Synthesis of 9-[(2-hydroxy-1-phosphonylethoxy)ethyl]guanine, 1-[(2-hydroxy-1-phosphonylethoxy)ethyl]cytosine and 9-[(2-hydroxy-1-phosphonylethoxy)ethyl] adenine

The acyclic nucleoside phosphonate analogues, 9-[(2-hydroxy-1-phosphonylethoxy)ethyl]guanine 6 , 1-[(2-hydroxy-1-phosphonylethoxy)ethyl]cytosine 7 and 9-[(2-hydroxy-1-phosphonylethoxy)ethyl]adenine 8 , have been prepared by the coupling of a tosylate of the phosphonate side chain 12 with a purine or pyrimidine base followed by deprotection of the blocking groups.     

Unexpected chelation interaction for 2-hydroxy-2-(1-oxy-pyridin-2-yl)-N,N-diphenyl acetamide with La(III)

The lanthanide coordination chemistry of the new ligand 2-hydroxy-2-(1-oxy-pyridin-2-yl)-N,N-diphenyl acetamide (5) has been examined. X-ray crystal structure determinations for the free ligand 5 and for one complex, [La(5)₆] (NO₃)₃·7H₂O, have been completed and the latter reveals an unexpected bidentate chelation mode for 5 that involves the amide carbonyl oxygen atom and the 2-hydroxy oxygen atom of each ligand. The six bidentate ligands generate an icosohedral inner coordination sphere. The N-oxide oxygen atom of each ligand also hydrogen bonds with a 2-hydroxyl hydrogen atom in a neighboring ligand molecule in the same molecular unit.     

Syntheses of 1,4-benzothiazepines and 1,4-benzoxazepines via cyclizations of 1-[2-arylthio(oxy)ethyl]-5-benzotriazolyl-2-pyrrolidinones and 3-benzotriazolyl-2-[2-arylthio(oxy)ethyl]-1-isoindolinones

1-[2-Arylthio(oxy)ethyl]-5-benzotriazolyl-2-pyrrolidinones 6a-e, 12 and 3-benzotriazolyl-2-[2-arylthio(oxy)ethyl]-1-isoindolinones 9a-f, 14 are readily available from reactions of benzotriazole (4), 2-(arylsulfanyl)ethylamines 3, or 2-phenoxyethylamine (11) with 2,5-dimethoxy-2,5-dihydrofuran (5) or 2-formylbenzoic acid (8). Lewis acid mediated cyclizations of 6 and 9 produced novel 1,4-benzothiazepines 7a-e and 10a-f, respectively. Cyclizations of 12 and 14 gave 1,4-benzoxazepines 13 and 15, respectively.     

Synthesis and optical properties of new chalcones containing 4-[bis(2-hydroxyethyl)amino]phenyl fragment

New chalcones with 4-[bis(2-hydroxyethyl)amino] phenyl fragment were obtained from 4-[bis(2-acetoxyethyl) amino]- benzaldehyde by the Claisen–Schmidt reaction. From their UV-VIS absorption and emission spectra, optical band gap values were calculated based on the Stokes shifts as well as the molar absorption coefficients and fluorescence quantum yields were estimated. The dependence of the absorption and emission maxima on solvent polarity and pH was evaluated.     

Synthesis of ethyl 2-[(1-aryl-1H-1,2,4-triazol-3-yl)oxy]propionates and related derivatives

Alkylation of 1-aryl-1H-1,2,4-triazol-3-ols with ethyl 2-bromopropionate under basic conditions resulted in the formation of 2-[(1-aryl-1H-1,2,4-triazol-3-yl)oxy]propionic acid, ethyl esters. No N-alkylated products were detected. Similar alkylation of 2-oxo-5-phenyl-1,3,4-thiazole and the corresponding 1,3,4-oxadiazole gave only N-alkylated derivatives. With 4-hydroxy-6-phenylpyrimidine and 2-oxo-4-phenylthiazole, both O- and N-alkylation occurred. Structure assignments were based on ir and ¹³C nmr spectral data.     

Efficient synthesis of achiral seco-cyclopropylbenz[2,3-e]indoline analogues: [4-amino-2-(5,6,7-trimethoxyindole-2-carboxamido)naphthalen-1-yl]ethyl chloride and [4-hydroxy-2-(5,6,7-trimethoxyindole-2-carboxamido)naphthalen-1-yl]ethyl chloride

Achiral seco-aminocyclopropylbenz[2,3-e]indoline and seco-hydroxycyclopropylbenz[2,3-e]indoline (seco-CBI) analogues of the duocarmycins and CC-1065, e.g., 7 and 8, are potent anticancer agents. This paper describes significantly improved synthetic strategies for preparing these compounds. Starting from Martius acid (9), the new strategy gave a 13-fold increase in the overall yield of 7, and the use of di-tert-butyl malonate was economically beneficial. For compound 8, the new strategy employed an Emmons-Horner reaction, followed by a Stobbe condensation, and the overall yield was improved 15-fold.     

Synthesis and in-vitro-antibacterial activity of [5-(furan-2-yl)-phenyl]-4,5-carbothioamide-pyrazolines

Cyclization of various different alkoxy [1-[2-(alkoxy)phenyl]-5-(furan-2-yl)-prop-2-en-1-one] chalcone with thiosemicarbazide in the presence of NaOH in ethanol afforded a series of novel 1-N-substituted cyclized pyrazoline analogues [5-(furan-2-yl)-3-[2-(alkoxy) phenyl]-4,5-dihydro-1H-pyrazole-1-carbothioamide 2a–2d. The structures of these compounds were elucidated by IR, ¹H NMR, ¹³C NMR, Fab mass spectrometry and their purities were confirmed by elemental analyses. In vitro antibacterial activity of these compounds were evaluated by the disk diffusion assay and then the minimum inhibitory concentration (MIC) strain of two Gram-positive and two Gram-negative bacteria like Aeromonas hydrophila, Yersinia enterocolitica, Listeria monocytogenes, and Staphylococcus aureus, among all the compounds, alkoxy [5-(furan-2-yl)-2-(benzyloxy)phenyl]-4,5-dihydro-1H-pyrazole-1-carbothioamide 2b and 5-(furan-2-yl)-1-[2-(naphthalen-2-ylmethoxy) phenyl]-4,5-dihydro-1H-pyrazole-1-carbothioamide 2d showed the most promising antibacterial agent when compared to gentamicin and tetracycline.     

Synthesis of 5-Alkyl-1,3-bis[2-hydroxy-3-(6-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-3-yl)propyl]-6-methyl-1,2,3,4-tetrahydropyrimidine-2,4-diones

6-Methyluracil sodium salt reacts with 1,3-bis(3-chloro-2-hydroxypropyl)-6-methyluracils in DMF, yielding products of alkylation at the nitrogen atom in position 3 of the uracil ring.     

Synthesis of 1-[2-(1H-Indol-3-yl)ethyl]-4-acetyl-3-hydroxy-5-phenyl-1H-pyrrol-2(5H)-ones

Russian Journal of General Chemistry - 1-[2-(1H-indol-3-yl)ethyl]-4-acetyl-3-hydroxy-5-phenyl-1H-pyrrole-2(5H)-ones were synthesized by the short heating of a mixture of tryptamine, aromatic...     

Discovery of a novel and potent human and rat beta3-adrenergic receptor agonist, [3-[(2R)-[[(2R)-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-1H-indol-7-yloxy]acetic acid

In search for potent and selective beta3-adrenergic receptor (beta3-AR) agonists as potential drugs for the treatment of type II diabetes and obesity, a novel series of 1-(3-chlorophenyl)-2-aminoethanol derivatives were prepared and evaluated for their biological activity at human beta1-, beta2-, and beta3-ARs and rat beta3-AR expressed in Chinese hamster ovary (CHO) cells. Replacement of the right-hand side (RHS, benzene ring) in the 'first generation' beta3-AR agonists BRL 37344 and CL 316243 with a 1H-indole ring gave compound 31 with unique pharmacological properties among beta3-AR agonists. Initial in vitro assays showed that 31 possesses modest rat and human beta3-ARs agonistic activity. Introduction of various substituent into the indole nucleus of 31 afforded a number of compounds with good beta3-ARs agonistic activity. In particular, 90 having a carboxylic acid functionality at the 7-position of the indole nucleus showed the most potent human beta3-AR agonistic activity. Finally, optical resolution of 90 led to the identification of the most promising compound, [3-[(2R)-[[(2R)-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-1H-indol-7-yloxy]acetic acid (96, AJ-9677). This compound exhibited potent human beta3-AR agonistic activity (EC50=0.062 nM, IA=116%) with 210- and 103-fold selectivity over human beta2-AR and beta1-AR, respectively. Compound 96 also exhibited potent rat beta3-AR agonistic activity (EC50=0.016 nM, IA=110%). Moreover, repeated oral administration of 96 inhibited body weight gain and significantly decreased glucose, insulin, free fatty acid, and triglyceride concentrations in plasma in KK-Ay/Ta mice. On the basis of this pharmacological profile, 96 entered clinical development as a drug for the treatment of type II diabetes and obesity.     

Alternative Synthesis of 5-(1H-Pyrazol-4-yl)-2-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazin-3-yl}phenol

A scalable and environmentally benign route to the free base of branaplam, a small molecule splicing modulator, was identified and developed. This alternative approach circumvented the inherent risk of dioxin formation associated with ortho-halo phenol derivatives present in the previous route. A Friedel–Crafts approach provided a reliable access to the key intermediate, subsequently followed by a Suzuki–Miyaura cross-coupling. Multiple process aspects of the synthetic approach were evaluated, and a robust process for its large-scale synthesis was developed and successfully demonstrated.     

Synthesis of substituted 1-[2-(adamantan-1-yl)ethyl]piperidines

Quaternary 1-[2-(adamantan-1-yl)ethyl]pyridinium bromides were reduced with sodium tetrahydridoborate in ethanol, and hydroarylation of the resulting 1-[2-(adamantan-1-yl)ethyl]-1,2,3,6-tetrahydropyridines with benzene in trifluoromethanesulfonic acid afforded phenylpiperidines with preferentially equatorial orientation of the phenyl substituent.     

The synthesis of several novel triazine ring hydrolysis products of n-[[(4-methoxy-6-methyl-1,3,5-triazin-2-yl)amino]carbonyl]-2-(3,3,3-trifluoropropyl)benzenesulfonamide

The syntheses of four hydrolysis products isolated from environmental studies on the title compound are reported. Spectral comparison of these synthetic standards with study isolates provided proof for sulfonyl urea intact triazine ring hydrolysis.     

Synthesis and Bioactivity of 5-Aryl-4-acyl-3-hydroxy-1-[2-(imidazolyl-3-yl)ethyl]3-pyrroline-2-ones

Russian Journal of General Chemistry - 5-Aryl-4-acyl-3-hydroxy-1-[2-(imidazolyl-3-yl)ethyl]-3-pyrroline-2-ones were synthesized by three-component reaction of methyl dioxobutanoates with aromatic...     

A practical synthesis of ethyl (R)- and (S)-2-hydroxy-4-phenylbutanoate and d-homophenylalanine ethyl ester hydrochloride from l-malic acid

With the readily available l-malic acid as starting material, both enantiomers of ethyl 2-hydroxyl-4-phenylbutanoates and d-homophenylalanine ethyl ester hydrochloride were prepared conveniently in excellent optical purity and 64, 53 and 49% overall yield, respectively.     

（E）-1-[4-（2-hydroxy-5-methoxybenzylideneamino）-phenyl]ethanone and （E）-1-[4-（2-hydroxy-4-methoxybenzylideneamino） phenyl]ethanone：X-ray and DFT-calculated structures

The isomeric structures of(E)-1-[4-(2-hydroxy-5-methoxybenzylideneamino)-phenyl] ethanone(I) and(E)-1-[4-(2-hydroxy-4-methoxybenzylideneamino) phenyl]ethanone(Ⅱ) ,both C16H15NO3,have been determined using X-ray diffraction techniques and characterized by IR,and their molecular structures have also been optimized at the B3LYP/6-31G(d,p) level using density functional theory(DFT) . The energetic behaviors of the title compounds in solvent media have been examined using B3LYP method with the 6-31G(d,p) basis set by applying the polarizable continuum model(PCM) . The total energies of the title compounds decrease with the increasing polarity of the solvent. In addition,DFT calculations of the title compounds' molecular electrostatic potentials(MEP) were performed at the B3LYP/6-31G(d,p) level of theory. X-ray study shows that the title compounds both have strong intramolecular O-H…N hydrogen bonds. The molecules of Ⅰ are linked into a one-dimensional framework structure by C-H…π interactions,while in Ⅱ,intermolecular π···π interactions result in the formation of infinite chains running along the [010].     

An unusual zinc-promoted decomposition of a bis(2-{pyrid-2-yl}ethyl)amine derivative

The complex [ZnBr(2)L(1)] (L(1) = ferrocenylmethyl-bis[2-{pyrid-2-yl}ethyl]amine) contains bidentate L(1) by crystallography and NMR spectroscopy and decomposes during recrystallization from CH(2)Cl(2)/pentane via both C-N bond cleavage and formation steps. Other [MBr(2)L(1)] (M = Co, Ni, Cu) compounds do not undergo this reaction and contain L(1) bound in the more usual tridentate coordination mode.