Journal Article•
Synthesis of (â)-Oxycodone
TL;DR: This novel synthetic route to (-)-oxycodone, a semisynthetic opioid analgesic, features a palladium-catalyzed direct intramolecular arylation of an aryl bromide, oxidative dearomatization of a dihydrophenanthrenol, formation of a benzylic quaternary carbon by an intramolescular Michael addition of a malonate moiety.
About: This article is published in Organic Letters.The article was published on 2014-01-01 and is currently open access. It has received 27 citations till now.
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TL;DR: This Review concisely compiles information on 71 medical substances that are synthesized by reductive amination according to the principle of action and a general synthetic scheme is provided for each compound.
Abstract: Reductive amination plays a paramount role in pharmaceutical and medicinal chemistry owing to its synthetic merits and the ubiquitous presence of amines among biologically active compounds. It is one of the key approaches to C-N bond construction due to its operational easiness and a wide toolbox of protocols. Recent studies show that at least a quarter of C-N bond-forming reactions in the pharmaceutical industry are performed via reductive amination. This Review concisely compiles information on 71 medical substances that are synthesized by reductive amination. Compounds are grouped according to the principle of action, which includes drugs affecting the central nervous system, drugs affecting the cardiovascular system, anticancer drugs, antibiotics, antiviral and antifungal medicines, drugs affecting the urinary system, drugs affecting the respiratory system, antidiabetic medications, drugs affecting the gastrointestinal tract, and drugs regulating metabolic processes. A general synthetic scheme is provided for each compound, and the description is focused on reductive amination steps. The green chemistry metric of reaction mass efficiency was calculated for all reactions.
303 citations
TL;DR: A comprehensive overview of top prescribed drugs containing nitrogen heterocycles, describing their pharmacological properties, medical applications and their selected synthetic pathways is presented in this paper, where the reported examples are actually limited to current top selling drugs and their synthetic information has been extracted from both scientific journals and the wider patent literature.
Abstract: Heteroatoms as well as heterocyclic scaffolds are frequently present as the common cores in a plethora of active pharmaceuticals natural products. Statistically, more than 85% of all biologically active compounds are heterocycles or comprise a heterocycle and most frequently, nitrogen heterocycles as a backbone in their complex structures. These facts disclose and emphasize the vital role of heterocycles in modern drug design and drug discovery. In this review, we try to present a comprehensive overview of top prescribed drugs containing nitrogen heterocycles, describing their pharmacological properties, medical applications and their selected synthetic pathways. It is worth mentioning that the reported examples are actually limited to current top selling drugs, being or containing N-heterocycles and their synthetic information has been extracted from both scientific journals and the wider patent literature.
271 citations
TL;DR: This review will focus on recent employment of 1,2-Carbon atom rearrangement in the total synthesis of natural products, highlighting the exceptional utility of such synthetic methodologies in the construction of intricate carbocycles, heterocycles or structurally complex motifs from synthetically more accessible precursors.
Abstract: 1,2-Carbon atom rearrangement has been broadly applied as a guiding strategy in complex molecule assembly. As it entails the carbon–carbon or carbon–heteroatom bond migration between two vicinal atoms, this type of reaction is capable of generating structural complexity through a molecular skeletal reorganization. This review will focus on recent employment of this strategy in the total synthesis of natural products, highlighting the exceptional utility of such synthetic methodologies in the construction of intricate carbocycles, heterocycles or structurally complex motifs from synthetically more accessible precursors.
112 citations
TL;DR: In this article, male and female Sprague-Dawley rats were implanted with jugular vein catheters and trained to self-administer oxycodone (0.03 milligram/kg/infusion) under fixed ratio 1 (FR1), FR2, and FR5 schedules of reinforcement followed by a dose-response study to assess sensitivity to the reinforcing effects of the drug.
Abstract: Oxycodone is one of the most widely prescribed painkillers in the USA. However, its use is complicated by high abuse potential. As sex differences have been described in drug addiction, the present study tested for sex differences in intravenous oxycodone self-administration in rats. Male and female Sprague-Dawley rats were implanted with jugular vein catheters and trained to self-administer oxycodone (0.03 mg/kg/infusion) under fixed ratio 1 (FR1), FR2, and FR5 schedules of reinforcement followed by a dose-response study to assess sensitivity to the reinforcing effects of oxycodone. In separate rats, sucrose pellet self-administration was assessed under an FR1 schedule to determine whether sex differences in oxycodone self-administration could be generalized across reinforcers. In separate rats, oxycodone distribution to plasma and brain was measured after intravenous drug delivery. In the first 3 trials under an FR1 schedule of reinforcement, male rats self-administered more oxycodone than females. In contrast, females self-administered more sucrose pellets. Under FR2 and FR5 schedules, no significant sex differences in oxycodone intake were observed, although female rats had significantly more inactive lever presses. Male and female rats showed similar inverted U-shaped dose-effect functions, with females tending to self-administer more oxycodone than males at higher doses. No significant sex differences were observed in plasma or brain oxycodone levels, suggesting that sex differences in oxycodone self-administration behavior were not due to pharmacokinetics. Our results suggest subtle sex differences in oxycodone self-administration, which may influence the abuse liability of oxycodone and have ramifications for prescription opioid addiction treatment.
79 citations
Cites background from "Synthesis of (â)-Oxycodone"
...Conclusion Our results suggest subtle sex differences in oxycodone self-administration, which may influence the abuse liability of oxycodone and have ramifications for prescription opioid addiction treatment....
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...Oxycodone is a semisynthetic opioid analgesic derived from thebaine, a minor constituent of opium (Kimishima et al. 2014)....
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TL;DR: In this paper, the authors used NBO hybridization coefficients for carbon atoms in the involved C-H bonds to simplify the parametric scaling of Fermi contacts to achieve fast and accurate prediction of proton-proton spin-spin coupling constants (SSCC) in 1H NMR.
Abstract: We previously developed a reliable method for multiparametric scaling of Fermi contacts to achieve fast and accurate prediction of proton–proton spin–spin coupling constants (SSCC) in 1H NMR. We now report that utilization of NBO hybridization coefficients for carbon atoms in the involved C–H bonds allows for a significant simplification of this parametric scheme, requiring only four general types of SSCCs: geminal, vicinal, 1,3-, and long-range constants. The method is optimized for inexpensive B3LYP/6-31G(d) molecular geometries. A new DU8 basis set, based on a training set of 475 experimental spin–spin coupling constants, is developed for hydrogen and common non-hydrogen atoms (Li, B, C, N, O, F, Si, P, S, Cl, Se, Br, I) to calculate Fermi contacts. On a test set of 919 SSCCs from a diverse collection of natural products and complex synthetic molecules the method gave excellent accuracy of 0.29 Hz (rmsd) with the maximum unsigned error not exceeding 1 Hz.
74 citations
References
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TL;DR: Conversion de cyclohexanol, octanol, alcool benzylique and des alcools dimethoxy-and trimethoxy benzyliques par oxydation avec le triacetoxy-1, 1, 1 benzoiodoxole-1 2 one-3
Abstract: Conversion de cyclohexanol, octanol, alcool benzylique et des alcools dimethoxy- et trimethoxy benzyliques par oxydation avec le triacetoxy-1,1,1 benzoiodoxole-1,2 one-3
2,732 citations
TL;DR: Experimental and computational evidence indicates that the pivalate anion is a key component in the palladium-pivalic acid cocatalyst system, that it lowers the energy of C-H bond cleavage and acts as a catalytic proton shuttle from benzene to the stoichiometric carbonate base.
Abstract: A palladium−pivalic acid cocatalyst system has been developed that exhibits unprecedented reactivity in direct arylation This reactivity is illustrated with the first examples of high yielding direct metalation−arylation reactions of a completely unactivated arene, benzene Experimental and computational evidence indicates that the pivalate anion is a key component in the palladation/C−H bond breaking event, that it lowers the energy of C−H bond cleavage and acts as a catalytic proton shuttle from benzene to the stoichiometric carbonate base Eight examples of substituted aryl bromides are included which undergo direct arylation with benzene in 55−85% yield
839 citations
TL;DR: Controlled-release oxycodone is an effective analgesic for the management of steady pain, paroxysmal spontaneous pain, and allodynia, which frequently characterize postherpetic neuralgia.
Abstract: Objective Although opioid analgesics are used in the management of neuropathic pain syndromes, evidence of their efficacy remains to be established. We evaluated the clinical efficacy and safety of oxycodone in neuropathic pain using postherpetic neuralgia as a model. Methods Patients with postherpetic neuralgia of at least moderate intensity were randomized to controlled-release oxycodone 10 mg or placebo every 12 hours, each for 4 weeks, using a double-blind, crossover design. The dose was increased weekly up to a possible maximum of 30 mg every 12 hours. Pain intensity and pain relief were assessed daily, and steady (ongoing) pain, brief (paroxysmal) pain, skin pain (allo-dynia), and pain relief were recorded at weekly visits. Clinical effectiveness, disability, and treatment preference were also assessed. Results Fifty patients were enrolled and 38 completed the study (16 men, 22 women, age 70± 2 11 years, onset of postherpetic neuralgia 31± 2 29 months, duration of pain 18 ± 5 hours per day). The oxycodone dose during the final week was 45 ±5 17 mg per day. Compared with placebo, oxycodone resulted in pain relief (2.9±2 1.2 versus 1.8 ± 1.1, p = 0.0001) and reductions in steady pain (34 ± 26 versus 55 ± 27 mm, p = 0.0001), allodynia (32 ±2 26 versus 50 ±2 30 mm, p = 0.0004), and paroxysmal spontaneous pain (22 ± 24 versus 42 ± 32 mm, p = 0.0001). Global effectiveness, disability, and masked patient preference all showed superior scores with oxycodone relative to placebo (1.8 ±.11 versus 0.7 ± 1.0, p = 0.0001; 0.3 ± 0.8 versus 0.7 ± 1.0, p = 0.041; 67% versus 11%, p = 0.001, respectively). Conclusions Controlled-release oxycodone is an effective analgesic for the management of steady pain, paroxysmal spontaneous pain, and allodynia, which frequently characterize postherpetic neuralgia.
647 citations
TL;DR: Mechanistic investigations have provided insight into the catalyst's mode of action and show the presence of a kinetically significant C-H bond cleavage in palladium-catalyzed direct arylation of simple arenes, opening the door for the development of other new direct aRYlation processes.
Abstract: A catalyst for the intramolecular direct arylation of a broad range of simple and heterocyclic arenes with aryl iodides, bromides, and chlorides has been developed. These reactions occur in excellent yield and are highly selective. Studies with aryl iodides substrates revealed that catalyst poisoning occurs due to the accumulation of iodide in the reaction media. This can be overcome by the addition of silver salts which also permits these reactions to occur at lower temperature. The utility of the methodology is illustrated by a rapid synthesis of a carbazole natural product and by the synthesis of sterically encumbered tetra-ortho-substituted biaryls via ring-opening reactions of the direct arylation products. Mechanistic investigations have provided insight into the catalyst's mode of action and show the presence of a kinetically significant C-H bond cleavage in palladium-catalyzed direct arylation of simple arenes. Knowledge garnered from these studies has led to the development of new intermolecular arylation reactions with previously inaccessible arenes, opening the door for the development of other new direct arylation processes.
591 citations