Synthesen und Reaktionen von Pyridazinderivaten, 11. Mitt.: 5-Acyl-4-pyridazincarbonsäurrester als „key intermediates” für 4-Acylpyridazine und 4-Alkyl-bzw. 4-Arylpyridazino[4,5-d]pyridazin-1 (2H) one

A convenient general method of preparing 4-acylpyridazines (4) is reported. It involves homolytic acylation of ethyl-4-pyridazinecarboxylate yielding ethyl-5-acyl-4-pyridazinecarboxylates (2) which easily can be converted to4 by alkaline hydrolysis followed by decarboxylation. The hitherto unknown pyridazino[4,5-d]pyridazine-1 (2H) ones bearing an alkyl- or arylsubstituent on C-4 (5a-g) were prepared in quantitative yields by reaction of2 with hydrazine.

10. Mitt.:G. Heinisch, A. Jentzsch undI. Kirchner, Tetrahedron Lett.1978, 619.     

Formal Total Synthesis of Ipomeamarone via the [2+3] Dihydrofuran Annulation

A formal synthesis of (2R-cis)-4-methyl-1-(2,3,4,5-tetrahydro-5-methyl-[2,3′-bifuran]-2-pentanone, or ipomeamarone (1) [494-23-5] was accomplished from 3-furaldehyde 5 and ethyl-2-bromocrotonate 4. The key step involved the formation of the dihydrofuran ring in 2 via a vinyloxirane rearrangement of 3 in the [2+3] dihydrofuran annulation. Mechanistic duality of reactions of those tetrahydrofurans possessing acidic hydrogens adjacent to the ring is addressed.     

Condensation of 4-chloro-2H-chromene-3-carbaldehydes and ethyl-3-aminocrotonates with p-TsOH: a facile approach for the synthesis of chromenyldihydropyridines

The investigated reaction of 4-chloro-2H-chromene-3-carbaldehyde 1a with ethyl 3-oxobutanoate 2a in the presence of ammonium acetate provided two compounds, 2H-chromenyldihydropyridine dicarboxylate 3a and chromenopyridine carboxylate 4a. However, the reaction of 1a with ethyl-3-aminocrotonate 5a in the presence of p-TsOH provided selectively 2H-chromenyldihydropyridine dicarboxylate 3a with very good yield. The established method was applied for the preparation of series of 2H-chromenyldihydropyridine dicarboxylates 3a–q.     

A CONVENIENT SYNTHESIS OF 2,3-DISUBSTITUTED DERIVATIVES OF 4H-PYRIMIDO[2,1-b]-BENZOTHIAZOLE-4-ONE

ABSTRACT

4H-Pyrimido[2,1-b ]benzothiazole-2-thiomethyl-3-cyano-4-one (3) has been prepared by the reaction of 2-amino benzothiazole (1) with ethyl-2-cyano-3,3-bismethyl thio acrylate (2) in the presence of dimethyl formamide and anhydrous potassium carbonate. Susceptibility of compound (3), towards condensation with different reagents like aryl amines, heteryl amines, phenols and compounds containing active methylene groups has been investigated.     

SYNTHESIS AND SOME REACTIONS OF 2-MERCAPTO-3,5,7-TRIPHENYLPYRIDO[2,3-d]-PYRIMIDINE-4(3H)-ONE

Abstract

2-Mercapto-3,5,7-triphenylpyrido[2,3-d]pyrimidine-4(3H)-one (II) was synthesized by the interaction of ethyl-2-amino-4,6-diphenylincotinate (I) with phenyl isothiocyanate in pyridine. The reaction of II with different reagents was carried out to give some condensed heterocyclic systems.     

Synthesis of 2-(Triazolyl,Oxadiazolyl, and Pyrazolyl) Substituted 1,5-Benzothiazepin-S,S-Dioxide Derivatives of Potential Medicinal Interest

Abstract

The synthetic potential of 2,3,4,5-tetrahydrobenzo[b] [1,5]thiazepine-1,1,4-trione-2-carbohydrazide (5) which resulted from ethyl-4-oxo-2,3,4,5-tetrahydrobenzo[b] [1,5]thiazepine-2-carboxylate (3), on its oxidation with H₂O₂/AcOH followed by treatment with NH₂NH₂.H₂O, was exploited to provide an access to 2-triazolo, 2-oxadiazolo, and 2-pyrazolo substituted derivatives of 1,5-benzothiazepin-4-oxo-1,1-dioxides (6–10), respectively.     

Investigations on the stability of bendamustin, a cytostatic agent of the nitrogen mustard type, I. Synthesis, isolation, and characterization of reference substances

Summary The following compounds were chosen as reference substances for HPLC investigations on 4-(6-bis(2-chloro-ethyl)amino-3-methylbenzimidazoyl(2))butyric acid (bendamustin), an antineoplastic agent of the N-lost type (synthesized or isolated from crude bendamustin): 4-(6-((2-chloroethyl)(2-hydroxyethyl)amino)-3-methylbenzimidazoyl(2))butyric acid (HP1), 4-(6-bis(2-hydroxyethyl)amino-3-methylbenzimidazoyl(2))butyric acid (HP2), ethyl-4-(6-bis(2-hydroxyethyl)amino-3-methylbenzimidazoyl(2))butyrate (dihydroxyester), and ethyl-4-(6-bis(2-chloroethyl)amino-3-methylbenzimidazoyl(2))butyrate (dichloroester). Furthermore, the so far unidentified side product 4-(7,8-dihydro-6-(2-chloroethylamino)-3-methyl-1,4-thiazino[3,2-g]benzimidazoyl(2))-butyric acid (NP1), formed in the last step of the synthesis, was isolated and identified.

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Untersuchungen zur Stabilität von Bendamustin, einem Cytostatikum vom N-Lost-Typ, 1. Mitt.: Synthese, Isolierung und Charakterisierung von Vergleichssubstanzen

Zusammenfassung Die folgenden Verbindungen wurden als Vergleichssubstanzen für HPLC-analytische Untersuchungen von 4-(6-Bis(2-chlorethyl)amino-3-methylbenzimidazoyl(2))buttersäure (Bendamustin), einem Antitumormittel des N-lost-Typs, synthetisiert oder aus Bendamustin-Rohstoff vor der Endreinigung isoliert: (4-(6-((2-Chlorethyl)(2-hydroxyethyl)amino)-3-methylbenzimidazoyl(2))buttersäure (HP1), 4-(6-Bis(2-hydroxyethyl)amino-3-methylbenzimidazoyl(2))buttersäure (HP2), 4-(6-Bis(2-hydroxyethyl)amino-3-methylbenzimidazoyl(2))buttersäureethylester (Dichlorester). Weiterhin konnte das bislang unbekannte Nebenprodukt 4-(7,8-Dihydro-6-(2-chlorethylamino)-3-methyl-1,4-thiazino[3,2-g]benzimidazoyl(2))buttersäure (NP1), welches sich im letzten Schritt der Synthese bildet, isoliert und identifiziert werden.

     

Dapson in Heterocyclic Chemistry,Part III: Synthesis,Antimicrobial, and Antitumor Activities of Some New Bisheterocyclic Compounds Containing Biologically Active Diphenylsulfone Moiety

The key intermediate diisothiocyanate 2 was allowed to react with 5-amino-3-methyl-pyrazole-4-carbonitrile 3, ethyl 5-amino-1-phenyl-pyrazole-4-carboxylate 6, 2-amino-tetrahydrobenzo[b]thiophene-3-car-bonitrile 9, ethyl-2-amino-tetra-hydrobenzo[b]thiophene-3-carboxylate 12, and/or 1,2,4-triazole 15 to give the corresponding biscompounds 4, 5, 7, 8, 10, 11, 13, 14, and 16, respectively. The structure of the synthesized compounds was elucidated by elemental analyses and spectral data. Some of the prepared compounds were tested for their antimicrobial and antitumor activities.     

Synthesis and Characterization of Some Novel 3-Bromo-2-acetylthiophene Chalcones and Biological Evaluation of Their Ethyl-4-(3-bromothien-2-yl)-2-oxo-6-(aryl)cyclohex-3-ene-1-carboxylate Derivatives

Novel chalcones 1-(3-bromothien-2-yl)-3-(aryl)prop-2-en-1-ones derived from 3-bromo-2-acetylthiophene and their cyclization product with ethylacetoacetate such as 4-(3-bromothien-2-yl)-2-oxo-6-(aryl)cyclohex-3-ene-1-carboxylate derivatives were synthesized and studied by X-ray, analytical, and spectral methods. Compounds were screened for their anti-inflammatory, analgesic, and antimicrobial activities. The compound ethyl-4-(3-bromothien-2-yl)-2-oxo-6-(4-propoxyphenyl) cyclohex-3-ene-1-carboxylate 5c exhibited promising anti-inflammatory, analgesic and antibacterial activities.     

Synthesen und Reaktionen von Pyridazinderivaten, 2. Mitt.: 4-Hydroxymethyl-pyridazin

While reduction of ethylpyridazine-4-carboxylate (1 b) by LiAlH₄ or NaBH₄ yields mixtures of 4-hydroxymethyl-pyridazine (1 a) and ethyl-2.5-dihydro-pyridazine-4-carboxylate (2), pyridazine-4-carbaldehyde and 4-acetyl-pyridazine quantitatively by NaBH₄ are reduced to the corresponding carbinols1 a, 1 d. 4-Chloromethyl-pyridazine easily can be prepared by reaction of1 a with SOCl₂. The structures of the new compounds are proved by¹H-NMR-, IR- and mass-spectroscopy.

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1. Mitt.:G. Heinisch, Mh. Chem.104, 953 (1973).     

Preparation of Calix[4]arene Alkylamine Derivatives by Mannich Reaction and use as Phase-Transfer Catalysts for Esterification Reaction

In this study, 5,11,17,23-tetrakis[(N-ethylpiperazine)methyl]-25,26,27,28-tetrahydroxycalix[4]arene (3) and 5,11,17,23-tetrakis[(4-carboethoxy-N-piperidino) methyl]-25,26,27,28-tetrahydroxycalix[4]arene (4) were synthesized in one step according to the Mannich reaction by the treatment of calix[4]arene with a secondary amine (N-ethylpiperazine, ethyl-4-piperidincarboxylate) and formaldehyde. The calix[4]arene derivatives (3, 4) were characterized by a combination of FTIR, ¹H NMR and elemental analyses. The synthesized compounds were used in an esterification reaction as the phase transfer catalyst. The catalytic efficiency of the calix[4]arenes 3 and 4 was evaluated by carrying out the ester-forming reaction of alkali metal carboxylates (sodium butyrate or sodium caprylate) with p-nitrobenzyl bromide. It was observed that the ester-forming reaction of alkali metal carboxylates with p-nitrobenzyl bromide, using calix[4]arene-based catalyst 3 as a phase-transfer catalyst in dichloromethan, provided the best yields.     

Traceable platinum(II) complexes with alkylene diamine-derived ligands: synthesis,characterization and in vitro studies

Diiodido- (6a/6b) and dichloridoplatinum(II) complexes (7a/7b) with fluorescent ligands 2-[(2-aminoethyl)amino]ethyl-2-(methylamino)benzoate (5a) and 2-amino-1-(aminoethyl)ethyl-2-(methylamino)benzoate (5b) were prepared and characterized by elemental analysis, ESI-MS analysis, fluorescence spectrometry, as well as ¹H, ¹³C, and ¹⁹⁵Pt NMR spectroscopy. All compounds have been tested against A2780 ovarian cancer, A549 lung carcinoma, and HT-29 colon cancer cell lines using sulforhodamine-B assay. The activity increased from ligand precursors, diiodido- to dichloridoplatinum(II) complexes, except against HT-29 cell line where diiodido and dichlorido expressed similar activity. These compounds enter the tumor cells and emit a bright fluorescence at ca. 470 nm, mainly targeting nuclei.     

Convenient Synthesis of 2-Vinylindoles

A convenient, two-step synthesis of 2-vinylindoles is described from the easily accessible (E)-ethyl-α-allyl-2-nitrocinnamates. Ethylcinnamates (1a and 1b) on reaction with triethylphosphite provide ethyl-2-allylindole-3carboxylates (2a and 2b ) along with minor amounts of their N-ethoxyderivatives (4a and 4b). Alkaline hydrolysis of 2a and 2b provide (E)-2-vinylindoles 3a and 3b in 60 and 67% yield respectively.     

Synthesis and Antibacterial Evaluation of Novel 3,6-Disubstituted Coumarin Derivatives

A novel series of 3,6-disubstituted coumarin derivatives were synthesized by the reaction of ethyl-2-(3-acetyl-2-oxo-2H-chromen-6-yl)-4-methylthiazole-5-carboxylate with thiosemicarbazide and various phenacyl bromides / 3-(2-bromoacetyl)-2H-chromen-2-ones / 2-(2-bromoacetyl)-3H-benzo[f]chromen-3-one in ethanol having catalytic amount of acetic acid under reflux conditions with good yields. All the synthesized compounds were fully characterized by spectral studies and evaluated for their in vitro antibacterial activity against Pseudomonas aeruginosa, Bacillus subtilis (Gram positive), Escherichia coli, and Azatobacter (Gram negative) bacterial strains. Activity results revealed that the compound 6h against Escherichia coli and compound 6i against Pseudomonas aeruginosa and Escherichia coli have shown maximum zones of inhibition. Remaining compounds showed moderate to good activity against all the tested bacterial strains compared with the standard drug cefotaxime.     

Three-component synthesis of novel trifluoromethyl-containing tetrahydropyran derivatives

l-Proline-catalyzed reaction of ethyl 4,4,4-trifluoroacetoacetate, cinnamaldehyde and anilines provide a novel method for preparation of ethyl-6-(arylamino)-2-hydroxy-4-phenyl-2-(trifluoromethyl)tetrahydro-2H-pyran-3-carboxylate derivatives in good yields. The reaction was conducted by initial Michael addition, followed by intra-molecular cyclization under mild conditions. The structure of a typical ethyl-2-hydroxy-4-phenyl-6-(m-tolylamino)-2-(trifluoromethyl)tetrahydro-2H-pyran-3-carboxylate (4h) was confirmed by XRD analysis. A plausible mechanism is presented.     

Synthesis,characterization and antimicrobial activity of novel sulphapiperazine containing arylazopyrazoles

Mannich reaction of benzotriazole (1), ethyl-4-amino benzoate (2) and formaldehyde in ethanol afforded 4-(1H)-benzotriazoyl methyl amino benzoate (3), which on treatment with hydrazine hydrate results in the 4-(1H)-benzotriazoyl methyl amino benzoyl hydrazide (4). This compound on condensation with pre-prepared various ethyl-2-substituted phenyl hydrazono-3-oxobutyrates (6a–h), furnished 1-(4-((1H-benzo[d][1,2,3]triazol-1-yl) methyl amino) benzoyl)-3-methyl-4-(2-(4-(4-alkylpiperazin-1-ylsulfonyl) phenyl) hydrazono)-1H-pyrazol-5(4H)-ones (7a–h). All these compounds (7a–h) were characterized by spectral studies. The compounds showed significant antimicrobial activity against various bacteria and fungi.     

Heterocycles structurally influenced by a side chain. X. Effect of temperature and side chain on the imine-enamine tautomerism in the quinoxalinone and pyridopyrazinone systems

3-(1-Benzoyl)ethyl-1H-pyrido[2,3-b]pyrazin-2-one ( 7 ), 3-(1-ethoxycarbonyl)ethyl-1H-pyrido[2,3-b]-pyrazin-2-one ( 8 ), and 3-(1-benzoyl)ethyl-1H-quinoxalin-2-one ( 9 ) exist only in the imine form due to the steric effect of the methyl substituent. As regards the imine-enamine tautomerism, 3-(β-carbonylmethylene) derivatives of 1,2-dihydro-4H-pyrido[2,3-b]pyrazin-3-one such as 12 and 15–18 gradually change from the enamine form to the imine form with elevated temperatures; however, 3-(carbonylmethylene) derivatives of 3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one such as 10, 19 and 20 show little temperature effect. 2-Phenacylidene-1,2-dihydro-4H-pyrido[3,4-b]pyrazin-3-one ( 21 ) and 3-phenacylidene-3,4-dihydro-1H-pyrido[3,4-b]pyrazin-2-one ( 22 ), which exist in the enamine form, show no temperature effect.     

Quinoline-3-carboxylates as potential antibacterial agents

The ethyl-2-chloroquinoline-3-carboxylates, 4, were achieved from o-aminobenzophenones in two steps. i.e. initially, the ethyl-2-oxoquinoline-3-carboxylates, 3, were obtained by base-catalyzed Friedlander condensations of o-aminobenzophenones, 1, and diethylmalonate, 2. The 2-chloroquinoline-3-carboxylates, 4, were then obtained by the reaction with POCl₃ in good yields. The chemical structures were confirmed by FTIR, mass and ¹H-NMR spectroscopic techniques. All the synthesized compounds were tested for their in vitro antibacterial activity against Bacillus subtilis and Vibrio cholera and found to possess moderate activity.     

Zur Umsetzung des 3,4,5,6-Tetrahydro-6-hydroxy-4,4,6-trimethyl-1,3-thiazin-2-thions mit primären Aminen

Tetrahydro-6-hydroxy-4,4,6-trimethyl-1,3-thiazine-2-thione (1 a) reacts with methyl-, ethyl- and n-butylamine to the corresponding 1-alkyl-6-alkylaminotetrahydro-2(1H)-pyrimidinethione12 but withi-propylamine to tetrahydro-6-isopropylamino-1,3-thiazine-2-thione (6 d). On treatment withDCC,6 d is rearranged to dihydro-4-isopropylamino-2(1H)-pyridinethione (8 d), and 6-amino-tetrahydro-1,3-thiazinethione (6 a) to dihydro-4,4,6-trimethyl-2(1H)-pyrimidinethione (10 a). The reaction of 6-aminothiazinethiones6 a, d and 6-(4-morpholinyl)-thiazinethione13 resp., with methylamine leads to 1-methyl-6-methylamino-pyridinethione12 b. 1-Alkyl-6-alkylamino-tetrahydro-2(1H)-pyrimidinethiones (12) react at reflux temperature to dihydro-1-alkylpyrimidinethiones10. With methylamine only 6-methylamino-3,4,4,6-tetramethyl-1,3-thiazine-2-thione (6 f) is formed from tetrahydro-6-hydroxy-tetramethyl-1,3-thiazine-2-thione (1 b).     

Synthesis of both enantiomers of ethyl-4-chloro-3-hydroxbutanoate from a prochiral ketone using Candida parapsilosis ATCC 7330

Candida parapsilosis ATCC 7330 when grown in a medium containing glycerol reduced ethyl-4-chloro-3-oxobutanoate to (R)-ethyl-4-chloro-3-hydroxybutanote (ee >99%, yield: 94%) while glucose and sucrose grown cells yielded (S)-ethyl-4-chloro-3-hydroxybutanote (ee >99%, yield: 96%). The activity of ethyl-4-chloro-3-oxobutanoate reductase was higher in glucose-grown cells (160 U/g protein) when compared to sucrose (158 U/g protein) and glycerol (22 U/g protein). Both the enantiomers of ethyl-4-chloro-3-hydroxybutanoate (ee >99%) can thus be obtained using Candida parapsilosis ATCC 7330 by altering the carbon source in the growth medium.