Palladium‐Catalyzed 2‐Phenylethenylation of Codeine: 8‐[(1E)‐2‐Phenylethenyl]codeinone Dimethyl Ketal as the Unexpected ‘Masked’ Diene for the Preparation of 19‐Substituted Diels–Alder Adducts of Thebaine

In a search for starting materials for the preparation of 7,8‐fused morphine alkaloid derivatives, 8‐[(1E‐2‐phenylethenyl]codeinone dimethyl ketal ( 4 ) and 8‐[(1E‐2‐phenylethenyl]codeine ( 5 ) were prepared. These dienes were used as substrates in the Diels–Alder reactions. Compound 5 formed the ‘normal’ adduct 12 with N‐phenylmaleimide, while compound 4 behaved in reactions with dienophiles as the ‘masked’ diene 11 , a 8‐[(1E)‐2‐phenylethenyl]‐substituted thebaine, yielding the corresponding 19‐substituted 6,14‐endo‐etheno‐6,7,8,14‐tetrahydrothebaines. Specifically, reaction of 4 with methyl vinyl ketone gave rise to 19‐[(1E)‐phenylethenyl]thevinone ( 14 ) whose structure was elucidated by an X‐ray diffraction analysis. The thebaine derivative 11 was also prepared from 4 .     

Preparation and characterization of a codeine responsive electrode

Summary The behaviour of codeine reineckate and codeine tetraphenylborate membrane electrodes has been observed with a respectiveNernstian response of 58 and 56 mV/decade for 9.3×10^–5–1.3×10^–3 M codeine sulfate solutions. The workingpH ranges were 5–8 and 4–8, respectively. The selectivity towards sugars, amines, amino acids, cations, and some pharmaceutical compounds was found to be satisfactory. The isothermal temperature coefficient was 0.0014 V/°C. The electrodes were applied successfully for the determination of codeine in some pharmaceutical dosage forms with a relative standard deviation range of 0.16–0.30% and an average recovery of 98.6±0.6%.

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Herstellung und Charakterisierung einer codeinselektiven Elektrode

Zusammenfassung Das Verhalten von Codeinreineckat- und Codeintetraphenylboratmembranelektroden in 9.3×10^–5–1.3×10^–3 M Codeinsulfatlösungen wurde untersucht (Nernstscher Response: 58 bzw. 56 mV/Dekade). Der verwendetepH-Bereich für die beiden Elektroden war 5–8 bzw. 4–8. Ihre Selektivität gegenüber Zuckern, Aminen, Aminosäuren, Kationen und einigen pharmazeutisch aktiven Verbindungen ist zufriedenstellend. Der isotherme Temperaturkoeffizient beträgt 0.0014V/°C. Die Elektroden wurden erfolgreich zur Bestimmung von Codein in einigen pharmazeutischen Präparaten eingesetzt (relative Standardabweichung: 0.16–0.30%).

     

Determination of Codeine,Dionin and Thebaine by Differential Pulse Polarography

Abstract

The method proposed for determining codeine, dionin and thebaine by differential pulse polarography is based on the reduction (in ammoniacal medium) of the nitroderivatives obtained by dissolving the substances in concentrated nitric acid. The values of the reduction potentials range between -0.45 and -0.69 V. Morphine and heroine do not interfere in the determination of the mentioned alkaloids.     

纳米二氧化钛-氧化锌/硅溶胶/导电胶复合材料固定联吡啶钌制备磷酸可待因电化学发光传感器

利用硅溶胶的成膜性、纳米二氧化钛-氧化锌大的比表面积及导电胶的粘结性,制备了纳米二氧化钛-氧化锌/硅溶胶/导电胶复合材料,基于此复合材料将联吡啶钌固定到金电极表面,制备了磷酸可待因电化学发光(ECL)传感器.在优化的实验条件(800 V负高压、扫描速度100 mV/s,磷酸盐缓冲体系(pH 6.5))下,可待因浓度在1.0×10-7～1.0×10-4 mol/L范围内与电化学发光强度呈良好的线性关系(r2=0.9973),检出限为2.56×10-8 mol/L (S/N=3).传感器表现出良好的重现性与稳定性,连续平行测定1.28×10-5 mol/L可待因溶液10次,发光强度的相对标准偏差(RSD)为2.7％;室温下保存10天后,发光强度为初始值的92％以上.测定可待因药物实际样品的加标回收率在99.3％ ～ 102.5％之间.     

A Facile Synthesis and Structural Verification of Etorphine and Dihydroetorphine from Codeine

In this study, an improved process for the synthesis of etorphine and dihydroetorphine from codeine with an overall yield of 2.7% and 1.5% respectively is described. The structure of 19‐propylthevinol 7 was verfied by X‐ray structure analysis. This result is promising for synthesizing various morphine‐based drugs.     

Disposable pipette extraction for gas chromatographic determination of codeine, morphine, and 6-monoacetylmorphine in vitreous humor

The availability of a sensitive and rapid analytical method for the determination of opiates, and other substances of forensic interest, in a variety of biological specimens is of utmost importance to forensic laboratories. Solid-phase extraction is very popular in the pre-treatment of forensic samples. Nevertheless, a new approach, disposable pipette extraction (DPX), is gaining increasing interest in sample preparation. DPX has already been applied to the analysis of drugs of abuse in common biological matrices, such as urine and blood, but has not yet been evaluated on alternative biological samples, such as vitreous humor. The objective of this study was to evaluate the applicability of DPX on the analysis of opiates in vitreous humor. The currently developed method is fast, reliable, and easy to perform. The sensitivity, precision, and accuracy are satisfactory. Recoveries obtained are within the range of 72-91%, whereas the sample volume of vitreous humor required is only 100 μL.     

The GC-MS detection and characterization of neopine resulting from opium use and codeine metabolism and its potential as an opiate-product-use marker

Neopine, a minor opium alkaloid and an isomer of codeine (also known as -codeine), has been detected in both the urine of opium users and pharmaceutical codeine users. The characterization of neopine was achieved by comparison of the mass spectra and GC retention times of the trimethylsilyl derivative. The presence of neopine in the urine of pharmaceutical codeine users was attributed to the metabolism of codeine through a double bond migration in ring C, from the 7–8 to the 8–14 position. The potential use of the alkaloid as a confirmation marker of opium and/or pharmaceutical codeine use and the ability to differentiate these from heroin use has been discussed.     

Rapid extraction of codeine and morphine in whole blood for HPLC analysis

Summary A rapid and efficient procedure is described for the extraction and analysis of codeine and morphine in whole blood. Red blood cells were fragmented by sonication and the blood sample extracted by passing through a bonded silica column (Bond Elute^?). The adsorbed drugs were washed and eluted followed by analysis by HPLC. Recoveries were between 95–100% at 5 ng/ml concentrations.     

Synthesis and Characterization of a Novel Diels–Alder Adduct of Codeine

The Diels–Alder reaction was applied to 4,5‐epoxymorphinan opioids to generate a novel aromatic cycloadduct at C(7) C(8): Thermolytic cleavage of sultine 8 produced the reactive diene o‐quinodimethane 7 which condensed favorably with codeine ( 11 ), but not with codeinone ( 9 ) or 14‐hydroxycodeinone ( 10 ), producing the desired tetrahydronaphtho adduct 12 with (7R,8R) geometry (Scheme). The configuration of the cycloadduct was determined by 1D‐ and 2D‐NMR experiments. The unanticipated reactivity of these codeine derivatives was investigated by quantum‐mechanical calculations, and it was determined that steric effects of the 6‐keto and 14‐hydroxy group likely precluded condensation by raising the molecular energy of their respective transition states.     

Rapid simultaneous determination of codeine and morphine in plasma using LC‐ESI‐MS/MS: Application to a clinical pharmacokinetic study

A rapid and sensitive high‐performance LC‐MS/MS method was developed and validated for the simultaneous quantification of codeine and its metabolite morphine in human plasma using donepezil as an internal standard (IS). Following a single liquid‐liquid extraction with ethyl acetate, the analytes were separated using an isocratic mobile phase on a C₁₈ column and analyzed by MS/MS in the selected reaction monitoring mode using the respective [M+H]⁺ ions, mass‐to‐charge ratio (m/z) 300/165 for codeine, m/z 286/165 for morphine and m/z 380/91 for IS. The method exhibited a linear dynamic range of 0.2–100/0.5–250 ng/mL for codeine/morphine in human plasma, respectively. The lower LOQs were 0.2 and 0.5 ng/mL for codeine and its metabolite morphine using 0.5 mL of human plasma. Acceptable precision and accuracy were obtained for concentrations over the standard curve range. A run time of 2.0 min for each sample made it possible to analyze more than 300 human plasma samples per day. The validated LC‐MS/MS method was applied to a pharmacokinetic study in which healthy Chinese volunteers each received a single oral dose of 30 mg codeine phosphate.