Concise Total Synthesis of (-)-Codeine.

Codeine and morphine are among the few natural products that are used directly as drugs for medical treatment. However, the availability of these is widely dependent on natural resources. Herein, we report an efficient enantioselective seven-step synthesis of (-)-codeine starting from simpler starting materials. The key steps involve microwave-assisted intramolecular cascade double heck cyclization to access the ABCE ring of opium alkaloids with the required stereocenters in one pot. A photoinduced intramolecular hydroamination of carboxamide forms the D ring and completes the pentacyclic core of the morphinans. Following that, an oxidation followed by global reduction leads to the formation of (-)-codeine. Our synthesis relies on simple and classical reactions to address the opium alkaloids and will serve as an efficient route to access the other morphinans.

Binding studies of promethazine and its metabolites with human serum albumin by high-performance affinity chromatography and molecular docking in the presence of codeine.

"Purple Drank", a soft drink containing promethazine (PMZ) and codeine (COD), has gained global popularity for its hallucinogenic effects. Consuming large amounts of this combination can lead to potentially fatal events. The binding of these drugs to plasma proteins can exacerbate the issue by increasing the risk of drug interactions, side effects, and/or toxicity. Herein, the binding affinity to human serum albumin (HSA) of PMZ and its primary metabolites [N-desmethyl promethazine (DMPMZ) and promethazine sulphoxide (PMZSO)], along with COD, was investigated by high-performance affinity chromatography (HPAC) though zonal approach. PMZ and its metabolites exhibited a notable binding affinity for HSA (%b values higher than 80%), while COD exhibited a %b value of 65%. To discern the specific sites of HSA to which these compounds were bound, displacement experiments were performed using warfarin and (S)-ibuprofen as probes for sites I and II, respectively, which revealed that all analytes were bound to both sites. Molecular docking studies corroborated the experimental results, reinforcing the insights gained from the empirical data. The in silico data also suggested that competition between PMZ and its metabolites with COD can occur in both sites of HSA, but mainly in site II. As the target compounds are chiral, the enantioselectivity for HSA binding was also explored, showing that the binding for these compounds was not enantioselective.

Development of a Potential-Modulated Electrochemiluminescence Measurement System for Selective and Sensitive Determination of the Controlled Drug Codeine.

Codeine is a common analgesic drug that is a pro-drug of morphine. It also has a high risk of abuse as a recreational drug because of its extensive distribution as an OTC drug. Therefore, sensitive and selective screening methods for codeine are crucial in forensic analytical chemistry. To date, a commercial analytical kit has not been developed for dedicated codeine determination, and there is a need for an analytical method to quantify codeine in the field. In the present work, potential modulation was combined with electrochemiluminescence (ECL) for sensitive determination of codeine. The potential modulated technique involved applying a signal to electrodes by superimposing an AC potential on the DC potential. When tris(2,2'-bipyridine)ruthenium(II) ([Ru(bpy)3]2+) was used as an ECL emitter, ECL activity was confirmed for codeine. A detailed investigation of the electrochemical reaction mechanism suggested a characteristic ECL reaction mechanism involving electrochemical oxidation of the opioid framework. Besides the usual ECL reaction derived from the amine framework, selective detection of codeine was possible under the measurement conditions, with clear luminescence observed in an acidic solution. The sensitivity of codeine detection by potential modulated-ECL was one order of magnitude higher than that obtained with the conventional potential sweep method. The proposed method was applied to codeine determination in actual prescription medications and OTC drug samples. Codeine was selectively determined from other compounds in medications and showed good linearity with a low detection limit (150 ng mL-1).

Polyoxometalate-Based Frameworks as Adsorbents for Drug of Abuse Extraction from Hair Samples.

The linkage of molecular components into functional heterogeneous framework materials has revolutionized modern materials chemistry. Here, we use this principle to design polyoxometalate-based frameworks as high affinity adsorbents for drugs of abuse, leading to their application in solid-phase extraction analysis. The frameworks are assembled by the reaction of a Keggin-type polyanion, [SiW12O40]4-, with lanthanoids Dy(III), La(III), Nd(III), and Sm(III) and the multidentate linking ligand 1,10-phenanthroline-2,9-dicarboxylic acid (H2PDA). Their reaction leads to the formation of crystalline 1D coordination polymers. Because of the charge mismatch between the lanthanoids (+3) and the dodecasilicotungstate (-4), we observe incorporation of the PDA2- ligands into crystalline materials, leading to four polyoxometalate-based frameworks where Keggin-type heteropolyanions are linked by cationic {Lnn(PDA)n} groups (Ln = Dy (1), La (2), Nd (3), and Sm (4)). Structural analysis of the polyoxometalate-based frameworks suggested that they might be suitable for surface binding of common drugs of abuse via supramolecular interactions. To this end, they were used for the extraction and quantitative determination of four model drugs of abuse (amphetamine, methamphetamine, codeine, and morphine) by using micro-solid-phase extraction (D-µSPE) and high-performance liquid chromatography (HPLC). The method showed wide linear ranges, low limits of detection (0.1-0.3 ng mL-1), high precision, and satisfactory spiked recoveries. Our results demonstrate that polyoxometalate-based frameworks are suitable sorbents in D-µSPE for molecules containing amine functionalities. The modular design of these networks could in the future be used to expand and tune their substrate binding behavior.

A Review of Analytical Methods for Codeine Determination.

Codeine is derived from morphine, an opioid analgesic, and has weaker analgesic and sedative effects than the parent molecule. This weak opioid is commonly used in combination with other drugs for over-the-counter cough relief medication. Due to the psychoactive properties of opioid drugs, the easily obtained codeine often becomes subject to misuse. Codeine misuse has emerged as a concerning public health issue due to its associated adverse effects such as headache, nausea, vomiting, and hemorrhage. Thus, it is very important to develop reliable analytical techniques to detect codeine for both quality control of pharmaceutical formulations and identifying drug misuse in the community. This review aims to provide critical outlooks on analytical methods applicable to the determination of codeine.

Identification of factors influencing tampering of codeine-containing medicines in England: a qualitative study.

BACKGROUND: Tampering of psychoactive medicines presents challenges to regulation and public health. However, little is currently known about what influences the decisions to treat codeine-containing medicines (CCM) with cold water extraction (CWE) from the perspective of individuals employing these techniques. The article identifies factors influencing utilisation of CWE to separate codeine from compounded analgesics, such as paracetamol and ibuprofen, found in CCM. METHODS: Purposive sampling of 27 participants residing in England who took part in a qualitative interview. Of these, 14 individuals (11 males and 3 females) reported tampering of psychoactive medicines, and the relevant transcripts were included in the analyses for the study. Participants were recruited from one addiction treatment service and from an online survey. The mean age of the participants was 31.5 years (range = 18-42 years). Qualitative data analysis followed the processes of iterative categorization (IC). The codes 'harm reduction', 'information sources' and 'changes on the drug markets' were grouped and summarised. The coding of the data was done in a Microsoft® Word document. RESULTS: Two groups of participants were identified in the data analysis: (i) individuals who used CCM (n = 5), and (ii) individuals who used CCM and heroin (n = 9). Participants in both groups used CWE due to concerns of paracetamol overdose from the use of excessive dosages of CCM. For both of them, information obtained from the internet encouraged the use of CWE. Participants using CCM described how the many steps involved in conducting CWE, including sourcing codeine boxes from pharmacies (over the counter), presented a barrier against using CWE. Participants using CCM and heroin explained how reduced availability in the local heroin supply influenced utilisation of CWE techniques to maintain their use of opioids and avoid withdrawal. Withdrawal symptoms and cravings outweighed the concerns about the quality of the extracted codeine mixtures in this participant group, especially the ability of CWE to remove paracetamol and tablet fillers. CONCLUSIONS: Utilisation of CWE of codeine was influenced by several factors including drug market supply, the availability of detailed information on the internet about CWE and restrictions on codeine sourcing in pharmacies. Risks identified with CWE include consumption of unknown doses of paracetamol if the CWE techniques are not used correctly. Attempts at extracting codeine from CCM should be considered in risk assessments of opioid medicines.

Solubility of codeine phosphate in carbitol + 2-propanol mixture at different temperatures.

The solubility profile of codeine phosphate in the carbitol and 2-propanol mixtures at 293.2-313.2 K are determined and correlated with some developed cosolvency models. Moreover, the density values of codeine phosphate saturated solutions are also determined and fitted with the Jouyban-Acree model. The model accuracy is investigated by calculating the mean relative deviations (MRDs%). The thermodynamic parameters of codeine phosphate dissolution in the non-aqueous mixtures of carbitol and 2-propanol are also computed by using van't Hoff and Gibbs equations.

Pharmacological Aspects of Over-the-Counter Opioid Drugs Misuse.

Several over-the-counter (OTC) drugs are known to be misused. Among them are opioids such as codeine, dihydrocodeine, and loperamide. This work elucidates their pharmacology, interactions, safety profiles, and how pharmacology is being manipulated to misuse these common medications, with the aim to expand on the subject outlined by the authors focusing on abuse prevention and prevalence rates. The reviewed literature was identified in several online databases through searches conducted with phrases created by combining the international non-proprietary names of the drugs with terms related to drug misuse. The results show that OTC opioids are misused as an alternative for illicit narcotics, or prescription-only opioids. The potency of codeine and loperamide is strongly dependent on the individual enzymatic activity of CYP2D6 and CYP3A4, as well as P-glycoprotein function. Codeine can also be utilized as a substrate for clandestine syntheses of more potent drugs of abuse, namely desomorphine ("Krokodil"), and morphine. The dangerous methods used to prepare these substances can result in poisoning from toxic chemicals and impurities originating from the synthesis procedure. OTC opioids are generally safe when consumed in accordance with medical guidelines. However, the intake of supratherapeutic amounts of these substances may reveal surprising traits of common medications.

Comparisons of In Vivo and In Vitro Opioid Effects of Newly Synthesized 14-Methoxycodeine-6-O-sulfate and Codeine-6-O-sulfate.

The present work represents the in vitro (potency, affinity, efficacy) and in vivo (antinociception, constipation) opioid pharmacology of the novel compound 14-methoxycodeine-6-O-sulfate (14-OMeC6SU), compared to the reference compounds codeine-6-O-sulfate (C6SU), codeine and morphine. Based on in vitro tests (mouse and rat vas deferens, receptor binding and [35S]GTPγS activation assays), 14-OMeC6SU has µ-opioid receptor-mediated activity, displaying higher affinity, potency and efficacy than the parent compounds. In rats, 14-OMeC6SU showed stronger antinociceptive effect in the tail-flick assay than codeine and was equipotent to morphine, whereas C6SU was less efficacious after subcutaneous (s.c.) administration. Following intracerebroventricular injection, 14-OMeC6SU was more potent than morphine. In the Complete Freund's Adjuvant-induced inflammatory hyperalgesia, 14-OMeC6SU and C6SU in s.c. doses up to 6.1 and 13.2 µmol/kg, respectively, showed peripheral antihyperalgesic effect, because co-administered naloxone methiodide, a peripherally acting opioid receptor antagonist antagonized the measured antihyperalgesia. In addition, s.c. C6SU showed less pronounced inhibitory effect on the gastrointestinal transit than 14-OMeC6SU, codeine and morphine. This study provides first evidence that 14-OMeC6SU is more effective than codeine or C6SU in vitro and in vivo. Furthermore, despite C6SU peripheral antihyperalgesic effects with less gastrointestinal side effects the superiority of 14-OMeC6SU was obvious throughout the present study.

Zwitterionic codeine-derived methacrylate monoliths for enantioselective capillary electrochromatography of chiral acids and chiral bases.

Thiol-ene click reaction of N-acetyl-L-cysteine methyl ester to codeine, followed by reaction with allyl isocyanate and hydrolysis to the corresponding zwitterionic chiral selector and its subsequent bonding to the surface of a methacrylate monolith provided a new chiral capillary column for enantiomer separation of chiral acids and chiral bases. First, the epoxy groups of a poly(glycidyl methacrylate-co-ethylene dimethacrylate) monolith were converted into amine residues, followed by reaction with allylglycidyl ether. In this way, a spacer arm was bonded to the surface before coating and cross-linking poly(3-mercaptopropyl methylsiloxane) (PMPMS) via radical addition (thiol-ene click reaction) to the surface. In order to improve the performance of the monolithic chiral stationary phase, thio ether and residual thiol groups were oxidized to sulfonyl and sulphonate groups, respectively. This novel chiral stationary phase (CSP) was evaluated by capillary electrochromatography (CEC) using two chiral model compounds, namely N-3,5-dinitrobenzoyl-R,S-leucine (retained by anion-exchange mechanism) and mefloquine (by cation-exchange process). The ion-exchange retention mechanism on the CSP was characterized for these two counterionic model solutes by varying the mobile phase composition, including the nature of solvents, the concentration of counter-ions and co-ions, and the acid-to-base ratio. A series of chiral ß-blockers and amino acid derivatives was used to further check the performance of the modified monolith under the optimal conditions. Several enantiomers were baseline resolved with reasonable peak efficiencies (up to 60,000 theoretical plates per meter for the second eluted enantiomer).

The Peripheral Versus Central Antinociception of a Novel Opioid Agonist: Acute Inflammatory Pain in Rats.

Opioid analgesics devoid of central side effects are unmet medical need in the treatment of acute pain (e.g. post-operative pain). Recently, we have reported on 14-O-methylmorphine-6-O-sulfate (14-O-MeM6SU), a novel opioid agonist of high efficacy producing peripheral antinociception in subchronic inflammatory pain in certain doses. The present study focused on the antinociceptive effect of 14-O-MeM6SU compared to morphine in formalin test of an early/acute (Phase I) and late/tonic (Phase II) pain phases. Subcutaneous 14-O-MeM6SU (253-1012 nmol/kg) and morphine (3884-31075 nmol/kg) dose dependently reduced the pain behaviors of both phases. Co-administered naloxone methiodide (NAL-M), a peripherally acting opioid antagonist, abolished the antinociceptive effect of 506 nmol/kg 14-O-MeM6SU. On the other hand, the effects of 14-O-MeM6SU (1012 nmol/kg) and morphine (15538 nmol/kg) were only partially affected by NAL-M, indicating the contribution of CNS to antinociception. Locally injected test compounds into formalin treated paws caused antinociception in both phases. Locally effective doses of test compounds were also injected into contralateral paws. Morphine showed effects in both phases, 14-O-MeM6SU in certain doses failed to produce antinociception in either phase. A NAL-M reversible systemic dose of 14-O-MeM6SU and the lowest systemic effective dose of morphine were evaluated for their sedative effects following isoflurane-induced sleeping (righting reflex). In contrast to morphine, 14-O-MeM6SU in certain antinociceptive doses showed no impact on sleeping time. These data highlight that high efficacy opioids of limited CNS penetration in certain doses mitigate somatic and inflammatory pain by targeting MOR at the periphery.

Linking Aromatic Hydroxy Metabolic Functionalization of Drug Molecules to Structure and Pharmacologic Activity.

Drug functionalization through the formation of hydrophilic groups is the norm in the phase I metabolism of drugs for the modification of drug action. The reactions involved are mainly oxidative, catalyzed mostly by cytochrome P450 (CYP) isoenzymes. The benzene ring, whether phenyl or fused with other rings, is the most common hydrophobic pharmacophoric moiety in drug molecules. On the other hand, the alkoxy group (mainly methoxy) bonded to the benzene ring assumes an important and sometimes essential pharmacophoric status in some drug classes. Upon metabolic oxidation, both moieties, i.e., the benzene ring and the alkoxy group, produce hydroxy groups; the products are arenolic in nature. Through a pharmacokinetic effect, the hydroxy group enhances the water solubility and elimination of the metabolite with the consequent termination of drug action. However, through hydrogen bonding, the hydroxy group may modify the pharmacodynamics of the interaction of the metabolite with the site of parent drug action (i.e., the receptor). Accordingly, the expected pharmacologic outcome will be enhancement, retention, attenuation, or loss of activity of the metabolite relative to the parent drug. All the above issues are presented and discussed in this review using selected members of different classes of drugs with inferences regarding mechanisms, drug design, and drug development.

Six years without pholcodine; Norwegians are significantly less IgE-sensitized and clinically more tolerant to neuromuscular blocking agents.

BACKGROUND: As a strong inducer of IgE antibodies to substituted ammonium ion epitopes (QAI), pholcodine (PHO) is a postulated cause of allergic anaphylaxis to neuromuscular blocking agents (NMBAs). Three years after withdrawal of PHO in Norway, a significant reduction in IgE sensitization and anaphylaxis reporting was seen. OBJECTIVE: Six-year follow-up study on the effects of PHO withdrawal on IgE sensitization and anaphylaxis reporting. METHODS: From 650 acute consecutive reports (2005-2013) to the Norwegian Network for Anaphylaxis under Anaesthesia (NARA), total number of reports on suspected anaphylactic reactions, number of reactions where NMBAs were administered, number of reactions where serum IgE antibodies (≥0.35 kUA /l) to suxamethonium (SUX) and PHO were present at time of reaction and anaphylaxis severity grades were retrieved. In addition, NMBA sales and prevalence of IgE sensitization to PHO and SUX among 'allergics' were monitored. RESULTS: From baseline period P0 (PHO on the market) through the first (P1) and second (P2), three-year periods after withdrawal, significant falls in total reports (P < 0.001) and reports with IgE antibodies to PHO (P = 0.008) and SUX (P = 0.001) at time of reaction were found. Total NMBA sales in P2 were 83% of P0, and SUX and rocuronium (ROC) together made up 86% of sales throughout the study. Five NMBA-related anaphylactic deaths occurred during P0 and P1 and, however, none during P2. Prevalence of IgE sensitization to SUX in 'allergics' fell to 0% at 4 and 5 years after withdrawal. CONCLUSIONS: Six years after PHO withdrawal, the Norwegian population has become significantly less IgE-sensitized and clinically more tolerant to NMBAs.

Drug-Excipient Interactions in the Solid State: The Role of Different Stress Factors.

Understanding properties and mechanisms that govern drug degradation in the solid state is of high importance to ensure drug stability and safety of solid dosage forms. In this study, we attempt to understand drug-excipient interactions in the solid state using both theoretical and experimental approaches. The model active pharmaceutical ingredients (APIs) under study are carvedilol (CAR) and codeine phosphate (COP), which are known to undergo esterification with citric acid (CA) in the solid state. Starting from the crystal structures of two different polymorphs of each compound, we calculated the exposure and accessibility of reactive hydroxyl groups for a number of relevant crystal surfaces, as well as descriptors that could be associated with surface stabilities using molecular simulations. Accelerated degradation experiments at elevated temperature and controlled humidity were conducted to assess the propensity of different solid forms of the model APIs to undergo chemical reactions with anhydrous CA or CA monohydrate. In addition, for CAR, we studied the solid state degradation at varying humidity levels and also under mechano-activation. Regarding the relative degradation propensities, we found that variations in the exposure and accessibility of molecules on the crystal surface play a minor role compared to the impact of molecular mobility due to different levels of moisture. We further studied drug-excipient interactions under mechano-activation (comilling of API and CA) and found that the reaction proceeded even faster than in physical powder mixtures kept at accelerated storage conditions.

The challenge of complex drug use: Associated use of codeine-containing medicines and new psychoactive substances in a European cross-sectional online population.

OBJECTIVE: Misuse of codeine-containing medicines in combination with new psychoactive substances (NPS) is inadequately described. This study characterises codeine consumption amongst NPS users and non-NPS users to provide warning of health issues. METHODS: Online survey conducted between July 2015 and March 2016. RESULTS: Out of 340 respondents, residing in a country in Europe and using codeine recently, 63.8% were female. Mean age: 34.9 years (SD = 12.4). Substance use included NPS (18.5%) and illicit controlled drugs (55.9%). Factors relating to codeine use found to significantly predict NPS use were consuming codeine extracted from combination tablets (OR = 16.79, 95% CI [8.67, 32.51]), obtaining codeine from friends, family, and acquaintances (OR = 3.98, 95% CI [1.82, 8.7]), use of illicit controlled drugs (OR = 34.99, 95% CI [8.39, 145.94]) and use of codeine to experience euphoria (OR = 6.41, 95% CI [3.42, 12.04]). CONCLUSIONS: Amongst NPS users, codeine is less likely to be used daily but more likely to be used for recreational purposes. Smaller populations engaging in high-risk use exist who take multiple drugs in high doses. Combinations of misused codeine and NPS highlight the need for policy to respond to a more complex drug situation.

Offset-compensated and zero-quantum suppressed ROESY provides accurate 1 H-1 H distances in small to medium-sized molecules.

A robust version of the off-resonance ROESY pulse scheme is suggested for the measurement of proton-proton distances or slow chemical exchange in small to medium-sized molecules. The method implements adiabatic ramps to establish a pair of opposite frequency off-resonance spin lock fields - with optionally randomized duration - and adiabatic inversion pulses with simultaneous gradients for efficient zero-quantum suppression. The amended pulse sequence yields pure absorption cross-peaks and works safely for small to medium-sized molecules. The applicability of the method has been demonstrated using small, rigid molecules (strychnine and codeine) and was also applied for a cyclic peptide and a small protein. We found that the pure phase cross-peaks of the new ROESY version are beneficial for distance measurements. The one-dimensional (selective) version of the new method is also powerful for measuring selected pair-wise interactions and distance determination. Copyright © 2016 John Wiley & Sons, Ltd.

Formulation optimization of a drug in adhesive transdermal analgesic patch.

CONTEXT: Conventional pain management approaches have limitations such as gastrointestinal side effects, frequent dosing, and difficulties in swallowing medications. Hence, to overcome these limitations, we developed a transdermal analgesic patch. OBJECTIVE: This study was designed to formulate a drug in adhesive transdermal patch with codeine (CDB) and acetaminophen (APAP) that may potentially treat moderate pain in children. MATERIALS AND METHODS: Three analgesic drugs hydrocodone bitartrate, CDB and APAP were screened by a slide crystallization study using polarized light microscope and their permeation profiles were studied using vertical Franz diffusion cells across porcine ear skin, dermatomed human skin and epidermis for 24 h, and the samples were quantified by high performance liquid chromatography. Patches used for permeation studies were prepared by dissolving sub-saturation concentration of the drug(s) in adhesive (with/without 5% w/w oleic acid [OA]), cast with a film casting knife. RESULTS AND DISCUSSION: Among the three drugs screened, CDB demonstrated the best permeation profile (660.21 µg/cm(2)), and shortest lag time (4.35 ± 0.01 h), and hence was chosen for patch studies. The highest concentration of CDB in the patch at which drug does not crystallize was determined as 40% of its saturation solubility (Cs) and that of APAP was determined as 200% of its Cs. CDB standalone patch delivered 105.48 µg/cm(2) of CDB, while the CDB-APAP combination patch with 5% w/w OA delivered 151.40 µg/cm(2) CDB and 58.12 µg/cm(2) APAP in 24 h. CONCLUSION: Drug-in-adhesive patches using CDB and APAP were developed for infants and children. Addition of OA enhanced solubility and permeation of drugs.

Formulation optimization of a drug in adhesive transdermal analgesic patch.

CONTEXT: Conventional pain management approaches have limitations such as gastrointestinal side effects, frequent dosing, and difficulties in swallowing medications. Hence, to overcome these limitations, we developed a transdermal analgesic patch. OBJECTIVE: This study was designed to formulate a drug in adhesive transdermal patch with codeine (CDB) and acetaminophen (APAP) that may potentially treat moderate pain in children. MATERIALS AND METHODS: Three analgesic drugs hydrocodone bitartrate, CDB and APAP were screened by a slide crystallization study using polarized light microscope and their permeation profiles were studied using vertical Franz diffusion cells across porcine ear skin, dermatomed human skin and epidermis for 24 h, and the samples were quantified by high performance liquid chromatography. Patches used for permeation studies were prepared by dissolving sub-saturation concentration of the drug(s) in adhesive (with/without 5% w/w oleic acid [OA]), cast with a film casting knife. RESULTS AND DISCUSSION: Among the three drugs screened, CDB demonstrated the best permeation profile (660.21 µg/cm2), and shortest lag time (4.35 ± 0.01 h), and hence was chosen for patch studies. The highest concentration of CDB in the patch at which drug does not crystallize was determined as 40% of its saturation solubility (Cs) and that of APAP was determined as 200% of its Cs. CDB standalone patch delivered 105.48 µg/cm2 of CDB, while the CDB-APAP combination patch with 5% w/w OA delivered 151.40 µg/cm2 CDB and 58.12 µg/cm2 APAP in 24 h. CONCLUSION: Drug-in-adhesive patches using CDB and APAP were developed for infants and children. Addition of OA enhanced solubility and permeation of drugs.

Total Synthesis of Codeine.

In this paper, a new strategy towards the synthesis of codeine and morphine is reported. This new approach features a cascade cyclization to construct the dihydrofuran ring, and an intramolecular palladium catalyzed C-H olefination of unactivated aliphatic alkene to install the morphinan ring system.

Economical synthesis of 13C-labeled opiates, cocaine derivatives and selected urinary metabolites by derivatization of the natural products.

The illegal use of opiates and cocaine is a challenge world-wide, but some derivatives are also valuable pharmaceuticals. Reference samples of the active ingredients and their metabolites are needed both for controlling administration in the clinic and to detect drugs of abuse. Especially, (13)C-labeled compounds are useful for identification and quantification purposes by mass spectroscopic techniques, potentially increasing accuracy by minimizing ion alteration/suppression effects. Thus, the synthesis of [acetyl-(13)C4]heroin, [acetyl-(13)C4-methyl-(13)C]heroin, [acetyl-(13)C2-methyl-(13)C]6-acetylmorphine, [N-methyl-(13)C-O-metyl-(13)C]codeine and phenyl-(13)C6-labeled derivatives of cocaine, benzoylecgonine, norcocaine and cocaethylene was undertaken to provide such reference materials. The synthetic work has focused on identifying (13)C atom-efficient routes towards these derivatives. Therefore, the (13)C-labeled opiates and cocaine derivatives were made from the corresponding natural products.