Facile synthesis of some novel pyrido[3',2':4,5]thieno[2,3-b][1,4]thiazine-8-carboxylic acids

Model tetrahydropyrido[3',2':4,5]thieno[2,3-b][1,4]thiazines 9a-c were synthesized via reductive lactamization, using sodium dithionite, of the respective 2-[(carboxyalkyl)thio]-3-nitro-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylic acids 7a-c. The latter derivatives were made via interaction of 2-chloro-7-cyclopropyl-3-nitro-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylic acid (6) with each of alpha-mercaptoacetic, alpha-mercaptopropionic, and alpha-mercaptosuccinic acids and triethylamine in aqueous acetone at room temperature. The structures of 7a-7c and 9a-9c are supported by microanalytical and spectral (IR, MS, NMR) data. Compounds 9a and 9c showed potent inhibitory activity against the IGROV1 (Ovarian Cancer) cell line.     

Heterocycles [h]-fused to 4-oxoquinoline-3-carboxylic acid. Part VII: synthesis of some 6-oxoimidazo[4,5-h]quinoline-7-carboxylic acids and esters

Abstract  

A series of ethyl 2-(substituted)-9-cyclopropyl-4-fluoro-6-oxo-1H-imidazo[4,5-h]quinoline-7-carboxylates has been prepared from ethyl 7,8-diamino-1,4-dihydroquinoline-3-carboxylate via thermally induced reactions with model alkanoic acids or via microwave-assisted cyclocondensation with some arene carboxaldehydes. Acid-catalysed hydrolysis of the resulting ester derivatives furnished the corresponding imidazoquinoline-7-carboxylic acids. The structures of these new acid and ester derivatives are based on microanalytical and spectral (IR, MS, and NMR) data.     

Derivatives of quinoline-7-carboxylic acid

The condensation of 4-oxo-1,2,3,4-tetrahydroquinoline-7-carboxylic acid and its 6-chloro analog with aromatic aldehydes has given the corresponding 3-benzyl-4-oxo-1,4-dihydroquinoline-7-carboxylic acids and their 4-chloro derivatives.For Communication II, see [1].Translated from Khimiya Geterotsiklicheskikh Soedinenii, Vol. 6, No. 8, pp.1115–1118, August, 1970.     

Heterocycles [<Emphasis Type="Italic">h</Emphasis>]-fused to 4-oxoquinoline-3-carboxylic acid. Part VII: synthesis of some 6-oxoimidazo[4,5-<Emphasis Type="Italic">h</Emphasis>]quinoline-7-carboxylic acids and esters

Abstract  A series of ethyl 2-(substituted)-9-cyclopropyl-4-fluoro-6-oxo-1H-imidazo[4,5-h]quinoline-7-carboxylates has been prepared from ethyl 7,8-diamino-1,4-dihydroquinoline-3-carboxylate via thermally induced reactions with model alkanoic acids or via microwave-assisted cyclocondensation with some arene carboxaldehydes. Acid-catalysed hydrolysis of the resulting ester derivatives furnished the corresponding imidazoquinoline-7-carboxylic acids. The structures of these new acid and ester derivatives are based on microanalytical and spectral (IR, MS, and NMR) data. Graphical abstract        

The synthesis of benzofuroquinolines. I. Some benzofuro[2,3-b]quinoline and benzofuro[3,2-c]quinoline derivatives

Benzofuro[2,3-b]quinoline ( Ia ) and its 11-methyl derivative ( Ib ) were synthesized by demethylcyclization of 3-(o-methoxyphenyl)-1,2-dihydroquinolin-2-ones (VIa,b). Benzofuro[2,3-b]quinoline-11-carboxylic acid (Id) was synthesized by chlorination followed by the action of potassium hydroxide of a lactone (IX) prepared by demethyl-cyclization of 3-(o-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-4-carboxylic acid (VIII). Isomeric benzofuro[3,2-c]quinoline (Ha) and its 6-methyl derivative (IIb) were synthesized by demethyl-cyclization of 3-(o-methoxyphenyl)-1,4-dihydroquinolin-4-ones (XIa,b). Both the methyl derivatives (Ib and IIb) were converted to the carboxylic acids (Id and IId) through condensation with benzaldehyde followed by oxidation. The benzofuroquinolines (Ia,b,d and IIa,b) thus obtained were oxidized to the corresponding N-oxides (IIIa,b,d and IVa,b).     

Reaction of 1,3-thiazolidine-4-carboxylic and 1,4-tetrahydro-thiazine-3-carboxylic acid esters with isocyanates and isothiocyanates and structures of the reaction products

7-Thia-1,3-diazabicyclo[3.3.0]octane-2,4-diones and 7-thia-1,3-diazabicyclo[4.3.0]-nonane-2, 4-diones, as well as their thio analogs, were obtained by the reaction of (S)-1,3-thiazolidine-4-carboxylic and 1,4-tetrahydrothiazine-3-carboxylic acid esters with isocyanates and isothiocyanates. Intermediate reaction products, viz., heterocyclic derivatives of urea, were isolated. The three-dimensional structures of the 3-methyl-4-oxo-7-thia-1,3-diazabicyclo[3.3.0]octane-2-thione and 3-methyl-4-oxo-7-thia-1, 3-diazabicyclo[4.3.0]nonane-2-thione molecules were determined by x-ray diffraction analysis.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1327–1332, October, 1985.     

Synthesis and transformations of di-endo-3-aminobicyclo-[2.2.2]oct-5-ene-2-carboxylic acid derivatives

all-endo-3-amino-5-hydroxybicyclo[2.2.2]octane-2-carboxylic acid (13) and all-endo-5-amino-6-(hydroxymethyl)bicyclo[2.2.2]octan-2-ol (10) were prepared via dihydro-1,3-oxazine or g-lactone intermediates by the stereoselective functionalization of an N-protected derivative of endo-3-aminobicyclo[2.2.2]oct-5-ene-2-carboxylic acid (2). Ring closure of b-amino ester 4 resulted in tricyclic pyrimidinones 15 and 16. The structures, stereochemistry and relative configurations of the synthesized compounds were determined by IR and NMR.     

A pentacyclic condensation product from 2,4-dimethyl-7-nitro-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acid

2,4-Dimethyl-7-nitro-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acid on preparation of a mixed anhydride, followed by reduction with sodium borohydride, affords 5,7a,13,13b-tetramethyl-2,10-dinitro-5a,7,7a,13,13a,13b-hexahydro-5H-[1,4]benzoxazino[3′,2′:4,5]pyrano[3,2-b][1,4]benzoxazine (3), the structure of which was established unambiguously by X-ray analysis.     

Synthesis of novel imidazo[1,2-a][3,1]benzothiazines 4, imidazo[1,2-a]-[1,2,4]benzotriazines 5, and 4H-imidazo[2,3-c]pyrido[2,3-e][1,4]oxazines 6

Starting from the readily available 2-aminobenzhydrols ( 7 ), 3-amino-1,2,4-benzotriazine ( 11 ) and 2-amino-3-pyridinol ( 12 ), novel derivatives of 5-phenyl-5H-imidazo[1,2-a][3,1]benzothiazine-2-carboxylic acid, ethyl ester ( 4 ), imidazo[2,1-c][1,2,4]benzotriazine-2-carboxylic acid, ethyl ester ( 5 ) and 4H-imidazo[2,3-c]pyrido-[2,3-e][1,4]oxazine ( 6 ) were prepared.     

Synthesis of New Fluorinated Derivatives of Quinolinecarboxylic Acids

Ethyl esters of 1-(7-Z-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carbamoyl)-5-X-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acids (X = H, F; Z = pyrrolidino-, piperidino-, hexamethylenimino-, morpholino-, thiomorpholino-) have been synthesized by the interaction of quinolone-3-carboxylic acid hydrazides with ethyl esters of 3-ethoxy-2-(polyfluorobenzoyl)acrylic acid . It was shown possible to cyclize intramolecularly the esters obtained with the formation of 1,3,4-oxadiazino[6,5,4-i,j]quinoline derivatives.     

Studies on antibacterial agents. II. Synthesis and antibacterial activities of substituted 1,2-dihydro-6-oxo-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acids

A series of substituted 1,2-dihydro-6-oxo-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acids for the treatment of systemic infections was synthesized via 7-bromo-3-ethylthio-4,5-difluoro-2-methylindole (3), which was prepared by Gassman's indole synthesis in excellent yield. The synthesized pyrroloquinolines were tested for their antibacterial activities. 8-Fluoro-1,2-dihydro-2-methyl-9-(4-methyl-1-piperazinyl)-6-oxo-6H- pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid showed a potent antibacterial activity against gram-positive and gram-negative bacteria.     

The synthesis of a pyrido[2,3-c]pyridazine: A cinnoline related to 6-fluoronalidixic acid

An analog of the pyrido[2,3-c]pyridazine ring system, 1-ethyl-6-fluoro-1,4-dihydro-7-methyl-4-oxopyrido-[2,3-c]pyridazine-3-carboxylic acid ( 13 ), related to both Cinoxacin ( 1 ) and nalidixic acid ( 2 ), has been synthesized. The reductive ring closure of 2-chloro-α-diazo-6-methyl-5-nitro-β-oxo-3-pyridinepropanoic acid, ethyl ester ( 7 ), proved to be the key reaction providing entry into the ring system.     

Synthesis of N-butyloxycarbonylalanyl-1,4dioxa-7-azaspiro[4,4]nonane-8(S)-carboxylic acid ethyl ester

A four-step method has been developed for the synthesis of N-buryloxycarbonylalanyl-1,4-dioxa-7-azaspiro[4,4]nonane-8(S)-carboxylic acid ethyl ester through the formation of N-benzyloxycarbonyl-1,4-dioxa-7-azaspiro[4,4]nonane-8(S)-carboxylic acid ethyl ester.Latvian Institute of Organic Synthesis, Riga LV-1006. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 663–665, May, 1996. Original article submitted January 31, 1996.     

4-Hydroxy-2-quinolones 123. Amidation of 2-bromomethyl-5-oxo-1,2-dihydro-5H-oxazolo[3,2-<Emphasis Type="Italic">a</Emphasis>]-quinoline-4-carboxylic acid

The reaction of 2-bromomethyl-5-oxo-1,2-dihydro-5H-oxazolo[3,2-a]quinoline-4-carboxylic acid with thionyl chloride is accompanied by a transformation of the oxazoloquinolone ring to give 4-chloro-1-(2,3-dichloropropyl)-2-oxo-1,2-dihydroquinoline-3-carboxylic acid chloride. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1034–1042, July, 2007.     

Synthese von 2,4-Diamino-thieno[2,3-d]pyrimidin-Derivaten

Synthesis of 2,4-Diamino-thieno[2,3-d]pyrimidines Condensation of 2-aminothiophene-3-carbonitrile ( 4 ) with guanidine or sequential addition of CS₂ and NH₃ to 4 provides 2,4-diaminothieno[2,3-d]pyrimidine ( 7 ). This compound yields, after sequential addition of sec-BuLi and either [3-(trifluoromethyl)benzene]sulfenyl chloride ( 8 ) or the corresponding disulfide 9 , followed by acidic work up, 2,4-diamino-6-{[3-(trifluoromethyl)phenyl]thio}thieno[2,3-d]pyrimidine ( 10 ). In another approach, 2-amino-5-{[3-(trifluoromethyl)phenyl]thio}thiophene-3-carbonitrile ( 11 ) obtained from 4 and 8 is transformed to 10 by condensation with guanidine. Corresponding to the second route, 2,4-diamino-6-[(naphth-2-yl)thio]thieno-[2,3-d]pyrimidine ( 16 ) is synthesized. Oxidation of 10 with m-chloroperbenzoic acid gives 2,4-diamino-6-{[3-(tri-fluoromethyl)phenyl]sulfinyl}thieno[2,3-d]pyrimidine ( 13 ).     

Synthesis of 1,4-dihydro-4-oxopyridazino[1,6-a]indole-3-carboxylic acids and 1,4-dihydro-4-oxopyrido[3′,2′:4,5]pyrrolo[1,2-b]-pyridazine-3-carboxylic acids as potential antibacterial agents

A few aza analogues of the quinolones have been prepared in the two families of the 1,4-dihydro-4-oxopyridazino[1,6-a]indole-3-carboxylic acids and the 1,4-dihydro-4-oxopyrido[3′,2′:4,5]pyrrolo[1,2-b]-pyridazine-3-carboxylic acids to check their antibacterial potential. One compound 6c shows antibacterial activities of the level of nalidixic acid and represents a new lead structure differing from the classical quinolones.     

Direct monobromination of substituted 4-oxoquinoline-3-carboxylic acid derivatives

N-Bromosaccharin in the presence of pyridinium poly(hydrogen fluoride) can be used for monobromination of ethyl esters of 6- and 7-substituted-4-oxo-1,4-dihydroquinoline-3-carboxylic acids. The reactions take place at the C₆ or C₈ positions, depending on the types and positions of the substituents.     

Short syntheses of 1,2,3,5-tetrahydro-5-oxopyrrolo-[1,2-a]quinoline-4-carboxylic acid and 1,2,3,4-tetrahydro-6H-6-oxopyrido[1,2-a]quinoline-5-carboxylic acid derivatives

Short and efficient syntheses of 7-fluoro-8-(4-methylpiperazin-1-yl)-1,2,3,5-tetrahydro-5-oxopyrrolo[1,2-a]-quinoline-4-carboxylic acid and 8-fluoro-9-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-6H-6-oxopyrido[1,2-a]-quinoline-5-carboxylic acid are described. Both basic heterocycles were synthesized in two steps by the condensation of a benzoylacetate with an imino ether followed by an intramolecular nucleophilic displacement cyclization reaction.     

Synthesis of 4-oxo-4H-quino[2,3,4-i,j][1,4]-benoxazine-5-carboxylic acid derivatives

The synthesis and antibacterial activity of 1-substituted amino-2-fluoro-4-oxo-4H-quino[2,3,4-i,j][1,4]benox-azine-5-carboxylic acid derivatives is described. Key steps in the synthesis include carbon homologation and two intramolecular nucleophilic displacement cyclization reactions to generate the 4-oxo-4H-quino[2,3,4-i,j]-[1,4]benoxazine-5-carboxylic acid nucleus.     

Synthesis and chromatographic enantioresolution of anti-HIV quinolone derivatives

The successful enantioseparation of five 6-desfluoroquinolones with three polysaccharide-based stationary phases (namely, the cellulose-based Chiralpak IB and the two amylose-based Chiralpak AD-H and Lux Amylose-2) is herein described. The investigated species differ for the nature of substituents and/or the position of the stereogenic centre on the quinolone scaffold.The effect on the enantioseparation performance exerted by the different morphology of the cellulose-based and amylose-based polymers, was systematically evaluated for all compounds. In this frame, the impact of alternative alcoholic (ethanol, 2-ethoxyethanol, methanol, 2-propanol) and acidic (acetic, methanesulfonic and trifluoroacetic acid) modifiers as well as of a “non-standard” solvent (chloroform), was investigated in normal phase conditions along with the stereo-electronic peculiarities of the selected polymers. While 7-[4-(1,3-benzothiazol-2-yl)-2-methyl-1-piperazinyl]-1-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (1) was enantioresolved with conventional normal-phase conditions by means of the largely employed amylose-based Chiralpak AD-H column, the recruitment of a bulky alcohol (2-ethoxyethanol) succeeded in the enantioresolution of 6-amino-1-methyl-7-[2-methyl-4-(2-pyridinyl)-1-piperazinyl]-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (2) and 6-amino-1-[1-(hydroxymethyl)propyl]-4-oxo-7-(4-pyridin-2-ylpiperazin-1-yl)-1,4-dihydroquinoline-3-carboxylic acid (3) with the same column. The use of the amylose-based Lux Amylose-2 column, carrying both an electro-withdrawing (chlorine) and an electro-donating (methyl) group on the carbamate residue, allowed to get 6-amino-1-methyl-4-oxo-7-[3-(2-pyridinyl)-1-pyrrolidinyl]-1,4-dihydro-3-quinolinecarboxylic acid hydrochloride (4) enanantioresolved, and 6-amino-1-methyl-4-oxo-7-(3-pyridin-2-ylpiperidin-1-yl)-1,4-dihydroquinoline-3-carboxylic acid (5) enantioseparated.