EP1871774A1 - Méthode de synthèse catalytique d'hydrocodone, d hydromorphone et de dérivés de ces substances - Google Patents

Méthode de synthèse catalytique d'hydrocodone, d hydromorphone et de dérivés de ces substances

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Publication number
EP1871774A1
EP1871774A1 EP06737475A EP06737475A EP1871774A1 EP 1871774 A1 EP1871774 A1 EP 1871774A1 EP 06737475 A EP06737475 A EP 06737475A EP 06737475 A EP06737475 A EP 06737475A EP 1871774 A1 EP1871774 A1 EP 1871774A1
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EP
European Patent Office
Prior art keywords
group
formula
aryl
alkyl
halide
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP06737475A
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German (de)
English (en)
Inventor
Peter Xianqi Wang
Frank W. Moser
Gary L. Cantrell
Daniel P. Magparangalan
Jian Bao
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Mallinckrodt Inc
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Mallinckrodt Inc
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Publication date
Application filed by Mallinckrodt Inc filed Critical Mallinckrodt Inc
Publication of EP1871774A1 publication Critical patent/EP1871774A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D489/00—Heterocyclic 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:
    • C07D489/02—Heterocyclic 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids

Definitions

  • the present invention relates to a method for the catalytic production of hydrocodone derivatives and hydromorphone derivatives.
  • Hydrocodone and hydromorphone are opioid analgesics having similar qualities to codeine and morphine. Development of new opioid derivatives is desirable to produce new intermediates and potential sources of new analgesics. Conventional methods for producing hydrocodone and hydromorphone typically involve a two step oxidation/reduction route from codeine and morphine. Unfortunately, these methods are expensive and inefficient. Attempts to improve efficiency have included the use of catalytic methods. Known methods include the use of metallics, typically Ru, Rh, Pd and Pt on activated carbon as well as metallic complexes. The preparation of these catalysts is difficult, yields are poor, and isolation of the product is often burdensome.
  • An aspect of the present invention is to provide a method for the catalytic conversion of a compound of Formula I into a compound of Formula II utilizing at least one transition metal complex as catalyst,
  • R 1 is H, alkyl, aryl or acyl.
  • Another aspect of the present invention is to provide a method for the catalytic conversion of a compound of Formula VI into a compound of Formula VII,
  • R is selected from but not limited to H, a benzyl , a substituted benzyl , an alkyl, an aryl, an acyl, an aryl sulfonyl, an alkyl sulfonyl, a carboxyester, a carboxyamide, trialkylsilyl, tetrahydropyranyl and tetrahydrofuranyl group; and R 3 is selected from but not limited to H, an alkyl, an allyl, a cycloalkylalkyl, a benzyl, an aryl sulfonyl, an alkyl sulfonyl, an aryl, an acyl group, a formyl, a hydroxyl, a carboxyester and a carboxyamide.
  • the transition metal complex is of the formula [M(PR 4 R 5 R 6 ) n X m ] p ; wherein M is a Group VHI transition metal; R 4 , R 5 and R 6 are selected from the group consisting of alkyl, aryl, alkoxyl, phenoxyl and combinations thereof; X is a halide or an anion; n is 1, 2, 3 or 4; m is 1 or 2; and p is at least 1.
  • R 1 is H, alkyl, aryl or acyl.
  • the method of the present invention is especially useful where R 1 is methyl or H, i.e., codeine or morphine, respectfully, leading to the formation of hydrocodone or hydromorphone, respectfully.
  • R is selected from but not limited to H, a benzyl , a substituted benzyl , an alkyl, an aryl, an acyl, an aryl sulfonyl, an alkyl sulfonyl, a carboxyester, a carboxyamide, trialkylsilyl, tetrahydropyranyl and tetrahydrofuranyl group; and
  • R 3 is selected from but not limited to H, an alkyl, an allyl, a cycloalkylalkyl, a benzyl, an aryl sulfonyl, an alkyl sulfonyl, an aryl, an acyl group, a formyl, a hydroxyl, a carboxyester and a carboxyamide.
  • the method of the present invention can be utilized with quaternary salts as shown below:
  • R 2 is selected from but not limited to H, a benzyl , a substituted benzyl , an alkyl, an aryl, an acyl, an aryl sulfonyl, an alkyl sulfonyl, a carboxyester, a carboxyamide, trialkylsilyl, tetrahydropyranyl and tetrahydrofuranyl group.
  • R and R are independently selected from but not limited to H, an alkyl group, an allyl group, a benzyl group, an aryl group and an alkylenecycloalkane. Alternatively, R and R taken together form an oxide.
  • Xi and X 2 are anions typically Cl or Br.
  • X 1 and X 2 are anions independently selected from but not limited to BF 4 , PF 6 , ClO 4 , CHO 2 , C 2 O 4 , CF 3 CO 2 , CF 3 SO 3 , CH 3 CO 2 , ArCO 2 , CH 3 SO 3 , p-tolylSO 3 , HSO 4 and H 2 PO 4 or mixtures thereof, the products of anion exchange.
  • Xj and X 2 are subject to exchange by the catalyst.
  • the transition metal catalysts of the present invention comprise at least one transition metal complex of the formula [MXPR ⁇ R ⁇ n X ⁇ J p -, wherein, M is a Group VIE transition metal; R 4 , R 5 and R 6 are selected from the group consisting of alkyl, aryl, alkoxyl, phenoxyl and combinations; thereof, X is a halide or an anion; n is 1, 2, 3 or 4; m is 1 or 2; and p is at least 1;
  • the transition metal catalysts of the present invention comprise a transition metal complex [M(PR 4 R 5 R 6 ) n X m ] p ; wherein, M is preferably a Group Vi ⁇ transition metal; R 4 , R 5 and R 6 are independently selected from alkyl, aryl, and alkoxyl, phenoxyl groups; X is a halide or an anion; n is 1, 2, 3 or 4; and m is 1 or 2. These complexes are capable of polymerizing, therefore p is at least 1. When all three of the R groups are alkoxyl, phenoxyl or combinations thereof, the ligand of the complex is termed a tertiary phosphite.
  • the ligand of the complex is termed a tertiary phosphine.
  • Preferred metals include Rh, Ru, Pd and Pt.
  • the halide, X is typically Cl or Br.
  • Anions include but are not limited to BF 4 , PF 6 , ClO 4 , CHO 2 , CaO 4 , CF 3 CO 2 , CF 3 SO 3 , CH 3 CO 2 , ArCO 2 , CH 3 SO 3 , p-tolylSO 3 , HSO 4 and H 2 PO 4 . Many of these catalysts are commercially available, or are easily prepared as is known in the art.
  • the transition metal catalysts of the present invention comprise a transition metal complex of a tertiary phosphine halide, [M(PR 7 3 ) n X m ] p , wherein M is preferably a Group VIII transition metal; R 7 is an alkyl or aryl; X is a halide or an anion; n is 1, 2, 3 or 4; and m is 1 or 2.
  • M is preferably a Group VIII transition metal
  • R 7 is an alkyl or aryl
  • X is a halide or an anion
  • n 1, 2, 3 or 4
  • m is 1 or 2.
  • Preferred metals include Rh, Ru, Pd and Pt.
  • the halide, X is typically Cl or Br.
  • Anions include but are not limited to BF 4 , PF 6 , ClO 4 , CHO 2 , C 2 O 4 , CF 3 CO 2 , CF 3 SO 3 , CH 3 CO 2 , ArCO 2 , CH 3 SO 3 , p-tolylSO 3 , HSO 4 and H 2 PO 4 .
  • R 7 is an alkyl or aryl group, with phenyl being preferred. Many of these catalysts are commercially available, or are easily prepared as is known in the art. It is noted that the catalysts of the formula [M(PR 7 3 ) n X m ]p are a subgroup of the broader group of catalysts [MCPR ⁇ R ⁇ n X ⁇ J p .
  • the complexes of the present invention may be comprised of solid supported tertiary phosphines/phosphites, including but not limited to polymer supported tertiary phosphines/phosphites, silical supported tertiary phosphines/phosphites and resin-bound tertiary phosphines/phosphites.
  • solid supported tertiary phosphines/phosphites one of the R groups typically contains a linking group connecting a phosphine/phosphite and a solid phase, as is well known in the art.
  • a non-limiting example of a solid supported tertiary phosphine useful in the present invention is the copolymer prepared from the monomer p-styryldiphenylphosphine also known as diphenyl(p-vinylphenyl)phosphine with styrene or silical supported tertiary phosphines made from treating silica with (EtO) 3 SiCH 2 CH 2 PPh 2 .
  • solid supported tertiary phosphines/phosphites that are commercially available.
  • the metal is Rh and the complex is of the formula [Rh(PR 4 R 5 R 6 )nX ⁇ J P ; wherein R 4 , R 5 and R 6 are selected from the group consisting of alkyl, aryl, alkoxyl, phenoxyl and combinations thereof; X is a halide or an anion; n is 1, 2, 3 or 4; m is 1 or 2; and p is at least 1.
  • the transition metal is Rh
  • the metal complex is of the formula [Rh(PR 7 3 ) n X] p , wherein R 7 is an alkyl or aryl, X is a halide, n is 1, 2 or 3, and p is at least 1, or of the formula [Rh(PR 7 3 ) n Y] p , wherein R 7 is an alkyl or aryl, n is 1, 2 or 3, p is at least 1 and Y is an anion, preferably including BF 4 , PF 6 , ClO 4 , CHO 2 , CF 3 CO 2 , CF 3 SO 3 , CH 3 CO 2 , C 2 O 4 , Ai-CO 2 , CH 3 SO 3 , p-tolylSO 3 , HSO 4 or H 2 PO 4 .
  • the transition metal is Ru and the metal complex is of the formula [Ru(PR 4 R 5 R 6 ) n X m ] p ; wherein R 4 , R 5 and R 6 are selected from the group consisting of alkyl, aryl, alkoxyl, phenoxyl and combinations thereof; X is a halide or an anion; n is 1, 2, 3 or 4; m is 1 or 2; and p is at least 1.
  • a suitable method for producing an illustrative Ru complex of the present invention involves refluxing a Ru salt, for example RuCl 3 XH 2 O with an excess of triphenylphosphine in alcohol to form the complex [Ru(P(C 6 H 5 ) 3 ) 3 Cl 2 ] p .
  • a Ru salt for example RuCl 3 XH 2 O
  • triphenylphosphine in alcohol
  • Rh complex of the present invention is also commercially available, or can be prepared by refluxing rhodium trichloride with triphenylphosphine in alcohol, typically methanol or ethanol.
  • Rh-, Ru-, and/or Ir- complex can be bound to a tertiary copolymer of styrene, divinylbenzene, and diphenyl(p- vinylphenyl)phosphine also known as p-styryldiphenylphosphine, illustrated below:
  • ethylene dimethacrylate ethylene dimethacrylate
  • p-bromostyrene and crosslinking agents such as divinylbenzene, butadiene, diallyl maleate, diallyl phthalate, glycol dimethacrylate, and other di- or triolefins.
  • Other phosphine containing monomers bound to the styrene ring can have, in addition to diaryl substitutions, dialkyl, branched and cyclic dialkyl, dialkoxyl or mixed substitutions or these.
  • Illustrative examples utilizing styrene are shown in Formulas 18 and 19.
  • the polymeric complex makes up a composition of matter consisting essentially of an intrinsically porous solid organic styrene-divinyl benzene copolymer; a substituent phosphine group chemically bonded through phosphorus to a carbon atom of said polymer; and a Group VIII metal chemically bonded to said substituent phosphine which composition is substantially insoluble in the solvent(s).
  • the polymeric support is composed of a styrene divinylbenzene copolymer containing 2 to 20 mole percent divinylbenzene, in which 0.5 to 7 mole percent, preferably 5 to 6 mole percent of the pendant phenyl groups from the copolymerized styrene contain the diphenylphosphine moiety at the para position.
  • the composition of the polymer support is 75 to 97.6 mole percent styrene, 2 to 20 percent divinylbenzene and 0.4 to 6 percent p-diphenylphosphenostyrene.
  • the Ru/pendant atom ratio is preferably at least 0.001 and is more preferably about 0.5 to an upper limit set by the point at which the polymer support will no longer take up complex, for example about 1.2.
  • the polymeric complex may be made by contacting a solution of the Group VIII metal salt complex in solution with the polymer support.
  • the metal complex is dissolved in a suitable solvent including but not limited to water, methanol, ethanol, isopropanol, isobutyl alcohol, t-butyl alcohol, chloroform, dichloromethane, fluorobenzene, chlorobenzene, toluene, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, methyl sulfoxide, methyl sulfone, tetrahydrofuran and mixtures thereof.
  • the Group V ⁇ I metal complex solution should be at least 10 ⁇ 6 M in the ruthenium complex but is preferably about 10 '3 M in the ruthenium complex.
  • the polymer portion of the catalyst is intrinsically porous. Porosity of the polymer portion of the catalyst imparts increased activity to the catalyst. With catalysts having an organic polymer portion which is not intrinsically porous, porosity may be induced into the polymer portion by solvent swelling. Combinations of the above-noted solvents can be manipulated to produce various degrees of swelling of the polymer portion of the catalyst, as is well known in the art.
  • the catalytic conversion of the present invention has the further economic advantage of being able to convert a salt of codeine or morphine, for example codeine hydrochloride or morphine hydrochloride, to hydrocodone, or hydromorphone, respectively.
  • the catalysts of the present invention facilitate high value metal recovery of the metal containing solid catalyst.
  • the metal of the present catalyst results in an improved recovery percentage. This further reduces material and labor costs, as well as simplifying processing/workup.
  • recovery is meant to encompass recovery, recycling and/or regeneration of the metal.
  • the catalyst/support can be placed in a column or container as part of a loop reactor.
  • codeine in alcohol that is heated in a reactor can be pumped or gravity fed through a catalyst bed and cycled back to the reactor until the desired conversion to hydrocodone is produced.
  • the advantages of this method include that many cycles (perhaps several batches) of product may be obtained with a given bed.
  • the catalyst value is then easily recovered and sent back for reprocessing.
  • the purification workup is simplified because the catalyst is not present in the solution. For practical reasons, the concentration of Group VJH metals must be below about 10 ppm in the product. On cooling, the product would crystallize out of solution in high purity, to be recovered by filtration or centrifugation.
  • the reaction of the present invention may be accomplished by any conventional process.
  • a suitable process includes dissolving the reactant of Formula I in a suitable solvent in a reaction vessel.
  • Suitable solvents include but are not limited to alcohols, preferably primary and secondary lower alkyl alcohols.
  • the reaction vessel is then flushed with an inert atmosphere, typically nitrogen.
  • the catalyst is added and the reaction mixture is refluxed under the inert atmosphere until the conversion is essentially complete, typically at least about an hour.
  • the reaction mixture is cooled and crystals of the product are collected.
  • the product may be purified by recrystallization in a suitable solvent as is well known in the art, or by any other suitable conventional method of purification.
  • a tertiary amine for example triethylamine, is added to the reaction mixture when the preferred Ru complex catalyst is used.
  • the tertiary amine reduces the formation of side products, primarily the alkaloid neopine, a potential side product in reactions of the present invention utilizing the preferred Ru catalyst.
  • the alkaloid compound is added to the reactants that form the catalyst and the catalyst formation reaction takes place in the presence of the alkaloid.
  • the ability to form the catalyst and subsequently accomplish the catalytic conversion in the same reaction vessel further enhances the economy of the reaction.
  • the flask was equipped with a condenser and nitrogen. The flask was flushed with nitrogen for five minutes with one neck opened. The catalyst, 0.50 g of RhCl(P(C 6 H 5 ) 3 ) 3 was added to the solution. The flask was then flushed with nitrogen for another five minutes, and the open neck was closed. The reaction mixture was stirred under nitrogen and heated to reflux for four hours, then cooled to O 0 C for 30 minutes. The resulting crystals were removed by filtration. The collected crystals were washed four times with 10ml cold methanol (5 0 C), and dried in air for one hour yielding pale yellow crystals (41.50 g, yield 83%). The filtrate was pumped down to dryness to give 6.14 g yellow solid.
  • Morphine 50.00 g, was suspended in 500 ml methanol in a three neck flask equipped with condenser and nitrogen input and outlet. After refluxing under nitrogen for five minutes, one neck of the flask was opened. A catalyst, 0.50 g RhCl(P(C 6 H 5 ) S ) 3 -WaS added to the container. The opened neck was closed with a stopper. The reaction mixture was stirred under nitrogen and heated to reflux for 6 hours, cooled down to O 0 C for 30 minutes, and filtered. The collected solid was washed four times with cold methanol (5 0 C) and dried in air for 20 minutes.
  • Ruthenium dimer was prepared by refluxing 1 g RuCl 3 XH 2 O with 3 equivalents P(C 6 HO 3 in EtOH (100 ml) overnight. The resulting catalyst, [Ru(P(C 6 H 5 ) 3 ) 2 Cl 2 ] 2 was obtained as a black precipitate after filtration, 63% yield.
  • Example 3 The catalyst of Example 3 was reacted with codeine in MeOH in the presence of triethylamine in the ratios shown in the table below.
  • the reaction mixtures were flushed with N 2 for 5 minutes, heated to reflux under N 2 , cooled to 0 0 C and filtered.
  • the recovered crystals were washed twice with 5 ml MeOH and air dried to yield white crystals.
  • Morphine, 1.0 g, and 80 mg [Ru(P(C 6 H 5 ) 3 ) 2 Cl 2 ] 2 was suspended in 10 ml MeOH. The reaction mixture was flushed with N 2 for 3 minutes, after which 0.25 ml triethylamine was added, and the mixture flushed with N 2 for another 3 minutes. The reaction mixture was heated to reflux with stirring under N 2 for 72 hours. The resulting solid was found to be hydromorphone.
  • Codeine 50.00 g, is added to 200 ml methanol contained in a three necked flask equipped with condenser and nitrogen input and outlet. The mixture is taken to reflux under nitrogen. A polymer phosphine anchored Ru catalyst, 5 g (1 mole % Ru) is added to the container. The reaction mixture is stirred under nitrogen at reflux for several hours. An additional 800 ml of methanol is added and heating is continued for 30 minutes. The polymer catalyst is recovered for recycle by filtration of the hot liquor. About 800 ml of methanol is removed from the filtrate by distillation. The liquor is then cooled to O 0 C and maintained at that temperature for at least about 30 minutes.
  • the product is collected by filtration, washed four times with cold methanol (5 0 C) and air dried. The product is placed under vacuum ( ⁇ 15 mm Hg) at room temperature for at least an hour. The product is obtained as a white powder weighing over 38 grams for a >75% yield. The purity and identity of the hydrocodone is confirmed by HPLC, H 1 and C 13 NMR and MS analyses.
  • N-Codeine methobromide 50 g is dissolved in 200 ml methanol in a three-neck flask at room temperature.
  • the flask is equipped with a condenser and nitrogen.
  • the flask is flushed with nitrogen for five minutes with one neck opened.
  • the catalyst, 0.50 g OfRhCl(P(C 6 Hs) 3 ) S is added to the solution.
  • the flask is then flushed with nitrogen for another five minutes, and the open neck was closed.
  • the reaction mixture is stirred under nitrogen and heated to reflux for six hours, then cooled.
  • Methanol, 100 ml is removed by distillation. Ethyl acetate 100 ml is added and cooling is continued to -1O 0 C for one hour.

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  • Chemical & Material Sciences (AREA)
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  • Health & Medical Sciences (AREA)
  • Pain & Pain Management (AREA)
  • Engineering & Computer Science (AREA)
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  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

La présente invention décrit une méthode de synthèse catalytique de dérivés d'hydrocodone et d'hydromorphone, respectivement, qui emploie un catalyseur de métal de transition de formule [M(PR4R5R6)nXm]p où M est un métal de transition du Groupe VIII ; R4, R5 et R6 sont sélectionnés au sein du groupe constitué par les groupements alkyle, aryle, alkoxy, phénoxy et les combinaisons de ces groupements ; X est un halogénure ou un anion ; n est égal à 1, 2, 3 ou 4 ; m est égal à 1 ou à 2 ; et p est au moins égal à 1.
EP06737475A 2005-03-28 2006-03-07 Méthode de synthèse catalytique d'hydrocodone, d hydromorphone et de dérivés de ces substances Withdrawn EP1871774A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US66578405P 2005-03-28 2005-03-28
PCT/US2006/008307 WO2006104656A1 (fr) 2005-03-28 2006-03-07 Méthode de synthèse catalytique d'hydrocodone, d’hydromorphone et de dérivés de ces substances

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EP1871774A1 true EP1871774A1 (fr) 2008-01-02

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EP (1) EP1871774A1 (fr)
JP (1) JP2008538746A (fr)
CN (1) CN101151266A (fr)
AU (1) AU2006229734A1 (fr)
CA (1) CA2602929A1 (fr)
MX (1) MX2007011752A (fr)
WO (1) WO2006104656A1 (fr)

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US7999104B2 (en) * 2007-06-29 2011-08-16 Brock University Methods for one-pot N-demethylation/N-acylation of morphine and tropane alkaloids
US8962841B2 (en) 2007-06-29 2015-02-24 Brock University Methods for one-pot N-demethylation/N-functionalization of morphine and tropane alkaloids
CN103619847A (zh) 2011-05-06 2014-03-05 布鲁克大学 通过金属催化n-脱甲基化/官能化以及分子内基团转移制备吗啡类似物的方法
GB201313211D0 (en) 2013-07-24 2013-09-04 Cambrex Karlskoga Ab New process
JP7231574B2 (ja) * 2020-02-27 2023-03-01 国立大学法人九州大学 新規な多孔性架橋ポリマー、それを用いた固定化触媒および装置
WO2022101408A1 (fr) 2020-11-13 2022-05-19 Ferrer Internacional, S.A. Synthèse d'une base d'hydromorphone

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GB9616253D0 (en) 1996-08-01 1996-09-11 Johnson Matthey Plc Preparation of narcotic analgesics
GB9622516D0 (en) * 1996-10-29 1997-01-08 Univ Cambridge Tech Enzymic cofactor cycling
MXPA02004678A (es) * 1999-11-09 2005-10-05 Abbott Laboratoires Composiciones de hidrocodeinona e hdromorfinona y metodos para su sintesis.
CA2545052C (fr) 2002-11-11 2011-01-11 Mallinckrodt, Inc. Procede de production catalytique d'hydrocodone et d'hydromorphone
US7323565B2 (en) 2002-11-11 2008-01-29 Mallinckrodt Inc. Method for the catalytic production of hydrocodone and hydromorphone

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AU2006229734A1 (en) 2006-10-05
MX2007011752A (es) 2007-11-21
CN101151266A (zh) 2008-03-26
CA2602929A1 (fr) 2006-10-05
WO2006104656A1 (fr) 2006-10-05
JP2008538746A (ja) 2008-11-06

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