Synthesis of 1,4-dihydro-2-methyl-4-oxo-3-quinolineglyoxylic acid and related compounds

The synthesis of 1,4-dihydro-1-methoxy or ethyl -2-methyl-4-oxo-3-quinolineglyoxylic acid derivatives are described. α-Acetoxy-1,4-dihydro-1-hydroxy-2-methyl-4-oxo-3-quinolineacetic acid esters ( 7a, 7a ), which are key intermediates, were prepared by catalytic hydrogenation of 2-acetoxy-3-acetyl-4-hydroxy-4-(2-nitrophenyl) crotonic acid lactone ( 6 ) in methanol or ethanol.     

Studies on quinoline derivatives and related compounds. II. Synthesis of 5-substituted 1-ethyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid

The cyclization of m-substituted anilinomethylenemalonates ( 1 ) in the presence of polyphosphate ester and some other cyclizing agents gave mixtures of the isomeric ethyl 5- ( 2 ) and 7-substituted 4-hydroxy-3-quinolinecarboxylates ( 3 ), which led to mixtures of the corresponding quinolinecarboxylic acids ( 4 and 5 ) by hydrolysis. The proportions of 4 and 5 in the mixtures were determined on the basis of their nmr spectra. Novel 5-chloro- ( 8a ), 5-methyl- ( 8b ) and 5-nitro-1-ethyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids were prepared and evaluated for antimicrobial activities. No significant activity, however, was noted.     

Studies on antiallergy agents. III. Synthesis of 2-anilino-1,6-dihydro-6-oxo-5-pyrimidinecarboxylic acids and related compounds

A series of 2-anilino-1,6-dihydro-6-oxo-5-pyrimidinecarboxylic acids with various substituents was synthesized and evaluated in the rat passive cutaneous anaphylaxis test for antiallergic activity. High activity by intraperitoneal and oral administrations was observed for the 3-trifluoromethyl and 2-alkoxyanilino derivatives (64, 79, 81, 82 and 85). Structure-activity relationships are discussed.     

Studies on chemotherapeutics I. Synthesis of 5-substituted-4-oxo-1,4-dihydro-3-pyridinecarboxylic acid derivatives

Ethyl 5-substituted-4-oxo-1,4-dihydro-3-pyridinecarboxylates were synthetized by reacting 1,3,5-triazine with 4-substituted ethyl acetoacetate derivatives in ethanol, in the presence of sodium ethoxide. The l-alkyl-5-substituted-4-oxo-1,4-dihydro-3-pyridinecarboxylic acids required for the antimicrobial studies were prepared by N-alkylation (with triethyl phosphate or alkyl halides) and alkaline hydrolysis of the pyridone esters.     

Non conventional syntheses of heterocyclic compounds. 2. Synthesis of 1H-4,5-dihydro-1,3,4-benzotriazepine derivatives

Arylazoanils carrying aromatic methyl or ethyl groups in the position ortho to the imine function thermally cyclize to give 1H-4,5-dihydro-1,3,4-benzotriazepine derivatives in fairly good yields. A study of the effect of the substituents on both the aryl rings is reported. The reaction is interpreted as an internal oxo-reduction process.     

Synthesis and properties of 3-chloro- and 3,7-dichloro-3,4-dihydro-1-hydroxycarbostyrils and related heterocyclic compounds

3-Chloro- and 3,7-dichloro-3,4-dihydro-1-hydroxycarbostyrils were synthesized by the catalytic hydrogenation of the α-chloro- and α,4-dichloro-β-(o-nitrophenyl)propionic acids in strong acidic solution over platinum-on-carbon sulfided catalyst. However, the catalytic hydrogenation of α-bromo-β-(o-nitrophenyl)propionic acid yielded 3,4-dihydro-1-hydroxycarbostyril under the same experimental conditions. The 3-chloro-3,4-dihydro-1-hydroxycarbostyril and the α-chloro-β-(o-nitrophenyl)propionic acid underwent facile dehydrochlorination in mild alkaline solution to give 1-hydroxycarbostyril and o-nitrocinnamic acid, respectively. Selective reduction of 3-chloro-3,4-dihydro-1-hydroxycarbostyril and 1-hydroxycarbostyril to the corresponding lactams, 3-chloro-3,4-dihydrocarbostyril and carbostyril, was effected by catalytic hydrogenation in hydrochloric acid over platinum black catalyst. The structures of the substituted carbostyril derivatives were correlated with their proton nmr spectra.     

Studies on quinoline derivatives and related compounds. IV. Synthesis of 4-substituted 1-alkyl-1,4-dihydro-3-quinolinecarboxylic acid

By the displacement reactions of 1-ethyl-4-chloro-3-carboethoxy-6,7-methylenedioxyquinolinium iodide ( 3a ), several 4-substituted derivatives including the 4-thioxo ( 1c ) and 4-amino derivatives ( 6 ) of oxolinic acid were prepared. The acid 1c and its N₁-substituted derivatives ( 18a-h ) were prepared alternatively by alkylation of ethyl 4-ethylmercapto-6,7-methylenedioxy-3-quinolinecarboxylate ( 15 ) followed by treatment with sodium hydrosulfide and hydrolysis.     

Synthesis of 2-substituted 4,5-dihydro-4-oxo-3-furancarboxylates using acylative intramolecular cyclization of sulfonium salts

A simple and efficient synthesis of 4,5-dihydro-4-oxo-3-furancarboxylates using an acylative intramolecular cyclization of sulfonium salts is described. The reaction involved the efficient formation of a mixed anhydride between a linear carboxylic acid and trifluoroacetic anhydride in the presence of N-methylimidazole, followed by the sequential conversion into a highly reactive acylammonium species in situ. This procedure is easily handled, uses readily available inexpensive reagents, and provides a variety of 2-substituted 4,5-dihydro-4-oxo-3-furancarboxylates.     

Triphenylphosphine-Catalyzed Simple Synthesis of Dimethyl 1-Aryl-4-ethoxy-5-oxo-4,5-dihydro-1 H -pyrrole-2,3-dicarboxylates

Ethyl 2-arylamino-2-oxo-acetates undergo a complex reaction with dimethyl acetylenedicarboxylate in the presence of triphenylphosphine to produce dimethyl 1-aryl-4-ethoxy-5-oxo-4,5-dihydro-1 H -pyrrole-2,3-dicarboxylates in good yields. Dynamic NMR study of dimethyl 1-(2-methylphenyl)-4-ethoxy-5-oxo-4,5-dihydro-1 H -pyrrole-2,3-dicarboxylate shows a fairly high energy barrier ( j G p = 53.2 kJmol m 1 ) for rotation around the N-aryl single bond, which leads to an observable atropisomerism.     

Total synthesis of antitumor agent at-125, (αS,5S)-α-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid

A short and efficient total synthesis of racemic AT-125 and its racemic threo isomer proceeds via an intramolecular Michael cyclization of a protected α,β-dehydroglutamic acid γ-hydroxamate. Separation of diastereomers and deprotection to racemic AT-125 followed by enzymatic resolution of the N-chloroacetamide with hog-kidney acylase provides the natural αS,5S isomer.     

Synthesis of heterocyclic compounds. XIII. 2-amino-3-benzyl-3,5-dieyano-6-methoxy-4-phenyl-3,4-dihydropyridines

A synthesis of 2-amino-3-benzyl-3,5-dicyano-6-methoxy-4-phenyl-3,4-dihydropyridines from benzylmalononitriles and benzylidenemalononitrile is described. The structures of the new compounds have been elucidated on the basis of spectral data (ir, nmr, ms), and in two cases (Vb and Ve) by chemical degradation.     

Synthesis of cyclopentathiophenacetic acid derivatives. Reactivity of methyl 6-oxo-4,5-dihydro-6H-cyclopenta[b]thiophen-4-acetate

Oxodihydrocyclopentathiophenacetic acids 4 , 5 and 6 were synthesized from suitable 2- or 3-formylthiophenes. Reactivity of the carbonyl group or the carboxylic group of these bicyclic systems was investigated. The Beckmann rearrangement of methyl 6-oximino4,5-dihydro-6H-cyclopenta[b]thiophen-4-acetate 12 is an interesting route to methyl 7-oxo-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-acetate ( 13 ).     

4,5-dihydro-5,5-dimethyl-3-oxo-3H-1,2,4-triazole-1-oxide. The unpredicted azoxy-regioisomer

Summary 4,5-Dihydro-5,5-dimethyl-3-oxo-3H-1,2,4-triazole (1) is converted to the title azoxy compound4 by peroxytrifluoroacetic acid. The structure assignment of4 is based on an X-ray analysis.Ab initio calculations were employed to rationalize the reaction path leading to the triazole-1-oxide4 and not to the expected regioisomer triazole-2-oxide3.

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4,5-Dihydro-5,5-dimethyl-3-oxo-3H-1,2,4-triazol-1-oxid. Das unerwartete Regioisomere

Zusammenfassung 4,5-Dihydro-5,5-dimethyl-3-oxo-3H-1,2,4-triazol (1) wird mit Trifluorperessigsäure in die Titel-Azoxy-Verbindung4 umgewandelt. Die Strukturzuordnung von4 basiert auf einer Röntgenstrukturanalyse. Mittelsab initio-Rechnungen wird versucht zu erklären, weshalb die Reaktion zum Triazol-1-oxid4 und nicht zum erwarteten regioisomeren Triazol-2-oxid3 führt.

     

Studies on chemotherapeutics III. Synthesis and cyclisation of 5-substituted-4-oxo-1,4-dihydro-3-pyridinecarbonyl-semicarbazide and- thiosemicarbazide

1,4-Disubstituted-semicarbazide and thiosemicarbazide derivatives were synthetized from 5-substituted-4-oxo-1,4-dihydro-3-pyridinecarbohydrazides and cyclized to 3-mercapto-4H-1,2,4-triazoles. The obtained compounds could be S-methylated with methyl iodide in methanol. The new compounds were tested for antibacterial and antifungal activities.     

Studies on quinoline derivatives and related compounds. 1. A new synthesis of 1-alkyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids

A novel preparative method for 1-alkyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids was developed. The key process is the cyclization of N-alkylanilinomethylenemalonales, which was effected successfully in the presence of polyphosphoric acid, polyphosphate ester, boron tri-fluoride or a mixture of acetic anhydride and sulfuric acid. With phosphorus oxychloride, N-alkylanilinomethylenemalonates yielded 1-alkyl-4-chloro-3-carbethoxyquinolinium salts which were hydrolyzed readily to ethyl 1-alkyl-1,4-dihydro-4-oxo-3-quinolineearboxylates or their acids. By means of this novel method several new 1-alkyl-1,4-dihydro-4-oxo-3-quinolineearboxylic acids were prepared.     

Reaction of 4-Amino-3-methylthio-5-oxo-6-R-4,5-dihydro-1,2,4-triazines with Sulfonylacetic Acid Nitriles

The reactions of 4-amino-3-methylthio-5-oxo-6-R-4,5-dihydro-1,2,4-triazines with arylsulfonylacetonitriles and with dinitriles of sulfonyldiacetic acid and methylenebis(sulfonylacetic) acid have been studied. 7-Amino-3-R-8-(R'-sulfonyl)-1,4-dihydropyrazolo[5,1-c][1,2,4]triazin-4-ones have been synthesized and these are the first representatives of geminal sulfones in which the heterocyclic ring is bound directly to the sulfur atoms of the sulfonyl groups.     

Synthesis and glutamate-agonistic activity of (S)-2-amino-3-(2,5-dihydro-5-oxo-3-isoxazolyl)-propanoic acid derivatives.

(S)-2-Amino-3-(2,5-dihydro-5-oxo-3-isoxazolyl)propanoic acid, (3a) and its analogs (3b--h) were prepared and evaluated for glutamate receptor-agonistic and antifungal activities. Several (S)- and (R)-2-amino-3-isoxazolylpropanoic acid derivatives (3a--d) were synthesized starting with (S)- and (R)-N-tert-butoxycarbonyaspartic acid alpha-methyl esters (4, n = 1) by means of Masamune's chain extension reaction followed by isoxazolone formation with hydroxylamine and subsequent deprotection reactions. Furthermore, (S)- and (R)-N-tert-butoxycarbonylglutamic acid alpha-methyl esters (4, n = 2) were converted to (S)- and (R)-2-amino-4-isoxazolylbutyric acid derivatives (3e-h) via the same sequence of reactions.