Synthesis of Quinolone Analogues： 7-[2-Aminomethylaziridin-l-yl]- quinolones

New quinolone derivatives of 7-[2-aminomethylaziridin-1-yl]quinolone-3-carboxylic acids were synthesized. The structures of these compounds were characterized by 1H NMR and HRESI-MS.     

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.     

(1R,3S,4S)-2-苄氧羰基-2-氮杂双环[2.2.1]庚烷-3-羧酸的合成

以(R)-(+)-α-甲基苄胺为原料,依次经缩合,Diels-Alder反应,还原,Cbz-保护和水解反应,合成了抗丙肝新药HCV NS3/4A蛋白酶拟肽类抑制剂的重要中间体——(1R,3S,4S)-2-苄氧羰基-2-氮杂双环[2.2.1]庚烷-3-羧酸,总收率66%,其结构经1H NMR和ESI-MS确证。     

Development of versatile cis- and trans-dicarbon-substituted chiral cyclopropane units: synthesis of (1S,2R)- and (1R,2R)-2-aminomethyl-1-(1H-imidazol-4-yl)cyclopropanes and their enantiomers as conformationally restricted analogues of histamine

The cyclopropane ring can be used effectively in restricting the conformation of biologically active compounds to improve activity and also to investigate bioactive conformations. We designed (1S,2R)- and (1R,2R)-2-aminomethyl-1-(1H-imidazol-4-yl)cyclopropanes (1 and 2, respectively) and their enantiomers (ent-1 and ent-2) as conformationally restricted analogues of histamine. The four types of chiral cyclopropanes bearing two differentially functionalized carbon substituents in a cis or trans relationship on a cyclopropane ring, (1S,2R)-2-(tert-butyldiphenylsilyloxy)methyl-1-formylcyclopropane (7) and (1R,2R)-2-(tert-butyldiphenylsilyloxy)methyl-1-formylcyclopropane (8) and their enantiomers (ent-7 and ent-8), were developed as the key intermediates for synthesizing 1, 2, ent-1, and ent-2. The reaction between (R)-epichlorohydrin [(R)-12] and phenylsulfonylacetonitrile (13a) in the presence of NaOEt in EtOH followed by treatment with acid gave the chiral cyclopropane lactone 11a with 98% ee in 82% yield. Compound 11a was converted into both the cis- and trans-chiral cyclopropane units 7 and 8, respectively, via reductive desulfonylation with Mg/MeOH as the key step. The corresponding enantiomers, the cis-substituted ent-7 and the trans-substituted ent-8, were also prepared starting from (S)-epichlorohydrin [(S)-12]. The four conformationally restricted target histamine analogues 1, 2, ent-1, and ent-2 were successfully synthesized from 7, 8, ent-7, and ent-8, respectively. The chiral cyclopropane units 7, 8, ent-7, and ent-8 should be useful as versatile intermediates for synthesizing various compounds having an asymmetric cyclopropane structure.     

New 7-substituted quinolone antibacterial agents. The synthesis of 1-ethyl-1,4-dihydro-4-oxo-7-(2-thiazolyl and 4-thiazolyl)-3-quinolinecarboxylic acids

A series of 1-ethyl-1,4-dihydro-4-oxo-7-(4-thiazolyl)-3-quinolinecarboxylic acids and 1-ethyl-1,4-dihydro-4-oxo-7-(2-thiazolyl)-3-quinolinecarboxylic acids were prepared. Also prepared was 10-[2-(aminomethyl)-4-thiazolyl]-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid. Analogs with basic amine substituents on the thiazole moiety were found to have antibacterial activity.     

Formation of furo[3,2- c ]quinolone-2-carbonitriles and 4-oxo-4,5-dihydrofuro[3,2- c ]quinolone-2-carboxamides from reaction of quinoline-2,4-diones with 2-[bis(methylthio)methylene]malononitrile

Quinoline-2,4-diones reacted with 2-[bis(methylthio)methylene]malononitrile in DMF/Et3N to produce 3-(methylthio)-4-oxo-4,5-dihydrofuro[3,2-c]quinolone-2-carbonitriles and 3-(methylthio)-4-oxo-4,5-dihydrofuro[3,2-c]quinolone-2-carboxamides in state of 2-imino-substituted 4-(methylthio)-5,6-dihydro-2H-pyrano[3,2-c]quinolone-3-carbonitriles. The structures of all new products were proved using NMR, IR, and mass spectral data. The possible mechanism for the reaction is also discussed.     

Study on the Stereoselective Synthesis of Carbapenem Sidechain (2S,4S)-4-Acetylsulphanyl-2-[(S)-1-phenylethylcarbamoyl]-pyrrolidine-1-carboxylic Acid 4-Nitrobenzyl Ester

A stereoselective and economic synthesis of the carbapenem sidechain (2S, 4S)-4-ace-tylsulphanyl-2-[(S)1-phenylethyl-carbamoyl] pyrrolidine-1-carboxylic acid 4-nitrobenzylester was developed. Due to the effect of spatial hindrance, only the (2S,4S) diastereomer 3 wasobtained by coupling 1 and the inexpensive racemic 2 catalyzed by EEDQ.     

Synthesis and antibacterial activity of 1-(substituted-benzyl)-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acids and their 6,8-difluoro analogs

Alkylation of 6,7-difluoro-4-hydroxyquinoline-3-carboxylic acid ethyl ester with substituted-benzyl chlorides gave 1-(substituted-benzyl)-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl esters. Their treatment with piperazine or N-methylpiperazine in pyridine yielded 1-(substituted-benzyl)-6-fluoro-1,4-dihydro-4-oxo-7-(l-piperazinyl)quinoline-3-carboxylic acid ethyl esters which were hydrolyzed with aqueous sodium hydroxide and then acidified with hydrochloric acid afforded the desired 1-(substituted-benzyl)-6-fluoro-1,4-dihydro-4-oxo-7-(1-iperazinyl)quinoline-3-carboxylic acids. The 6,8-difluoro analogs were prepared similarly using 6,7,8-trifluoro-4-hydroxyquinoline-3-carboxylic acid ethyl ester as a starting material. Some of these quinolones demonstrated fairly good antibacterial activities. Among them, 6-fluoro-1-(4-fluorophenylmethyl)-1,4-dihydro-7-(1-iperazinyl)-4-oxoquinoline-3-carboxylic acid ( 7d ) and 6,8-difluoro-1-(3-fluorophenylmethyl)-1,4-dihydro-7-(1-piperazinyl)-4-oxoquinoline-3-carboxylic acid ( 8c ) are two of the best.     

Synthesis and pharmacological effects of optically active 2-[4-(4-benzhydryl-1-piperazinyl)phenyl]-ethyl methyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate hydrochloride

Optically active 2-[4-(4-benzhydryl-1-piperazinyl)phenyl]ethyl methyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate [(S)-(+)-1 and (R)-(-)-1] hydrochlorides were synthesized with high optical purities from (R)-(-)- and (S)-(+)-1,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)- 3-pyridinecarboxylic acids [(R)-(-)-6 and (S)-(+)-6], which are available from (+/-)-6 by optical resolution using quinidine and cinchonidine, respectively. From pharmacological investigations of (S)-(+)-1 and (R)-(-)-1 such as the antihypertensive effect on spontaneously hypertensive rats and inhibition of [3H]nimodipine binding to rat cardiac membrane homogenate, the active form of 1 was defined to be the (4S)-(+)-enantiomer of 1.     

4-Quinolone fused heterocyclic ring systems by intramolecular reactions of 4-quinolone-2-carboxamides

A versatile synthetic route to new 4-quinolone-based polycyclic systems is described. TFA-catalyzed intramolecular reaction of N-unsubstituted quinolone-2-carboxylic acid amides gives structurally diverse compounds, depending on the length of the chain. Acid treatment of β-oxoamides furnishes 3H-pyrazino[1,2-a]quinoline-4,6-diones, due to the nucleophilic attack of N-1 to the carbonyl group, whereas TFA treatment of δ- and ε-oxoamides leads to the formation of tetracyclic compounds by a tandem heteroannulation reaction.     

Synthesis and anticancer activity evaluation of 3-(4-oxo-2-thioxothiazolidin-5-yl)-1H-indole-carboxylic acids derivatives

Abstract

A mild and efficient method for the synthesis of 1-oxo-9H-thiopyrano[3,4-b]indole-3-carboxylic acids and dimerized 3-(4-carboxy-1H-3-indolyl)-2-propenoic acids via alkaline hydrolysis of 3-(rhodanin-5-yl)-1H-indole-2-carboxylic acids derivatives was elaborated. Anticancer activity screening in NCI60-cell lines assay allowed identification of 5-fluoro-3-(4-oxo-2-thioxothiazolidin-5-ylidenemethyl)-1H-indole-2-carboxylic acid methyl ester 2a with significant antimitotic activity at micromolar and submicromolar concentrations.     

Combinatorial solution-phase synthesis of (2S,4S)-4-acylamino-5-oxopyrrolidine-2-carboxamides

Solution-phase combinatorial synthesis of (2S,4S)-4-acylamino-5-oxopyrrolidine-2-carboxamides was studied. First, di-tert-butyl (2S,4S)-4-amino-5-oxopyrrolidine-1,2-dicarboxylate hydrochloride was prepared as the key intermediate in five steps from (S)-pyroglutamic acid. Acylation of the amino group followed by acidolytic deprotection gave (2S,4S)-4-acylamino-5-oxopyrrolidine-2-carboxylic acids, which were then coupled with amines to furnish a library of (2S,4S)-4-acylamino-5-oxopyrrolidine-2-carboxamides. Four coupling reagents, BPC, EEDQ, TBTU, and PFTU, were tested for the amidation reactions in the final step. Amidations with EEDQ and TBTU led to the desired carboxamides. On the other hand, BPC and PFTU were not suited, since diketopiperazines were sometimes obtained instead of the desired carboxamides.     

A convenient and new approach to the synthesis of ω-heterocyclic amino acids from carboxy lactams through ring-chain-transformation. Part 2: Synthesis of (2R)-/(2S)-2-aminomethyl-3-(1-aryl-/1,5-diaryl-1H-pyrazol-3-yl)-propionic acid

Making use of amide activation, a convenient and short path synthesis of optically pure ω-heterocyclic-β-amino acids has been achieved from (1R,3R)- and (1R,3S)-5-oxo-1-(1-phenyl-ethyl)-pyrrolidine-3-carboxylic acid methyl ester. The key step of the synthesis involves a regiospecific ring-chain-transformation of the enaminones when subjected to 1,2-binucleophilic attacks. The method is illustrated by the synthesis of (2R)-/(2S)-2-aminomethyl-3-(1-aryl-/1,5-diaryl-1H-pyrazol-3-yl)-propionic acid.     

Synthetic antibacterials. VIII. 7-(1′-alkylhydrazino)-1,8-naphthyridines and related compounds

Synthesis and in vitro antibacterial activity of 7-(1′-alkylhydrazino)-1,8-naphthyridines related to nalidixic acid were investigated. Namely, treatment of 7-alkylamino-1-ethyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acids 1a-d with sodium nitrite in the presence of hydrochloric acid gave the 1-ethyl-1,4-dihydro-7-(N-nitrosoalkylamino)-4-oxo-1,8-naphthyridine-3-carboxylic acids 2a-d , which upon reacting with zinc dust in acetic acid gave the 7-(1′-alkylhydrazino)-1-ethyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacids 3a-d. The compound 3a was alternately obtained by the reaction of 7-chloro-1-ethyl-1,4-dihydro-4-oxo-1,8-naphth-yridine-3-carboxylic acid ( 4 ) with methylhydrazine. The reaction of 7-chloro-4-hydroxy-1,8-naphthyridine-3-carboxylic acid ( 5 ) with methylhydrazine gave the 4-hydroxy-7-(1′-methylhydrazino)-4-oxo-1,8-naphthyridine-3-carboxylic acid ( 6 ), which upon treatment with alkyl halides afforded the 1-alkyl-1,4-dihydro-7-(1′-methyl-hydrazino)-4-oxo-1,8-naphthyridines 3a and 3e-g. The reaction of the appropriate 3 with ketones gave the corresponding 7-(1′-methylalkylidenehydrazino)-1,8-naphthyridines 7a-c and 8a-b. Among the compounds prepared, certain 3 and 7 exhibited good activity against Gram-negative bacteria.     

(R)-2-硫代四氢噻唑-4-羧酸及其酯的合成

L-半胱氨酸盐酸盐与二硫化碳, 氢氧化钠在硝酸铅存在下进行成环反应得到(R)-四氢噻唑-2-硫酮-4-羧酸产率76% , 后者与 醇在硫酸铁水合物催化下反应得到(R)-四氢噻唑-2-硫酮-4-羧酸酯, 产率40～82% .     

New 4-quinaldinol derivatives XVII. 2-Methyl-3-(3-chloro-2-buten-1-yl)-4-hydroxyquinoline-6-carboxylic acid and some of its transformations

1-(2-Methyl-4-hydroxy-6-carboxy-3-quinolinyl)-3-butanone and 1-(2-methyl-4-chloro-6-carboxy-3-quinolinyl)-3-butanone were obtained by the acid hydrolysis of 2-methyl-3-(3-chloro-2-buten-1-yl)-4-hydroxy(chloro)quinoline-6-carboxylic acids and their esters.See [6] for communication XVI.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1681–1682, December, 1971.     

4-hydroxy-2-quinolones. 18. Synthesis and antithyroid activity of 1-R-2-oxo-3-(4-oxo-3H-quinazolin-2-yl)-4-hydroxyquinolines

Preparative methods for the synthesis of 1-R-2-oxo-3-(4-oxo-3H-quinazolin-2-yl)-4-hydroxyquinolines based on ethyl esters or nitrites of 1-R-2-oxo-4-hydroxyqidnoline-3-carboxylic acids and anthranilamide or ethyl anthranilate correspondingly were proposed. The antithyroid activity of the compounds synthesized was studied.For Communication 17, see [1].Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1223–1226, September, 1993.     

Asymmetric synthesis of the cis- and trans-stereoisomers of 4-aminopyrrolidine-3-carboxylic acid and 4-aminotetrahydrofuran-3-carboxylic acid

The diastereoselective conjugate addition of lithium (S)-N-benzyl-N-[small alpha]-methylbenzylamide has been successfully applied to the first asymmetric syntheses of cis-(3S,4R)- and trans-(3R,4R)-4-aminotetrahydrofuran-3-carboxylic acids (26% and 25% overall yield respectively, >98% d.e. and >97% e.e. in each case). Furthermore, the most efficient asymmetric synthesis to date of cis-(3R,4R)- and trans-(3R,4S)-4-aminopyrrolidine carboxylic acids is delineated: for cis-(3R,4R), four steps, >98% d.e., 52% overall yield; for trans-(3R,4S), five steps, >98% d.e., 50% overall yield.     

Synthesis of 1-[6-Fluoro-(2S)-3H,4H-dihydro-2H-2-chromenyl]-(1R)-1,2- ethanediol and 1-[6-Fluoro-(2R)-3H,4H-dihydro-2H-2-chromenyl]- (1R)-1,2-ethanediol

Benzopyran compounds possess diverse pharmacological properties such as β-blockade, anticonvulsant and antimicrobial.[1,2] Our interest has been focused on the synthesis of 1-[6-Fluoro-2S]-3H,4H-dihydro-2H-2-chromenyl]-(1R)-1,2-ethanediol (6) and 1-[6-fluoro-(2R)-3H,4H-dihydro-2H-2-chromenyl]-(1R)-1,2-ethanediol (7) which are particularly convenient precursor to (S,R,R,R)-NE (8). 8 containing four asymmetrical carbon atoms was reported to be the most active isomer.[3] Chandrasekhar[4] has reported on the synthesis of 8. The key step to synthesize this compound is to obtain the chiral chromanone 6 and 7. 6 was accomplished in 8 steps by the Clasien rearrangement and a one-pot Sharpless asymmetric epoxidation, but the compound 7 was accomplished in 10 steps. Johannes[5] used Zr-catalytic kinetic resolution of allylic ethers and Mo-catalyzed chromene formation to synthesize 8 in 14 steps. However both of the methods request many synthetic steps and expensive reagents.     

Doubly Decarboxylative Synthesis of 4-(Pyridylmethyl)chroman-2-ones and 2-(Pyridylmethyl)chroman-4-ones under Mild Reaction Conditions

The doubly decarboxylative Michael–type addition of pyridylacetic acid to chromone-3-carboxylic acids or coumarin-3-carboxylic acids has been developed. This protocol has been realized under Brønsted base catalysis, providing biologically interesting 4-(pyridylmethyl)chroman-2-ones and 2-(pyridylmethyl)chroman-4-ones in good or very good yields. The decarboxylative reaction pathway has been confirmed by mechanistic studies. Moreover, attempts to develop an enantioselective variant of the cascade are also described.