US008 168790B2

(12) United States Patent (10) Patent No.: US 8,168,790 B2 Bao et al. (45) Date of Patent: May 1, 2012

(54) PROCESS FOR THE PREPARATION OF OTHER PUBLICATIONS 6-BETA HYDROXY MORPHINAN COMPOUNDS Uwai et al., “Syntheses and receptor-binding studies of derivatives of the antagonist '. Bioorganic & Medicinal Chemis (75) Inventors: Jian Bao, Chesterfield, MO (US); Tao try, 2004, 12, pp. 417-421 XP002499242. Jiang, St. Louis, MO (US); Gary L. Kalinin et al., “Palladium-catalyzed 2-phenylethenylation of Cantrell, Troy, IL (US) : 8-(1E)-2-phenylethenyl dimethyl ketal as the unexpected masked diene for the preparation of 19-substituted (73) Assignee: Mallinckrodt LLC, Hazelwood, MO Diels-Alder adducts of ', Helvetica chimica Acta, 2006, vol. 89, No. 5, 2006, pp. 861-869 XP002538221. (US) Olofson et al., “A new reagent for the selective, high-yield (*) Notice: Subject to any disclaimer, the term of this N-dealkylation of tertiary amines: Improved syntheses of Naltrexone patent is extended or adjusted under 35 and ”, Journal of Organic Chemistry, 1984, vol. 49, No. 11, pp. 2081-2082 XP002538222. U.S.C. 154(b) by 402 days. Hamad et al., “Synthesis and hydrolytic behavior of two novel tri partite codrugs of Naltrexone and 6beta-naltrexol with (21) Appl. No.: 12/485,200 hydroxybupropion as potential alcohol abuse and Smoking cessation agents'. Bioorganic & Medicinal Chemistry, vol. 14, No. 20, 2006, (22) Filed: Jun. 16, 2009 pp. 7051-7061 XPO25133617. (65) Prior Publication Data Chatterjie et al., “Stereospecific synthesis of the 6beta-hydroxy metabolites of Naltrexone and '. Journal of Medicinal US 2009/0312552 A1 Dec. 17, 2009 Chemistry, 1975, vol. 18, No. 5, pp. 490-492 XP002538223. Kayakiri et al., “Probes for receptor mediated phenomena. Related U.S. Application Data 24. Synthesis, single crystal X-ray analyses, in vitro and in vivo properties of 6alpha-and 6beta-IODO-3, 14-dihydroxy-17 methyl-4, (60) Provisional application No. 61/073,076, filed on Jun. 5alpha-epoxymorphinans'. Medicinal Chemistry Research, 1996, 17, 2008. vol. 6, pp. 427-438 XP008108680. Chatterjie et al., “Stereospecific Synthesis of the 6b-hydroxy (51) Int. Cl. Metabolites of Naltrexone and Naloxone'. Journal of Medicinal C07D 489/02 (2006.01) chemistry, 1975, 18(5), pts. 490-492. CO7D 489/08 (2006.01) Brine et al., “Formamidinesulfinic Acid Reduction of (52) U.S. Cl...... 546/44; 546/45 Dihydrocodeinone Derivatives”, Journal of Organic Chemistry, (58) Field of Classification Search ...... 546/46, 1978, 43(8), pp. 1555-15557. 546/45, 44 Primary Examiner — Charanjit Aulakh See application file for complete search history. (57) ABSTRACT (56) References Cited The invention provides processes for the conversion of a U.S. PATENT DOCUMENTS 6-keto morphinan to a 6-hydroxy morphinan. In particular, the invention provides a stereoselective process for the con 4,912,114 A 3, 1990 ReveSZ version of a 6-keto morphinan to a 6-beta-hydroxy morphi FOREIGN PATENT DOCUMENTS a. WO WO 2007 1241.14 11, 2007 WO WO 2008/070462 6, 2008 11 Claims, No Drawings US 8,168,790 B2 1. PROCESS FOR THE PREPARATION OF 6-BETA HYDROXY MORPHINAN R5 COMPOUNDS R-O R4 R3 CROSS-REFERENCE TO RELATED 2 Second R Proton APPLICATIONS O Reducing Agent Acceptor He -se First Proton This application claims priority from Provisional Applica R8 N-R- Pl Acceptor tion Ser. No. 61/073,076 filed on Jun. 17, 2008, which is 10 hereby incorporated by reference in its entirety. O R7 R6 FIELD OF THE INVENTION (I) 15 R5 The present invention generally relates to processes for the conversion of a 6-keto morphinan to a 6-hydroxy morphinan. R-O R4 In particular, the invention provides a stereoselective process R3 for the conversion of a 6-keto morphinan to a 6-beta-hydroxy R2 morphinan. O N-R BACKGROUND OF THE INVENTION R8 25 HO R7 The stereoselective reduction of the 6-keto group of certain morphinan compounds is a necessary step in the preparation R6 of many -based compounds. For example, 6-beta-hy (II) droxy morphinan derivatives have valuable medical potential for the unmet needs of pain management and addiction 30 therapy. Traditionally, a 6-beta-hydroxy epimer has been pre wherein: pared by reducing the corresponding 6-keto compound in a R is selected from the group consisting of hydrogen, hydro carbyl, Substituted hydrocarbyl, and hydroxy protecting large Volume of an alkaline Solution of formamidine Sulfinic group acid. Not only are the yields of the reaction low, but the 35 reaction also generates large Volumes of caustic waste mate R" is selected from the group consisting of hydrogen, rial. If the reaction is run in a more concentrated environment, hydrocarbyl, and substituted hydrocarbyl, however, one of the components precipitates out of Solution R° and Rare independently selected from the group con and the reaction stalls prior to completion. As a consequence, sisting of hydrogen, OH, NH, SH, hydrocarbyl, substi the resulting 6-hydroxy morphinan product is contaminated 40 tuted hydrocarbyl, alkylketal, alkylthiol ketal, and alkyl dithiol ketal, wherein when R and Rare different they with large amounts of the unconverted Starting material. form an epimeric pair, and wherein R' and R together Accordingly, a need exists for an efficient and Scalable pro may form a group selected from the group consisting of cess for converting 6-keto-morphinans to 6-beta-hydroxy cycloalkyl ketal, cycloalkyl thiol ketal, and cycloalkyl morphinans in pharmaceutical grade quality. The process 45 dithiol ketal; should ensure high yield, high epimeric purity, and simple R. R. R. and R7 are independently selected from the isolation of the desired compound. group consisting of hydrogen, halogen, NH, CN, SH, CF, OR, hydrocarbyl, and substituted hydrocarbyl; SUMMARY OF THE INVENTION R is selected from the group consisting of hydrogen and 50 hydroxy; and Among the various aspects of the present invention is a R is selected from the group consisting of hydrogen, provision of a process for the conversion of a 6-keto morphi hydrocarbyl, substituted hydrocarbyl, and hydroxy pro nan compound comprising Formula (I) to a 6-beta-hydroxy tecting group. morphinan compound comprising Formula (II). The process 55 Another aspect of the present invention encompasses a comprises two sequential steps. The first step comprises con process for the conversion of a 6-keto morphinan compound tacting compound (I) with a reducing agent and a first proton comprising Formula (III) to a 6-hydroxy morphinan com acceptor to form a first homogeneous reaction mixture, pound comprising Formula (IV). The first step of the process wherein some of compound (I) is converted to compound (II) comprises contacting compound (III) with a reducing agent to produce a Substantially heterogeneous reaction mixture. 60 and a first proton acceptor to form a first homogeneous reac tion mixture, wherein some of compound (III) is converted to The second step comprises contacting the heterogeneous compound (IV) to form a Substantially heterogeneous reac reaction mixture with a second proton acceptor to form a tion mixture. The second step of the process comprises con second homogeneous reaction mixture, wherein some of tacting the heterogeneous reaction mixture with a second compound (i) that was not converted to compound (II) in step 65 proton acceptor to form a second homogeneous reaction mix (a) is converted to compound (II). The following reaction ture, wherein some of compound (III) that was not converted scheme depicts steps (a) and (b) of the process: to compound (IV) in step (a) is converted to compound (IV). US 8,168,790 B2 3 4 The following reaction scheme depicts steps (a) and (b) of the nans, salts, intermediates, and analogs thereof. It has been process: discovered that contacting the heterogeneous reaction mix ture formed during the reduction of a 6-keto morphinan com pound in a concentrated reaction mixture with additional R5 proton acceptor leads to the formation of a homogeneous R-O R4 reaction mixture, wherein the rest of the 6-keto compound may be converted to the 6-hydroxy morphinan compound. R3 2 Second Surprisingly, addition of all of the proton acceptor at the start R Proton of the reaction or before the reaction becomes heterogeneous HO Reducing Agent Acceptor 10 He -- First results in lower yields, less stereoselective conversion, and Proton increased impurities. As detailed in the Examples, this pro R8 N-R- D1 Acceptor cess produces high yields of the beta isomer.

O R7 15 (I) Process for Preparing 6-Beta-Hydroxy R6 Morphinan Derivatives (III) Provided herein is a process for preparing 6-beta-hydroxy morphinan compounds. The process comprises two sequen tial steps. The first step comprises contacting the starting 6-keto morphinan compound with a reducing agent and a first R5 proton acceptor to form a first homogeneous reaction mix ture, wherein some of the 6-keto compound is converted to R-O R4 25 the corresponding 6-hydroxy morphinan compound until a R3 Substantially heterogeneous reaction mixture is formed. The R2 second step of the process comprises contacting the hetero HO geneous reaction mixture with a second proton acceptor to form a second homogeneous reaction mixture, wherein the N-R 30 6-keto morphinan compound that was not converted to the R8 6-hydroxy morphinan compound in the first step is converted to the 6-hydroxy morphinan compound. The predominant HO R7 isomer of the 6-hydroxy morphinan compound is the 6-beta R6 hydroxy epimer. (IV) 35 For the purposes of discussion, the ring atoms of a morphi nan compound are numbered as diagrammed below, Morphi nan compounds have asymmetric centers. In particular, the core morphinan compound may have fur chiral carbons; wherein: 40 namely, C-5, C-13, C-14, and C-9. Ris Selected from the group consisting of hydrogen, hydro carbyl, Substituted hydrocarbyl, and hydroxy protecting

group R" is selected from the group consisting of hydrogen, hydrocarbyl, and substituted hydrocarbyl, 45 R and Rare independently selected from the group con sisting of hydrogen, OH, NH, SH, hydrocarbyl, substi tuted hydrocarbyl, alkylketal, alkylthiol ketal, and alkyl dithiolketal, wherein when R' and Rare different they form an epimeric pair, and wherein R' and R together may form a group selected from the group consisting of 50 cycloalkyl ketal, cycloalkyl thiol ketal, and cycloalkyl dithiol ketal; R. R. R. and R7 are independently selected from the group consisting of hydrogen, halogen, NH, CN, SH, CF, OR, hydrocarbyl, and substituted hydrocarbyl: 55 R is selected from the group consisting of hydrogen and hydroxy; and R is selected from the group consisting of hydrogen, (a) Preparation of 6-beta-hydroxy Morphinan hydrocarbyl, substituted hydrocarbyl, and hydroxy pro Derivative Comprising Formula (II) tecting group. 60 Other aspects and features of the invention will be in part A first aspect of the present invention is the provision of a apparent and in part pointed out hereinafter. process for the conversion of a 6-keto morphinan compound comprising Formula (I) to a 6-hydroxy morphinan compound DETAILED DESCRIPTION OF THE INVENTION comprising Formula (II). For the purposes of illustration, 65 Reaction Scheme 1 depicts the formation of the 6-hydroxy The present invention provides a process for the selective morphinan compound comprising Formula (II) according to conversion of 6-keto morphinans to 6-beta-hydroxy morphi one aspect of the invention: US 8,168,790 B2 5 6 (I) may be (+) or (-). Furthermore, the configuration of the Reaction Scheme 1: chiral carbons, C-5, C-13, C-14, and C-9, respectively, of the compound may be RRRR, RRSR, RRRS, RRSS, RSRR, RSSR, RSRS, RSSS, SRRR, SRSR, SRRS, SRSS, SSRR, R-O R4 5 SSSR, SSRS, or SSSS, provided that the C-15 and the C-16 STEPB: carbons are both either on the alpha face or the beta face of the R2 STEPA: Scott molecule. Reducing Agent Acceptor The optical activity of a 6-hydroxy morphinan correspond O — - —- ing to Formula (II) may be (+) or (-), and the configuration of Proton the chiral carbons, C-6, C-5, C-13, C-14, and C-9, respec R8 Acceptor tively, may be RRRRR, RRRRS, RRSRR, RRSRS, RRRSR, 7 RRRSS, RRSSR, RRSSS, RSRRR, RSRRS, RSSRR, O R RSSRS, RSRSR, RSRSS, RSSSR, RSSSS, SRRRR, SRRRS, R6 SRSRR, SRSRS, SRRSR, SRRSS, SRSSR, SRSSS, SSRRR, (I) SSRRS, SSSRR, SSSRS, SSRSR, SSRSS, SSSSR, or R5 SSSSS, provided that the C-15 and the C-16 carbons are both either on the alpha face of the molecule or the beta face of the molecule, and the 6-hydroxy is on the beta face of the mol R3 20 ecule. (b) Preparation of 6-beta-hydroxy Morphinan Derivative Comprising Formula (IV) R8 25 Another aspect of the present invention provides of a pro cess for the conversion of a 6-keto morphinan compound HO R7 comprising Formula (III) to a 6-hydroxy morphinan com R6 pound comprising Formula (IV). For the purposes of illustra (II) tion, Reaction Scheme 2 depicts the formation of the 6-hy 30 droxy morphinan compound comprising Formula (IV) wherein: according to one aspect of the invention: Ris Selected from the group consisting of hydrogen, hydro carbyl, Substituted hydrocarbyl, and hydroxy protecting Reaction Scheme 2: group 35 R" is selected from the group consisting of hydrogen, R5 hydrocarbyl, and substituted hydrocarbyl, R and Rare independently selected from the group con sisting of hydrogen, OH, NH, SH, hydrocarbyl, substi- R3 SE B tuted hydrocarbyl, alkylketal, alkylthiol ketal, and alkyl 40 R2 STEPA: E. dithiol ketal, wherein when R' and Rare different they HO Reducing Agent Acceptor form an epimeric pair, and wherein R' and R together First may form a group selected from the group consisting of N-R AS, cycloalkyl ketal, cycloalkyl thiol ketal, and cycloalkyl R8 dithiol ketal; 45 R. R. R. and R7 are independently selected from the group consisting of hydrogen, halogen, NH, CN, SH, R6 CF, OR, hydrocarbyl, and substituted hydrocarbyl; (III) R is selected from the group consisting of hydrogen and R5 hydroxy; and 50 R is selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, and hydroxy pro- R3 tecting group. R2 In a preferred iteration, the constituents of the reaction HO comprise: 55 R is selected from the group consisting of hydrogen, alkyl, N-R and methyl; R8 R" is selected from the group consisting ofhydrogen, alkyl, cycloalkyl, alkenyl, aryl, benzyl, and C(O),R': HO R7 R. R. R. R. and Rare each hydrogen; 60 R6 R is selected from the group consisting of H, Br, Cl, F, OH, O-methyl, and O-benzyl: R' is selected from the group consisting of alkyl and aryl; and wherein: n is an integer from 1 to 2. 65 R is selected from the group consisting of hydrogen, hydro The optical activity, with respect to the rotation of polar- carbyl, Substituted hydrocarbyl, and hydroxy protecting ized light, of a 6-keto morphinan corresponding to Formula group US 8,168,790 B2 7 8 R" is selected from the group consisting of hydrogen, ferred embodiment, the reducing agent may be a sulfinic acid. hydrocarbyl, and substituted hydrocarbyl, In an exemplary embodiment, the Sulfinic acid may be for R and Rare independently selected from the group con mamidine Sulfinic acid. sisting of hydrogen, OH, NH, SH, hydrocarbyl, substi The amount of reducing agent contacted with the 6-keto tuted hydrocarbyl, alkylketal, alkylthiol ketal, and alkyl morphinan compound can and will vary. Typically, the molar/ dithiol ketal, wherein when R' and Rare different they molar ratio of the 6-keto morphinan compound to the reduc form an epimeric pair, and wherein R' and R together ing agent may range from 1:2 to about 1:8. In a preferred may form a group selected from the group consisting of embodiment, the molar/molar ratio of the 6-keto morphinan cycloalkyl ketal, cycloalkyl thiol ketal, and cycloalkyl compound to the reducing agent may range from 1:3 to about dithiol ketal; 10 1:5. In an exemplary embodiment, the molar/molar ratio of R. R. R. and R7 are independently selected from the the 6-keto morphinan compound to the reducing agent may be group consisting of hydrogen, halogen, NH, CN, SH, about 1:4. CF, OR, hydrocarbyl, and substituted hydrocarbyl; In general, the first proton acceptor will have a pKa of R is selected from the group consisting of hydrogen and greater than about 10.0. Non-limiting examples of suitable hydroxy; and 15 proton acceptors include hydroxides of alkali metals and R is selected from the group consisting of hydrogen, alkaline earth metals (such as, for example, NaOH, KOH, hydrocarbyl, substituted hydrocarbyl, and hydroxy pro Ca(OH) and the like), carbonate salts (such as, for example, tecting group. Na2CO, KCOs, Li2CO, and the like), borate salts (such as, In a preferred iteration, the constituents of the reaction for example, NaBO7), di- and tri-basic phosphate salts comprise: (such as, for example, NaHPO and NaPO, and the like), R is selected from the group consisting of hydrogen, alkyl, bicarbonate salts (such as, for example, NaHCO, KHCO, and methyl; LiHCO, and the like), and mixtures of any of the above. In a R" is selected from the group consisting ofhydrogen, alkyl, preferred embodiment, the proton acceptor may be NaOH, cycloalkyl, alkenyl, aryl, benzyl, and C(O).R': KOH, NaCO, or KCO. In an exemplary embodiment, the R. R. R. R. and Rare each hydrogen; 25 proton acceptor may be NaOH. R is selected from the group consisting of H, Br, Cl, F, OH, The amount of first proton acceptor contacted with the O-methyl, and O-benzyl: 6-keto morphinan compound can and will vary. The molar/ R" is selected from the group consisting of alkyl, alkenyl, molar ratio of the 6-keto morphinan compound to the first and aryl; and proton acceptor may range from about 1:2 to about 1:11. In a n is an integer from 1 to 2. 30 preferred embodiment, the molar/molar ratio of the 6-keto The optical activity of a 6-keto morphinan corresponding morphinan compound to the first proton acceptor may range to Formula (III) may be (+) or (-). Furthermore, the configu from about 1:3 to about 1:9. In an exemplary embodiment, the ration of the chiral carbons, C-13, C-14, and C-9, respec molar/molar ratio of the 6-keto morphinan compound to the tively, of the compound may be RRR, RRS, RSR, RSS, SRR, first proton acceptor may be about 1:4. SRS, SSR, or SSS, provided that the C-15 and the C-16 35 The reaction is typically conducted in the presence of a carbons are both either on the alpha face or the beta face of the Solvent. In general, the choice of a solvent will depend upon molecule. the solubility of the morphinan compounds. Accordingly, the The optical activity of a 6-hydroxy morphinan correspond Solvent may be a protic solvent, an aprotic solvent, or a ing to Formula (IV) may be (+) or (-), and the configuration combination thereof. Non-limiting examples of suitable pro of the chiral carbons, C-6, C-13, C-14, and C-9, respectively, 40 tic solvents include, water, an aqueous Solution (such as, e.g., may be RRRR, RRSR, RRRS, RRSS, RSRR, RSSR, RSRS, a dilute acid, a dilute base, a simple salt solution, a buffered RSSS, SRRR, SRSR, SRRS, SRSS, SSRR, SSSR, SSRS, or Solution, etc.), a lower chain alcohol (such as methanol, etha SSSS, provided that the C-15 and the C-16 carbons are both nol, and the like), and combinations thereof. Non-limiting either on the alpha face or the beta face of the molecule, and examples of aprotic solvents include ether solvents, acetone, the 6-hydroxy is on the beta face of the molecule. 45 acetonitrile, benzene, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N,N-dimethylpropionamide, 1,3-dim (c) Step A: Contact with a Reducing Agent and a ethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, 1,3-dimethyl First Proton Acceptor 2-imidazolidinone, 1,2-dimethoxyethane, N,N-dimethylac etamide, N-methylpyrrolidinone, ethyl acetate, ethyl Step A of the process comprises contacting the 6-keto 50 formate, ethyl methyl ketone, formamide, hexamethylphos morphinan compound (I) with a reducing agent and a first phoramide, methyl acetate, N-methylacetamide, N-methyl proton acceptor to form a first homogeneous reaction mix formamide, methylene chloride, nitrobenzene, nitromethane, ture. In general, the reducing agent will be an agent for use in propionitrile, Sulfolane, tetramethylurea, tetrahydrofuran, a chemical reduction. Suitable reducing agents for the stereo toluene, trichloromethane, and combinations thereof. In a selective reduction of the 6-keto morphinan derivative 55 preferred embodiment, the solvent may be a protic solvent. In include Sulfinic acids (e.g., formamidine Sulfinic acid, an exemplary embodiment, the protic solvent may be water. hydroxymethane Sulfinic acid, and the like); organic com The volume of solvent added to the reactants can and will pounds having thiol or disulfide groups; reductive inorganic vary depending upon the embodiment. In general, the amount alkali metal and ammonium salts of Sulfur-containing acids of solvent will be less that about 40 liters per kilogram of (e.g., sodium Sulfite, disulfite, thiosulfate, hydrosulfite, 60 starting material. In a preferred embodiment, the Volume of acetone bisulfite, bisulfite salts, sulfide, hydrosulfide, Solvent contacted with the 6-keto morphinan compound may dithionite salts, and so forth); and combinations of a metal range from about 8 liters to about 20 liters of solvent per (e.g., tin, Zinc, or iron, and so forth) or a metal compound kilogram of 6-keto morphinan compound. In another pre (e.g., chromium chloride, chromium acetate, and the like) ferred embodiment, the volume of solvent contacted with the with an organic or inorganic acid (e.g., acetic acid, ascorbic 65 6-keto morphinan compound may range from about 9 liters to acid, formic acid, propionic acid, trifluoroacetic acid, p-tolu about 16 liters of solvent per kilogram of 6-keto morphinan enesulfonic acid, hydrochloric acid, and the like). In a pre compound. In an exemplary embodiment, the Volume of sol US 8,168,790 B2 9 10 vent contacted with the 6-keto morphinan compound may be increases by less that 20%, less than about 15%, less than about 10 liters per kilogram of 6-keto morphinan compound. about 10%, less than about 5%, less than about 2%, or less The reaction generally is conducted at a temperature that than about 1%. ranges from about 20° C. to about 75° C. In a preferred Without being bound by any particular theory, it appears embodiment, the temperature of the reaction may range from 5 that addition of the second proton acceptor creates an over about 50° C. to about 70° C. In another preferred embodi saturation of the 6-keto compound, wherein the reaction mix ment, the temperature of the reaction may be about 60°C. In ture becomes homogeneous. Formation of a homogeneous an exemplary embodiment, the temperature of the reaction reaction, therefore, allows for the conversion of the unreacted may be about 65° C. The reaction is preferably performed 6-keto compound to the 6-hydroxy compound. The reaction under ambient pressure, and preferably in an inert atmosphere 10 is conducted at a temperature and conditions as detailed (e.g., nitrogen or argon). above. Typically, the reaction is allowed to proceed for a Typically, the reaction is allowed to proceed until the reac Sufficient period of time until the reaction is complete, as tion mixture becomes Substantially heterogeneous. In the determined using a standard technique. In this context, a context of the present invention, a heterogeneous reaction “completed reaction' generally means that the reaction mix mixture comprises a solid phase and a liquid phase. The 15 ture contains a significantly diminished amount of the starting physical state of the reaction mixture may be monitored visu material (i.e., the 6-keto morphinan compound) and a signifi ally or spectrophotometrically. In general, the reaction is cantly increased amount of the product (i.e., the 6-hydroxy Substantially heterogeneous when no additional Solid phase is morphinan compound) compared to the amounts of each formed. When the reaction mixture is substantially heteroge present at the beginning of the reaction. neous, the reaction stalls and the conversion of the 6-keto The yield of 6-hydroxy morphinan product may vary compound to the 6-hydroxy compound essentially stops. As depending on the compound being synthesized. Typically, the used herein, the term “stall refers to a reaction in which the yield of the product may be at least about 70%. Stated another conversion stops completely or slows to Such a slow rate that way, at least about 70% of the 6-keto compound may be it is essentially stopped. converted to the 6-hydroxy compound during both Steps A Prior to the stalling of the reaction in Step A, however, 25 and B of the reaction. In one embodiment, at least about 80% typically at least about 40% of the 6-keto compound is con of the 6-keto compound may be converted to the 6-hydroxy Verted to the 6-hydroxy compound. In one embodiment, at compound during Steps A and B. In another embodiment, at least about 50% of the 6-keto compound may be converted to least about 90% of the 6-keto compound may be converted to the 6-hydroxy compound during Step A. In another embodi the 6-hydroxy compound during Steps A and B. In still ment, at least about 60% of the 6-keto compound may be 30 another embodiment, at least about 95% of the 6-keto com converted to the 6-hydroxy compound during Step A. In still pound may be converted to the 6-hydroxy compound during another embodiment, at least about 70% of the 6-keto com Steps A and B. pound may be converted to the 6-hydroxy compound during The product of the reaction may comprise a mixture of Step A. In an alternate embodiment, at least about 80% of the 6-beta-hydroxy and 6-alpha-hydroxy epimers. Typically, the 6-keto compound may be converted to the 6-hydroxy com 35 epimeric ratio of 6-beta-hydroxy to 6-alpha-hydroxy will be pound during Step A. In another alternate embodiment, at at least about 4:1. In one embodiment, the epimeric ratio of least about 90% of the 6-keto compound may be converted to 6-beta-hydroxy to 6-alpha-hydroxy may be at least about the 6-hydroxy compound during Step A. The conversion of 20:1. In another embodiment, the epimeric ratio of 6-beta the 6-keto compound to the 6-hydroxy compound may be hydroxy to 6-alpha-hydroxy may be at least about 50:1. In determined using a standard technique. Such as chromatog 40 still another embodiment, the epimeric ratio of 6-beta-hy raphy (e.g., HPLC). droxy to 6-alpha-hydroxy may be at least about 99:1. (d) Step B: Contact with a Second Proton Acceptor (e) Exemplary Embodiment Step B of the process comprises adding a second proton 45 In an exemplary embodiment, the reducing agent is forma acceptor to the Substantially heterogeneous reaction mixture, midine Sulfinic acid, the first and second proton acceptors are wherein a second homogeneous reaction mixture is formed sodium hydroxide, and the protic solvent is water. The molar and the 6-keto compound that was not converted to the 6-hy ratios of 6-keto morphinan compound to reducing agent to droxy compound in Step A is converted to the 6-hydroxy first proton acceptor to second proton acceptor may be 1:4:7: compound. In general, the second proton acceptor will have a 50 1, wherein about 10 liters of protic solvent is used per kilo pKa of greater than about 10.0. Suitable proton acceptors are gram of 6-keto morphinan compound. The reaction is con presented above in (II)(c). The identity of the second proton ducted at a temperature of about 65° C. under an inert acceptor used in Step B may be the same as that of the first atmosphere. proton acceptor used in Step A. Alternatively, the identity of the second proton acceptor may be different from that of the 55 (II) Compounds Prepared from 6-Beta-Hydroxy first proton acceptor. In a preferred embodiment, the second Morphinans proton acceptor may be sodium hydroxide. The molar/molar ratio of the 6-keto compound to the sec The process for the conversion of the 6-keto group to the ond proton acceptor may range from about 1:0.5 to about 1:2. 6-beta-hydroxy group may yield an end product morphinan Preferably, the molar/molar ratio of the 6-keto compound to 60 oran intermediate morphinan, which may be modified in one the second proton acceptor may be about 1:1. Stated another or more additional steps to achieve the desired end com way, the molar/molar ratio of the first proton acceptor to the pound. Furthermore, the conversion of a 6-keto morphinan to second proton acceptor may range from about 3:1 to about the corresponding 6-beta-hydroxy morphinan may occur at 15:1, or more preferably about 7:1. In general, the second any step of the overall process in the preparation of the desired proton acceptor is added in a Volume Such that the total 65 morphinan. For example, the reduction of the 6-keto group Volume of the reaction mixture increases by no more that may occur before or after alkylation (or other modification) of about 20%. In some embodiments, the volume of the reaction the morphinan nitrogen. US 8,168,790 B2 11 12 Exemplary 6-beta-hydroxy morphinan compounds having DEFINITIONS Formula (II) include nalbuphine, , oxycodol. noroxymorphol, naloxol, naltrexol, hydrocodol, and hydro The compounds described herein may have asymmetric morphol: centers. Compounds containing an asymmetrically Substi tuted atom may be isolated in optically active or racemic form. Cis and trans geometric isomers of the compounds of HO the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric 10 forms of a structure are intended, unless the specific stere ochemistry or isomeric form is specifically indicated. O The term “acyl as used herein alone or as part of another N group, denotes the moiety formed by removal of the hydroxy OH group from the group COOH of an organic carboxylic acid, 15 e.g., RC(O)—, wherein R is R, RO—, RRN , or RS HO R is hydrocarbyl, heterosubstituted hydrocarbyl, or hetero Nalbuphine cyclo, and R is hydrogen, hydrocarbyl or Substituted hydro carbyl. The term “alkyl as used herein describes groups which are HO CHO preferably lower alkyl containing from one to eight carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain or cyclic and include methyl, ethyl, propyl, isopropyl, butyl, hexyl and the like. O O The term “alkenyl as used herein describes groups which 25 are preferably lower alkenyl containing from two to eight N N carbon atoms in the principal chain and up to 20 carbon OH N OH N atoms. They may be straight or branched chain or cyclic and HO HO include ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, Oxymorphol Oxycodol hexenyl, and the like. 30 The term “alkynyl' as used herein describes groups which are preferably lower alkynyl containing from two to eight HO HO carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain and include ethynyl, propynyl, butynyl, isobutynyl, hexynyl, and the like. 35 The term “aromatic' as used herein alone or as part of O O another group denotes optionally substituted homo- or het NH N erocyclic aromatic groups. These aromatic groups are pref OH OH \= erably monocyclic, bicyclic, or tricyclic groups containing from 6 to 14 atoms in the ring portion. The term “aromatic' HO HO 40 encompasses the “aryl and "heteroaryl groups defined Noroxymorphol Naloxol below. The term “aryl' as used herein alone or as part of another group denote optionally Substituted homocyclic aromatic HO groups, preferably monocyclic or bicyclic groups containing 45 from 6 to 12 carbons in the ring portion, such as phenyl, biphenyl, naphthyl, substituted phenyl, substituted biphenyl or substituted naphthyl. Phenyl and substituted phenyl are the O more preferred aryl. N The terms “halogen' or “halo' as used herein alone or as OH 50 part of another group refer to chlorine, bromine, fluorine, and HO iodine. The term "heteroatom' shall mean atoms other than carbon Naltrexol and hydrogen. The terms "heterocyclo” or "heterocyclic” as used herein - O HO 55 alone or as part of another group denote optionally Substi tuted, fully saturated or unsaturated, monocyclic or bicyclic, aromatic or non-aromatic groups having at least one heteroa tom in at least one ring, and preferably 5 or 6 atoms in each O O ring. The heterocyclo group preferably has 1 or 2 oxygen 60 atoms and/or 1 to 4 nitrogenatoms in the ring, and is bonded to the remainder of the molecule through a carbon or heteroa N N tom. Exemplary heterocyclo groups include heteroaromatics HO HO as described below. Exemplary substituents include one or Hydrocodol Hydromorphol more of the following groups: hydrocarbyl, substituted 65 hydrocarbyl, hydroxy, protected hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, halogen, amido, amino, cyano, ketals, acetals, esters and ethers. US 8,168,790 B2 13 14 The term “homogeneous reaction' as used herein refers to disclosure, appreciate that many changes could be made in a reaction in which the reactants are in the same phase (e.g., the specific embodiments that are disclosed and still obtain a all of the reactants are liquids, all of the reactants are gases, like or similar result without departing from the spirit and etc.). The term "heterogeneous reaction” refers to a reaction scope of the invention, therefore all matter set forth is to be in which the reactants are in two or more phases. 5 interpreted as illustrative and not in a limiting sense. The terms “hydrocarbon and “hydrocarbyl as used herein describe organic compounds or radicals consisting exclusively of the elements carbon and hydrogen. These moi EXAMPLES eties include alkyl, alkenyl, alkynyl, and aryl moieties. These 10 moieties also include alkyl, alkenyl, alkynyl, and aryl moi The following examples illustrate various embodiments of eties substituted with other aliphatic or cyclic hydrocarbon the invention. groups, such as alkaryl, alkenaryland alkynary1. Unless oth erwise indicated, these moieties preferably comprise 1 to 20 Example 1 carbon atoms. 15 The term "hydroxy protecting group’ as used herein Preparation of 6-Beta-Oxymorphol by Reduction of denote a group capable of protecting a free hydroxy group (“protected hydroxy') which, subsequent to the reaction for which protection is employed, may be removed without dis turbing the remainder of the molecule. Exemplary hydroxy The synthesis of 6-beta-oxymorphol is depicted in the fol protecting groups include oxygen protecting groups of alkyl Sulfonates and arylsulfonates, ethers (e.g., allyl, triphenylm lowing scheme: ethyl (trity1 or Tr), benzyl, p-methoxybenzyl (PMB), p-meth oxyphenyl (PMP)), acetals (e.g., methoxymethyl (MOM), B-methoxyethoxymethyl (MEM), tetrahydropyranyl (THP), ethoxyethyl (EE), methylthiomethyl (MTM), 2-methoxy-2- propyl (MOP), 2-trimethylsilylethoxymethyl (SEM)), esters (e.g., benzoate (BZ), allyl carbonate, 2.2.2-trichloroethyl car Foramidine Sulfinic Acid bonate (Troc), 2-trimethylsilyiethyl carbonate), silyl ethers (e.g., trimethylsilyl (TMS), triethylsilyl (TES), triisopropyl silyl (TIPS), triphenyisilyl (TPS), t-butyldimethylsilyl (TB DMS), t-butyldiphenylsilyl (TBDPS) and the like. A variety of protecting groups for the hydroxy group and the synthesis 35 thereof may be found in “Protective Groups in Organic Syn thesis” by T. W. Greene and P. G. M. Wuts, John Wiley & Sons, 1999. The “substituted hydrocarbyl moieties described herein are hydrocarbyl moieties which are substituted with at least 40 one atom other than carbon, including moieties in which a carbon chain atom is Substituted with a hetero atom such as nitrogen, oxygen, silicon, phosphorous, boron, Sulfur, or a halogen atom. These Substituents include halogen, heterocy 45 clo, alkoxy, alkenoxy, aryloxy, hydroxy, protected hydroxy, acyl, acyloxy, nitro, amino, amido, nitro, cyano, ketals, acetals, esters and ethers. When introducing elements of the present invention or the preferred embodiments(s) thereof, the articles “a”, “an', 50 1.00 gram of oxymorphone HCl and 1.28 grams of forma “the' and “said are intended to mean that there are one or midine Sulfinic acid (4 equivalents) were added to a three more of the elements. The terms “comprising”, “including neck flask that was equipped with a stirrer, a heating appara tus, and a nitrogen source. 10.0 mL of an aqueous Solution of and “having are intended to be inclusive and mean that there 2N NaOH was then added under nitrogen protection. The may be additional elements other than the listed elements. 55 stirrer is turned on and the mixture was heated to 65°C. The AS Various changes could be made in the above compounds reaction was run for 2 hours at this temperature, wherein the and processes without departing from the scope of the inven mixture formed a white slurry. After 1 mL of an aqueous tion, it is intended that all matter contained in the above solution of 3N NaOH was added to the slurry, a clear solution description and in the examples given below, shall be inter 60 was produced. The reaction was kept at this temperature for preted as illustrative and not in a limiting sense. another 2 hours and then cooled. The pH of the reaction The following examples are included to demonstrate pre Solution was adjusted to 10-10.5 using an aqueous Solution of ferred embodiments of the invention. It should be appreciated saturated NHC1. The product precipitated as a white solid by those of skill in the art that the techniques disclosed in the and was separated by filtration. The conversion rate was typi following examples represent techniques discovered by the 65 cally greater than 98% at this point. The recovery was typi inventors to function well in the practice of the invention. cally great than 95%. The stereoselectivity of the beta isomer Those of skill in the art should, however, in light of the present was about 95:5. US 8,168,790 B2 15 16 Example 2 -continued Preparation of 6-Beta-Naltrexol by Reduction of Naltrexone HO The synthesis of 6-beta-naltrexol is depicted in the follow ing scheme:

10 HO

-O

Foramidine Sulfinic Acid 1.00 gram of naltrexone HCl and 1.00 grams of formami 15 dine Sulfinic acid (4 equivalents) were added to a three-neck flask that was equipped with a stirrer, a heating apparatus, and a nitrogen source. 10.0 mL of an aqueous solution of 2N NaOH was then added under nitrogen protection. The mix ture was stirred and heated to 60°C. The reaction was run for 2 hours at this temperature, wherein the mixture formed a white slurry. After 1 mL of an aqueous solution of 3N NaOH was added to the slurry, a clear solution was formed. The reaction was kept at this temperature for another 2 hours and then cooled. The pH of the reaction solution was adjusted to 25 10-10.5 using an aqueous solution of saturated NHC1. The product precipitated as a white Solid and was separated by filtration. The conversion rate was typically greater than 99% at this point. The recovery was typically great than 90%. The stereoselectivity of the beta isomer was about 85:15. 1.00 gram of naltrexone HCl and 1.07 grams of formami 30 dine Sulfinic acid (4 equivalents) were added to a three-neck Example 4 flask that was equipped with a stirrer, a heatingapparatus, and a nitrogen Source. 10.0 mL of an aqueous Solution of 2N Preparation of 6-Beta-Hydroxyl Bromo- NaOH was then added under nitrogen protection. The mix Derivative ture was stirred and heated to 65°C. The reaction was run for 35 2 hours at this temperature, wherein the mixture formed a The synthesis of 6-beta-hydroxyl bromo-simomenine is white slurry. After 1 mL of an aqueous solution of 3N NaOH depicted in the following scheme: was added to the slurry, a clear solution was formed. The reaction was kept at this temperature for another 2 hours and then cooled. The pH of the reaction solution was adjusted to 40 O Br 10-10.5 using an aqueous solution of saturated NHC1. The 1. product precipitated as a white Solid and was separated by filtration. The conversion rate was typically greater than 99% HO Foramidine Sulfinic Acid at this point. The recovery was typically great than 98%. The -- N-H stereoselectivity of the beta isomer was about 97:3. 45 HBr Example 3 O O Br Preparation of 6-Beta-Hydroxyl Sinomenine by 1. Reduction of Sinomenine 50 HO The synthesis of 6-beta-hydroxyl simomenine is depicted in the following scheme: N-H 55 1. O HO 1.03 grams of naltrexone HCl and 1.00 grams of formami HO Foramidine Sulfinic Acid 60 -- dine Sulfinic acid (4 equivalents) were added to a three-neck N flask that was equipped with a stirrer, a heating apparatus, and a nitrogen source. 10.0 mL of an aqueous solution of 2N NaOH was then added under nitrogen protection. The mix ture was stirred and heated to 60°C. The reaction was run for O 65 2 hours at this temperature, wherein the mixture formed a white slurry. After 1 mL of an aqueous solution of 3N NaOH was added to the slurry, a clear solution was formed. The US 8,168,790 B2 17 18 reaction was kept at this temperature for another 2 hours and Example 6 then cooled. The pH of the reaction solution was adjusted to 10-10.5 using an aqueous solution of saturated NHC1. The Preparation of (+)-B-Naloxol product precipitated as a white Solid and was separated by filtration. The conversion rate was typically greater than 90% 5 (+)-B-Naloxol was prepared from (+)-naloxone according at this point. The recovery was typically great than 85%. The to the following reaction scheme: stereoselectivity of the beta isomer was about 80:20.

Example 5 10 Formamidine Sulfenic acid, NaOH Preparation of (+)-B-Naltrexol ---

(+)-B-Naltrexol was prepared from (+)-maltrexone accord 15 ing to the following reaction scheme: (+)-Naloxone

HO

Formamidine Sulfenic acid, NaOH O -- He

25 Hy HO (+)-B-Naloxol (+)-Naltrexone major

HO 30

35

(+)-B-Naltrexol (+)-C-Naloxol major minor

(+)-Naloxol (250 mgs) was suspended in water (3 mL). The Solution was purged with nitrogen with stirring and then kept under a nitrogen atmosphere. Formamidine Sulfenic acid (1.0 g) was added. A drop of 4N sodium hydroxide (NaOH) was added for dissolution of the reactants. The reaction was stirred at room temperature for 30 min and then heated to 60° C. for 3 h. HPLC analysis indicated that the reaction was complete. Water (15 mL) was added. The pH was adjusted (+)-C-Naltrexol 50 with glacial acetic acid until pH=9 to 10. The aqueous con minor tents were extracted with chloroform (3x10 mL). The com bined chloroform layers were washed with water (2x5 mL). (+)-Naltrexone (250 mgs) was suspended in water (3 mL). The volatile solvents were removed under reduced pressure The solution was purged with nitrogen with stirring and then with mild heating. (+)-B-Naloxol (190 mgs) were recovered 55 as an off-white solid. kept under a nitrogen atmosphere. Formamidine Sulfenic acid What is claimed is: (1.0 g) was added. A drop of 4N sodium hydroxide (NaOH) 1. A process for preparing a compound, the process com was added for dissolution of the reactants. The reaction was prising: stirred at room temperature for 30 min and then heated to 60° (a) contacting a 6-keto morphinan compound comprising C. for 3 h. HPLC analysis indicated that the reaction was 60 Formula (I) with a reducing agent, a first protonacceptor complete. Water (15 mL) was added. The pH was adjusted and a solvent, wherein the concentration of the 6-keto with glacial acetic acid until pH=9 to 10. The aqueous con morphinan of Formula (I) in the solvent is at least 25 tents were extracted with chloroform (3x10 mL). The com grams per liter, to form a first homogeneous reaction bined chloroform layers were washed with water (2x5 mL). mixture, wherein some of compound (I) is converted to The volatile solvents were removed under reduced pressure 65 a 6-hydroxy morphinan compound comprising Formula with mild heating. (+)-B-Naltrexol (100 mgs) were recovered (II) to produce a substantially heterogeneous reaction as an off-white solid. mixture; and US 8,168,790 B2 19 20 (b) contacting the heterogeneous reaction mixture with a 2. The process of claim 1, wherein: Second proton acceptor to form a second homogeneous R is chosen from hydrogen, alkyl, and methyl; reaction mixture, wherein some of compound (I) that R" is chosen from hydrogen, alkyl, cycloalkyl, alkenyl, was not converted to compound (II) in step (a) is con aryl, benzyl, and C(O).R'; Verted to compound (II), the process of steps (a) and (b) 5 R. R. R. R. and Rare each hydrogen; R is chosen from H, Br, Cl, F, OH, O-methyl, and O-ben proceeding according to the reaction scheme: Zyl; R" is chosen from alkyl, alkenyl, and aryl; and n is an integer from 1 to 2. 10 3. The process of claim 1, wherein the 6-hydroxy morphi R-O R4 nan compound (II) is a mixture of 6-alpha-hydroxy and 3 6-beta-hydroxy morphinan epimers. R 2 Second 4. The process of claim 3, wherein the epimeric ratio of R Proton 6-beta-hydroxy to 6-alpha-hydroxy morphinan epimers is O Reducing Agent Acceptor -o-, -e- chosen from at least 4:1, at least 50:1, and at least about 99:1. First 15 5. The process of claim 1, wherein the reducing agent is a N-R Proton Sulfinic acid chosen from formamidine sulfinic acid and R8 Acceptor hydroxymethane sulfinic acid; and the first proton acceptor and the second proton acceptor are independently chosen O R7 from sodium hydroxide, potassium hydroxide, potassium R6 carbonate, and sodium bicarbonate. (I) 6. The process of claim 1, wherein the molar/molar ratio of R5 compound (I) to reducing agentis from about 1:2 to about 1:8: the molar/molar ratio of compound (I) to the first proton R-O R acceptor is from about 1:3 to about 1:11; and the molar/molar R3 25 ratio of compound (I) to the second proton acceptor is from R2 about 1:0.5 to about 1:2. 7. The process of claim 1, wherein the reaction is con O ducted in the presence of a protic solvent. N-R 8. The process of claim 1, wherein the reaction is con R8 30 ducted at a temperature ranging from about 20° C. to about 750 C. HO R7 9. The process of claim 1, wherein at least about 40% of R6 compound (I) is converted to compound (II) in step (a). (II) 10. The process of claim 1, wherein at least about 70% of 35 compound (I) is converted to compound (II) in both steps (a) and (b). wherein: 11. The process of claim 2, wherein the optical activity of R is chosen from hydrogen, hydrocarbyl, substituted compound (I) is (+) or (-), and the configuration of C-5, C-13. hydrocarbyl and hydroxy protecting group; C-14, and C-9, respectively, is chosen from RRRR, RRSR, 40 RRRS, RRSS, RSRR, RSSR, RSRS, RSSS, SRRR, SRSR, R" is chosen from hydrogen, hydrocarbyl, and substi SRRS, SRSS, SSRR, SSSR, SSRS, and SSSS, provided that tuted hydrocarbyl; the C-15 and the C-16 carbons are both either on the alpha R and R are independently chosen from hydrogen, face of the molecule or the beta face of the molecule; and the OH, NH, SH, hydrocarbyl, substituted hydrocarbyl, optical activity of compound (II) is (+) or (-), and the con alkyl ketal, alkylthiol ketal, and alkyl dithiol ketal, 45 figuration of C-6, C-5, C-13, C-14, and C-9, respectively, is wherein when R' and R are different they form an chosen from RRRRR, RRRRS, RRSRR, RRSRS, RRRSR, epimeric pair, and wherein R' and R together may RRRSS, RRSSR, RRSSS, RSRRR, RSRRS, RSSRR, form a group chosen from cycloalkylketal, cycloalkyl RSSRS, RSRSR, RSRSS, RSSSR, RSSSS, SRRRR, SRRRS, thiol ketal, and cycloalkyl dithiol ketal; SRSRR, SRSRS, SRRSR, SRRSS, SRSSR, SRSSS, SSRRR, R. R. R', and Rare independently chosen from hydro 50 SSRRS, SSSRR, SSSRS, SSRSR, SSRSS, SSSSR, and gen, halogen, NH, CN, SH, CFs, OR, hydrocarbyl, SSSSS, provided that the C-15 and the C-16 carbons are both and substituted hydrocarbyl, either on the alpha face of the molecule or the beta face of the R is chosen from hydrogen and hydroxy; and molecule, and the 6-hydroxy is on the beta face of the mol R is chosen from hydrogen, hydrocarbyl, substituted ecule. hydrocarbyl, and hydroxy protecting group.