TITLE: PROCESS FOR THE PREPARATION OF MORPHINE ANALOGS VIA THE REACTION OF ORGANOMETALLIC REAGENTS WITH AN OXAZOLID1NE DERIVED FROM MORPHINANS

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims the benefit of priority from copending U.S. provisional application no. 61/594,678 filed on February 3, 2012, the contents of which are incorporated herein by reference in their entirety.

FIELD OF THE APPLICATION

[0002] The present application relates to new processes useful in the preparation of morphine analogs such as naloxone, naltrexone, nalbuphone and nalbuphine via the reaction of a Grignard, or other suitable organometallic or metallic reagent, with an oxazolidine derived from a morphinan.

BACKGROUND OF THE APPLICATION

[0003] Various opiate-derived antagonists such as naloxone, naltrexone, nalbuphone and nalbuphine are prepared by semi-synthesis from natural opiates such as morphine, thebaine or oripavine, Scheme 1. These compounds are used extensively in medicine as antagonists (naltrexone and naloxone) or mixed agonist/antagonist (nalbuphine). Naltrexone is used in the treatment of alcoholism and opioid dependence. Naloxone is the active ingredient in Narcan ^® for the reversal of opioid overdose and is also used in combination with buprenorphine (Suboxone®) for the treatment of opioid addiction. It is also employed with tilidine (Valoron N®) for the treatment of pain and with oxycodone (Targin®) for the prophylaxis and/or treatment of opioid-induced constipation, Nalbuphine is the active ingredient in Nubain®, which is used as an analgesic.

naltrexone nalbuphons nalbuphine thebatne, R = Me oxymorphone

oripavine, = H

Scheme 1

[0004] The synthesis of compounds such as naloxone, naltrexone and nalbuphone requires the oxidation of natural opiate alkaloids at the C-14 position. The synthesis of compounds such as naloxone, naltrexone, nalbuphone and nalbuphine requires the eventual replacement of an N-methyl group with, for example, an allyl, methylcyclopropyl, methylcydobutyl, or other group. The synthesis of naloxone, naltrexone, nalbuphone and nalbuphine by several methods differing in concept as well as execution has been reported.

[0005] For example, naltrexone as well as R-methy!naltrexone, were prepared by N-demethylation of quaternary salts derived from oripavine followed by oxidation of W-methylcyclopropyl nororipavine. ¹ Similarly, nalbuphone and nalbuphine became available. ² A/-Methylcyclopropyl nororipavine served as a convenient starting material for the improved synthesis of buprenorphine. ³ Buprenorphine was also synthesized from oripavine by a newly discovered palladium-catalyzed N- demethylation/acylation protocol. ⁴ In addition, it has been reported that the N- oxide of oxymorphone is easily demethy!ated with the Burgess reagent and that the intermediate iminium ion is trapped to form oxazolidines a and b in excellent yield and in a one-pot sequence from oxymorphone, as shown in Scheme 2. ⁵

a: R = Ac a: 78% b: R = EtOGO b: B4%

Scheme 2

[0006] All of these efforts were the result of a focused program implemented to discover more efficient and environmentally friendly methods for the replacement of the W-methyl group in natural opiates with the appropriate alkyi group required for the medicinal agents.

SUMMARY OF THE APPLICATION

[0007] A comparison of overall efficiency and the potential for scale-up by process groups of above-described processes has now been undertaken. The above-mentioned N-demethylation protocols for naltrexone and methylnaltrexone were found to be suitable for process scale-up. However, the N-demethylation of quaternary salts containing an N-allyl group could not be used for the synthesis of naloxone, as the treatment of such salts with nucleophiles would lead to N-deallylation rather than N-demethylation. Nucleophilic cleavage of oxazolidines containing, for example, a suitably protected C-6 ketone was therefore investigated.

[0008] If an oxazolidine derived from, for example, the reaction shown in Scheme 2, could be cleaved by a suitable organometallic reagent, for example a suitable Grignard, organolithium, organocuprate, organozinc or organoaluminum reagent, or other suitable metallic reagent, then the original N-methyl group carbon would remain in the product, and the process for the synthesis of naloxone and other derivatives would be more atom economical. The present application reports a general method of synthesis for naloxone, naltrexone, nalbuphone, nalbuphine and other morphine analogs via oxazolidines derived from, for example, oxymorphone. [0009] Accordingly, the present application includes a process for the preparation of a compound of Formula 1:

wherein

— - represents a single or double bond, provided that two double bonds are not adjacent to each other;

R is selected from C _3- iocycloalkyl, C _3- ioCycloalkenyl, C^ioalkyl, C ₂ --i ₀ alkenyl,

C ₆ -ioaryl, Ci.-ioalk leneC6-ioaryl and Ci-ioalkyleneC3.iocycloalkyl; and

R ² and R ³ are independently selected from H, C-i_ioa!kyl, Ci_i _Q acyl. C ₆ -ioa yi,

C _3- iocycloalkyl, Ci-i ₀ alkyleneC ₆ -ioaryl and C- _M oalkyleneCs-iocycloalkyl, except w en represents =0, then R ³ is not present;

comprising

(a) reacting a compound of Formula II or a protected form thereof:

II

wherein

represents a single or double bond, provided that two double bonds are not adjacent to each other; and

R ² and R ³ are independently selected from H, Ci.i ₀ alkyl, Ci-i ₀ acyl, C _6- -ioaryl, C ₃ .iocycloalkyl, Ci-i ₀ alkyleneC _S -ioaryl and C _1-10 alkyleneC3-ioCycloalkyl, except when— o represents =0, then R ³ is not present;

with a reagent of Formula III: R ¹ A III,

wherein R is selected from C- oalkyl, C2-ioalkenyl, C ₃ .-:ocycloalkyl, C ₃ -iocycloalkenyl, C ₆ -ioaryi, Ci.ioalkyleneCe-ioaryl and Ci-i ₀ alkyleneC ₃ „ _l ocycloalkyl; and

A is a suitable metallic or organometallic countercation; and

(b) optionally deprotecting the compound derived from reacting the compound of Formula II or protected form thereof with the reagent of Formula III;

under conditions to provide a compound of Formula I;

wherein in the compounds of Formulae I, II and III one or more available hydrogens in R ¹ , R ² and R ³ is/are optionally replaced with F and/or one or more of available atoms in R ¹ , R ² and R ³ is/are optionally replaced with an isotopic label.

[0010] Other features and advantages of the present application will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples while indicating embodiments of the application are given by way of illustration only, since various changes and modifications within the spirit and scope of the application will become apparent to those skilled in the art from this detailed description.

DETAILED DESCRIPTION OF THE APPLICATION

I Definitions

[0011] Unless otherwise indicated, the definitions and embodiments described in this and other sections are intended to be applicable to all embodiments and aspects of the application herein described for which they are suitable as would be understood by a person skilled in the art.

[0012] As used in this application, the singular forms "a", "an" and "the" include plural references unless the content clearly dictates otherwise. For example, an embodiment including "a reducing agent" should be understood to present certain aspects with one reducing agent, or two or more additional reducing agents. [0013] In embodiments comprising an "additional" or "second" component, such as an additional or second reducing agent, the second component as used herein is chemically different from the other components or first component. A "third" component is different from the other, first, and second components, and further enumerated or "additional" components are similarly different.

[0014] The term "suitable" as used herein means that the selection of the particular compound or conditions would depend on the specific synthetic manipulation to be performed, and the identity of the molecule(s) to be transformed, but the selection would be well within the skill of a person trained in the art. All process/method steps described herein are to be conducted under conditions sufficient to provide the product shown. A person skilled in the art would understand that all reaction conditions, including, for example, reaction solvent, reaction time, reaction temperature, reaction pressure, reactant ratio and whether or not the reaction should be performed under an anhydrous or inert atmosphere, can be varied to optimize the yield of the desired product and it is within their skill to do so.

[0015] in embodiments of the application, the compounds described herein have at least one asymmetric centre. Where compounds possess more than one asymmetric centre, they may exist as diastereomers. It is to be understood that all such isomers and mixtures thereof in any proportion are encompassed within the scope of the present application. It is to be further understood that while the stereochemistry of the compounds may be as shown in any given compound listed herein, such compounds may also contain certain amounts (e.g. less than 20%, suitably less than 10%, more suitably less than 5%) of compounds of the application having alternate stereochemistry.

[0016] In understanding the scope of the present disclosure, the term

"comprising" and its derivatives, as used herein, are intended to be open ended terms that specify the presence of the stated features, elements, components, groups, integers, and/or steps, but do not exclude the presence of other unstated features, elements, components, groups, integers and/or steps. The foregoing also applies to words having similar meanings such as the terms, "including", "having" and their derivatives. The term "consisting" and its derivatives, as used herein, are intended to be closed terms that specify the presence of the stated features, elements, components, groups, integers, and/or steps, but exclude the presence of other unstated features, elements, components, groups, integers and/or steps. The term "consisting essentially of, as used herein, is intended to specify the presence of the stated features, elements, components, groups, integers, and/or steps as well as those that do not materially affect the basic and novel characteristic(s) of features, elements, components, groups, integers, and/or steps.

[0017] Terms of degree such as "substantially", "about" and "approximately" as used herein mean a reasonable amount of deviation of the modified term such that the end result is not significantly changed. These terms of degree should be construed as including a deviation of at least ±5% of the modified term if this deviation would not negate the meaning of the word it modifies.

[0018] The term "Burgess reagent" as used herein refers to a reagent of the formula: also known as methyl A/-(triethylammoniumsulfonyl)carbamate. This reagent is commercially available (for example from Sigma Aldrich, St. Louis, MO, USA) or may be prepared from chlorosulfonylisocyanate by treatment with methanol, followed by triethylamine in benzene. ⁶

[0019] The term "countercation" as used herein refers to a positively charged species consisting of a single element, or a positively charged species consisting of a group of elements connected by ionic and/or covalent bonds. [0020] The term "Grignard reagent" as used herein refers to a reagent of Formula III, wherein A is MgX; i.e. a reagent of the formula R MgX, wherein X is selected from CI, Br and I, and R is as defined herein. Such reagents may be commercially available {for example from Sigma-Aldrich Co.) and/or they may be prepared from the reaction of a suitable organohalide with a suitable source of magnesium metal under conditions suitable for the formation of the required Grignard reagent. The selection of a suitable synthetic route to the Grignard reagent required can be made by a person skilled in the art. A number of synthetic routes are known in the art, for example as described in Smith, M.B. and March, J., "March's Advanced Organic Chemistry: Reactions, Mechanisms and Structure" 5th ed., John Wiley & Sons, Inc., 2001 (New York) at, for example, pages 805ff.

[0021] The term "organolithium reagent" as used herein refers to a reagent of Formula III, wherein A is Li; i.e. a regent of the formula LiR ¹ , wherein R ¹ is as defined herein. Such reagents may be commercially available (for example from Sigma-Aldrich Co.) and/or they may be prepared, for example, from the reaction of a suitable organohalide with lithium metal or by halogen-metal exchange using suitable reagents under conditions suitable for the formation of the required organolithium reagent. The selection of a suitable synthetic route to the organolithium reagent required can be made by a person skilled in the art. A number of synthetic routes are known in the art, for example as described in Loudon, G.M., Organic Chemistry" Addison- Wesiey Publishing Company, 1984 (Reading, Massachusetts) at, for example, page 652.

[0022] The term "organocuprate reagent" as used herein refers to a reagent of Formula III, wherein A is LiCuL ¹ ; i.e. a reagent of the formula R ¹ L ¹ CuLi, wherein R ¹ is as defined herein and L ¹ is selected from C-|. ₁₀ alkyl, C _2- ioalkenyl _J C ₃ . ₁₀ cyc!oalkyl, C ₃ . _1Q cycloalkenyl, C ₆ -ioaryl, C-i_ioalkyleneC ₆ -ioaryl and Ci-ioalk leneCa-iocycloalkyl. Such reagents may be prepared from, for example, the reaction of about two equivalents of a suitable organolithium reagent with about one equivalent of CuCI under conditions suitable for the formation of the required organocuprate reagent. The selection of a suitable synthetic route to the organocuprate reagent required can be made by a person skilled in the art. Synthetic routes are known in the art, for example as described in Loudon, G.M., Organic Chemistry" Addison-Wesley Publishing Company, 1984 (Reading, Massachusetts) at, for example, page 345.

[0023] The term "organozinc" reagent as used herein refers to a reagent of Formula III, wherein A is ZnL ² ; i.e. a reagent of the formula ZnR ¹ L ² , wherein R ¹ is as defined herein, and each L ² is independently selected from CI, Br, I, C-i_i ₀ alkyl, C ₂ -ioalkenyl, C ₃ _iocycioalkyl, C ₃ .i ₀ cycloalkenyl, C ₆ -ioaryl, Ci.-ioalkyleneCe-ioary! and Ci-ioalkyleneC ₃ -iocycloalkyl. Such reagents may be commercially available (for example from Sigma-Aldrich Co.) and/or they may be prepared, for example, from the reaction of a suitable organohalide with a suitable source of zinc metal under conditions suitable for the formation of the required organozinc reagent. The selection of a suitable synthetic route to the organozinc reagent required can be made by a person skilled in the art, A number of synthetic routes are known in the art, for example as described in Smith, M.B. and March, J., "March's Advanced Organic Chemistry: Reactions, Mechanisms and Structure" 5th ed., John Wiley & Sons, Inc., 2001 (New York) at, for example, pages 805ff .

[0024] The term "organoaluminum reagent" as used herein refers to a reagent of Formula III, wherein A is AI(L ) ₂ ; i.e. a reagent of the formula AIR (L ³ ) ₂ , wherein R ¹ is as defined herein, and each L ³ is independently selected from CI, Br, I, Ci_-ioalkyl, C _2- ioalkenyl, C ₃ . ₀ cycloalkyl, C ₃ . ₁₀ cycloalkenyl, C6-ioaryl, C-i ioalkyleneC ₆ -ioaryl and C _1-10 alkyleneC3- locycloalkyl. Such reagents may be commercially available (for example from Sigma-Aldrich Co.) and/or they may be prepared from the reaction of suitable reagents. A number of synthetic routes are known in the art, for example, as described in Downs, A.J., "Chemistry of Aluminium, Gallium, Indium and Thallium" Chapman & Hall, 1993 (London, UK) at, for example, page 324ff. The selection of a suitable synthetic route to the organoaluminum regent required can be made by a person skilled in the art. [0025] The term "ketone activating reagent" as used herein refers to a reagent that catalyzes the reaction between a suitable ketone and a suitable alcohol to form the corresponding ketal. The selection of a suitable ketone activating reagent can be made by a person skilled in the art. A number of ketone activating reagents are known in the art, for example as described in Smith, M.B. and March, J., "March's Advanced Organic Chemistry: Reactions, Mechanisms and Structure" 5th ed , John Wiley & Sons, Inc., 2001 (New York) at, for example, pages 1180ff. It is an embodiment of the application that the ketone activating reagent is a silyl chloride, such as trimethylsilyl chloride (TMSCI).

[0026] The term "acyl" as used herein, whether it is used alone or as part of another group, means straight or branched chain, saturated acyl groups. The term Crsacyl means an acyl group having 1, 2, 3, 4, 5 or 6 carbon atoms. It is an embodiment of the application that, in the acyl groups, one or more, including ail of the available hydrogen atoms are optionally replaced with F or ² H and thus include, for example trifluoroacetyl and the like.

[0027] The term "alky!" as used herein, whether it is used alone or as part of another group, means straight or branched chain, saturated alkyl groups. The term C _h alky! means an alkyl group having 1 , 2, 3, 4, 5, or 6 carbon atoms. It is an embodiment of the application that, in the alkyl groups, one or more, including all, of the hydrogen atoms are optionally replaced with F or ² H and thus include, for example trifluoromethyl, pentafluoroethyl and the like.

[0028] The term "alkylene" as used herein, whether it is used alone or as part of another group, refers to a bivalent alkyl group.

[0029] The term "alkenyl" as used herein, whether it is used alone or as part of another group, means straight or branched chain, unsaturated alkenyl groups. The term C^alkenyl means an alkenyl group having 2, 3, 4, 5, or 6 carbon atoms and at least one double bond. It is an embodiment of the application that, in the alkenyl groups, one or more, including ai!, of the hydrogen atoms are optionally replaced with F or ² H and thus include, for example trifluoroethenyl, pentaf!uoropropenyl and the like.

[0030] The term "cycloalkyl" as used herein, whether it is used alone or as part of another group, means cyclic, saturated alky! groups. The term C3_iocycloalkyl means a cycloalkyl group having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. It is an embodiment of the application that, in the cycloalkyl groups, one or more, including all, of the hydrogen atoms are optionally replaced with F or ² H.

[0031] The term "cycloalkenyl" as used herein, whether it is used alone or as part of another group, means cyclic, unsaturated alkyl groups. The term C _3- iocycloalkenyl means a cycloalkenyl group having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms and at least one double bond. It is an embodiment of the application that, in the cycloalkenyl groups, one or more, including all, of the hydrogen atoms are optionally replaced with F or ² H.

[0032] The term "aryl" as used herein refers to cyclic groups that contain at least one aromatic ring. In an embodiment of the application, the aryl group contains from 6, 9 or 10 atoms, such as phenyl, naphthyl or indanyl. It is an embodiment of the application that, in the aryl groups, one or more, including all, of the hydrogen atoms are optionally replaced with F or ² H and thus include, for example pentafiuorophenyl and the like.

[0033] The term "halo" as used herein refers to a halogen atom and includes F, CI, Br and I.

[0034] The term "reducing agent" as used herein means any compound or combination of compounds that reduces a desired functional group(s) but does not otherwise react with or degrade the substrate comprising the functional group(s). A reducing agent results in the overall gain of electrons, or in the case of organic chemistry, hydrogen atoms to the functional group.

[0035] t-Boc as used herein refers to the group f-butyloxycarbonyl.

[0036] Ac as used herein refers to the group acetyl. [0037] Ts (tosyl) as used herein refers to the group p-toluenesu!fonyl.

[0038] Ms as used herein refers to the group methanesulfonyl.

[0039] TBDMS as used herein refers to the group f-butyldimethylsilyl.

[0040] TBDPS as used herein refers to the group i-butyldiphenylsilyl.

[0041] TMS as used herein refers to the group trimethylsilyl.

[0042] Tf as used herein refers to the group trifluoromethanesulfonyl.

[0043] Ns as used herein refers to the group naphthalene sulphonyl.

[0044] Bn as used herein refers to the group benzyl.

[0045] Fmoc as used herein refers to the group fluorenylmethoxycarbonyl.

[0046] mCPBA as used herein refers to meta-chloroperbenzoic acid.

[0047] THF as used herein refers to the compound tetrahydrofuran.

[0048] The terms "protective group" or "protecting group" or "PG" or the like as used herein refer to a chemical moiety which protects or masks a reactive portion of a molecule to prevent side reactions in those reactive portions of the molecule, while manipulating or reacting a different portion of the molecule. After the manipulation or reaction is complete, the protecting group is removed under conditions that do not degrade or decompose the remaining portions of the molecule. The selection of a suitable protecting group can be made by a person skilled in the art. Many conventional protecting groups are known in the art, for example as described in "Protective Groups in Organic Chemistry" McOmie, J.F.W. Ed. , Plenum Press, 1973, in Greene, T.W. and Wuts, P.G.M. , "Protective Groups in Organic Synthesis", John Wiley & Sons, 3 ^rd Edition, 1999 and in Kocienski, P. Protecting Groups, 3rd Edition, 2003, Georg Thieme Verlag (The Americas). Examples of suitable protecting groups include, but are not limited to t-Boc, Ac, Ts, Ms, silyl ethers such as TMS, TBDMS, TBDPS, Tf, Ns, Bn, Fmoc, benzoyl, dimethoxytrityl, methoxyethoxymethyl ether, methoxymethyl ether, pivaloyl, p-methyoxybenzy! ether, tetrahydropyranyl, trityl, ethoxyethyl ethers, carbobenzyloxy, benzoyl and the like.

[0049] The expression "proceed to a sufficient extent" as used herein with reference to the reactions or process steps disclosed herein means that the reactions or process steps proceed to an extent that conversion of the starting material or substrate to product is maximized. Conversion may be maximized when greater than about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 100% of the starting material or substrate is converted to product.

II. Methods of the Application

[0050] The present application includes a process for the preparation of a compound of Formula I:

I

wherein

---- represents a single or double bond, provided that two double bonds are not adjacent to each other;

R is selected from C ₃ -ioCycloalkyl, C3_iocycloalkenyl, Ci--| ₀ alkyl, C _2- ioalkenyl,

C _3- ioaryl, and C-i_ioalkyleneC ₃ -iccycloalkyl; and

2 and R ³ are independently selected from H, C- oalkyl, Ci-i ₀ acyl, C ₆ „ioaryl,

C ₃ -iocycloalkyl, C- _M oalkyleneCg.-ioaryl and C _M oalkyleneCa-ioCycloalkyl, except when— O represents =0, then R ³ is not present;

comprising

(a) reacting a compound of Formula II or a protected form thereof:

II

wherein

-— represents a single or double bond, provided that two double bonds are not adjacent to each other; and

R ² and R ³ are independently selected from H, Ci_i ₀ alkyl, Ci.i ₀ acyl, C _6- i ₀ aryl, C _3-1 ocycloalkyl, Ci-ioalkyleneCe-ioaryl and Ci.ioalkyleneC ₃ .iocycloalkyl, except when ^™ 0 represents =0, then R ³ is not present;

with a reagent of Formula III:

R A III

wherein R ¹ is selected from C<|. ₁₀ alkyl, C2-ioalkenyl, C3_iocycloalkyl, C3-iocycloalkenyl, C _6- ioaryl, Ci-i ₀ alkyleneC ₆ -ioaryl and Ci.i ₀ aikyleneC ₃ - ₁₀ cycloalkyl; and

A is a suitable metallic or organometallic countercation; and

(b) optionally deprotecting the compound derived from reacting the compound of Formula II or protected form thereof with the reagent of Formula Hi;

under conditions to provide a compound of Formula I;

wherein in the compounds of Formulae I, II and III one or more available hydrogens in R ¹ , R ² and R ³ is/are optionally replaced with F and/or one or more of available atoms in R ¹ , R ² and R ³ is/are optionally replaced with an isotopic label.

[0051] In an embodiment of the application R ¹ is selected from Ci- ₆ alkyl, C2- ₆ alkenyl, C _3-6 cycloalkyl, C ₃ _ _G cycloalkenyl, Cs ioary!, Ci. ₆ alkyleneC ₆ -ioaryl, and C _1-6 alkyleneC ₃ - ₆ cycloalkyi. In another embodiment of the application, R is selected from Me, Et, vinyl, ally!, Ph, cyclopropyl, cyclobutyl, cyclopentyl, cyciohexyl, Bn, cyclopropyl methyl, cyclobutylmetbyl, cyclopentylmethyl and cyclohexylmethyl. It is a further embodiment of the application that R ¹ is selected from vinyl, cyclopropyl and cyclobutyl.

[0052] In an embodiment of the application R ² and R ³ are independently selected from H, Ci^alkyl, C-i^ac l, Cs-ioar l, C3.6cycloalk.yl, C3_6cycloalkenyl, C-i_6a!kyieneCg_ioaryl, and C-i_6alkyleneC ₃ - ₆ cycloalkyl. In a further embodiment of the application, R ² and R ³ are independently selected from H, Ac, Me, Et, Ph, cyclobutyl, cyclopentyi, cyclohexyl, Bn, cyclobutylmethy!, cyclopentylmethyi and cyclohexylmethyl. It is an embodiment of the application that R ² is Ac. In another embodiment of the application, R ³ is H.

[0053] In an embodiment of the application, the reagent of Formula III; i.e. the reagent of formula R ¹ A is selected from a G ignard reagent, an organolithium reagent, an organocuprate reagent, an organozinc reagent and an organoaluminum reagent. It is an embodiment of the application that R A is a Grignard reagent of formula R MgX, wherein X is selected from CI, Br and I. In a further embodiment of the application, X is selected from CI and Br. It is an embodiment that X is Br.

[0054] In an embodiment, the compound of Formula II is selected from a compound of Formula ll a), ll{b) and ll(c):

ll(a) "(b)

wherein

— - represents a single or double bond; and

R ² and R ³ are independently selected from H, Ci_i ₀ alkyl, Ci-i ₀ acyl, C ₆ -ioaryl, C ₃ _iocycloalk l, Ci-i ₀ alkyleneC ₆ .ioaryl, and C-i-i ₀ alkyleneC3.iocycloalkyl;

which provide, respectively, a compound of Formula l(a), l(b) and l(c) using the process of the present application:

wherein

— represents a single or double bond;

R ¹ is selected from C-M oalkyl, C2-ioalkenyl, C ₃ .i ₀ cycloa!kyl, C ₃ . ₀ cycloalkenyl, C ₆ -ioaryf, Ci-ioalkyleneC ₆ -ioaryl and Ci.i ₀ alkyleneC _3- iocycloalkyl;

R ² and R ³ independently selected from H, CMoalkyl, C- oacyl, Ce-ioaryl, C ₃ _iocycloalkyl, C- oal yleneCe-ioaryl, and Ci_ioalkyleneC3-iocycloalkyl; and wherein in the compounds of Formulae l(a), l(b), l(c), ll(a), ll(b) and ll(c) one or more available hydrogens in R ¹ , R ² and R ³ is/are optionally replaced with F and/or one or more of available atoms in R ¹ , R ² and R ³ is/are optionally replaced with an isotopic label.

[0055] In an embodiment of the application, the conditions to provide the compounds of Formula I from the compounds of Formula II using the reagents of Formula III comprise adding the reagent of Formula I II dropwise to a stirred solution of the oxazolidine of Formula I) in a suitable solvent, for example, THF, at about -5 °C to about 5 °C, or about 0 °C, allowing the mixture to warm up to a temperature of about 0 °C to about 30 °C, or about room temperature, and stirring for a time for the conversion of the compound of Formula II to the compound of Formula I to proceed to a sufficient extent, for example, about 15 hours to about 6 hours, or about 2 hours, at which time the mixture is quenched with a suitable reagent, for example, saturated NH ₄ CI solution. In an embodiment, the molar ratio of the reagent of Formula III to the compound of Formula II is about 3:1 to about 8:1 or about 5:1 .

[0056] In an embodiment, the compound of Formula I II is selected from a compound of Formula lll(i), lll(ii) and lll{iii): -MgBr [^>-MgBr and ^>— MgBr ltl(i) lll(ii) lll(iii) which provide, respectively, a compound of Formula l{i), l(ii) and l(iii) using the process of the present application:

wherein

— represents a single or double bond, provided that two double bonds are not adjacent to each other;

R ² and R ³ are independently selected from H, Ci-i ₀ alkyl, C-Moacyl, C _6- ioaryl, C ₃ ^ocycloalkyl, Ci-ioalkyleneC ₆ - ₀ aryl and Ci-i ₀ alkyleneC3.-iocycloalkyl, except when — O represents =0, then R ³ is not present; and

wherein in the compounds of Formulae l(i), l(ii) and l(iii), one or more available hydrogens in R ² and R ³ is/are optionally replaced with F and/or one or more of available atoms in R ² and R ^J is/are optionally replaced with an isotopic label.

[0057] In an embodiment, the compounds of Formula ll(b) are protected prior to reaction with the reagents of Formula III. In an embodiment, the protected form of the compounds of Formula ll(b) is a ketai of Formula IV:

w erein

— represents a single or double bond;

R ² is selected from H, C-Moalkyi, C-Moacyl, Ce-ioaryl, C3.-iocycloalkyl, Ci_

₁₀ alkyleneCg-ioaryl and Ci-ioalkyleneC ₃ iocycloalkyl; and

R ⁴ and R ⁵ are each independently the same or different hydrolysab!e protecting group, or R ⁴ and R ⁵ , together with the oxygen atom to which each is bonded, form a hydrolysable cyclic protecting group; and

wherein one or more available hydrogens in R ² , R ⁴ and R ⁵ is/are optionally replaced with F and/or one or more of available atoms in R ² , R ⁴ and R ⁵ is/are optionally replaced with an isotopic label.

[0058] The compounds of Formula IV are prepared by reacting a compound of Formula ll(b) under conditions to provide the compounds of Formula IV. In an embodiment, the conditions to provide the compounds of Formula IV comprise adding a suitable ketone activating reagent, for example T SCI to a stirred suspension or solution of the compound of Formula ll(b) and a suitable alcohol, for example, methanol or ethylene glycol, optionally in a suitable solvent, for example, CH ₂ Cl2, and allowing the mixture to stir for a time and temperature for the conversion of the compound of Formula ll(b) to the compound of Formula IV to proceed to a sufficient extent, for example at about

-10 °C to about 50 °C, about 0 °C to about 25 °C or about room temperature for about 30 minutes to about 10 hours, about 2 hours to about 6 hours, or about 2 hours. In this embodiment, TLC monitoring of the reaction mixture using a suitable solvent mixture, for example CHC /MeOH/NhUOH in a ratio of, for example, about 5:1 :0.01 as eluent can be optionally used to indicate the reaction is complete.

[0059] In an embodiment of the application, the suitable alcohol is a monofunctiona! alcohol. It is an embodiment that the monofunctional alcohol is methanol. In this embodiment, both R ⁴ and R ⁵ are Me. In another embodiment, the suitable alcohol is a difuncttonal alcohol. It is an embodiment that the difunctional alcohol is ethylene glycol. In this embodiment, R ⁴ and R ⁵ , together with the oxygen atom to which each is bonded, and the carbon atom to which each oxygen atom is bonded, form a dioxolane moiety.

[0060] Reaction of the compounds of Formula IV with the reagents of Formula ill provides compounds of Formula V:

— represents a single or double bond;

R ¹ is selected from C _{- 0} alkyl, C ₂ -ioalkenyl, C ₃ . ₁₀ cycloalkyl, C ₃ -i ₀ cycloalkenyl,

Ce-ioaryl, Ci_ ₀ alkyleneC ₆ -ioaryl and Ci-ioalkyleneC ₃ -i ₀ cycloalkyl;

R ² is selected from H, Ci-i ₀ alkyl, Ci-i ₀ acyl, C _6- ioaryl, C _3- iocycloalkyl, Ci_

₁₀ alkyleneC _S -ioaryl and Ci-ioa!kyleneC3.-| ₀ cycloalkyl; and

R ⁴ and R ⁵ are each independently the same or different hydrolysab!e protecting group, or R ⁴ and R ⁵ , together with the oxygen atom to which each is bonded, form a hydrolysable cyclic protecting group; and

wherein one or more available hydrogens in R ¹ , R ² , R ⁴ and R ⁵ is/are optionally replaced with F and/or one or more of available atoms in R ¹ , R ² , R ⁴ and R ⁵ is/are optionally replaced with an isotopic label.

[0061] Deprotection of the compounds of Formula V under hydrolysis conditions provides ketones of Formula l b):

Kb) wherein

~~- represents a single or double bond;

R ¹ is selected from Ci-i ₀ alkyl, C ₂ -<oalkenyl, C ₃ .-| ₀ cycloa!kyl, C3--iocycloalkenyl,

C _6- ioaryl, C-i-ioalky(eneC ₆ --oaryl and Ci.-oalkyleneC ₃ -iocycloalkyl;

R ² is selected from H, Ci.i ₀ alkyl, Ci-i ₀ acy[, C ₆ -ioaryl, C ₃ -iocycloalkyl,

Ci-ioal yleneCs-ioaryl and Ci-ioalkyleneC ₃ .i ₀ cycloalkyl; and

wherein one or more available hydrogens in R ¹ and R ² is/are optionally replaced with F and/or one or more of available atoms in R ¹ and R ² is/are optionally replaced with an isotopic label.

[0062] In this embodiment, it is possible to prepare the known morphine analogs, naloxone l{b)(i), naltrexone l(b)(ii) and nalbuphone l(b)(iii):

i(b)(i) l(b)(ii) l(b)(iii)

[0063] In an embodiment, the hydrolysis conditions to provide the compounds of Formula l(b) comprise treating the compounds of Formula V under suitable acidic conditions for a time and temperature for the conversion of the compounds of Formula V to the compounds of Formula l(b) to proceed to a sufficient extent, for example at a temperature of about 25 °C to about 100 °C, about 60 °C to about 80 °C, or about 60 °C for about 30 minutes to about 8 hours, about 2 hours to about 4 hours, or about 2 hours. It is an embodiment that the suitable acidic conditions comprise adding a suitable acid, for example, about 2 N to about 6 N HCI to a stirred solution of the compound of Formula V in a suitable organic solvent, for example, THF or acetone.

[0064] In a further embodiment of the application, prior to reaction with the reagents of Formula III, the compounds of Formula ll(b) are treated under reducing conditions to provide compounds of Formula ll(a):

11 (a)

wherein

— represents a single or double bond;

R ² is selected from H, Ci.i ₀ aikyl, C-Moacyl, C ₅ -ioaryl, C _3- iocycloalkyl, Ci-ioalkyleneC6-ioary] and Ci.-ioalkyleneC3.-iocycloalkyl;

R ³ is H; and

wherein one or more available hydrogens in R ² is/are optionally replaced with F and/or one or more of available atoms in R ² and R ³ is/are optionally replaced with an isotopic label.

[0065] The compounds of Formula ll(a), wherein R ³ = H are available by treating compounds of Formula ll(b) under reducing conditions. In an embodiment, the reducing conditions to provide the compounds of Formula il(a) wherein R ³ is H comprise treating the compounds of Formula ll(b) in a suitable solvent, for example, methanol with a suitable reducing agent, for example metal hydride reducing agents, for example, aBH^ for a time and temperature for the conversion of the compounds of Formula ll(b) to the compounds of Formula ll(a), wherein R ³ is H to proceed to a sufficient extent, for example at about 0 °C to about 30 °C, or about room temperature for about 0.5 hours to about 2 hours, or about 1 hour.

[0066] Reaction of the compounds of Formula ll(a), wherein R ³ is H with the reagents of Formula III provides compounds of Formula l(a),

wherein

— represents a single or double bond;

R ¹ is selected from Ci. ₁₀ alkyl, C2-i ₀ alkenyl, C ₃ -iocycloalkyl, C ₃ -iocycloalkenyl,

Ce-ioaryl, C- oalkyleneCe-i oaryl and Ci- ₀ alkyleneC _3- iocycloa]kyl ;

R ² is selected from H, Ci. ₁₀ alkyl, Ci- ₁₀ acyl, C6-ioar l , C ₃ _iocycloalkyl,

Ci-ioalkyleneC6-ioaryi and Ci.ioalkyleneC3. ocycloalkyl;

R ³ is H; and

wherein one or more available hydrogens in R ¹ and R ² is/are optionally replaced with F and/or one or more of available atoms in R ¹ , R ² and R ³ is/are optionally replaced with an isotopic label,

[0067] In this embodiment, it is possible to prepare the known morphine analog nalbuphine l(a)(iii):

l(a)Ciii)

[0068] It is a further embodiment of the application that morphine analogs of Formula I can be prepared from the oxazolidines of Formula II in a one-pot synthesis without the isolation of intermediates.

[0069] The processes of the present application may be performed using continuous or batch processes. For commercial scale preparations, continuous processes are suitable, Methods of performing chemical processes in continuous or batch modes are known in the art. When continuous processes are used, the reaction temperature and/or pressure may be higher than those used in batch processes.

[0070J The following non-iimiting examples are illustrative of the present application:

EXAMPLES

Example 1: (SaR^R^aS^laR^lbS^-acetoxy-S^a^lO-tetrahydro-H _^ H- dimeth ole

[0071] To a stirred suspension of the oxazolidine of Formula l!{b) (R ^z = Ac, ₌ represents a single bond; 60 mg, 0.18 mmol) in eOH (5 mL) was added TMSCi (0.50 mL). After the addition of TMSCI, a homogenous yellowish solution was observed. The mixture was allowed to stir at room temperature for 2 h, at which time TLC monitoring of the reaction mixture using CHCI ₃ /MeOH/NH ₄ OH (5: 1 :0.01 ) as eluent indicated the reaction was complete. The reaction mixture was diluted with dichloromethane (10 mL) and the resulting solution was washed with saturated NaHC0 ₃ (5 mL). The organic layer was dried with MgS0 ₄ , filtered and evaporated to dryness via rotary evaporation to afford 50 mg (82%) of a compound of Formula IV(a) (R ² = Ac, R ⁴ and R ⁵ = Me. represents a single bond) as an oil which was used in the next step without further purification. Example 2: General procedure for Grignard reactions of ketal IV(a)

[0072] To a stirred solution of the oxazo!idine of Formula IV(a) from Example 1 (1 mmol) in THF ,(10 mL) at 0 °C was added a reagent of Formula III wherein A is MgX; lll(i) (R = vinyl, X = Br); l ll{ii) (R ¹ = cyclopropyl, X = Br); or Ml(iv) (R = cyclobutyl, X = CI) (5 mmol) dropwise. The mixture was allowed to warm up to room temperature and stirred for a further 2 h, then it was quenched with saturated NH ₄ CI solution (10 mL) and was diluted with EtOAc (10 mL), The layers were separated and the aqueous layer was extracted further with EtOAc (2 x 10 mL). The combined organic extracts were dried over MgS0 ₄ , filtered and concentrated using rotary evaporation to afford crude compounds of Formula V. Chromatography on silica gel using mixtures of CH2CI2 and MeOH afforded compounds of Formula V(a)(i), V(a)(ii) and V(a)(iii) as white solids (56-83% yield).

(a) 17-allyl-4, 5a-epoxy-3, 14-dihydroxy-6, 6-dimet oxymorphinan, V(a) (i)

[0073] 83% yield. [a] _D ²⁰ -92.3 (c = 0.8, CHCI ₃ ); R, = 0.26 (7:2;

CH ₂ CI ₂ /MeOH): IR (CHCI3) v 3435, 2957, 2834, 1642, 1458, 1333, 1 141 , 11 10, 1047, 989 _; 908, 732 cm ^"1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 6.71 (d, J=8.1 Hz, 1 H), 6.55 (d, J=8.1 Hz, 1 H), 5.77-5.86 (m, 1 H), 5.21 (d, J=18.0 Hz, 1 H), 4.60 (s, 1 H), 3.38 (s, 3H), 3.03-3.11 (m, 2H), 3.12 (s, 3H), 3.03 (s, 1 H), 2.94 (d, J=5.7 Hz, 1H), 2.62 (d, J=5.7 Hz, 1H), 2.53-2.57 (m, 1H), 2.31 (ddd, J=12.3, 12.0, 3.0 Hz, 1H), 2.19 (ddd, 12.3, 12.0, 3.0 Hz, 1H), 1.87-1.96 (m, 1H), 1.40-1.59 (m, 5H); ¹³ C NMR (75 MHz, CDCI ₃ ) δ 144.8, 137.7, 135.4, 130.8, 124.5, 118.4, 117.8, 116.8, 99.8, 91.8, 69.9, 62.7, 57.7, 49.1, 48.2, 48.1, 43.6, 31.9, 27.9, 24.6, 22.5; MS (EI+) m/z (%) 373(5), 358 (10), 342(28), 341(100), 326(12), 139(12), 101(14), 57(21), 56(20), 43(25); HRMS (EI+) calcd for C21H27NO5373.1889, found 373.1891.

(b) 17-cyclopropylmethyl-4, 5a-epoxy-3, 14-dihydroxy-6, 6-dimethoxymorphinan, V(a)(ii)

[0074] 67% yield. ¹ H NMR (300 MHz, CDC ) δ 6.68 (d, J=8.1 Hz, 1H), 6.51 (d, J=8.1 Hz, 1H), 5.40 (s, 1H), 4.58 (s, 1H), 3.36 (s, 3H), 3.10 (s, 4H), 2.99 (d, J=18.2 Hz, 1H), 2.50-2.70 (m, 2H), 2.35 (m, 2H), 2.22-2.31 (m, 1H), 2.06-2.22 (m, 1H), 1.83-1.96 (m, 1H), 1.34-1.60 (m, 4H), 0.75-0.92 (m, 1H), 0.42-0.60 (m, 1H), 0.08-0.20 (m, 2H).

(c) 17-cyclobutylmethyl-4, 5a-epoxy-3, 14~dihydroxy-6, 6-dimethoxymorphinan, V(a)(iH)

[0075] 56% yield. [a] _D ^ -110.5 (c = 1.0, CH ₂ C! ₂ ); R _f = 0.37 (10:1; CH ₂ CI ₂ /MeOH): IR (CHCI ₃ ) v 3399, 2929, 2832, 2854, 1642, 1621, 1504, 1456, 1330, 1239, 1141, 1049, 988, 751 cm ¹ ; ¹ H NMR (300 MHz, CDCI ₃ ) δ 6.70 (d, J=8.1 Hz, 1 H), 6.53 (d, J=8.1 Hz, 1 H), 4.56 (s, 1 H), 3.37 (s, 3H), 3.13 (s, 3H), 3.05 (d, J=18.3 Hz, 1 H), 2.84 (d, J=5.7 Hz, 1 H), 2.60 (dd, 7=18.3, 6.0 Hz, 1 H), 2.46-2.55 (m, 4H), 2.20-2.30 (m, 2H), 2.04-2.09 (m, 2H), 1.84-1.96 (m, 2H), 1.65-1.70 (m, 2H), 1.38-1.45 (m, 5H); ¹³ C NMR (75 MHz, CDCI ₃ ) δ 144.8, 137.7, 130.8, 124.5, 118.4, 1 17.0, 99.7, 91.5, 69.7, 60.5, 49.01 , 48.2, 48.1 , 44.0, 33.7, 32.1 , 28.0, 27.0, 26.7, 24.5, 22.8, 18.7; MS (EI+) m z (%) 401 (9), 315(20), 314(100), 139(1 1), 97(12), 89(31), 71 (59), 55(46), 43(94); HRMS (EI+) calcd for C ₂₃ H _a iN0 ₅ 401.2202, found 401.2203.

Example 3: General procedure for the hydrolysis of V(a)(i)-V(a)(iii)

[0076] To a stirred solution of a compound of Formula V from Example 2 (0.10 mmol) in THF (2 mL) was added 3 N HCI (1 mL). The resulting solution was heated to 60 °C for 2 h. The mixture was concentrated via rotary evaporation to remove THF. A saturated solution of NaHC0 ₃ was added to adjust the pH of the mixture to 8. It then was extracted with CH ₂ C! ₂ (3 x 5 mL). The combined organic extracts were dried, filtered and concentrated via rotary evaporation to afford naloxone, naltrexone or naibuphone as white solids (76- 87% yield).

(a) Naloxone, 1(b) (i)

[0077] 81 % yield, mp 179-180 °C (EtOAc hexanes); lit. ⁷ 179.5 °C

(toluene). (b) Naltrexone, 1(b)(0)

[0078] 76% yield, mp 164-165 °C (CH ₂ CI ₂ /hexanes); lit. ^B 167-169 °C,

(CH ₂ CI ₂ ).

(c) Nalbuphone, l(b)(0i)

[0079] 87% yield, mp 164-165 °C (CH ₂ CI ₂ /hexanes); lit. ⁹ 168-169 °C (cyclohexane).

Example 4: One-pot preparation of naloxone

[0080] To a stirred suspension of the oxazolidine of Formula ll(b) {R ² = Ac, — represents a single bond; 100 mg, 0.293 mmol) in MeOH (5 mL) was added TMSCI (0.5 mL). The reaction mixture was stirred for 2 h at room temperature. All the vo!atiles were removed using rotary evaporation and further drying in vacuum. The resulting yellow oil was cooled to 0 °C and to it was added dropwise 1 M vinylmagnesium bromide (2 mL). The resulting mixture was allowed to warm up to room temperature and stirred for another 2 h. The pH of the reaction mixture was adjusted to 1.5 using 6 N HCI. A 1 : 1 mixture of THF/H ₂ 0 (2 mL) was added to clarify the cloudy solution. The resulting clear solution was heated to 60 °C for 2 h. The cooled reaction mixture was concentrated via rotary evaporation to remove THF. The pH was adjusted to 8 using saturated NaHC0 ₃ solution and was extracted with EtOAc (3 15 mL). The combined EtOAc extracts were dried over MgSO^ filtered and concentrated to afford a crude residue that was chromatographed on silica gel using CH ₂ CI ₂ /MeOH (10:1) as eluent to afford Naloxone l(b)(i) (72 mg, 75% yield).

Example 5: Preparation of nalbuphine, l(a)(iii)

[0081] To a stirred solution of the oxazoiidine of Formula ll(b) (R ² = Ac, — represents a single bond; 50 mg, 0.15 mmol) in MeOH (1 mL) was added NaBH ₄ (8 mg, 0.22 mmol). The solution was stirred at room temperature for 1 h. Acetone {1 mL) was added and the resulting mixture was concentrated using rotary evaporation. The crude residue was diluted with diethyl ether (10 mL) and was washed with water (3 mL). The organic layer was separated and the aqueous was further extracted with EtOAc (2 x 5 mL). The combined organic extracts were dried over MgS0 ₄ , filtered and evaporated to afford the intermediate alcohol of Formula II (a) (R ² = Ac, R ³ = H, represents a single bond; 40 mg) which was used as crude in the next step. To a stirred solution of this crude intermediate alcohol (40 mg, 0.12 mmol) in THF at 0 °C was added cyc!obutylmagnesium chloride (60 mmol). The resulting solution was stirred at room temperature for 2 h. The reaction mixture was quenched with saturated NH ₄ CI solution (3 mL). The resulting suspension was extracted with EtOAc (3 x 10 mL). The combined organic extracts were dried over gS0 ₄ , filtered and concentrated using rotary evaporation. The crude residue was chromatographed on silica gel using CH ₂ CI ₂ /MeOH as eluent to afford nalbuphine l(a){iii) as a solid (21 mg, 40% yield).

[0082] ¹ H NMR (300 MHz, DMSO) 5 8.81 (s, 1 H), 6.55 (d, J=8.0 Hz,

1 H), 6.42 (d, J=8.0 Hz, 1 H), 4.75 (s, 1 H), 4.43 (d, J=5.6 Hz, 1 H), 4.38 (d, J=4.5 Hz, 1 H), 4.00 (m, 1 H), 2.96 (d, J=18.4 Hz, 1 H), 2.75 (m, 1 H), 2.50-2.53 (m, 2H), 2.39-2.45 (m, 2H), 2.10 (m, 2H), 1 .85 (m, 2H), 1.81 (m, 1 H), 1.63 (m, 2H), 1.45 (m, 2H), 1.31 (m, 2H), 0.97 (m, 1 H).

Example 6: (5aR, 6R, 8aS, 11aR, 11 bS)-2-acetoxy- 5, 5a, 9, 1 O-tetrahydro-

11(11aH)-spiro-2-(1,3-dioxolan)-,6, 11b-Ethano-7H- furo[2 ',3',4',5 ':4, 5]phenanthro[9, 8a-d]oxazo!e

[0083] To a stirred solution of the oxazolidine of Formula ll(b) (R ² = Ac, — represents a single bond; 650 mg, 2.16 mmol) and ethylene glycol (14.3 mL, 260 mmol) in CH ₂ CI _Z (15 mL) was added TMSCI (1.46 mL, 11 .0 mmol). The mixture was allowed to stir at room temperature for 2 h, at the end of which TLC monitoring of the reaction mixture using CHCb/MeOH/NH ₄ OH (5:1 :0.01 ) as eluent indicated the reaction was complete. The reaction mixture was diluted with dichloromethane (30 mL) and the resulting solution was carefully washed with saturated aHC0 ₃ (15 mL). The organic layer was dried with MgS0 ₄ , filtered and evaporated to dryness via rotary evaporation to afford the ketal of Formula IV(b) (437 mg, 67%) as an oil which was used in the next step without further purification.

Example 7: General procedure for Grignard reactions of ketal IV(b)

[0084] To a stirred solution of the oxazolidine of Formula IV(b) from Example 6 (1 mmol) in THF (1 0 mL) at 0 °C was added a reagent of Formula III wherein A is MgX; Ml(i) (R ¹ = vinyl, X = Br); \\\(\\) (R ¹ = cyclopropyl, X = Br); or lll(iv) (R ¹ = cyclobutyl, X = CI) (5 mmol) dropwise. The mixture was allowed to warm up to room temperature and stirred for a further 2 h, then it was quenched with saturated NH ₄ CI solution (10 mL) and was diluted with EtOAc (10 mL). The layers were separated and the aqueous was extracted further with EtOAc (2 x 10 mL). The combined organic extracts were dried over gS0 ₄ , filtered and concentrated using rotary evaporation to afford crude compounds of Formula V. Chromatography on silica gel using mixtures of CH ₂ CI ₂ and MeOH afforded compounds of Formulas V(b)(i)-V(b)(iii) as white solids (46-70% yield).

(a) 4, 5a-epoxy-3, 14^-d\hydroxy-17-{prop-2-eny\)- orp inane-Q-sp\ro-2'-{ 1, 3- dioxolan) _: V(b)(i)

[0085] 46% yield. H NMR (600 MHz, CDCI ₃ ) δ 6.72 (d, J=8.1 Hz, 1 H), 6.58 (d, J=8.1 Hz, 1 H), 5.78-5.84 (m, 1 H), 5.14-5.23 (m, 2H), 4.60 (s, 1 H), 4.12-4.18 (m, 1 H), 3.84-3.99 (m, 4H), 3.15 (d, J=6.0 Hz, 13H), 3.06 (d, J=18.6 Hz, 1 H), 2.93 (s, 1H), 2.53-2.62 (m, 2H), 2.15-2.29 (m, 3H), 1.53-1.57 (m, 3H), 1.43 (d, J=12.6 Hz, 2H); MS (EI+) m/z (%) 371(100), 358 (10), 330(22), 289(32), 272(45), 242(27), 99(94), 82(50), 70(39), 55(31); HRMS (EI+) calcd for C21 H25NO5 371.1733, found 371.1734.

(b) 17-cyclopropylmethyt-4, 5a-epoxy-3, 14frdihydroxy-morphinane-6-spiro-2- (1,3-dioxolan), V(b)(ii)

[0086] 70% yield. ¹ H NMR (300 MHz, CDCI ₃ ) δ 6.72 (d, J=8.1 Hz, 1H),

6.56 (d, J=8A Hz, 1H), 4.61 (s, 1H), 4.16-4.19 (m, 1H), 3.83-3.98 (m, 4H), 3.03 (d, J=18.3 Hz, 1H), 2.55-2.66 (m, 2H), 2.28-2.42 (m, 3H), 2.16-2.23 (m, 3H), 1.48-1.68 <m, 5H), 0.85-0.87 (m, 1H), 0.54-0.56 (m, 2H), 0.15-0.16 (m, 2H); MS (EI+) m/z (%) 385(100), 344(22), 330(12), 288(14), 256(16), 110(31), 99(62).

(c) 17-cyctobutylmethyl-4, 5o-epoxy-3, 14β-dihydroxy-morphinane-6-spiro-2- (1,3-dioxolan), V(b)(iii)

[0087] 49% yield. [α ^υ -51.2 (c = 1.0, CHCI ₃ ); IR (CHCI ₃ ) v 3417, 2957, 1642, 1502, 1456, 1324, 1157, 1035, 799, 752 cm ^"1 ; ¹ H NMR (300 MHz, CDCI ₃ ) δ 6.72 (d, J=8.1 Hz, 1H), 6.57 (d, J=8.1 Hz, 1H), 4.59 (s, 1H), 4.15- 4.18 (m, 1H), 3.82-3.87 (m, 5H), 3.06 (d, J=18.3 Hz, 1H), 2.86 (d, J=5.7, 1H), 2.61 (dd, J=18.3, 5.7 Hz, 1H), 2.49-2.59 (m, 4H), 2.17-2.28 (m, 2H), 2.06-2.17 (m, 3H), 1.86-1.94 (m, 2H), 1.66-1.71 (m, 2H), 1.53-1.57 (m, 3H), 1.41-1.45 (m, 1H); MS (EI+) m/z (%) 399(12), 315(20), 344(100), 243(11), 139(9), 99(14), 86(39), 84(76), 60(10), 43(31); HRMS (EI+) calcd for C23H29NO5 399.2046, found 399.2043. Example 8: General procedure for the hydrolysis of V(b)(i)-V(b)(iii)

[0088] To a stirred solution of a compound of Formula V from Example 7 (0.10 mmol) in acetone (2 m!_) was added 6 N HCl (0.5 mL). The resulting solution was heated to 60 °C for 2 h. The mixture was concentrated via rotary evaporation to remove acetone. A saturated solution of NaHC0 ₃ was added to adjust the pH of the mixture to 8. It was then extracted with CH ₂ CI ₂ (3 x 5 mL). The combined organic extracts were dried, filtered and concentrated via rotary evaporation to afford naloxone l(b)(i), naltrexone l(b)(ii) and nalbuphone l(b)(iii) as white solids, with yields of 63%, 71 %, and 78%, respectively.

[0089] While the present application has been described with reference to what are presently considered to be the preferred examples, it is to be understood that the application is not limited to the disclosed examples. To the contrary, the application is intended to cover various modifications and equivalent arrangements included within the spirit and scope of the appended claims.

[0090] All publications, patents and patent applications are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety. Where a term in the present application is found to be defined differently in a document incorporated herein by reference, the definition provided herein is to serve as the definition for the term. FULL CITATIONS FOR DOCUMENTS REFERRED TO IN THE

SPECIFICATION

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