WO2009003272A1 - Methods for n-demethylation of morphine and tropane alkaloids - Google Patents

Methods for n-demethylation of morphine and tropane alkaloids Download PDF

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Publication number
WO2009003272A1
WO2009003272A1 PCT/CA2008/001179 CA2008001179W WO2009003272A1 WO 2009003272 A1 WO2009003272 A1 WO 2009003272A1 CA 2008001179 W CA2008001179 W CA 2008001179W WO 2009003272 A1 WO2009003272 A1 WO 2009003272A1
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catalyst
equivalents
group
oxidizing agent
present
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PCT/CA2008/001179
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French (fr)
Inventor
Robert Carroll
Hannes Leisch
Tomas Hudlicky
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Brock University
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Priority to EP08772839.0A priority Critical patent/EP2170898B1/en
Priority to NZ582676A priority patent/NZ582676A/en
Priority to AU2008271864A priority patent/AU2008271864B2/en
Priority to CN200880022634.XA priority patent/CN101801977B/en
Priority to ES08772839.0T priority patent/ES2584028T3/en
Priority to JP2010513590A priority patent/JP5370865B2/en
Priority to CA2692433A priority patent/CA2692433C/en
Priority to MX2010000073A priority patent/MX2010000073A/en
Publication of WO2009003272A1 publication Critical patent/WO2009003272A1/en
Priority to IL202995A priority patent/IL202995A/en

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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C07D451/06—Oxygen atoms

Definitions

  • the present invention relates to ⁇ /-methylated compounds and methods for ⁇ /-demethylation of same.
  • the present invention relates to morphine and tropane alkaloids and their derivatives and methods for N- demethylation of same.
  • ⁇ /-Demethylation of morphine-type alkaloids has been extensively studied.
  • the standard procedures for ⁇ /-demethylation of substrates including morphinan derived compounds include the use of cyanogen bromide (the von Braun reaction), the reaction of a tertiary amine with chloroformates followed by hydrolysis, as well as a photochemical demethylation procedure.
  • Other methods that have been used to effect demethylation include amongst others, Polonovski-type reactions.
  • Pd-catalyzed oxidative demethylation procedure using stoichiometric amounts of Pd/C appears in a single report by Chaudhuri
  • the present invention provides a one-pot method for N- demethylation of /V-methylated compounds.
  • the present invention provides a one-pot method for the N- demethylation of an ⁇ /-methylated heterocycle comprising mixing the ⁇ /-methylated heterocycle with a metal catalyst in the presence of an oxidizing agent.
  • the ⁇ /-methylated heterocycle is selected from the group consisting of a morphine alkaloid, a tropane alkaloid and derivatives thereof.
  • the morphine alkaloid is selected from the group below: thebaine, oripavine, 14-hydroxycodeinone, 14-hydroxymorphinone, morphine, codeine, hydromorphone, hydrocodone, oxymorphone, oxycodone, hydromorphol and oxymorphol.
  • a preferred morphine alkaloid is hydrocodone.
  • the tropane alkaloid is preferably selected from the group consisting of tropinone, tropane, tropine, atropine, cocaine or any other bicyclo-[3.2.1]-azabicyclic methylamines.
  • the metal catalyst can also act as the oxidizing agent.
  • the oxidizing agent is selected from the group consisting of oxygen, ammonium persulfate, hydrogen peroxide, m- CPBA, peracetic acid, magnesium mono peroxyphthalate; palladium, palladium acetate and combinations thereof.
  • the oxidizing agent is palladium acetate or ammonium persulfate.
  • the catalyst is selected from the group consisting of: CuCI, CuI, CuOAc 2 , CuCO 3 , CuSO 4 , CuCI 2 , CuO, Pd(OAc) 2 , PdCI 2 , PdCI 2 (PPh 3 ) 4 , PdBr 2 , Pd(acac) 2 , Pd 2 (dba) 3 , Pd(dba) 2 , Pd(PPh 3 ) 4 , Fe dust, Cu, Fe, Ru, Co, Rh, Ir, Ni, Pd, Pt, Ge, Sn 1 Os, Ag, Au, Pb.
  • the catalyst is a copper catalyst selected from the group consisting of Cu, CuCI, CuI, Cu(OAc) 2 , CuCO 3 , CuSO 4 , CuCI 2 , and CuO. In a further preferred embodiment the catalyst is Cu(OAc) 2 .
  • the preferred catalyst is selected from the group consisting of Pd(OAc) 2 , PdCI 2 , PdCI 2 (PPh 3 J 4 , PdBr 2 , Pd(acac) 2 , Pd 2 (dba) 3 , Pd(dba) 2 , Pd(PPh 3 ) 4 , most preferably Pd(OAc) 2 .
  • the catalyst is preferably present in the range of from about 0.1 equivalents to about 5.0 equivalents, more preferably in the range of from about 1.0 equivalents to 2.5 equivalents, most preferably in about 2.5 equivalents. [0018] In a preferred embodiment the catalyst is present in the range of from about 1.0 equivalents to 2.5 equivalents and the oxidizing agent is present in the range of 2.0 equivalents to 4.0 equivalents.
  • the catalyst is a copper salt and the oxidizing agent is ammonium persulfate.
  • At least one solvent is added to the reaction mixture.
  • the solvent is selected from the group consisting of water, benzene, dioxane, toluene, acetonitrile, C1 to C4 alcohols and mixtures thereof.
  • One preferred solvent is acetonitrile: water in a ratio of about 5:1.
  • demethylated products obtained by the method of the invention are also encompassed within the invention.
  • the present invention provides a one-pot method for catalysed N- demethylation of N-methylated heterocycles.
  • the method is particularly useful for the demethylation morphine alkaloids or tropane alkaloids to provide highly desired products.
  • the method of the invention is highly reproducible and efficient.
  • the method comprises reacting an alkaloid substrate with a metal catalyst in the presence of an oxidizing agent.
  • the metal itself can act as an oxidizing agent.
  • Atmospheric oxygen can also act as an oxidizing agent.
  • an additional oxidizing agent is added.
  • alkaloids such as oripavine, morphine, codeine, hydromorphone, hydrocodone, oxymorphone, oxycodone, tropinone, tropane, tropine, atropine, cocaine, and bicyclo-[3.2.1]-azabicyclic methylamines can be demethylated using the methods of the invention.
  • a preferred morphine alkaloid derivative is hydrocodone and the examples focus on the demethylation of hydrocodone, it is apparent that other alkaloids can also be demethylated by the present methods.
  • Palladium-based catalyst such as PdCI 2 , Pd(OAc) 2 , Pd(PPh 3 J 4 and Pd(dba) 2 have been shown to be particularly useful.
  • Pd(OAc) 2 in particular, results in significant yields of product.
  • Copper based catalysts have also been shown to be excellent catalysts for use in the method.
  • a particularly effective catalyst is Cu(OAc) 2 .
  • the solvent is typically water, benzene, dioxane, toluene, acetonitrile, Ci to C 4 alcohols or a mixture of any of these.
  • the optimal conditions for demethylation vary, depending upon the starting substrate, the catalyst used, the solvent used, the length of the reaction and temperature of the reaction. As discussed above, various types of substrate, catalyst and oxidants can be used. Reaction times typically vary from about 8 to 40 hours depending on the catalyst and temperature. Demethylated compounds have been recovered at reaction temperatures ranging from room temperature to about 90'. For example, when palladium acetate is used as a catalyst for the demethylation of hydrocodone in the presence of benzene, optimal yield is achieved when the reaction is heated to about 80' and the reaction proceeds for 36 hours.
  • the amount of catalyst is typically in the range of about 1 equivalent to
  • Dioxane, benzene and acetonitrile are preferred solvents. In particular a ratio of about 5:1 acetonitrile to water is effective.
  • Codeine was demethylated using following conditions: 2 eq. Cu(OAc) 2 , 4 eq. (NH) 4 S 2 O 8 , CH 3 CN : H 2 O; 5 :1 , RT, 16 hrs.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Catalysts (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

The present invention relates to a method for N-demethylation of a tertiary N-methylated heterocycle, particularly a morphine or tropane alkaloids or derivatives thereof. The method, comprises reacting said tertiary N-methylated heterocycle with a metal catalyst, for example Pd(OAc)2 or Cu(OAc)2 in the presence of an oxidizing agent such as oxygen or ammonium persulfate.

Description

METHODS FOR Λ/-DEMETHYLATION OF MORPHINE AND TROPANE
ALKALOIDS
FIELD OF THE INVENTION
[0001] The present invention relates to Λ/-methylated compounds and methods for Λ/-demethylation of same. In particular the present invention relates to morphine and tropane alkaloids and their derivatives and methods for N- demethylation of same.
BACKGROUND OF THE INVENTION
[0002] The semisynthesis of morphine-derived antagonists, such as naloxone, see compound 5 below, and naltrexone see compound 6 below, and other medicinally significant compounds, from opium-derived natural products traditionally involves standard procedures for demethylation followed by subsequent procedures such as oxidative procedures for the introduction of a C-14 hydroxyl group.
t naloxone • na'fr8*006
Figure imgf000002_0001
[0003] Most commercial procedures for the production of C-14 hydroxylated species take advantage of Δ7-8 unsaturated species, however compounds containing α, β-unsaturated ketones have recently been identified as potential genotoxins because of their Michael acceptor character, and therefore routes to the oxygenated derivatives must avoid these intermediates.
[0004] Therefore any method that avoids these standard procedures may hold immense commercial potential for the production of morphine-derived antagonists, such as naloxone 5, naltrexone 6, and other medicinally significant compounds. [0005] The development of a mild catalytic protocol for Λ/-demethylation of ring-C saturated morphinans would simplify strategies toward C-14 oxygenated derivatives via potential use of an intramolecular process by tethered functionalisation anchored at the nitrogen atom.
[0006] Λ/-Demethylation of morphine-type alkaloids has been extensively studied. The standard procedures for Λ/-demethylation of substrates including morphinan derived compounds include the use of cyanogen bromide (the von Braun reaction), the reaction of a tertiary amine with chloroformates followed by hydrolysis, as well as a photochemical demethylation procedure. Other methods that have been used to effect demethylation include amongst others, Polonovski-type reactions. Precedent for a Pd-catalyzed oxidative demethylation procedure using stoichiometric amounts of Pd/C, appears in a single report by Chaudhuri
[0007] Chaudhuri's method describes the use of Pd/C (1g/1g substrate) in
MeOH at room temperature to dealkylate tertiary amines. On occasion he notes that small amounts of Λ/-formyl species were isolated. This was an undesired side reaction for his methodology. Application of the conditions described in this paper to hydrocodone results in no Λ/-demethylation. The only product recovered was N- formyl hydrocodone. Thus, there remained a need for a truly practical method for the production of demethylated morphine derivatives.
SUMMARY OF THE INVENTION
[0008] An investigation of the chemistry of morphine alkaloids and their derivatives, such as hydrocodone 3, and oxycodone 4, led to the present invention, which involves a method for a one-pot oxidative Λ/-demethylation.
[0009] In one aspect the present invention provides a one-pot method for N- demethylation of /V-methylated compounds.
[0010] The present invention provides a one-pot method for the N- demethylation of an Λ/-methylated heterocycle comprising mixing the Λ/-methylated heterocycle with a metal catalyst in the presence of an oxidizing agent. [0011] In a preferred embodiment, the Λ/-methylated heterocycle is selected from the group consisting of a morphine alkaloid, a tropane alkaloid and derivatives thereof. The morphine alkaloid is selected from the group below: thebaine, oripavine, 14-hydroxycodeinone, 14-hydroxymorphinone, morphine, codeine, hydromorphone, hydrocodone, oxymorphone, oxycodone, hydromorphol and oxymorphol. A preferred morphine alkaloid is hydrocodone. The tropane alkaloid is preferably selected from the group consisting of tropinone, tropane, tropine, atropine, cocaine or any other bicyclo-[3.2.1]-azabicyclic methylamines.
[0012] In one embodiment of the invention the metal catalyst can also act as the oxidizing agent.
[0013] In another embodiment of the invention the oxidizing agent is selected from the group consisting of oxygen, ammonium persulfate, hydrogen peroxide, m- CPBA, peracetic acid, magnesium mono peroxyphthalate; palladium, palladium acetate and combinations thereof. In a further preferred embodiment, the oxidizing agent is palladium acetate or ammonium persulfate.
[0014] In a preferred embodiment of the invention, the catalyst is selected from the group consisting of: CuCI, CuI, CuOAc2, CuCO3, CuSO4, CuCI2, CuO, Pd(OAc)2, PdCI2, PdCI2(PPh3)4, PdBr2, Pd(acac)2, Pd2(dba)3, Pd(dba)2, Pd(PPh3)4, Fe dust, Cu, Fe, Ru, Co, Rh, Ir, Ni, Pd, Pt, Ge, Sn1 Os, Ag, Au, Pb.
[0015] In another preferred embodiment, the catalyst is a copper catalyst selected from the group consisting of Cu, CuCI, CuI, Cu(OAc)2, CuCO3, CuSO4, CuCI2, and CuO. In a further preferred embodiment the catalyst is Cu(OAc)2.
[0016] In yet another embodiment the preferred catalyst is selected from the group consisting of Pd(OAc)2, PdCI2, PdCI2(PPh3J4, PdBr2, Pd(acac)2, Pd2(dba)3, Pd(dba)2, Pd(PPh3)4, most preferably Pd(OAc)2.
[0017] The catalyst is preferably present in the range of from about 0.1 equivalents to about 5.0 equivalents, more preferably in the range of from about 1.0 equivalents to 2.5 equivalents, most preferably in about 2.5 equivalents. [0018] In a preferred embodiment the catalyst is present in the range of from about 1.0 equivalents to 2.5 equivalents and the oxidizing agent is present in the range of 2.0 equivalents to 4.0 equivalents.
[0019] In a further preferred embodiment the catalyst is a copper salt and the oxidizing agent is ammonium persulfate.
[0020] In another aspect at least one solvent is added to the reaction mixture.
The solvent is selected from the group consisting of water, benzene, dioxane, toluene, acetonitrile, C1 to C4 alcohols and mixtures thereof. One preferred solvent is acetonitrile: water in a ratio of about 5:1.
[0021] In another aspect of the invention, demethylated products obtained by the method of the invention are also encompassed within the invention.
[0022] The development of a Pd or Cu catalyst mediated demethylation method for the Λ/-demethylation of morphinan alkaloids provides a very practical way to obtain normorphine products.
DETAILED DESCRIPTION
[0023] The present invention provides a one-pot method for catalysed N- demethylation of N-methylated heterocycles. The method is particularly useful for the demethylation morphine alkaloids or tropane alkaloids to provide highly desired products. The method of the invention is highly reproducible and efficient.
[0024] Briefly, the method comprises reacting an alkaloid substrate with a metal catalyst in the presence of an oxidizing agent. In some cases, the metal itself can act as an oxidizing agent. Atmospheric oxygen can also act as an oxidizing agent. In other cases, an additional oxidizing agent is added.
[0025] Various types of alkaloids such as oripavine, morphine, codeine, hydromorphone, hydrocodone, oxymorphone, oxycodone, tropinone, tropane, tropine, atropine, cocaine, and bicyclo-[3.2.1]-azabicyclic methylamines can be demethylated using the methods of the invention. [0026] While a preferred morphine alkaloid derivative is hydrocodone and the examples focus on the demethylation of hydrocodone, it is apparent that other alkaloids can also be demethylated by the present methods.
[0027] Various types of catalyst can be used to obtain demethylated products.
Palladium-based catalyst such as PdCI2, Pd(OAc)2, Pd(PPh3J4 and Pd(dba)2 have been shown to be particularly useful. Pd(OAc)2 in particular, results in significant yields of product.
[0028] Copper based catalysts have also been shown to be excellent catalysts for use in the method. A particularly effective catalyst is Cu(OAc)2.
[0029] Under certain conditions, it is desirable to include a solvent. The solvent is typically water, benzene, dioxane, toluene, acetonitrile, Ci to C4 alcohols or a mixture of any of these.
[0030] Without being limiting, the following conditions are usually used:
(a) The substrate is dissolved in a solvent;
(b) A catalyst is added;
(c) An oxidant is added;
(d) The reaction proceeds from about 8 to 40 hours, optionally at room temperature, optionally at an elevated temperature;
(e) The solvent is removed;
(f) The residue is resuspended in an aqueous basic medium;
(g) The aqueous phase is extracted, dried and filtered, and
(h) Any remaining volatiles are removed.
[0031] While the basic steps of the methods remain constant, the optimal conditions for demethylation vary, depending upon the starting substrate, the catalyst used, the solvent used, the length of the reaction and temperature of the reaction. As discussed above, various types of substrate, catalyst and oxidants can be used. Reaction times typically vary from about 8 to 40 hours depending on the catalyst and temperature. Demethylated compounds have been recovered at reaction temperatures ranging from room temperature to about 90'. For example, when palladium acetate is used as a catalyst for the demethylation of hydrocodone in the presence of benzene, optimal yield is achieved when the reaction is heated to about 80' and the reaction proceeds for 36 hours. On the other hand, the combination of Cu(OAc)2 as a catalyst with (NHU)2S2O8 as the oxidizing agent was shown to be highly efficient after a reaction time of 9 hours at room temperature. The relative amounts of the substrate, the catalyst and the oxidant also affects the yield.
[0032] Concentrations of about 0.01 - 100 mL solvent/gram of alkaloid is typically used in a small scale reaction.
[0033] The amount of catalyst is typically in the range of about 1 equivalent to
4 equivalents, more preferably about 2.0 equivalents to 2.5 equivalents, most preferably about 2.5 equivalents.
[0034] Dioxane, benzene and acetonitrile are preferred solvents. In particular a ratio of about 5:1 acetonitrile to water is effective.
[0035] A few exemplary procedures are shown in the Examples below.
Although these examples focus on the demethylation of hydrocodone and codeine, it is apparent that the general chemistry can be applied to other morphine and tropane alkaloids and that other catalysts and oxidants that function in a similar manner to those used in the specific examples are also useful in the invention.
[0036] The above disclosure generally describes the present invention. It is believed that one of ordinary skill in the art can, using the preceding description, make and use the compositions and practice the methods of the present invention. A more complete understanding can be obtained by reference to the following specific examples. These examples are described solely to illustrate preferred embodiments of the present invention and are not intended to limit the scope of the invention. Changes in form and substitution of equivalents are contemplated as circumstances may suggest or render expedient. Other generic configurations will be apparent to one skilled in the art. All journal articles and other documents such as patents or patent applications referred to herein are hereby incorporated by reference.
EXAMPLES
[0037] Although specific terms have been used in these examples, such terms are intended in a descriptive sense and not for purposes of limitation. Methods of molecular biology, biochemistry and chemistry referred to but not explicitly described in the disclosure and these examples are reported in the scientific literature and are well known to those skilled in the art.
Example 1. General procedure for demethylation using palladium acetate
[0038] Tertiary amine (O.i mmol, 1.0 eq.) was dissolved in benzene (1 ml) and
Pd(OAc)2 (0.25 mmol, 2.5 eq.) added. The reaction was heated at reflux for 36 hours, cooled to room temperature and passed through a plug of silica using CHCl3:MeOH:NH4OH 80:20:1 as eluent. The volatiles were removed in-vacuo, and the residue suspended in a saturated aqueous solution of NaHCO3. The aqueous phase was extracted with CHCb, dried over magnesium sulphate, filtered and the volatiles removed in-vacuo. Column chromatography (silica gel;
CHCI3:MeOH:NH4OH 96:4:1 ) of the crude material affords analytically pure demethylated product.
Figure imgf000008_0001
Table 1 : N-demethylation of hydrocodone bitartrate 3
Figure imgf000008_0002
Figure imgf000009_0003
Example 2. General procedure for demethylation using copper(ll) acetate
[0039] Tertiary amine (O.i mmol, 1.0 eq.) was dissolved in CH3CN : H2O; 5 : 1 and Cu(OAc)2 (0.2 mmol, 2.0 eq.) and (NH4J2S2O8 (0.4 mmol, 4.0 eq.) were added. The reaction was stirred at room temperature for 12 hours. The reaction mixture was quenched by the addition of aqueous 10 % Na2S2O3 solution. The organic solvent was removed in-vacuo, and the residue was basified to pH 9 using concentrated aqueous NH4OH. The aqueous phase was extracted with DCM, dried over magnesium sulphate, filtered and the volatiles were removed in-vacuo. Column chromatography (silica gel; CHCI3:MeOH:NH4OH 96:4:1) of the crude material affords analytically pure demethylated product.
oxidation
+ 1 major sideproduct
Figure imgf000009_0001
Figure imgf000009_0002
Figure imgf000009_0004
Figure imgf000010_0001
Variation of catalyst and oxidant loading:
All reactions were carried out at room temperature and under an atmosphere of air, utilising CH3CN : H2O 5 : 1 as solvent and 9 hours reaction time.
Figure imgf000010_0002
Reaction temperature 5O0C
Figure imgf000010_0003
Various Atmospheres
Reaction conditions: 2 eq. Cu(OAc)2, 4 eq. (NH)4S2O8, CH3CN : H2O; 5 :1 , RT, 16 hrs
Figure imgf000011_0003
Solvent Screening
Reaction conditions: 2 eq. Cu(OAc)2, 4 eq. (NH)4S2O8, RT, 16 hrs.
Figure imgf000011_0004
Example 3. Demethylation of codeine
Codeine was demethylated using following conditions: 2 eq. Cu(OAc)2, 4 eq. (NH)4S2O8, CH3CN : H2O; 5 :1 , RT, 16 hrs.
oxidation
Figure imgf000011_0001
Figure imgf000011_0002
22 % yield
[0040] All analytical data for compounds are in agreement with that reported in the literature. [0041] One or more currently preferred embodiments have been described by way of example. It will be apparent to persons skilled in the art that a number of variations and modifications can be made without departing from the scope of the invention as defined in the claims.

Claims

What is claimed is:
1. A one pot method for the Λ/-demethylation of an Λ/-methylated heterocycle comprising mixing the Λ/-methylated heterocycle with a metal catalyst in the presence of an oxidizing agent.
2. A method according to claim 1 wherein the metal catalyst and the oxidizing agent are the same.
3. A method according to claim 1 wherein the oxidizing agent is selected from the group consisting of oxygen, ammonium persulfate, hydrogen peroxide, m- CPBA, peracetic acid, magnesium mono peroxyphthalate; palladium, palladium acetate and combinations thereof.
4. A method according to claim 3 wherein the oxidizing agent is oxygen.
5. A method according to claim 4 wherein in the oxidizing agent is palladium acetate.
6. The method according to claim 4 wherein the oxidizing agent is ammonium persulfate.
7. A method according to claim 1 wherein the catalyst is selected from the group consisting of: CuCI, CuI, CuOAc2, CuCO3, CuSO4, CuCI2, CuO, Pd(OAc)2, PdCI2, PdCI2(PPh3)4, PdBr2, Pd(acac)2, Pd2(dba)3, Pd(dba)2, Pd(PPh3)4> Fe dust, Cu, Fe, Ru, Co, Rh1 Ir, Ni, Pd, Pt, Ge, Sn, Os, Ag, Au, Pb.
8. A method according to claim 7 wherein the catalyst is selected from the group consisting of: Os, Ag, Au, Pb.
9. A method according to claim 7 wherein the catalyst is selected from the group consisting of: Cu, Fe, Ru, Co, Rh, Ir, Ni, Pd, Pt, Ge, Sn.
10. A method according to claim 7 wherein the catalyst is selected from the group consisting of: CuCI, CuI, CuOAc2, CuCO3, CuSO4, CuCI2, CuO, Pd(OAc)2, PdCI2, PdCI2(PPh3)4, PdBr2, Pd(acac)2, Pd2(dba)3, Pd(dba)2, Pd(PPh3)4, Fe dust.
11. The method according to claim 1 , wherein the catalyst is a palladium catalyst.
12. The method according to claim 11 , wherein the catalyst is selected from the group consisting of PdCI2, Pd(OAc)2, Pd(PPh3)4, Pd2(dba)3 and Pd(dba)2.
13. The method according to claim 11 , wherein the catalyst is Pd(OAc)2.
14. The method according to claim 7, wherein the metal catalyst is a copper catalyst.
15. The method according to claim 14, wherein the catalyst is selected from the group consisting of Cu, CuCI, CuI, Cu(OAc)2, CuCO3, CuSO4, CuCI2, and CuO.
16. The method according to claim 15, wherein the catalyst is Cu(OAc)2.
17. The method according to claim 1 , wherein the catalyst is present in the range of from about 0.1 equivalents to about 5.0 equivalents.
18. The method according to claim 17, wherein the catalyst is present in the range of from about 1.0 equivalents to 2.5 equivalents.
19. The method according to claim 18, wherein the catalyst is present in about 2.5 equivalents.
20. The method according to claim 1 , wherein the catalyst is present in the range of from about 0.1 equivalents to 5.0 equivalents and the oxidizing agent is present in the range of about 1.0 equivalents to 8.0 equivalents.
21. The method according to claim 20, wherein the catalyst is present in the range of from about 1.0 equivalents to 2.5 equivalents and the oxidizing agent is present in the range of 2.0 equivalents to 4.0 equivalents.
22. The method according to claim 21 , wherein the catalyst is a copper salt and the oxidizing agent is ammonium persulfate.
23. The method according to claim 22, wherein the copper salt is present in about 2.0 equivalents and the ammonium persulfate is present in 4.0 equivalents.
24. The method according to claim 1 , wherein the Λ/-methylated heterocycle is selected from the group consisting of a morphine alkaloid, a tropane alkaloid and derivatives thereof.
25. The method according to claim 24, wherein the morphine alkaloid is selected from the group below: thebaine, oripavine, 14-hydroxycodeinone, 14- hydroxymorphinone, morphine, codeine, hydromorphone, hydrocodone, oxymorphone, oxycodone, hydromorphol and oxymorphol
26. The method according to claim 25, wherein the morphine alkaloid is hydrocodone.
27. The method according to claim 24, wherein the tropane alkaloid is selected from the group consisting of tropinone, tropane, tropine, atropine, cocaine or any other bicyclo-[3.2.1]-azabicyclic methylamines.
28. The method according to claim 1 , further comprising the addition of at least one solvent wherein said solvent is selected from the group consisting of water, benzene, dioxane, toluene, acetonitrile, C1 to C4 alcohols and mixtures thereof.
29. The method according to claim 28, wherein the at least one solvent is dioxane.
30. The method according to claim 28, wherein the at least one solvent is acetonitrile.
31. The method according to claim 28, wherein the solvent comprises acetonitrile and water.
32. The method according to claim 31 , wherein the acetonitrile and water are present in a ratio of about 10:0.5.
33. The method of claim 32 wherein the solvent comprises an acetonitrile: water ratio of about 5:1.
PCT/CA2008/001179 2007-06-29 2008-06-30 Methods for n-demethylation of morphine and tropane alkaloids WO2009003272A1 (en)

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