structures of (R)- and (S)-N-methylamphetamine bitartrates (RMERTA and SMERTA)

The structures of the diastereoisomeric salts of (R)- and (S)-N-methylamphetamine bitartrates (RMERTA and SMERTA) have been determined by X-ray crystallography. Comparison of these crystal structures provides an insight into the mechanism of optical resolution via diastereoisomeric salt formation. The very small difference between the two crystal structures indicates that specific interactions such as CH⋯O interactions may play an important role in molecular recognition.

The chemical-transformation products of 1,6-dibromo-1,6-dideoxygalactitol and 1,2: 5,6-dianhydrogalactitol in aqueous solution

Abstract After hydrolysis of 1,6-dibromo-1,6-dideoxygalactitol ( 1 ) and 1,2:5,6-dianhydrogalactitol ( 2 ), 11 compounds were isolated, three of them as tritylated derivatives. Their structures were established on the basis of chemical evidence and, for four compounds, by X-ray diffraction. The main product of the hydrolysis of 1 was 3,6-anhydro-1-bromo-1-deoxy- dl -galactitol; the end-products of the hydrolysis of 2 were 1,5-anhydro- dl -galactitol, 2,5-anhydro- dl -altritol, and galactitol.

Stability and Chemical Reactivity of 7-Isopropoxyisoflavone (Ipriflavone)

The stability (hydrolysis and oxidation) of ipriflavone (7-isopropoxyisoflavone, 1) was studied under basic and acidic conditions in different solvents; the effects of irradiation were investigated in methanol. Identification of the isolated products enabled suggestions to be made concerning the mechanisms of decomposition.

Racemic compound formation–conglomerate formation. Part. 1. Structural and thermoanalytical study of hydrogen malonate, hydrogen phthalate and hydrogen succinate of α-phenylethylamine

The crystal structure of (R,S)-α-phenylethylammonium hydrogen phthalate (RACPHP)[P21/a; a= 8.503(3), b= 16.748(5), c= 10.544(3)A, β= 104.48(2)°; Z= 4; R= 0.058 based on 2412 observed reflections] and (R,S)-α-phenylethylammonium hydrogen malonate (RACPHM)[P; a= 8.768(1), b= 9.014(1), c= 7.485(1)A, α= 104.31(1), β= 96.95(1), γ= 91.68(1)°; Z= 2; R= 0.069 based on 2061 observed reflections] were determined and compared with each other and with the known crystal structure of the (R)-α-phenylethylammonium hydrogen succinate (KACBEV). The structural and thermoanalytical investigations of the salts proved that the hydrogen phthalate and hydrogen malonate anions form racemic compounds while the hydrogen succinate anion forms a conglomerate, the latter being the only one which could be resolved by preferential crystallization.The comparison of the structures revealed that the hydrogen bonding network of RACPHP [S(7)C22(9)R44(18)R88(30)C44(12)] and RACPHM [S(6)C22(8)R44(12)R44(16)] are very similar (represented by graph theory), while KACBEV [C11(7)C22(9)R33(8)R33(13)] is different. Intramolecular hydrogen bonds through acidic hydrogens are formed only between the carboxylic groups of the racemic compounds.

Studies on naphthyridines. An unexpected product in Hantzsch pyridine synthesis

Besides the expected pyridinedicarboxylate (4), triethyl 2,7,8a-trimethyl-1,4,4a,5,8,8a-hexahydro-1,8-naphthyridine-3,4a,6-tricarboxylate (6) was also isolated in the Hantzsch pyridine synthesis starting from ethyl acetoacetate and hexamethylenetetramine in acetic acid. The 1,8-naphthyridine (6) was probably formed in the [4 + 2]cycloaddition of heterodiene (5) and the 1,4-dihydropyridinedicarboxylate (3). The observed regioselectivity was explained in terms of simple Huckel molecular orbital calculations. Diethyl 2,6-dimethylpyridine-3,5-dicarboxylate (4) gave ethyl 2-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate (9) in high yield in a one-step reaction with 1,3,5-triazine in the presence of ethanolic sodium ethoxide, or in a two-step procedure with DMF diethyl acetal followed by ring closure with ammonia.

Chemical development of the vasopressin receptor 2 antagonist SR-121463

A facile convergent total synthesis of the selective, potent, and orally active V2 non-peptide antagonist, SR-121463, was developed by modification of the discovery route. One of the late intermediates, the sulfonyl chloride 1, was synthesized from 3-hydroxybenzoic acid (19) by regioselective sulfonation, O-methylation and amidation in four steps. Another late intermediate, indolin-2-one 2, was prepared from p-phenetidine (8) through the indolin-2-one 16, where the cyclohexanone moiety of 27 was introduced into the active 3-methylene group of 16 by sequential transformation using methyl acrylate and KOtBu. After formation of the cyclic ketal moiety of 13, its ring-opening was achieved by using NaBH4 in the presence of CCl3COOH. The morpholino group in 2 was introduced in accordance with the discovery approach, starting from the 2-hydroxyethoxy derivative 14 through the tosyloxy derivative 15 with morpholine in a one-pot reaction. In this way, the indolin-2-one 2 was synthesized from 8 in six steps. Finally, acylation of the indolin-2-one 2 was achieved with the sulfonyl chloride 1 in the presence of KOtBu in dimethyl sulfoxide (DMSO) at room temperature. This synthetic route proved to be applicable for the large-scale synthesis of SR-121463.

Chiral Recognition of Alcohols in the Crystal Lattice of Simple Metal Complexes ofO,O′-Dibenzoyltartaric Acid: Enantiocomplementarity and Simultaneous Resolution

The hidden resolving power of O,O′-dibenzoyltartaric acid can be revealed in its metal complexes (for example, 1) upon coordinative resolution of alcohols featuring enantiocomplementarity and one-step resolution of two different compounds.

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.

Prolyl Oligopeptidase Inhibition by N-Acyl-pro-pyrrolidine-type Molecules †

Three novel, N-acyl-pro-pyrrolidine-type, inhibitors of prolyl oligopeptidase (POP) with nanomolar activities were synthesized and their binding analyzed to the host enzyme in the light of X-ray diffraction and molecular modeling studies. We were interested in the alteration in the binding affinity at the S3 site as a function of the properties of the N-terminal group of the inhibitors. Our studies revealed that, for inhibitors with flat aromatic terminal groups, the optimal length of the linker chain is three C-C bonds, but this increases to four C-C bonds if there is a bulky group in the terminal position. Molecular dynamics calculations indicate that this is due to the better fit into the binding pocket. A 4-fold enhancement of the inhibitor activity upon replacement of the 4-CH2 group of the proline ring by CF2 is a consequence of a weak hydrogen bond formed between the fluorine atom and the hydroxy group of Tyr473 of the host enzyme. There is notably good agreement between the calculated and experimental free energies of binding; the average error in the IC50 values is around 1 order of magnitude.