WO2000066588A1

WO2000066588A1 - Direct c-14 oxidation of opioids

Info

Publication number: WO2000066588A1
Application number: PCT/US2000/012357
Authority: WO
Inventors: Andrew Coop; Kenner C. Rice
Original assignee: The Government Of The United States Of America, Represented By The Secretary, Departmentof Health A Nd Human Services
Priority date: 1999-05-05
Filing date: 2000-05-04
Publication date: 2000-11-09
Also published as: AU4823900A

Abstract

The present invention provides a method of preparing a 14-hydroxy opioid of Formula (II): which includes reacting the correponding 14-H opioid (possessing a hydrogen at the C-14 position) with a cobalt (III) oxidant which can oxidize the 14 position, to produce the above 14-hydroxy derivative. R1 is a C¿1?-C6 alkyl, a C2-C6 alkenyl, a C2-C6 alkynyl, a C3-C6 cycloalkyl, an aryl, a cycloalkylalkyl, or an aralkyl. R?2¿ is a C¿1?-C6 alkyl, a C2-C6 alkenyl, a C2-C6 alkynyl, a C3-C6 cycloalkyl, an aryl, a cycloalkylalkyl, and aralkyl, C(O)R?3¿, or C(O)NR3R4, wherein R?3 and R4¿ are the same or different and each is H, a C¿1?-C6 alkyl, a C2-C6 alkenyl, a C2-C?6¿ alkynyl, a C¿3?-C6 cycloalkyl, an aryl, a cycloalkylalkyl, or an aralkyl. R?1-R4¿ can be the same or different and each can be substituted or unsubstituted.

Description

DIRECT C-14 OXIDATION OF OPIOIDS

TECHNICAL FIELD OF THE INVENTION The present invention relates to the synthesis of opioids .

BACKGROUND OF THE INVENTION The 14-hydroxy substituted opioid antagonists are a class of compounds that are useful in a variety of medicinal applications. For example, 14-hydroxy opioids, such as naltrexone (1, in which X=0) and naloxone (2) , are valuable medications for the treatment of opiate abuse, opiate overdose, and alcohol addiction. See, e.g., U.S. Patent 3,332,950; U.S. Patent 3,254,088; Mello et al . , J. Pharmacol . Exp. Ther . , 216, 45 (1981); Martin, Ann .

Intern . Med . , 85, 765 (1976); and Altshuler, Drug Al e . Dep . , 4 , 333 (1979). Nalmefene (1, in which X=CH₂) , for example, is a 14-hydroxy opioid which is structurally similar to naltrexone, and is used to induce immobilization of large animals. See, e.g., U.S. Patent 3,814,768; and U.S. Patent 4,535,157.

naltrexone i (X=0 ) naloxone nalmefene ( X=CH₂ )

The demand for these medicinal opioids is ever increasing. Moreover, recent findings suggest that delta subtype selective derivatives of such compounds can be therapeutically useful in immunosuppression and the prevention of morphine tolerance. See, e.g., K. Arakawa et al., Transplant Proc . , 25, 738 (1993); and Abdelhamid et al., J. Pharmacol . Exp . Ther . , 258 , 299 (1991). Thus, in addition to well-established indications, the 14- hydroxy opioids also are valuable research tools that can be used in the identification and development of new, medicinally useful opioids with new indications .

One of the primary building blocks for producing 14- hydroxy opioids is 14-hydroxycodeinone (4), a key intermediate from which important antagonists can be prepared. See, e.g., Casy et al . , Opioid Analgesics , Plenum Press, New York and London, 1986; Iijima et al . , J^". Med . Chem . , 21 , 398 (1978); Hauser et al . , J^". Med. Chem . , 17, 1117 (1974); and Coop et al . , J^". Org . Chem . , 61 , 67 '4 (1996) . 14-hydroxycodeinone can be obtained directly from thebaine (3) by peracid oxidation. Consequently, the increased demand for 14-hydroxy opioids has placed a premium on thebaine, the common starting material for producing 14-hydroxy opioids.

thebaine 14-hydroxycodeinone

However, thebaine has only a low natural abundance in opium. See, e.g., Casy et al . ( supra) ; and Bentley, The Chemistry of the Morphine Alkaloids , Clarendon Press, Oxford, 1954. As thebaine is a valuable intermediate with low natural abundance, various research efforts have focused on the synthesis of thebaine starting from more available opioids, such as codeine (5) . In one approach, thebaine is produced by the treatment of codeinone (6) with potassium tert-butoxide and dimethyl sulfate in the presence of 18-crown-6. See, Coop et al . , Heterocycles, 49, p. 43-47 (1998) . Codeinone can be readily obtained by a simple Oppenhauer oxidation of codeine. See, e.g., Findlay et al . , J. Am. Chem . Soc . , 951, 73 , 4001 (1951).

codeine codeinone

However, this approach, particularly (5)- (6) —» (3) —> (4), still requires thebaine (3) as an intermediate. As such, the avoidance of thebaine as an intermediate would alleviate the pressure on thebaine, and greatly simplify the synthesis of 14-hydroxy opioids generally.

One way to avoid thebaine as an intermediate, theoretically, is by the direct conversion of codeinone (6) to 14-hydroxycodeinone (4). However, an industrially practical method of directly converting codeine or codeinone to its 14-hydroxy derivative has not heretofore been reported. Although various methods for converting codeinone to 14-hydroxy codeinone are known, such methods are not practical in several important aspects. For example, the preparation of 14-hydroxy codeinone from codeinone is described in Seki, Chem. Pharm . Bull . , 18, 671-676 (1969) . The Seki process has disadvantages in that it is a two-step process, requiring the conversion of codeinone to a pyrrolidine dienamine intermediate, which is then oxidized. The overall yields reported by Seki also are low compared to the yields obtained from producing the same product via oxidation of thebaine. This is purportedly due to instability of the pyrrolidine dienamine under the oxidation conditions employed. An analogous two-step approach also has been described in which N- (ethoxycarbonyl) norcodeinone is converted to its 14-hydroxy derivative via conversion to the dienol acetate intermediate, followed by oxidation. See, e.g., Schwartz et al., J. Med . Chem . , 24 (12), 1525-1528 (1981), and U.S. Patent 5,112,975. A direct procedure would offer the advantages of fewer synthetic steps and would obviate the need for preparing and isolating a diene intermediate. Previous attempts at such a direct oxidation have met with limited success due to competing oxidation at other positions on the opioid skeleton. See, e.g., Schwartz et al . { supra) ; and Holmes et al . , J. Med . Chem . Soc . , 69 , 1996 (1947). The only reported direct method resulting in a reasonable yield involves the use of Mn0₂, wherein prolonged treatment of codeine with Mn0₂ initially produces codeinone, and eventually leads to 14-hydroxycodeinone in

30% yield (Brown et al . , J. Chem . Soc , 4139 (I960)). Although this has been subsequently improved using a 3- silyl ether derivatives (59%) , the large quantities of Mn0₂ employed in this process limits its practicality for industrial scales. See, e.g., Nina et al . , Tetrahedron, 48, 6709 (1992) .

In view of the foregoing problems, there exists a need for a practical method of directly converting an opioid to its 14-hydroxy derivative. The present invention provides such a method. These and other advantages of the present invention, as well as additional inventive features, will be apparent from the description of the invention provided herein.

BRIEF SUMMARY OF THE INVENTION The present invention provides a method of preparing a 14-hydroxy opioid of Formula II:

Formula II, which includes reacting the corresponding 14 -H opioid (possessing a hydrogen at the C-14 position) with a cobalt (III) oxidant that can oxidize the 14 position, to produce the above 14-hydroxy derivative. R¹ is an alkyl, an alkenyl, an alkynyl, a cycloalkyl, an aryl, a cycloalkylalkyl, or an aralkyl. R² is an alkyl, an alkenyl, an alkynyl, a cycloalkyl, an aryl, a cycloalkylalkyl, an aralkyl, C(0)R³, or C(0)NR³R⁴, wherein R³ and R⁴ are the same or different and each is H, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, an aryl, a cycloalkylalkyl, or an aralkyl. R¹-R⁴ can be the same or different and each can be substituted or unsubstituted. The cobalt (III) oxidant includes a species of Formula III:

Co^m(X⁾„

Formula III, wherein n is an integer from 1 to 3 , and X is a fluoride, a nitrate, 0₂CR⁷, 0S0₂R⁸, OB(OH)₂, 0₂B(OH), OP(0) (OH)₂, 0₂P(0) (OH), NHR⁹, NHS0₂R¹⁰, or NHCOR¹⁰. R⁷ is H, NH₂, an alkyl, an aryl, or an aralkyl, wherein R⁷ is unsubstituted or substituted with one or more members, which can be the same or different, selected from the group consisting of a halo group, a nitro group and a cyano group. R⁸ is OH (or the anion thereof), NH₂, an alkyl, a camphor group, an aryl, or an aralkyl. R⁹ is an aryl which is substituted with at least one nitro group; and R¹⁰ is a trifluoromethyl group or an aryl which is substituted with at least one nitro group.

The cobalt (III) oxidant also includes a multidentate cobalt (III) species of Formula IV:

Co^m(Y)_ra Formula IV, wherein m is 1 or 2, and Y is a multidentate ligand with two or more heteroatoms that can form a multidentate complex with the cobalt atom of Formula IV. The cobalt (III) oxidant also can be a cobalt (III) oxide species. The cobalt (III) oxidant also includes solvates of the aforesaid cobalt (III) species. DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention is predicated on the surprising and unexpected discovery that Co (III) oxidants produce the desired 14-hydroxy opioid directly from the corresponding 14 -H opioid in good yield. The use of a Co (III) oxidant is advantageous in that the purification is relatively simple, requiring no chromatography . Moreover, the cobalt (III) oxidant is incapable of performing Baeyer-Villiger side reactions, which is believed to be one of the primary reasons why direct oxidation with peracids is rendered impractical. The process is amenable to being performed on commercial scales. Accordingly, the present invention provides a method of preparing a 14-hydroxy opioid, which method includes reacting an opioid of Formula I :

Formula I with a cobalt (III) oxidant to produce a 14-hydroxy opioid of Formula II:

Formula II. R¹ can be any suitable substituent, preferably one that does not impede an oxidation reaction at the C-14 position (e.g., by impeding coordination of the opiate nitrogen with cobalt) . Suitable substituents for R¹ include, for example, substituents that promote desirable biological activity with respect to the molecule or precursors thereof. Desirable biological activity can include, for example, potency with respect to opioid antagonism, receptor subtype selectivity, and the like. Desirable biological activity also includes, for example, resistance to metabolic or enzymatic degradation, high oral bioavailability, predictable dose-response patterns, desirable tissue distribution patterns, and the like. Suitable substituents for R¹ also include substituents that promote oxidation of the C-14 position, for example, by promoting coordination of the opioid nitrogen with cobalt. Suitable substituents for R¹ also include substituents that can be removed under mild conditions, for example, protecting groups. It is preferred that R¹ is a substituent that is not oxidized by the Co (III) oxidant employed; however, it may be desirable in certain applications also to oxidize a particular R¹ substituent (e.g., to obtain a particular oxidized R¹ substituent) under the C-14 oxidation conditions of the present invention. Preferably, R¹ is an alkyl, an alkenyl, an alkynyl, a cycloalkyl, an aryl, a cycloalkylalkyl, or an aralkyl . When R¹ is an alkyl, it is preferably a C₁-C₁₂ alkyl as defined herein, but is more preferably a C^C^ alkyl, and most preferably a

alkyl. In a preferred embodiment, the alkyl group is a methyl, as is present in known drugs with a 14-hydroxy modification (e.g., 14- hydroxycodeinone) .

When R¹ is an alkenyl, it is preferably a C₂-C₁₂ alkenyl as defined herein, but is more preferably a C₂-C₁₀ alkenyl, and most preferably is a C₂-C₆ alkenyl. In a preferred embodiment, R¹ is an allyl group, which modification is present, for example, in the drug naloxone .

When R¹ is an alkynyl, it is preferably a C₂-C₁₂ alkynyl as defined herein, but is more preferably a C₂-C₁₀ alkynyl, and most preferably a C₂-C₆ alkynyl. When R¹ is a cycloalkyl, it includes monocyclic substituents and polycyclic (e.g., bicyclic) substituents, but is preferably a monocyclic substituent. When R¹ is a monocyclic cycloalkyl, it is preferably a C₃-C₁₀ cycloalkyl, more preferably a C₃-C₈ cycloalkyl, and most preferably a C₃-C₆ cycloalkyl. R¹ further includes a cycloalkylalkyl substituent, in which the cycloalkyl is attached to the opioid nitrogen via an alkyl, alkenyl, or alkynyl spacer. When R¹ is a cycloalkylalkyl substituent, it is preferably an alkyl, for example, a C₁-C₆ alkyl in which at least one hydrogen is replaced by a cycloalkyl, for example, a C₃-C₆ cycloalkyl, substituent. In a particularly preferred embodiment, the cycloalkylalkyl substituent is a methyl group in which a methyl hydrogen is replaced by a cyclopropyl (cyclopropylmethyl) , which modification is present in the drugs naltrexone and nalmefene .

When R¹ is an aryl, it includes monocyclic aryl substituents (e.g., phenyl) and polycyclic aryl substituents (e.g., bicyclic, for example, naphthyl, and the like) , as defined herein. R¹ further includes an aralkyl substituent, in which the aryl substituent is attached to the opioid nitrogen via an alkyl spacer. When R¹ is an aralkyl substituent, it is preferably a C - C₆ alkyl in which at least one hydrogen is replaced by an aryl , for example , a phenyl . R² can be any suitable substituent. For example, R² can be a substituent that enhances the biological activity of the molecule, a precursor of such a substituent, including substituents described herein with respect to R¹. It is preferred that R² is a substituent that is not oxidized by the Co (III) oxidant employed.

However, it may be desirable in certain applications also to oxidize a particular R² substituent (e.g., to produce a particular oxidized R² substituent) under the oxidation conditions of the present invention. Preferably, R² is an alkyl, an alkenyl, an alkynyl, a cycloalkyl, an aryl, a cycloalkylalkyl, an aralkyl, an ester (e.g., C(0)R³), or a carbamate (e.g., C(0)NR³R⁴).

When R² is an alkyl, it is preferably a C₁-C₁₂ alkyl as defined herein, more preferably a C^C^ alkyl, and most preferably a

alkyl. In a particularly preferred embodiment, R² is a methyl group, which modification is present in several known drugs including, for example, naltrexone, nalmefene, and naloxone.

When R² is an alkenyl, it is preferably a C₂-C₁₂ alkenyl as defined herein, more preferably a C₂-C₁₀ alkenyl, and most preferably a C₂-C₆ alkenyl.

When R² is an alkynyl, it is preferably a C₂-C₁₂ alkynyl as defined herein, more preferably a C₂-C₁₀ alkynyl, and most preferably a C₂-C₆ alkynyl.

When R² is a cycloalkyl, it can be a monocyclic or polycyclic (e.g., bicyclic) substituent, but is preferably a monocyclic substituent. Preferably, R² is a C₃-C₁₀ cycloalkyl, more preferably a C₃-C₈ cycloalkyl, and most preferably a C₃-C₆ cycloalkyl. R² further includes a cycloalkylalkyl substituent, in which the cycloalkyl is attached to the opioid nitrogen via an alkyl, alkenyl, or alkynyl spacer.

When R² is an aryl, it can be a monocyclic aryl substituent (e.g., phenyl) or a polycyclic aryl substituent (e.g., bicyclic, for example, naphthyl , and the like), as defined herein. R² also includes an aralkyl substituent, in which the aryl substituent is attached to the opioid nitrogen via an alkyl spacer. R² further includes suitable carbonyl derivatives, for example, esters (e.g., C(0)R³), carbamates (e.g., C(0)NR³R⁴), and the like, wherein R³ are R⁴ are as defined herein.

While R³ can be any suitable substituent, R³ is preferably H, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, an aryl, a cycloalkylalkyl, or an aralkyl, as defined herein. While R⁴ can be any suitable substituent, R⁴ is preferably H, an alkyl, an alkenyl, an alkynyl, an aryl, a cycloalkyl, a cycloalkylalkyl, or an aralkyl, as defined herein. R³ and R⁴ can be the same or different and either can be unsubstituted or substituted.

When R³ or R⁴ is an alkyl, either substituent is preferably a C_x-C₁₂ alkyl as defined herein, more preferably a

alkyl .

When R³ or R⁴ is an alkenyl, it is preferably a C₂-C₁₂ alkenyl as defined herein, more preferably a C₂-C₁₀ alkenyl, and most preferably a C₂-C₆ alkenyl.

When R³ or R⁴ is an alkynyl, it is preferably a C₂-C₁₂ alkynyl as defined herein, more preferably a C₂-C₁₀ alkynyl, and most preferably a C₂-C₆ alkynyl.

When R³ or R⁴ is a cycloalkyl, it can be a monocyclic substituent or a polycyclic (e.g., bicyclic) substituent, but is preferably a monocyclic substituent. Preferably, R³ is a C₃-C₁₀ cycloalkyl, more preferably a C₃-C₈ cycloalkyl, and most preferably a C₃-C₆ cycloalkyl. R³ and R⁴ further include cycloalkylalkyl substituents, in which a cycloalkyl is attached via an alkyl, alkenyl, or alkynyl spacer.

When R³ or R⁴ is an aryl, it can be a monocyclic aryl substituent (e.g., phenyl) or a polycyclic aryl substituent (e.g., bicyclic, such as naphthyl) , as defined herein. R³ and R⁴ further include an aralkyl substituent, in which the aryl substituent is attached to the carbonyl of R² via an alkyl, alkenyl, or alkynyl spacer .

R¹-R⁴ can be the same or different. All of substituents R^x-R⁴ can be unsubstituted. Alternatively, one or more of R¹-R⁴ can be substituted with one or more suitable substituents. Suitable substituents include, for example, one or more members (which are the same or different) selected from the group consisting of an alkyl, an alkenyl, an alkynyl, an cycloalkyl, an aryl, a cycloalkylalkyl, an aralkyl, a halogen, an amino, and the like.

When any of R¹-R⁴ is substituted with an alkyl, it is preferably substituted with a C₁-C₁₂ alkyl as defined herein, but is more preferably substituted with a C₁-C₁₀ alkyl, and is most preferably substituted with a

alkyl .

When any of R^x-R⁴ is substituted with an alkenyl, it is preferably substituted with a C₂-C₁₂ alkenyl as defined herein, but is more preferably substituted with a C₂-C₁₀ alkenyl, and is most preferably substituted with a C₂-C₆ alkenyl .

When any of R¹-R⁴ is substituted with an alkynyl, it is preferably substituted with a C₂-C₁₂ alkynyl as defined herein, but is more preferably substituted with a C₂-C₁₀ alkynyl, and is most preferably substituted with a C₂-C₆ alkynyl .

When any of R¹-R⁴ is substituted with a cycloalkyl substituent, the cycloalkyl can be a monocyclic substituent or a polycyclic (e.g., bicyclic) substituent, but is preferably a monocyclic substituent . When any of R-R⁴ is substituted with a cycloalkyl, it is preferably substituted with a C₃-C₁₀ cycloalkyl, more preferably a C₃- C₈ cycloalkyl, and most preferably with a C₃-C₆ cycloalkyl . Further included among the substituents of R¹-R⁴ is a cycloalkylalkyl substituent, in which the cycloalkyl is attached to any of R¹-R⁴ via an alkyl, alkenyl , or alkynyl spacer .

When any of R¹-R⁴ is substituted with an aryl substituent, the aryl can be a monocyclic aryl substituent (e.g., phenyl) or a polycyclic aryl substituent (e.g., bicyclic, such as naphthyl) , as defined herein. Further, R¹-R⁴ also can be substituted with an aralkyl substituent, in which an aryl is attached to any of R²-R⁴ via an alkyl, alkenyl, or alkynyl spacer. As indicated above, suitable substituents of R¹-R⁴ also include one or more halogens (e.g., F, Cl, Br, and I) . As further indicated, suitable substituents of R¹-R⁴ also include amino substituents. Suitable amino substituents include, for example, substituents of the formula NR⁵R⁶, wherein R⁵ and R⁶ are organic substituents that are covalently bonded to the amine nitrogen. While R⁵ or R⁶ can be any suitable substituent, it is preferred that R⁵ and R⁶ are the same or different and each is H, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, an aryl, a cycloalkylalkyl, or an aralkyl, as defined herein.

When R⁵ or R^δ is an alkyl, either substituent is preferably a C₁-C₁₂ alkyl, more preferably a C^C-^ alkyl, and most preferably a

alkyl, as defined herein.

When R⁵ or R⁶ is an alkenyl, it is preferably a C₂-C₁₂ alkenyl, more preferably a C₂-C₁₀ alkenyl, and most preferably a C₂-C₆ alkenyl, as defined herein.

When R⁵ or R⁶ is an alkynyl, it is preferably a C₂-C₁₂ alkynyl, more preferably a C₂-C₁₀ alkynyl, and most preferably a C₂-C₆ alkynyl, as defined herein. When R⁵ or R⁶ is a cycloalkyl, it can be a monocyclic substituent or a polycyclic (e.g., bicyclic) substituent, but is preferably a monocyclic substituent. When R⁵ or R⁶ is a cycloalkyl, it is preferably a C₃-C₁₀ cycloalkyl, more preferably a C₃-C₈ cycloalkyl, and most preferably a C₃-C₆ cycloalkyl. R⁵ further includes a cycloalkylalkyl substituent, in which a cycloalkyl is attached to the amine nitrogen of the amino substituent of R¹-R⁴ via an alkyl, alkenyl, or alkynyl spacer.

When R⁵ is an aryl, it includes monocyclic aryl substituents (e.g., phenyl) and polycyclic aryl substituents (e.g., bicyclic, for example, naphthyl and the like) , as defined herein. R⁵ further includes an aralkyl substituent, in which an aryl substituent is attached to the amine nitrogen of the amino substituent of R¹-R⁴ via an alkyl, alkenyl, or alkynyl spacer. Alternatively, R⁵ and R⁶, together with the nitrogen to which they are covalently bonded, comprise a heterocyclic substituent (e.g., a heterocycle, for example, a heterocycloalkyl, a heteroaryl, or the like) , as defined herein. As utilized herein, the term "alkyl" means a straight-chain or branched alkyl substituent containing from about 1 to about 20 carbon atoms chain, preferably from about 1 to about 10 carbon atoms, more preferably from about 1 to about 8 carbon atoms, still more preferably from about 1 to about 6 carbon atoms. Examples of such substituents include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isoamyl, hexyl , octyl , dodecanyl, and the like.

The term "alkenyl" means a straight-chain or branched alkenyl substituent having one or more double bonds and containing from about 2 to about 20 carbon atoms chain, preferably from about 2 to about 10 carbon atoms, more preferably from about 2 to about 8 carbon atoms, still more preferably from about 2 to about 6 carbon atoms. Examples of such substituents include vinyl, allyl, 1,4- butadienyl, isopropenyl, and the like.

The term "alkynyl" means a straight-chain or branched alkynyl substituent having one or more triple bonds and containing from about 2 to about 20 carbon atoms chain, preferably from about 2 to about 10 carbon atoms, more preferably from about 2 to about 8 carbon atoms, still more preferably from about 2 to about 6 carbon atoms. Examples of such substituents include ethynyl, propynyl (propargyl) , butynyl, and the like.

It will be appreciated that the alkenyl and alkynyl substituents defined herein can have combinations of double and triple bonds. For example, the alkenyl substituent can comprise one or more triple (alkynyl) bonds in addition to the one or more double bonds of the alkenyl substituent. Likewise, the alkynyl substituent can comprise one or more double (alkenyl) bonds in addition to the one or more triple bonds of the alkynyl substituent .

The term "cycloalkyl" means a monocyclic cycloalkyl substituent, or a polycyclic alkyl substituent, defined by a carbocyclic ring, or by one or more carbocyclic rings, which can be the same or different, when it is polycyclic. When the cycloalkyl substituent is monocyclic, it preferably has from 3 to about 10 carbon atoms in the carbocyclic skeleton thereof, more preferably about 4 to about 7 carbon atoms, and most preferably 5 to 6 carbons atoms. Examples of monocyclic cycloalkyl substituents include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclodecyl, and the like. When the cycloalkyl substituent is polycyclic, each ring in the substituent preferably has from 3 to about 10 carbon atoms in the carbocyclic skeleton thereof, more preferably from about 4 to about 7 carbon atoms, and most preferably 5 to 6 carbons atoms . Examples of polycyclic cycloalkyl substituents include decahydronaphthyl, bicyclo [5.4.0] undecyl, adamantyl, hexahydroindan, and the like.

The term "aryl" refers to an aromatic carbocyclic substituent, as commonly understood in the art, and includes monocyclic and polycyclic aromatics such as, for example, phenyl, naphthyl, and the like. The term "cycloalkylalkyl" as used herein means an alkyl, alkenyl, or alkynyl substituent, as defined herein, in which at least one hydrogen thereof is replaced by a cycloalkyl, as defined herein. Alternatively, a cycloalkylalkyl can be defined as a cycloalkyl which is attached by way of an alkyl, alkenyl, or an alkynyl spacer. Cycloalkylalkyl substituents include, for example, cyclopropylmethyl, cyclohexylmethyl, cyclopentylbutyl, cyclopentylbutenyl, cyclopentylbutynyl, 1-cyclopropyl -2 -butenyl, and the like.

The term "aralkyl" as utilized herein means an alkyl, alkenyl, or alkynyl, as defined herein, wherein at least one hydrogen atom is replaced with an aryl substituent, as defined herein. Alternatively, a aralkyl can be defined as a aryl which is attached by way of an alkyl, alkenyl, or an alkynyl spacer. Arylalkyls include, for example, benzyl, phenethyl, 1-phenyl-2- butenyl, 1 -phenyl-2 -butynyl, and the like.

The term "heterocycle" or "heterocyclic" encompasses both hetercycloalkyls and heteroaryls. The term "heterocycloalkyl" means a cycloalkyl substituent as defined herein (including polycyclics) , wherein at least one carbon in the carbocyclic skeleton thereof is substituted with a heteroatom such as, for example, O, N, or S, and optionally comprises one or more double bonds within the ring. The heterocycloalkyl preferably has 3 to about 10 atoms (members) in the carbocyclic skeleton (or for each ring in the case of polycyclic rings) , more preferably about 4 to about 7 atoms, and most preferably 5 to 6 atoms. Examples of heterocycloalkyl substituents include epoxy, aziridyl, oxetanyl, tetrahydrofuranyl, dihydrofuranyl, piperadyl, piperidinyl, pyperazyl, piperazinyl, pyranyl, morpholinyl, hexahydroindolyl, decahydroquinolyl, and the like.

The term "heteroaryl" means a substituent defined by an aromatic heterocyclic ring, as is commonly understood in the art, including monocyclic and polyclic heteroaryls. Monocyclic heteroaryls include, for example, imidazole, thiazole, pyrazole, pyrrole, furane, pyrazoline, thiophene, oxazole, isoxazol, pyridine, pyridone, pyrimidine, pyrazine, and triazine substituents. Polycyclic heteroaryls include, for example, quinoline, isoquinoline, indole, purine, benzimidazole, benzopyrrole, and benzothiazole substituents, which heteroaryl substituents are optionally substituted with one or more substituents selected from the group consisting of a halogen, an alkyl, alkoxy, amino, cyano, nitro, and the like. It will be appreciated that the heterocycloalkyl and heteroaryl substituents can be coupled to the compounds of the present invention via a heteroatom, such as nitrogen (e.g., 1-imidazolyl) .

It will also be appreciated that certain polycyclic heterocyclic substituents may contain an aromatic ring and a non-aromatic ring. Examples of such polycyclic substituents include, for example, benzotetrahydrofuranyl, benzopyrrolidinyl, and the like.

Of course, the tendency of a particular heterocycle to oxidize should be take into account when performing the oxidation reaction of the present invention. It is possible that certain heterocycles that have a tendency to oxidize (e.g., thiazole and indole) also may react with the cobalt (III) oxidant in the method of the present invention. In some applications, it may be desirable to oxidize a particular heterocyclic substituent under the C- 14 oxidation conditions of the method of the present invention. In other applications, it may be desirable to protect certain heterocycles from undergoing an oxidation reaction under the conditions of the method of the present invention, for example, by introducing a suitable protecting group to the heterocyclic substituent. Any suitable Co (III) ("cobalt (III)") oxidant can be used to carry out the oxidation reaction in accordance with the present invention. Suitable Co (III) oxidants include Co (III) species that are capable of converting the C-H at the C-14 position of formula (I) to the 14-hydroxy derivative of formula (II) . In one aspect, the Co (III) oxidant includes a cobalt (III) species of Formula III:

Co^III(X)_n Formula III, wherein n is an integer from 1 to 3 , and X is a suitable ligand which promotes desirable oxidation properties in the Co (III) oxidizing species. The Co (III) oxidant also includes one or more solvates of the cobalt (III) species.

Suitable X groups can be chosen from among those having particular electronic properties, steric properties, coordination properties, dissolution properties in a particular solvent, or a combination of such properties, and the like, which properties can be tailored to suit a particular application. It will be appreciated that the properties of X can have a significant influence on the chemical properties of the Co (III) oxidant, for example, the oxidizing power of the Co (III) species. For example, cobalt (III) trifluoroacetate was found to be a significantly more powerful oxidant than cobalt (III) acetate. Co (III) oxidants with suitable ligands can be obtained commercially, or by methods that are know to those of skill in the art, for example, by oxidation of a Co (II) species to a Co (III) species in the presence of the acid corresponding to one or more particular ligands.

As indicated above, the X group can be tailored to promote desirable properties in a particular synthesis application. For example, a particular X can be chosen which has properties that promote selective oxidation of the C-14 position without competing oxidation of the opiate nitrogen atom. Alternatively, the properties of X can be adjusted, for example, to modify the oxidizing strength of the oxidant. For example, X ligands having properties that increase oxidizing strength can be chosen for purposes of oxidizing opiate molecules that react sluggishly or which require low reaction temperatures. On the other hand, the properties of X can be tailored, for example, to promote a higher degree of coordination with the opiate nitrogen for molecules in which the C-14 position is less reactive or hindered.

In a preferred embodiment, X is the conjugate base of an organic acid or an inorganic acid. In this respect, suitable X ligands include, for example, fluoride, nitrate, carboxylates, sulfur oxides, borates, phosphates, conjugate bases with a nitrogen-centered anion, and the like.

When X is a carboxylate ligand, it is preferably a carboxylic acid anion or a carbamic acid anion. Preferably, the carboxylate ligand is of the formula

0₂CR⁷, wherein R⁷ is H, NH₂, an alkyl (e.g. a C^C_g alkyl) , an aryl, or an aralkyl. R⁷ can be unsubstituted, or it can be substituted with one or more members, which are the same or different, selected from the group consisting of a halo group, a nitro group and a cyano group. When R⁷ is an aryl, it is preferably phenyl (e.g., X is benzoate, p-nitrobenzoate, or the like) . When R⁷ is an aralkyl, it is preferably a

alkyl in which at least one alkyl hydrogen atom is substituted with an aryl (preferably phenyl) . When R⁷ is an alkyl, it is preferably a

alkyl which is unsubstituted or substituted.

In a preferred embodiment, X is a carboxylic acid ligand in which R⁷ is a C₁-C₃ alkyl, which is most preferably methyl, in which case X is an acetate ligand. Co (III) species with acetate ligands can be prepared, for example, by oxidation of cobalt (II) acetate tetrahydrate (which is commercially available) , to provide cobalt (III) acetate. For the preparation of various cobalt (III) carboxylates, see, e.g., Lande et al . , J^". Am . Chem . Soc . , 90 , 5196 (1968) .

Suitable sulfur oxide ligands include, for example, sulfate, sulfonates, and sulfamates. Preferably, the sulfur oxide ligand is of the formula OS0₂R⁸, wherein R⁸ is OH or the anion thereof, NH₂, an alkyl (e.g., a C_α-C₆ alkyl), a camphor group, an aryl, or an aralkyl. Camphor sulfonates can be readily obtained, e.g., from camphorsulfonic acids, which are commercially available. Various aryl and aralkyl sulfonates also are known, e.g., bezenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, and the like. Various alkylsulfonates also can be readily obtained using methods that are well known in the art (e.g., mesylate, and the like) . Suitable ligands also include borates (e.g., OB (OH) ₂ and 0₂B(OH)), phosphates (e.g., OP (O) (OH)₂ and 0₂P(0) (OH)), fluoride (e.g., cobalt (III) fluoride which is commercially available) , and conjugate bases having a nitrogen-centered anion. Suitable nitrogen-centered ligands include analides of the formula NHR⁹, sulfonamides of the formula NHSO,R¹⁰, and acetamides of the formula NHCOR¹⁰. When the ligand is an analide, R⁹ is an electron-withdrawing aryl substituent, which is preferably an aryl substituted with at least one electron-withdrawing group, for example, a nitro group (e.g., p-nitrophenyl), and the like. When the ligand is a carbamate or a sulfamate, R¹⁰ is preferably an electron-withdrawing alkyl such as, for example, a trifluoromethyl group, or an electron- withdrawing aryl substituent, for example, an aryl which is substituted with at least one electron-withdrawing group, for example, a nitro group (e.g., p-nitrophenyl).

When R⁸, R⁹, or R¹⁰ is an aryl, it is preferably phenyl (e.g., X is benzoate in the case of R⁸, or is p- nitrobenzoate in the case of R⁹ or R¹⁰, and the like) . When R⁸ is an aralkyl, it is preferably a C₁-C₆ alkyl in which at least one alkyl hydrogen atom is substituted with an aryl (preferably phenyl) .

In another aspect, the cobalt (III) oxidant includes a multidentate cobalt (III) species of Formula IV: Cθ^m(Y)_m

Formula IV, wherein m is 1 or 2, and Y is a multidentate ligand comprising two or more heteroatoms capable of forming a multidentate complex with the cobalt atom of Formula IV. The Co (III) oxidant also includes one or more solvates of the cobalt (III) species.

Suitable multidentate ligands include those which promote desirable oxidation properties in the Co (III) oxidizing species. Suitable multidentate ligands can be chosen from among those having particular electronic properties, steric properties, coordination properties, dissolution properties in a particular solvent, or a combination of such properties, and the like. As with ligand X, it will be appreciated that the properties of the multidentate ligand Y also can have a significant influence on the chemical properties of the Co (III) oxidant, for example, the oxidizing strength of the Co (III) species. The factors that apply to X of Formula III also apply to Y for purposes of choosing appropriate multidentate ligands for the oxidizing species of Formula IV.

Co (III) oxidants with suitable multidentate ligands can be obtained commercially (e.g., cobalt (III) acetylacetonoate) , or by methods that are know to those of skill in the art (e.g., by oxidation of a Co (II) species in the presence of the acid corresponding to the multidentate ligand) .

Exemplary multidentate ligands include ligands selected from the group consisting of tartrate, oxalate, maleate, malate, succinate, citrate, acetylacetonoate, benzoylacetonoate, pyruvate, and phthalate, and the like.

Suitable multidentate ligands also include derivatives of tartrate, oxalate, maleate, malate, succinate, citrate, acetylacetonoate, benzoylacetonoate, pyruvate, and phthalate, and the like, that can form a multidentate complex with the cobalt atom of the cobalt (III) species. Suitable derivatives of the aforesaid multidentate ligands, and analogous multidentate ligands, can be obtained by methods that are known in the art, and include, for example, suitable ether or ester derivatives. Exemplary ester derivatives include esters of tartaric acid, some of which can be purchased, for example, dibenzoyltartaric acid and di-p-toluoyltartaric acid (available from Aldrich Chemical Co., Milwaukee, WI) . Suitable ester derivatives also include, for example, di-O-acetyltartaric acid, O-acetylmalic acid, O- benzoylmalic acid, O-toluoylmalic acid, and the like. In another aspect, the cobalt (III) oxidant is a cobalt (III) oxide (e.g., cobalt (II, III) oxide, which is commercially available) , or a solvate or derivative thereof . The cobalt (III) oxidant can be used in any suitable ratio with respect to the opioid of Formula I . In one aspect, the cobalt (III) oxidant is used in a stoichiometric ratio or greater. In this aspect the molar ratio of the cobalt (III) oxidant with respect to the opioid of Formula I is at least about 1:1.

In another aspect, the cobalt (III) oxidant can be used as a catalyst. When it is desired to use the cobalt (III) oxidant catalytically (i.e., as a catalyst in the oxidation reaction) , it can be generated/produced in si tu, for example, by one or more co-oxidants present in the reaction medium. There are many advantages for using the cobalt (III) oxidant catalytically. Possible advantages include the use of a less expensive co-oxidant for the oxidation reaction, better control over the reaction, simplified isolation, and avoiding the use of large quantities of cobalt (III) oxidants. Moreover, there is a larger choice of commercially available cobalt (II) compounds, which can serve as in si tu precursors to the cobalt (III) catalyst. Any suitable catalytic ratio can be used in the method of the present invention. The catalytic species of cobalt (III) oxidant can be present in si tu in a ratio ranging from about 50 mole percent (0.50) to about 0.1 mole percent (0.001) or even less, with respect to the starting material of Formula I . Suitable catalytic ratios of the cobalt (III) oxidant relative to the starting material of Formula I can range from about 45 mole percent (0.45) to about 0.1 mole percent (0.001), from about 40 mole percent (0.40) to about 0.1 mole percent (0.001), from about 35 mole percent (0.35) to about 0.1 mole percent (0.001), from about 30 mole percent (0.30) to about 0.1 mole percent (0.001), from about 25 mole percent (0.25) to about 0.1 mole percent (0.001), from about 20 mole percent (0.20) to about 0.1 mole percent (0.001), from about 15 mole percent (0.15) to about 0.1 mole percent (0.001), from about 10 mole percent (0.10) to about 0.1 mole percent (0.001), from about 5 mole percent (0.05) to about 0.1 mole percent (0.001), and from about 1 mole percent (0.01) to about 0.1 mole percent (0.001) . Other suitable catalytic ratios of the cobalt (III) oxidant relative to the starting material of Formula I can range from about 15 mole percent (0.15) to about 1 mole percent (0.01), from about 10 mole percent to about 1 mole percent (0.01), from about 10 mole percent to about 5 mole percent (0.05), and from about 5 mole percent (0.05) to about 1 mole percent (0.01) .

Preferably, the cobalt (III) oxidant, when used catalytically, is present in a molar ratio which is less than about 0.25 (25 mole percent), but is more preferably present in a molar ration of less than about 0.1 (10 mole percent), with respect to the opioid of Formula I. More preferably, the cobalt (III) oxidant is present in a molar ratio of less than about 0.05 (5 mole percent) with respect to the opioid of Formula I. Most preferably, the cobalt (III) oxidant is such that it need only be present in a molar ratio of less than about 0.01 (1 mole percent) with respect to the opioid of Formula I .

The cobalt (III) oxidant can be reacted with the opioid of Formula I in one single portion, or it can be reacted in two or more portions added successively. When the cobalt (III) oxidant is used in a stoichiometric ratio (or greater) with respect to the opioid of Formula I, it can be advantageous to react the cobalt (III) oxidant in two or more portions added successively. In certain cases, successive addition of two or more portions can produce a higher yield of the 14-hydroxy opioid.

When the cobalt (III) oxidant is reacted with the opioid of Formula I in two or more successive portions, it is preferred that each portion of cobalt (III) oxidant be allowed to react with the opioid of Formula I for at least about one hour. More preferably, the cobalt (III) oxidant is reacted with the opioid of Formula I in two successive portions. When the cobalt (III) oxidant is reacted with the opioid of Formula I in two successive portions, the molar ratio of cobalt (III) oxidant with respect to the opioid of Formula I in each of the two portions is preferably about 1:1. In a preferred embodiment, the second portion of the two portions is reacted with the opioid of Formula I after allowing the first portion of the two portions to react with the opioid of Formula I for at least about twenty four hours . In a particularly preferred embodiment, the second portion of the two portions is allowed to react with the opioid of Formula I for at least about four hours.

The cobalt (III) oxidant also can be reacted with the opioid of Formula I in a continuous manner. For example, the cobalt (III) oxidant can be added to the opioid of Formula I continuously. Continuous addition of the cobalt (III) oxidant can be advantageous in certain applications. For example, continuous addition can be utilized when a strong cobalt (III) oxidant is used in a stoichiometric ratio or greater, and where a single addition or successive additions would result in over- oxidation, excessive heat, or the like. Cobalt (III) trifluoroacetate, for example, can result in over- oxidation of codeinone in some instances, if it is added in a single portion to a codeinone solution. In this respect, it can be advantageous to add continuously the cobalt (III) oxidant to the opioid to control the reaction by adding it to the opioid, for example, at about the rate of consumption of the cobalt (III) oxidant. When the cobalt (III) oxidant is added continuously, it is preferred that the addition rate of the cobalt (III) oxidant is at most about equal to the rate of reaction of the cobalt (III) oxidant with the opioid of Formula I. The reaction can be further controlled, if desired, by using lower reaction temperatures (e.g., about 0-5 °C) .

The method of the present invention can be performed at any suitable reaction temperature. It will be appreciated that a suitable reaction temperature (or an optimum reaction temperature) can vary significantly depending on the nature of the particular application. Factors that can influence the choice of a suitable reaction temperature include reactivity, for example, the reactivity of the opioid and the reactivity of the cobalt (III) oxidant. Concentration also can be a factor in choosing an appropriate reaction temperature. For example, the concentration of the opioid starting material (Formula I) or the concentration of the oxidizing species (e.g., Formula III or IV) can influence the optimum or the most practical temperature range at which the oxidation reaction is carried out. The nature of the particular solvent or solvents used in the reaction also can influence the choice of a suitable temperature. Solvent factors that can influence the reaction temperature (as well as the choice of solvent) include, for example, the freezing or boiling point of the solvent, the reactivity of the reactants in the particular solvent used, the stability of the reactants and product in the solvent, and the like. Other factors include consideration of thermal stability, for example, the thermal stability of the opioid of Formula I or Formula II, the stability of any co-oxidant that may be present in the reaction mixture, and the like. The heat of reaction (e.g., in an exothermic reaction) also can influence the choice of a suitable reaction temperature. Depending on the particular application, the reaction temperature can range from about -78 °C to about 200 °C. Preferably, the reaction temperature is at least about -10 °C, more preferably at least about 0 °C, and still more preferably at least about 15 °C . Most preferably, the reaction is performed at about ambient temperature (i.e., about 20-25 °C) .

EXAMPLES The following examples further illustrate the present invention but, of course, should not be construed as in any way limiting its scope.

Example 1

This example demonstrates the preparation of a cobalt (III) oxidant, particularly cobalt (III) acetate.

Using the procedure described in Lande et al . , J^". Am. Chem . Soc , 90 , 5196 (1968), cobalt (II) acetate tetrahydrate (Co (OAc) ₂.4H₂0) was treated with ozone in acetic acid, to produce cobalt (III) acetate (Co (OAc) ₃) .

Example 2 This example demonstrates the preparation of 14- hydroxycodeinone by the direct oxidation of codeinone with a cobalt (III) oxidant, in which the oxidant is added in one portion.

To a solution of codeinone (400 mg, 1.35 mmol) in acetic acid (4 mL) at ambient temperature was added, in one portion, cobalt (III) acetate (2.7 mmol, 2 equivalents) prepared in accordance with Example 1. After stirring for 24 hours at ambient temperature (under an argon atmosphere) , the mixture was diluted with water (30 mL) , and the excess oxidant was destroyed with

NaHS0₃. The solution was basified with NaHC0₃, and extracted with chloroform (3X) . The chloroform extracts were combined, washed with brine, and dried (Na₂S0₄) . The solvent was evaporated to dryness on a rotary evaporator, and the crude product was purified by recrystallization from ethanol containing a trace of chloroform, to produce 14-hydroxycodeinone (160 mg (38%)). The NMR, MS, and IR spectral data, and other physical data (m.p.), agreed with the literature values for 14-hydroxycodeinone. The product was further shown to be identical to an authentic sample.

This example demonstrates that 14-hydroxycodeinone can be obtained directly from codeinone using a cobalt (III) oxidant. Isolation of the purified product was simple, requiring no chromatography whatsoever.

Example 3

This example demonstrates the preparation of 14- hydroxycodeinone by the direct oxidation of codeinone with a cobalt (III) oxidant, in which the oxidant is added in two successive stoichiometric portions.

To a solution of codeinone (400 mg, 1.35 mmol) in acetic acid (4 mL) at ambient temperature was added, in one portion, cobalt (III) acetate (1.35 mmol, 1 equivalent) , which was prepared in accordance with Example 1. After stirring for 24 hours at ambient temperature (under an argon atmosphere) , an additional portion of cobalt (III) acetate (1.35 mmol, 1 equivalent) was added, and the solution was stirred an additional 4 hours. The mixture was diluted with water (30 mL) , and the excess oxidant was destroyed with NaHS0₃. The solution was basified with NaHC0₃, and extracted with chloroform (3X) . The chloroform extracts were combined, washed with brine, and dried (Na₂S0₄) . The solvent was evaporated to dryness on a rotary evaporator, and the crude product was purified by recrystallization from ethanol containing a trace of chloroform, to produce 14- hydroxycodeinone (215 mg (51%)). The NMR, MS, and IR spectral data, and other physical data (m.p.), agreed with the literature values for 14-hydroxycodeinone. The product was further shown to be identical to an authentic sample.

This example demonstrates that 14-hydroxycodeinone can be obtained directly from codeinone using a cobalt (III) oxidant. Although the same amount of cobalt (III) oxidant was used in the present example as was used in Example 2, the yield was improved (51% vs. 38%) by adding the cobalt (III) oxidant in two successive portions. Isolation of the purified product was simple. No chromatography was required.

Example 4

This example demonstrates that 14-hydroxycodeinone can be obtained directly from codeinone using a cobalt (III) catalyst.

To a solution of codeinone (130 mg, 0.44 mmol) and cobalt (II) acetate tetrahydrate (Co (OAc) ₂.4H₂0, 5 mg, 0.02 mmol, 4.5 mole percent) in acetic acid (2 mL) was added NaI0₄ (95 mg, 0.44 mmol) . After stirring for 24 hours at ambient temperature (under an argon atmosphere) , the mixture was diluted with water (30 mL) , and the excess oxidant was destroyed with NaHS0₃. The solution was basified with NaHC0₃, and extracted with chloroform (3X) . The chloroform extracts were combined, washed with brine, and dried (Na₂S0₄) . The solvent was evaporated to dryness on a rotary evaporator, and the crude product was purified by chromatography, to produce 14- hydroxycodeinone (16 mg (12%) ) . The NMR, MS, and IR spectral data, and other physical data (m.p.), agreed with the literature values for 14-hydroxycodeinone. The product was further shown to be identical to an authentic sample . The balance of the material showed iodinated products by MS (m/z 423; codeinone + 126), indicating that the periodate co-oxidant was involved in the formation of the reaction by-products.

This example demonstrates that 14-hydroxycodeinone can be obtained directly from codeinone using a cobalt (III) oxidant catalytically. It is believed that the use of a suitable co-oxidant that produces the requisite cobalt (III) catalyst, but does not result in the formation of opioid by-products, will produce higher yields of the desired 14-hydroxy opioid. It is also believed that a suitable Co (III) catalyst/co-oxidant combination can be developed and optimized for commercial scales .

All of the references cited herein, including patents and publications, are hereby incorporated in their entireties by reference.

While this invention has been described with an emphasis upon preferred embodiments, it will be obvious to those of ordinary skill in the art that variations of the preferred embodiments may be used and that it is intended that the invention may be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications encompassed within the spirit and scope of the invention as defined by the following claims.

Claims

WHAT IS CLAIMED IS

1. A method of preparing a 14-hydroxy opioid, said method comprising reacting an opioid of Formula I :

Formula II, wherein:

R¹ is an alkyl, an alkenyl, an alkynyl, a cycloalkyl, an aryl, a cycloalkylalkyl, or an aralkyl; R² is an alkyl, an alkenyl, an alkynyl, a cycloalkyl, an aryl, a cycloalkylalkyl, an aralkyl,

C(0)R³, or C(0)NR³R⁴, wherein each of R³ and R⁴ is H, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, an aryl, a cycloalkylalkyl, or an aralkyl; and wherein R^x-R⁴ are the same or different and each is unsubstituted or substituted.

2. The method of claim 1, wherein R^R⁴ are independently substituted with one or more members, which are the same or different, selected from the group consisting of an alkyl, an alkenyl, an alkynyl, a cycloalkyl, an aryl, a cycloalkylalkyl, an aralkyl, a halogen, and NR⁵R^δ, wherein R⁵ and R⁶ are the same or different and each is H, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, an aryl, a cycloalkylalkyl, or an aralkyl .

3. The method of claim 1 or 2, wherein R¹ is a C_λ- C₆ alkyl, a C₂-C₆ alkenyl, a phenyl, a cycloalkylalkyl, or an aralkyl, wherein said cycloalkylalkyl is a

alkyl in which at least one hydrogen is substituted with a C₃-C₆ cycloalkyl, and said aralkyl is a

alkyl in which at least one hydrogen is substituted with a phenyl .

4. The method of any of claims 1-3, wherein R¹ is a C-_L-Cg alkyl, a C₂-C₆ alkenyl, or a cycloalkylalkyl which is a C-_L-Cg alkyl in which at least one hydrogen is substituted with a C₃-C₆ cycloalkyl.

5. The method of any of claims 1-4, wherein R¹ is a methyl, an allyl, or a cyclopropylmethyl .

6. The method of any of claims 1-5, wherein R² is a alkyl or C(0)R³, wherein R³ is H, a

alkyl, a C₂-C₆ alkenyl, a C₂-C₆ alkynyl, a C₃-C_ε cycloalkyl, an aryl, a cycloalkylalkyl, or an aralkyl.

7. The method of any of claims 1-6, wherein R² is a C.-Cg alkyl.

8. The method any of claims 1-7, wherein R² is methyl .

9. The method of claim 1 or 2 , wherein said cobalt (III) oxidant comprises a cobalt (III) species of Formula III:

Co^m(X)_n

Formula III, wherein n is an integer from 1 to 3 , and X is a fluoride, a nitrate, 0₂CR⁷, OS0₂R⁸, OB(OH)₂, 0₂B (OH) , OP(0) (OH)₂, 0₂P(0) (0H), NHR⁹, NHS0₂R¹⁰, or NHCOR¹⁰, wherein:

R⁷ is H, NH₂, an alkyl, an aryl, or an aralkyl, wherein R⁷ is unsubstituted or substituted with one or more members, which are the same or different, selected from the group consisting of a halo group, a nitro group and a cyano group;

R⁸ is OH or the anion thereof, NH₂, an alkyl, a camphor group, an aryl, or an aralkyl; R⁹ is an aryl which is substituted with at least one electron-withdrawing group; and

R¹⁰ is a trifluoromethyl group or an aryl which is substituted with at least one electron-withdrawing group; or a solvate of said cobalt (III) species.

10. The method of claim 9, wherein said aryl is a phenyl, and said aralkyl is a alkyl in which at least one hydrogen is substituted with a phenyl.

11. The method of claim 9, wherein X is 0₂CR⁷ or

OS0₂R⁸, wherein R⁷ is a C_j,-C₆ alkyl or an aryl, and R⁸ is a C_j-Cg alkyl or an aryl.

12. The method of claim 11, wherein X is 0₂CR⁷, wherein R⁷ is a C₁-C₆ alkyl.

13. The method of claim 12, wherein R⁷ is methyl.

14. The method of claim 9, wherein said cobalt (III) oxidant comprises a cobalt (III) species of Formula IV:

Co¹¹¹^), Formula IV, wherein m is 1 or 2, and Y is a multidentate ligand comprising two or more heteroatoms that can form a multidentate complex with the cobalt atom of said cobalt (III) species.

15. The method of claim 14, wherein Y is selected from the group consisting of tartrate, oxalate, maleate, succinate, citrate, acetylacetonoate, benzoylacetonoate, pyruvate, phthalate, and derivatives of any one of the foregoing that can form a multidentate complex with the cobalt atom of said cobalt (III) species.

16. The method of claim 14, wherein Y is selected from the group consisting of tartrate, oxalate, maleate, succinate, citrate, acetylacetonoate, benzoylacetonoate, pyruvate, and phthalate.

17. The method of claim 1, wherein said cobalt (III) oxidant comprises a cobalt (III) oxide or a solvate thereof .

18. The method of any one of claims 1-17, wherein the molar ratio of said cobalt (III) oxidant with respect to the opioid of Formula I is at least about 1:1.

19. The method of any one of claims 1-17, wherein said cobalt (III) oxidant is produced in si tu by at least one co-oxidant.

20. The method of claim 19, wherein said cobalt (III) oxidant is present in a molar ratio from about 0.5 (50 mole percent) to about 0.001 (0.1 mole percent) with respect to the opioid of Formula I .

21. The method of claim 19, wherein said cobalt (III) oxidant is present in a molar ratio of less than about 0.25 (25 mole percent) with respect to the opioid of Formula I .

22. The method of claim 19 or 21, wherein said cobalt (III) oxidant is present in a molar ratio of less than about 0.1 (10 mole percent) with respect to the opioid of Formula I .

23. The method of claim 19 or 22, wherein said cobalt (III) oxidant is present in a molar ratio of less than about 0.05 (5 mole percent) with respect to the opioid of Formula I .

24. The method of claim 19 or 23, wherein said cobalt (III) oxidant is present in a molar ratio of less than about 0.01 (1 mole percent) with respect to the opioid of Formula I .

25. The method of any one of claims 1-24, wherein said cobalt (III) oxidant is reacted with the opioid of Formula I in two or more successive portions.

26. The method of claim 25, wherein said cobalt (III) oxidant is reacted with the opioid of Formula I in two successive portions.

27. The method of claim 26, wherein the molar ratio of said cobalt (III) oxidant and said opioid of Formula I in each of the two successive portions is about 1:1.

28. The method of claim 26 or 27, wherein the second portion of the two successive portions is reacted with the opioid of Formula I after allowing the first portion of the two successive portions to react with the opioid of Formula I for at least about twenty four hours .

29. The method of any of claims 26-28, wherein the second portion of the two portions is allowed to react with the opioid of Formula I for at least about four hours .

30. The method of any of claims 1-24, wherein said cobalt (III) oxidant is added continuously to the opioid of Formula I such that the addition rate of said cobalt (III) oxidant is at most about equal to the rate of reaction of said cobalt (III) oxidant with said opioid of Formula I .

31. The method of any of claims 1-30, wherein the opioid of Formula I is reacted with the cobalt (III) oxidant at a temperature of at least about 0 °C.

32. The method of claim 31, wherein said temperature is at least about 15 °C.

33. The method of claim 32, wherein said temperature is at least about 20 °C.