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USOO843 1701 B2

(12) United States Patent (10) Patent No.: US 8431,701 B2 Hudson et al. (45) Date of Patent: Apr. 30, 2013

(54) PROCESS FOR THE REDUCTIVE (58) Field of Classification Search ...... 546/44, ALKYLATION OF NORMORPHINANS 546f 74 See application file for complete search history. (75) Inventors: Edmund C. Hudson, Clayton, MO (US); Sharon Woods, Florissant, MO (56) References Cited (US) U.S. PATENT DOCUMENTS (73) Assignee: Mallinckrodt LLC, Hazelwood, MO 2,578.787. A 12, 1951 De Benneville (US) 2008/0045715 A1 2/2008 Mitchell et al. - FOREIGN PATENT DOCUMENTS (*) Notice: Subject to any disclaimer, the term of this WO WO 2007/083839 A1 T 2007 patent is extended or adjusted under 35 WO WO 2007 137785 A2 12/2007 U.S.C. 154(b) by 396 days. WO WO 2009/O12005 A1 1/2009 (21) Appl. No.: 12/706,909 OTHER PUBLICATIONS Grant & Hackh's Chemical Dictionary (5th Ed. 1987) at p. 148.* (22) Filed: Feb. 17, 2010 De Benneville et al., “The Behavior of aliphatic Aldehydes in the Leuckart-Wallach Reaction”. J. Am. Chem. Soc., 1950, 72, pp. 3073 (65) Prior Publication Data 3075. US 2010/0210843 A1 Aug. 19, 2010 * cited by examiner Primary Examiner — Samantha Shterengarts Related U.S. Application Data (57) ABSTRACT (60) Provisional application No. 61/153,021, filed on Feb. The invention provides a process for the N-alkylation of 17, 2009. normorphinan compounds to produce N-alkylated morphi (51) Int. Cl nan compounds. In particular, the process relates to the alky

yO 7D l89/00 (2006.01) ane presence of a replacedOI a reduc1ng agent to by Iorm assists an N-alkylate t (52) Sept2 (2006.01) . USPC ...... 546/44; 546/74 20 Claims, No Drawings US 8,431,701 B2 1. 2 PROCESS FOR THE REDUCTIVE formate, formamide, a mixture of formic acid and an alkali ALKYLATION OF NORMORPHINANS salt of formic acid, and combinations thereof, to form a com pound comprising Formula (IIIa) according to the following CROSS REFERENCE TO RELATED reaction scheme: APPLICATIONS

H This application claims the benefit of U.S. Provisional N Application No. 61/153,021 filed Feb. 17, 2009, which is incorporated herein in its entirety. R4 R5 R6 10 Alkylating Agent Ho FIELD OF INVENTION R3 R7 Proton Acceptor The present invention generally relates to a method for the synthesis of N-alkylated . In particular, the pro R2 X R8 15 cess provides a method for reducing an iminium salt formed (Ia) from the reaction of a normorphinan and a carboxaldehyde. R10 BACKGROUND OF THE INVENTION Nt2 N-alkylated morphinans are important pharmaceuticals, typically used as analgesics, agonists, and opiate R4 R5 R6 Reducing Agent antagonists. With the increasing use of these agents, a prac He tical and effective method of preparation of these compounds is vital to synthesizing diverse N-alkyl substituted morphin R3 R7 aS. 25 Currently, the methods for synthesis of N-alkylated mor R2 X R8 phinans known in the art have at least one of two primary limitations: (a) their dependence on a transition metal cata (IIa) lyst, and (b) the use of hydrogen gas as a source of hydrogen R10 for the alkylation. Transition metal catalysts are expensive 30 and toxic, which requires testing of the finished product to - ensure that the final product does not contain more than a specified parts per million of the transition metal. Addition R4 R5 R6 ally, hydrogen gas is hazardous, and methods of synthesis typically employ high pressures. Some prior art methods have 35 R3 R7 incorporated a borohydride to catalyze the reaction. It was desired to avoid this method because the side products are difficult to separate from the desired product, and the reac R2 X R8 tions may require lower temperatures, -20° to -30°C., when (IIIa) a keto group is present. In light of the current limitations, 40 there is a need for an efficient, cost-effective method of the synthesis of N-alkylated normorphinans. wherein: R. R. and Rare independently selected from the group SUMMARY OF THE INVENTION consisting of hydrogen, hydrocarbyl, Substituted hydro 45 carbyl, and { }OR'': The present invention provides processes for the synthesis R, and Rare independently selected from the group con of N-alkylated morphinans from the corresponding normor sisting of hydrogen, hydrocarbyl, Substituted hydrocar phinan compounds. byl, halogen, and { }OR'': One aspect of the present invention encompasses a process R is selected from the group consisting of hydrogen, and for the preparation of an N-alkylated morphinan. The method 50 hydroxyl: comprises contacting a normorphinan comprising a second R is selected from the group consisting of {=}O, and ary amine at position 17 with an alkylating agent comprising hydroxyl: R", wherein R' is selected from the group consisting of R" is selected from the group consisting of hydrocarbyl, hydrocarbyl and Substituted hydrocarbyl, a proton acceptor, and substituted hydrocarbyl; and a reducing agent selected from the group consisting of 55 R'' is selected from the group consisting of hydrogen, formic acid, methyl formate, formamide, a mixture of formic hydrocarbyl, substituted hydrocarbyl, and a hydroxyl acid and an alkali Salt of formic acid, and combinations protecting group; and thereof, to form the N-alkylated morphinan comprising NR' X is selected from the group consisting of oxygen and at position 17. Sulfur. In an additional aspect, the current invention encompasses 60 In another aspect the current invention encompasses a pro a process for the preparation of a compound comprising For cess for the preparation of a compound comprising Formula mula (IIIa). The process comprises: (a) contacting a com (IIIb). The process comprises: (a) contacting a compound pound comprising Formula (Ia) with an alkylating agent com comprising Formula (Ib) with an alkylating agent comprising prising R' in the presence of a proton acceptor to form a R" in the presence of a proton acceptor to form a compound compound comprising Formula (IIa); and (b) contacting the 65 comprising Formula (IIb); and (b) contacting the compound compound comprising Formula (IIa) with a reducing agent comprising Formula (IIb) with a reducing agent selected from selected from the group consisting of formic acid, methyl the group consisting of formic acid, methyl formate, forma US 8,431,701 B2 3 4 mide, a mixture of formic acid and an alkali salt of formic (a) Process for the Synthesis of N-Alkylated Morphinans acid, and combinations thereof, to form a compound com One aspect of the present invention provides an efficient prising Formula (IIIb) according to the following reaction process for the production of N-alkylated morphinan com scheme: pounds. The process comprises contacting a normorphinan comprising a secondary amine at position 17 with an alkylat ing agent comprising R', wherein R' is selected from the H N group consisting of hydrocarbyl and Substituted hydrocarbyl, a proton acceptor, and a reducing agent selected from the R4 R5 R6 group consisting of formic acid, methyl formate, formamide, Alkylating Agent 10 He a mixture of formic acid and an alkali salt of formic acid, and R3 R7 Proton Acceptor combinations thereof to form the N-alkylated morphinan comprising NR'' at position 17. Generally, the normorphinan comprises any compound R2 R1 R9 R8 15 having a morphinan structure, in which the nitrogen at posi (Ib) tion 17 comprises a secondary amine. It will be understood by R10 one skilled in the art that the “nor compound may be pro duced by methods known in the art or purchased as a starting 2 material. Non-limiting examples of normorphinans include Nt , , northebaine, nororipavine, R4 R5 R6 Reducing Agent , nordihydromorphine, nordihydrocodeine, He , norhydromorphone, , nor , nordextrorphan, norlevomethorphan, R3 R7 , , noroxymomorphol, 25 noroxycodol norsinomenine, nordihydrosinominine, and R2 R1 R9 R8 combinations thereof. In a preferred embodiment, the nor morphinan comprises noroxymorphone. (IIb) The N-alkylated morphinan comprises any morphinan R10 compound comprising a tertiary amine at position 17, 30 wherein the amine at position 17 comprises a hydrocarbyl or - substituted hydrocarbyl group. Suitable examples of N-alky R4 R5 R6 lated morphinans include, but are not limited to , , , , , dihydromor phone, , , , oxy R3 R7 35 codone, oxycodeinone, , , , , , , , butor phanol, dextromethorphan, , , R2 R1 R9 R8 , , Sinomenine, dihydrosinome (IIIb) 40 nine, and combinations thereof. In a preferred embodiment, the N-alkylated morphinan comprises naltrexone, nalbu wherein: phine, or 6-ketonalbuphine. R. R. R. R', and Rare independently selected from the In general, the R" group used to alkylate the nitrogen at group consisting of hydrogen, hydrocarbyl, Substituted position 17 is a hydrocarbyl or substituted hydrocarbyl group. hydrocarbyl, and { }OR'': 45 In a preferred embodiment, the R' group may be an alkyl, R, and Rare independently selected from the group con cycloalkyl, cycloalkylmethyl, alkenyl, alkynyl, oraryl group. sisting of hydrogen, hydrocarbyl, Substituted hydrocar In an exemplary embodiment, the R' group may be methyl, byl, halogen, and { }OR'': cyclopropylmethyl, cyclobutylmethyl, or allyl. R is selected from the group consisting of hydrogen, and The process comprises formation of an intermediate com hydroxyl: 50 pound comprising an iminium salt of the normorphinan com R is selected from the group consisting of {=}O, and pound, prior to the formation of the N-alkylated morphinan. hydroxyl: The iminium salt serves as the substrate for reduction by R" is selected from the group consisting of hydrocarbyl, formic acid, methyl formate, formamide, a mixture of formic and substituted hydrocarbyl; and acid and an alkali salt of formic acid, or combinations thereof, R'' is selected from the group consisting of hydrogen, 55 thereby forming the N-alkylated morphinan. The iminium hydrocarbyl, substituted hydrocarbyl, and a hydroxyl salt is generally considered a protonated or Substituted imine protecting group. compound comprising the formula N'=CR'at position 17, wherein R' is a hydrocarbyl or substituted hydrocarbyl DETAILED DESCRIPTION group as defined above. In a preferred embodiment, the R' 60 group of iminium salt may be an alkyl, cycloalkyl, cycloalky The present invention provides an efficient process for the lmethyl, alkenyl, alkynyl, or aryl group. In an exemplary production of N-alkylated morphinans in high yield. In par embodiment, the R" group may be methyl, cyclopropylm ticular, the process of the present invention avoids the use of ethyl, cyclobutylmethyl, or allyl. toxic metal catalysts and dangerous hydrogen gas. Moreover, (b) Synthesis of Compounds Comprising Formula (IIIa) the process of the invention may be conducted in a one-pot 65 In one embodiment, an N-alkylated morphinan comprising process, without isolation or purification of the intermediate Formula (IIIa) is synthesized from a normorphinan compris products. ing Formula (Ia). For purposes of illustration, Reaction US 8,431,701 B2 5 6 Scheme 1 depicts the production of the compound compris propylmethyl, or cyclobutylmethyl. In one exemplary ing Formula (IIIa) in accordance with one aspect of the embodiment, R. R. R. and R7 are each hydrogen, X is present invention: oxygen, R is hydroxyl, R is {-OH), R is {=}O, and R' is cyclopropylmethyl. In another exemplary embodiment, R, R. R. and R7 are each hydrogen, X is oxygen, R is { }OH, Reaction Scheme 1: R is { }OH, R is {=}O, and R' is cyclobutylmethyl. H Representative compounds comprising Formula (IIIa) N include, but are not limited to oxymorphone, dihydromor R4 R5 R6 phone, hydrocodone, hydromorphone, , oxyco 10 Alkylating Agent deinone, naloxone, naltrexone, nalbuphine, nalmefene. HerProton Acceptor (c) Synthesis of Compound Comprising Formula (IIIb) R3 R7 In an additional embodiment, an N-alkylated morphinan comprising Formula (IIIb) is synthesized from a normorphi R2 X R8 nan comprising Formula (Ib). For purposes of illustration, 15 Reaction Scheme 2 depicts the production of the compound (Ia) comprising Formula (IIIb) in accordance with one aspect of R10 the present invention: Nt2 Reaction Scheme 2: R4 R5 R6 Reducing Agent -- H N R3 R7 R4 R5 R6 25 Alkylating Agent He R2 X R8 R3 R7 Proton Acceptor (IIa) R10 30 R2 R1 R9 R8 (Ib) - R10 R4 R5 R6 Nt2 35 R3 R7 R4 R5 R6 Reducing Agent --

R2 X R8 R3 R7 (IIIa) 40 R2 R1 R9 R8 wherein: (IIb) R. R. and R' are independently selected from the group R10 consisting of hydrogen, hydrocarbyl, Substituted hydro carbyl, and { }OR'; 45 R, and Rare independently selected from the group con - sisting of hydrogen, hydrocarbyl, Substituted hydrocar R4 R5 R6 byl, halogen, and { }OR'': R is selected from the group consisting of hydrogen, and 50 hydroxyl: R3 R7 R is selected from the group consisting of {=}O, and hydroxyl: R2 R1 R9 R8 R' is selected from the group consisting of hydrocarbyl, (IIIb) and substituted hydrocarbyl; 55 R'' is selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, and a hydroxyl wherein: protecting group; and R", R. R. R', and Rare independently selected from the X is selected from the group consisting of oxygen and group consisting of hydrogen, hydrocarbyl, Substituted Sulfur. 60 hydrocarbyl, and { }OR'; In preferred iterations, R. R. R. and R7 are each hydro R, and Rare independently selected from the group con gen and X is oxygen. R is preferably { }OR'', wherein R' sisting of hydrogen, hydrocarbyl, Substituted hydrocar is selected from the group consisting of hydrogen, hydrocar byl, halogen, and { }OR'': byl, Substituted hydrocarbyl, and a hydroxyl protecting R is selected from the group consisting of hydrogen, and group. R is preferably hydroxyl. R is preferably {=}O. 65 hydroxyl: Furthermore, R' is preferably alkyl, cycloalkyl, cycloalkyl R is selected from the group consisting of {=}O, and methyl, allyl, or aryl; or more preferably methyl, allyl, cyclo hydroxyl: US 8,431,701 B2 7 8 R" is selected from the group consisting of hydrocarbyl, formamide, mixtures of formic acid and a salt of formic acid, and substituted hydrocarbyl; and or any combination thereof. Suitable esters of formic acid R'' is selected from the group consisting of hydrogen, include but are not limited to methyl formate, ethyl formate, hydrocarbyl, substituted hydrocarbyl, and a hydroxyl trimethyl formate, triethyl formate, methyl chloroformate, protecting group. and the like. Non-limiting examples of suitable alkali salts of In preferred embodiments, R. R. and Rare each hydro formic acid include Sodium formate, lithium formate, potas gen. Additionally, R is preferably hydrogen or hydroxyl. R sium formate, and cesium formate. In an exemplary embodi is preferably { }OR'', wherein R'' is selected from the ment, the reducing agent may be formic acid. group consisting of hydrogen, hydrocarbyl, Substituted Generally, the mole-to-mole ratio of the compound com hydrocarbyl, and a hydroxyl protecting group. R’ is prefer 10 prising Formula (Ia) or (Ib) to the reducing agent will range ably hydrogen or { }OR''. R is preferably hydroxyl or from about 1:1 to about 1:20. In a preferred embodiment, the {=}O. R' is preferably alkyl, cycloalkyl, cycloalkylmethyl, mole-to-mole ratio of the compound comprising Formula (Ia) allyl, or aryl; or more preferably methyl, allyl, cyclopropyl or (Ib) to the reducing agent may range from about 1:10 to methyl, or cyclobutylmethyl. about 1:15. In an exemplary embodiment, the mole-to-mole Representative compounds comprising Formula (IIIb) 15 ratio of the compound comprising Formula (Ia) or (Ib) to the include, but are not limited to , dextromethor reducing agent may be about 1:12. phan, dextrorphan, levomethorphan, and levorphanol. The process of this invention is also conducted in the pres (d) Reaction Mixture ence of a proton acceptor. In general, the proton acceptor has The process of the invention commences with formation of a pKa of between about 7 and about 13, preferably between a reaction mixture by combining the compound comprising about 8 and about 10. Representative proton acceptors that Formulas (Ia) or (Ib) with an alkylating agent in the presence may be employed include, but are not limited to, borate salts of a proton acceptor. A variety of alkylating agents are Suit (such as, for example, NaBOs), di- and tri-basic phosphate able for use in the process of the invention. Generally, the salts (such as, for example, NaHPO, and NaPO), bicar alkylating agent transfers an alkyl group from the alkylating bonate salts (such as, for example, NaHCO. KHCOs, mix agent to the nitrogen at position 17 of the normorphinan, and 25 tures thereof, and the like), hydroxide salts (such as, for can therefore be thought of as any compound capable of example, NaOH, KOH, mixtures thereof, and the like), car transferring an alkyl group. In a preferred embodiment, the bonate salts (such as, for example, NaCO, KCOs, mixtures alkylating agent may be an aldehyde, having the general thereof, and the like), alkylamine bases (such as, for example, formula R'CHO, wherein R' may be hydrocarbyl or sub triethylamine, trimethylamine, tributylamine, diethylamine, stituted hydrocarbyl. In preferred embodiments, R' may be 30 and diisopropylethylamine), organic bases (such as, for alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, example, pyridine, N-methylmorpholine, N,N-dimethylami cycloalkylmethyl, alkenyl, alkynyl, aryl, cyclopropylmethyl, nopyridine, and mixtures thereof), organic buffers (such as, cyclobutylmethyl, or allyl. Examples of aldehydes that may for example, N-(2-acetamido)-2-aminoethane Sulfonic acid be used include, but are not limited to alkyl-aldehydes such as (ACES), N-(2-acetamido)-iminodiacetic acid (ADA), N.N- methanal, ethanal, propanal, Substituted propanal, butanal, 35 bis(2-hydroxyethyl) (BICINE), 3-(cyclohexy Substituted butanal, pentanal, Substituted pentanal, hexanal, lamino)-1-propanesulfonic acid (CAPS), 2-(cyclohexy Substituted hexanal, heptanal, Substituted heptanal, octanal, lamino)ethanesulfonic acid (CHES), 4-(2-hydroxyethyl)-1- Substituted octanal, nonanal, Substituted nonanal, decanal, piperazinepropanesulfonic acid (EPPS), 4-(2-hydroxyethyl) Substituted decanal, undecanal, Substituted undecanal, dode piperazine-1-ethanesulfonic acid (HEPES), 2-(4- canal, Substituted dodecanal, and Substituted variations 40 morpholinyl) ethanesulfonic acid (MES), thereof cycloalkyl-aldehydes such as cyclopropanecarbox 4-morpholinepropanesulfonic acid (MOPS), 1,4-pipera aldehyde, cyclobutanecarboxaldehyde, cyclopentanecarbox Zinediethanesulfonic acid (PIPES), (2-hydroxy-1,1-bis(hy aldehyde, cyclohexancarboxaldehyde, cycloheptanecarbox droxymethyl)ethyl)amino-1-propanesulfonic acid (TAPS), aldehyde, cyclooctanecarboxaldehyde, 2-(2-hydroxy-11-bis(hydroxymethyl)ethyl)aminoethane cyclononanecarboxaldehyde, cyclodecanecarboxaldehyde, 45 sulfonic acid (TES), salts and/or mixtures thereof, and the benzalaldehyde, cinnamaldehyde, tolualdehyde (4-methyl like), and combinations thereof. In a preferred embodiment, benzaldehyde), and substituted variations thereof; and alde the proton acceptor may be triethylamine, trimethylamine, hydes having two terminal carbonyl groups such as tributylamine, or pyridine. In an exemplary embodiment, the ethanedial, propanedial, butanedial, pentanedial, hexanedial, proton acceptor may be triethylamine. The mole-to-mole heptanedial, octanedial, nonanedial, decanedial, unde 50 ratio of the compound comprising Formula (Ia) or (Ib) to the canedial, dodecanedial, and Substituted variations thereof. In proton acceptor may range from about 1:1 to about 1:20. In a a preferred embodiment, the alkylating agent may be cyclo preferred embodiment, the mole-to-mole ratio of the com propanecarboxaldehyde or cyclobutanecarboxaldehyde. pound comprising Formula (Ia) or (Ib) to the proton acceptor The mole-to-mole ratio of the compound comprising For may range from about 1:5 to about 1:10. In an exemplary mulas (Ia) or (Ib) to the alkylating agent can and will vary. In 55 embodiment, the mole-to-mole ratio of the compound com general, the mole-to-mole ratio of the compound comprising prising Formula (Ia) or (Ib) to the proton acceptor may be Formulas (Ia) or (Ib) to the alkylating agent may range from about 1:8. about 1:0.5 to about 1:5. In a preferred embodiment, the ratio In addition, the process of this invention is generally con of compound comprising Formulas (Ia) or (Ib) to the alkylat ducted in the presence of a solvent. The solvent may be a ing agent may range from about 1:1 to about 1:2. In an 60 protic solvent, an aprotic Solvent, oran organic solvent. Suit exemplary embodiment, the mole-to-mole ratio of the com able examples of protic solvents include, but are not limited pound comprising Formulas (Ia) or (Ib) to the alkylating to, methanol, ethanol, isopropanol, n-propanol, isobutanol, agent may be about 1:1.4. n-butanol, S-butanol, t-butanol, formic acid, acetic acid, The process of this invention additionally requires an agent water, and combinations thereof. Non-limiting examples of for reducing the intermediate compound comprising Formula 65 Suitable aprotic solvents include acetone, acetonitrile, (IIa) or (IIb). In general, the reducing agent will be formic diethoxymethane, N,N-dimethylformamide (DMF), dim acid, an ester of formic acid, an alkali salt of formic acid, ethyl sulfoxide (DMSO), N,N-dimethylpmpionamide, 1,3- US 8,431,701 B2 9 10 dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), (f) Stereochemistry and Enantiomers 1,3-dimethyl-2-imidazolidinone (DMI), 1,2-dimethoxy Any of the compounds comprising any of Formulas (I) or ethane (DME), dimethoxymethane, bis(2-methoxyethyl) (II) may have a (-) or (+) orientation with respect to the ether, N,N-dimethylacetamide (DMAC), 1,4-dioxane, N-me rotation of polarized light, based on whether the starting thyl-2-pyrrolidinone (NMP), ethyl acetate, ethyl formate, material used is in the (-) or (+) opiate absolute form. More ethyl methyl ketone, formamide, hexachloroacetone, hexam specifically, each chiral center may have an R or an S con ethylphosphoramide, methyl acetate, N-methylacetamide, figuration. The compounds formed by the processes of the N-methylformamide, methylene chloride, nitrobenzene, invention comprise morphinans. For purposes of illustration, nitromethane, propionitrile, Sulfolane, tetramethylurea, tet the carbonatoms of a morphinan compound are numbered as rahydrofuran (THF), 2-methyl tetrahydrofuran, , 10 diagrammed below. trichloromethane, and combinations thereof. Suitable

examples of organic solvents include, but are not limited to, alkane and Substituted alkane solvents (including cycloal kanes), aromatic hydrocarbons, esters, ethers, ketones, com binations thereof, and the like. Specific organic solvents that 15 may be employed, include, for example, acetonitrile, ben Zene, butyl acetate, t-butyl methylether, t-butyl methylketone, chlorobenzene, , chloromethane, cyclohexane, dichloromethane, dichloroethane, , ethyl acetate, diethylene glycol, fluorobenzene, heptane, hexane, isobutyl methylketone, isopropyl acetate, methylethylketone, meth yltetrahydrofuran, pentyl acetate, n-propyl acetate, tetrahy drofuran, toluene, and combinations thereof. In a preferred embodiment, the solvent may be the protic solvent methanol. These morphinan compounds are recognized to have an In general, the weight ratio of the Solvent to the compound 25 alpha face and a beta face. Some compounds described comprising Formula (Ia) or (Ib) will range from about 0.5:1 to herein, may have at least three chiral centers, namely carbons about 100:1. In preferred embodiments, the weight ratio of C13, C14, and C9, provided that the C15 and C16 atoms are the solvent to the compound comprising Formula (Ia) or (Ib) both on the alpha face of the molecule or both on the beta face may range from about 2:1 to about 5:1. of the molecule. Additionally, if the compound comprises a (e) Reaction Conditions 30 heterocyclic ring between carbons C4 and C5, C5 may also be In general, the reaction may be conducted at a temperature a chiral center. At each chiral center, the stereochemistry at that ranges from about 20° C. to about 120° C. for a period of the carbon atom is independently R or S. time that is sufficient to convert a substantial portion of the Some compounds described herein, Such as compounds compound comprising Formula (Ia) or (Ib) to the compound comprising Formula (Ia), (IIa) and (IIIa), may have at least comprising Formula (IIIa) or (IIIb). In a preferred embodi 35 four chiral centers, namely carbons C5, C9, C13, and C14. At ment, the reaction may be conducted at a temperature that each chiral center, the stereochemistry at the carbon atom is ranges from about 40°C. to about 100°C. In an exemplary independently R or S. The configuration of carbons 5, 13, 14, embodiment, the reaction may be conducted at a temperature and 9, respectively, may be RRRR, RRRS, RRSR, RSRR, that ranges from about 50° C. to about 80° C. SRRR, RRSS, RSSR, SSRR, SRRS, SRSR, RSRS, RSSS, Typically, the reaction is allowed to proceed for a sufficient 40 SRSS, SSRS, SSSR, or SSSS, provided that the C15 and C16 period of time until the reaction is complete, as determined by atoms are both on the alpha face of the molecule or both on the any method known to one skilled in the art, Such as chroma beta face of the molecule. Additionally, the nitrogen at posi tography (e.g., HPLC). In this context, a “completed reac tion 17 may be either R or S, and depending on the R8 group tion' generally means that the reaction mixture contains a chosen, C6 may also be a chiral center, with a stereochemistry significantly diminished amount of the compound compris 45 of either R or S. ing Formula (Ia) or (Ib) and a significantly increased amount Additional compounds described herein, such as com of the compound comprising Formula (IIIa) or (IIIb) com pounds comprising Formula (Ib), (IIb), and (IIIb), may have pared to the amounts of each present at the beginning of the at least three chiral centers, namely carbons C13, C14, and reaction. Typically, the amount of the compound comprising C9. At each chiral center, the stereochemistry at the carbon Formula (Ia) of (Ib) remaining in the reaction mixture may be 50 atom is independently R or S. The configuration of carbons less than about 3%, and preferably less than about 1%. 13, 14, and 9, respectively, may be RRR, RRS, RSR, SRR, The yield of the compound comprising Formula (IIIa) or SRS, SSR, RSS, or SSS, provided that the C15 and C16 atoms (IIIb) can and will vary. Typically, the yield of the compound are both on the alpha face of the molecule or both on the beta comprising Formula (IIIa) or (IIIb) may beat least about 50%. face of the molecule. Additionally, the nitrogen at position 17 In preferred embodiments of the invention, the yield of the 55 may be either R or S. and depending on the R8 group chosen, compound comprising Formula (IIIa) or (IIIb) may be at least C6 may also be a chiral center, with a stereochemistry of about 65%. either R or S. The reaction may also be performed in a one-pot process, whereby all reagents are added in one step to form the reac DEFINITIONS tion mixture. Accordingly, the reaction mixture comprises the 60 compound comprising Formula (Ia) or (Ib), the alkylating To facilitate understanding of the invention, several terms agent, the proton acceptor, and the reducing agent, as defined are defined below: above. The one-pot process of the invention substantially The compounds described herein may have asymmetric eliminates the need to isolate or purify the intermediate com centers. Compounds of the present invention containing an pound comprising Formula (IIa) or (IIb) and/or to manually 65 asymmetrically substituted atom may be isolated in optically add the reducing agent to the reaction mixture upon comple active or racemic form. Cis and transgeometric isomers of the tion of the reaction with the alkylating reagent. compounds of the present invention are described and may be US 8,431,701 B2 11 12 isolated as a mixture of isomers or as separated isomeric erably 5 or 6 atoms in each ring. The heteroaryl group pref forms. All chiral, diastereomeric, racemic forms and all geo erably has 1 or 2 oxygen atoms and/or 1 to 4 nitrogen atoms in the ring, and is bonded to the remainder of the molecule metric isomeric forms of a structure are intended, unless the through a carbon. specific stereochemistry or isomeric form is specifically indi The terms “hydrocarbon' and “hydrocarbyl as used cated. All processes used to prepare compounds of the present 5 herein describe organic compounds or radicals consisting invention and intermediates made therein are considered to be exclusively of the elements carbon and hydrogen. These moi part of the present invention. eties include alkyl, alkenyl, alkynyl, and aryl moieties. These The term “acyl, as used herein alone or as part of another moieties also include alkyl, alkenyl, alkynyl, and aryl moi group, denotes the moiety formed by removal of the hydroxy eties substituted with other aliphatic or cyclic hydrocarbon group from the group COOH of an organic carboxylic acid, 10 groups, such as alkaryl, alkenaryland alkynary1. Unless oth e.g., RC(O), wherein R is R', RO , RRN , or R'S R' erwise indicated, these moieties preferably comprise 1 to 20 is hydrocarbyl, heterosubstituted hydrocarbyl, or heterocy carbon atoms. clo, and R is hydrogen, hydrocarbyl or substituted hydrocar The term “protecting group' as used herein denotes a byl. group capable of protecting an oxygen atom, wherein the protecting group may be removed, Subsequent to the reaction The term “acyloxy.” as used herein alone or as part of 15 for which protection is employed, without disturbing the another group, denotes an acyl group as described above remainder of the molecule. Exemplary protecting groups bonded through an oxygen linkage (O), e.g., RC(O)O— include ethers (e.g., allyl, triphenylmethyl (trityl or Tr), wherein R is as defined in connection with the term “acyl.” p-methoxybenzyl (PMB), p-methoxyphenyl (PMP)), acetals The term “alkyl as used herein describes groups which are (e.g., methoxymethyl (MOM), B-methoxyethoxymethyl preferably lower alkyl containing from one to eight carbon (MEM), tetrahydropyranyl (THP), ethoxyethyl (EE), meth atoms in the principal chain and up to 20 carbonatoms. They ylthiomethyl (MTM), 2-methoxy-2-propyl (MOP), 2-trim may be straight or branched chain or cyclic and include ethylsilylethoxymethyl (SEM)), esters (e.g., benzoate (BZ). methyl, ethyl, propyl, isopropyl, butyl, hexyl and the like. allyl carbonate, 2.2.2-trichloroethyl carbonate (Troc), 2-tri The term “alkenyl as used herein describes groups which methylsilylethyl carbonate), silyl ethers (e.g., trimethylsilyl are preferably lower alkenyl containing from two to eight (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), triph carbon atoms in the principal chain and up to 20 carbon 25 enylsilyl (TPS), t-butyldimethylsilyl (TBDMS), t-butyl atoms. They may be straight or branched chain or cyclic and diphenylsilyl (TBDPS) and the like. A variety of protecting include ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, groups and the synthesis thereof may be found in “Protective hexenyl, and the like. Groups in Organic Synthesis” by T. W. Greene and P. G. M. The term “alkynyl' as used herein describes groups which Wuts, John Wiley & Sons, 1999. are preferably lower alkynyl containing from two to eight 30 The “substituted hydrocarbyl moieties described herein carbon atoms in the principal chain and up to 20 carbon are hydrocarbyl moieties which are substituted with at least atoms. They may be straight or branched chain and include one atom other than carbon, including moieties in which a ethynyl, propynyl, butynyl, isobutynyl, hexynyl, and the like. carbon chain atom is substituted with a hetero atom such as The term “aromatic” as used herein alone or as part of nitrogen, oxygen, silicon, phosphorous, boron, Sulfur, or a another group denotes optionally substituted homo- or het halogen atom. These Substituents include halogen, heterocy erocyclic aromatic groups. These aromatic groups are pref 35 clo, alkoxy, alkenoxy, aryloxy, hydroxy, protected hydroxy, erably monocyclic, bicyclic, or tricyclic groups containing acyl, acyloxy, nitro, amino, amido, nitro, cyano, ketals, from 6 to 14 atoms in the ring portion. The term “aromatic' acetals, esters and ethers. encompasses the “aryl and "heteroaryl groups defined When introducing elements of the present invention or the below. preferred embodiments(s) thereof, the articles “a”, “an', The term “aryl' or 'Ar' as used herein alone or as part of 40 “the' and “said are intended to mean that there are one or another group denote optionally substituted homocyclic aro more of the elements. The terms “comprising”, “including matic groups, preferably monocyclic or bicyclic groups con and “having are intended to be inclusive and mean that there taining from 6 to 12 carbons in the ring portion, such as may be additional elements other than the listed elements. phenyl, biphenyl, naphthyl, substituted phenyl, substituted Having described the invention in detail, it will be apparent biphenyl or substituted naphthyl. Phenyl and substituted phe 45 that modifications and variations are possible without depart nyl are the more preferred aryl. ing from the scope of the invention defined in the appended The terms “halogen' or “halo' as used herein alone or as claims. part of another group refer to chlorine, bromine, fluorine, and iodine. EXAMPLES The term "heteroatom' shall mean atoms other than carbon 50 and hydrogen. The following examples are included to demonstrate pre The terms "heterocycle' or "heterocyclic” as used herein ferred embodiments of the invention. It should be appreciated alone or as part of another group denote optionally Substi by those of skill in the art that the techniques disclosed in the tuted, fully saturated or unsaturated, monocyclic or bicyclic, examples that follow represent techniques discovered by the aromatic or non-aromatic groups having at least one heteroa inventors to function well in the practice of the invention, and tom in at least one ring, and preferably 5 or 6 atoms in each thus can be considered to constitute preferred modes for its ring. The heterocycle group preferably has 1 or 2 oxygen practice. However, those of skill in the art should, in light of atoms and/or 1 to 4 nitrogenatoms in the ring, and is bonded the present disclosure, appreciate that many changes can be to the remainder of the molecule through a carbon or heteroa made in the specific embodiments which are disclosed and tom. Exemplary heterocycle groups include heteroaromatics still obtain a like or similar result without departing from the as described below. Exemplary substituents include one or 60 spirit and scope of the invention. more of the following groups: hydrocarbyl, substituted hydrocarbyl, hydroxy, protected hydroxy, acyl, acyloxy, Example 1 alkoxy, alkenoxy, alkynoxy, aryloxy, halogen, amide, amino, cyano, ketals, acetals, esters and ethers. Production of Naltrexone The term "heteroaryl' as used herein alone or as part of 65 another group denote optionally Substituted aromatic groups A quantity of 0.50 grams noroxymorphone was placed having at least one heteroatom in at least one ring, and pref within a test tube. A stir bar was added to the test tube, which US 8,431,701 B2 13 14 was Subsequently sealed with a rubber septum. Subsequently, chill, 0.83 mL formic acid was added to the methanol and 1.0 mL methanol was added to the test tube to create a reac triethylamine mixture. During addition of formic acid, care tion mixture. Next, 1.0 mL of methanol was mixed with 2.0 was taken to ensure that the temperature of the mixture was mL of triethylamine in a separate test tube, and the mixture less than 30° C. After addition of formic acid, 0.19 mL was chilled in an ice bath. After the mixture was allowed to 5 cyclobutanecarboxaldehyde (CBCA) was added to the mix chill, 0.83 mL formic acid was added to the methanol and ture, with care to ensure that the temperature was maintained triethylamine mixture. During addition of formic acid, care below 25° C. was taken to ensure that the temperature of the mixture was Once the separate reaction mixture comprising methanol, less than 30°C. After addition of formic acid, 0.19 mL cyclo triethylamine, formic acid, and CBCA mixture was formed, propanecarboxaldehyde (CPCA) was added to the mixture, 10 the mixture was added to the test tube containing the noroxy with care to ensure that the temperature was maintained morphone and methanol mixture at a temperature of approxi below 25° C. mately 8°C. The combined reaction mixture was then heated Once the separate reaction mixture comprising methanol, by means of a J-Kem Personal Reaction Station (PRS) under triethylamine, formic acid, and CPCA mixture was formed, an inert nitrogen environment. The temperature of the heating the mixture was added to the test tube containing the noroxy 15 block was 74°C., but the internal temperature of the reaction morphone and methanol mixture at a temperature of approxi mixture was measured at 72°C. Additionally, the temperature mately 8°C. The combined reaction mixture was then heated of the upper block was chilled to 0°C., and the reaction by means of a J-Kem Personal Reaction Station (PRS) under mixture was allowed to react. an inert nitrogen environment. The temperature of the heating After three hours, the reaction mixture was removed from block was 74°C., but the internal temperature of the reaction heating and a sample was taken. Approximately one drop of mixture was measured at 72°C. Additionally, the temperature the reaction mixture was placed in 0.5 mL of 1% acetic acid, of the upper block was chilled to 0°C., and the reaction to prepare a sample for verification of reaction product. Upon mixture was allowed to react. analysis, the sample was shown to have a mass recovery of After three hours, the reaction mixture was removed from approximately 108%. Testing by high performance liquid heating and a sample was taken. Approximately one drop of 25 chromatography (HPLC) revealed a 6-ketonalbuphine con the reaction mixture was placed in 0.5 mL of 1% acetic acid, centration of approximately 77% (w/w) of the sample, result to prepare a sample for verification of reaction product. Upon ing in a yield of approximately 83%. sample analysis, it was shown to have a mass recovery of Once the production of 6-ketonalbuphine was verified, 4.0 approximately 96%. Testing by high performance liquid mL of water was added to the remaining reaction mixture. chromatography (HPLC) revealed analtrexone concentration 30 The reaction mixture was cooled to approximately 10°C. in of approximately 73% (w/w) of the sample, resulting in a an ice bath and the pH was adjusted to approximately 9, using yield of approximately 70%. concentrated ammonium hydroxide. The product was then Once the production of naltrexone was verified by the extracted using 8 mL of dichloromethane. The product-con sample, 4.0 mL of water was added to the remaining reaction taining layer was then separated and the product was further mixture. The reaction mixture was cooled to approximately 35 extracted with 3 mL dichloromethane. Subsequently, the 10°C. in an ice bath and the pH was adjusted to approxi product plus additional organic extracts were gathered and mately 9, using concentrated ammonium hydroxide. The washed with 2 mL water. The organic extracts were filtered product was then extracted using 8 mL of dichloromethane. through cotton and concentrated on a rotary evaporator (ro The product-containing layer was then separated and the tovap) to create a foamy tan Solid, weighing approximately product was further extracted with 3 mL dichloromethane. 40 0.685 grams. Next, the vial containing the reaction product Subsequently, the product plus additional organic extracts was placed in a vacuum oven at ambient temperature under were gathered and washed with 2 mL water. The organic approximately 40 mm Hg vacuum pressure to further dry the extracts were filtered through cotton and concentrated on a sample. After approximately 19 hours in the vacuum oven, rotary evaporator (rotovap) to create a foamy yellow solid, the sample was removed resulting in a tan Solid weighing weighing approximately 0.592 grams. Next, the vial contain 45 approximately 0.666 grams, which was Subsequently verified ing the reaction product was placed in a vacuum oven at to be 6-ketonalbuphine by HPLC assay. ambient temperature under approximately 40 mm Hg Thus, 0.50 grams of noroxymorphone was reacted accord vacuum pressure to further dry the sample. After approxi ing to the process described above to produce 0.666 grams mately 19 hours in the vacuum oven, the sample was removed 6-ketonalbuphine. resulting in a tan Solid weighing approximately 0.570 grams, 50 What is claimed is: which was subsequently verified to be naltrexone by HPLC 1. A process for the preparation of an N-alkylated morphi assay. nan having NR'' at position 17, the process comprising con Thus, 0.50 grams of noroxymorphone was reacted accord tacting a normorphinan having a secondary amine at position ing to the process described above to produce 0.570 grams 17 with an alkylating agent having R', wherein R' is chosen maltrexone. 55 from hydrocarbyl and substituted hydrocarbyl, a proton acceptor, and a reducing agent chosen from formic acid, Example 2 methyl formate, formamide, a mixture of formic acid and an alkali salt of formic acid, and combinations thereof to form Production of 6-Ketonalbuphine the N-alkylated morphinan having NR'' at position 17, 60 wherein the process occurs without the use of a transition A quantity of 0.50 grams noroxymorphone was placed metal catalyst. within a test tube. A stir bar was added to the test tube, which 2. The process of claim 1, wherein the reaction forming the was Subsequently sealed with a rubber septum. Subsequently, N-alkylated morphinan having NR'' at position 17 is con 1.0 mL methanol was added to the test tube to create a reac ducted in a one-pot process. tion mixture. Next, 1.0 mL of methanol was mixed with 2.0 65 3. The process of claim 1, wherein the normorphinan is mL of triethylamine in a separate test tube, and the mixture chosen from norcodeine, normorphine, northebaine, norori was chilled in an ice bath. After the mixture was allowed to pavine, noroxymorphone, nordihydromorphine, nordihydro US 8,431,701 B2 15 codeine, norhydrocodone, norhydromorphone, noroxyc -continued odone, nordextromethorphan, nordextrorphan, R1 O norlevomethorphan, norlevorphanol, norbuprenorphine, noroxymomorphol, noroxycodol, norsinomenine, and nordi - hydrosinomenine; the N-alkylated morphinan is chosen from 5 codeine, morphine, thebaine, oripavine, Oxymorphone, dihy R4 R5 R6 dromorphone, dihydrocodeine, hydrocodone, hydromor phone, oxycodone, oxycodeinone, naloxone, naltrexone, nal buphine, nalmefene, malfurafine, morphinone, R3 R7 ethylmorphine, butorphanol, dextromethorphan, dextror 10 phan, levomethorphan, levorphanol, buprenorphine, Sinome R2 X R8 nine, and dihydrosinomenine; the alkylating agent is an alde hyde; and R' is chosen from alkyl, cycloalkyl, cycloalkylmethyl, alkenyl, alkynyl, and aryl. 15 4. The process of claim 1, wherein the normorphinan is wherein: chosen from norcodeine, normorphine, northebaine, noroxy R. R', and Rare independently chosen from hydrogen, morphone, nordihydromorphine, nordihydrocodeine, norhy hydrocarbyl, substituted hydrocarbyl, and { }OR'': drocodone, norhydromorphone, noroxycodone, nordex R, and R are independently chosen from hydrogen, tromethorphan, nordextrorphan, norlevomethorphan, hydrocarbyl, Substituted hydrocarbyl, halogen, and norlevorphanol, norsinomenine, and nordihydrosinomenine; { }OR'': the proton acceptor is triethylamine; the alkylating agent is an R is chosen from hydrogen, and hydroxyl: aldehyde, and R' is chosen from alkyl, cycloalkyl, R is chosen from {=}O, and hydroxyl: cycloalkylmethyl, alkenyl, alkynyl, and aryl. 25 R" is chosen from hydrocarbyl, and substituted hydrocar 5. The process of claim 1, wherein an intermediate com byl: pound of animinium salt of the normorphinan is formed in the R'' is chosen from hydrogen, hydrocarbyl, substituted reaction prior to the formation of the N-alkylated morphinan. hydrocarbyl, and a hydroxyl protecting group; and 6. The process of claim 5, wherein the N-alkylated mor X is chosen from oxygen and Sulfur. phinan is Formula (IIIa), the process comprising: 30 7. The process of claim 6, wherein R. R. R. and R7 are (a) contacting a compound of Formula (Ia) with the alky hydrogen, R is {=}O, R' is a cycloalkyl group, and X is lating agent having R' in the presence of a proton OXygen. 8. The process of claim 6, wherein R. R. R. and R7 are acceptor to form a compound of Formula (IIa); and hydrogen, R is a hydroxyl group, R' is a cycloalkylmethyl (b) contacting the compound of Formula (IIa) with the 35 group, and X is oxygen. reducing agent chosen from formic acid, methyl for 9. The process of claim 6, wherein the alkylating agentis an mate, formamide, a mixture of formic acid and an alkali aldehyde of the formula R'CHO, the reducing agent is for salt of formic acid, and combinations thereof, to form mic acid, and the reaction is performed in the presence of a the compound of Formula (IIIa) according to the follow 40 protic solvent. ing reaction scheme: 10. The process of claim 6, wherein the proton acceptor is triethylamine; the alkylating agent is a carboxaldehyde, R' is selected from the group consisting of cyclopropylmethyl and H N cyclobutylmethyl; and the reaction is conducted in the pres 45 ence of a protic solvent comprising an group. R4 R5 R6 11. The process of claim 6, wherein the reaction is con Alkylating Agent Her ducted in a one-pot process. R3 R7 Proton Acceptor 12. The process of claim 6, wherein the optical activity of compounds of Formulas (Ia), (IIa), and (IIIa) is (-) or (+), and 50 the configuration of carbons 5, 13, 14, and 9, respectively, is R2 X R8 chosen from RRRR, RRRS, RRSR, RSRR, SRRR, RRSS, (Ia) RSSR, SSRR, SRRS, SRSR, RSRS, RSSS, SRSS, SSRS, SSSR, and SSSS, provided that the carbons at positions 15 R10 and 16 are both either on the alpha face of the molecule or the 2 55 beta face of the molecule. Nt 13. The process of claim 5, wherein the N-alkylated mor R4 R5 R6 Reducing Agent phinan is Formula (IIIb), the process comprising: --- (a) contacting a compound of Formula (Ib) with the alky 60 lating agent having R' in the presence of a proton R3 R7 acceptor to form a compound of Formula (IIb); and (b) contacting the compound of Formula (IIb) with the R2 X R8 reducing agent chosen from formic acid, methyl for mate, formamide, a mixture of formic acid and an alkali (IIa) 65 salt of formic acid, and combinations thereofto form the compound comprising of Formula (IIIb) according to the following reaction scheme: US 8,431,701 B2 18 R, and R are independently chosen from hydrogen, H hydrocarbyl, Substituted hydrocarbyl, halogen, and N { }OR'': R4 R5 R6 R is chosen from hydrogen, and hydroxyl: Alkylating Agent 5 He R is chosen from {=}O, and hydroxyl: R3 R7 Proton Acceptor R" is chosen from hydrocarbyl, and substituted hydrocar byl; and R'' is chosen from hydrogen, hydrocarbyl, substituted R2 R1 R9 R8 10 hydrocarbyl, and a hydroxyl protecting group. (Ib) 14. The process of claim 13, wherein R', R. R. R. R. R10 and R are hydrogen, R is { }O, and R' is a cycloalkyl group. 15. The process of claim 13, wherein R', R. R. R. R. Nt2 15 and R are hydrogen, R is a hydroxyl group, and R' is a R4 R5 R6 Reducing Agent cycloalkylmethyl group. --- 16. The process of claim 13, wherein the alkylating agentis an aldehyde of the formula R'CHO, the reducing agent is R3 R7 formic acid, and the reaction is performed in the presence of 2O a protic solvent. 17. The process of claim 13, wherein the proton acceptor is R2 R1 R9 R8 triethylamine; the alkylating agent is a carboxaldehyde, R' is (IIb) chosen from cyclopropylmethyl and cyclobutylmethyl; and R10 the reaction is conducted in the presence of a protic Solvent ! 25 comprising an alcohol group. N 18. The process of claim 13, wherein the reaction is con ducted in a one-pot process. R4 R5 R6 19. The process of claim 13, wherein the optical activity of compounds of Formulas (Ib), (IIb), and (IIIb) is (-) or (+) and R3 R7 30 the configuration of C13, C14, and C9, respectively, is chosen from RRR, RRS. RSR, SRR, SRS, SSR, RSS, and SSS, provided that the carbons at positions 15 and 16 are both R2 R1 R9 R8 either on the alpha face of the molecule or the beta face of the (IIIb)IIIb. 35 molecule. 20. The process of claim 1, wherein the process comprises wherein: forming an initial reaction mixture consisting of the normor R. R. R. and R', and Rare independently chosen from phinan, the alkylating agent, the protonacceptor, the reducing hydrogen, hydrocarbyl, Substituted hydrocarbyl, and agent and a solvent. { }OR'':