Synthesis and antibacterial activity of some 7-substituted 1-ethyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acids: Ethers,secondary amines and sulfides as c-7 substituents

A series of 7-substituted 1-ethyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acids were prepared from 1-ethyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 8 . Those derivatives reported contain acyclic and heterocyclic substituents linked to the quinolone C-7 position via O, NH or S. The in vitro antibacterial data of some of these derivatives against 4 Gram positive and 4 Gram negative organisms are reported.     

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.     

A new synthetic route to 7-halo-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid,an intermediate for the synthesis of quinolone antibacterial agents

Starting from m-fluorotoluene, 7-chloro-6-fluoro- and 6,7-difluoro-1-cyclopropyl-1,4-dihydro-4-oxoquino-line-3-carboxylic acids, 3 and 16 were synthesized. Compounds 3 and 16 are useful intermediates for the synthesis of a class of quinolone antibacterial agents. The synthetic route involves two processes; i) construction of the quinoline ring by an intramolecular cyclization accompanied by the elimination of a nitro group and ii) introduction of fluorine atom by replacement of a nitro group with potassium fluoride. 7-(3-Amino-1-pyrroli-dinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (18) was prepared from 3 or 16. The antibacterial activity of 18 compares favorably with that of ciprofloxacin (2) .     

Synthesis of esters of 3-fluoro-3-nitroacrylic acid

Conclusions The reaction of 1,3-difluoro-1,1,3,3-tetranitropropane with alkanols was used for the preparation of alkyl esters of 3-fluoro-3-nitroacrylic acid. 1,3-Difluoro-1,3,3-trinitro-1- propene and 1,3-difluoro-1,3-dinitro-2-alkoxy-1-propene were also isolated as intermediates.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 3, pp. 709–711, March, 1989.     

Synthesis of 24,24-difluoro- and 24ξ-fluoro-25-hydroxyvitamin D3

From cholenic acid 24,24-difluoro-25-hydroxyvitamin D₃ and 24ξ-fluoro-25-hydroxyvitamin D₃ were prepared.     

The synthesis of a series of 7-amino-1-cyclopropyl-8-fluoro-1,4-dihydro-4-oxo-1,6-naphthyridine-3-carboxylic acids as potential antibacterial agents

A series of 7-amino-1-cyclopropyl-1,4-dihydro-8-fluoro-4-oxo-1,6-naphthyridine-3-carboxylic acids has been prepared and evaluated for antibacterial activity. These compounds were prepared by the displacement of the chloro substituent from 7-chloro-1-cyclopropyl-1,4-dihydro-8-fluoro-4-oxo-1,6-naphthyridine-3-carboxylic acid employing the requisite nitrogen nucleophile to produce the title compounds. The naphthyridine acid was synthesized in ten steps from ethyl 2,4-dihydroxy-3-nitro-5-pyridinecarboxylate. The key step in the sequence was a Schiemann reaction carried out using the hexafluorophosphate salt of the diazonium ion derived from ethyl 3-amino-2,4-dichloro-5-pyridinecarboxylate.     

新型2-取代氨基-3-氟-4-吡啶氟硼酸钾盐的合成

以2,3-二氟-5-氯吡啶为原料,依次经取代和还原反应制得2-取代氨基-3-氟吡啶化合物(2a~2g); 2a~2g与正丁基锂及硼酸三异丙酯经有机锂化法制得相应的硼酸化合物(3a~3g); 3a~3g分别与氟化氢钾经取代反应合成了7个新型的2-取代氨基-3-氟-4-吡啶氟硼酸钾盐,其结构经¹H NMR, ¹³C NMR, IR, ESI-MS和元素分析表征。     

Synthesis of 7-ethoxy- and 7-fluoro-phenothiazines

Synthesis of 7-ethoxy- and 7-fluoro-phenothiazines is reported by Smiles rearrangement of 5-ethoxy- and 5-fluoro-2-formamido-2′-nitrodiphenylsulfides. The later were obtained by the formylation of 2-amino-5-ethoxy/5-fluoro-2′-nitrodiphenylsulfides which were prepared by the condensation of 2-amino-5-ethoxy/5-fluoro-benzenethiols with o-halonitrobenzenes.     

Studies on pyridonecarboxylic acids . 2. Synthesis and antibacterial activity of 8-substituted-7-fluoro-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylic acids

A series of 8-substituted-7-fluoro-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylic acids was prepared and evaluated for antibacterial activity. These compounds were synthesized from ethyl 2-mercaptoquinoline-3-carboxylates 17 which were obtained from anilines 11 by a route involving an intramolecular cyclization reaction.     

2-取代-3-N-酰基-5-氟-4-嘧啶酮的合成及其抗肿瘤活性

在丙酮溶液中,于Et3N存在下使2-取代-5-氟-4-嘧啶酮与酰氯反应,合成了14个未见文献报道的2-取代-3-N-酰基-5-氟-4-嘧啶酮类化合物,它们的结构经IR,1H NMR,元素分析或MS确定.其中有些化合物具有一定的抗肿瘤活性.     

An intramolecular cyclization of 7-substituted 6-fluoro- 1,8-naphthyridine and -quinoline derivatives

A synthesis of 1,4-oxazine and pyrazine ring systems by an intramolecular cyclization of 7-substituted 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine and -quinoline derivatives having a nitrogen or oxygen nucleophilic site in the C-7 appendage was studied. The in vitro antibacterial activities of compounds prepared by this method were tested.     

4-Hydroxy-2-quinolones. 108. N-R-amides of 9-fluoro-1-hydroxy-5-methyl-3-oxo-6,7-dihydro-3H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylic acid and their antitubercular activity

The reaction of 6-fluoro-2-methyl-1,2,3,4-tetrahydroquinoline with triethylmethanetricarboxylate gives di(9-fluoro-1-hydroxy-5-methyl-3-oxo-6,7-dihydro-3H,5H-pyrido[3,2,1-ij]quinolin-2-yl)methane and ethyl 9-fluoro-1-hydroxy-5-methyl-3-oxo-6,7-dihydro-3H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylate from which alkyl-, dialkylaminoalkyl-, and hetarylamides as well as hydrazides were prepared. The structure and antitubercular properties of the compounds synthesized are discussed. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1391–1407, September, 2006.     

Fluorinated heterocyclic compounds. 2. 2,4-difluoro and 4-amino-2-fluoropyrimidines,nucleoside base analogs

Nucleoside base analogs in which fluoro substituents replace the enolic hydroxy groups of uracil, thymine and cytosine have been prepared. Improved methods for the preparation and isolation of the known 2,4-di-fluoropyrimidine, 2,4-difluoro-6-methylpyrimidine and the new 2,4-difluoro-5-methylpyrimidine, 2-fluoro-4-aminopyrimidine, 4-fluoro-2-aminopyrimidine, and other alkylaminofluoropyrimidines are described.     

A simple route to 6- and 7-fluoro-substituted naphthalene-1-carboxylic acids

A simple one-pot method for the synthesis of 6-fluoro- and 6,7-difluoro-1-naphthoic acid is described. 6-Fluoro-1-naphthoic acid can be converted into 7-fluoro-1-naphthoic acid in three straightforward steps.     

Facile synthesis of 9-（N-amino-4-fluoromethyl-3-pyrrolidinyl）-2- fluoro-6-aminopurine from trans-4-hydroxy-L-proline

A novel and simple procedure for synthesis of azanucleoside by Mitsunobu reaction between N-(p-nitrobenzyloxycarbonyl)- trans-4-hydroxy-D-proline methyl ester obtained from trans-4-hydroxy-L-proline after six-step reaction and 2-fluoro-6-azidopurine is described,and azanucleoside is fluorinated by new fluridizer 2,2-difluoro-1,3-dimethylimidazolidine (DFI).All reactions could be carded out under mild condition.     

Synthesis and antibacterial activity of new 5-substituted 1-cyclopropyl-6-fluoro-7-piperazinyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acids

The 5-hydroxymethyl and the 5-formyl-1-cyclopropyl-6-fluoro-7-piperazinyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acids have been prepared via a 5-trimethylsilyl group and were tested in vitro as potential antibacterials.     

Novel and versatile reactions of trifluoroamine oxide: a new route to polyfluorinated ethers

A series of pyrimidine methyl and polyfluoroalkyl ethers were synthesized from the reactions of trifluoroamine oxide (1) with several 5-substituted uracils in the presence of tetrabutylammonium hydroxide and methanol, 2,2,2-trifluoroethanol (6), or 1H,1H-pentafluoropropanol (7). With 5-(trifluoromethyl)uracil (2), the new ethers formed were 5-fluoro-5-(trifluoromethyl)-6-methoxypyrimidine-2,4-dione (8), 5-fluoro-5-(trifluoromethyl)-6-(trifluoroethoxy)pyrimidine-2,4-dione (9), and 5-fluoro-5-(trifluoromethyl)-6-(1H,1H- pentafluoropropoxy)pyrimidine-2,4-dione (10). With 5-chlorouracil (3), the new ethers 5-chloro-5-fluoro-6-methoxypyrimidine-2,4-dione (11), 5-chloro-5-fluoro-6-(trifluoroethoxy)pyrimidine-2,4-dione (12), and 5-chloro-5-fluoro-6-(1H,1H-pentafluoropropoxy)pyrimidine-2,4-dione (13) were obtained. With 5-fluorouracil (4), the new ethers 5,5-difluoro-6-methoxypyrimidine-2,4-dione (14), 5,5-difluoro-6-(trifluoroethoxy)pyrimidine-2,4-dione (15) and 5,5 difluoro-6-(1H,1H-pentafluoropropoxy)pyrimidine-2,4-dione (16) were found. By reaction of 5-nitrouracil (5), the new ethers 5-nitro-5-fluoro-6 methoxypyrimidine-2,4-dione (17), 5-nitro-5-fluoro-6-(trifluoroethoxy)pyrimidine-2,4-dione (18), and 5-nitro-5-fluoro-6-(1H,1H-pentafluoropropoxy)pyrimidine-2,4-dione (19) were obtained. Each of the new compounds was characterized by using IR, 19F and 1H NMR, and mass spectroscopy, and elemental analysis. A single-crystal X-ray diffraction study of 8 was helpful in confirming compound structure.     

Direct SNAr amination of fluorinated imidazo[4,5-c]pyridine nucleosides: efficient syntheses of 3-fluoro-3-deazaadenosine analogs

This paper describes the ready preparation of 3,6-difluoro-3-deazapurine (4,7-difluoroimidazo[4,5-c]pyridine). This novel base was glycosylated under mild conditions using three different ribose sugar analogs. 3,6-Difluoro-3-deazapurine ribonucleoside analogs underwent direct S_NAr amination reactions with liquid ammonia to give 3-fluoro-3-deazaadenosine analogs in excellent yield; in contrast, 6-chloro-3-fluoro-3-deazapurine nucleosides were inert under similar reaction conditions.     

Bis(acylsilanes) and trifluoromethyltrimethylsilane: a useful system for the synthesis of cyclic 2,2-difluoro-3-trialkylsilyl-1,3-ketols and cyclic 2-fluoro-1,3-diketones(1).

We report a one-pot reaction of bis(acylsilanes) with trifluoromethyltrimethylsilane (TFMTMS) leading to a new family of 2,2-difluoro-3-trialkylsilylketols 4. These compounds were submitted to a facile and effective defluorosilylation. The overall process constitutes a new synthesis of cyclic six- and seven-membered 2-fluoro-1,3-diketones 8, with regiospecific introduction of fluorine. The keto-enol equilibrium of cyclic 1,3-diketones and the mechanism of the defluorosilylation reaction were also studied.     

Reduction of 4-fluoro-5-(1,1,2,2-tetrafluoroethyl)-3H-1,2-dithiole-3-thione with sodium sulfide: Synthesis of fluoro-containing sulfur-rich heterocycles

Treatment of 4-fluoro-5-(1,1,2,2-tetrafluoroethyl)-3H-1,2-dithiole-3-thione with 2 equivalents of sodium sulfide gives after acidification 3,4-difluoro-2-mercapto-1,6,6aλ⁴-trithiapentalene, which can be further reduced by sodium sulfide to 3,5-difluoro-4-mercapto-thiopyran-2-thione.