New designer drug 2,5-dimethoxy-4-ethylthio-beta-phenethylamine (2C-T-2): studies on its metabolism and toxicological detection in rat urine using gas chromatography/mass spectrometry

Studies are described on the metabolism and the toxicological analysis of the phenethylamine-derived designer drug 2,5-dimethoxy-4-ethylthio-beta-phenethylamine (2C-T-2) in rat urine using gas chromatography/mass spectrometry (GC/MS) after enzymatic cleavage of conjugates, liquid-liquid extraction and derivatization. The structures of 14 metabolites were assigned tentatively by detailed interpretation of their mass spectra. Identification of these metabolites indicated that 2C-T-2 was metabolized by sulfoxidation followed by N-acetylation and either hydroxylation of the S-ethyl side chain or demethylation of one methoxy group, O-demethylation of the parent compound followed by N-acetylation and sulfoxidation, deamination followed by reduction to the corresponding alcohol followed by partial glucuronidation and/or sulfation or by oxidation to the corresponding acid followed either by partial glucuronidation or by degradation to the corresponding benzoic acid derivative followed by partial glucuronidation. Furthermore, 2C-T-2 was metabolized by N-acetylation of the parent compound followed either by O-demethylation and sulfoxidation or by S-dealkylation, S-methylation and sulfoxidation. The authors' systematic toxicological analysis (STA) procedure using full-scan GC/MS after acid hydrolysis, liquid-liquid extraction microwave-assisted acetylation allowed the detection of an intake of a dose of 2C-T-2 in rat urine, which corresponds to a common drug users' dose. Assuming similar metabolism, the described STA procedure should be suitable for proof of an intake of 2C-T-2 in human urine.     

Synthesis of Some New Pyrazole,Pyrimidine, Pyridazine,and Their Fused Derivatives from 3‐Oxo‐3,N‐diphenylpropionamide

The title compounds were obtained from the reactions of 3‐oxo‐3,N‐diphenylpropionamide 3 with dimethylformamide dimethylacetal followed by hydrazine to afford the pyrazole 7 , condensation with benzaldehyde followed by cyclocondensation with guanidine to afford the pyrimidine derivative 13 , condensation with active methylenes followed by azo coupling of the products followed by cyclization to afford the pyridazines 17a , 17b . The pyridazinone 17b was explored for the synthesis of some novel pyridazine‐fused heterocyclic compounds 19 , 21 , 24a , 24b , 24c , and 26 . All structures were proved via their elemental analyses and spectral data.     

Novel Pyrrolo[2,3-d]pyrimidine Ring forming Methodology

A short, succinct route to biologically active and medicinally important pyrrolo[2,3-d]pyrimidines has been developed starting from readily available acyclic aldehydes. A very efficienttwo step sequence involving a Knoevenagel condensation followed by copper mediated 1,4-conjugate of vinyl magnesium bromide sets up the acyclic precursor. Then, guanidine cyclization followed by a palliduim catalyzed amination reaction or ozonolytic cleavage of the vinyl substituent followed by guanidine cyclization and intramolecular imine formation complete the synthesis.     

Characterization of UV-curable Poly(ethylene glycol)Diacrylate Based Hydrogels

Poly(ethylene glycol) diacrylate/polyvinyl alcohol(PEGDA/PVA) hydrogels were prepared from PEGDA and PVA as precurors by means of single UV radiation(UV ra.), UV radiation followed by high energy electron beam irradiation(Irra.), UV radiation followed by freeze-thawing(FT) or UV ra. and Irra. followed by FT, respectively. 2-Hydroxy-1-[4-(hydroxyethoxy)phenyl]-2-methyl-1-propanone(Irgacure 2959) was used as a photoinitiator. The effects of the various methods on the swelling and mechanical properties of the hydrogels were investigated. The results show that hydrogels made by UV ra. plus high energy electron beam irradiation followed by FT showed a higher crosslinking density and a larger tensile strength than those made by the other methods.     

(Star PS)-block-(Linear PI)-block-(Star PS) Triblock Copolymers – Thermoplastic Elastomers with Complex Branched Architectures

Polystyrene-block-polyisoprene-block-polystyrene triblock copolymers were synthesized with star-shaped branching in the polystyrene phase. The block copolymers were formed through sequential anionic polymerization by first synthesizing linear polystyrene, followed by star coupling using 4-(chlorodimethylsilyl)styrene, then the polymerization of isoprene, followed by difunctional coupling with dichlorodimethylsilane. The polymerization was followed by gel permeation chromatography and the resulting copolymers were characterized by ¹H NMR spectroscopy to examine the polyisoprene microstructure.     

Synthesis of 3,4-Dihydro-2-methyl-3-oxo-N-aryl-2H-[1]benzothieno[3,2-e1,2-thiazine-4-carboxamide 1,1-Dioxides

A novel synthesis of the title compounds, representing a new heterocyclic ring system, is described. Chlorosulphonation of 3-methylbenzo[b]thiophene followed by reaction with methylamine gave sulfonamide, 4 . Lithiation of 4 , followed by quenching with carbon dioxide yielded acetic acid, 5 . Cyclodehydration of 5 to benzothienothiazine 6 followed by reaction with aryl isocyanates afforded the desired benzothieno[3,2-e]-1,2-thiazine-4-carboxamides 1a-f.     

Identification of circulatory and excretory metabolites of meisoindigo in rat plasma,urine and feces by high‐performance liquid chromatography coupled with positive electrospray ionization tandem mass spectrometry

Meisoindigo has been a routine therapeutic agent in the clinical treatment of chronic myelogenous leukemia in China since the 1980s. However, information relevant to in vivo metabolism of meisoindigo is absent so far. In this study, in vivo circulatory metabolites of meisoindigo in rat plasma, as well as excretory metabolites in rat urine and feces, were identified by liquid chromatography/tandem mass spectrometry (LC/MS/MS). Integration of multiple reaction monitoring with conventional metabolic profiling methodology was adopted to enable a more sensitive detection of in vivo metabolites. By comparing with the MS/MS spectra and retention times of the in vitro reduced metabolites, the major metabolites in rat plasma were proposed to form from 3,3′ double bond reduction, whereas the minor metabolites were formed from reduction followed by N‐demethylation, and reduction followed by phenyl mono‐oxidation. The major metabolites in the rat urine were proposed to form from reduction followed by phenyl mono‐oxidation, and its glucuronide conjugation and sulfate conjugation, whereas the minor metabolites were formed from 3,3′ double bond reduction, N‐demethylation, reduction followed by N‐demethylation, phenyl di‐oxidation, phenyl mono‐oxidation and its glucuronide conjugation and sulfate conjugation. The major metabolites in the rat feces were proposed to form from reduction followed by phenyl mono‐oxidation, whereas the minor metabolites were formed from reduction followed by N‐demethylation, and reduction followed by phenyl di‐oxidation. The phase I metabolic pathways showed a significant in vitro–in vivo correlation in rat. Copyright © 2010 John Wiley & Sons, Ltd.     

Synthesis of tri- and tetrasubstituted furans catalyzed by trifluoroacetic acid

Substituted 2-hydroxy-3-acetylfurans are synthesized by alkylation of tert-butyl acetoacetate with an alpha-haloketone followed by treatment of the obtained intermediate with trifluoroacetic acid (TFA). A second alkylation of the intermediate followed by treatment with trifluoroacetic acid provides access to disubstituted 2-methylfurans.     

Analysis of C10-C20 hydrocarbons in natural gas by solid phase extraction and CGC

A method is described for the determination of C10-C20 hydrocarbons in natural gas. Enrichment by solid phase extraction on ODS followed by liquid desorption was found to give better results than adsorption on Tenax or charcoal followed by liquid or thermal desorption.     

An efficient asymmetric synthesis of (3S)-3-amino-1-(4-cyanophenyl)-2-oxopyrrolidine hydrochloride salt

Reaction of 4-aminobenzonitrile with 2-bromo-4-chlorobutyryl bromide in the presence of sodium phosphate followed by treatment of the coupled product with sodium hydroxide followed by ammonium hydroxide in acetonitrile yielded the title compound as the racemic (R)-(−)-mandelic acid salt in an overall yield of 64%. The title compound was then obtained with an ee >96% and in 78% yield after a dynamic resolution of the racemic salt in IPA using a catalytic amount of salicylaldehyde followed by salt exchange.     

Solid-phase synthesis of trisubsituted guanidines

The solid-phase library synthesis of trisubstituted guanidines was accomplished. Amines were loaded onto the 4-formyl-3,5-dimethoxyphenoxymethyl linker via reductive amination. Subsequent acylation with Fmoc-4-aminomethylbenzoic acid followed by Fmoc deprotection gave solid-supported primary amines. Alternatively, sulfonylation of resin-bound secondary amines with 4-cyanobenzenesulfonyl chloride followed by borane reduction also gave solid-supported primary amines. Both resins were acylated with isocyanates to furnish solid-supported ureas. Dehydration of ureas with p-toluenesulfonyl chloride in pyridine gave solid-supported carbodiimides. Nucleophilic addition of amines to the carbodiimide bond followed by cleavage off the solid support gave trisubstituted guanidines.     

Synthesis of orthogonally protected (R)- and (S)-2-methylcysteine via an enzymatic desymmeterization and Curtius rearrangement

A synthesis of differentially protected (R)- and (S)-2-methylcysteines is described. Monomethylation of dimethylmalonate followed by alkylation with tert-butylchloromethyl sulfide gave an achiral diester. Desymmeterization by selective hydrolysis of one ester with pig-liver esterase gave the acid in 97% chemical yield and 91% enantiomeric excess. Heating this acid with diphenylphosphoryl azide followed by 4-methoxybenzyl alcohol gave protected (R)-2-methylcysteine. Alternately, the acid and ester groups were interchanged and heated with diphenylphosphoryl azide followed by 4-methoxybenzyl alcohol, giving protected (S)-2-methylcysteine.     

Simple unprecedented conversion of phosphine oxides and sulfides to phosphine boranes using sodium borohydride

A variety of phosphine oxides and sulfides can be efficiently converted directly to the corresponding phosphine boranes using oxalyl chloride followed by sodium borohydride. Optically active P-stereogenic phosphine oxides can be converted stereospecifically to phosphine boranes with inversion of configuration by treatment with Meerwein's salt followed by sodium borohydride.     

A highly stereoselective synthesis of (-)-(ent)-julifloridine from the cyclization of an alanine-derived chloroamine with an acetylenic sulfone

The cyclization of gamma-chloroamine 11, derived from l-alanine, and acetylenic sulfone 12 afforded the dehydropiperidine 19 via conjugate addition followed by intramolecular alkylation of the corresponding sulfone-stabilized anion. An unexpected acid-catalyzed desulfonylation of 19 occurred in one step via desilylation and tautomerization of the enamine moiety to the corresponding aldehyde, followed by elimination of p-toluenesulfinic acid. The highly stereoselective reduction of the resulting unsaturated aldehyde 25 with sodium cyanoborohydride produced piperidine 23 with a diastereomeric ratio of >98:2. (-)-(ent)-Julifloridine (8) was obtained by Swern oxidation of 23, followed by Wittig olefination and hydrogenation/debenzylation.     

A reliable synthesis of 2- and 6-amino-β-cyclodextrin and permethylated-β-cyclodextrin

A new, reliable method for the introduction of an amine group at positions 2 or 6 of β-cyclodextrin and permethyl-β-cyclodextrin is described. It involves selective tosylation followed by azide substitution and almost quantitative reduction with triphenylphosphine followed by hydrolysis of the phosphinimine intermediate.     

An expedient route to Montanine-type Amaryllidaceae alkaloids: total syntheses of (-)-brunsvigine and (-)-manthine

The first total syntheses of (-)-brunsvigine (1) and (-)-manthine (2) were accomplished in 10 and 18 steps, respectively. (-)-Quinic acid was converted to enone 12 in five steps. Iodination of enone 12 followed by stereoselective reduction yielded alpha-iodo allylic alcohol 16. Conversion of alcohol 16 into Weinreb amide 11 followed by anionic cyclization gave bicyclic enone 10. Stereoselective reduction of enone 10 and subsequent protection afforded pivaloate 9. Grignard addition of 8 to 9 and detosylation afforded amine derivative 19. Pictet-Spengler cyclization of 19 with Eschenmoser's salt and subsequent hydrolysis gave enantiomerically pure (-)-brunsvigine (1). For the total synthesis of (-)-manthine (2), the key intermediate 7 was hydrolyzed to diol 21. Conversion of 21 into 22 followed by regioselective cleavage with DIBAL furnished alcohol 25. Alcohol 25 was converted to the corresponding triflate 26, which on treatment with CsOAc and 18-crown-6 gave stereoinverted acetate 27. Hydrolysis of acetate 27 followed by methylation afforded compound 29. Detosylation of 29 afforded amine derivative 30. Pictet-Spengler cyclization of 30 followed by debenzylation gave alcohol 33. Finally, methylation of alcohol 33 afforded (-)-manthine (2).     

Detection of the chemical warfare agents bis-(2-chloroethyl)ethylamine (HN-1) and tris-(2-chloroethyl)amine (HN-3) in air.

This paper describes the method development and validation for detection of the chemical warfare agents HN-1 and HN-3 in air using C8 solid-phase extraction disks followed by liquid desorption and analysis by gas chromatography. The method is contrasted to the standard approach which uses solid sorbent tubes followed by thermal desorption and analysis by gas chromatography.     

A new polymer-supported reagent for the synthesis of beta-lactams in solution

A modified Mukaiyama reagent was prepared on a PS-DVB resin. This reagent was used for the preparation of beta-lactams, using the Staudinger reaction. The products were obtained by generating the ketene from a carboxylic acid under sonication with the resin followed by reaction with the imine. Excess of the imine was removed by reduction followed by acid scavenging.     

The synthesis of sterically demanding amino acid-derived cyclic phosphonamides

The preparation and utilization of C(2)-symmetric 1,4-diamines in the synthesis of amino acid-derived cyclic phosphonamides 1-3 are described. The 1,4-diamines are synthesized via three methods: (i) amino acid/fumaryl chloride coupling followed by amide reduction, (ii) amino acid/1,4-diamine coupling followed by amide reduction, and (iii) a template-supported ring-closing metathesis/hydrolysis sequence. The pseudo C(2)-symmetric cyclic phosphonamides 1-3 are prepared by condensation of the C(2)-symmetric 1,4-diamines to P(III) centers, followed by oxidation.     

Synthesis of Two Natural Furan‐Cyclized Diarylheptanoids via 2‐Furaldehyde

Two natural diarylheptanoids, 2‐benzyl‐5‐(2‐phenylethyl)furan ( 1 ) and 2‐methoxy‐4‐{[5‐(2‐phenylethyl)furan‐2‐yl]methyl}phenol ( 2 ), were synthesized starting from 2‐furaldehyde. A Wittig reaction of 2‐furaldehyde with benzyltriphenylphosphonium bromide followed by reduction of the alkene C?C bond with Mg gave 2‐(2‐phenylethyl)furan ( 5 ). Lithiation of 5 with BuLi at ?78° followed by alkylation with benzyl bromide gave natural product 1 . In another approach, Friedel? Crafts acylation of compound 5 with benzoyl chloride followed by deoxygenation of the C?O group afforded 1 . The natural product 2 was also synthesized by acylation of 5 with 4‐acetoxy‐3‐methoxybenzoyl chloride ( 16 ) followed by deoxygenation and deacetylation.