# Patent

## Title
Preparation of 6-alpha-amino N-substituted morphinans by catalytic hydrogen transfer

## Abstract

The present invention provides processes for the stereoselective synthesis of 6-alpha-amino N-substituted morphinans. In particular, the invention provides processes for the reductive amination of 6-keto N-substituted morphinans by catalytic hydrogen transfer.

## Background
CROSS REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of U.S. Provisional Application No. 61/186,091 filed Jun. 11, 2009, which is incorporated herein in its entirety.


FIELD OF THE INVENTION
The present invention generally relates to the stereoselective synthesis of 6-alpha-amino N-substituted morphinans. In particular, the invention relates to the reductive amination of 6-keto N-substituted morphinans by catalytic hydrogen transfer.
BACKGROUND OF THE INVENTION
Morphinans, including N-alkylated morphinans and normorphinans, are important pharmaceuticals, typically used as analgesics or drug/alcohol cessation agents. Substituted morphinans, such as 6-amino derivatives, may be useful therapeutically because they have higher efficacy, greater potency, and/or may function as prodrugs. Although several methods for forming 6-amino morphinans from 6-keto morphinans have been reported in the literature, none provides the stereoselective synthesis of 6-alpha-amino epimers in good yield. Furthermore, the existing methods require the use of highly reactive reducing agents and/or hydrogen gas. There is a need, therefore, for simple, mild, and efficient processes for the preparation of 6-alpha-amino morphinans of high enantiomeric purity.
SUMMARY OF THE INVENTION
The present invention provides processes for the stereoselective synthesis of 6-alpha-amino epimers from 6-keto N-substituted morphinans. In particular, 6-keto N-substituted morphinans undergo reductive amination in a hydrogen transfer donor environment.
Briefly, therefore, one aspect of the present invention encompasses a process for preparing a 6-alpha-amino N-substituted morphinan. The process comprises contacting a 6-keto N-substituted morphinan with an amine source, a hydrogen donor comprising a formate ion, a transition metal catalyst, and a proton acceptor to form the 6-alpha-amino N-substituted morphinan.
Another aspect of the invention provides a process for preparing a compound comprising Formula (IV):




The process comprises reducing a compound comprising Formula (I) in the presence of an amine source (R6NH2), a hydrogen donor comprising a formate ion, a transition metal catalyst, and a proton acceptor to form the compound comprising Formula (IV). The compound of Formula (I) comprises:




For each of the compounds comprising Formulas (I) or (IV), the variable stand for the following:

    
    
        R is selected from the group consisting of hydrocarbyl and substituted hydrocarbyl;
        R1 and R2 are independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, halogen, and {—}OR15;
        R3, R7, and R8 are independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, and {—}OR15;
        R6 is selected from the group consisting of hydrogen, hydrocarbyl and substituted hydrocarbyl;
        R14 is selected from the group consisting of hydrogen and {—}OR15; and
        R15 is selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, and a hydroxy protecting group.
    
    


A further aspect of the invention encompasses a composition comprising a compound of Formula (IV) and less than about 5% of a 6-beta amino epimer of the compound comprising Formula (IV):




wherein:

    
    
        R is selected from the group consisting of hydrocarbyl and substituted hydrocarbyl;
        R1 and R2 are independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, halogen, and {—}OR15;
        R3, R7, and R8 are independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, and {—}OR15;
        R6 is selected from the group consisting of hydrogen, hydrocarbyl and substituted hydrocarbyl;
        R14 is selected from the group consisting of hydrogen and {—}OR15; and
        R15 is selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, and a hydroxy protecting group.
    
    


Other features and iterations of the invention are described in more detail below.


DETAILED DESCRIPTION OF THE INVENTION
The present invention provides improved processes for the stereoselective synthesis of 6-alpha-amino N-substituted morphinans, salts, intermediates, or analogs thereof. In particular, the 6-keto moiety of a N-substituted morphinan is enantioselectively reduced to the 6-alpha-amino epimer. The stereoselective synthesis the 6-alpha-amino epimer encompasses reductive amination by catalytic hydrogen transfer. In particular, the 6-keto moiety is condensed with an amine source in the presence of a transition metal catalyst and a hydrogen donor comprising a formate ion. The processes of the invention, therefore, avoid the use of hydrogen gas and highly reactive main group reducing agents. Accordingly, the processes are quite mild and tolerate many functional groups that may be reduced in the presence of less hazardous main group reducing agents. Advantageously, the processes of the invention provide high yield and high epimeric purity of 6-alpha-amino N-substituted morphinans. The present invention also provides compositions comprising a 6-alpha-amino N-substituted morphinan epimer and less than 5%, preferably less than 2%, and even more preferably less than 1% of a 6-beta amino N-substituted morphinan epimer.
(I) Processes for the Preparation of 6-Alpha-Amino N-Substituted Morphinans
One aspect of the invention encompasses processes for the stereoselective synthesis of 6-alpha-amino N-substituted morphinans. The processes comprise contacting a 6-keto N-substituted morphinan with an amine source such as a primary amine or an ammonium salt, a hydrogen donor comprising a formate ion, a transition metal catalyst, and a proton acceptor to form the 6-alpha-amino N-substituted morphinan.
In general, the N-substituted morphinans detailed herein comprise any compound having a morphinan structure in which the nitrogen at position 17 comprises a tertiary amine. That is, the nitrogen at position 17 has a hydrocarbyl or substituted hydrocarbyl substituent. For the purposes of illustration, the ring atoms of the core morphinan structure are numbered as diagrammed below:




wherein R is hydrocarbyl or substituted hydrocarbyl. Preferred R groups include alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, and heterocyclo. Even more preferred R groups include methyl, ethyl, propyl, cyclopropyl, cyclopropylmethyl, butyl, isobutyl, t-butyl, cyclobutyl, cyclobutylmethyl, pentyl, isopenyl, neopentyl, cyclopenyl, and allyl.
The process comprises formation of a first intermediate compound comprising a formate salt of a 6-imine morphinan after reaction of the 6-keto N-substituted morphinan with the amine source, the transition metal catalyst, and the hydrogen donor. The first intermediate compound is converted in situ to a second intermediate compound comprising a formate salt of a 6-alpha-amino N-substituted morphinan. Contact between the second intermediate compound with the proton acceptor leads to formation of the 6-alpha-amine N-substituted morphinan.
(II) Processes for the Preparation of Compounds Comprising Formula (IV)
In one embodiment of the invention, a 6-alpha-amino morphinan comprising Formula (IV) is prepared from a 6-keto morphinan comprising Formula (I). The process comprises reducing the compound comprising Formula (I) in the presence of an amine source (R6NH2), a hydrogen donor comprising a formate ion, and a transition metal catalyst to form an intermediate compound comprising Formula (II). The compound comprising Formula (II) is converted in situ to a compound comprising Formula (III). The process further comprises contacting the compound comprising Formula (III) with a proton acceptor to form the compound comprising Formula (IV). For purposes of illustration, Reaction Scheme 1 depicts the synthesis of the compound comprising Formula (IV) in accordance with one aspect of the invention:




wherein:

    
    
        R is selected from the group consisting of hydrocarbyl and substituted hydrocarbyl;
        R1 and R2 are independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, halogen, and {—}OR15;
        R3, R7, and R8 are independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, and {—}OR15;
        R6 is selected from the group consisting of hydrogen, hydrocarbyl and substituted hydrocarbyl;
        R14 is selected from the group consisting of hydrogen and {—}OR15; and
        R15 is selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, and a hydroxy protecting group.
    
    


In a preferred embodiment, each of R1, R2, R7, and R8 are hydrogen. In another preferred embodiment, R14 is hydrogen or hydroxy. In yet another preferred embodiment, R is selected from the group consisting of alkyl, cycloalkyl, cycloalkylmethyl, alkenyl, aryl, and heterocyclo. In still another preferred embodiment, R3 is selected from the group consisting of alkoxy, hydroxy, and protected hydroxy. In exemplary embodiments, R is methyl, cyclopropylmethyl, or allyl, and R3 is hydroxy or methoxy.
(a) Step A of the Process
The process commences with the formation of a reaction mixture by combining a 6-keto morphinan comprising Formula (I) with an amine source, a hydrogen donor, and a transition metal catalyst, wherein the compound comprising Formula (I) undergoes reductive amination. A variety of compounds comprising Formula (I) are suitable for use in the process. In exemplary embodiments, R is methyl, allyl, or cyclopropylmethyl; R1, R2, R7, and R8 are hydrogen; R3 is hydroxy or methoxy; and R14 is hydrogen or hydroxy. Representative compounds comprising Formula (I) include, but are not limited to, hydrocodone, hydromorphone, oxycodone, oxymorphone, naloxone, and naltrexone, which are depicted below:




(i) Amine Source
The reaction mixture also comprises an amine source comprising formula R6NH2, wherein R6 is selected from the group consisting of hydrogen, hydrocarbyl, and substituted hydrocarbyl. In embodiments in which R6 is hydrogen, the amine source, ammonia (NH3), is provided by an ammonium salt. The ammonium salt may comprise an inorganic anion or an organic anion. Non-limiting examples of suitable inorganic anions include bicarbonate, carbonate, chloride, hydroxide, nitrate, phosphate, sulfide, and sulfate. Examples of suitable organic anions include, but are not limited to, benzoate, butanoate, acetate, citrate, formate, fumarate, glutamate, lactate, malate, propionate, oxalate, succinate, and tartarate. In a preferred embodiment, the ammonium salt is ammonium acetate.
In embodiments in which R6 is hydrocarbyl or substituted hydrocarbyl, the amine source is a primary amine. In preferred embodiments, R6 is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl, carbocyclic, or heterocyclic. Non-limiting examples of suitable primary amines include methylamine, ethylamine, isopropylamine, allylamine, n-benzylamine, aniline (i.e., phenylamine), methanolamine, ethanolamine, and amino acids such as alanine or the methyl ester of alanine.
The molar ratio of the compound comprising Formula (I) to the amine source can and will vary depending on whether the amine source is an ammonium salt or a primary amine. In embodiments in which the amine source in an ammonium salt, the molar ratio of the compound comprising Formula (I) to the ammonium salt typically will range from about 1:2 to about 1:20. In some embodiments in which the amine source in an ammonium salt, the molar ratio of the compound comprising Formula (I) to the ammonium salt may range from about 1:2 to about 1:5, from about 1:5 to about 1:10, from about 1:10 to about or 1:15, or from about 1:15 to about 1:20. In a preferred embodiment in which the amine source in an ammonium salt, the molar ratio of the compound comprising Formula (I) to the ammonium salt may range from about 1:11 to about 1:13, or more preferably about 1:12. In embodiments in which the amine source is a primary amine, the molar ratio of the compound comprising Formula (I) to the primary amine typically will range from about 1:1 to about 1:5. In various embodiments in which the amine source is a primary amine, the molar ratio of the compound comprising Formula (I) to the primary amine may be range from about 1:1 to about 1:2, from about 1:2 to about 1:3, or from about 1:3 to about 1:5. In a preferred embodiment in which the amine source is a primary amine, the molar ratio of the compound comprising Formula (I) to the primary amine may be range from about 1:1.25 to about 1:2.
(ii) Hydrogen Donor Comprising a Formate Ion
In addition to the compound comprising Formula (I) and the amine source, the reaction mixture also comprises a hydrogen donor comprising a formate ion, such that a transfer hydrogenation reaction may occur. Non-limiting example of suitable hydrogen donors comprising a formate ion include formic acid, an inorganic salt of formic acid, an organic salt of formic acid, or a mixture of formic acid and an organic base. Suitable inorganic salts of formic acid include, but are not limited to, calcium formate, cesium formate, lithium formate, magnesium formate, potassium formate, and sodium formate. Non-limiting examples are suitable organic salts of formic acid include ammonium formate, ethyl formate, methyl formate, amine formate, butyl formate, propyl formate, triethyl orthoformate, triethyl orthoformate, triethylammonium formate, trimethylammonium formate, and the like. Suitable organic bases for combining with formic acid include, but are not limited to, pyridine, triethylamine, diisopropylethylamine, N-methylmorpholine, and N,N-dimethylaminopyridine. In an exemplary embodiment, the hydrogen donor comprises a mixture of formic acid and an organic base, wherein the organic base is triethylamine.
The molar ratio of the compound comprising Formula (I) to the hydrogen donor can and will vary. In general, the molar ratio of the compound comprising Formula (I) to the hydrogen donor will range from about 1:1 to about 1:20. In various embodiments, the molar ratio of the compound comprising Formula (I) to the hydrogen donor may range from 1:1 to about 1:3, from about 1:3 to about 1:10, or from about 1:10 to about 1:20. In preferred embodiments, the molar ratio of the compound comprising Formula (I) to the hydrogen donor may range from 1:11 to about 1:13. In exemplary embodiments in which the hydrogen donor comprises formic acid and triethylamine, the molar ratio of the compound comprising Formula (I) to triethylamine may range from about 1:1 to about 1:10, or more preferably from about 1:3 to about 1:5. The hydrogen donor may be slowly introduced into the reaction mixture. For example, the hydrogen donor may be added in small aliquots or drops to the reaction mixture.
(iii) Transition Metal Catalyst
The reaction mixture also comprises a transition metal catalyst. As used herein, the transition metal catalyst comprises at least one metal complexed with at least one ligand. The metal of the catalytic transition metal complex may be ruthenium, osmium, rhodium, iridium, palladium, or platinum. In a preferred embodiment, the transition metal may be ruthenium, iridium, or rhodium. The valence state of the transition metal may vary. For example, non-limiting examples of suitable transition metals include ruthenium(II), ruthenium(III), ruthenium(IV), osmium(II), osmium(III), osmium(IV), rhodium(I), rhodium(III), iridium(III), iridium(IV), palladium(II), palladium(IV), platinum(II), and platinum(IV). Typically, the ratio of metal to ligand in the complex is about 1:1. The ligand of the catalytic transition metal complex may be a mono- or bidentate nitrogen donor, a phosphorous donor ligand, a cyclopentadienyl ligand, an arene ligand, an olefin ligand, an alkyne ligand, a heterocycloalkyl ligand, a heteroaryl ligand, a hydride ligand, an alkyl ligand, or a carbonyl ligand.
In preferred embodiments, the catalytic transition metal complex may be dichloro(arene)Ru(II) dimer, dichloro(pentamethylcyclopentadienyl)Rh(II) dimer, BINAP-Ru(II) diacetate, BINAP-Ru(II) dichloride, BINAP-Ru(II) dibromide, BINAP-Ru(II) diiodide, [RuCl((R or S)BINAP)(C6H6)]Cl, dichloro(pentamethylcyclopentadienyl)iridium(III) dimer, Ru(III) chloride, RuCl3 hydrate, Ru(III) acetylacetonate, tetraalkylammonium RuCl4, or pyridinium RuCl4. In an exemplary embodiment, the transition metal catalyst may be dichloro(p-cymene)Ru(II) dimer.
In other embodiments, the catalytic transition metal complex may be an asymmetric catalyst in which at least one metal is complexed with at least one bidentate, chiral ligand using nitrogen, oxygen, or phosphorous donor atoms. These catalysts are sometimes referred to as Noyori catalysts, and are more fully described in, for example, U.S. Pat. No. 5,693,820 (Helmchen et al.) and R. Noyori et al., Asymmetric Catalysts by Architectural and Functional Molecular Engineering: Practical Chemo- and Stereoselective Hydrogenation of Ketones, Agew. Chem. Int. Ed. 2001, 40, pp. 40-73. In one example, the chiral ligand may comprise Formula (670), (680), (690), or (700), as shown below,




wherein R671, R672, R673, R681, R691, R692, R701, and R702 are independently alkyl or aryl and wherein R691 and R692 of Formula (690) and R701 and R702 of Formula (700), and the carbon atoms to which they are attached, may optionally form a cyclic or bicyclic compound. In the above structures, the “*” indicates a chiral carbon atom. The configuration of the chiral carbons of the asymmetric catalyst may be RR, RS, SR, or SS.
In one embodiment, the ligand comprises Formula (670) and R672 and R673 are each phenyl and R671 is aryl. In another example of this embodiment, R671 is tolyl, mesityl, or naphthyl. In an alternative embodiment, the ligand comprises Formula (680) and R681 is tolyl, mesityl, 2,4,6-triisopropylphenyl, or naphthyl. In another example, the ligand comprises Formula (690) and R691 and R692 are hydrogen thus forming the compound, aminoethanol. In an alternative example, the ligand comprises Formula (690) and R691 and R692 are selected to form the following compound:




In another embodiment, the ligand corresponds to Formula (700) and R701 and R702 are hydrogen thus forming the compound, ethylenediamine.
In a preferred example, the chiral ligand may be p-toluenesulfonyl-1,2-diphenylethylenediamine, (1S,2S)-(+)-N-4-toluenesulfonyl-1,2-diphenylethylene-1,2-diamine, (1R,2R)-(−)—N-4-toluenesulfonyl-1,2-diphenylethylene-1,2-diamine, dl-N-tosyl-1,2-diphenylethylenediamine, N-tosyl-1,2-diphenylethylenediamine, N-tosyl-1,2-ethylenediamine, or N-tosyl-1,2-diaminocyclohexane.
Suitable ruthenium or rhodium asymmetric catalysts include the following:







The molar ratio of the compound comprising Formula (I) and the transition metal catalyst can and will vary depending, for example, on the nature of the transition metal catalyst. In general, the molar ratio of the compound comprising Formula (I) and the transition metal catalyst will range from about 1:0.0001 to about 1:0.01. In some embodiments, the molar ratio of the compound comprising Formula (I) and the transition metal catalyst may range from about 1:0.0001 to about 1:0.001, or more preferably from about 1:0.001 to about 1:0.01.
(iv) Solvent
The reaction mixture, as detailed herein, also comprises a solvent. The solvent can and will vary depending on the starting substrate and the reactants used in the process. The solvent may be a protic solvent, an aprotic solvent, a non-polar solvent, or combinations thereof, Suitable examples of protic solvents include, but are not limited to, methanol, ethanol, isopropanol, n-propanol, isobutanol, n-butanol, s-butanol, t-butanol, water, and combinations thereof. Non-limiting examples of suitable aprotic solvents include acetonitrile, diethoxymethane, N,N-dimethylacetamide (DMAC), N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N,N-dimethylpropionamide, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), 1,3-dimethyl-2-imidazolidinone (DMI), 1,2-dimethoxyethane (DME), dimethoxymethane, bis(2-methoxyethyl)ether, 1,4-dioxane, N-methyl-2-pyrrolidinone (NMP), ethyl formate, formamide, hexamethylphosphoramide, N-methylacetamide, N-methylformamide, methylene chloride, nitrobenzene, nitromethane, propionitrile, sulfolane, tetramethylurea, tetrahydrofuran (THF), 2-methyl tetrahydrofuran, trichloromethane, and combinations thereof. Suitable examples of non-polar solvents include, but are not limited to, alkane and substituted alkane solvents (including cycloalkanes), aromatic hydrocarbons, esters, ethers, combinations thereof, and the like. Specific non-polar solvents that may be employed, include, for example, benzene, butyl acetate, t-butyl methylether, chlorobenzene, chloroform, chloromethane, cyclohexane, dichloromethane, dichloroethane, diethyl ether, ethyl acetate, diethylene glycol, fluorobenzene, heptane, hexane, isopropyl acetate, methyltetrahydrofuran, pentyl acetate, n-propyl acetate, tetrahydrofuran, toluene, and combinations thereof. Exemplary solvents include acetonitrile, chloroform, dichloromethane, N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidinone, ethyl acetate, ethanol, and methanol. In embodiments in which the amine source is a primary amine, the preferred solvent is acetonitrile. In embodiments in which the amine source is an ammonium salt, the preferred solvent is ethanol.
In general, the weight ratio of the solvent to the compound comprising Formula (I) will range from about 0.5:1 to about 100:1. In various embodiments, the weight ratio of the solvent to the compound comprising Formula (I) may range from 0.5:1 to about 5:1, from about 5:1 to about 25:1, or from about 25:1 to about 100:1. In preferred embodiments, the weight ratio of the solvent to the compound comprising Formula (I) may range from about 2:1 to about 10:1.
(v) Reaction Conditions
In general, the reaction will be conducted at a temperature that ranges from about 20° C. to about 100° C., or more preferably from about 20° C. to about 60° C. In various embodiments, the temperature of the reaction may be about room temperature (−23° C.), about 30° C., about 40° C., about 50° C., or about 60° C. In exemplary embodiments, the temperature of the reaction may be about room temperature. The reaction typically is performed under ambient atmosphere and pressure.
Generally, the reaction is allowed to proceed for a sufficient period of time until the reaction is complete, as determined by any method known to one skilled in the art, such as chromatography (e.g., HPLC). The duration of the reaction may range from about 12 hours to more than 3 days. In some embodiments, the reaction may be allowed to proceed for 12 hours, 18 hours, 24 hours, 36 hours, 48 hours, 60 hours, 72 hours, or 84 hours. In this context, a “completed reaction” generally means that the reaction mixture contains a significantly diminished amount of the compound comprising Formula (I). Typically, the amount of the compound comprising Formula (I) remaining in the reaction mixture may be less than about 3%, and preferably less than about 1%.
(b) Intermediate Compounds
During step A of the process, the compound comprising Formula (I) is converted into a first intermediate compound comprising Formula (II), as depicted in Reaction Scheme 1. Specifically, the 6-keto moiety is converted to a 6-imine moiety, such that the compound comprising Formula (IL) is a bis-formate salt of the 6-imine morphinan. The 6-imine moiety of the compound comprising Formula (II) is converted in situ to the 6-alpha-amine epimer of the compound comprising Formula (II), as shown in Reaction Scheme 1. Additionally, the solvent of reaction mixture may be azeotropically dried, thereby further driving formation of the compound comprising Formula (III).
The bis-formate salt of the 6-alpha-amine morphinan comprising Formula (III) may precipitate out of the reaction mixture, and may be recovered from the reaction mixture using standard procedures. In other embodiments, the compound comprising Formula (III) may be isolated from the reaction mixture using standard procedures known to those of skill in the art.
(c) Step B of the Process
The process further comprises contacting the compound comprising Formula (III) with a proton acceptor, wherein the compound comprising Formula (IV) is formed. A variety of proton acceptors are suitable for use in this step of the process. In general, the proton acceptor will have a pKa greater than about 9. Suitable proton acceptors having this characteristic include ammonia, borate salts (such as, for example, NaBO3), bicarbonate salts (such as, for example, NaHCO3, KHCO3, LiCO3, and the like), carbonate salts (such as, for example, Na2CO3, K2CO3, Li2CO3, and the like), hydroxide salts (such as, for example, NaOH, KOH, and the like), organic bases (such as, for example, pyridine, methylamine, diethylamine, triethylamine, diisopropylethylamine, N-methylmorpholine, N,N-dimethylaminopyridine), and mixtures of any of the above. In preferred embodiments, the proton acceptor may be ammonia, ammonium hydroxide, potassium hydroxide, or sodium hydroxide. In an exemplary embodiment, the proton acceptor may be ammonia.
Typically, the amount of proton acceptor that is added to the reaction will be sufficient to adjust the pH of the reaction mixture to a value between 9 and 10. Preferably, the pH of the reaction mixture does not exceed 10. In some embodiments, the pH of the reaction mixture may range from about 9.0 to about 9.2, from about 9.2 to about 9.4, from about 9.4 to about 9.6, from about 9.6 to about 9.8, or from about 9.8 to about 10.0. In exemplary embodiments, the pH of the reaction mixture may range from about 9.3 to about 9.6. The proton acceptor may be may be added in small aliquots or dropwise to the reaction mixture until the desired the pH is reached.
The reaction mixture may further comprise a protic solvent. Suitable protic solvents are listed above in section (II)(a)(iv). In exemplary embodiments, the protic solvent may be water.
Typically, the reaction is allowed to proceed at room temperature for a sufficient period of time until the reaction is complete. Generally, the compound comprising Formula (IV) precipitates out of the reaction mixture. Accordingly, the reaction may be complete when no further precipitate is formed. Alternatively, the reaction may be determined complete by any known to those of skill in that, such as chromatography (e.g., HPLC). In this context, a “completed reaction” generally means that the reaction mixture contains a significantly diminished amount of the compound comprising Formula (III) and a significantly increased amount of the compound comprising Formula (IV) compared to the amounts of each present at the beginning of the reaction. Typically, the amount of the compound comprising Formula (III) remaining in the reaction mixture may be less than about 3%, and preferably less than about 1%.
The compound comprising Formula (IV) may be isolated from the reaction mixture using techniques known to those of skill in the art. Non-limiting examples of suitable techniques include precipitation, extraction, chromatography, and crystallization.
The yield of the compound comprising Formula (IV) can and will vary. Typically, the yield of the compound comprising Formula (IV) may be at least about 60%. In one embodiment, the yield of the compound comprising Formula (IV) may range from about 60% to about 70%. In another embodiment, the yield of the compound comprising Formula (IV) may range from about 70% to about 80%. In a further embodiment, the yield of the compound comprising Formula (IV) may range from about 80% to about 90%. In still another embodiment, the yield of the compound comprising Formula (IV) may be greater than about 90%.
In embodiments in which the amine source is an ammonium salt, the final product further comprises an N-formyl-6-alpha-amino morphinan comprising Formula (V):




wherein R, R1, R2, R3, R7, R8, and R14 are as defined above in Reaction Scheme 1.
The compound comprising Formulas (IV) or (V) may be used as is or may be converted to another compound using techniques familiar to those of skill in the art. The compound comprising Formulas (IV) or (V) may also be converted into a pharmaceutically acceptable salt, Pharmaceutically acceptable cations include metallic ions and organic ions. More preferred metallic ions include, but are not limited to, appropriate alkali metal salts, alkaline earth metal salts, and other physiologically acceptable metal ions. Exemplary cations include aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc in their usual valences. Preferred organic cations include protonated tertiary amines and quaternary ammonium cations including, in part, trimethylamine, diethylamine, N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N methylglucamine) and procaine. Exemplary pharmaceutically acceptable acids include, without limitation, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, acetic acid, formic acid, tartaric acid, maleic acid, malic acid, citric acid, isocitric acid, succinic acid, lactic acid, gluconic acid, glucuronic acid, pyruvic acid, oxalacetic acid, fumaric acid, propionic acid, aspartic acid, glutamic acid, benzoic acid, and the like.
In general, the compound(s) prepared by the processes of the invention are enantiomerically pure in that the final product comprises less than about 5% of the 6-beta-amino epimer. In some embodiments, the final product may comprise less than about 2% of the 6-beta-amino epimer. In further embodiments, the final product may comprise less than about 1% of the 6-beta-amino epimer.
The compounds comprising any of Formulas (I), (II), (III), (IV), or (V) may have a (−) or a (+) orientation with respect to the rotation of polarized light. More specifically, each chiral center of the morphinans may have an R or an S configuration. The compounds described herein may have at least four chiral centers, namely carbons C-5, C-9, C-13, and C-14. At each chiral center, the stereochemistry at the carbon atom is independently R or S. The configuration of C-5, C-9, C-13, and C-14, respectively, may be RRRR, RRRS, RRSR, RSRR, SRRR, RRSS, RSSR, SSRR, SRRS, SRSR, RSRS, RSSS, SRSS, SSRS, SSSR, or SSSS, provided that the C-15 and C-16 atoms are both on the alpha face of the molecule or both on the beta face of the molecule. The 6-alpha-amino group, i.e., {—}NHR6, may be R or S, depending on the identity (or priority) of R6.
In preferred embodiments, the compound produced by the process of the invention is a compound as diagrammed below or a pharmaceutically acceptable salt of the compound:




wherein:

    
    
        R is selected from the group consisting of alkyl, cycloalkyl, cycloalkylmethyl, alkenyl, aryl, and heterocyclo;
        R3 is selected from the group consisting of hydrogen, alkyl, and a protecting group;
        R6 is selected from the group consisting of hydrogen, hydrocarbyl, and substituted hydrocarbyl; and
        R14 is selected from the group consisting of hydrogen and hydroxy.
    
    


In preferred embodiments, R is methyl, cyclopropylmethyl, or allyl, and R3 is hydrogen or methyl.
(III) Compositions
A further aspect of the invention encompasses an epimerically pure composition comprising a compound of Formula (IV) and less than about 5% of a 6-beta amino epimer of the compound comprising Formula (IV):




wherein R, R1, R2, R3, R6, R7, R8, and R14 are as defined above in Reaction Scheme 1.
Moreover, the compounds of the composition may comprise pharmaceutically acceptable salts of the compound comprising Formula (IV), as detailed above in section (II)(c).
In one embodiment, the composition of the invention comprises less than about 2% of the 6-beta amino epimer. In another embodiment, the composition of the invention comprises less than 1% of the 6-beta amino epimer. In a further embodiment, the composition of the invention comprises more than about 95% of the 6-alpha-amino epimer. In still another embodiment, the composition of the invention comprises more than about 98% of the 6-alpha-amino epimer. In a further embodiment, the composition of the invention comprises more than 99% of the 6-alpha-amino epimer.
The composition of the invention may be formulated for administration by a number of different means that will deliver a therapeutically effective dose. Such formulations may be administered orally, parenterally, by inhalation spray, rectally, intradermally, transdermally, or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. Topical administration may also involve the use of transdermal administration such as transdermal patches or iontophoresis devices. The term parenteral as used herein includes subcutaneous, intravenous, intramuscular, or intrasternal injection, or infusion techniques. Formulation of drugs is discussed in, for example, Gennaro, A. R., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. (18th ed, 1995), and Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Dekker Inc., New York, N.Y. (1980).
DEFINITIONS
The compounds described herein have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic form. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated.
The term “acyl,” as used herein alone or as part of another group, denotes the moiety formed by removal of the hydroxy group from the group COOH of an organic carboxylic acid, e.g., RC(O)—, wherein R is R1, or R1O—, R1R2N—, or R1S—, R1 is hydrocarbyl, heterosubstituted hydrocarbyl, or heterocyclo, and R2 is hydrogen, hydrocarbyl, or substituted hydrocarbyl.
The term “acyloxy,” as used herein alone or as part of another group, denotes an acyl group as described above bonded through an oxygen linkage (O), e.g., RC(O)O— wherein R is as defined in connection with the term “acyl.”
The term “allyl,” as used herein not only refers to compound containing the simple allyl group (CH2═CH—CH2—), but also to compounds that contain substituted allyl groups or allyl groups forming part of a ring system.
The term “alkyl” as used herein describes groups which are preferably lower alkyl containing from one to eight carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain or cyclic and include methyl, ethyl, propyl, isopropyl, butyl, hexyl and the like.
The term “alkenyl” as used herein describes groups which are preferably lower alkenyl containing from two to eight carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain or cyclic and include ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, hexenyl, and the like.
The term “alkynyl” as used herein describes groups which are preferably lower alkynyl containing from two to eight carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain and include ethynyl, propynyl, butynyl, isobutynyl, hexynyl, and the like.
As used herein, the term “6-amino” encompasses primary and secondary amine moieties conjugated to C-6 of a morphinan.
The term “aromatic” as used herein alone or as part of another group denotes optionally substituted homo- or heterocyclic conjugated planar ring or ring system comprising delocalized electrons. These aromatic groups are preferably monocyclic (e.g., furan or benzene), bicyclic, or tricyclic groups containing from 5 to 14 atoms in the ring portion. The term “aromatic” encompasses “aryl” groups defined below.
The terms “aryl” or “Ar” as used herein alone or as part of another group denote optionally substituted homocyclic aromatic groups, preferably monocyclic or bicyclic groups containing from 6 to 10 carbons in the ring portion, such as phenyl, biphenyl, naphthyl, substituted phenyl, substituted biphenyl, or substituted naphthyl.
The terms “carbocyclo” or “carbocyclic” as used herein alone or as part of another group denote optionally substituted, aromatic or non-aromatic, homocyclic ring or ring system in which all of the atoms in the ring are carbon, with preferably 5 or 6 carbon atoms in each ring. Exemplary substituents include one or more of the following groups: hydrocarbyl, substituted hydrocarbyl, alkyl, alkoxy, acyl, acyloxy, alkenyl, alkenoxy, aryl, aryloxy, amino, amido, acetal, carbamyl, carbocyclo, cyano, ester, ether, halogen, heterocyclo, hydroxy, keto, ketal, phospho, nitro, and thio.
The terms “halogen” or “halo” as used herein alone or as part of another group refer to chlorine, bromine, fluorine, and iodine.
The term “heteroatom” refers to atoms other than carbon and hydrogen.
The term “heteroaromatic” as used herein alone or as part of another group denotes optionally substituted aromatic groups having at least one heteroatom in at least one ring, and preferably 5 or 6 atoms in each ring. The heteroaromatic group preferably has 1 or 2 oxygen atoms and/or 1 to 4 nitrogen atoms in the ring, and is bonded to the remainder of the molecule through a carbon. Exemplary groups include furyl, benzofuryl, oxazolyl, isoxazolyl, oxadiazolyl, benzoxazolyl, benzoxadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl, carbazolyl, purinyl, quinolinyl, isoquinolinyl, imidazopyridyl, and the like. Exemplary substituents include one or more of the following groups: hydrocarbyl, substituted hydrocarbyl, alkyl, alkoxy, acyl, acyloxy, alkenyl, alkenoxy, aryl, aryloxy, amino, amido, acetal, carbamyl, carbocyclo, cyano, ester, ether, halogen, heterocyclo, hydroxy, keto, ketal, phospho, nitro, and thio.
The terms “heterocyclo” or “heterocyclic” as used herein alone or as part of another group denote optionally substituted, fully saturated or unsaturated, monocyclic or bicyclic, aromatic or non-aromatic groups having at least one heteroatom in at least one ring, and preferably 5 or 6 atoms in each ring. The heterocyclo group preferably has 1 or 2 oxygen atoms and/or 1 to 4 nitrogen atoms in the ring, and is bonded to the remainder of the molecule through a carbon or heteroatom. Exemplary heterocyclo groups include heteroaromatics as described above. Exemplary substituents include one or more of the following groups: hydrocarbyl, substituted hydrocarbyl, alkyl, alkoxy, acyl, acyloxy, alkenyl, alkenoxy, aryl, aryloxy, amino, amido, acetal, carbamyl, carbocyclo, cyano, ester, ether, halogen, heterocyclo, hydroxy, keto, ketal, phospho, nitro, and thio.
The terms “hydrocarbon” and “hydrocarbyl” as used herein describe organic compounds or radicals consisting exclusively of the elements carbon and hydrogen. These moieties include alkyl, alkenyl, alkynyl, and aryl moieties. These moieties also include alkyl, alkenyl, alkynyl, and aryl moieties substituted with other aliphatic or cyclic hydrocarbon groups, such as alkaryl, alkenaryl and alkynaryl. Unless otherwise indicated, these moieties preferably comprise 1 to 20 carbon atoms.
The term “protecting group” as used herein denotes a group capable of protecting an oxygen atom (and hence, forming a protected hydroxy), wherein the protecting group may be removed, subsequent to the reaction for which protection is employed, without disturbing the remainder of the molecule. Exemplary protecting groups include ethers (e.g., allyl, triphenylmethyl (trityl or Tr), p-methoxybenzyl (PMB), p-methoxyphenyl (PMP)), acetals (e.g., methoxymethyl (MOM), β-methoxyethoxymethyl (MEM), tetrahydropyranyl (THP), ethoxy ethyl (EE), methylthiomethyl (MTM), 2-methoxy-2-propyl (MOP), 2-trimethylsilylethoxymethyl (SEM)), esters (e.g., benzoate (Bz), allyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-trimethylsilylethyl carbonate), silyl ethers (e.g., trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), triphenylsilyl (TPS), t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS) and the like. A variety of protecting groups and the synthesis thereof may be found in “Protective Groups in Organic Synthesis” by T. W. Greene and P. G. M. Wuts, John Wiley & Sons, 1999.
The “substituted hydrocarbyl” moieties described herein are hydrocarbyl moieties which are substituted with at least one atom other than carbon, including moieties in which a carbon chain atom is substituted with a heteroatom such as nitrogen, oxygen, silicon, phosphorous, boron, or a halogen atom, and moieties in which the carbon chain comprises additional substituents. These substituents include alkyl, alkoxy, acyl, acyloxy, alkenyl, alkenoxy, aryl, aryloxy, amino, amido, acetal, carbamyl, carbocyclo, cyano, ester, ether, halogen, heterocyclo, hydroxy, keto, ketal, phospho, nitro, and thio.
When introducing elements of the present invention or the preferred embodiments(s) thereof, the articles “a”, “an”, “the” and “said” are intended to mean that there are one or more of the elements. The terms “comprising”, “including” and “having” are intended to be inclusive and mean that there may be additional elements other than the listed elements.
Having described the invention in detail, it will be apparent that modifications and variations are possible without departing from the scope of the invention defined in the appended claims.
EXAMPLES
The following examples are included to demonstrate preferred embodiments of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the examples represent techniques discovered by the inventors to function well in the practice of the invention. Those of skill in the art should, however, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments that are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention, therefore all matter set forth is to be interpreted as illustrative and not in a limiting sense.
Example 1
Reductive Amination of (−)-Oxymorphone with Benzylamine
The following reaction scheme depicts the preparation of a 6-alpha amino derivative of (−)-oxymorphone:




Into a round bottom flask was added oxymorphone (1.22 g, 0.004 mole), triethylamine (2.15 g, 0.021 moles, 2.96 mL), benzylamine (0.91 g, 0.008 moles, 0.9 mL), and acetonitrile (6.0 mL). To this solution was added >96% formic acid (2.44 g, 0.053 moles, 2.00 mL) dropwise. After stirring for 5 minutes, dichloro(p-cymene)ruthenium (II) dimer (Ru(II) dimer) (13 mg) was added and the reaction mixture was stirred at room temperature for 48 h. LC indicated that the reaction was  ̃75% complete. To the reaction mixture was added an additional amount of benzylamine (0.91 g, 0.008 moles, 0.9 mL) and Ru(II) dimer (13 mg). The reaction was stirred for an additional 3 days. LC indicated that the reaction was complete. Under reduced pressure, the reaction mixture was evaporated to a thick oil. To the thick oil was added distilled water (10 mL) and acetonitrile (1 mL). 29% NH3/H2O was added dropwise until the pH of reaction mixture was 9.3. A precipitate formed. The precipitate was isolated by filtration, and the precipitate was washed with distilled water (10 mL). After drying in an oven at 75° C. for 24 h, the product (1.37 g, 86% yield) was isolated as a tan solid.
Example 2
Reductive Amination of (−)-Naltrexone with Benzylamine
A 6-alpha amino derivative of naltrexone was prepared according to the following reaction scheme:




Into a round bottom flask was added naltrexone (2.18 g, 0.006 mole), triethylamine (3.23 g, 0.032 moles, 4.45 mL), benzylamine (2.05 g, 0.019 moles, 2.01 mL), and acetonitrile (10.0 mL). To this solution was added >96% formic acid (3.67 g, 0.08 moles, 3.00 mL) dropwise, After stirring for 10 minutes, dichloro(p-cymene)ruthenium (II) dimer (20 mg) was added and the reaction mixture was stirred at room temperature for 72 h. LC indicated that the reaction was complete. Under reduced pressure, the reaction mixture was evaporated to a thick oil. To the thick oil was added distilled water (10 mL) and acetonitrile (1 mL). 29% NH3/H2O was added dropwise until the pH of the mixture was 9.3. A precipitate formed and the mixture was stirred at room temperature for 18 h. The precipitate was then isolated by filtration, and the precipitate was washed with distilled water (10 mL). After drying in an oven at 75° C. for 24 h, the product (2.59 g, 93% yield) was isolated as a tan solid.
Example 3
Reductive Amination of (−)Naltrexone with Ammonium Acetate
The following reaction scheme depicts the preparation of 6-alpha-naltrexamine:




Into a round bottom flask equipped with a reflux condenser was added naltrexone (2.95 g, 0.009 mole), ammonium acetate (7.99 g, 0.104 mole), and absolute ethanol (30 mL). This mixture was refluxed for 2 hours. After replacing the reflux condenser with a short path distillation set-up,  ̃10 mL of reaction solvent was removed. The mixture was cooled to room temperature, then triethylamine (4.37 g, 0.043 mole, 6.02 mL) was added, and >96% formic acid (4.97 g, 0.108 mole, 4.08 mL) was added dropwise. After 10 minutes of stirring, dichloro (p-cymene) ruthenium (II) dimer (26 mg) was added. The reaction stirred for 18 h at 60° C. LC indicated that two products were present, 6-α-naltrexamine and N-formyl-6α-naltrexamine. This reaction mixture stirred for an additional 24 h at 60° C. LC indicated that no 6-α-naltrexamine remained. The mixture was evaporated under reduced pressure to a thick oil. To this oil was added distilled water (10 mL) and acetonitrile (1 mL). 29% NH3/H2O was added dropwise until the pH of the mixture was 9.3. A precipitate formed which was isolated by filtration. The precipitate was washed with distilled water (5 mL), and then dried at 75° C. for 24 h yielding N-formyl-6-α-naltrexamine (2.87 g, 89% yield).
Example 4
Reductive Amination of (−)-Naltrexone with Alanine-Methyl Ester—Reaction I
A 6-alpha amino derivative of naltrexone was prepared according to the following reaction scheme:




Into a round bottom flask was added naltrexone (3.05 g, 0.009 moles), methyl ester of alanine hydrochloride (2.49 g, 0.018 mole), triethylamine (4.52 g, 0.045 mole, 6.23 mL), and dichloro(p-cymene)ruthenium (II) dimer (27 mg). >96% Formic acid (5.14 g, 0.112 mole, 4.21 mL) was added dropwise. The mixture was warmed to 40° C. for 24 h. LC indicated that the reaction was complete. Under reduced pressure, the solvent was evaporated to a thick oil. The residue was dissolved in chloroform (50 mL), and washed with distilled water (2×10 mL). After drying over anhydrous MgSO4, filtering, and evaporating to an oil, the product was isolated by column chromatography (Silica Gel G60, 20 g) eluting with 100% ethyl acetate. The desired fractions were evaporated to a solid (2.52 g, 66% yield), then dried overnight under vacuum at room temperature.
Example 5
Reductive Amination of (−)Naltrexone with Ethanolamine
The following reaction scheme depicts the preparation of a 6-alpha-amino derivative of naltrexone:




Into a round bottom flask was added naltrexone (1.70 g, 0.005 moles), ethanolamine (0.61 g, 0.01 mole, 0.59 mL), triethylamine (3.02 g, 0.030 mole, 4.16 mL), and dichloro(p-cymene)ruthenium (II) dimer (15 mg). >96% Formic acid (2.87 g, 0.062 mole, 2.35 mL) was added dropwise. The mixture was stirred at 25° C. for 72 h. LC indicated that the reaction was complete. Under reduced pressure, the solvent was evaporated to a thick oil. The residue was dissolved in distilled water (10 mL) and the pH was adjusted to 9.6 using 29% NH3/H2O. A gummy semi solid resulted. The entire aqueous solution was extracted with chloroform (3×50 mL). The extracts were combined, dried over anhydrous MgSO4 (2 g), filtered, and the filtrate was evaporated to a thick oil. The product (1.56 g, 81% yield) was isolated by gravity column chromatography eluting with 100% ethyl acetate. The desired fractions were evaporated, and the residue was dried under vacuum for 24 h at room temperature.
Example 6
Reductive Amination of (−)-Naltrexone with Aniline
A 6-alpha-amino derivative of naltrexone was prepared in accordance with the following reaction scheme:




Into a round bottom flask was added naltrexone (2.51 g, 0.007 moles), aniline (1.37 g, 0.015 mole, 1.34 mL), triethylamine (4.46 g, 0.044 mole, 6.15 mL), and dichloro(p-cymene)ruthenium (II) dimer (23 mg). >96% Formic acid (4.23 g, 0.092 mole, 3.8 mL) was added drop wise. The mixture was stirred at 25° C. for 72 h. LC indicated that the reaction was complete. Under reduced pressure, the solvent was evaporated to a thick oil. The residue was dissolved in distilled water (10 mL) and the pH was adjusted to 9.6 using 29% NH3/H2O. A gummy semi solid resulted. This mixture was stirred for 16 h at room temperature. The solid subsequently redissolved. The organic components were extracted with chloroform (3×25 mL). The extracts were combined, dried over anhydrous MgSO4 (2 g), filtered, and evaporated to a thick oil. The product (2.40 g, 78% yield) was isolated after gravity column chromatography Silica Gel G60, 15 g) eluting with 2.5% MeOH/CHCl3. The desired fractions were combined, evaporated under reduced pressure, and the residue was dried under vacuum overnight at room temperature.
Example 7
Reductive Amination of (−)-Naltrexone with Alanine-Methyl Ester—Reaction II
The following reaction scheme depicts the preparation of a 6-alpha-amino derivative of naltrexone:




Into a round bottom flask was added naltrexone (2.80 g, 0.008 moles), β-alanine methyl ester hydrochloride (2.23 g, 0.016 mole), and acetonitrile (20 mL). This mixture was stirred at 25° C. for 3 h. Then, triethylamine (4.98 g, 0.049 mole, 6.86 mL) was added followed by a dropwise addition of >96% formic acid (4.72 g, 0103 mole, 3.87 mL). Dichloro(p-cymene)ruthenium (II) dimer (25 mg) was added followed by acetonitrile (2 mL) to ensure the catalyst was introduced into the reaction. The reaction was stirred at room temperature (23° to 25° C.) for 36 h. A fine precipitate was present in the flask. LC/MS indicated the presence of product (MH+: 429 g/mole) and some naltrexol (MH+: 344 g/mole). Under reduced pressure, the mixture was evaporated to a thick oil/semi solid. The residue was dissolved in distilled water (20 mL) and the pH was adjusted to 9.4 using 29% NH3/H2O ( ̃1.5 mL). The mixture was stirred at 25° C. for 72 h. Initially, a solid formed after the addition of the ammonia but the solid subsequently redissolved. The organic components were extracted with chloroform (3×25 mL) and discarded. The aqueous layer was evaporated to a semi-solid under reduced pressure. LC/MS indicated that the main product was the free carboxylic acid (MH+: 415 g/mole). The residue was dissolved in isopropanol (20 mL), heated to reflux, and then filtered. Upon standing, the product crystallized from the filtrate. An additional crop of crystals was obtained yielding the free acid (2.45 g, 72% yield).
Example 8
Reductive Amination of (−)-Naltrexone with Alanine-Methyl Ester—Reaction III
A 6-alpha-amino derivative of naltrexone was prepared in accordance with the following reaction scheme:




Into a round bottom flask was added naltrexone (2.44 g, 0.007 moles), β-alanine methyl ester hydrochloride (2.00 g, 0.014 mole), and acetonitrile (15 mL). This mixture was stirred at 25° C. for 2 h. Then, triethylamine (4.98 g, 0.049 mole, 6.86 mL) was added followed by a dropwise addition of >96% formic acid (4.72 g, 0103 mole, 3.87 mL). Dichloro(p-cymene)ruthenium (II) dimer (22 mg) was added followed by acetonitrile (5 mL) to ensure the catalyst was introduced into the reaction. The reaction was stirred at room temperature (23° to 25° C.) for 24 h. LC/MS indicated that the presence of product (MW: 429 g/mole) and some naltrexol (MH+: 344 g/mole). A fine precipitate was present in the reaction flask. The precipitate was removed by filtration, washed with acetonitrile (10 mL), and dried under vacuum (24 h, 23° C.). (Wt:=1.52 g) The filtrate was evaporated under reduced pressure to a thick oil. Acetonitrile (20 mL) was added and the solution was stirred at room temperature for 48 h. A precipitate formed. The precipitate was removed by filtration, washed with acetonitrile (5 mL), and then dried under vacuum. (Wt 1.28 g. Total: 2.80 g, 75% yield.)
Example 9
Reductive Amination of (−)-Naltrexone with Methylamine
The following reaction scheme depicts the preparation of a 6-alpha-amino derivative of naltrexone:




Into a round bottom flask was added naltrexone (1.55 g, 0.005 moles), methylamine hydrochloride (0.61 g, 0.009 mole), and acetonitrile (5 mL). This mixture was stirred at 25° C. for 5 minutes. Then, triethylamine (2.75 g, 0.027 mole, 3.80 mL) was added, followed by a dropwise addition of >96% formic acid (2.61 g, 0.057 mole, 2.14 mL). Dichloro(p-cymene)ruthenium (II) dimer (14 mg) was added followed by acetonitrile (5 mL) to ensure the catalyst was introduced into the reaction. The reaction was stirred at room temperature (23° to 25° C.) for 24 h. LC/MS indicated that the reaction was complete. A fine precipitate was present in the reaction flask. The precipitate (identified as the formate salt) was removed by filtration, washed with acetonitrile (10 mL), and dried under vacuum (24 h, 23° C.). (Wt: 1.20 g) The filtrate was evaporated under reduced pressure to a thick oil. Distilled water (10 mL) was added, followed by dropwise addition of 29% NH3/H2O until the pH of the mixture was 9.4. This solution was extracted with ethyl acetate (3×25 mL). The extracts were combined, dried over anhydrous MgSO4 (2.5 g), filtered, and evaporated to a pasty solid forming the product (0.51 g). The initially obtained formate salt was dissolved in distilled water (5 mL). 29% NH3/H2O was added until the pH was 9.4. This solution was cooled to 0° C., and then stirred for 1 h, wherein a precipitate formed. The precipitate was isolated by filtration, the solid was washed with distilled water (5 mL), and dried under vacuum at 25° C. for 48 h. Solid weight: 0.97 g. Combined weight of the product (1.48 g, 92% yield).
Example 10
Reductive Amination of (+)-Naltrexone with Methylamine
A 6-alpha-amino derivative of (+)-naltrexone was prepared in accordance with the following reaction scheme:




Into a round bottom flask was charged (+)-naltrexone (0.60 g, 0.002 moles), acetonitrile (4.0 mL), then methylamine hydrochloride (0.24 g, 0.004 moles). This mixture was stirred at room temperature for 5 minutes, and then triethylamine (0.89 g, 0.009 moles, 1.22 mL) was added. This mixture was cooled to 5° C. (ice/water bath). >96% Formic Acid (1.01 g, 0.022 moles, 0.83 mL) was added dropwise. After the addition of formic acid was complete, dichloro(p-cymene) Ru(II) dimer (5 mg, 0.008 mmole) was added. The side of the reaction flask was rinsed with acetonitrile (1.0 mL). The reaction mixture was stirred at room temperature for 24 h, wherein analysis by HPLC indicated the reaction was complete. The mixture was evaporated under reduced pressure to a thick oil. To this oil was added distilled water (10 mL), and then the pH of this solution was adjusted to 9.5 using 29% NH3/H2O. After stirring, a precipitate formed. The product (540 mg, 0.0015 moles, 86% yield) was isolated by filtration. The solid was washed with distilled water (5.0 mL) and dried under vacuum for 24 h to yield an off white product.

## Claims

1. A process for preparing a 6-alpha-amino N-substituted morphinan, the process comprising contacting a 6-keto N-substituted morphinan with an amine source, a hydrogen donor comprising a formate ion, a transition metal catalyst, and a proton acceptor to form the 6-alpha-amino N-substituted morphinan, wherein the amine source comprises the formula R6NH2, wherein R6 is selected from the group consisting of hydrogen, hydrocarbyl, and substituted hydrocarbyl.

2. The process of claim 1, wherein the 6-keto N-substituted morphinan is selected from the group consisting of hydrocodone, hydromorphone, oxycodone, oxymorphone, naloxone, and naltrexone; the amine source is selected from the group consisting of a primary amine and an ammonium salt; the hydrogen donor comprising a formate ion is selected from the group consisting of formic acid, a salt of formic acid, and a mixture of formic acid and an organic base; the transition metal catalyst comprises ruthenium, rhodium, or iridium; and the proton acceptor has a pKa of great than about 9.

3. The process of claim 1, wherein contact between the 6-keto N-substituted morphinan, the amine source, the hydrogen donor, and the transition metal catalyst forms a first intermediate comprising a formate salt of a 6-imine N-substituted morphinan, the first intermediate being converted in situ to a second intermediate comprising a formate salt of a 6-alpha-amino morphinan, and contact between the second intermediate and the proton acceptor forms the 6-alpha-amino N-substituted morphinan.

4. The process of claim 1, wherein the process produces a product comprising the 6-alpha-amino N-substituted morphinan and no more than about 2% of a 6-beta-amino morphinan epimer.

5. A process for preparing a compound of Formula (IV):



the process comprising:
reducing a compound of Formula (I) in the presence of an amine source (R6NH2), a hydrogen donor comprising a formate ion, a transition metal catalyst, and a proton acceptor to form the compound of Formula (IV), the compound of Formula (I) having the structure:





wherein:
R is selected from the group consisting of hydrocarbyl and substituted hydrocarbyl;
R1 and R2 are independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, halogen, and {—}OR15;
R3, R7, and R8 are independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, and {—}OR15;
R6 is selected from the group consisting of hydrogen, hydrocarbyl and substituted hydrocarbyl;
R14 is selected from the group consisting of hydrogen and {—}OR15; and
R15 is selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, and a hydroxy protecting group.

6. The process of claim 5, wherein R1, R2, R7, and R8 are hydrogen; R14 is hydrogen or hydroxyl; R is selected from the group consisting of alkyl, cycloalkyl, cycloalkylmethyl, alkenyl, aryl, and heterocyclo; R3 is selected from the group consisting of alkoxy, hydroxy, and protected hydroxyl; the hydrogen donor comprising a formate ion is selected from the group consisting of formic acid, a salt of formic acid, and a mixture of formic acid and an organic base; R6 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, and aryl, and the amine source is a primary amine; the molar ratio of the compound of Formula (I) to the primary amine to the hydrogen donor is from about 1:1:1 to about 1:5:20; the transition metal catalyst comprises ruthenium, rhodium, or iridium; the molar ratio of the compound of Formula (I) to the transition metal catalyst is about 1:0.0001 to about 1:0.01; the reaction between the compound of Formula (I), the amine source, the transition metal catalyst, and the hydrogen donor occurs in the presence of a solvent selected from the group consisting of an aprotic solvent, a protic solvent, a non-polar solvent, and combinations thereof; the reaction between the compound of Formula (I), the amine source, the transition metal catalyst, and the hydrogen donor occurs at a temperature from about 20° C. to about 100° C.; and the proton acceptor has a pKa of greater than about 9 and is selected from the group consisting of ammonia, ammonium hydroxide, potassium hydroxide, and sodium hydroxide.

7. The process of claim 5, wherein R6 is hydrogen and the amine source is an ammonium salt.

8. The process of claim 7, wherein the molar ratio of the compound of Formula (I) to the ammonium salt to the hydrogen donor is from about 1:2:1 to about 1:20:20.

9. The process of claim 5, wherein the hydrogen donor comprises formic acid and triethylamine.

10. The process of claim 9, wherein the molar ratio of the compound of Formula (I) to triethylamine is from about 1:1 to about 1:10.

11. The process of claim 5, wherein the transition metal catalyst is selected from the group consisting of dichloro(arene)Ru(II) dimer, dichloro(pentamethylcyclopentadienyl)Rh(II) dimer, BINAP-Ru(II) diacetate, BINAP-Ru(II) dichloride, BINAP-Ru(II) dibromide, BINAP-Ru(II) diiodide, [RuCl((R or S)BINAP)(C6H6)]Cl, dichloro(pentamethylcyclopentadienyl)iridium(III) dimer, Ru(III)chloride, RuCl3 hydrate, Ru(III) acetylacetonate, tetraalkylammonium RuCl4, and pyridinium RuCl4.

12. The process of claim 5, wherein the transition metal catalyst is a Noyori catalyst.

13. The process of claim 5, wherein a first intermediate comprising Formula (II) is formed after the compound of Formula (I) is contacted with the amine source, the hydrogen source, and the transition metal catalyst, and the first intermediate is converted in situ to a second intermediate comprising Formula (III):



wherein:
R is selected from the group consisting of hydrocarbyl and substituted hydrocarbyl;
R1 and R2 are independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, halogen, and {—}OR15;
R3, R7, and R8 are independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, and {—}OR15;
R6 is selected from the group consisting of hydrogen, hydrocarbyl and substituted hydrocarbyl;
R14 is selected from the group consisting of hydrogen and {—}OR15; and
R15 is selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, and a hydroxy protecting group.

14. The process of claim 5, wherein the compound of Formula (IV) has a structure of Formula (V):



wherein:
R is selected from the group consisting of hydrocarbyl and substituted hydrocarbyl;
R1 and R2 are independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, halogen, and {—}OR15;
R3, R7, and R8 are independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, and {—}OR15;
R14 is selected from the group consisting of hydrogen and {—}OR15; and
R15 is selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, and a hydroxy protecting group.

15. The process of claim 5, wherein the amine source is a primary amine; the molar ratio of the compound of Formula (I) to the primary amine is about 1:2; the hydrogen donor comprises formic acid and triethylamine; the molar ratio of the compound of Formula (I) to formic acid to triethylamine is about 1:12:3; the transition metal catalyst is dichloro(p-cymene)Ru(II) dimer; the molar ratio of the compound of Formula (I) to the Ru(II) dimer is from about 1:0.001 to 1:0.01; reaction with the primary amine, Ru(II) dimer, and formic acid/triethylamine occurs in the presence of acetonitrile and at a temperature from about 20° C. to about 60° C.; the proton acceptor is ammonia; and reaction with the proton acceptor occurs in a protic solvent system comprising water, at a pH of about 9.5, and at room temperature.

16. The process of claim 5, wherein the amine source is ammonium acetate; the molar ratio of the compound of Formula (I) to ammonium acetate is about 1:12; the hydrogen donor comprises formic acid and triethylamine; the molar ratio of the compound of Formula (I) to formic acid to triethylamine is about 1:12:5; the transition metal catalyst is dichloro(p-cymene)Ru(II) dimer; the molar ratio of the compound of Formula (I) to the Ru(II) dimer is from about 1:0.001 to 1:0.01; reaction of the ammonium acetate, the Ru(II) dimer, and the formic acid/triethylamine occurs in the presence of ethanol and at a temperature from about 20° C. to about 60° C.; the proton acceptor is ammonia; and reaction with the proton acceptor occurs in a protic solvent system comprising water, at a pH of about 9.5, and at room temperature.

17. The process of claim 5, wherein the optical activity of the compounds of Formulas (I) or (IV) is (−) or (+), the configuration of C-5, C-13, C-14, and C-9, respectively, is selected from the group consisting of RRRR, RRRS, RRSR, RSRR, SRRR, RRSS, RSSR, SSRR, SRRS, SRSR, RSRS, RSSS, SRSS, SSRS, SSSR, and SSSS, provided that C-15 and C-16 are both either on the alpha face or the beta face of the molecule; and the process produces a product comprising the compound of Formula (IV) and less than 2% of a 6.beta-amino epimer.