WO2005100361A1 - Methode de preparation de derives de 4,5$g(a)-epoxy-6-oxomorphinane - Google Patents

Methode de preparation de derives de 4,5$g(a)-epoxy-6-oxomorphinane Download PDF

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Publication number
WO2005100361A1
WO2005100361A1 PCT/SK2005/000008 SK2005000008W WO2005100361A1 WO 2005100361 A1 WO2005100361 A1 WO 2005100361A1 SK 2005000008 W SK2005000008 W SK 2005000008W WO 2005100361 A1 WO2005100361 A1 WO 2005100361A1
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Prior art keywords
palladium
hydrogen
ruthenium
hydrocodone
bound
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PCT/SK2005/000008
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English (en)
Inventor
Dusan Vandak
Dusan Berkes
Andrej Kolarovic
Milan Marko
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Zentiva, A.S.
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Publication of WO2005100361A1 publication Critical patent/WO2005100361A1/fr

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D489/00Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
    • C07D489/02Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: with oxygen atoms attached in positions 3 and 6, e.g. morphine, morphinone
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02PCLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00Technologies relating to chemical industry
    • Y02P20/50Improvements relating to the production of bulk chemicals
    • Y02P20/55Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention relates to a new method of preparation of derivatives of 4,5 ⁇ -epoxy-6- oxomorphinan of formula I, wherein R 1 is hydrogen, methyl or ethyl, R 2 is hydrogen, methyl, cyclobutylmethyl, or benzyl, from derivatives of 7,8-dehydro-4,5-epoxymorphinan of formula 1 - ⁇
  • Hydromorphone is a strong analgesic agent, 7 - 8 times more effective than morphine (AMA Drug Evaluations, 5th ed. American Medical Association, Chicago, 1983).
  • AMA Drug Evaluations 5th ed. American Medical Association, Chicago, 1983.
  • hydrocodone and hydromorphone Several methods of preparation of hydrocodone and hydromorphone have been described so far. One of them uses catalytic hydrogenation of codeine/morphine and subsequent oxidation of dihydrocodeine/dihydromorphine to the desired product.
  • Oxidation of dihydroco-character to hydrocodone with chromium (VI) salts is the subject of DE 415097; Oppenauer oxidation of dihydrocodeine/dihydromorphone to the respective oxo compounds in the presence of, for example, alkyl aryl ketones catalyzed with aluminium t-butanolate with the yield of max. 40 % (US 2,628,962, US 2,654,756), aluminium phenolate with the 60 % yield (US 2,715,626) and in the presence of potassium t-butanolate in benzene with the yield of 71 to 83 % (US 2,649,454) has been known.
  • Hydrocodone was prepared also by oxidation of dihydro- codeine with silver carbonate (75% yield; J. Heterocyclic Chem. 13, 1976, 525). A process with changed sequence of reaction steps is described in US 2,654,756. In the first step, codeinone is obtained by Oppenauer oxidation of codeine, in the second step, codeinone is hydro- genated to hydrocodone. Codeinone can be prepared from codeine also by Swern oxidation in the presence of dimethylsulfoxide and oxalyl chloride at -78 °C (US 6,008,355), or by oxidation with silver carbonate (J. Am. Chem. Soc. 77, 1955, 490).
  • hydrocodone/hydromorphone is prepared from codeine/morphine by a two-step synthesis with low selectivity and in relatively low yields.
  • Another method involves catalytic rearrangement of codeine/morphine to hydrocodone/hydromorphone.
  • German patents DE 365 683 and DE 380 919 describe a method of preparation of hydrocodone/hydromorphone by catalytic action of free palladium or platinum in an acidic aqueous environment in the presence of hydrogen.
  • Documents DE 607 931 and DE 617238 describe a similar method, but without the presence of hydrogen, with yields 40 to 95 %.
  • Patent US 2,544,291 describes a method of preparation of hydrocodone from codeine in aqueous sulfuric acid by isomerization on palladium anchored on charcoal.
  • US 6,512,117 describes a method of preparation of hydrocodone/ hydromorphone that is again based on the principle of the previous methods. Codeine/morphine is stirred in an acidic aqueous environment in the presence of metallic palladium and the resulting product is purified via the bisulfite adduct. Yields of hydromorphone hydrochloride in the mentioned examples range from 23 to 30 %.
  • Patent US 6,589,960 describes a similar method, while claiming a defined profile of impurities in hydromorphone obtained in this way. In all the mentioned patents, isomerization of opium alkaloids is catalyzed with metallic free or anchored palladium, or platinum.
  • This patent provides a method of preparing derivatives of 4,5 ⁇ -epoxy-6-oxomorphinan of formula I, wherein R 1 is hydrogen, methyl or ethyl and R 2 is hydrogen, methyl, cyclobutylmethyl or benzyl, from derivatives of 7,8-dehydro-4,5-epoxymorphinan of formula II, wherein R and R are as defined with respect to compounds I, in the presence of a mixed catalyst from the group of platinum metals.
  • the compounds of formula I enter the reaction in the form of a base, or in the form of salts with mineral or organic acids.
  • the process takes place in an aqueous environment, or in an environment of a mixture of water with a water-miscible solvent such as methanol, ethanol, tetrahydrofuran, acetonitrile, and in the presence of acids such as sulfuric acid, hydrochloric acid, phosphoric acid, formic acid, acetic acid, and the like, at temperatures ranging from room temperature to the boiling point of the solvent, preferably at the boiling point of the solvent, for 0.25 h to 10 h, preferably for 0.5 h to 3 h, preferably in an inert atmosphere.
  • a hydroxyl protecting group may be used.
  • the catalyst used in the process contains a mixture of at least two elements from the group of platinum metals (palladium, platinum, ruthenium, rhodium, iridium), preferably palladium and ruthenium.
  • the mentioned elements are present in the form of metals (oxidation number 0), which are free or bound onto a carrier, in the form of salts, preferably halides, or of a combination of these forms.
  • the soluble forms of the catalyst are removed from the reaction mixture by reduction with hydrogen, or another reduction agent, or by precipitation of metals in the form of an insoluble salt, for example sulfide, sulfite or iodide.
  • the reaction mixture is processed to the product using methods known in the art.
  • the method as described herein has the advantage of using low concentrations of the catalyst, while the reaction proceeds with high selectivity.
  • the method allows to obtain the product having low content of impurities in yields highly exceeding those described in the art by low-demanding isolation procedures.
  • the following examples describe in more detail the method of executing the invention; however, they do not limit the extent of the invention in any respect.
  • codeine base (20 g, 66.8 mmol) is dissolved in aqueous sulfuric acid (4.5 %, 130 ml); after codeine has dissolved, 10 % Pd/C (1.42 g) and 5 % Ru/C (2.21 g) axe further added to the flask at increased temperature. The mixture is heated until reflux under nitrogen atmosphere for 3 hours. After completion of isomerization, the flask is flushed with hydrogen and the reaction mixture is subsequently stirred in hydrogen atmosphere at 50 °C for 1 h. The cooled reaction mixture is filtered, pH of the filtrate is adjusted to 10 - 10.5, the precipitated substance is separated and dried. Crude hydrocodone base is obtained (16.1 g; yield 74 %) in the form of a light brown powder.
  • hydrocodone base is dissolved in hot ethanol, the solution is decoloured with active carbon, and by gradual cooling down to 10 °C pure hydrocodone base is crystallized, which is separated by filtration, then dissolved in ethanol and a 50% aqueous solution of tartaric acid is added when hot. After cooling down, the mixture is filtered and the obtained crystals are dried. Hydrocodone bitartrate hemipentahydrate is obtained (18.9 g; yield 58 %) in the form of a white crystalline substance (HPLC content 99.82 area %).
  • Example 2 Example 2
  • codeine base (20 g, 66.8 mmol) is dissolved in diluted sulfuric acid (5.5 %, 100 ml) at 30 - 40 °C, a solution of PdCl 2 (0.1 M, 3.35 ml) and a solution of RuCl 3 (0.1 M, 2.5 ml) are added to the solution.
  • the mixture is heated until reflux under nitrogen atmosphere for 3 hours, after completion of the reaction, the flask is flushed with hydrogen and the reaction mixture is subsequently stirred in hydrogen atmosphere at 50 °C for 1 h, the mixture is cooled down, filtered, and sodium pyrosulfite (1.6 g) is added to the filtrate and pH of the solution is adjusted to 6.0, a solution of sodium disulfide (0.25 M, 9.4 ml) is added and the mixture is heated until reflux for 1 hour. The suspension is filtered and pH of the filtrate is adjusted to 10.0 - 10.5. The precipitate is filtered off, washed with water and dried. Crude hydrocodone base is obtained (18.8 g; yield 92 %).
  • the crude hydrocodone base is dissolved in hot ethanol, the solution is decoloured with active carbon, and by gradual cooling down to 10 °C pure hydrocodone base is crystallized, which is separated by filtration.
  • the pure hydrocodone base is dissolved in hot ethanol, hot 50% aqueous solution of tartaric acid is added, the mixture is cooled down, and the precipitated crystals are filtered off and dried.
  • Hydrocodone bitartrate hemipentahydrate is obtained (23.0 g; yield 70 %) in the form of a white crystalline substance (HPLC content 99.91 area %).
  • Morphine sulfate pentahydrate (10 g; 26.36 mmol) is dissolved in diluted sulfuric acid (2 %, 50 ml), at increased temperature a solution of PdCl 2 (0.1 M, 2.6 ml) and a solution of 5 % Ru/C (0.49 g) are added. The mixture is heated until reflux under nitrogen atmosphere for 3 hours. The flask is flushed with hydrogen and the reaction mixture is subsequently stirred in hydrogen atmosphere at 50 °C for 3 h. The cooled reaction mixture is filtered, ethanol (10 ml) is added to the filtrate, pH of the filtrate is adjusted to 10 - 10.5. The precipitated substance is separated and dried.
  • hydrocodone base is obtained (6.65 g; yield 84 %), which is dissolved in hot 90% ethanol, the solution is decoloured with active carbon, filtered, and concentrated hydrochloric acid (2.3 ml) is added to the filtrate. The mixture is cooled down to 10 °C, the precipitated crystals are filtered out and dried. Hydromorphone hydrochloride is obtained (5.6 g; yield 75 %, HPLC content 99.75 area %).
  • the crude base is dissolved in 300 ml of hot ethyl acetate, purified with active carbon (2 g), the suspension is filtered, and the filtrate is concentrated under reduced pressure to a volume of about 100 ml and let to crystallize. After the crystals are separated and dried, 18.5 to 19 g (74 to 76 %) of white crystalline dihydrocodeinone having b.p. 198-199 °C are obtained.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Méthode de préparation de dérivés de 4,5α-époxy-6-oxomorphinane représentés par la formule (I), dans laquelle R1 représente hydrogène, méthyle ou éthyle et R2 représente hydrogène, méthyle, cyclobutylméthyle ou benzyle, dans laquelle des composés représentés par la formule (II), dans laquelle R1 et R2 représentent une définition analogue à celle des composés représentés par la formule (I), sont isomérisés en composés de formule (I) en présence d'un catalyseur mixte contenant au moins deux éléments du groupe de métaux platine. Cette méthode permet d'obtenir un produit en quantité élevée contenant peu d'impuretés.
PCT/SK2005/000008 2004-04-13 2005-04-07 Methode de preparation de derives de 4,5$g(a)-epoxy-6-oxomorphinane WO2005100361A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SK176-2004A SK286047B6 (sk) 2004-04-13 2004-04-13 Spôsob prípravy derivátov 4,5alfa-epoxy-6-oxomorfínanu
SKPP0176-2004 2004-04-13

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Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006099351A2 (fr) * 2005-03-11 2006-09-21 Noramco Inc. Polymorphes d'hydrocodone
US7399859B1 (en) 2007-02-06 2008-07-15 Cody Laboratories Inc. Method for catalytic preparation of hydromorphone and hydrocodone
WO2008137672A1 (fr) * 2007-05-04 2008-11-13 Mallinckrodt Inc. Procédé amélioré pour la préparation d'opiacés 6-alpha-hydroxy-n-alkylés
US7625918B2 (en) 2005-03-11 2009-12-01 Noramco, Inc. Hydrocodone polymorphs
WO2010118275A1 (fr) * 2009-04-09 2010-10-14 Mallinckrodt Inc. Préparation de composés cétone morphinanes saturées
WO2010118274A1 (fr) * 2009-04-09 2010-10-14 Mallinckrodt Inc. Préparation de 6-céto, 3-alcoxy morphinanes
WO2010118273A1 (fr) * 2009-04-09 2010-10-14 Mallinckrodt Inc. Catalyseurs au ruthénium pour la production d'hydrocodone, d'hydromorphone ou d'un dérivé de celles-ci
WO2011035276A3 (fr) * 2009-09-21 2011-06-16 Mallinckrodt Inc. Catalyseur métallique au ruthénium hétérogène pour la production d'hydrocodone, d'hydromorphone ou d'un dérivé de celles-ci
WO2011137086A1 (fr) * 2010-04-29 2011-11-03 Mallinckrodt Llc Préparation de composés morphinane à cétone saturée ayant une faible teneur en métal
US8269006B2 (en) 2008-09-30 2012-09-18 Mallinckrodt Llc Processes for the selective amination of ketomorphinans
US20130035488A1 (en) * 2011-08-02 2013-02-07 Mallinckrodt Llc Stepwise Process for the Production of Alkaloid Salts
US8471023B2 (en) 2009-06-11 2013-06-25 Mallinckrodt Llc Reductive amination of 6-keto normorphinans by catalytic hydrogen transfer
US8519133B2 (en) 2009-06-11 2013-08-27 Mallinckrodt Llc Preparation of 6-alpha-amino N-substituted morphinans by catalytic hydrogen transfer
US8624031B2 (en) 2011-09-08 2014-01-07 Mallinckrodt Llc Production of alkaloids without the isolation of intermediates
US8729266B2 (en) 2007-07-17 2014-05-20 Mallinckrodt Llc Preparation of N-alkylated opiates by reductive amination
US8946419B2 (en) 2009-02-23 2015-02-03 Mallinckrodt Llc (+)-6-hydroxy-morphinan or (+)-6-amino-morphinan derivatives
EP2417139B1 (fr) * 2009-04-09 2016-03-23 Mallinckrodt LLC Préparation de composés cétone saturée morphinanes par isomérisation catalytique
US9296699B2 (en) 2011-06-09 2016-03-29 Mallinckrodt Llc Reductive amination of 6-keto morphinans by catalytic hydrogen transfer
WO2016067054A1 (fr) * 2014-10-31 2016-05-06 Cambrex Charles City, Inc. Procédé de production de bitartrate d'hydrocodone
WO2016169662A1 (fr) * 2015-04-24 2016-10-27 Grünenthal GmbH Sels cristallins de bitartrate d'hydrocodone
EP3255051A1 (fr) 2016-06-09 2017-12-13 Siegfried AG Catalyseur métallique supporté pour la production d' hydrocodone et hydromorphon
US10081636B2 (en) 2016-07-08 2018-09-25 Cody Laboratories, Inc. Method for catalytic preparation of hydromorphone, hydrocodone, and other opiates
WO2022101408A1 (fr) 2020-11-13 2022-05-19 Ferrer Internacional, S.A. Synthèse d'une base d'hydromorphone

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DE380919C (de) * 1921-03-22 1923-09-13 Chem Fab Verfahren zur Darstellung von Ketoderivaten der Morphinreihe
DE617238C (de) * 1934-01-26 1935-10-02 Knoll Ag Verfahren zur Darstellung von Dihydromorphinonen
US5847142A (en) * 1996-08-01 1998-12-08 Johnson Matthey Public Limited Company Preparation of narcotic analgesics
WO2001034608A1 (fr) * 1999-11-09 2001-05-17 Abbott Laboratories Compositions d'hydromorphinone et d'hydrocodeinone, procedes de synthese de ces dernieres

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US2577947A (en) * 1951-12-11 Manufacture of dihydrocodeinone
US2544291A (en) * 1949-04-05 1951-03-06 New York Quinine And Chemical Alkaloid manufacture
US2649454A (en) * 1951-08-20 1953-08-18 Univ California Method for preparing dihydromorphinone, dihydrocodeinone, and dihydropseudocodeinone
US5869669A (en) * 1996-07-26 1999-02-09 Penick Corporation Preparation of 14-hydroxynormorphinones from normorphinone dienol acylates
US7321038B2 (en) * 2002-11-11 2008-01-22 Mallinckrodt Inc. Method for the catalytic production of hydrocodone and hydromorphone
US6946556B1 (en) * 2004-05-21 2005-09-20 Acura Pharmaceuticals, Inc. Preparation of opioid analgesics by a one-pot process

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Publication number Priority date Publication date Assignee Title
DE380919C (de) * 1921-03-22 1923-09-13 Chem Fab Verfahren zur Darstellung von Ketoderivaten der Morphinreihe
DE617238C (de) * 1934-01-26 1935-10-02 Knoll Ag Verfahren zur Darstellung von Dihydromorphinonen
US5847142A (en) * 1996-08-01 1998-12-08 Johnson Matthey Public Limited Company Preparation of narcotic analgesics
WO2001034608A1 (fr) * 1999-11-09 2001-05-17 Abbott Laboratories Compositions d'hydromorphinone et d'hydrocodeinone, procedes de synthese de ces dernieres
US6512117B1 (en) * 1999-11-09 2003-01-28 Abbott Laboratories Hydromorphone and hydrocodone compositions and methods for their synthesis

Cited By (36)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7625918B2 (en) 2005-03-11 2009-12-01 Noramco, Inc. Hydrocodone polymorphs
WO2006099351A3 (fr) * 2005-03-11 2007-02-22 Noramco Inc Polymorphes d'hydrocodone
WO2006099351A2 (fr) * 2005-03-11 2006-09-21 Noramco Inc. Polymorphes d'hydrocodone
US7399859B1 (en) 2007-02-06 2008-07-15 Cody Laboratories Inc. Method for catalytic preparation of hydromorphone and hydrocodone
EP2189460A1 (fr) * 2007-05-04 2010-05-26 Mallinckrodt Inc. Procédé amélioré pour la préparation d'opiacés 6-alpha-hydroxy-n-alkylés
EP2180000A1 (fr) * 2007-05-04 2010-04-28 Mallinckrodt Inc. Procédé amélioré pour la préparation d'opiacés 6-alpha-hydroxy-n-alkylés
WO2008137672A1 (fr) * 2007-05-04 2008-11-13 Mallinckrodt Inc. Procédé amélioré pour la préparation d'opiacés 6-alpha-hydroxy-n-alkylés
AU2008207580B2 (en) * 2007-05-04 2011-04-14 SpecGx LLC Improved process for the preparation of 6-alpha-hydroxy-N-alkylated opiates
US8524904B2 (en) 2007-05-04 2013-09-03 Mallinckrodt Llc Process for the preparation of 6-alpha-hydroxy-N-alkylated opiates
US7985858B2 (en) 2007-05-04 2011-07-26 Mallinckrodt Inc. Process for the preparation of 6-alpha-hydroxy-N-alkylated opiates
US8273888B2 (en) 2007-05-04 2012-09-25 Mallinckrodt Llc Process for the preparation of 6-alpha-hydroxy-N-alkylated opiates
US8729266B2 (en) 2007-07-17 2014-05-20 Mallinckrodt Llc Preparation of N-alkylated opiates by reductive amination
US8269006B2 (en) 2008-09-30 2012-09-18 Mallinckrodt Llc Processes for the selective amination of ketomorphinans
US8946419B2 (en) 2009-02-23 2015-02-03 Mallinckrodt Llc (+)-6-hydroxy-morphinan or (+)-6-amino-morphinan derivatives
EP2417139B1 (fr) * 2009-04-09 2016-03-23 Mallinckrodt LLC Préparation de composés cétone saturée morphinanes par isomérisation catalytique
WO2010118273A1 (fr) * 2009-04-09 2010-10-14 Mallinckrodt Inc. Catalyseurs au ruthénium pour la production d'hydrocodone, d'hydromorphone ou d'un dérivé de celles-ci
WO2010118275A1 (fr) * 2009-04-09 2010-10-14 Mallinckrodt Inc. Préparation de composés cétone morphinanes saturées
US9040705B2 (en) 2009-04-09 2015-05-26 Mallinckrodt Llc Preparation of saturated ketone morphinan compounds
WO2010118274A1 (fr) * 2009-04-09 2010-10-14 Mallinckrodt Inc. Préparation de 6-céto, 3-alcoxy morphinanes
US8471023B2 (en) 2009-06-11 2013-06-25 Mallinckrodt Llc Reductive amination of 6-keto normorphinans by catalytic hydrogen transfer
US8519133B2 (en) 2009-06-11 2013-08-27 Mallinckrodt Llc Preparation of 6-alpha-amino N-substituted morphinans by catalytic hydrogen transfer
WO2011035276A3 (fr) * 2009-09-21 2011-06-16 Mallinckrodt Inc. Catalyseur métallique au ruthénium hétérogène pour la production d'hydrocodone, d'hydromorphone ou d'un dérivé de celles-ci
WO2011137086A1 (fr) * 2010-04-29 2011-11-03 Mallinckrodt Llc Préparation de composés morphinane à cétone saturée ayant une faible teneur en métal
US8563725B2 (en) 2010-04-29 2013-10-22 Mallinckrodt Llc Preparation of saturated ketone morphinan compounds having low metal content
AU2011245437B2 (en) * 2010-04-29 2014-10-02 SpecGx LLC Preparation of saturated ketone morphinan compounds having low metal content
US9296699B2 (en) 2011-06-09 2016-03-29 Mallinckrodt Llc Reductive amination of 6-keto morphinans by catalytic hydrogen transfer
WO2013019825A1 (fr) * 2011-08-02 2013-02-07 Mallinckrodt Llc Procédé par étapes pour obtention de sels d'alcaloïdes
US20130035488A1 (en) * 2011-08-02 2013-02-07 Mallinckrodt Llc Stepwise Process for the Production of Alkaloid Salts
US8624031B2 (en) 2011-09-08 2014-01-07 Mallinckrodt Llc Production of alkaloids without the isolation of intermediates
WO2016067054A1 (fr) * 2014-10-31 2016-05-06 Cambrex Charles City, Inc. Procédé de production de bitartrate d'hydrocodone
US9981979B2 (en) 2014-10-31 2018-05-29 Cambrex Charles City, Inc. Process for the formation of hydrocodone bitatrate
WO2016169662A1 (fr) * 2015-04-24 2016-10-27 Grünenthal GmbH Sels cristallins de bitartrate d'hydrocodone
EP3255051A1 (fr) 2016-06-09 2017-12-13 Siegfried AG Catalyseur métallique supporté pour la production d' hydrocodone et hydromorphon
WO2017211879A1 (fr) 2016-06-09 2017-12-14 Siegfried Ag Catalyseur métallique supporté pour la production d'hydrocodone et d'hydromorphone
US10081636B2 (en) 2016-07-08 2018-09-25 Cody Laboratories, Inc. Method for catalytic preparation of hydromorphone, hydrocodone, and other opiates
WO2022101408A1 (fr) 2020-11-13 2022-05-19 Ferrer Internacional, S.A. Synthèse d'une base d'hydromorphone

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CZ2005210A3 (cs) 2006-09-13
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SK1762004A3 (sk) 2005-11-03

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