Optically active antifungal azoles. XIII. Synthesis of stereoisomers and metabolites of 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-1-tetrazolyl)phenyl]-2-imidazolidinone (TAK-456)

1-[(1R,2R)-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-1-tetrazolyl)phenyl]-2-imidazolidinone [(1R,2R)-1: TAK-456] is a new antifungal agent selected as a candidate for clinical trials. The three stereoisomers [(1S,2R)-, (1S,2S)- and (1R,2S)-1] of this compound were prepared as authentic samples to determine the enantiomeric and diastereomeric purity of TAK-456 as well as to compare their in vitro antifungal activity. Pharmacokinetic studies of TAK-456 using rats identified the existence of metabolites in the liver homogenate. The structures of the major metabolites were assigned as 4-hydroxy-2-imidazolidinone (3) and/or 5-hydroxy-2-imidazolidinone (4), based on HPLC and LC/MS/MS analyses. These hydroxylated compounds, 3 and 4, were prepared by reduction of the corresponding imidazolidinediones, 11 and 12, and confirmed to be identical to the metabolites by HPLC. In vitro antifungal activities of the three stereoisomers and the synthesized metabolites were considerably weaker than TAK-456.     

Optically active antifungal azoles. IX. An alternative synthetic route for 2-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4- triazol-1-yl)propyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]- 3(2H,4H)-1,2,4-triazolone and its analogs

A new route for the synthesis of the optically active antifungal azole TAK-187, 2-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-tria zol-1- yl)propyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-3(2H,4H)-1,2,4 - triazolone, was established. The key synthetic intermediate, 2-[(1R)-2-(2,4-difluorophenyl)-2-oxo-1-methylethyl]-4-[4-(2,2,3,3- tetrafluoropropoxy)phenyl]-3(2H,4H)-1,2,4-triazolone (8), was prepared starting from the esters (11a, b) of (S)-lactic acid in a stereocontrolled manner. This optically active propiophenone derivative 8 was converted to the one carbon-elongated (1R,2S)-diol 7, which was then reacted with 1H-1,2,4-triazole to yield TAK-187. This newly developed route was applied to the synthesis of the analogs (25a, b--28a, b) containing an imidazolone or imidazolidinone nucleus.     

Optically active antifungal azoles. XI. An alternative synthetic route for 1

New routes for the synthesis of the optically active antifungal triazoles 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-1-tetrazolyl)phenyl]-2-imidazolidinone (1b) and the 3-14-(1H-1,2,3-triazol-1-yl)phenyl]-2-imidazolidinone analog (1a) that possess an imidazolidine nucleus were established. The key synthetic intermediates, (2R,3R)-3-(2,2-diethoxvethyl)amino-2-(2,4-difluorophenyl)-1-(1H1,2,4-triazol-1-yl)-2-butanol (8) and (2R,3R)-2-(2,4-difiuorophenyl)-3-(2-h ydroxyethyl)amino-1-(1H-1,2,4-triazol-1-yl)-2-butanol (14), were prepared by the ring-opening reaction of the oxirane (2) with the corresponding 2-substituted ethylamines. The acetal (8) was converted to the imidazolidinones (1a, b) by condensation with the carbamates (10a, b) followed by treatment with hydrochloric acid and subsequent catalytic hydrogenation. The candidate selected for the clinical trials, 1b (TAK-456), was alternatively prepared from the hydroxyethylamino intermediate (14) via two reaction steps: condensation with the carbamate (10b) to the urea (15) and subsequent cyclization to the imidazolidinones. This newly developed synthetic route could be applied to a large scale preparation of 1b.     

Optically active antifungal azoles. VIII. Synthesis and antifungal activity of 1-[(1R,2R)-2-(2,4-difluoro- and 2-fluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]- 3-(4-substituted phenyl)-2(1H,3H)-imidazolones and 2-imidazolidinones

New optically active antifungal azoles, 1-[(1R,2R)-2-(2,4-difluoro- and 2-fluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl ]-3-(4- substituted phenyl)-2(1H,3H)-imidazolones (1,2) and 2-imidazolidinones (3,4), were prepared in a stereocontrolled manner from (1S)-1-[(2R)-2-(2,4- difluoro- and 2-fluorophenyl)-2-oxiranyl]ethanols (15, 16). Compounds 1-4 showed potent antifungal activity against Candida albicans in vitro and in vivo, as well as a broad antifungal spectrum for various fungi in vitro. Furthermore, the imidazolidinones, 3b--e and 4d, e, were found to exert extremely strong growth-inhibitory activity against Aspergillus fumigatus.     

Synthesis of azoles from 3-[(3-hydrazino-3-oxopropyl)anilino]-and 3-[(3-hydrazino-3-oxopropyl)-4-methylanilino]propane hydrazides

Condensation of 3-[(3-hydrazino-3-oxopropyl)anilino]-and 3-[(3-hydrazino-3-oxopropyl)-4-methylanilino]propane hydrazides with 2,4-pentanedione, phenyl isocyanate or phenyl isothiocyanate (with subsequent work up of the semicarbazides obtained by base), and carbon disulfide gave respectively: 1-(3,5-dimethyl-1H-1-pyrazolyl)-3-[3-(3,5-dimethyl-1H-1-pyrazolyl)-3-oxopropylanilino]-1-propanone, 3-(2-{[2-(5-oxo-4-phenyl-4,5-dihydro-1H-1,2,4-triazol-3-yl)ethyl]anilino}ethyl)-4-phenyl-4,5-dihydro-1H-1,2,4-triazol-5-one and its thio analog, and 5-(2-{[2-(2-thioxo-2,3-dihydro-1,3,4-oxadiazol-5-yl)ethyl]anilino}ethyl)-2,3-dihydro-1,3,4-oxadiazole-2(3H)-thione plus their methyl derivatives. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1353–1358, September, 2007.     

Optically active antifungal azoles. X. Synthesis and antifungal activity of N

New optically active antifungal azoles, N-14-(azolyl)phenyl]- and N-14-(azolylmethyl)phenyl]-N'-[(IR,2R)-2(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(IH-1,2,4-triazol-1-yl)propyllazolones (1, 2, 3), were prepared in a stereocontrolled manner. Compounds 1-3 showed strong antifungal activity against Candida albicans in vitro. Among them, the imidazolidinones 3 showed a broad antifungal spectrum in vitro as well as potent in vivo activity against candidiasis and aspergillosis in mice. The imidazolidinones (3i, j, k) having 1H-1,2,3-triazol-1-yl, 2H-2-tetrazolyl and IH-1-tetrazolyl moieties were found to exert strong protective effect against aspergillosis.     

Synthesis and Crystal Structure of 2-(4-Fluoro-2-(4-fluorophenoxy) phenyl)-1-(1H-1,2,4-triazol-l-ylmethyl)-3-methoxy-isopropy Alcohol

The title compound 2-(4-fluoro-2-(4-fluorophenoxy)phenyl)-1-(1H-1,2,4-triazol-z 1-ylmethyl)-3-methoxy-isopropy alcohol has been synthesized by the treatment of 1-[2-(4-fluoro-2-(4-fluorophenoxy)phenyl)-2,3-epoxypropyl]-1H-1,2,4-tdazole with sodium methoxide. It be-longs to orthorhombic, space group P212121, with a=9.7229(19), b=11.516(2), c=16.047(3) A, C18H17F2N3O3, Mr-361.35, V=1796.7(6) A3, Z=4, Dc=1.3359 g/cm3, F(000)=752,μ=0.106 mm-1, the final R=0.0329 and wR=0.0803 for 1821 unique reflections. The dihedral angles made by the triazole ring with two benzene rings are 43.56(3) and 54.78(2)°, respectively. The intermolecular hydrogen bond in the crystal lattice plays an important role in stabilizing the structure.     

Synthesis and Crystal Structure of 2-（4-Fluoro-2-（4-fluorophenoxy）phenyl）-1-（1H- 1,2,4-triazol-1-ylmethyl）-3-methoxy-isopropy Alcohol

The title compound 2-（4-fluoro-2-（4-fluorophenoxy）phenyl）-1-（1H-1,2,4-triazol- 1-ylmethyl）-3-methoxy-isopropy alcohol has been synthesized by the treatment of 1-[2-（4-fluoro- 2-（4-fluorophenoxy）phenyl）-2,3-epoxypropyl]-1H-1,2,4-triazole with sodium methoxide. It belongs to orthorhombic, space group P212121, with a = 9.7229（19）, b = 11.516（2）, c = 16.047（3）A, C18H17F2 N3O3, Mr = 361.35, V = 1796.7（6）A^3, Z = 4, Dc = 1.3359 g/cm^3, F（000） = 752, p = 0.106 mm^-1, the final R = 0.0329 and wR = 0.0803 for 1821 unique reflections. The dihedral angles made by the triazole ring with two benzene rings are 43.56（3） and 54.78（2）°, respectively. The intermolecular hydrogen bond in the crystal lattice plays an important role in stabilizing the structure.     

Synthesis and Crystal Structure of 5-[（1H-1,2,4-Triazol-1- yl）methyl]-4-（2,3-dimethoxybenzylideneamino）-2- 2H-1,2,4-triazole-3（4H）-thione Monohydrate

1 INTRODUCTION Heterocyclic compounds bearing the 1,2,4-tri- azole moiety have attracted considerable attention over the past few decades since they exhibit some fungicidal activities against Puccinia recondite and applications in the field of root-growth regu- lation[1~3]. Meanwhile, 4-amino-5-mercapto-1,2, 4-triazole moiety has great versatility in fusing tovarious ring systems and possesses a broad spec- trum of biological activities[4, 5]. In our con- tinuous work directed towards the…     

Synthesis of 1-methyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazin-4(3H)-one 2,2-dioxide

The reaction of methyl 2-bromo-6-(trifluoromethyl)-3-pyridinecarboxylate ( 1 ) with methanesulfonamide gave methyl 2-[(methylsulfonyl)amino]-6-(trifluoromethyl)-3-pyridine-carboxylate ( 2 ). Alkylation of compound 2 with methyl iodide followed by cyclization of the resulting methyl 2-[methyl(methylsulfonyl)amino]-6-(trifluoromethyl)-3-pyridinecarboxylate ( 3 ) yielded 1-methyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazin-4(3H)-one 2,2-dioxide ( 4 ). The reaction of compound 4 with α,2,4-trichlorotoluene, methyl bromopropionate, methyl iodide, 3-trifluoromethylphenyl isocyanate, phenyl isocyanate and 2,4-dichloro-5-(2-propynyloxy)phenyl isothiocyanate gave, respectively, 4-[(2,4-dichlorophenyl)methoxy]-1-methyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazine 2,2-dioxide ( 5 ), methyl 2-[[1-methyl-2,2-dioxido-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazin-4-yl]oxy]propanoate ( 6 ), 1,3,3-trimethyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazin-4(3H)-one 2,2-dioxide ( 7 ), 4-hydroxy-1-methyl-7-(trifluoromethyl)-N-[3-(trifluoromethyl)phenyl]-1H-pyrido[2,3-c][1,2]thiazine-3-carboxamide 2,2-dioxide ( 8 ), 4-hydroxy-1-methyl-7-(trifluoromethyl)-N-phenyl-1H-pyrido[2,3-c][1,2]thiazine-3-carboxamide 2,2-dioxide ( 9 ) and N-[2,4-dichloro-5-(2-propynyloxy)phenyl]-4-hydroxy-1-methyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2] thiazine-3-carboxamide 2,2-dioxide ( 10 ).     

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.     

1H and 13C NMR study of 5-substituted-4- (arylidene)amino-2,4-dihydro-3H-1,2,4-triazole-3-thiones and 6-aryl-3-(D-gluco- pentitol-1-yl)-7H-1,2,4-triazolo[3,4-b] [1,3,4]thiadiazines

Five 5-substituted-4-(arylidene)amino-2,4-dihydro-3H-1, 2,4-triazole-3-thiones (2a-2e) and seven 6-aryl-3-(D-gluco-pentitol-1-yl)-7H-1,2,4-triazolo[3,4-b][1,3,4]thiadiazines (3a-3g) were synthesized. The complete 1H and 13C NMR chemical shift assignments were analyzed on one- and two-dimensional NMR techniques, including DEPT, NOE-DIF, COSY, gHMBC, and gHSQC.     

Synthesis and study of 3-(pyrimidin-2-yl)amino-1(2)H-1,2,4-triazole derivatives

The previously unknown 3-[4(3H)-pyrimidinon-2-yl]amino-1H-1,2,4-triazoles, which were converted to 3-[4-chloro-, 3-(4-ethoxy)-, 3-(4-hydrazinopyrimidin-2-yl)]-amino-2(4)H-1,2,4-triazoles, were obtained by the reaction of 2-nitroamino-4(3H)-pyrimidinones with 3-amino-5-hexyl-1H-1,2,4-triazole. The condensation of the initial products with -diketones gave 3-[4-(1H-pyrazol-1-yl)pyrimidin-2-yl]-amino-2(4)H-1,2,4-triazoles. The IR, UV, and PMR spectra of the synthesized compounds were studied.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1678–1681, December, 1980.     

Synthesis and antimicrobial activity of some derivatives of (7-hydroxy-2-oxo-2H-chromen-4-yl)-acetic acid hydrazide

(7-Hydroxy-2-oxo-2H-chromen-4-yl)-acetic acid hydrazide (2) was prepared from (7-hydroxy-2-oxo-2H-chromen-4-yl)-acetic acid ethyl ester (1) and 100% hydrazine hydrate. Compound 2, is the key intermediate for the synthesis of several series of new compounds such as Schiff's bases 3a-l, formic acid N'-[2-(7-hydroxy-2-oxo-2H- chromen-4-yl)acetyl] hydrazide (4), acetic acid N'-[2-(7-hydroxy-2-oxo-2H-chromen-4- yl)-acetyl] hydrazide (5), (7-hydroxy-2-oxo-2H-chromen-4-yl)-acetic acid N'-[2-(4- hydroxy-2-oxo-2H-chromen-3-yl)-2-oxoethyl] hydrazide (6), 4-phenyl-1-(7-hydroxy-2- oxo-2H-chromen- 4-acetyl) thiosemicarbazide (7), ethyl 3-{2-[2-(7-hydroxy-2-oxo-2H- chromen-4-yl)-acetyl]hydrazono}butanoate (8), (7-hydroxy-2-oxo-2H-chromen-4-yl)- acetic acid N'-[(4-trifluoromethylphenylimino)methyl] hydrazide (9) and (7-hydroxy-2- oxo-2H-chromen-4-yl)acetic acid N'-[(2,3,4-trifluorophenylimino)-methyl] hydrazide (10). Cyclo- condensation of compound 2 with pentane-2,4-dione gave 4-[2-(3,5- dimethyl-1H-pyrazol-1-yl)-2-oxoethyl]-7-hydroxy-2H-chromen-2-one (11), while with carbon disulfide it afforded 7-hydroxy-4-[(5-mercapto-1,3,4-oxadiazol-2-yl)methyl]-2H- chromen-2-one (12) and with potassium isothiocyanate it gave 7-hydroxy-4-[(5- mercapto-4H-1,2,4-triazol-3-yl)methyl]-2H-chromen-2-one (14). Compound 7 was cyclized to afford 2-(7-hydroxy-2-oxo-2H-chromen-4-yl)-N -(4-oxo-2-phenylimino- thiazolidin-3-yl) acetamide (15).     

Extraction of palladium(II) with (RS)-1-[2-(2,4-dichlorophenyl)pentyl]-1H-1,2,4-triazole from nitric acid solutions

Russian Journal of General Chemistry - Palladium(II) is efficiently extracted with (RS)-1-[2-(2,4-dichlorophenyl)pentyl]-1H-1,2,4-triazole from 0.2–5.0 M HNO3 solutions and can be selectively...     

2-{2-[3-(取代苯基)-3-氧代-2-1,2,4-三唑-1-基-丙基]-苯基}-2-甲氧亚氨基乙酸甲酯和乙酰甲胺类衍生物的合成与杀菌活性研究

以2-甲基苯甲酰甲酸甲酯为起始原料, 通过与甲氧基胺的盐酸盐、甲胺、N-溴代丁二酰亚胺(NBS)和1H-1,2,4-三氮唑钠反应合成了两个系列共计22个2-{2-[3-(取代苯基)-3-氧代-2-1,2,4-三唑-1-基-丙基]-苯基}-2-甲氧亚氨基乙酸甲酯和乙酰甲胺类的衍生物. 经IR, 1H NMR和MS对目标化合物进行了结构表征. 用浓度为 10 µg•mL－1的目标化合物进行了初步离体杀菌活性试验, 结果表明: Ha4, Ha5, Ha7对油菜菌核病有杀菌活性; Ha2, Hb8对小麦纹枯病有杀菌活性; Hb4对蔬菜灰霉病有杀菌活性; Hb4, Hb5对小麦赤霉病和小麦纹枯病均有杀菌活性.     

Synthesis,crystal structure,DFT, molecular docking and antitumor activity of 4-(2-chlorobenzyl)-1-(5-fluoro-2-hydroxy-3-((4-methylpiperidin-1-yl)methyl)phenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one

Research on Chemical Intermediates - In this study, the compound 4-(2-chlorobenzyl)-1-(5-fluoro-2-hydroxy-3-((4-methylpiperidin -1-yl)methyl)phenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one (1)...     

Synthesis of Derivatives of 4-Hydroxy-2-methyl-3-[2-(5-mercapto-1H-1,2,4-triazol-3-yl)ethyl]quinoline and 2-[2-(4-Hydroxy-2-methyl-3-quinolyl)ethyl]-4H-3,1-benzoxazin-4-one

From 4-hydroxy-2-methylquinoline-3-propionyl chlorides hydrochlorides the corresponding thiosemicarbazides were synthesized. The cyclization of the latter both in alkaline and acidic media furnished 4-hydroxy-2-methyl-3-[2-(5-mercapto-1H-1,2,4-triazol-3-yl)ethyl]quinolines. The reaction of the above propionyl chlorides with anthranilic acid afforded the corresponding 2-[2-(4-hydroxy-2-methyl-3-quinolyl)ethyl]-4H-3,1-benzoxazin-4-ones.     

Microwave Assisted Synthesis and Antimicrobial Activity of (E)-1-{2/3/4-[(1-Aryl-1H-1,2,3-triazol-4-yl)methoxy]phenyl}-3-(2-morpholinoquinolin-3-yl)prop-2-en-1-ones

Russian Journal of General Chemistry - A novel series of (E)-1-{2/3/4-[(1-aryl-1H-1,2,3-triazol-4-yl)methoxy]phenyl}-3-(2-morpholinoquinolin-3-yl)prop-2-en-1-ones is synthesised from terminal...     

Cu(II), Ni(II) and Fe(II) complexes with a new substituted [1,2,4] triazole Schiff base derived from 4-amino-5-(thien-2-yl ethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one and 2-hydroxy-1-naphthaldehyde: synthesis,characterization and a comparison of theoretical and experimental results by Ab inito calculation

The synthesis and structural properties of two novel compounds, 4-amino-5-(thien-2-yl ethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one and 4-{[(2-hydroxy-1-naphthyl)methyl-ene]amino}-5-(thien-2-ylmethyl) − 2,4-dihydro-3H-1,2,4-triazol-3-one have been described. 4-Amino-5-(thien-2-ylmethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one was synthesized by treating N-propionyl-2-thien-2-ylethane-hydrazonoate with hydrazine hydrate and the Schiff base was obtained from condensation of substituted amine with 2-hydroxy-1-naphthaldehyde. The Cu(II), Ni(II) and Fe(II) complexes were prepared and characterized by elemental analyses, IR, magnetic moment, UV–Vis, mass spectral data and ¹H- and ¹³C-NMR IR spectra. The Schiff base is coordinated to the metal ions in a tridentate manner with OON donors of the phenolic O, carbonyl O and triazolic N. From the magnetic and UV spectral data, it was found the geometrical structure of Cu(II) and Fe(II) ions are octahedral while Ni(II) ion is square planar.Ab-inito 6-31 G* level calculations provided structural information and IR data that were in good agreement with experimental results.