Determination of the site of glucuronidation in an N-(3,5-dichlorophenyl)succinimide metabolite by electrospray ionization tandem mass spectrometry following derivatization to picolinyl esters

Derivatization using 3-pyridylcarbinol coupled with liquid chromatography electrospray ionization tandem mass spectrometry (LC/MS/MS) was used to characterize a novel Phase II metabolite of the nephrotoxic agricultural fungicide, N-(3,5-dichlorophenyl)succinimide (NDPS). A glucuronide conjugate of N-(3,5-dichlorophenyl)-2-hydroxysuccinamic acid (2-NDHSA) was identified in the urine from a rat dosed with [14C]NDPS. However, 2-NDHSA contains an aliphatic hydroxyl group and a carboxylic acid group, both of which are potential sites for glucuronidation. Mass spectrometry alone was unable to distinguish between these possibilities. Since the position of glucuronidation may be important in the mechanism of NDPS-induced nephrotoxicity, chemical derivatization in conjunction with mass spectrometry was used to characterize the glucuronide. The 2-NDHSA glucuronide conjugate was isolated from rat urine, derivatized with 3-pyridylcarbinol, and the derivatized metabolite was then analyzed by LC/MS/MS. Two known NDPS metabolites, 2-NDHSA and N-(3,5-dichlorophenyl)succinamic acid (NDPSA), were also isolated from rat urine and derivatized similarly. 3-Pyridinylcarbinol reacted rapidly with the carboxylic acid groups and formation of the picolinyl esters increased the ionization potential under positive ion conditions. The urinary glucuronide of 2-NDHSA was identified as an alcohol-linked glucuronide by examination of the molecular ions and the collision-induced dissociation (CID) product ion spectra of the derivatized products. When used in combination with mass spectrometry, derivatization of carboxylic acids with 3-pyridylcarbinol provided useful mass fragmentations and is a rapid way to obtain structural information about the position of glucuronidation of NDPS metabolites.     

Diels-Alder reaction of fulvenes with N-(3,5-dichlorophenyl)-maleimide

Summary N-(3,5-Dichlorophenyl)-maleimide reacts smoothly with a variety of substituted fulvenes (1) to give onlyendo adducts (3) independent of the nature of fulvene substituent,Lewis acid catalyst, and reaction solvent and temperature. The structure of theDiels-Alder adduct3f was determined by X-ray crystallography. Semi-empirical quantum methods (AM1) were used to rationalize theendo stereoselectivity.Dedicated to Professor Fritz Sauter on the occasion of his 65^th birthday     

Cyclization of a cysteine conjugate of N-(3,5-Dichlorophenyl)succinimide

N-(3,5-Dichlorophenyl)-2-cysteinylsuccinimide methyl ester hydrochloride ( 5 ) was prepared from N-(3,5-dichlorophenyl)maleimide ( 3 ) and cysteinyl methyl ester hydrochloride. Attempted neutralization of the cysteine conjugate salt with triethylamine resulted in spontaneous cyclization of 5 to form the more stable 2-(N-3,5-dichlorophenylcarbamoylmethyl)-5-carbomethoxy-1,4-thiazine- 3-one ( 6 ). Similar results might be expected in vivo should these metabolites of succinimides be formed.     

Synthesis and Crystal Structure of N-(Biphenyl-2-thiocarbamoyl)-4-(1,3-dichlorophenyl) Carboxamide

The synthesis of the title molecule was achieved by the reaction of 2,4-dichlorobenzoyl chloride with potassium thiocyanate in 1:1 molar ratio in dry acetonitrile to afford the corresponding isothiocyante in situ followed by the treatment with 2-aminobiphenyl. The structure of the target compound was established by elemental analysis, FTIR, 1H, 13 C NMR and mass spectroscopy and unequivocally confirmed by the crystallographic data. The title compound crystallizes in the monoclinic space group P21/n with a = 13.356(2), b = 7.0761(11), c = 20.539(3) , β = 105.723(4)°, V = 1868.5(5) 3 and Z = 4.     

Reaction of N-(2-pyridylmethyl)-3,5-dimethylbenzamide and N-(3-pyridylmethyl)-3,5-dimethylbenzamide N-oxides with acetic anhydride

As a continuation of our work on the reaction of N-pyridylmethyl-3,5-dimethylbenzamide N-oxides with acetic anhydride, we now report a study of the reaction of N-(2-pyridylmethyl)-3,5-dimethylbenzam.de N-oxide ( 5 ) and N-(3-pyridylmethyl)-3,5-dimethylbenzamide N-oxide ( 6 ) with acetic anhydride. Compound 5 gave N,N′-di(3,5.dimethylbenzoyl)-1,2-di(2.pyridyl)ethenediamine ( 7 ) and 3,5-dimethylbenzamtde ( 8 ). Compound 6 afforded three products formulated as 2-acetoxy-3-(3,5-dimethylbenzoylaminomethyl)pyridine ( 12 ), 3-(3,5-dimethylbenzoylaminomethyl)-2-pyridone ( 13 ) and 5-(3,5-dimethylbenzoylaminomethyl)-2-pyridone ( 14 ). Analytical and spectral data are presented which support the structures proposed.     

Regioselectivity in the 1,3-dipolar cycloaddition of nitrile oxides to N-(3,5-dichlorophenyl)itaconimide

Summary The regioselectivity of the nitrile oxide cycloaddition with 3,3-methylene-1-(3,5-dichlorophenyl)-2,5-pyrrolidindione (1) is discussed. Arylnitrile oxides add regioselectively to the carboncarbon double bond of1, giving exclusively spiro-isoxazolines3a–k, whereas acetonitrile oxide gives both adducts3l and4l. AM1 calculations of the reactants and cycloadducts were performed, the regiochemistry of the cycloaddition seems to be controlled by steric effects. Reduction of3a with NaBH₄ in the presence of magnesium perchlorate at –20 °C was regio-and stereoselective to yield the hydroxylactams9a and10a, whereas hydroxymethylisoxazoline14a was obtained in the absence of Mg(ClO₄)₂.Part XXX in the series 1,3-Dipolar Cycloaddition on Heterocycles. Part XXIX [27]     

Synthesis and cyclizations of N-(2,3-, 3,4- and 3,5-dimethylphenyl)-beta-alanines

A series of 1-aryl substituted dihydro-, 5-methyl-dihydro- and 6-methyl-dihydro-2,4(1H,3H)pyrimidinediones and their 2-thio analogues were obtained by reaction of the corresponding beta-alanines or alpha-methyl- and beta-methyl-beta-alanines with urea or potassium thiocyanate. The reaction of N-(2,3- and 3,5-dimethylphenyl)-alpha-methyl-beta-alanines with ethyl acetoacetate gave 1-(2,3- or 3,5-dimethylphenyl)-2,5-dimethyl-1,4,5,6-tetrahydro-4(1H)pyridones. The combined spectral data obtained by (1)H-, (13)C-,(1)H/(13)C (HETCOR) NMR and IR provided useful information about the structure of the products synthesized in this work.     

N-取代苄基-3,5-双苄叉基-哌啶-4-酮的合成及其抗癌活性的测定

以取代苄胺或伯胺为原料,依次经过Michael加成、Dieckmann缩合、水解脱羧和羟醛缩合反应,合成了10种新化合物(8a～8j),目标化合物的结构经1H NMR、IR、MS和元素分析确证。 初步的MTT法生物活性测试表明,目标化合物在100 mg/L浓度下能有效抑制白血病K562细胞、乳腺癌HO8910PM细胞和卵巢癌MDR-MB-231细胞的增殖,具有潜在的抗癌活性。     

Synthesis, spectroscopic and redox properties of the copper(II) complexes of N-(di-methylphenyl)-3,5-Bu2t-salicylaldimines

A series of copper(II) complexes (CuL2x) with new N-di-methylphenyl-3,5-Bu2t-salicylaldimines (L(x)H) were prepared and characterized by IR, UV/vis, 1H NMR, ESR, cyclic voltammetry techniques and chemical oxidation. L(x)H ligands have been found selectively bind to a Cu(II), rather than to Ni(II), Co(II), Mn(II), VO(IV), Zn(II) and Cd(II). ESR examinations of the CuL2x complexes demonstrate that they exist in magnetically diluted mononuclear or coupled triplet-state structures in the solid. The temperature dependent (113-283 K) intensity of the powder ESR spectra for some CuL2x is characteristic of ferromagnetic coupling (J > 0). The reduction potentials of CuL2x in DMSO are sensitive to aniline moieties. Chemical oxidation of CuL2x with (NH4)2[Ce(NO3)6] in CHCl3 and MeCN solutions at 300 K affords gradually disappearance of their ESR signals and dramatic changes in the electronic spectra as well as the appearance of new maximum bands at 530-672 (CHCl3) and 670-700 nm (MeCN), suggesting generation of Cu(II)-phenoxyl radical species.     

N-(2-氨基苯基)-2-喹唑啉酮乙酰胺盐酸盐的合成

本文通过2-溴-N-(2-硝基苯)乙酰胺和取代的喹唑啉酮在NaH催化下发生亲核取代反应,再经过氢化、酸化合成了4个新型常山碱类抗球虫药物-N-(2-氨基苯基)-2-喹唑啉酮乙酰胺盐酸盐(1∶1)。其中,2-溴-N-(2-硝基苯)乙酰胺通过溴乙酰氯与邻硝基苯胺反应制备,取代的喹唑啉酮使用取代的邻氨基苯甲酸与甲酰胺反应合成。所有目标化合物的结构均经1H NMR,IR和HRMS等方法确证。     

6-取代苯并噻唑-2-氨基硫代磷酸二烷基酯的合成

用6-位取代的2-氨基苯并噻唑与三氯硫磷反应,合成了3个苯并噻唑-2-氨基硫代磷酰二氯,并由此合成了9个苯并噻唑-2-氨基硫代磷酸二烷基酯.讨论了苯并噻唑环上取代基对反应的影响和产物中硫代磷酸酯的烷基的空间效应对反应的影响.所合成的部分化合物对人喉鳞状细胞癌(Hep-2)具有一定的抑制能力.     

Synthesis and structural studies of N-(p-toluenesulfonyl)-amino acid 3,5-di-tert-butyl-2-phenolamides

This paper describes the synthesis and structural studies of N-(p-toluenesulfonyl)-amino acid 3,5-di-tert-butyl-2-phenolamides by ¹H, ¹³C, and ¹⁵N. The presence of intra- and intermolecular hydrogen bonds were studied by variable temperature NMR spectroscopy. The molecular structure of two amides in the solid state was determined by X-ray diffraction experiments. The results show that tert-butyl substituents in the phenolic ring have important effects in the nature of hydrogen bonds and conformation of these amides. © 2004 Wiley Periodicals, Inc. Heteroatom Chem 15:114–120, 2004; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.10223     

Synthesis of 1-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-r-benzimidazoles

Reaction of 2,6-di-tert-butyl-1,4-benzoquinone with o-phenylendiamine gives 2,6-di-tert-butyl-1,4-benzoquinone-4-(N-o-aminophenyl)imine which reacts smoothly with heterocyclic, aromatic and aliphatic aldehydes to form (1-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-substituted benzimidazoles.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 483–485, April, 1990.     

Synthesis of N-(2-Benzene-2,2-dichloroethylidene)-4-chlorobenzenesulfonamide and N-(2-Benzene-2,2- dichloroethylidene)-4-methylbenzenesulfonamide

In reaction of N,N-dichloro-4-chlorobenzene- and N,N-dichloro-4-methylbenzenesulfonamides with phenylacetylene were obtained in good yield N-(2-benzene-2,2-dichloroethylidene)arenesulfonamides. The latter undergo nucleophilic addition of water, ethanol, and arenesulfonamides.