508-54-3

An efficient, practical and expeditious method has been developed for the oxidation of thebaine to 14-hydroxycodeinone in excellent yield by employing 20 mol% of V2O5 in the presence of 30% H2O 2 in aqueous medium. The method provides a clean technological process for the preparation of a key drug intermediate, 14-hydroxycodeinone. Georg Thieme Verlag Stuttgart.

Reaction of 14-codeinone (1b) with lithium dimethylcuprate gave a 2:1 isomeric mixture of the corresponding 8α-methyl (2) and 8β-methyl (3) 14-(trimethylsilyl)oxydihydro derivatives.Selective removal of the silyl group from α isomer 2 to give 4, by use of silica gel, allowed resolution of the mixture. 8β-Methyl-14-hydroxydihydrocodeinone (5) was prepared from 3 by cleavage of the silyl ether with n-Bu4NF.Treatment of 14-hydroxycodeinone with Me2CuLi gave a 4:1 mixture of alkylated products 4 and 5.The (tert-butyldimethylsilyl)oxy ether 1c under similar conditions gave exclusively the stable 8α isomer 6.Reaction of trimethylsilyl compound 1b with Et2CuLi or n-Bu2CuLi gave approximately equal amounts of the corresponding 8-alkyl 14-O-silylated isomers.These results are in contrast to previous work with codeinone which demonstrated that lithium organocopper reagents add almost exclusively to the β face of "T-shaped" morphinone derivatives.

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The direct oxidation of codeinone (5) to 14-hydroxycodeinone (6) was investigated with a wide range of oxidizing agents. The majority of reagents gave little or no desired product. Peracids were found to be moderately successful, with dimethyl peracetic acid giving the greatest yield (37%). Metallic oxidants generally gave rise to competing oxidations, however Co(AcO)3 was found to conveniently oxidize 5 to 6 in 51% yield, representing a practical, non-chromatographic procedure for the preparation of 14- hydroxycodeinone.

Codeinone (3) was efficiently and directly converted to 14-hydroxycodeinone (1) by catalytic air oxidation in aqueous solution. A number of simple manganese and copper salts were identified to be effective catalysts, including MnSO4, KMnO4, and CuSO4. An appropriate reducing agent, such as sodium thiosulfate, is required in the reaction mixture presumably for the reduction of a detrimental peroxide intermediate. This discovery allows the more abundant codeine to be employed as the starting material for the synthesis of 14-hydroxylated opiate drugs without recourse to a thebaine-like intermediate. These discoveries were inspired from our study of microbial transformation of codeine to 14-hydroxycodeine by Mycobacterium neoaurum, where we found the actual 14-hydroxylation step is a chemical reaction rather than an enzymatic reaction, as previously believed. Copyright

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The invention belongs to the field of chemical engineering, and particularly relates to a preparation method of oxycodone hydrochloride impurity B. To the method, 14 - hydroxycodeinone is taken as a raw material, impurities Michael are obtained through B addition reaction under basic conditions, the method is simple and easy to operate, and the product purity is high. The yield is high, and can be used for researching the quality of oxycodone hydrochloride.

The present invention relates to a process for preparing a nor-opioid compound wherein an opioid precursor compound is electrochemically N-demethylated. The present invention further relates to a process for preparing an opioid antagonist compound, wherein an opioid precursor compound is electrochemically N-demethylated and the thus obtained nor-opioid compound is alkylated again at its secondary amine functional group.

The most challenging step in the preparation of many opioid antagonists is the selective N-demethylation of a 14-hydroxymorphinan precursor. This process is carried out on a large scale using stoichiometric amounts of hazardous chemicals like cyanogen bromide or chloroformates. We have developed a mild reagent- and catalyst-free procedure for the N-demethylation step based on the anodic oxidation of the tertiary amine. The ensuing intermediates can be readily hydrolyzed to the target nor-opioids in very good yields.

Processes for preparing oxycodone are provided. Said processes encompass a step which is a hydrogenation of an 14-hydroxycodeinone salt in the presence of trifluoroacetic acid and/or a glycol.

Improved processes for making opioid products having low impurity levels including making 14-hydroxycodeinone and 14-hydroxymorphinone from thebaine and oripavine, respectively.

The present invention is directed to a process for the preparation oxymorphone freebase, comprising hydrogenation of 14-hydroxymorphinone in DMF, to yield oxymorphone freebase, preferably oxymorphone freebase of improved appearance, purity and / or yield. The present invention is further directed to oxymorphone freebase with improved impurity profile. The present invention is further directed to an HPLC or UPLC system/method for analysis of opioid compounds.

Thebaine was converted into its iron tricarbonyl complex, which underwent successive N- and O-demethylation with BrCN and BBr3, respectively. Decomplexation of the iron tricarbonyl moiety was accomplished with ammonium cerium(IV) nitrate (CAN) and base-catalyzed hydrolysis furnished nororipavine. When excess CAN was used the methoxydiene unit was converted into its C-14 nitrate that on hydrogenation and further hydrolysis furnished noroxymorphone. Full experimental and spectral data are provided for all key compounds.

Synthetic methods are provided for preparation of oxycodone and salts thereof with an improved impurity profile. Thebaine is converted to 14-hydroxycodeinone sulfate intermediate to minimize a 7,8-dihydro-8,14-dihydroxycodeinone impurity. Efficient methods for conversion of oxycodone base to oxycodone hydrochloride are provided to minimize 14-hydroxycodeinone impurity in the final product.

The present invention provides a process for preparing a saturated 6,14-dihydroxy morphinan. The process comprises contacting an unsaturated 6-O-hydrocarbyl morphinan with hydrogen peroxide and an organic acid to form an unsaturated 6-keto-14-hydroxy morphinan. The unsaturated 6-keto-14-hydroxy morphinan is contacted with a first reducing agent to form an unsaturated 6,14-dihydroxy morphinan, and the unsaturated 6,14-dihydroxy morphinan is contacted with a second reducing agent to form the saturated 6,14-dihydroxy morphinan.

Synthetic methods are provided for preparation of oxycodone and salts thereof with an improved impurity profile. Thebaine is converted to 14-hydroxycodeinone sulfate intermediate to minimize a 7,8-dihydro-8,14-dihydroxycodeinone impurity. Efficient methods for conversion of oxycodone base to oxycodone hydrochloride are provided to minimize 14-hydroxycodeinone impurity in the final product.

Compounds and compositions for use as starting materials or intermediate materials in the preparation of opioids including, e.g., oxycodone base and/or an oxycodone salt; processes for preparing these compounds and compositions; uses of these compounds and compositions in the preparation of APIs and pharmaceutical dosage forms; and uses of said APIs and pharmaceutical dosage forms in the treatment of medical conditions.

In this work, two important opioid antagonists, naltrexone and oxycodone, were prepared from thebaine and were characterized by IR, 1H NMR and 13C NMR spectroscopy. Moreover, computational NMR and IR parameters were obtained using density functional theory (DFT) at B3LYP/6-311++G* * level of theory. Complete NMR and vibrational assignment were carried out using the observed and calculated spectra. The IR frequencies and NMR chemical shifts, determined experimentally, were compared with those obtained theoretically from DFT calculations, showed good agreements. The RMS errors observed between experimental and calculated data for the IR absorptions are 85 and 105 cm-1, for the 1H NMR peaks are 0.87 and 0.17 ppm and for those of 13C NMR are 5.6 and 5.3 ppm, respectively for naltrexone and oxycodone.

Under Polonovski-type conditions, ferrocene has been found to be a convenient and efficient catalyst for the N-demethylation of a number of N-methyl alkaloids such as opiates and tropanes. By judicious choice of solvent, good yields have been obtained for dextromethorphan, codeine methyl ether, and thebaine. The current methodology is also successful for the N-demethylation of morphine, oripavine, and tropane alkaloids, producing the corresponding N-nor compounds in reasonable yields. Key pharmaceutical intermediates such oxycodone and oxymorphone are also readily N-demethylated using this approach.

(Figure Presented) A mild and simple two-step Fe(0)-mediated N-demethylation of a number of tertiary N-methyl alkaloids is described. The tertiary N-methylamine is first oxidized to the corresponding N-oxide, which is isolated as the hydrochloride salt. Subsequent treatment of the N-oxide hydrochloride with iron powder readily provides the N-demethylated amine. Representative substrates include a number of opiate and tropane alkaloids. Key intermediates in the synthesis of semisynthetic 14-hydroxy pharmaceutical opiates such as oxycodone and oxymorphone are also readily N-demethylated using this method.

The present invention is directed to a process for using n-butanol to prepare an oxycodone base compositions having reduced levels of impurities such as 14-hydroxycodeinone and DHDHC.

The present invention is directed to processes for preparing oxycodone base and oxycodone hydrochloride compositions having less than 10 ppm of 14-hydroxycodeinone.

An improved opiate synthesis scheme is provided. An improvement to the oxidation of oripavine and oripavine derivatives comprises the in-situ formation of the peroxacids required to oxidize the oripavine and oripavine derivatives to form an intermediate. An improvement to the reduction of the intermediate to form oxycodone and oxycodone derivatives comprises reduction utilizing a hydrogen transfer reagent. These improvements allow the production of oxycodone and oxycodone derivatives without isolation of the intermediate, providing a one-pot synthesis method.

A method of preparation of Oxycodone of formula (I) by reacting thebaine of formula (II), or its analogue of formula (III), wherein R represents a C2 to C5 alkyl, an alkylaryl, preferably benzyl, methoxybenzyl, or alkyl, with hydrogen peroxide or peroxoacids in the presence of oxalic acid in admixture with acetic or formic acid. From the resulting crystalline precipitate of 14-hydroxycodeinone oxalate, by addition of a base, 14-hydroxycodeinone of formula (IV) is released, which is hydrogenated with hydrogen in the presence of a catalyst to yield Oxycodone (I): Oxycodone is transformed to hydrochloride, which is used as the active ingredient in analgesic formulations.

A process for preparing oxycodone or an oxycodone salt, wherein the oxycodone or oxycodone salt has low levels of impurities (especially 14-hydroxycodeinone) is disclosed. The process comprises the steps of: a) preparing a mixture comprising oxycodone and a solvent and adjusting the pH of the mixture to less than 6; and subsequently b) exposing the mixture to hydrogenation reagents for a period of at least 1 hour.

Oxycodone is manufactured in high yields and with a high purity using a composition including a thebaine component into 14-hydroxycodeinone and then reduction of 14-hydroxycodeinone to oxycodone.

(Chemical Equation Presented) 2-Fluoro-11-hydroxy-N-propylnoraporphine 4 (2-F-11 -OH-NPa) was synthesized from thebaine in 13 steps with an overall yield of 1.35%. The key steps included the Pd-catalyzed 3-dehydroxylation of 14-hydroxymorphine, SN2 substitution of Ts- by F -, and CH3SO2OH-promoted rearrangement of the substituted morphinandiene. The dopamine binding affinity of this compound was also investigated on rat brain membranes, and as expected, this compound displayed high affinity and selectivity at the D2 receptor.

A method for the preparation of oxycodone, and salts thereof, from codeine comprising oxidation of codeine to codeinone, formation of an dienolsilyl ether congener of codeinone in strong amine base, oxidation of the dienolsilyl ether congener using peracetic acid, and hydrogenation of the resulting 14-hydroxycodeinone product.

trans-10-Hydroxythebaine and (8S)-8-hydroxyoxycodone were identified as by-products of thebaine oxidation with hydrogen peroxide in acidic medium. Structures of isolated compounds were determined by spectral methods.

The invention provides processes for the conversion of normorphinone and its derivatives, which can be synthesized from morphine, to the corresponding 14-hydroxynormorphinone and its derivatives including oxycodone, oxymorphone, noroxymorphone and naltrexone. Noroxymorphone is a key intermediate for the production of important narcotic analgesics and antagonists. The invention also provides certain novel intermediates.

A bacterial strain belonging to the genus Bacillus islolated by enrichment culture technique using morphine as a sole source of carbon transforms morphine and codeine into 14-hydroxymorphinone and 14-hydroxycodeinone as major and 14-hydroxymorphine and 14-hydroxycodeine as minor metabolites, respectively. When the N-methyl group in morphine and codeine are replaced by higher alkyl groups, the organism still retains its ability to carry out 14-hydroxylation as well as oxidation of the C6-hydroxyl group in these N-variants, although the level of metabolites formed are considerably low. The organism readily transforms dihydromorphine and dihydrocodeine into only dihydromorphinone and dihydrocodeinone, respectively, suggesting that the 7,8-double bond is a necessary structural feature to carry out 14-hydroxylation reaction. The cell free extract (20,000 × g supernatant), prepared from morphine grown cells, transforms morphine into 14-hydroxymorphinone in the presence of NAD+, but fails to show activity against testosterone. However, the cell free extract prepared from testosterone grown cells contains significant levels of 17β- hydroxysteroid dehydrogenase but shows no activity against morphine.

L-Selectride was shown to be an efficient and general O-demethylating agent for the opium alkaloids and their derivatives and also an efficient reagent for the cleavage of methyl carbamates, thus offering a convenient method for the N-demethylation of opioids. Further, it was shown that by choice of reaction conditions it is possible to achieve both N- decarbomethoxylation and O-demethylation in one pot, or only render N- decarbomethoxylation in high yield without accompanying O-demethylation.

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