Hyperpolarization of Pyridyl Fentalogues by Signal Amplification By Reversible Exchange (SABRE)

Fentanyl, also known as ‘jackpot’, is a synthetic opiate that is 50–100 times more potent than morphine. Clandestine laboratories produce analogues of fentanyl, known as fentalogues to circumvent legislation regarding its production. Three pyridyl fentalogues were synthesized and then hyperpolarized by signal amplification by reversible exchange (SABRE) to appraise the forensic potential of the technique. A maximum enhancement of -168-fold at 1.4 T was recorded for the ortho pyridyl ¹H nuclei. Studies of the activation parameters for the three fentalogues revealed that the ratio of ligand loss trans to hydride and hydride loss in the complex [Ir(IMes)(L)₃(H)₂]⁺ (IMes=1,3-bis(2,4,6-trimethylphenyl)imidazole-2-ylidene) ranged from 0.52 to 1.83. The fentalogue possessing the ratio closest to unity produced the largest enhancement subsequent to performing SABRE at earth's magnetic field. It was possible to hyperpolarize a pyridyl fentalogue selectively from a matrix that consisted largely of heroin (97 : 3 heroin:fentalogue) to validate the use of SABRE as a forensic tool.     

Development of a liquid chromatography–isotope dilution mass spectrometry method for quantification of fentanyl in human plasma

Fentanyl is a potent analgesic drug in relieving chronic pain in patients. In this report, we present a simple, reliable and sensitive LC–ID/MS method for the quantification of fentanyl in human plasma. LC‐ID/MS analysis was carried out on a triple quadrupole mass spectrometer operated in positive electrospray ionization multiple‐reaction‐monitoring using the transitions m/z 337.6 → 187.9 for fentanyl and m/z 342.6 → 187.9 for the internal standard (D5‐fentanyl). The calibration curve covered the range 0.02–10 ng/mL. The intra‐ and inter‐batch precision were less than 6.739 and 3.126% for fentanyl and IS, with accuracy from 94.16 to 102.0%. The lower limit of quantification was identifiable and reproducible at 0.02 ng/mL. The validated method offered increased sensitivity and wide linear concentration range. This method was successfully adopted for the evaluation of bioequivalence of two fentanyl transdermal preparations after single dose administration to 20 Chinese pain‐patients. Copyright © 2009 John Wiley & Sons, Ltd.     

芬太尼类化合物与阿片受体相互作用的构象分析

本文用X光衍射结晶学, 计算机辅助构象分析和分子图形学方法, 对芬太尼类μ型阿片受体激动剂中七个典型代表物进行了研究。结果表明, 芬太尼类化合物哌啶环4位丙酰苯胺基位置与生物活性有关。4-取代和顺式3-甲基芬太尼类化合物的晶体结构是一个能量较为合理的体系, 在该体系下的构象有可能是生物活性构象, 即哌啶环1-位苯乙基为伸展构象, 哌啶环4-位扭角τ_4(C_(11)—C_(12)—N_(15)—C_(16))为100°左右时有利于与受体相互作用。并在构象分析和分子图形拟合的基础上, 提出了芬太尼类化合物与阿片受体之间相互作用的结构要求。     

Determination of fentanyl in human breath by solid-phase microextraction and gas chromatography–mass spectrometry

Fentanyl, a kind of intravenous narcotic analgesic, is widely used in clinical anesthesia. As a potential pollution, it was detected in both the air of the cardiothoracic operating room and patients' expiratory circuit. However, whether the fentanyl in patients' expiratory circuit is exhaled by patients is unknown. In this study, breath samples were taken from the expiratory circuits of anesthetic machine linked to the patients who received intravenous fentanyl, a solid-phase microextraction (SPME) coupled with gas chromatography–mass spectrometry (GC–MS) method was developed to detect and quantify fentanyl in breath samples. The parameters influencing adsorption (extraction time, temperature,) and desorption (desorption time) of the analyte on the fiber were investigated and validated for method development. The developed method was proved to be simple, easy, and inexpensive and offer high sensitivity and reproducibility. Linear range was obtained from 0.05 ng/mL to 0.8 ng/mL. The limit of detection was 0.01 ng/mL while an interday precision of less than 12.13% (n = 5) could be achieved. Six patients were involved in this study; results showed presence of fentanyl in the breath of patients who received intravenous fentanyl, and fentanyl concentrations in breath varied from 6.00 to 20.89 pg/mL. In conclusion, fentanyl can be exhaled by patients who received intravenous fentanyl.     

Use of multiple-reaction monitoring ratios for identifying incompletely resolved fentanyl homologs and analogs via ultra-high-pressure liquid chromatography–tandem mass spectrometry

Fentanyl and 16 of its corresponding homologs and analogs were distinguished using ultra-high-pressure liquid chromatography–tandem mass spectrometry (UHPLC–MS/MS). A 1.7 μm Acquity BEH C18 column (150 mm × 2.1 mm) was used with a 1% formic acid (pH 2.2), methanol gradient. Multiple-reaction monitoring (MRM) was employed for MS/MS detection. All selected fentanyl-related compounds, including incompletely resolved compounds, were uniquely identified using retention times and dual MRMs.     

A New Fentanyl-Selective Electrode and Its Application to Pharmaceutical Analysis

Fentanyl is a controlled substance (opiate) listed in the US code of Federal Regulations, Title 21 Part 1308,12(1987). It may be habit forming. Various methods have been developed for its determination,e.g. GC-MS,HPLC,RIA, ELISA,etc. Although potentiometric membrane sensors have been widely used in pharmaceutical analysis,no data has so far been reported for determination of fentanyl by potentiometric membrane sensors.     

Adsorptive stripping voltammetric properties of fentanyl at Hg electrode

Cyclic voltammetry shows that in a supporting electrolyte of NaOH, fentanyl (FENT) has a pair of cathodic and anodic peaks at Hg electrode. The peak potentials, E(pc) and E(pa), are -1.47 and -1.44 V (vs. Ag/AgCl), respectively. Fentanyl can be adsorbed on Hg surface, so the cathodic peak shows adsorptive properties. The adsorptive characteristics of fentanyl are explored in detail with various methods. The adsorbed species is considered to be fentanyl neutral molecule. The method for measuring trace amount of fentanyl by adsorptive stripping voltammetry is established. Under the optimised condition, the detection limit may reach 5 x 10(-8)M with a 10-min preconcentration.     

Use of single-drop microextraction for determination of fentanyl in water samples

Fentanyl is a very potent synthetic narcotic analgesic. Because of its strong sedative properties, it has become an analogue of illicit drugs such as heroin. Its unambiguous detection and identification in environmental samples can be regarded as strong evidence of its illicit preparation. In this paper we report application of single-drop microextraction (SDME) for analysis of water samples spiked with fentanyl. Experimental conditions which affect the performance of SDME, for example the nature of the extracting solvent, sample stirring speed, extraction time, ionic strength, and solution pH, were optimized. The method was found to be linear in the concentration range 0.10–10 ng mL⁻¹. The limits of quantitation and detection of the method were 100 pg mL⁻¹ and <75 pg mL⁻¹, respectively. This technique is superior to other sample-preparation techniques because of the simple experimental set-up, short analysis time, high sensitivity, and minimum use of organic solvent.     

Simultaneous Quantification of 25 Fentanyl Derivatives and Metabolites in Oral Fluid by Means of Microextraction on Packed Sorbent and LC–HRMS/MS Analysis

Fentanyl and fentalogs’ intake as drugs of abuse is experiencing a great increase in recent years. For this reason, there are more and more cases in which it is important to recognize and quantify these molecules and related metabolites in biological matrices. Oral fluid (OF) is often used to find out if a subject has recently used a psychoactive substance and if, therefore, the person is still under the effect of psychotropics. Given its difficulty in handling, good sample preparation and the development of instrumental methods for analysis are essential. In this work, an analytical method is proposed for the simultaneous determination of 25 analytes, including fentanyl, several derivatives and metabolites. OF was collected by means of passive drool; sample pretreatment was developed in order to be fast, simple and possibly semi-automated by exploiting microextraction on packed sorbent (MEPS). The analysis was performed by means of LC–HRMS/MS obtaining good identification and quantification of all the analytes in less than 10 min. The proposed method was fully validated according to the Scientific Working Group for Forensic Toxicology (SWGTOX) international guidelines. Good results were obtained in terms of recoveries, matrix effect and sensitivity, showing that this method could represent a useful tool in forensic toxicology. The presented method was successfully applied to the analysis of proficiency test samples.     

Analysis of fentanyl derivatives by ultra high performance liquid chromatography with diode array ultraviolet and single quadrupole mass spectrometric detection

Fentanyl has become pervasive as a drug of abuse and as adulterant in seized drugs. Positional isomers analyzed by gas chromatography with mass spectrometry can follow the same fragmentation pathway and therefore may not be differentiated. Additionally, electron ionization leads to lack of discernible molecular ion for most fentanyl related compounds. Liquid chromatography may be used as an orthogonal identification technique with diode array ultraviolet and mass spectrometric detection. Here we provide a chromatographic method for the separation of 20 different fentanyl analogues, homologues and positional isomers using ultra high performance liquid chromatography with photodiode array ultraviolet and mass spectrometry detection. Five different columns were investigated utilizing reverse phase chromatography and hydrophilic interaction chromatography. Chromatographic systems were evaluated to determine which could separate the most compounds overall, as well as the most positional isomers. We found that isocratic elution, with a methanol modifier (35%) and formic acid (0.1%) as an additive, on a C18 column at a temperature of 25°C could resolve 10/20 compounds overall and 16/20 positional isomers. Using electrospray ionization, compounds with different masses could easily be distinguished based on their pseudo molecular ions. Ultraviolet detection facilitated differentiation of positional isomers that could not be distinguished by either electron ionization or electrospray ionization mass spectrometry alone.     

Simple and rapid HPLC-UV method using an ultrafine particle octadecylsilane for determination of residual fentanyl in applied Durotep MT transdermal matrix patches and its clinical application

A few complicated and time-consuming methods are available for the determination of residual fentanyl in Durotep MT transdermal patches, however, their application to clinical settings is limited. The aim of this study was to develop a simple and rapid HPLC-UV method using an ultrafine particle octadecylsilane (ODS) for the determination of residual fentanyl in applied Durotep MT transdermal matrix patches. Patch extraction involved sonicating a shredded Durotep MT patch in acetonitrile for 15 min. Fentanyl separation was completed within 2 min using a 2.3-μm particle ODS column (50 × 4.6 mm i.d.) at a flow rate of 1.5 mL/min. No peaks interfering with fentanyl (1.27 min) and papaverine (0.89 min) as an internal standard were observed. The calibration curve for fentanyl was linear over the range of 0.015-9.0 mg as a Durotep MT patch. The intra- and inter-assay precisions and accuracies of each patch were within 5.3% and 103.9-110.5% and within 8.2% and 97.1-104.3%, respectively. The validated method was applied to determine residual fentanyl in Durotep MT patches used in 35 cancer patients. Although the plasma fentanyl concentration was significantly correlated with its measured absorption rate, the measured absorption rate normalized fentanyl concentration showed a large inter-individual variation. The validated simple and rapid HPLC-UV method established in the present study is helpful for evaluating the absorption rate of fentanyl in patients receiving Durotep MT patches.     

New Stereoselective GC Phases: Immobilized Chiral Polysiloxanes with (S)-(–)-t-Leucine Derivatives as Selectors

New chiral polysiloxanes have been prepared as stationary phases for gas chromatography, with (S)-(–)-t-leucine-t-butylamide, (S)-(–)-t-leucine-(S)-(–)-1-phenylethylamide, (S)-(–)-t-leucine-(S)-(–)-1-(α-naphthyl)ethylamide, (S)-(–)-t-leucine-(R)-( + )-1-phenylethylamide, and (S)-(–)-t-leucine-(R)-( + )-1-(α-naphthyl)ethylamide as selectors. Immobilization is achieved by radical-induced cross-linking with 1,3,5,7-tetravinyl-1,3,5,7-tetramethylcyclotetrasiloxane (V₄) and dicumyl peroxide (DCUP) as cross-linking reagents and cured at 170°C. Under these conditions, racemization of (S)-(–)-t-leucine is less than 4.5% (R) for 1 h curing, while for polysiloxanes with the conventional (S)-(–)-valine selectors about 20% of R-enantiomers are formed by racemization. In the presence of 5% (w/w) V₄ and 6% of DCUP with regard to the phases, 70–80% immobilization is achieved; without V₄, the degree of immobilization is about 50% for both the (S)-(–)-t-leucine and (S)-(–)-valine selectors. As the size of the amide moieties of the selectors increases from t-butyl to 1-(α-naphthyl)ethyl, the degree of immobilization decreases. If the curing time is prolonged to 2 h, the extent of racemization increases. The selectivity factors achieved for amino acid enantiomers and similar pharmaceuticals are generally higher than those obtained with the corresponding non-immobilized Chirasil-Val phases.     

Component composition of essential oils from four species of the genus Achillea growing in Kazakhstan

The component composition of the four species Achillea filipendulina, A. sudetica, A. ledebourii, and A. cartilaginea was studied by GC-MS. It was found that the principal components of the essential oil (%) were santolina alcohol (29.1) and borneol (27.9) for A. filipendulina, linalool (11.8) and caryophyllene (8.9) for A. sudetica, germacrene D (20.55) for A. ledebourii, and α-thujone (26.15) and β-thujone (11.76) for A. cartilaginea. The chemical composition of the essential oils from A. sudetica, A. ledebourii, and A. cartilaginea was studied for the first time. __________ Translated from Khimiya Prirodnykh Soedinenii, No. 3, pp. 243–245, May–June, 2006.     

Effect of a plant fortifier (Boundary) on pests and predators of greenhouse vegetable crops

Boundary, a plant fortifier composed of extracts of Sophora flavescens Aiton and brown algae, was tested for control of the leaf miner Tuta absoluta (Meyrick) on tomato (three trials) and of the red spider mite Tetranychus urticae Koch on eggplant (one trial) and for side effects on the whitefly predator Macrolophus pygmaeus (Kambur) (two trials) on tomato and on the thrips predators Orius laevigatus (Fieber) and Amblyseius swirskii Athias-Henriot (two trials) on pepper, all in cold greenhouses in South Italy. Control rates for T. absoluta were moderate (40–70%) in the autumn crop but very high and comparable to those for emamectin benzoate in the spring crops (96–100%). Boundary compared well with abamectin against T. urticae, with near complete control. M. pygmaeus was moderately injured in late autumn, but not in early autumn. At the tested application rate and predator population density Boundary was safe for O. laevigatus and A. swirskii.     

Acridine N-Heterocyclic Carbene Gold(I) Compounds: Tuning from Yellow to Blue Luminescence

The synthesis and the luminescence features of three gold(I)-N-heterocyclic carbene (NHC) complexes are presented to study how the n-alkyl group can influence the luminescence properties in the crystalline state. The mononuclear gold(I)-NHC complexes, [( L¹ )Au(Cl)] ( 1 ), [( L² )Au(Cl)] ( 2 ), and [( L³ )Au(Cl)] ( 3 ) were isolated from the reactions between [(tht)AuCl] and corresponding NHC ligand precursors, [N-(9-acridinyl)-N’-(n-butyl)-imidazolium chloride, ( L¹ .HCl)], [N-(9-acridinyl)-N’-(n-pentyl)-imidazolium chloride, ( L² .HCl)] and [N-(9-acridinyl)-N’-(n-hexyl)-imidazolium chloride, ( L³ .HCl)]. Their single-crystal X-ray analysis reveals the influence of the n-alkyl groups on solid-state packing. A comparison of the luminescence features of 1 – 3 with n-alkyl substituents is explored. The molecules 1 – 3 depicted blue emission in the solution state, while the yellow emission (for 1 ), greenish-yellow emission (for 2 ), and blue emission (for 3 ) in the crystalline phase. This paradigm emission shift arises from n-butyl to n-pentyl and n-hexyl in the crystalline state due to the carbon-carbon rotation of the n-alkyl group, which tends to promote unusual solid packing. Hence n-alkyl group adds a novel emission property in the crystalline state. Density Functional Theory and Time-Dependent Density Functional Theory calculations were carried out for monomeric complex, N-(9-acridinyl)-N’-(n-heptyl)imidazole-2-ylidene gold(I) chloride and dimeric complex, N-(9-acridinyl)-N’-(n-heptyl)imidazole-2-ylidene gold(I) chloride to understand the structural and electronic properties.     

Bimanes (1,5-diazabicyclo[3.3.0]octadienediones): Laser activity in syn-bimanes

The conversion of 3-methyl-4-benzyl-4-chloro-2-pyrazolin-5-one 10b was catalyzed by a mixture of potassium fluoride and alumina to give syn-(methyl, benzyl)bimane 6 (62%) without detectable formation of the anti isomer, A6 [a 1 : 1 mixture (87%) of the isomers 6 and A6 was obtained when the catalyst was potassium carbonate]. In a similar reaction syn-(methyl,carboethoxymethyl)bimane 7 (15%) with the anti isomer A7 (36%) was obtained from 3-methyl-4-carboethoxymethyl-4-chloro-2-pyrazolin-5-one 10c . syn-(Methyl, β-acetoxyethyl)bimane 8 (70%) was obtained from 3-methyl-4-β-acetoxyethyl-4-chloro-2-pyrazolin-5-one 10d (potassium carbonate catalysis) and was converted by hydrolysis to syn-(methyl, β-hydroxyethyl)bimane 9 (40%). Acetyl nitrate (nitric acid in acetic anhydride) converted anti-(amino,hydrogen)bimane 11 to anti-(amino,nitro)bimane 15 (91%), anti-(methyl,hydrogen)bimane 13 to anti-(methyl,nitro)(methyl,hydrogen)bimane 16 (57%), and degraded syn-(methyl,hydrogen)bimane 12 to an intractable mixture. Treatment with trimethyl phosphite converted syn-(bromomethyl,methyl)bimane 17 to syn-(dimethoxyphosphinylmethyl,methyl)bimane 18 (78%) that was further converted to syn-(styryl,methyl)bimane 19 (29%) in a condensation reaction with benzaldehyde. Treatment with acryloyl chloride converted syn-(hydroxymethyl,methyl)bimane 20 to its acrylate ester 21 (22%). Stoichiometric bromination of syn-(methyl,methyl)bimane 1 gave a monobromo derivative that was converted in situ by treatment with potassium acetate to syn-(acetoxymethyl,methyl)(methyl,methyl)bimane 47 . N-Amino-μ-amino-syn-(methylene,methyl)bimane 24 (68%) was obtained from a reaction between the dibromide 17 and hydrazine. Derivatives of the hydrazine 24 included a perchlorate salt and a hydrazone 25 derived from acetone. Dehydrogenation of syn-(tetramethylene)bimane 26 by treatment with dichlorodicyanobenzoquinone (DDQ) gave syn-(benzo,tetramethylene)bimane 27 (58%) and syn-(benzo)bimane 28 (29%). Bromination of the bimane 26 gave a dibromide 29 (92%) that was also converted by treatment with DDQ to syn-(benzo)bimane 28 . Treatment with palladium (10%) on charcoal dehydrogenated 5, 6, 10, 11-tetrahydro-7H,9H-benz [6, 7] indazol [1, 2a]benz[g]indazol-7,9-dione 35 to syn-(α-naphtho)bimane 36 (71%). The bimane 35 was prepared from 1,2,3,4-tetrahydro-1-oxo-2-naphthoate 37 by stepwise treatment with hydrazine to give 1,2,4,5-tetrahydro-3H-benz[g]indazol-3-one 38 , followed by chlorine to give 3a-chloro-2,3a,4,5-tetrahydro-3H-benz[g]indazol-3-one 39 , and base. Dehydrogenation over palladium converted the indazolone 34 to 1H-benz[g] indazol-3-ol 36 . Helicity for the hexacyclic syn-(α-naphtho)bimane 36 was confirmed by an analysis based on molecular modeling. The relative efficiencies (RE) for laser activity in the spectral region 500–530 nm were obtained for 37 syn-bimanes by reference to coumarin 30 (RE 100): RE > 80 for syn-bimanes 3, 5, 18 , and μ-(dicarbomethoxy)methylene-syn-(methylene,methyl)bimane 22 : RE 20–80: for syn-bimanes 1,2,4,20,24,26 , and μ-thia-syn-(methylene,methyl)bimane 50 : and RE 0-20 for 26 syn-bimanes. The bimane dyes tended to be more photostable and more water-soluble than coumarin 30. The diphosphonate 18 in dioxane showed laser activity at 438 nm and in water at 514 nm. Presumably helicity, that was demonstrated by molecular modeling, brought about a low fluorescence intensity for syn-(α-naphtho)bimane 36 , Φ0.1, considerably lower than obtained for syn-(benzo)bimane 28 , Φ0.9.     

Synthesis of (E)- and (Z)-3(5)-(2-hydroxyphenyl)-4-styrylpyrazoles

Abstract  

An efficient synthesis method for the preparation of a series of new (Z)- and (E)-3(5)-(2-hydroxyphenyl)-4-styrylpyrazoles was developed. The reaction of (Z)- and (E)-3-styrylchromones with hydrazine hydrate afforded the corresponding (Z)- and (E)-3(5)-(2-hydroxyphenyl)-4-styrylpyrazoles, except for nitro derivatives, where both (Z)- and (E)-4′-nitro-3-styrylchromones afforded (E)-3(5)-(2-hydroxyphenyl)-4-(4-nitrostyryl)pyrazoles. The reaction mechanism for these transformations is discussed and the stereochemistries of all products were established by NMR experiments.     

Reaction of Early Transition Metal Complexes With Macrocycles III. Synthesis and Structure of 18-Crown-6·l4 (M = Ti,Sn)

Abstract

18-Crown-6 reacts with either TiCl₄ or SnCl₄ in toluene to form an addition complex in which the macrocycle functions as a bidentate ligand. The two compounds are isostructural and belong to the monoclinic space group P2₁/n. For Ti. the cell parameters are a = 10.501(6), b = 18.104(5), c = 10.955(5) Å, β = 109.76(3)°, and D_c = 1.55 g/cm³ for Z = 4; for Sn, a = 10.572(9), b = 18.139(6), c = 11.056(5) Å, β = 109.16(4)°, and D_c = 1.75 g/cm³. Least-squares refinement led to a final R = 0.037 for 1735 observed reflections for the Ti complex, and R = 0.038 for 2940 observed reflections for the Sn derivative. The M-Cl lengths range from 2.221(2)–2.285(2) Å for M = Ti, and from 2.353(2)–2.357(2) Å for M = Sn. The M—O bonds are 2.102(4) and 2.138(4) Å for M = Ti, and 2.212(4) and 2.237(4) Å for M = Sn.