RESUMEN
The total synthesis of (+)-10-keto-oxycodone was attained from phenethyl acetate in a stereoselective manner. Absolute stereochemistry was established via enzymatic dihydroxylation of phenethyl acetate with the recombinant strain JM109 (pDTG601A) that furnished the corresponding cis-cyclohexadienediol whose configuration corresponds to the absolute stereochemistry of the ring C of (+)-10-keto-oxycodone. Intramolecular Heck reaction was utilized to establish the quaternary carbon at C-13, along with the dibenzodihydrofuran functionality. The C-14 hydroxyl and C-10 ketone were installed via SmI2-mediated radical cyclization, and oxidation of a benzylic alcohol (obtained from an intermediate nitrate azide), respectively. The synthesis of (+)-10-keto-oxycodone was completed in a total of 14 operations (21 steps) and an overall yield of ~2%. Experimental and spectral data are provided for key intermediates and new compounds.
Asunto(s)
Acetatos/química , Oxicodona/análogos & derivados , Oxicodona/síntesis química , Catálisis , Técnicas de Química Sintética , Estructura Molecular , Oxicodona/química , EstereoisomerismoRESUMEN
Here we report a total synthesis of the pharmacologically significant morphinan alkaloid, oxycodone. The centerpiece of the developed strategy features the first application of the Rovis desymmetrization of peroxyquinol in target-oriented total synthesis to access an optically active phenanthrene framework shared by the morphinans. A Stork-Ueno radical cyclization under photoredox conditions installed the all-carbon quaternary stereocenter, and a late-stage reductive detosylation with concomitant piperidine formation secured the core structure of the target molecule.
Asunto(s)
Oxicodona/síntesis química , Ciclización/efectos de la radiación , Luz , Oxidación-Reducción , EstereoisomerismoRESUMEN
Humankind has used and abused psychoactive drugs for millennia. Formally, a psychoactive drug is any agent that alters cognition and mood. The term "psychotropic drug" is neutral and describes the entire class of substrates, licit and illicit, of interest to governmental drug policy. While these drugs are prescribed for issues ranging from pain management to anxiety, they are also used recreationally. In fact, the current opioid epidemic is the deadliest drug crisis in American history. While the topic is highly politicized with racial, gender, and socioeconomic elements, there is no denying the toll drug mis- and overuse is taking on this country. Overdose, fueled by opioids, is the leading cause of death for Americans under 50 years of age, killing ca. 64,000 people in 2016. From a chemistry standpoint, the question is in what ways, if any, did organic chemists contribute to this problem? In this targeted review, we provide brief historical accounts of the main classes of psychoactive drugs and discuss several foundational total syntheses that ultimately provide the groundwork for producing these molecules in academic, industrial, and clandestine settings.
Asunto(s)
Estimulantes del Sistema Nervioso Central/síntesis química , Alucinógenos/síntesis química , Alcaloides Opiáceos/síntesis química , Psicotrópicos/síntesis química , Anfetaminas/síntesis química , Anfetaminas/química , Anfetaminas/historia , Benzodiazepinas/síntesis química , Benzodiazepinas/química , Benzodiazepinas/historia , Estimulantes del Sistema Nervioso Central/química , Estimulantes del Sistema Nervioso Central/historia , Cocaína/síntesis química , Cocaína/química , Cocaína/historia , Cocaína Crack/síntesis química , Cocaína Crack/química , Cocaína Crack/historia , Industria Farmacéutica , Sobredosis de Droga/epidemiología , Tolerancia a Medicamentos , Epidemias , Alucinógenos/química , Alucinógenos/historia , Historia del Siglo XIX , Historia del Siglo XX , Historia del Siglo XXI , Historia Antigua , Humanos , N-Metil-3,4-metilenodioxianfetamina/síntesis química , N-Metil-3,4-metilenodioxianfetamina/química , N-Metil-3,4-metilenodioxianfetamina/historia , Alcaloides Opiáceos/química , Alcaloides Opiáceos/historia , Opio/historia , Oxicodona/síntesis química , Oxicodona/química , Oxicodona/historia , Psicotrópicos/química , Psicotrópicos/historia , Trastornos Relacionados con Sustancias/epidemiología , Drogas Sintéticas/síntesis química , Drogas Sintéticas/química , Drogas Sintéticas/historia , Estados Unidos/epidemiologíaRESUMEN
BACKGROUND: The development of abuse deterrent formulations is one strategy for reducing prescription opioid misuse and abuse. A putative abuse deterrent formulation of oxycodone extended release (OxyContin®) was introduced in 2010. Early reports demonstrated reduced abuse and diversion, however, an analysis of social media found 32 feasible methods to circumvent the abuse deterrent mechanism. We measured trends of diversion, abuse and street price of OxyContin to assess the durability of the initial reduction in abuse. METHODS: Data from the Poison Center Program, Drug Diversion Program, Opioid Treatment Program, Survey of Key Informant Patients Program and StreetRx program of the Researched Abuse, Diversion, and Addiction-Related Surveillance (RADARS®) System were used. The average quarterly rates of abuse and diversion for OxyContin were compared from before reformulation to the rate in second quarter 2015. Rates were adjusted for population using US Census data and drug availability. RESULTS: OxyContin abuse and diversion declined significantly each quarter after reformulation and persisted for 5 years. The rate of abuse of other opioid analgesics increased initially and then decreased, but to lesser extent than OxyContin. Abuse through both oral and non-oral routes of self-administration declined following the reformulation. The geometric mean difference in the street price of reformulated OxyContin was 36% lower than the reformulated product in the year after reformulation. DISCUSSION: Despite methods to circumvent the abuse deterrent mechanism, abuse and diversion of OxyContin decreased promptly following the introduction of a crush- and solubility- resistant formulation and continued to decrease over the subsequent 5 years.
Asunto(s)
Analgésicos Opioides/síntesis química , Trastornos Relacionados con Opioides/prevención & control , Oxicodona/síntesis química , Desvío de Medicamentos bajo Prescripción/tendencias , Mal Uso de Medicamentos de Venta con Receta/tendencias , Analgésicos Opioides/provisión & distribución , Química Farmacéutica/métodos , Preparaciones de Acción Retardada , Composición de Medicamentos , Femenino , Humanos , Masculino , Trastornos Relacionados con Opioides/etiología , Oxicodona/provisión & distribución , Desvío de Medicamentos bajo Prescripción/estadística & datos numéricos , Mal Uso de Medicamentos de Venta con Receta/prevención & control , Honorarios por Prescripción de Medicamentos , Medios de Comunicación Sociales , Encuestas y Cuestionarios , Estados UnidosAsunto(s)
Analgésicos Opioides/química , Química Farmacéutica/métodos , Trastornos Relacionados con Opioides/prevención & control , Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/efectos adversos , Analgésicos Opioides/síntesis química , Química Farmacéutica/tendencias , Combinación de Medicamentos , Sobredosis de Droga/epidemiología , Sobredosis de Droga/prevención & control , Consumidores de Drogas/psicología , Consumidores de Drogas/estadística & datos numéricos , Humanos , Morfina/administración & dosificación , Morfina/efectos adversos , Morfina/síntesis química , Morfina/química , Naltrexona/administración & dosificación , Naltrexona/efectos adversos , Naltrexona/síntesis química , Naltrexona/química , Trastornos Relacionados con Opioides/economía , Oxicodona/administración & dosificación , Oxicodona/efectos adversos , Oxicodona/síntesis química , Oxicodona/química , Profármacos/administración & dosificación , Profármacos/síntesis química , Profármacos/químicaRESUMEN
Our 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 intramolecular Michael addition of a malonate moiety, and construction of the morphinan skeleton via a Hofmann rearrangement/lactamization cascade.
Asunto(s)
Analgésicos Opioides/síntesis química , Oxicodona/síntesis química , Paladio/química , Analgésicos Opioides/química , Analgésicos Opioides/farmacología , Catálisis , Hidrocarburos Bromados/química , Estructura Molecular , Oxicodona/química , Oxicodona/farmacología , EstereoisomerismoRESUMEN
The title compound, (5R,9R,13S,14S,17R)-14-hydroxy-3-methoxy-17-methyl-4,5-epoxymorphinan-6-one N-oxide, C(18)H(21)NO(5), has been prepared in a diastereomerically pure form by the reaction of oxycodone with 3-chloroperbenzoic acid and subsequent crystallization of the product from chloroform. The crystal packing shows that the molecule exhibits intramolecular O-H···O [D···A = 2.482 (2) Å] hydrogen bonding. In addition, there are weak intermolecular C-H...O interactions which, along with van der Waals forces, stabilize the structure. The new chiral center at the 17-position is demonstrated to be R.
Asunto(s)
Clorobenzoatos/química , Oxicodona/química , Oxicodona/síntesis química , Cristalografía por Rayos X , Enlace de Hidrógeno , Estructura MolecularRESUMEN
The photooxidation of thebaine (3) with a sun lamp affords two main products: hydrodibenzofuran 10 (major) and benzofuran 11 (minor). The latter compound becomes predominant if a Hg lamp is used instead of a sun lamp. The formation of 10 proceeds via an endoperoxide intermediate that undergoes oxidation at the nitrogen atom. Protection of the nitrogen either by protonation or quaternization prevents its oxidation and thus the photooxidation of 3 in acid media constitutes a one-pot procedure for the preparation of 14-hydroxycodeinone 35. Photooxidation of the thebaine ammonium salt 31 allows the isolation in good yields of the corresponding to thebaine endoperoxide 32. The selective protection and reduction of the keto, aldehyde, and olefinic groups of hydrodibenzofuran 10 allowed the preparation of several diol and keto alcohol derivatives. This is the first report on the use of photooxidation to functionalize thebaine at C(6) and C(14) and also the first on the isolation of opioid endoperoxides.