Processes for preparing morphinan-6-one products with low levels of alpha, beta-unsaturated ketone c

专利摘要:
The present invention generally relates to processes for preparing highly pure morphinan-6 one products. The processes involve reducing the concentration of a,j-unsaturated ketone compounds present as impurities in morphinan-6-one products or reactions mixtures including morphinan-6-one compounds by treatment with a sulfur-containing compound.
公开号:AU2013205836A1
申请号:U2013205836
申请日:2013-05-13
公开日:2013-05-30
发明作者:Dennis C Aubuchon；Henry J. Buehler；William E. Dummitt；Hong Gu；Anthony Mannino
申请人:Mallinckrodt LLC；
IPC主号:C07D489-08

专利说明:
PROCESS FOR PREPARING MORPHINAN-6-ONE PRODUCTS WITH LOW LEVELS OF ALPHA, BETA-UNSATURATED KETONE COMPOUNDS This application is a divisional of Australian Patent Application No. 2007224221, the entire contents of which are to be taken as incorporated herein by this reference. QFJj OF TH. E NVElNTRQ [0001) The prwsent Vrseiongenereny rates to process (& for preparg morphinanU one product. The pfocenaes; Involve reducing ht eoncentmIlon of unsaWated ketena comnpom~rds kom i readion mdiures incluiro morph~Inant5one compouris. BACKGROUND OFTH IVNO [00021 The morphinan nk3lds represent s family of silwcturlly-related prodlucls of great meadicfaIarmponrice. Particular r mov phinari comnpuunds or pherma~ceUtoiC relevance include, for e ample, cadcine hydrcodone, ydromorphonas rorphine, atuphine, nlmvkni nht iaOxore, narxopne, nxyeodone, and oxyrnorphoine. Generally, thse compournds am anslgaeS, which are unode4s9y toe pain enkai In Io oid of mnld W:Fl dueq to thoir wnn n s opat o r nis. Howovev 1 n almefela, r 1 ;Ikxone, naltrexon and nrexons methyl brornido ae Dplate receptor nn1aganitst, and are used for reveresl of narcouchespIr8ory deptossion dua to opiat receptor agonistP, as addiclon therapy e And to rvease other undesirable sie efttects of opiate a200st 0LC. vuch as severe {0003] Mcrphinan compounds and aralogs thereof ypicaqy havG a ring strucltlra generally crrespondiing to FormulJa (I' 2 A II C N [O0041 various mbndi aware known for the synhels of morphian. compounds correspoing to Formula (1), Convenlond metlcs mead In %e grformercial prndi dcan af morphinan onpounds typically Involve lhe exractio vf opium aikuloids from popples (papaver somrrerum. GnerpIly speaking, theeu processes involve the extrfaion of the 8iK3Ads from opium in;a liquid, prpet nialoi of the eikaoids 6eparsdorr of the raw aidds (e-9 1 notphine and secondary alkaloids such as papaverrne, codeine, and thebaine), aid puriFicaUQn of theC verbuallkaaids, opUonalty foIlowed by semksynthess sdeps to pRQduc parftcutr morphNen ;ompoldes See, for exmple, Brbier, A, Thte ExlractFon of OpiuM Twentytve years 0" comrneril e xpertice in 1he treatments of oplum4 An. Fharm. Frmnx, 1947, 5. 121.40; Barber, A Yhe Extractkin of Opium ANkIds," Bull Narcokc,-. 1950, vot 2, 22.29; Heumnn, W, 'The Manufacatw o Alkaloids fram Opumv R4ll Narcflics, 1957. vol, 2, S440; Ledinler and M~s cher, Qqanlc, Ghe rmisisy of Drug 1 Synthesis, chapter 15, (Wiley 1977); French Patent No. 1,000,543 to Penau et alt: British Patent No. 713,689 to Wood et al; and U.S. Patent No. 2,009,181 to Kabay. [00051 Synthetic methods for producing various morphinan compounds are also known. These methods commonly utilize 3-methoxy-phenylethylamine as a starting material and include a 5 Grewe cyclization step, For example, In U.S, Patent No. 4,368,326, Rice discloses a process for preparing a nordihydrothebainone (e.g., 1-bromo-N-formylnordihydrothebainone) from a OrY hexahydroisoquinolone (e.g., 1-(2'-bromo-4'-methoxy-5'-hydroxybenzyl)-2formy-1,3,4,5,7,8 hexahydroquinoin-6-one) by Grewe cyclization catalyzed using a super acid catalyst alone or with a combination of an ammonium fluoride complex and trifluoromethanesufonic acid. 10 [0006] Many pharmaceutically desirable morphinan compounds and analogs thereof have a ketone group on the C-ring of Formula (1) and a saturated bond between the two carbon atoms positioned a and @ to the ketone on the C-ring of Formula (1). According to the common nomenclature, the ketone Is present on the C(6) carbon atom, with the a and 0 carbon atoms being the C(7) and C(8) positions (see, e.g., Formula (1)). Thus, these compounds may be referred to as morphinan-6-one 15 compounds. Various processes for producing morphinan-6-one compounds are known, many of which involve some form of catalytic hydrogenation of a43-unsaturated ketone intermediate compounds at particular points in the process, Commonly used catalysts include, for example, palladium and platinum. For example, in U.S. Patent No. 6,177,567 to Chiu et al., 14-hydroxycodeinone (an o,@ unsaturated ketone compound) is converted to oxycodone by hydrogenating the a, P-unsaturation 20 using conventional methods such as reduction by diphenylsilane and Pd(PhsP)ZnC 2 , or with sodium hypophosphile in conjunction with a Pd/C catalyst in aqueous acetic acid, or by Pd/C catalytic transfer hydrogenation. 10007] While these and otI ier methods of reducing or removing the oP-unsaturation are generally effective, OP-unsaturated ketone compounds may persist as impurities in the final products of 25 desirably a,p-saturated morphlnan-6-one products, such as oxycodone. Additionally, known hydrogenation methods may tend to undesirably reduce the ketone as well as reducing or removing the a,p -unsaturation. Further, these and other hydrogenation methods are not normally capable of efficiently and economically reducing the levels of 7,8-unsaturation to below 10 to 100 parts per million, or less, 30 [00081 Some oR-unsaturated ketone compounds show mutagenric activity in certain tests. Therefore, a need persists for processes for preparing highly pure morphinan-6-one products having a relatively low concentration of o,p-unsaturated ketone compounds present as impurities therein. The discussion of documents, acts, materials, devices, articles and the like is included in this 35 specification solely for the purpose of providing a context for the present invention. It is not suggested or represented that any or all of these matters formed part of the prior art base or were common general knowledge in the field relevant to the present invention a It existed before tho priority date of each dln of this application. Throughout the description and claims of this specification, use of the word "comprise" and 40 variations of the word, such as "comprising" and "comprises", is not intended to exclude other additives, components, integers or steps. SUMMARY OF THE INVENTION [0009] Among the various aspects of the present invention is the provision of a process 2 for the preparation of morphinan-6-one products. The process involves reducing the concentration of ap -unsaturated ketone compounds which are present as impurities In reaction mixtures including morphinan-6-one compounds. The process generally involves forming a reaction mixture including a 2a WO 2007/103105 PCTJUS2007/00 5 256 morphinan-6-one compound and an aP-unsaturated ketone compound and treating the reaction mixture with a sulfur-containing compound. in one embodiment, the sulfur-containing compound is a sulfur-containing inorganic acid or salt thereof. {00103 Briefly, therefore, the present invention Is directed to a process for the preparation of a morphinan-6-one product, the process comprising: forming n mauntnn mire comprising a morphinan-0-One compound and an ari-unsaturated kotone compound; treating the reaction mixture with a suifur-containing compound to reduce the concentration of the ao-unsaturated ketone compound In the reaction mixture: and recovering the morphinan-6-one compound to produce the morphinan-6-one product; wherein [00111 the morphlnan-B-one compound corresponds to Formula (2); R2
R
3
R
1 Ro X
R
1 4 o (2) [0 0121 the a-unsaturated ketone compound corresponds to Formula (3): R2 R3 R, gRe R 14 [0 013] X is -N(R 17 )- or -N'(RRob 10014] R 1 and R 2 are independently selected from hydrogen, substituted and unsubstituted acyl, acyloxy, alkenyb alkoxy, alkoxyaryl, alkyl, alkylamino, alkylthlo, alkynyl amino, aryl, arylatkoxy, carboalkoxy, carbonyl, carboxyalkenyl. carboxyalkyl, carboxyl, cyano, cyainoalkyt, cycloalkyl, cycloalkylalkyl, cycloalkylether, halo, heloelkoxy, haloalkyl, heteroaryl, heterocyclic, hydroxyaikyl, hydroxyl, or nitro: [0015} R3 is hydrogen, hydroxy, protected hydroxy, alkoxy, or acytoxy; WO 200/103105 PCT/US2007/0052 5 6 [0016] RID Is hydrogen, hydroxy, protected hydroxy, halo, keto, tosyl. mesyl. or trifluoromesyl; [0 017 ] R 14 is hydrogen, hydroxy, or protected hydroxy; [0018 ) R 17 is hydrogen. alkyl, cyctoalky, alkylcarboxy, alkylenecycloalkyt, alkoxycarbony ally), alkenyl, acyl, aryl, formyl, formyl ester, formamide, benzyl, or an amino. proterdino g roup: nnrl (0 019) R,7, and R 1 m are Independently selected from hydrogen, alkyl, alkenyl, allyl, cycloalkyl, aryl, or benzylyl, and [0020) the morphinan-6-one compound comprises less than about 0.1% (by weight) morphinan-6-one product of the op-unsaturated ketone compound. [0021] The present invention is also directed to a process for preparing a morphinan-6 one product, the process comprising: forming a reaction mIxture comprising an ap-unsaturated ketone compound; treating the reaction mixture with a sulfur-contalning compound to reduce the aO-unsaturaid ketone compound to form a morphinan-6-one compound; and recovering the morphinan-6-one compound to form the morphinar6-one product, wherein 10022] the morphinan-6-one compound corresponds to Formula (2):
-
R2 R3 R1 * R 10 R14 o (2) [ 023) the o,p-unaatuated ketone compound corresponds to Formula (3): R2
R
3 RN 0R (0024) X Is -N(RW)- or-N*(R7Rj) 4 (0025] R 1 and R 2 are independently selected from hydrogen, substituted and unsubstituted acyl, acyloxy, alkeny. a!koxy, alkoxyaryl, alkyl, alkylamino. alkylthio, alkyny, amino, aryl, aryIlkoxy, carboalkoxy, cerbonyl, catoxyalkenyl, carboxyalkyl, cerboxyl, cyano, cyancalkyl, cycloalkyl cycloal'kytalkyl, cycloalkylether, halo, haloalkoxy, haloelkyt, tieteroary heterocylic, hydroxyalkyl, hydroxyl, or nilro: [00261 R5 is hydrogen, hydroxy, protected hydroxy, alkoxy, or acyloxy; [0027] R 10 Is hydrogen, hydroxy, protected hydroxy, halo, keto, tosy, mesyl, or triffuerornesy; fOD20] R 14 is hydrogen hydroxy, or protected hydroxy; f00291 Ri, ;s hydrogen, elky], cycloalkyi, alkyicarboxy. aikylenecycloalkyl, alkoxycarhonyl, ally), elkeny[ ecy ryl, formyl formyl ester, formarnide, benzyi, or an amino protectIng group; and [0030] R 37 o and Rh are independently selected from hydrogen, alky , alkenyl, aby cycloalky, aryl, or beuzylyt [0031] Other aspects and features will be in part apparent and in part pointed out hereinafter. [0031a] The invention is further directed to a process for the preparation of a morphinan-6-one product, the process comprising: providing a morphinan product produced from a conventional morphinan processing method, wherein said product comprises a morphinan-6-one compound and less than 2% by weight of an a,j-unsaturated ketone compound; forming a reaction mixture comprising said morphinan product; treating the reaction mixture with a sulfur-containing compound to reduce the concentration of the a,j-unsaturated ketone compound in the reaction mixture, wherein the sulfur-containing compound is a sulfur-containing inorganic acid or salt thereof, wherein the sulfur-containing inorganic acid is selected from the group consisting of sulfurous acid (H 2
SO
3 ); dithionous acid (H 2
S
2 0 4 ); disulfurous acid (H 2
S
2 0 5 ); salts thereof; and combinations thereof; and recovering the morphinan-6-one compound to produce the morphinan-6-one product; wherein the morphinan-6-one compound is recovered from the reaction mixture without the use of an organic solvent; wherein the morphinan-6-one compound corresponds to Formula (2): 5 R2 R3 R1 at x R14 0 (2) the a,j-unsaturated ketone compound corresponds to Formula (3): R2
R
3 Ri X 0 14R14(3 X is -N(R 1 7 )- or -N*(R1 7 aR1 7 b)-;
R
1 and R 2 are independently selected from hydrogen, substituted and unsubstituted acyl, acyloxy, alkenyl, alkoxy, alkoxyaryl, alkyl, alkylamino, alkynyl, amino, aryl, arylalkoxy, carboalkoxy, carbonyl, carboxyalkenyl, carboxyalkyl, carboxyl, cyano, cyanoalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylether, halo, haloalkoxy, haloalkyl, heteroaryl, heterocyclic, hydroxyalkyl, hydroxyl, or nitro;
R
3 is hydrogen, hydroxy, protected hydroxy, alkoxy, or acyloxy;
R
10 is hydrogen, hydroxy, protected hydroxy, halo, keto, tosyl, mesyl, or trifluoromesyl;
R
14 is hydrogen, hydroxy, or protected hydroxy; 5a
R
17 is hydrogen, alkyl, cycloalkyl, alkylcarboxy, alkylenecycloalkyl, alkoxycarbonyl, allyl, alkenyl, acyl, aryl, formyl, formyl ester, formamide, benzyl, or an amino protecting group; R17 and R17b are independently selected from hydrogen, alkyl, alkenyl, allyl, cycloalkyl, aryl, or benzylyl, and the morphinan-6-one product comprises less than about 0.1% (by weight morphinan-6- one product) of the a,j-unsaturated ketone compound. DETAILED DESCRlPTION OF THE INVTN [0032] The present invention is generally directed to processes for preparing highly pure morphinanone products. The processes generally involve treating 2 reaction mixture inchading a morphinan4-one compound and an oabunsaturated kelone compound wth a suifur-containing cormpourd. Advantageously, the process effectively reduces the concentration of undesirable aP Unsaturated ketone compounds to acceLptable Ievels without removing 0,r cthorwise affecting other more (jsirable compounds or substitueni groups or unseturation thereon. Moreover, the sulfur-containlng compound may be utilfzed to reduce the concentration of Zip-unsaturated ketone compounds present in the r~ection rniturO from leves of about 0,5% (by weight) or more to levels of not more Ihan about 0.1% (by weight), or DOwer (eg, aboul 001% (by weight), about 0,001% (by weight), or lower), with minimal side reactions, ketone reduction, and/or any other undesirable effects. . MORPHINAN PRODUCTS AND PROCESSES FOR PREPARING THE SAME [0D33} Generally speaking, the morphinans-one products of interest in the process of the present inveantion include morphinan compounds having a keto group at the C(6) carbon torn En the C-ring and a saturated bond between the C(7) and C(O) carbon atoms on The C-ring (i.e., rm'orphinan-6-one compounds). More specifiWcaly, the morphinan6-one compounds are opiate receptor agonists or antagonists generally corresponding to Formula (2): 5b WO 207/103105 PCT/US2007100525 6 R2 R3 R1 wherein [0034] X Is-N(Rl)-or-N(R 7 R,7b 100351 R 1 and R 2 are Independently selected from hydrogen, substituted and unsubstituted acyl, acyloxy, alkenyl, alkoxy, olkoxyaryl, alkyl, alkylarnino, alkyithlo, alkynyl, zmnino, aryl, arylalkoxy, carboaikoxy, carbonyl, carboxyalkenyl, carboxyalkyl, carboxyl, cyano, cyanoalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylether. hnin, hPIoalkoxy, haloalkyt hetoroaryl, haterocyclic, hydroxyalkyl, hydroxyl, or nitro; [00363 Rs is hydrogen, hydroxy, protected hydroxy. alkoxy, or acyloxy; [0037] R, 0 is hydrogen, hydroxy, protected hydroxy, halo, keto, tosyl, mesyl, or trifluoromesyl; [00 38) R1 4 is hydrogen, hydroxy, or protected hydroxy; [0039) R 7 is hydrogen, alkyl, cydoalkyl, alkylcarboxy, alkyleneoycloalkyl, alkoxycarlbuijy alyl, alKenyt, acyl, aryl, formyl, formyl ester, formamide, benzyl, or an amino protecting group; and [0040] Rfla and Rim are independently selected from hydrogen, alkyl, alkenyl, ally[, cycloalkyl, aryl, or banzyl. [00 41) When R11 is hydrogen, alkyl, akenyl, cyc!oalkyl, aryl, or benzyl, salts of the secondary or tertiary amine can be formed wherein the anion Is chloride, bromide, acetate, formate, sulfate, bisuffate, bisufite, oxalate, citrate, malate, tartrate, triflate, trifluoroacetate, methane sulfonate, and the like. When X is -N 4
(R
17 ,Rit-. the cniintr-inn con be chloride, bromide, iodide, trifIvoroacetate, Irifluoro methanesulfonate, methane sulfonate, acetate, p-toluenesulfonate, sulfate, bisulfate, bisulfite, phosphate, hydrogen phosphate, dihydrogen phosphate, fumarate, oxalale, formate, tartrate, benzoate, and tho like. 10042] In one preferred embodiment, R1 4 is hydroxy or protected hydroxy. In another preferred embodiment, R, 4 is hydrogen. 10043) In either of the embodiments described above (i.e.. when R1 4 is hydroxy or protected hydroxy or R1 4 Is hydrogen), Ra Is either alkoxy, hydroxy, or protected hydroxy. In one particular embodiment, R3 is methoxy. 6 WO 2007/103105 PC/US2007/1005256 [004 4 ] In any one of the embodiments described above, X is -N(R.)- or -N'(RmRl). wherein Ri . Rim, and R7o are defined as above. Where X is -N(R 1 )-, in one particularly preferred embodiment R 4 , Is hydrogen, alkyl, alkenyl, alkylcarboxy, or cycloalkyl. Where X is -N'(RiR b)-, in one particularly preferred embodiment Rna and Rim are independently hydrogen, alkyl, alkenyl, or cycloalkyt. [0045) Representative morphinan-6-one compounds corresponding to Formula (2) (and the various preferred substituant group definitions described above) which can be treated accordIng to the process described herein include, for example, oxymorphone, naloxone, naltrexone, naltrexone methylbromide, nalbuphone, noroxymorphone, hydromorphone, hydrocodone, oxycodone, diethoxycarbonyl-noroxymorphone, satts thereof, and the like. Additionally, derivatives of the above morphinan-6-one compounds which can be treated according to the process described herein include, for example, N-demethylated-, 10-hydroxy-, 10-halo, and 10-keto- morphinan-6-one derivatives, their protected analogs, and the like. [00461 The method of producing the above-described morphinan-6-one compounds for use in the present invention is not narrowly critical, and various methods for producing morphinan-6-one compounds are well known in the art. For example, commercial processing rneLhods for producing morphinan compounds typically involve the extraction of an opium alkaloid (e.g., thebalne) from poppies, followed by various conventional precipitation and purification steps known to those of skill in the art. Dy way of further example, the morphinan-6-one compound oxycodone may be produced from ihebaine in a substantially two-step process, as Illustrated in Reaction Scheme 1: 7 WO 2007/103105 PCT/US2007/005256 Reaction Scheme 1
H
3 CO 1H 3 CO QO -oxidation 0 N OH
H
3 O0 , O Theba ne 14-hydroxycodeinone catalytic hydrogenation
H
3 CO N oxycodone [0047] Alternatively, various synthetic methods for producing the above-doscribed morphinan-6-one compounds are also known. in these synthetic methods, a Grewe cyclization reaction Is commonly used to form nordlhydrothebainone products such as by the processes described in U.S. Patent Nos. 4,368,326, 4,410,700, 4,521,601, 4,556,712, 4,613,666, 4,727,146, the entire disclosures of which are hereby incorporated by reference herein. Additionally, various methods useful for the semI-synthesIs of morphinan compounds and intermediates are known, For example, U.S. Patent No. 6,177,567 to Chiu et al. and U.S. Patent No. 6,00B,355 to Huang et al, (eact of whkch is hureby irAuuipultesd by iefertnce herein) describe method for the zynthosis of oxycodone from codeine. These and other conventional practices are generally applicable in carrying out the preparation of morphlnen-6-one compounds and a4s-unsaturated ketone compounds that may be treated according to the processes described herein. [0 04 8 3 As noted above, in the various conventional processes for producing morphinan-6-one compounds described above, the resulting morphinan product typically also includes some amount of an o.p-unsaturated ketone compound present efa an impurity in addition to the desired morphinan-6-ono compound. The op-unsaturated ketone compounds present as Impurities generally correspond to Formula (3): 6 WO 20071103105 PC'[US2007/00525 6 R2 R3 R 1
R
1 x 0R1 O (3) wherein X, R 1 , R 2 , RD, Rio, and R 1 4 are defined as above. REACTION CONDITIONS (0049] As noted above, the morphinan products produced from conventional processes for preparing morphinan-6-one compounds also yield some amount of an ctpunsaturated ketone present as an impurity; that is, both the morphinan-6-one compound corresponding to Fornula (2) and the aP-unsaturated ketone compound corresponding to Formula (3) are present In the morphinan product [0050] The morphinan products produced from conventional morphinan processing methods typically comprise less than about 2% by weight of an oaS-unsaturated ketone compound. Preferably, the morphinan products comprise less than about 1% by weight of an oa-unsaturated ketone compound. More preferably, the morphine products comprise less than about 0 8% by weight of an op-unsaturated ketone compound. Still more preferably, the morphinan products comprise less than about 0.5% by weight of an oO.unsaturated ketone compound. As noted above, however, it is desirable to minimize or further minimize the concentration of ap-unsaturated ketone compounds present in such products. (0051] AccordIng to the present invention, a reaction mixture is formed including a morphinan-6-one compound of Formula (2) and an op-unsaturated ketone compound of Formula (3). The morphinan-6one compound and the ap-unsaturated ketone compound may be produced by any conventional method (such as those described above), and the morphinan-6-one compound may exist as the free base or as a salt, such is the hydrochloride salt, The reaction mixture is treated with n sulfur uontoining compoursd to reduce the concentraion of the np-iinsaturated ketone compound (either by forming additional morphinan-6-one compound or by facilitating the removal of the aop-unsaturated ketone compound), and the morphinan-6-one compound is recovered to produce the desired morphinan-6-one product. This process is generically Illustrated in Reaction Scheme 2, wherein the reaction mixture including. the morphinan-6-one compound and the a0-unsaturated ketone compound is shown in brackets, and X, R 1 , R 2 , R3, Rio, and R 14 are defined as above.
WO 2007/103105 P(T/US2007/00525 6 Feaclion SChe me 2 R2 R-2 7:R2 R-, R, * 1R3 R, RI 8 Ri/ Rio R C, + 0X X sulfur-containing R, 4 RA R 14 compound [0052] Various reacton mixtures (bracketed) Including a morphinan-6-one compound and an aP-unsaiurated ketone compound may be treated according to the processes described herein to yield various highly pure morphinan-6-one products, as Illustrated in Reaction Schemes 3 10. 10 WO 2007/103105 pC'r/US2o07f0052 56 N compound N 0Y hydrcodom uoeIlone jhydrorodore NO N 7 HO L ~ 0 j compound O oxymnriphno 14.hydroKymnorpbinonu oxymorphoflo NR NH ] opn HH (D j nioroxymcrhn 7.~hdxnrxphonhon noroxymorphefle HOH N7 HO ' u'+Ncompound - N cy0 0 hydrornerphoflo 7opiin hydmamofphoflD WO 2007/103105 PC'/US2007/005256 [Reaclion, Schemo_7 HO>t HO ]HO 0 o eu coon o nalooe7,B-didohydronlreona natirexane BC Br
B
0 .. r' * HX H compounrdo natroxano mQethy bromntd m,~ieyronallmxono oftltroxono rnethyr bsom[do Renoa&aoSriroc_9 HoHO HO j . / 0 ulfurconbniO 5 N N + - N compound OH No .o OH OH OMM H io ne7,5-didonydrondiOXOo nauOXOfl Roefnc oSchmerngL -HO HO. Ho I ,ttfrcoantnit I N compound N SR'UanOOR 7,O-didehydroabuphone rmalbupoone [0 053 ] Acrngtvausembodirnents, the reaction mixture Is formed by dissolving or otherwise dispersing the morphinan-6-one compound and the aj3-unsaturated ketone compound In a media material (i.e., a morphinan product including the morphinan-0one compound end the afj-unsaturoted ketone compound Is dispersed In the media material). The reaction mixture is then treated with a sulfur-containing compound, Ideally, the morphinan-one compound and the amp-unsaturated Icetone compound are in solution. taut a heterogeneous mifxture may also be treated according to the processes described heroin, [0054] The media material is desirable an aqueous media or an aqueous/organic solvent biphasic media. Exemplary aqueous media for use in the process of the present invention Includes, for example, water, water/alcohol mixtures, dilute inorganic solvents such as dilute sulfuric acid, ethereal solvento euch ae dioxano or letrohydrofuron, combinationc thereof, 2nd the liko. FxrmpVry organic solvents for use in aqueous/organic solvent biphasic media includes, for example, butanone, 12 WO 2007/103105 PC'T/US2007/005256 ethyl acetate, butano, diathyl ether, benzene, chloroform, letrachloroethylene, toluene, 1,1,1 trichloroethane, carbon tetrachloride, dibutyl ether, cyclohexane, hexare, dipentyl ether, heptane, hexadecane, combinations thereof, and the lUke. [00 55 ] Generally, a sufficient amount of media material to substantially sclubilize the morphinan-6-one compound and the ap-unsaturated ketone compound In the reaction mixture is desired, Higher amounts of media material may increase the costs of manufacturing, as the rnore dilute reaction mixture may require additional process cycle time, or require the removal or excess media material during subsequent processing steps. 1005 6) The weight ratio of media material to morphinan-6-one compound in the reaction mixture is preferably from about 1:1 to about 50:1. More preferably, the weight ratio of media material to morphinan-6-one compound in the reaction mixture is from about 1:1 to about 25:1. For example, the weight ratio of media material to morphlnan-6-one compound in the reaction mixture may be from about 1:1 to about 5:1, from about 1:1 to about 10:1, from about 1:1 to about 15:1, or from about 1:1 to about 20:1. Still more preferably, the weight ratio of media material to morphinan-6-one compound in the reaction mixture is from about 5:1 to about 25:1. For example, the weight ratio of media material to morphinan-6-one compound In the reaction mixture may be from about 5:1 to about 10:1, from about 5:1 to about 15:1, or from about 5:1 to about 20:1. Still more preferably, the weight ratio of media material to morphinan-6-one compound in the reaction mixture is from about 5:1 to about 15:1. For example, the weight ratio of media material to morphinen-6-one compound in the reaction mixture may be from about 5:1 to about 6:1, from about 5:1 to about 7:1, from about 5:1 to about 5:1, from about 5:1 to about 9:1, from about 5;1 to about 10:1, from about 5:1 to about 11:1, from about 5:1 to about 12:1, from about 5:1 to about 13:1, or from about 5:1 to about 14:1. Most preferably, the weight ratio of media material to morphinan-6-one compound in the reaction mixture is from about 5:1 to about 11:1. It will be understood that some portion of the media material may be derived from the sulfur-containing compound itself (e.g,, as water of hydration). [0057) Optionally, a phase transfer catalyst may also be added to the aqueous/organic solvent biphasic media. The phase transfer catalyst Is preferably any suitable composition for use in the transfer of reactants (i.e., morphinan-6-one compounds, ap-unsaturated ketone compounds, and/or sulfur-containing compounds) between the aqueous and organic solvent interface. Typically, the phase transfer catalyst is an ammoniujm-based compound. such as a quaternary ammonium salt, Suitable quaternary ammonium salts for use as phase transfer catalysts include tetraalkylammonium salts such as. for example, tetramethyl-, tetraethyl-, tetrabutyl-. lotrahexyl-, tetraoctyl-, methyltriphenyl-. methyltrioctyl-. benzyltrimethyl-, benzyttriethyl-. benzyltributyl-, hexadecyltrimethyl ammonium salts, arid the like. Suitable salts include, for example, halide, hydroxide, bicarbonate, bisulfate, thiocyanate, tetrafiuoroborate, and the like. Other phase transfer catalysts such as phosphonium salts may be suitable as well. [00581 A variety of sulfur-containing compounds may be utilized to treat the reaction mixture and reduce me concentration of the op-unsaurated weit omnipound according to the processes described herein, In various embodiments, the sulfur-contalning compound is a sulfur 13 WO 2007/103105 PCT/US2007/005 2 5 6 containing nucleophile. As utilized herein, "nucleophile" refers to an ion or molecule that donates a pair of electrons to an atomic nucleus to form a covalent bond. in other embodiments, the sulfur containing compound Is a sulfur-contalning reducing agent. As utilized herein, "reducing agent" refers to an agent having the ability to add one or more electrons to an atom, ion or molecule, in either of the two embodiments described above (i.e., when the sulfur-containing compound is a sulfur-containing nucleophile or a sulfur-containing reducing agent), the sulfur-containing compound is a compound having the ability to effect the reduction o[ arid/u a 1,4 addion across the ap-unsaturated bond of the aO-unsaturatod hetone compound. [0059] In one embodiment, the sulfur-containing compound IS a suIfur-conlaining inorganic acid or salt thereof. Suitable sulfur-contalning inorganic acids include, for example, hydrosulfuric acid (H2S): sulfurous acid (l-aSO); persulfuric acid (H2SOB); thiosulfurous acid (H2S202); dithlonous acid (HaS20}4); disulfurous acid (HrS2O); dithionic acid (H 2 8 2 00); pyrosulfuric acid
(H
2
S
2 0 7 ); peroxydisulfuric acid (H 2
S
2 0 8 ); trlthionic acid (H 2
S
3 10); tetrathlonic acid (H2S4Oe); ponlathionic acid (HzSs0); chlorosulfonic acid (HS03CI): furosulfonic acid (HSO3F); sulfamic acid
(HSO
3 NH2); salts thereof; and the like, [00 60] Generally, the sulfur-containing inorganic acid salt may be an alkali metal salt or an alkaline earth metal salt. For example, tie salt may be a monovalent or divalent cation selected from Li, Nat K, Rb', Cs', Fr, Be 2 , Mg 2 -, Ca, Sr 2 , Ba 2 . or Ra 2 t Preferably, the salt is selected from the group consisting of t Na, K*, Mg 2 t Ca 2 t and combinations thereof. [00 613 Alternatively, the sulfur-containing inorganic acid salt may be an ammonium .ait (NH:) or a quaternary ammonium salt. For example, the sulfur-containing inorganic acid salt may be a telruakylater aimmunium salt; that Is, a quaternary amrnonium colt substituted with four sikyl orOups preferably having from I to abnut 18 carbon atoms. Suitable tetraalkylated ammonium salts include, for example, tetramethylammonium salts, telroethylammoniorn salts, tetrapropylammonium salts, tetrabutylammonium salis, and the like, [0062) In one particular embodiment, the sulfur-containing inorganic acid is dithionous acid (H 2
S
2 0 4 ) or salts thereof. By way of example, salts of dithionous acid include MHS 2 0 4 and
M
2 S2,0, wherein M Is selected from alkali metal salts, alkaline earth metal selts. ammonlurm salt
(NH
4 ). and quaternary ammonium salts. According to this embodiment, the u4P-unsaturated ketone compound is chemically reduced to form the morphinan-6-one compound upon treatment with the sulfur-containing compound, discussed in further detail below, [00 63 ] in another particular embodiment, the sulfur-containing inorganic acid is selected from the group consisting of sulfurous acid (H2S03); disuilfurous acid (H2SzOS); and salts thereof. By way of example, sals of sulfurous acid and disulfurous acid include MHSO 3 , M 2 SO, MHS 2 0S, and
M
2
S
2 0s wherein M is selected from alkali metal salts, alkaline earth metal salts, ammonium salt
(NH
4 *), and quaternary ammonium salts. According to this embodiment, the sulfur-containing inorganic acid or salt thereof is one which dissociates into the bisulfite Ion (HSO&) and/or the sulfite Ion (SOt) in the reaction mixture. It will be understood by one of ordinary skill in the art that 14 WO 20071103105 PCT/US200710052 5 6 sulfurous acid (H 2 S0 3 ) generally exists as a solution of SO2 (commonly about 6%) in water. The pKa of sulfurous acid (H2SOa) is about 1.7B and its ionization expression Is;
H
2 0 + SOz HzSOa - H* + HSO' - H* + SO3 According to this embodiment, various 1,2- and 1,4- sulforated addition products are formed from the morphlnan-6-one compound and the aop-unsaturated kotone compound by reaction with the bisulflte ion and/or the sulfite ion, discussed in further detail below. [00 64 ] in another particular embodiment, the suifur-containing compound is a thiol having the formula: R-SH, wherein R is hydrocarbyl substituted hydrocarby, or heterocyclo. For example, R may be substituted or unsubstituted alkyl, alkenyl, altynyl, or aryl. Exemplary thiols having the formula R-SH, wherein R is defined as above, Include alkyl or aryl thiols such as rnothanethlol, ethanethlol, benzenethlo, and the like. Other exemplary thiols Include thioarboxyllo acids and salts thereof (eg., thiobenzoic acid) and thlol-terminated carboxylic acids and salts thereof (e.g., thioglycolic acid (mercaptoacetic acid), mercaptopropionic acid, and the like), Still other exemplary thiole include amino acids (e.g, L- or D,L-cystoino), other thiol-containing amines and/lor quaternary salts thereof (e.g, cysteamine -10. thiocholine, and the like), or polymer-bound thiols (e.g., polycysteine, polyvInylarylthiol, and the like). In one preferred embodiment, the thiol is benzenethiol. Without being bound to one theory, it is believed that the thiol forms various 1,2- and 1,4- sulfonated addition products from the morphinan-6-one compound and the a,0-unsaturated ketone compound. [00 65] The amount of sulfur-containing compound utilized to treat the reaction mixture may vary considerably according to the various reaction mixture components (such as the particular morphinan-6-one compound, the oP-unsaturated Ketone compound, and/or tne mediu malrild) and concentrations thereof, time of reaction, temperature, pressure, and the like. Relatively high usage rates of sulfur-containing compound generally offer no significant advantages and tend to waste chemicals and/or reactor volume. [00 66 ] The molar ratio of sulfur-containing compound to morphlnan-6-one compound in the reaction mixture is typically greater than about 0.5:1. Preferably, the molar ratio of sulfur-containing compound to morphinan-6-one compound in the reaction mixture is from about 0.5:1 to about 3.0:1. Fur example, the molar ratio of sulfur-containing compound to morphinan-6-one compound In the reaction mixture may be from about 0.5:1 to about 0.13:1, from about 0.5:1 to about 1.0:1. from about 0.5:1 to about 15:1, from about 0.6:1 to about 2.0:1, or from about 0.5:1 to about 2.5:1. More preferably. the molar ratio of sulfur-containing compound to morphinan-6-ore compound in the reaction mixture is from about 0.6:1 to about 2.8:1, For example, the molar ratio of sulFur containIng compound to morphinan-6-one compound in the reaction mixture may be from about 0,6:1 to about 0,8:, from about 0-6:1 to about 10:1, from about 0.6:1 to about 1,5:1, trom about 0.6:1 to about 2.0:1, or from about 0,6:1 to about 2.5:1. Most preferably, the molar ratio of sulfur-containing compound to mcrphinan-6-one compound in the reaction mixture is from about 0,8:1 to about 2.5:1. For example, the molar ratio of sulfur-containing compound to morphinan-6-one compound In the 15 WO 2007/103105 PCT/US2007/00525 6 reaction mixture may be from about 0.8:1 to about 1.0:1, from about 0.8:1 to about 1.2:1, from about 0,8:1 to about 1.4:1, from about 0.a:1 to about 1,6:1, from about 0.5:1 to about 1.8:1, from about 0.1 to about 2.0:1, from about 0.8:1 to about 2,2:1, or from about 0.8:1 to about 2A:1. [00 67 ) The treatment of the reaction mixture with the sulfur-containing compound may be carried out in ambient air or in an oxygen-free environment. Preferably, the treatment Is carried out In an inert atmosphere such as, for example, argon or nitrogen gas, The treatment is preferably carried out at a pressure of from about 0.5 atm to about 2.0 atm. More preferably, the treatment is carried out at a pressure of from about 0.75 atm to about 1.5 atm: most preferably from about 0.9 aim to about 1.25 atm. [00 68) In various embodiments, the pH of the reaction mixture during treatment with the sutfur-contoining compound Is greater than about 3. Typically, the pH of the reaction mixture during treatment is less than about 10, although the upper pH limit may depend on the treatment time and/or solubility of the various reaction mixture components. Preferably, the pH of the reaction mixture during treatment with the sulfur-containing compound Is from about 3 to about 9; more preferably from about 6 to about 9. For example, the pH of the reaction mixture during treatment with the sulfur containing compound may be about 3, about 4, about 5, about 6, about 7, about 8, or about 9, Most preferably, the treatment occurs at a pH of from about 6 to about 7.25. Upon the addition of the sulfur-containing compound to the reaction mixture including the morphinrian-6-one compound and the op-unsaturated ketone compound, the pH may be adjusted to the desired level (e.g. using a base such e ammonium hydroxide). Other suitable bases include, for example, sodium hydroxide, potassium hydroxide, and the like. [O0 691' The u-re of reaction i* generally a function of the other variahleA in the reaction, such as pH, ratio of media material to morphinan-6-one compound, amount of sulfur-containing compound, and the ie. Typically, some reduction of the concentration of op-unsaturated ketone compound in the reaction mixture can be observed after about 1 houf, Preferably, the reaction mixture is treated with the sulfur-containing compound for at least about 1 hour. In some embodiments, the time of reaction is less than about 24 hours. in other embodiments, the time of reaction is from about 1 hour to about 18 hours; in still other embodiments from about 1 hour to about 15 hours; in still other embodiments from about 1 hour to about 10 hours. More preferably, the reaction mixture is treated with the si lfur-nnntaning compound for about 1 hour to about 5 hours. For example, the reaction mixture may be treated with the sulfur-containing compound for about 1 hour, for about 2 hours, for about 3 hours, for about 4 hours, or for about 5 hours. [00703 The temperature of the reaction mixture during treatment with the sulfur containing compound is generally from about O'C to about 100'C. For example, the temperature of the reaction mixture during treatment with the sulfur-containing compound rray be from about 10'C to about 90"C, from about 20'C to about 80*C, or from about 30'0 to about 70'C. Preferably, the temperature of the reaction mixture during treatment with the sulfur-containing compound is above room temperature. I lie preferred reaction temperature muy vaiy for each morphinan ono. More preferably, the temperature of the reaction mixture during treatment with the sulfur-oontaining 16 WO 207/13195PCT/US20J07/ 0 0 5256 WO 2007/103105 compound is from about 300C to about 500C, For example, the temperature of the reaction mixture during treatment with the sulfur-containing compound may be about 30*C, about 35"C, about 40'0, about 45C, or about 500C, {00711 Once the treatment is complete or has proceeded as long as desired, the treated morphinan-O-one compound a recovered to produce the morphinan-6-one product. Advantageously, the morphinan-6-one compound may be recovered from the reaction mixture without the use of an organic solvent. The absence of the need for organic solvents in the recovery process not only provides various environmental and material handling benefits, but also results in a more efficient process suitable for Industrial scale applications, Typically, the morphinan-6-one compound is precipitated from the reaction mixture as a base ( or salt If desirable) and may then be readily converted into a generally more pharmaceutcally acceptable form, if so desired. For example, the pH of the reaction mixture is typically adjusted to about 9-10 or greater with a suitable base such as ammonium hydroxide, and the (desired) precipitated compound recovered, Generally speeldng, this pH is at the point wherein opium alkaloids are not Ionized. The morphinan-6-one compounds can then be optionally converted Into a form more physiologically tolerable, such as the hydrochloride sel, e.g., oxycodono HCt, using conventional methods known to those of skill in the art. For example, the morphinan-8-one base can be dissolved or otherwise dispersed in water, reacted with an acid such as HiC, heated, and cooled to precipitate the morphinar-6-one salt, By way of an alternative example, the morphinan-6-one base can be dissolved or otherwise dispersed in an alcohol solvent (e.g., methanol, ethanol. etc.) or a solvent system (i.e., a mixture of solvents), reacted with concentrated HCI or an HCI/alcohol mixture, and cooled to precipitate the mrphinan-5-ore hydrochloride salt. By way of another example, the morphinan-6-one base can be dissolved or otherwise dispersed In water, alcohol solvent, or a solvent system, reacted with gaseous HC, heated, end cooled to preclpitate the morphinan-6-one hydrochloride salt. TREATMENT REACTION MECHANISMS {0072) Without being bound to one theory, it is believed that the reduction of the concentration of ct,j-unsaturated ketone compounds in the reaction mixture is performed via different mechanisms, depending on the particular sulfur-containing compound selected to treat the reaction mixture. [00 73 ] In one embodiment, the ai-Unssurated ketone compound 1s reduced by tho sulfur-containing compound to form the desired o,p-saturated morphinan-6-one compound. See, e.g., Camps at al., Tetrahedron Letters, Vol, 29, No. 45, 1988, 5811-5614; Louis-Andre et aL., Tetrahedron Letters, Vol. 26, No. 7, 1985, 831-832), 5y way of exanmpl, dithlonous acid (H2S 2 04) and salts thereof (e.g., MHS2O4 or MaS 2 Oh, wherein M is defined as above) operate according to this mechanism; other sulfur-containing compounds, however, may also operate according to the same or a similar mechaism. Reaction Scheme 11 generally illustrates the reduction of the oP3unsaturated ketone compound (3) to form the desired morphinan-6-one compound (2) according to this embodiment, wherein X, Rf1, R 2 , t 3 , Rie, end R1 cse deei d as above. 17 WO 2007/103105 PCT/US207/0525 6 Reaction chamgil R2 R R, R2 R1 R3 R3 10 , . 1 Ri sulfur-contaliin9 Rg R compound 0 (2)(3) [0074] In an alternative embodiment, various 1,2- and 1,4- sulfonated addition products are formed during treatment that assist in the removal of the otAunsaturated ketone compounds from the reaction mixture. As noted above, several sulfur-conhalning compounds dissociate into various sulfur-containing species. In particular, sulfurous acid (HzSO3), dlsulfurous acid (H 2 S20 5 ), and their salts dissociate into, among other things, Usulfite (HSOs) and sulfite (SO ). f00751 Blsulrite has been shown to ori via rAdical initiation across isolated double bonds (see, e.g, March, J., Advanced Organic Chemistry, p. 688, J. Wiley & Sons, 1985, 3d. ed.) and/or add via an Ionic mechanism (see, e.g., Gilbert, E.; Sulfonalol and Related Reactions, p, 152, Interscience, N.Y. 1965; Patel et al, The Chem/stry ofAlkenes, p. 478, IntersCience, London 1965). Without being bound to one theory, It Is believed that when the reaction mixture is treated with sulfurous acid, disulfurous acid, or salts thereof and the pH is adjusted to between about 3 and about 9, certain 1,2- and 1,4- addition products and adducts ore stably and/or reversibly formed from the af-unsaturated ketone compound and the morphinan-6-one compound. It li further believed that the prnrtnnts Rim onnarally stable within the pH range of from about 3 to about 9, and adjusting the pH outside of this range after their formation from the ap-unsaturated ketone compounds and the morphinan-6-cne compounds facilitates the removal of the a,-unsaturated ketone compound from the reaction mixture, resulting in a highly pure morphinan-6-one product. [0076] One preferred embodiment of the present invention is lustrated in Reaction Schemes 12A and 12B, wherein X, R1, R2, R3, Rjn, and R 4 are defined as above and M is a monovalent or divalent cation, For example, M may be one or more alkali metal or alkaline earth metal monovalent or divalent cations from the .sulfur-containlrig compound. Alternatively, M may be onO or rmore monovalent or divolont cotlons from the alkanne compound ( g, NOH, KOH, Ni1OH, etc.) used to adjust the pH of the reaction mixture to between about 3 and about 9 after the addition of the sulfur-containing compound to the reaction mixture, 18 WO 20071103105 PCT/US2007100 5 2 5 6 Reaction Scheme 12A R3 R 1
R
3 R RIO sulfur-containing 3<pHC9 + compound na R-14 R4 Ho R o (22) OMoS (2A) RenactlonSchre 1J R2 R-2 R sRi R3, R1 R io 3<pH< O /-~ +it sums-containing 3<iC9 -x compound O, R (3) HO14 acp~cRM0 3 5 (A) 3<pH4-I9 R, R2
R
3
NR
1
R
3
R,
1 RIO 3<pH<9-Tm i : Ft 1 'XH <
R
14 compound HO R1 0 So 1 M (3B) MQ 3 S $0 3 M (35)M~aS(3C) [00771 As shown in Reaction Schemeu 12A and 12B, various 1,2- and 1,4- sulfonated compounds are formed from the morphinan-6-one compound (2) (scheme 12A) and the ap-unsaturated ketone compound (3) (scheme 12B) upon treatment of a reaction mixture including these compounds with a sulfur-containing compound at a pH of between aboul 3 and about 9. While i is understood that sulfurous acid, disulfurous acid, and salts thereof operate according to the mechanism illustrated in Reaction Schemes 12A, 12B, and 120, other sulfur-contaiing compounds may also operate according to the same or a similar mechanism. For example, thiols (e.g., benzenethiol) may also operate according to the mechanism described in connection with Reaction Ochemco 12/, 12B, and 120. 19 WO 2007/103105 PCT/US200/005256 [0078] Particularly, when the reaction mixture is treated with a sulfur-contaIning compound and the pH of the reaction mixture Is adjusted to between about 3 and about 9, the morphlnan-6-one compound (2) forms the reversible, water-soluble 1,2-bIsulfite adduct (2A). Once the reaction Mixture is sufficiently in solution in the media material and/or the sulfur-containIng compound, dissociated sulfur specie (such as sulfite and bisulfite) react more readily with the ap.-unsaturated ketone compound (3) also present in the reaction mixture. [007 91 As illustrated in Reaction Scheme 128, one reaction between the a 1 -unsaturated ketone compound (3) and the sulfur-containing compound Involves the rapid and reversible 1,2 addition of the bisulfite to the carbonyt (similar to the reaction of the sulfur-containing compound with the morphInan-6-one compound illustrated in Reaction Scheme 12A) to form the reversible 1,2-adduct (3A) from the e,3-unseturated ketone compound (3). Another reaction between the sulfur-containing compound and the a,-unsaturated ketone compound (3) Is the slower 1,4-addition, forming the more stable 1,4-addition product (3B). The Introduction of the sulfonate group in the p.posltion generally enhances the reactivity of the carbonyl group by destroying its conjugation with the double bond, such that the reversible product Is a 1,2- and 1,4-bis adduct (3C) (see Patai et al., The Chemistry of Alkenes, p. 478, linterscience, London 1965). [0080] Reaction Scheme 12C Illustrates the removal of certain addition products formed in the reaction mixture according to Reaction Schemes 12A and 12B and the resulting highly pure morphinan-6-one product, wherein X, RI, R , R 3 , RIO, R,., and M are defined as above. Reacion scheO.12& R al 0,, - , -4x0 Ho RHo RRk3H>94R ( A) c[B S2. ramnovilT vf J38) p1111 rothor liquor m uo R1Z X (2) [0BI) As illustrated in Reaoion Scheme 120, the removal of the a,-unsaturatod ketone addition products Is generally based In the differences in solubility of the 1,4-addition product (3D) generated from the o,p-unsaturated ketone compound and the desired morphinan-6-one compound (2), Adjusting the pH1 outside of the range between about 3 and about 9 (i.e., the pH is 20 WO 20071103105 PCT/US20071005 2 5 6 adjusted to less than about 3 or the pH is adjusted to greater than about 9) with an acid (e.g., sulfuric acid (H 2 SO4) or a base (e.g., ammonium hydroxide (NHAOH)) results in the decomposition of the 1.2 addition products of each compound, rendering the desired morphinan-6-one compound (2) insoluble in water. The relatively more stable 1,4-addilion product (31) formed from the ap-unsaturated ketone compound remains and Is water-soluble in the final mixture at an alkaline pI (e.g., pH -9 or greater). The 1,4-addition product (38) may thus be removed from the mixture with the mother liquor, leaving the insoluble morphlnan-6-one Daseo 2. tne desired morphlndn-O-oe base may then be converted Into a more physiologically-tolcrablS salt form, such asthe hydrochloride salt, using methods known to those of skill In the art. [00 823 One particularly preferred embodiment of the present invention is illustrated in Reaction Schemes 13A and 133, whereIn M is defined as above. ReactIon Scheme 13A
H
3 00 N sulfur-containin -r' s + compound . 0HN- HO-_ OH OH O (20) MO'S (20A) R~nqoajpacbsme 139
H
3 CO - H3CO + sulfur-conlaining , N compound 1. N OH HO
MO
3 S (30A) 3<pH<o HCO ~H0 3<pH<9 N-_ sulfur-containing OH- OH compound HO O O SO 3 M MO 3 S (30) (a308) 21 WO 2001/103105 PCiYUS20071005256 [0083] As shown In Reaction Schemes 13A and 130, various sulfonated compounds are formed from oxycodone (20) (scheme 13A) and the a,0-unsaturated keton e com pound 14 hydroxycodelnone (30) (scheme 13B) upon treatment of a reaction mixture including these compounds with a sulfur-containing compound at a pH1 of between about 3 and about 9, As discussed above, while it Is generally understood that sulfurous acid, disulfurous acid, and salts thereof operate according to the mechanism described in Reaction Schemes 13A and 138, other sulfur-containing compounds may also operate according lu Vim eine or a similar mechanism. (00841 Particularly, when the reaction mixture Is treated with a sulfur-containing compound end the pH of the reaction mixture is adjusted to between about 3 and about 9, oxycodone (20) forms the reversible, water-soluble 1,2-blsulfite adduct (20A), Once the reaction mixture is sufficiently in solution ;n the media material and the sulfur-containing compound, dissociated sulfur specie (such as sulfite and bisulfite) react more readily with the 14-hydroxycodeinone (30) also present in the reaction mIxture. [0085) As illustrated in Reaction Scheme 138, one reaction between 14 hydroxycodeinone (30) and the sulfur-containing compound involves the rapid and reversible 1,2-addition of the aulfite to the carbonyl (similar to the reaction of the sulfur-containing compound with oxycodone illustrated in Reacton Scheme 13A) to form the reversible 1,2-adduct (30A) from 14-hydroxycodeinone. Another reaction between the sulfur-containing compound and 14-hydroxycodeinone (30) is the slower 1,4-addition, forming the more stable 1,4-addition product (301). The introduction of the sulfonate group in the p-position generally enhances the reactivity of the carbonyl group by destroying its conjugation with the double bond, such that the reversible product Is a 1,2- and 1,4-bis adduct (30C) (see Patai et at, The Chcmistry ofAlkenes, p. 47B, Interscience, London 1965). [0086] Reaction Scheme 13C illustrates the removal of certain addition products formed in the reaction mixture according to Reaction Schemes 13A and 13B and the resuming highly pure oxycodone, wherein M is defined as above. 22 WO 2007/103105 PCT/US2007/005256 t--- No- 3>1h9 OH 0oH "3CO ItOH0 HO 0H HO jOHc i (3000 S1. aIkZ[IPB pH4 2. remBoval of (308) veBB mothli ipuor mixtu {00 87 As llustrated in Reaction Scheme 130, the removal of the 14-hydroxycodelnone addition products is generally based on the differences in solubility of the 1,4-addition product (30B) generated from 14-hydroxycodeinoe and the desired oxycodone (20). Adjusting the pH outside of the range between about 3 and about 9 (i.e., the pH is adjusted to less than about 3 or greater than about 9) with an acid (e,g., sulfuric acid (H12SO 4 )) or a base (e.g., ammonlurn hydroxide (NH 4 0H)) results in the decomposition of the 1,2-addiltlon products of each compound, rendering the desired oxycodone (20) insoluble in water. The relatively more stable 1,4-addton product (30B) formed from 14-hydroxycodelnone remains and is water soluble in the final mixture at an alkaline pH (e.g., pH -9 or greater). The 1,4-addition product (300) may thus be removed from the mixture with the mother liquor, leaving the insoluble oxycodone base (20). The oxycodone base rnay then be converted into a more physiclogically-tolerable salt form, such as the hydrochloride salt, using methods known to those of skill in the art. REMOVAL OF RESIDUAL SULFUR-CONTAtNING SPECIES FROM THE REACTION MIXTURE [0088) Using the process described herein to reduce the concentration of a1 unsaturated ketone compounds from a reaction mixture by treating the reaction mixture with a sulfur containing compound may result In the undesirable accumulation of residual suifur-contalning species (such as sulfites and bisulfites) in the reaction mixture and/or final morphinan-6-one product. Accordingly, the residual sultur-containing species may be optionally substantially removed from the reaction mixture following the treatment with the sulfur-containing compound using a variety of methods known to those of skill in the art. {00 89) As described above, In various embodiments 1,2- and 1,4- sulfonated addition products may be formed by the reaction of a sulfur-contoining compound with the rerphilnan--nnn compound and the a4-unsaturated ketone compound at a pH of between about 3 to about 9. The 23 WO 2007/103105 PCTIUS2007/005256 adjustment of the pH outsIde of this range eliminales the 1,2-addition products, renders the morphinan-6-one compound insoluble in water, and the remaining water soluble 1,4-addition product can be removed in the waste stream. [00901 To optionally substantially remove the residual sulfur-containing species upon completion of the reaction with the sulfur-containing compound, the pH of the reaction mixture may be adjusted to less than about 3 (instead of adjusting the pH to greater than 9) with an acid (e.g., sulfuric acid (H 2
SO
4 )) and manipulated prior to the precipitation of the morphinan-6-one compound as described in detail above, More preferably, the pH is adjusted to less than about 2. The reduction in pH converts any residual sulfur species that may be present in the reaction mixture into $02 gas, which typically has a limited solubility in water. In one embodiment, the S02 gas may then be optionally heat refluxed out of the reaction mixture by conventional means known la those of k11 in the art, Typically, the reaction mixture is heat refluxed for about 2 hours to about 5 hours. The temperature and pressure during reflux are also generally variable. For example, the temperature of the reaction mixture during reflux is typically from about 20"C to about 100*C, and the reflux may be pedormed at a pressure 6f from about 0.003 atm to about 1,0 atm, Alternatively. substantially all or the water (and the S02 gas) may be optionally distilled off to a receiver tank and discarded. This procedure is also generally known to those of skill in the art. [C 0 91] As discussed above, after treatment of the reaction mixture with the sulfur containing compound to reduce the concentration of the ap-unsaturated ketone compound in the reaction mixture, the morphinan-6-one compound is recovered to produce the desired morphinan-6 one product. Generally speaking, recovery refers to one or more of the precipitation, filtraton and drying of the morphinan-6-One base, the formation of the physiologically acceptable morphinan-6-one salt (e.g.. the hydrochloride salt), the removal of ths residual sulfur-containing species, and/or combinations thereof, to produce a morphinan-6-one product. 10092) The treatment of the reaction mixture with a sulfur-containing compound according to the various processes and embodiments described herein significantly reduces the concentration of oP-unsaturated ketone compounds in the reaction mixture, and a highly pure morphinan-6-one product may be produced therefrom. Typically, the morphinan-5-one product comprises less than about 0.1% (by weight morphinan-B-one product) of an op-unsaturated ketone compound. For example, the morphinan-6-nne prodtint may comprise less than about 0.05% (by weight morphinan-6-one product) of an aP-unsaturated ketone compound Preferably, the morphlnan-6-one product comprises less than about 0.01% (by weight morphinan-6-one product) of en ua-unsaturated ketone compound. For example, the morphinan-S-one product may comprise less than about 0.005% (by weight rmorphinan--one product) of an aP-unsaLuratod ketone compound. More preferably, the morphinan-6-one product comprises less than about 0.001% (by weight morphinan-6-one product) of an op-unsaturated ketone compound. For example, the morphinan-6 one product may comprise less than about 0.0005% (by weight morphinan-l6-one product) of an a-uneaturated kntonr compound. Sill more preferably, no detectable amount of an ap-unsalurated ketone compound is present in the morphinan-6-one product. 24 WO 2007/103105 PCTUS2007/005256 ABBREVIAT1ONS AND DEFINITIONS [0093) The following definitions and methods are provided to better define the present invention and to gulde those of ordinary skill in the art in the practice of the present invention. Unless otherwise noted, terms are to be understood according to conventional usage by those of ordinary skill in the relevant art. 00 94) The term alkyll as used herein d'rriben groups which are preferably lower alkyl containing from one to eight carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain or cyclic and include methyl, ethyl, propyl, Isopropyl, allyl, benzyl, hexyl and the like. [00 9 5) The term "alkeny as used herein describes groups which are preferably lower alkenyl containing from two to eight carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain or cyclic and Include ethenyl, propenyl, isopropenyl, butenyl, Isobutenyt, hexenyl, and the like. [009 6) The term 'alkynyr as used herein describes groups which are preferably lower alkynyl containing from two to eight carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain and include ethynyl. propynyl. butynyl. leobuiynyl, hexynyl, and the like. [0097 1 The term "aromatic" as used herein alone or as part of another group denotes optionally substituted homo- or heterocyclic aromatic groups. These aromatic groups are preferably monocyclic, bicyclic, or tricyclic groups containing from 6 to 14 atoms in the ring portion. The term "aromatic" encompasses the "aryl" end "heteroary' groups defined below. 1009B] The term "aryl' as used herein alone or as part of another group denote optionally substituted homocyclic aromatic groups, preferably monocyclic or bicyclic groups containing from 6 to 12 carbons in the ring portIon, such as phenyl, biphenyl, naphthyl, substituted phenyl, substituted biphenyls or substituted naphithyl, Phenyl and substituted phenyl are the more preferred aryi. [00 99 ) The terms "halogen," "halide" or "halo" as used herein alone or as part of another group refer to chlorine, bromine, fluorine, and iodine. [0100 J The term "hoteroatom" shall mean atoms other than carbon and hydrogen. [01013 The terms "helerocyclo" or "heterocyclic" as used herein alone or as part of another group denote optionally substituted, fully saturated or unsaturated, monocyclic or bicyclic, aromatic or non-aromatic groups having at least one heteroatom In at least one ring, and preferably 5 or 6 atoms in each ring, The heterocyclo group preferably has 1 or 2 oxygen atoms snd/or I to 4 nitrogen atoms in the ring, and is bonded to the remainder of the molecule through a carbon or heteroatom. Exemplary heterocyclo groups include heteroaromatics such as furyl, pyridyl, oxazolyl, pyrrolyl, Indolyl, quinoinyl, or isoquinol[nyl and the like. Exemplary substituents Include one or more of the following group: hydrocarbyt, subatitutod hydrocarbyt, hydroxy, protected hydroty, acyl. 25 WO 2007/103105 PCT/US2007/005256 acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, halogen, amido, amino, cyano, ketais, acetals, esters and others, [0 102) The term "hoteroarornatid' as used herein alone or as part of another group denote optionally substituted aromatic groups having at least one haleroatom In at least one ring, and preferably 6 or 6 atoms in each ring. The heteroaromatic group preferably has 1 or 2 oxygen atoms, 1 or 2 sulfur atoms, andlor 1 to 4 nitrogen atoms in the ring, and may be bonded to the remainder of the molecule through a carbon or heteroatom, Exemplary heteroaromat[cs include furyl, thienyl, pyridyl, oxazolyl. pyrrolyl, Indolyl, quinolinyl, or isoquinolinyl and the like. Exemplary substituents include one or more of the following groups; hydrocarbyl, substituted hydrocArbyl, keto, hydroxy, protected hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, arytoxy, halogen, amido, amino. nitro, cyano, thiol, ketels, acetals, esters and others. [0103] The term "acy," as used herein alone or as part of another group, denoles the moiety formed by removal of the hydroxy group from the group -COOlH of an organic carboxylic acid, e.g., RC(O)-, wherein R is R', R'O-, R' R 2 N-, or R'S-, R' is hydrocarbyl, heterosubstituted hydrocarbyl, or heterocyclo, and R' Is hydrogen, hydrocarbyl or substituted hydrocarbyl. [0104 3 The term "acyloxy," as used herein alone or as part of another group, denotes an acyl group as described above bonded through an oxygen linkage (-0-). e.g., RC(O)O~, wherein R is as deined in connection with the term "acyl." [0105) The term "heteroaryl" as used herein alone or as part of another group denote optionally substituted aromatic groups having at least one heteroatom in at least one ring, and preferably 5 or 6 atoms in each ring. The heteroaryl group preferably has I or 2 oxygen atoms and/or I to 4 nitrogen atoms in the ring, and is bonded to the remainder or the molecule througn a carbon. Exemplary heteroaryls include furyl, benzofuryl, oxazolyl, isoxazolyt, oxedlazolyl, benzoxazoly, benzoxadiazolyl, pyrrolyl, pyrazolyl, imidazoly, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, indolyt, isoindolyl, indoliziny, benzimidazolyl, indazolyl, benzotriazotyl, tetrazolopyridazInyl, carbazolyl, purinyl, qulnolnyl, isoquinoliny, imidazopyrldyl and the like. Exemplary substituenta include one or more of the following groups: hydrocarbyl, substituted hydrocarby, hydroxy, protected hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy. halogen, amido, amino, cyano, ketals, acetals, esters and others, [0106) The terms "hydrocarbon" and "hydrocarbyl" as used herein describe organic compounds or radicals consisting exclusively of the elements carbon and hydrogen. These moieties Include alkyl, alkenyl, alkynyl, and aryl moieties. These moieties also include alkyl. alkenyl, alkynyl, and aryl moieties substituted with other aliphatic or cyclic hydrocarbon groups, such as alkaryl, alkenaryl and alkynaryl, Unless otherwise Indicated, these moieties preferably comprise 1 to 20 carbon atoms, (0107) The "substituted hydrocarbyl" moieties described herein are hydrocarbyl moieties which are substituted with at least one atom other than carbon, including moieties in which a carbon chain atom Is substituted with a hetero atom such as nitrogen, oxygen, silicon, phosphorous, boron, 26- WO 2007/103105 PCT/US2007/005256 sulfur, or a halogen atom. These substituents include halogen, hateracyclo, alkoxy, alkenoxy, aryloxy, hydroxy, protected hydroxy, acyl, acyloxy, nitro, amino, amido, nitro, cyano, ketals, naDetls, esters and ethers. [01081 The term "hydroxy protecting group' refers to hydrocarbyl and substituted hydrocarbyl moieties which bond to an hydroxy oxygen atom in a molecule so as to protect that oxygen atom from further reaction during synthess. This protection allows reactions to occur selectively at another reaction site on the same molecule. Examples of hydroxy protecting groups include, but are not limited to, others such as methyl, t-butyl, bcnzyl, p-methoxybenzy. p-nltrobenzyl. allyl, trityl, methoxymethyl, methoxyethoxymethy, ethoxyethyl, tetrahydropyrany. tetrahydrothiopyranyi, and trialkylsllyl ethers such as trimethylsilyl ether, triethylsllyl ether, dimethylarysily ether, trilsopropysilyl ether and t-butyldimethylsilyl ether: estors such as benzoyl, acetyl, phenylacety, formyl, mono, di-, and trihaloacelyi such as chfofoacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl; and carbonates including but not limited to elkyl carbonates having from one to six carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl; isobutyl, and n pentyl; alkyl carbonates having from one to six carbon atoms and substituted with one or more halogen atoms such as 2,2,2-trichlorcethoxymethyl and 2,2,2-trichloroathyh alkenyl carbonates having from two to six carbon atoms such as vinyl and allyl; cycloalkyl carbonates have front three to six carbon atoms such as cyciopropyl, cyclobutyl, cyclopentyl and cyclohexyl; and phanyl or benzyl carbonates optionally substituted on the ring with one or more C- alkoxy, or nitro, [010 9] Having described the invention in detail, it will be apparent that modifications and variations are possible without departing the scope of the Invention defined in the appended claims. Furthermore, it should be appreciated that all examples in the present disclosure are provided as non limitIng examples. EXAMPLE [01101 In this Example, an oxycodone HCI sample was treated with a sulfur-containing compound according to the processes described herein, [01113 To a 250 ml, 3 neck round bottom lask equipped with a mechanical stirrer, N 2 inlet, and thermocouple for temperature control was added 10 g of oxycodone HCI (0,028 motes; N0.3% by wolght l4-hydroxycodelnone (14-OHOC) impLrity). Next, with mixing 100 C of deoxygenated water (10 minute N 2 purge) was added. The solution pH was adjusted to about 6 with ammonium hydroxide. Next, 5,0 g of sodium dithlonitoe (Na 2 2
O
4 ) was added. The pH was then adjusted to about 7 with concentrated ammonium hydroxide. Tho resulting mixture was stirred at 701C for about 16 hours. [ 01 12 1 After about 16 hours, the pH was adjusted to about 9 with ammonium hydroxide, precipitating the oxycodone base, The mixture was stirred for about 1 hour, and the precipitated oxycodone base was filtered, washed with water, and dried overight at 40'C under reduced pressure. 27 WO 2002/103105 PCTJUS2007005Z56 [01131 The oxycodone base sample was converted to the oxycodone HCI sat by dIssolving about 14.5 g of the oxycodone base in a 100 rm, 3 neck round bottom flask equipped with a mechanical stirrer, N 2 inlet, and thermocouple for temperature control. Next, with mixing about 29 g of HA20 and about 12.6 g of concentrated HCI was added. The resulting mixture was heated to about 65*C-75"C until substantially all was in solution, The heat was then removed, resulting In the precipitation of the oxycodone HCU salt. The precipitated mixture was stirred for about 1-3 hours at less 0hI about 1o"C arid filtered to collect the preciptated oxyaodone HCl, [0114 ] The 14-hydroxycodeinone (14-OHC) content was analyzed In the oxycodone base sample and ihe oxycodone HCI sample using an Agilent HPLC with MS Interface capability. The results are illustrated in Table 1. TABLE 1 Initial 14- Final 14-OHC content OHC content (%/ by wt.) Oxycodone base % Oxycodone HCI by wt.) {% by W.) 0.3 0.0005 0.0005 EXAMPLES 2A-2G [0115) In Examples 2A-2G, an oxycodone HCI sample was treated with a sulfur containing compound according to the processes described herein. The treatment was performed at various temperatures, times of reaction, concentration of reactants, and pH. EXAMPLE 2A [0116) To a 100 ml, 3 neck round bottom flask equipped with a mechanical stirrer, N 2 inlet, and thermocouple for temperature control was added 9.2 g of wet oxycodone HCI (0.02 moles; 0,13% by weight 14-hydroxycodoinone (14-01-C) impurity). Next, with mixing 36.2 g of H 2 0 and 40.3 o of 6 wt. % S0 2 1H 2 0 solution was added, The resulting mixture was heated to about 30'C and the solution pH was adjusted to about 6 with ammonium hydroxide. The mixture was stirred for about 3 hours. The pH of the mixture was then adjusted tr about 8.8-9.8 with concentrated ammonium hydroxide and stirred for about 30 minutes. The precipitated oxycodone base was then filtered from the mother liquor, washed with about 25.73 g of H20, and dried. The 14-hydroxycodelnone content (14-OHC) in the oxycodone base was then measured as described in the preceding Example. [0117) The experiment was repeated using identical reagents, amounts thereof, and conditions to form the oxycodone base sample. This oxycodone base sample was converted to the oxycodone HCI salt as described in the preceding example, The 14-hydroxycodeinone content (14 OHC) in the oxycodone base sample and the oxycodone HCI sample were then measured. [0118) Results and reaction condItlons for this experiment are Illustrated In Table 2, 28 WO 2007/103195 PCT/US2007/0052 5 6 TABLE 2 Initial Final 14-HC content Concentration Molar 144 eRatio of OH xcooeOxcdn Trial Temperadure Time pH (g H 2 0 per g so 2 to OHC Oxycdone Oxycodne ("C) (hr.) Oxycodone Oxycodane content base (% by HCI (% by HCl) HC b wt,) wt.) 1 30 $ 6 10.2 1 8A 0.13 0.0007 Not tested 2 30 3 6 10.2 1.1:1 013 0.0007 0,0007 ExAMPLE 2B [0119] This Example was performed according to the process described in Example 2A. However, In this Example 9.4 g of wet oxycodone HCI (0,02 moles; 0.13% by weight 141iydiroxycoduirono (I1 ONC) impurity) was mixed with about 34,6 g of HO- and about 27 4 a of R wt. '%a SO/iH;20 solution. The mixture was heated to about 50*C. Next, the pH was adjusted to about 7 using ammonium hydroxide. [0120) The resulting mixture was allowed to react for either 1 hour or 8 hours. At the end of the desired reaction time, the solution was adjusted to a pH of 8.8-9.8 with about 2.0 g of concentrated ammonium hydroxide and stirred for about 30 minutes. The solids were filtered and washed with about 28.0 g of H 2 0 and dried. The 14-hydroxycodelnune (14-OHC) content In the resulting oxycodone base was measured, as was the 14-hydroxycodel none (I4-OHC) content in the oxycodone HI sait formed according to the method descrOed in the preceding example. The wtiuitb and reaction conditions in the various trials are illustrated in Table 3. TABLE 3 initial Final 14-O H C content Concentraon Molar 14 Trial Temperature TmeP (g Hv0 per g so o OHC Oxycodone Oxycodone (hr.) Oxycodone Oxycodone content base (% by HC (% by HCI) H CI (% by wl.) wt.) wt) _ 3 so 1 7 8.2 1.2;1 0,13 None None detected detected 4 50 5 7 8.2 1,2:1 0.13 0.00005 0.0005 EXAMPLE 20 [0121] This Example was performed according to the process described in Example 2A. However, In this Example 9.1 g of wet oxycodone HCt (0,02 moles; 0.13-0,14% by weight 14-hydroxycodeinone (14-OHC) Impurity) was mixed with about 7.0 g of H 2 0 and about 52.8 g of 6 29 WO 2007103105 PCT/US200'/005256 wt. % S0 2 /H0 solution. The mixture was heated to either 10*0 or 50'O, Next, the pH was adjusted to 7 using anmonium hydroxide. [0122 } The resulting mixture was allowed to react for either 1 hour or 5 hours. At the end of the desired reaction time, the solution was adjusted to a pH of 8.8-9.8 with about 2.0-2.5 g of concentrated ammonium hydroxide and stirred for about 30 minutes. The solids were filtered and washed with about 2809 of H20 and dried. The 14-hydroxycodeinone (14-OHC) content In the resulting oxycodone base was measured, as was the 14-hydroxycodeinone (14-OHC) content in the oxycodone HUl salt formed by the method described in the preceding example. The results and reaction conditions in the various trials are illustrated in Table 4. TABLE 4 Initial Final 14-OHC content Concentration Molar 14 Temperature Time (g perg Ratio of 0 xyc Trial TeprtueTm pH g9 H20 per g SO2 to HC Oxycodone Oxycodlone *C) {hr.) Oxycodone reyenrOne content base(% by HCi (% by MCI) Hl (%by wt) wt.) 5 50 1 7 8.2 2.4:1 0.13 None 0,0006 detected 6 50 5 7 a,2 2.4:1 0.13 0.00015 0.0004 7 10 5 7 8.2 2A:1 0.14 0.001 Not tested EXAMPLE 20 [0123) This Example was performed according to the process described in Example 2A. However, in this Example 9.52 g of wet oxycodone HCI (0.02 moles: 0.13% by weight 14-hydro xycodelnone (14-OHC) impurity) was mixed with about 72.24 9 of H20 and about 27.76 9 of 6 wt, % SO,/H1-2O solution. The mixture was heated to about 500C, Next, the pH was adjusted to about 7 using ammonium hydroxide. [0124 J 'rhe resulting mixture was allowed to react for either 1 hour or 5 hours. At the end of the desire rc n liumm , the sututiun wets adjusted to a pH of 6,0-0.0 with about 2.0-2. g of concentrated ammonium hydroxide and stirred for about 30 minutes. The solids were Filtered and washed with about 28.0 g of H20 and dried. The 14-hydroxycodeinone (14-OHC) content in the resultng oxycodone base was measured, as was the 14-hydroxycodelnone (14-OHC) content in the oxycodone HC salt formed by the method described in the preceding example, The results and reaction conditions in the various trials are illustrated in Table 5. 30 WO 2007/103105 PCT/US2007/005256 TABLE S Initial Final 14-OHO content Concentration Mar 14 Ratio of 1 Trial Temperature Time pH (g HZO per 9 S02 to Oxycodone Oxycodone (C) (hr.) Oxycodone oxycodone content base (% by HCI (% by HGl) HCl (%1otby wt.) wt.) w w.) a 5o r 31 1.2:1 0.13 0,0002 0.0003 9 50 5 7 13.1 1.2:1 0.13 None 0.0004 detected ExAMPLE 2E [0125] This Example was performed according to the process described in Example 2A. However. In this Example 9.5 q of wet oxycodone HCI (0.02 moles; 0.13-0.14 % by weight 14-hydroxycodeinone (14-OHC) impurity) was mixed with about 39.7 g of 420 and about 55.6 g of 6 wt % SOz/H 2 0 solution. The mixture was heated to either 10*C or 50*C. Next, the pH was adjusted to about 7 using ammonium hydroxide. [ 012 6) The resulting mixture was allowed to react for either 1 hour or 5 hours. At the end of the desired reaction time, the solution was adjusted to a pH of 8.8-0.8 with about 2.0-2.5 j of concentrated ammonium hydroxide and stirred for about 30 minutes. The solids were filtered and washed with about 30.6 g of H 2 0 and dried. The 14-hydroxycodeinone (14-OHC) content in the rcoulting oxycodono booo woo moascurod, ca was the 14--hydroxycodeinne (1 4-OHC) content in the oxycodone MCI salt formed by the method described in the preceding example, The results and reaction conditions in the various trials are illustrated in Table 6, TABLE 6 initial Final 14-OHC content Concentration Maler 1 Ratio of 4 Trial Temperature Time pH (0 H2O per g S02 to OHC Oxycodone Oxycodone (*C) (hr.) Oxycodone Oxycodone content base(% by HOt (% by HCt) H wt) wt) wt.) 10 50 1 7 12.3 2.4:1 0.13 None 0.0004 detected 11 so 5 7 12.3 2.4:1 0.13 None 0.0004 detected 12 10 5 7 12.3 2.4:1 0.13 0.0008 Not listed 31 WO 2007/103105 PC'T/US2007/005256 EXAMPLE 2F t01271 To a 22 L, 3 neck round bottom fiask equipped with a mechanical stirrer, N 2 inlet, and thermocouple for temperature control was added 1840 g of wet oxycodone HCI (4.27 moles: 0.13% by weight 14-hydroxycodeinone (14-OHC) impurity). Next, with mixing 2706 g of H20 and 7717 g of 6.4 wt % S02/1120 solution was added, The resulting mixture was heated to about 40"C and the solution p11 was adjusted to about 7 using concentrated ammonium hydroxide, The mixture was stirred for about 5 hours. [01283 After about 5 hours, the solution was adjusted to a pH of about 1.7 with the addition of 293.0 g concentrated sulfuric acid (96-98%), The pressure was slowly reduced to about 0.20 atm to facilitate the distilation/removal of unreacted 02. As the distillation progressed, 23.4 g of concentrated sulfuric acid was added as the pressure was decreased to about 0.11 atm and the solution temperature was increased to about 50-55C. [0129] The solution was then cooled to about 30C and the solution pH adjusted to bout 0.5-10 with c.oncentrated atmmonlum hydroxide. The solution was stirred for about 30 minutes and filtered, The solids were filtered and washed with about 2000 g of H20 and dried. The 14-hydroxycodeinone (14-01HC) content in the resulting oxycodone base was measured, as was the 14-hydroxycodelnone (14-OHC) content in the oxycodone HC1 salt formed by the method described In the preceding example. The results and reaction conditions are illustrated in Table 7. TABLE 7 Initial Final 14-HC content Concentration Molar Trial Temperature Tim PH (g H20 per g SO to OH Q Oxycodone Oxycodone (hr.) Oxycodone Oxycodone bnt base (% by HCI (% by HCI) HCI M b w) wt.) wt.) 13 40 5 7 6.6 1,8:1 ] 0.13 0.0001 0.0005 EXAMPLE 2G [0130] To a 50 ml, 3 neck round bottom flask equipped with a mechanIcal sUrrer, N 2 Inlet, and thermocouple for temperature control was added 3.33 g of oxycodone HCI (0.0095 moles; 0.2% by weight 14-hydroxycodelnone (14-OHC) Impurity). Next, with mixing 33.3 g of H20 and 0.83 g of sodium bisulfite was added, The resulting mixture was heated to about 30'C and the solution pH was adjusted to about 7 with ammonium hydroxide. The mixture was stirred for about 15 hours. The pH of the mixture was then adjusted to about 8,8-9.8 with concentrated ammoniurn hydroxide and stirred for about 60 minutes. The precipitated oxycodone base was then filtered from tho mother liquor, washed with about 10,0 9 of H2O, and dried, The 14-hydroxycodeinone (14-OHC) content in the resulting oxycodone base was measured, as was the 14-hydroxycodeinone (14-0HC) content In 32 WO 2007/103105 PCT/US2O07/U05256 the oxycodone HCI salt formed by the method described in the preceding example. The results and reaction conditions in the various trials are illustrated in Table 8. TABLE 8 Initial Final 14-01-IC content Concentration Mo 14 Til Temperature Time pIi (R OOHC () 502 to OHC Oxycodono osynodone (*C) (hr.) Oxycodone O xycodone content base (% by HI (%by 1-C)MI (% by bs yHI(,b HCw) HC w wt.) 14 30 15 7 10 0,84:1 0,2 0.0004 0.0004 EXAMPJ1U [0131] In this Example, an oxymorplone HC sample was treated with a sulfur containing compound according to Lho proccoos docoribod herein. [0132] To a 250 ml, 3 neck round bottom flask equipped with a mechanical stirrer, N 2 inlet, and thermocouple for temperature control was added 150 g H 2 0 and 15 g oxymorphone HCI sample (0.044 moles; 0.3-0,5% by weight 14-hydroxymorphinone (14-OHM) impurity). Next, 7.5 g of sodium bisulfite (NaHSO 2 ) was added, The pH was then adjusted to about 7 with concentrated ammonium hydroxide, and the resulting mixture was stirred at 23*C for about 16 hours, [ 0133) After about 16 hours, the pH was adjusted to about 8,8-9.8 with ammonium hydroxide and the solution was cooled to about 20'C. The precipitated oxymorpione base was filtered, washed with water (about 45 g), and dried for 4 hours at 65*C. (0134 3 The oixymorphone base sample was analyzed using the methods described above, and the sample contained no detectable amount of 14-hydroxymorphinone or 14 hydroxycodelnone. This experiment was repeated using a B wt. % S02/120 solution in place of sodium bisulfite and similar results were obtained. EX AMPLE 4 '01351 In thick Example, oxycodone base wit treated with a thiol nccnrdirln to the processes described herein. [0136) To a 25 ml, 3 neck round bottom flask equipped with a mechanical stirrer, N 2 Inlet, and thermocouple for temperature control was added 3.0 g oxycodone base (0.01 moles; 0.3 0.5% by weight 14-hydroxycodeinone (14-OHC) impurity). Next, 18 g of chloroform was added, and the mixture was stirred at 70'C until the oxycodone base was dissolved. After the mixture was substantially homogenous, 1.5 g of benzenethol was added to the mixture with stirring. 33 WO 2007/103105 PCT/US2007/005256 t01373 After about 10 hours, a sample was analyzed using the methods described In the preceding examples. HPLO area percent analysis indicated a 14-hydroxycodeinone level of less than about 0.0022%. 34

权利要求:
Claims (10)
[1] 1. A process for the preparation of a morphinan-6-one product, the process comprising: providing a morphinan product produced from a conventional morphinan processing method, wherein said product comprises a morphinan-6-one compound and less than 2% by 5 weight of an a,p-unsaturated ketone compound; forming a reaction mixture comprising said morphinan product; treating the reaction mixture with a sulfur-containing compound to reduce the concentration of the a,p-unsaturated ketone compound in the reaction mixture, wherein the sulfur-containing compound is a sulfur-containing inorganic acid or salt thereof, 10 wherein the sulfur-containing inorganic acid is selected from the group consisting of sulfurous acid (H 2 SO 3 ); dithionous acid (H 2 S 2 0 4 ); disulfurous acid (H 2 S 2 0 5 ); salts thereof; and combinations thereof; and recovering the morphinan-6-one compound to produce the morphinan-6-one product; wherein the morphinan-6-one compound is recovered from the reaction mixture 15 without the use of an organic solvent; wherein the morphinan-6-one compound corresponds to Formula (2): R2 Ra3 R1 X R 1 4 200 (2) the a,p-unsaturated ketone compound corresponds to Formula (3): 25 35 R 2 R 3 R 1 O Ra (3) X is -N(R 1 7 )- or -N*(R1 7 aR1 7 b)-; 5 R1 and R 2 are independently selected from hydrogen, substituted and unsubstituted acyl, acyloxy, alkenyl, alkoxy, alkoxyaryl, alkyl, alkylamino, alkynyl, amino, aryl, arylalkoxy, carboalkoxy, carbonyl, carboxyalkenyl, carboxyalkyl, carboxyl, cyano, cyanoalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylether, halo, haloalkoxy, haloalkyl, heteroaryl, heterocyclic, hydroxyalkyl, hydroxyl, or nitro; 10 R 3 is hydrogen, hydroxy, protected hydroxy, alkoxy, or acyloxy; R 10 is hydrogen, hydroxy, protected hydroxy, halo, keto, tosyl, mesyl, or trifluoromesyl; R 14 is hydrogen, hydroxy, or protected hydroxy; R 1 7 is hydrogen, alkyl, cycloalkyl, alkylcarboxy, alkylenecycloalkyl, alkoxycarbonyl, 15 allyl, alkenyl, acyl, aryl, formyl, formyl ester, formamide, benzyl, or an amino protecting group; R1 7 a and R17b are independently selected from hydrogen, alkyl, alkenyl, allyl, cycloalkyl, aryl, or benzylyl, and the morphinan-6-one product comprises less than about 0.1% (by weight morphinan-6 20 one product) of the a,p-unsaturated ketone compound.
[2] 2. The process as set forth in claim 1 wherein at least one of the following conditions are present: (i) the molar ratio of sulfur-containing compound to morphinan-6-one compound in the 25 reaction mixture is from about 0.5:1 to about 3.0:1; (ii) the reaction mixture is treated with the sulfur-containing compound for at least about 1 hour; or 36 (iii) the reaction mixture is treated with the sulfur-containing compound at a temperature greater than room temperature.
[3] 3. The process as set forth in any one of claims 1-2 wherein the salt is selected from the group 5 consisting of alkali metal salts, alkaline earth metal salts, ammonium salt (NH 4 ), and quaternary ammonium salts.
[4] 4. The process as set forth in any one of claims 1-3 wherein the molar ratio of sulfur containing compound to morphinan-6-one compound in the reaction mixture is from 0.5:1 to 10 3.0:1.
[5] 5. The process as set forth in any one of claims 1-4 wherein the morphinan-6-one product comprises less than 0.05% (by weight morphinan-6-one product) of an a,p-unsaturated ketone compound. 15
[6] 6. The process as set forth in any one of claims 1-5 wherein the morphinan-6-one product comprises no detectable amount of an a,p-unsaturated ketone compound.
[7] 7. The process as set forth in any one of claims 1-6 wherein after treatment of the reaction 20 mixture with the sulfur-containing compound a residual sulfur-containing species is substantially removed from the reaction mixture.
[8] 8. The process as set forth in any one of claims 1-7 wherein the reaction mixture has a pH of from 3 to 9. 25
[9] 9. The process as set forth in any of claims 1-8, wherein the morphinan-6-one product is of pharmaceutical relevance.
[10] 10. A morphinan-6-one product prepared by the process as set forth in any of claims 1-9. 30 37

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CA2395774C|2009-09-15|New polymorphic forms of olanzapine

---

AU2009260875B2|2014-07-10|Methods of synthesis of morphinans

---

US20220079938A1|2022-03-17|Processes for preparing morphinan-6-one products with low levels of alpha, beta-unsaturated ketone compounds

---

EP0242417A1|1987-10-28|Morphinane-skeletoned hydrazone derivatives, process for preparing them, pharmaceutical composition and use

---

GB2246778A|1992-02-12|Propylamine derivatives

---

WO2013159283A1|2013-10-31|Method for preparing |-oxiracetam

---

DK171695B1|1997-03-17|14-Hydroxydihydromorphinone derivatives, their preparation, pharmaceutical preparations thereof, and their use for producing an analgesic medicament

---

US2946797A|1960-07-26|N-aminotetrahydroisoquinolinium salts

---

JP2917497B2|1999-07-12|Method for producing optically active 1,2-propanediamine

---

Borowitz et al.1975|The preparation and synthetic utility of O‐substituted normethylmorphines

---

KR890003843B1|1989-10-05|Process for producing the double sulfate of desoxyfructosyl serotonin and creatinine

---

Ötvös et al.1995|Synthesis of high specific activity [15, 16‐3H2] buprenorphine

---

Manda et al.1992|Opioid receptor antagonist affinity ligands: 6β-bromoacetamido-6-desoxynaltrexone and 6β-thioglycolamido-6-desoxynaltrexone

---

Zhou1993|Fundamental practicum: A naphthalene cyclophane as a selective enolate anion receptor

同族专利:

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公开号 | 公开日

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AU2013205836B2|2015-12-10|

引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
2016-04-07| FGA| Letters patent sealed or granted (standard patent)|

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2018-01-18| PC| Assignment registered|Owner name: SPECGX LLC Free format text: FORMER OWNER(S): MALLINCKRODT LLC |

优先权:

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申请号 | 申请日 | 专利标题

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US60/778,258||2006-03-02||

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AU2007224221A|AU2007224221B2|2006-03-02|2007-03-02|Processes for preparing morphinan-6-one products with low levels of alpha, beta-unsaturated ketone compounds|

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AU2013205836A|AU2013205836B2|2006-03-02|2013-05-13|Processes for preparing morphinan-6-one products with low levels of alpha, beta-unsaturated ketone compounds|AU2013205836A| AU2013205836B2|2006-03-02|2013-05-13|Processes for preparing morphinan-6-one products with low levels of alpha, beta-unsaturated ketone compounds|