(19) TZZ ¥ ZZ_T

(11) EP 2 328 900 B1

(12) EUROPEAN PATENT SPECIFICATION

(45) Date of publication and mention (51) Int Cl.: C07D 489/08 (2006.01) C07D 489/02 (2006.01) of the grant of the patent: B01J 23/42 (2006.01) 28.08.2013 Bulletin 2013/35 (86) International application number: (21) Application number: 09806216.9 PCT/AU2009/000925

(22) Date of filing: 21.07.2009 (87) International publication number: WO 2010/017573 (18.02.2010 Gazette 2010/07)

(54) PROCESS FOR MAKING MORPHINAN-6 alpha-OLS VERFAHREN ZUR HERSTELLUNG VON MORPHINAN-6 alpha-OLS PROCÉDÉ DE FABRICATION DE MORPHINAN-6 alpha -OLS

(84) Designated Contracting States: (74) Representative: Almond-Martin, Carol et al AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Ernest Gutmann - Yves Plasseraud S.A.S. HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL 88, Boulevard des Belges PT RO SE SI SK SM TR 69452 Lyon Cedex 06 (FR) Designated Extension States: AL BA RS (56) References cited: WO-A1-2008/137672 WO-A1-2010/121369 (30) Priority: 11.08.2008 US 188574 P US-A- 3 830 819

(43) Date of publication of application: • UWAI K ET AL: "Synthesis and receptor- binding 08.06.2011 Bulletin 2011/23 studies of derivatives of the opioid antagonist naltrexone", BIOORGANIC & MEDICINAL (73) Proprietor: Tasmanian Alkaloids Pty. Ltd. CHEMISTRY, PERGAMON, GB, vol. 12, 1 January Westbury, TAS 7303 (AU) 2004 (2004-01-01), pages 417-421, XP002488979, ISSN: 0968-0896, DOI: 10.1016/J.BMC. (72) Inventors: 2003.10.039 • BAILEY, Timothy S. • GOTO, K.: ’Formation of (+) Dihydrocodeine and Blackstone Heights (+)Dihydromorphine from Sinomenine.’ Tasmania 7259 (AU) PROCEEDINGS OF THE IMPERIAL ACADEMY • REZAIE, Robert (TOKYO). vol. 16, 1940, pages 403 - 4, Prospect XP008144789 Tas 7250 (AU) • GOTO, K. ET AL.: ’(+)-Dihydrocodein und (+) Dihydromorphin aus Sinomenin.’ JUSTUS LIEBIGS ANNALEN DER CHEMIE. vol. 547, 1941, pages 194 - 200, XP002607494

Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 328 900 B1

Printed by Jouve, 75001 PARIS (FR) EP 2 328 900 B1

Description

FIELD OF THE INVENTION

5 [0001] This invention relates to a process for the manufacture of morphinan-6α-ols stereospecifically and in high chemical yield by catalytic hydrogenation of the corresponding morphinan- 6-ones under alkaline conditions.

BACKGROUND OF THE INVENTION

10 [0002] Morphinan-6α-ols, including such compounds as dihydrocodeine, oxymorphol, oxycodol and nalbuphine are important morphine derivatives due to their behaviour as potent analgesics or antagonists. Some prior synthetic routes to these compounds include;

• from codeine or morphine, where the 6α- stereochemistry of the 6-hydroxy morphinan was already fixed by the 15 stereo-chemistry of the natural product (see for example US 6887999 for the hydrogenation of codeine to dihydroc- odeine), • Reduction of the 7,8-didehydro derivatives morphinan-6-ones using metal hydride reducing agents (e.g. sodium borohydride, lithium tri-sec-butyl borohydride) followed by hydrogenation to give the pure 6α- isomer of the corre- sponding morphinan-6-ol. (Sargent et al., "Hydroxylated codeine derivatives", Journal of Organic Chemistry, 23, 20 1247 - 1251, (1958), and A.C. Currie et al., J. Chem. Soc., 1960, 773.) This strategy was also used to convert 14- hydroxynormorphinones preferably to the 6α-epimer of the corresponding 14-hydroxydihydromorphine (preferably N-O3-bis(ethoxycarbonyl)-14-hydroxynormorphinone to N- O3-bis(ethoxycarbonyl)-14-hydroxydihydronormorphine; Kavka, "Preparation of nalbuphine having low levels of β-epimer", US 5756745). Similarly, Cheng et al. converted methoxymethyl-protected naloxone to the corresponding 6- α epimer using potassium and sodium tri- sec-butylboro- 25 hydride (Na and K-selectride respectively), sodium triethylborohydride and sodium triacetoxyborohydride in high chemical yield and > 99% selectivity for the α-epimer (Stereoselective reduction of a morphinone, WO 2007/121114). US Patent Nos. 5,208,338 and 5,336,483 describe the preparation of radiolabeled N-substituted-6-iodo-3, 14-dihy- droxy-4,5-α-epoxymorphinans (Scheme 4) which includes the selective reduction of the 6-carbonyl group using K-selectride, specifically described for the synthesis of 6 α-naltrexol from naltrexone. TLC measurements indicated 30 the absence of the epimeric 6β-isomer. • By contrast, reduction of oxymorphone (the morphinan- 6-one saturated at the 7,8 position) using sodium borohydride promoted formation of the 6α morphinan-6-ol contaminated with significant amounts of the 6β isomer. (Burke and Rice., "Probes for narcotic receptor mediated phenomena. 11. Synthesis of 17-methyl-and 17-cyclopropylmethyl- 3,14-dihydroxy-4,5α-epoxy-6β-fluoromorphinans (FOXY and CYCLOFOXY) as models of opioid ligands suitable 35 for positron emission transaxial tomography." Heterocycles, 23, 1985, 99 - 106.) • Similarly, lithium aluminum hydride or sodium borohydride reduction of 8,14-dihydroxydihydrocodeinone (oxyco- done) leads to epimeric dihydroxydihydrocodeines (oxycodols) (Sargent et al., "Hydroxylated codeine derivatives", Journal of Organic Chemistry, 23, 1247 - 1251, (1958)). • Similarly, reduction of naltrexone with either sodium borohydride in tetrahydrofuran or lithium tri- sec-butylborohydride 40 in tetrahydrofuran at -78°C gave α6-naltrexol contaminated with traces of the 6β epimer. (Brine et al., "Ring C conformation of 6β-naltrexol and 6α-naltrexol. Evidence from Proton and Carbon- 13 nuclear magnetic resonance." Journal of Organic Chemistry, 41, (1976) 3445 - 3448.) • Other literature report the reduction of naltrexone to 6α-naltrexol, e.g. L.D. Olsen et al., J. Med. Chem., 1990, 33, 737-741 or the reduction of 3 -O-tert-butyldimethylsilyl protected naltrexone to the corresponding alpha isomer (G.A. 45 Brine et al., J. Org. Chem., 1976, 41(21), 3445-3448) by using L-selectride in THF at -78°C. Traces of the beta isomer formed during the reduction were removed by chromatography or recrystallization.

[0003] The main drawbacks of the aforementioned procedures from the literature are low selectivities of the reductions (formation of 5-10% beta-isomer) resulting in a tedious procedure for the removal of the contaminant. Such removal 50 requires either several recrystallizations giving an unacceptable loss of yield or a purification by column chromatography, which is not a commercially viable procedure. In case of the preparation of 6α-naltrexol from naltrexone, L-selectride was used as reducing agent at very low temperatures of -78°C, or 3- O-tert-butyldimethylsilyl protected naltrexone was used, making the process more complicated and expensive due to the need for special refrigerating equipment and/or expensive protecting groups. 55 [0004] In contrast to the metal hydride reducing agents traditionally used for the reduction of ketones to alcohols, hydrogenation does not require very low temperatures, or prior protection of thehydroxy 3- group, followed by de- protection to the desired 3-hydroxy-6α-morphinol and is operationally simpler and creates little or no waste during the processing. Few examples exist for the hydrogenation of the ketone group of morphinan- 6-ones.

2 EP 2 328 900 B1

• Hydrogenation of dihydrohydroxycodeinone (also known as oxycodone) in 10% aqueous acetic acid as solvent and platinum oxide as catalyst gave a mixture of 6α- and 6β- epimers of oxycodol with the 6α- epimer being the major product (Lutz R.E., and Small L., "Reduction studies in the morphine series. X. Hydroxycodeinone." Journal of Organic Chemistry, 4, 220 - 233, (1939)). In this solvent mixture the reaction clearly was not stereo- selective. 5 • There is only one example of a hydrogenation of a morphinan- 6-one to a morphinan- 6-ol. Hydrocodone was hydro- genated in ethanol as solvent using platinum oxide as catalyst (Grew and Powles, "Manufacture of 1- Dihydrocodeine" US 3830819). The epimeric purity of the morphin-6-ol product was not mentioned in this example.

[0005] There remains a need for an efficient stereo- selective and environmentally friendly route to the pure 6 α-epimer 10 of morphinan-6-ols, particularly 14-hydroxymorphinan-ols. Increasingly, morphinan-6-ones and 14-hydroxymorphinan- 6-ones are being used as intermediates in the synthesis of the corresponding morphinan- 6-ols because they are available conveniently and in high yield from opiate raw materials thebaine and oripavine, both of which became commercially available in large quantities only relatively recently.

15 SUMMARY OF THE INVENTION

[0006] In one aspect of the invention there is provided a process for producing a morphinan- 6α-ol compound of formula (IIa)

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and pharmaceutically acceptable salts thereof, 35 comprising hydrogenating a morphinan-6-one compound of formula (I)

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50 in an aqueous solvent and a water soluble base wherein the aqueous solvent is selected from the group consisting of water and a mixture of water and a water-miscible co-solvent in the presence of a catalyst wherein said catalyst is platinum or platinum oxide at a pH between about 11 and about 14, more preferably, between about 12.0 and about 13.5) toprovide the compoundof formula (IIa)having less than one percent of a morphinan- 6β-olcompound offormula (IIb) 55

3 EP 2 328 900 B1

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15 wherein 1 R is selected from hydrogen, C 1-C10 alkyl, C 3-C6 cycloalkylC1 - C 10 alkyl, -C (O)-C1-C10alkyl or -C(O)-OC1-C10alkyl; and 2 3 3 3 R is selected from H, OR or OC(O)R wherein R is selected from hydrogen or C 1-C10 alkyl. [0007] One embodiment of the present invention is the process wherein the catalyst is platinum; preferably, platinum 20 oxide. [0008] Another embodiment of the invention is the process wherein R 1 is selected from H, 1 [0009] C1 - C6 alkyl, or C3-C6 cycloalkylC1 - C6 alkyl. Preferably, R is selected from hydrogen, methyl, ethyl, propyl,

25

30 [0010] Illustrative of the invention is the process wherein the amount of the morphinan-6β-ol compound of formula (IIb) is less than 0.5 per cent, preferably, less than 0.20%, more preferably, less than 0.10% and most preferably, less than 0.05%. [0011] Exemplifying the invention is the process wherein the compound of formula (I) is selected from the group consisting of hydromorphone, oxymorphone, norhydromorphone, noroxymorphone, naltrexone and nalbuphone. 35 [0012] Illustrating the invention is the process wherein the compound of formula (IIa) is selected from the group consisting of 6α-7,8-dihydromorphine, 6α-oxymorphol, 6α-norhydromorphol, 6α-noroxymorphol, 6α-naltrexol and 6α- nalbuphine. In a preferred embodiment, the compound of formula (IIa) is α6-noroxymorphol or 6α-nalbuphine, most preferably, 6α-nalbuphine. [0013] Further exemplifying the invention is the process wherein the hydrogenation is performed with a hydrogen 40 donor selected from the group consisting of hydrogen gas, formic acid, sodium hypophosphite, and combinations thereof. Preferably, the hydrogen donor is hydrogen gas. [0014] An illustration of the invention is the process wherein the aqueous solvent is water or water mixed with a water-

miscible co-solvent selected from a C1 to C4 alcohol, dimethylformamide, dimethylacetamide, N-methylpyrrolidone or tetrahydrofuran. Preferably, the aqueous solvent is water or water mixed with a C1 to C4 alcohol, most preferably, the 45 aqueous solvent is water or water mixed with 2- propanol. [0015] Another illustration of the invention is the process wherein the water soluble base is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, caesium hydroxide or ammonium hydroxide. Preferably, the base is selected from sodium hydroxide or potassium hydroxide. [0016] Further illustrating the invention is the process wherein the compound of formula (IIa) is α6-noroxymorphol 50 which further comprises the step of reacting the 6 α-noroxymorphol with 3-bromo-1-propene to provide 6α-naloxol. This process for making 6α-naloxol may further comprise the step of isolating the 6α-naloxol. [0017] It is also described a process for preparing 6 α-naloxol of formula III

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4 EP 2 328 900 B1

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15 and pharmaceutically acceptable salts thereof, comprising hydrogenating a compound of formula (Ia)

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in an aqueous solvent and a water soluble base wherein the aqueous solvent is selected from the group consisting of water and a mixture of water and a water-miscible co-solvent in the presence of a catalyst at a pH between about 8.5 and about 14 (preferably, between about 11 and about 14, more preferably, between about 12.0 and about 13.5) to 35 provide a compound of formula (IIc) having less than one percent (preferably less than 0.5 per cent, more preferably, less than 0.20%, still more preferably, less than 0.10% and most preferably, less than 0.05%) of a morphinan-6β-ol compound of formula (IId)

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50 and reacting the compound IIc with 3-bromo-1-propene to provide 6α-naloxol of formula III. [0018] Further illustrating the invention is the process for making 6 α-naloxol wherein the catalyst is platinum. Preferably, the catalyst is platinum oxide. [0019] An illustration of the invention is the process for making 6α-naloxol wherein the hydrogenation is performed 55 with a hydrogen donor selected from the group consisting of hydrogen gas, formic acid, sodium hypophosphite, and combinations thereof. Preferably, the hydrogen donor is hydrogen gas. [0020] An example of the invention is the process for making 6 α-naloxol wherein the aqueous solvent is water or water mixed with a water-miscible co-solvent selected from a C1 to C4 alcohol, dimethylformamide, dimethylacetamide, N-

5 EP 2 328 900 B1

methylpyrrolidone or tetrahydrofuran. Preferably, the aqueous solvent is water or water mixed with a C1 to C4 alcohol, most preferably, the aqueous solvent is water or water mixed with 2-propanol. [0021] Another example of the invention is the process for makingα 6-naloxol wherein the water soluble base is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, caesium hydroxide or ammonium hydroxide. 5 Preferably, the water soluble base is selected from sodium hydroxide or potassium hydroxide.

DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION

[0022] The present invention provides a method for the conversion of a morphinan- 6-one to a morphinan- 6-ol wherein 10 the 6α-epimer of the morphinan-6-ol is produced with only very small amount of the 6β-epimer present as an impurity as shown in Scheme 1, wherein R 1 and R2 are as defined herein.

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[0023] Thus, the present invention is directed to a method of producing a morphinan- 6α-ol compound of formula (IIa)

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and pharmaceutically acceptable salts thereof, 45 comprising hydrogenating a morphinan-6-one compound of formula (I)

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55

6 EP 2 328 900 B1

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15 in an aqueous solvent and a water soluble base wherein the aqueous solvent is selected from the group consisting of water and a mixture of water and a water-miscible co-solvent in the presence of a catalyst wherein said catalyst is platinum or platinum oxide at a pH between about 11 and about 14 to provide the compound of formula (IIa) having less than one percent of a morphinan-6β-ol compound of formula (IIb)

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35 wherein 1 R is selected from hydrogen, C1-C10 alkyl, C3-C6 cycloalkylC1 - C10 alkyl (e.g., cyclopropylmethyl, cyclobutylmethyl), -C(O)-C1-C10alkyl or -C(O)-OC1-C10alkyl; preferably R1 is selected from hydrogen, methyl,

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45 or

50

; and 55 2 3 3 3 R is selected from H, OR or OC(O)R wherein R is selected from hydrogen or C 1-C10 alkyl. [0024] In accordance with the present invention, the conversion of a morphinan-6-one to a morphinan-6-ol can be achieved in a number of ways. The morphinan-6-one, particularly 3-hydroxymorphinan-6-ones can be dissolved in aqueous base at temperatures from about 0 to about 100°C. The solvent of choice is water either alone or mixed with

7 EP 2 328 900 B1

any water miscible co-solvent inert to hydrogenation and readily apparent to one of ordinary skill in the art. Examples of water miscible co-solvents which can be used in the process of the present invention include, but are not limited to, C1 to C4 alcohols, dimethylformamide (DMF), dimethylacetamide, N-methylpyrrolidone, and tetrahydrofuran, with the preferred co-solvent being a C1 to C4 alcohol, most preferably, 2-propanol. 5 [0025] The base can be chosen from the Group 1 metal (lithium, sodium, potassium, cesium) hydroxides or ammonium hydroxide, preferably sodium hydroxide or potassium hydroxide. The pH of the reaction mixture may be maintained at from pH about 8.5 to about 14. In a preferred embodiment, the pH is maintained at a pH between about 11 and about 14, preferably, between about 12.0 and about 13.5, more preferably, between about 12.5 and about 13.5. [0026] Suitable hydrogenation reagents are well known to those skilled in the art and typically include a hydrogenation 10 catalyst and either hydrogen or a hydrogen transfer reagent such as sodium hypophosphite. Preferred hydrogenation catalysts are metal catalysts such as nickel, palladium, rhodium, or platinum either alone or dispersed on a support such as carbon or barium sulfate. The preferred catalyst is unsupported platinum oxide at a weight/ weight (w/w) ratio relative to the 3- hydroxymorphinan-6-one from about 0.01% to about 10%, preferably about 1% w/w. In a preferred embodiment, hydrogen is then passed through the mixture at about 5 psi (80 kPa) or more. The hydrogenation step is carried out at 15 a temperature from about 0 to about 100°C, preferably ambient temperature (25°C). The temperature should be sufficient to dissolve the solids in the mixture, thereby providing a solution. The mixture is exposed to the hydrogenation reagents for at least about 1 hour and up to about 24 hours, preferably from about 3 to about 10 hours. [0027] Upon completion, hydrogenation catalysts may be removed by filtration. If precious metal catalysts are used in the hydrogenation step, it is possible that unacceptable levels of metals remain in the final product (desirably, the 20 level of heavy metals in the final product is < 20 ppm). In one embodiment of the present invention, the solution of morphinan-6α-ol is subjected to a further process wherein the mixture is subjected to an activated carbon treatment. Suitably the mixture is stirred with activated carbon from about 15 minutes to about 5 hours at ambient temperature to about 100°C, preferably at about 50 to about 70°C. The hot mixture is then filtered to remove the carbon. Adjusting the pH to about 8.0 to about 10, preferably about 8.5 to about 10, more preferably, to about 10, and cooling the mixture to 25 crystallize the product. The product is then collected by filtration. Suitably, the weight ratio of morphinan- 6α-ol to activated carbon is from about 1:1 to about 40:1, preferably from about 10:1 to about 20:1. [0028] The inventors of this new process found that platinum oxide catalyzed hydrogenations of morphinan-6-ones, particularly 14-hydroxy-morphinan-6-ones, gives the pure 6α-epimer of the corresponding morphinan-6-ol when a pre- dominantly aqueous solvent with a water-soluble base is used. Use of aqueous base is particularly advantageous for 30 the 3-hydroxymorphinan-6-one series, as the phenolic morphinans are readily soluble in aqueous base. Furthermore, adjusting the pH of the hydrogenation mixture to 12.0 - 13.5 is advantageous for the reaction rate and the selectivity of the hydrogenation to provide the α-epimer. [0029] The resulting morphinan-6α-ol has very low levels (< 1.0%) of the 6 β-epimer and are advantageously incorpo- rated into pharmaceutical products. 35 [0030] Compounds of formula (II) wherein R 1 is hydrogen may be further derivatized by one of ordinary skill in the art using known methods. For example, such compounds of formula (IIa) wherein R 1 is hydrogen (e.g., 6 α-noroxymorphol) 1 may be reacted with C 3-C10 alkenyl halides (e.g., 3- bromo-1-propene) to provide compounds of formula (II) wherein R is C3-C10 alkenyl (e.g., propenyl) such as 6α-naloxol. Similarly, 6α-noroxymorphol can be reacted with C1-C10 alkyl halides such as methyl bromide, or with C3-C6 cycloalkylC1-C10 alkyl halides such as cyclopropylmethyl bromide and 40 cyclobutylmethyl bromide to provide alternative processes for preparing compounds such as(α )-oxymorphol, 6 6α- naltrexol and 6α-nalbuphine, respectively. [0031] More particularly, 6α-Naloxol can be prepared from 6α-Noroxymorphol by warming 6α-noroxymorphol (pre- pared as shown in Example 1) with 1.0 - 1.5 equivalents of 3-bromo-1-propene and 1.0 - 1.5 equivalents of sodium hydrogen carbonate in either dimethylformamide or N-methylpyrrolidinone as solvent at 45 - 90°C for 2 - 24 hours. The 45 crude product is isolated by adding water, adjusting the pH to 8.5 - 9.0 with ammonia and filtering. The crude product can be purified by re-crystallization to provide 6α-Naloxol. [0032] The following Examples are set forth to aid in the understanding of the invention, and are not intended and should not be construed to limit in any way the invention set forth in the claims which follow thereafter.

50 EXAMPLE 1

Conversion of Noroxymorphone to Noroxymorphol (14-Hydroxydihydronormorphine)

[0033] 55

8 EP 2 328 900 B1

5

10 [0034] Noroxymorphone (5 g) was suspended in water (75 ml). The pH was adjusted to 13.3 with aqueous solution of NaOH (40% weight/ volume (w/v)). The solution was warmed to ∼ 50°C and aged with stirring until complete dissolution

was observed. To this solution was added Adams catalyst (PtO2, 50 mg) and the mixture was hydrogenated at 40 psi at room temperature for 3.5 h with 1200 rpm agitation speed. The catalyst was then removed with 5 ml water rinse. The 15 pH was adjusted to 9.1 with glacial acetic acid and the resulting suspension was aged for 1 h. The suspension was filtered with a small volume of water rinse. The solid was dried at 60°C under vacuum for 5 h (3.80 g, 76% yield by weight, overall yield/accountability was estimated to be approximately 90% taking into account the aliquots taken for sampling and the material lost to the mother liquor). The solid isolated was characterised to be 6 (α)-noroxymorphol (14- hydroxydihydronormorphine). The level of β-isomer was 0.12% by HPLC analysis (Example 9, Method A). 20 EXAMPLE 2

Conversion of Oxymorphone to Oxymorphol (14-Hydroxydihydromorphine)

25 [0035]

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[0036] Oxymorphone (5 g, assay=84.7%) was suspended in water (200 ml). The pH was adjusted to 13.2 with aqueous solution of NaOH (40% w/v). The solution was warmed to ∼ 50°C and aged with stirring until complete dissolution was observed. To this solution was added Adams catalyst (PtO2, 50 mg) and the mixture was hydrogenated at 40 psi at 40 room temperature for 9 h with 1200 rpm agitation speed. The catalyst was then removed with 5 ml water rinse. The pH was adjusted to 9.1 with glacial acetic acid. No precipitation was observed. The solution was then concentrated in vacuo at 65°C to a volume of approximately 75 ml. The resulting suspension was cooled to room temperature, aged for 1h and filtered with 5 ml water rinse. The solid was dried at 60°C under vacuum for 4 h (3.45 g, 82% yield by weight). The solid was characterised to be 6 (α)-oxymorphol (14-hydroxydihydromorphine). The β-isomer was at 0.02% by HPLC analysis 45 (Example 9, Method A).

EXAMPLE 3

Conversion of Nalbuphone to Nalbuphine 50 [0037]

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[0038] A 500 ml three necked round bottom flask was charged with crude Nalbuphone Hydrochloride (50 grams, 93.14 mmol), sodium acetate (0.77 grams, 9.31 mmol), activated charcoal (2 grams, Norit CAP Super) and water (300 mL). Subsequently, the mixture was heated (batch temperature of 80°C) under reduced pressure (p = 250 mbar). A total 15 amount of 16.7 g distillate was collected at an internal temperature of 55-65°C during 40 minutes. The vacuum supply was then removed and the mixture stirred at a temperature of 65°C for 1 hour. Subsequently, the mixture was filtered through a 2 cm pad of diatomaceous earth (Celite) and the filter cake rinsed with water (two 15 mL aliquots) to give: 359.5 g of a yellow solution containing 89.1 mg/g = 32.02 g = 90.1 mmol = 96.7% nalbuphone (as the hydrochloride salt). [0039] A 1 liter round bottom flask was charged with sodium hydroxide solution (30%, 24.8 grams, 186.3 mmol) and 20 2-propanol (160 mL). The above solution of Nalbuphone Hydrochloride was poured to the stirred mixture of aqueous sodium hydroxide and 2-propanol. The pH of the obtained golden solution was found to be 11.8 and was adjusted to 12.7 by adding an additional amount of 30% aqueous sodium hydroxide. The solution was distributed between two 500 ml Parr hydrogenation flasks. After inerting with argon, platinum oxide catalyst (0.561 gram, 2.33 mmol) and activated charcoal (Norit CAP Super, 1.0 gram) were added and the mixtures hydrogenated at 40-50 pounds/ square inch (psi) at 25 room temperature in a Parr shaker.

time conversion flask A conversion flask B remarks 2h 99.6% 90.6% precipitate in B 4h 99.6% 93.4% precipitate in A + B 30 6h - 99.8%

(after 4 hours, the precipitate in flask B was dissolved by heating to 40°C). Both flasks were then heated to an internal temperature of 35°C to ensure complete dissolution of the product and then filtered over a 2 cm pad of celite. The filter 35 cake was rinsed with water (two 15 ml aliquots) to give 569 grams of a copper-colored solution containing 55.35 mg/g = 31.49 g = 94.6% nalbuphine. The solution was treated with aqueous ammonia solution (25% 1.4 g) and thereafter the pH was adjusted to 9.1 - 9.2 by adding acetic acid. At a pH of about 10, the mixture was seeded with some crystals of Nalbuphine. The beige slurry was then stirred for 1 hour at room temperature and then the product was filtered off and

washed with H2O to give: 44.0 g of crude, wet nalbuphine (purity = 98.7%) and 627 g mother liquor (golden) containing: 40 0.65 mg/g = 0.41 g = 1.2% yield. [0040] The crude wet product was charged together with methanol (100 ml) in a 250 ml three necked flask and heated to reflux for 15 minutes and then cooled slowly (over night in the hot oil bath) to room temperature. After stirring another 2 hours at 0-5°C, the product was isolated by filtration. The wet product was rinsed with methanol (two 15 ml aliquots) (wet product 36 g) and dried in the cabinet at 75°C for 3 hours at a pressure of about 20 mbar to give 29.88 g (86.9%) 45 of a light beige solid.

- purity: 99.3% - Impurities

50 s N-Cyclopentyl derivative: 0.08% s Nalbuphone: 0.10%, s β-isomer: 0.02%, (Example 9, Method A)

s unknown (tR = 17.0’): 0.10%, s 3(O)-cyclobutylmethyl nalbuphine: 0.22%, 55 s 3(O)-cyclobutylmethyl nalbuphine: 0.19%.

- assay: 96.8%

10 EP 2 328 900 B1

EXAMPLE 4

[0041] A series of experiments were run according to the procedure in Example 3 with the exception of changing the pH of the reaction mixture. The effect of the change of pH on the stereo- selectivity (as determined by Example 9, Method 5 A) and the rate of reaction is shown below.

pH Time Ratio of α/β epimer (%) Reaction completion (%) 11.0 2 hours 99.55/0.45 83.55

10 4.25 hours 99.47/0.43 98.13 11.5 2 hours 99.78/0.22 90.68 4.25 hours 99.86/0.14 99.73 12.0 2 hours 99.88/0.12 95.60 15 4.5 hours 99.88/0.12 99.80 AB 12.7 2 hours 99.6 90.6 (from Example 3 above) 4 hours 99.6 93.4 20 6 hours 99.98/0.02 -- 99.8

EXAMPLE 5

Conversion of Naltrexone to Naltrexol 25

[0042]

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[0043] Crude naltrexone hydrochloride (25.0 g) was dissolved in deionized water ("DIW") (200 mL). The pH was adjusted from 2.1 to 13.1 by dropwise addition of 40% NaOH to the stirred solution. (note: precipitate formed at pH 40 (aq) ∼8 and re-dissolved at pH ∼12). Platinum oxide catalyst (200 mg) was added and the mixture hydrogenated with stirring

(Parr Hydrogenator: T = 45°C; H2 pressure = 45 psi; stirrer = 1500 rpm) for 3 hours. The reaction mixture was filtered through Celite and the cake washed with DIW (20 mL). Isopropyl alcohol (20 mL) was added to the filtrate and the solution stirred and heated to 45°C. The pH of the solution was adjusted to 10.8 by dropwise addition of glacial acetic acid. The mixture was aged for 20 min. at 45°C. The pH was further adjusted to 8.8 by slow addition of glacial acetic 45 acid (total volume added = 5.5 mL). The stirred mixture was aged for 15 min. and then filtered. Solids were washed with DIW (2 x 10 mL) and dried overnight under vacuum at 60°C to afford an off- white powder (mass = 15.0 g). The product,

naltrexol, was analysed by HPLC (Example 10, Method B): Purity % area = 98.6.

EXAMPLE 6 50

[0044] A series of experiments were run under acidic conditions:

A) Experiment 1

55 [0045]

1. Noroxymorphone (5 g) was dissolved in a mixture of water (100 ml) and concentrated sulfuric acid ∼( 1.5 ml).

11 EP 2 328 900 B1

The pH of solution was measured to be at 0.9. 2. The mixture was hydrogenated at 40°C -100°C and 40 psi using PtO 2 (50 mg) with an agitation speed of 1200 rpm. 3. After 5 h, no significant reaction was observed by HPLC analysis (Example 9, Method A).

5 B) Experiment 2

[0046]

1. Oxymorphone (5 g) was dissolved in a mixture of water (75 ml) and concentrated sulfuric acid ( ∼ 1.5 ml). The pH 10 of solution was measured to be at 0.7.

2. The mixture was hydrogenated at 40°C- 65 °C and 40 psi using PtO 2 (50 mg) with an agitation speed of 1200 rpm. 3. After 5 h, no significant reaction was observed by HPLC analysis (Example 9, Method A).

C) Experiment 3 15 [0047]

1. Noroxymorphone (21 g) was dissolved in a mixture of water (102 ml) and acetic acid (8 ml) at 50°C. The pH of the solution was measured to be at 4.2. 20 2. The solution was cooled to room temperature and PtO 2 (105 mg) was added. 3. The mixture was hydrogenated at 40 psi for 4 h and 45 min with an agitation speed of 1200 rpm. 4. After the initial 3 h into hydrogenation, only 21% conversion toα -noroxymorphol was seen by HPLC analysis. Temperature was increased to 45°C for the remaining 1h and 45 min. No further reaction was observed in this period. 5. The catalyst was removed by filtration with a water rinse (46 ml). 25 6. The filtrate was allowed to cool to room temperature and then fresh PtO 2 (100 mg) was added. The solution was further hydrogenated at 40 psi room temperature for 1 h with an agitation speed of 1200 rpm. 7. The solution was then kept under hydrogen without agitation for approximately 70 h. 8. The agitation was re- commenced and the mixture was hydrogenated for further 5 h using the conditions described in step 6. 30 9. After this time, the HPLC analysis (Example 9, Method A) showed that only 28% conversion to noroxymorphol took place. The epimeric purity was not examined.

EXAMPLE 7

35 Conversion of Noroxymorphol to Naloxol

[0048]

40

45

[0049] To a stirred mixture of noroxymorphol (4.75 g) and sodium bicarbonate (1.70 g) inmethyl- N- 2-pyrrolidone ("NMP") (11.0 mL) at 45°C was added allyl bromide (2.2 mL) all at once. The mixture was stirred at 45°C and reaction 50 progress was monitored by HPLC. A further two aliquots of allyl bromide were added (0.12 eqv. at t= 26 hrs and 0.14 eqv. at t=31 hrs) in order to drive the reaction to completion. The reaction was halted after 52 hours, however, HPLC analysis indicated that the reaction was complete after 46 hrs. Slight over- alkylation resulting in O-allylnaloxol (∼2% by HPLC area) was indicated by HPLC analysis. Ethyl acetate (55 mL) was added to the reaction mixture which led to unwanted gum formation (a precipitate was desired). Aqueous sodium hydroxide solution (8% w/v; 50 mL) was added 55 and the mixture transferred to a separatory funnel. A further 50 mL of NaOH (aq) (8% w/v) was added and the two layers mixed well before being separated. To the combined aqueous layer (- 100 mL) was added ethanol (20 mL). The pH of the aqueous ethanolic mixture was adjusted to 9.1 with glacial acetic acid at 35°C. The mixture was stirred at 35°C for 30 min and then filtered. The collected solid was washed with 2 x 5 mL of DIW. The solid was dried under vacuum at

12 EP 2 328 900 B1

60°C overnight to give a pale beige powder (3.69 g). The product, naloxol, was analysed by HPLC (Example 10, Method B): Purity %area = 99.36. [0050] Solid (3.69 g) was mostly dissolved in a minimum of hot methanol (60 mL; 50 °C) and filtered. The filtrate was allowed to cool slowly to room temperature and then cooled overnight at 4°C. A white crystalline solid (2.3 g) was obtained 5 by filtration, washing with cold methanol (10 mL, T=0°C) followed by drying under vacuum overnight at 60°C. The product,

purified naloxol, (beige crystalline solid) was analysed by HPLC (Example 10, Method B): Purity % area = 99.63.

EXAMPLE 8

10 Conversion of Noroxymorphol to Naltrexol

[0051]

15

20

[0052] To a stirred mixture of noroxymorphol (4.80 g) and sodium bicarbonate (1.25 g) in NMP (11 mL) at 45°C was added cyclopropylmethyl bromide ("CPMB ") (2.4 mL) all at once. The mixture was stirred and slowly heated to 35°C 25 over 45 minutes. A thick precipitate formed. A further 5 mL of NMP was added and the mixture stirred and heated at 45°C and reaction progress monitored by HPLC. A further 0.5 molar equivalents of CPMB was added at t=28 hrs. The reaction was halted after 74 hours, however, HPLC analysis indicated that the reaction was complete after 68 hrs. Slight over-alkylation resulting in O-allylnaltrexol (∼2% by HPLC area) was indicated by HPLC analysis. Ethyl acetate (55 mL) was added to the reaction mixture with stirring. Solids were collected by filtration and washed with ethyl acetate (20 mL). 30 The solid was dried under vacuum at 60°C for 2 hrs to give a beige powder. The product, naltrexol, was analysed by

HPLC (Example 10, Method B): Purity % area = 98.70. [0053] To this solid (5.6 g) was added 22.5 mL of DIW followed by 5 mL of ethanol (initial pH=7.8). The pH of the stirred mixture was adjusted to 3.1 by dropwise addition of glacial acetic acid (- 12 mL). A further 20 mL of DIW was added and the stirred mixture was heated to 60°C (most of the material dissolved). The pH was then adjusted slowly to 35 8.8 with aqueous ammonia (28% w/v; ∼ 25 mL). The mixture was aged for 1hr at 55°C. The pH was further adjusted to 8.46 from 8.80 by adding a few drops of glacial acetic acid. The mixture was stirred at 55°C for 10 min. and then filtered with water rinses (10ml + 5 ml). The product, purified naltrexol, was dried under vacuum overnight at 60°C to give an off-white powder (mass = 3.1 g). The solid was analysed by HPLC [0054] (Example 10, Method B): Purity %area = 99.59. 40 EXAMPLE 9

HPLC Method A

45 [0055] HPLC Method A was used to determine the purity of all of the Examples except for Examples 5, 7 and 8. [0056] HPLC method for analysis of oxymorphone and related impurities at pH 10 using a Waters Xbridge™ Shield Phenyl column (Waters Corporation, Milford, Massachusetts). [0057] Materials & Equipment:

50 Potassium Formate 99.995+% Ammonia 28% Reagent grade Acetonitrile HPLC grade Methanol HPLC grade Purified water - Milli-Q® water (Millipore Corporation, Billerica, Massachusetts) Waters Xbridge™ Phenyl column, 55 150 x 3.0 mm, 3.5 mm

[0058] Testing Instructions:

13 EP 2 328 900 B1

Mobile Phase Instructions: Line A - 1.32 6 0.01 g of potassium formate was dissolved in 1L of Milli-Q® water and the pH of the buffer adjusted to 10.0 with ammonia 28% Line B - acetonitrile 5 Line C -methanol (this solvent used for line storage only) Line D - Milli-Q® water (1 day expiry) Needle Wash - 50% methanol/50% Milli-Q® water

[0059] Instrument Settings: 10 Flow Rate Oven Temp Detector λ Injection Volume Vacuum Degassing Run time 0.65 mL/min 40 °C 284 nm 5 mL Continuous 30 min

15 [0060] Mobile Phase Composition:

Time (min) Line A Line B Line C Line D Curve 0 95% 5% 0% 0% 1 20 2 95% 5% 0% 0% 1 26 60% 40% 0% 0% 6 30 95% 5% 0% 0% 1

25 [0061] The samples were injected and chromatographed along with standard reference samples. After the sample set was run by the HPLC, the peaks were identified by comparison with the standards that were run in the sample set. [0062] The oxymorphol product formed in example 2 was analysed using this HPLC method. Retention times of oxymorphone, α-oxymorphol and β-oxymorphol on this method were 13.4, 12.9 and 12.1 min respectively, all confirmed 30 by spiking experiments. [0063] Since noroxymorphol elutes quite early on in this HPLC method, it was modified as follows for noroxymorphol. The buffer solution potassium formate was replaced with di-potassium hydrogen phosphate* but all other parameters remained the same. The retention times of noroxymorphone,α -noroxymorphol and β-noroxymorphol on this method were 7.6, 6.4 and 5.6 min respectively, all confirmed by spiking experiments. 35 *Preparation of hydrogen phosphate buffer solution:

[0064]

40 38.8 g of di-potassium hydrogen was added into 1000 ml of Mill- Q water and the pH adjusted to 6.2+/- 0.05 with phosphoric acid after filtration.

Example 10

45 HPLC Method B

[0065] The following HPLC Method B was used for Examples 5, 7 and 8.

Column: AlltimaC 8, 150mm x 4.6 mm x 3 mm 50 Flow Rate: 1.30 mL/min Oven Temperature: 50°C λ: 230 nm Injection Volume: 5 mL Run Time: 46 min 55

14 EP 2 328 900 B1

Line Reagent:

A 29mL H 3PO4(85%) dilutedto 1.00L in MilliQ water B Acetonitrile C Methanol (not used) 5 D MilliQ water

T / min%A%B%Dcurve/ T 10 010090- 5103876 10 10 10 80 6

15 20 10 10 80 6 35 10 90 0 6 38 10 90 0 6 46 10 0 90 1 20

[0066] The samples were injected and chromatographed along with standard reference samples. After the sample set was run by the HPLC, the peaks were identified by comparison with the standards that were run in the sample set. [0067] One or more currently preferred embodiments have been described by way of example. It will be apparent to 25 persons skilled in the art that a number of variations and modifications can be made without departing from the scope of the invention as defined in the claims.

Claims 30 1. A process for producing a morphinan-6α-ol compound of formula (IIa)

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and pharmaceutically acceptable salts thereof, comprising hydrogenating a morphinan-6-one compound of formula (I)

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15 EP 2 328 900 B1

5

10

in an aqueous solvent and a water soluble base wherein the aqueous solvent is selected from the group consisting 15 of water and a mixture of water and a water- miscible co-solvent in the presence of a catalyst wherein said catalyst is platinum or platinum oxide at a pH between about 11 and about 14 to provide the compound of formula (IIa) having less than one percent of a morphinan-6β-ol compound of formula (IIb)

20

25

30

wherein 1 R is selected from hydrogen, C 1-C10 alkyl, C 3-C6 cycloalkylC1 - C 10 alkyl, -C (O)-C1-C10alkyl or -C(O)-OC1-C10alkyl; 35 and 2 3 3 3 R is selected from H, OR or OC(O)R wherein R is selected from hydrogen or C1-C10 alkyl.

2. The process of claim 1, wherein the pH is between about 12.0 and about 13.5.

40 1 3. The process of claim 1, wherein R is selected from H, C1 - C6 alkyl, or C3-C6 cycloalkylC1 - C6 alkyl.

4. The process of claim 3, wherein R 1 is selected from hydrogen, methyl, ethyl, propyl,

45

50 5. The process of claim 1, wherein the amount of the morphinan- 6β-ol compound of formula (IIb) or of formula (IId) is less than 0.5 per cent.

6. The process of claim 1, wherein the compound of formula (I) is selected from the group consisting of hydromorphone, 55 oxymorphone, norhydromorphone, noroxymorphone, naltrexone and nalbuphone.

7. The process of claim 1, wherein the compound of formula (IIa) is selected from the group consisting ofα -7,8-6 dihydromorphine, 6α-oxymorphol, 6α-norhydromorphol, 6α-noroxymorphol, 6α-naltrexol and 6α-nalbuphine.

16 EP 2 328 900 B1

8. The process of claim 1 wherein the hydrogenation is performed with a hydrogen donor selected from the group consisting of hydrogen gas, formic acid, sodium hypophosphite, and combinations thereof.

9. The process of claim 8 wherein the hydrogen donor is hydrogen gas. 5 10. The process of claim 1, wherein the aqueous solvent is water or water mixed with a water-miscible co-solvent selected from a C1 to C4 alcohol, dimethylformamide, dimethylacetamide, N-methylpyrrolidone or tetrahydrofuran.

11. The process of claim 10 wherein the aqueous solvent is water or water mixed with a C 1 to C4 alcohol. 10 12. The process of claim 11 wherein the aqueous solvent is water or water mixed with 2- propanol.

13. The process of claim 1 wherein the water soluble base is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, caesium hydroxide or ammonium hydroxide. 15 14. The process of claim 13 wherein the base is selected from sodium hydroxide or potassium hydroxide.

15. The process of claim 5, wherein the amount of the morphinan- 6β-ol compound of formula (IIb) or of formula (IId) is less than 0.20%. 20 16. The process of claim 5, wherein the amount of the morphinan- 6β-ol compound of formula (IIb) or of formula (IId) is less than 0.10%.

17. The process of claim 5, wherein the amount of the morphinan- 6β-ol compound of formula (IIb) or of formula (IId) is 25 less than 0.05%.

18. The process of claim 7, wherein the compound of formula (IIa) is 6 α-noroxymorphol or 6α-nalbuphine.

19. The process of Claim 18, wherein the compound of formula (IIa) is α6-noroxymorphol and wherein the process 30 further comprises the step of reacting the 6 α-noroxymorphol with 3-bromo-1-propene to provide 6α-naloxol.

20. The process of claim 19 further comprising the step of isolating the 6 α-naloxol.

35 Patentansprüche

1. Verfahren zum Herstellen einer Morphinan-6α-ol Verbindung der Formel (IIa)

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und pharmazeutisch verträgliche Salze davon, 50 umfassend hydrieren einer Morphinan-6-on Verbindung der Formel (I)

55

17 EP 2 328 900 B1

5

10 in einem wässrigen Lösemittel und einer wasserlöslichen Base wobei das wässrige Lösemittel ausgewählt ist aus der Gruppe bestehend aus Wasser und einer Mischung von Wasser und einem wasser- mischbaren Co-Lösemittel in der Gegenwart eines Katalysators, wobei der Katalysator Platin oder Platinoxid ist, bei einem pH zwischen etwa 11 und etwa 14 um die Verbindung der Formel (IIa) mit weniger als ein Prozent einer Morphinan- 6β-ol Verbindung 15 der Formel (IIb)

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25

bereit zu stellen, wobei 1 R ausgewählt ist aus Wasserstoff, C 1-C10 Alkyl, C 3-C6 CycloalkylC1-C10 Alkyl, -C (O)-C1-C10 Alkyl oder -C (O)-OC1- C10 Alkyl; und 30 2 3 3 3 R ausgewählt ist aus H, OR oder OC(O)R wobei R ausgewählt ist aus Wasserstoff oder C 1-C10 Alkyl.

2. Verfahren nach Anspruch 1, wobei der pH zwischen etwa 12,0 und etwa 13,5 liegt.

1 3. Verfahren nach Anspruch 1, wobei R ausgewählt ist aus H, C1-C6 Alkyl, oder C3-C6 CycloalkylC1-C6 Alkyl. 35 4. Verfahren nach Anspruch 3, wobei R1 ausgewählt ist aus Wasserstoff, Methyl, Ethyl, Propyl,

40

5. Verfahren nach Anspruch 1, wobei die Menge der Morphinan-6β-ol Verbindung der Formel (IIb) oder der Formel (IId) weniger als 0,5 % beträgt.

45 6. Verfahren nach Anspruch 1, wobei die Verbindung der Formel (I) ausgewählt ist aus der Gruppe bestehend aus Hydromorphon, Oxymorphon, Norhydromorphon, Noroxymorphon, Naltrexon und Nalbuphon.

7. Verfahren nach Anspruch 1, wobei die Verbindung der Formel (IIa) ausgewählt ist aus der Gruppe bestehend aus 6α-7, 8-Dihydromorphin, 6α-Oxymorphol, 6α-Norhydromorphol, 6α-Noroxymorphol, 6α-Naltrexol und 6α-Nalbu- 50 phin.

8. Verfahren nach Anspruch 1, wobei die Hydrierung mit einem Wasserstoffdonor ausgewählt aus der Gruppe beste- hend aus Wasserstoffgas, Ameisensäure, Natriumhypophosphit und Kombinationen davon durchgeführt wird.

55 9. Verfahren nach Anspruch 8, wobei der Wasserstoffdonor Wasserstoffgas ist.

10. Verfahren nach Anspruch 1, wobei das wässrige Lösemittel Wasser oder Wasser gemischt mit einem wassermisch- baren Co-Lösemittel ausgewählt aus einem C 1 bis C4 Alkohol, Dimethylformamid, Dimethylacetamid, N- Methylpyr-

18 EP 2 328 900 B1

rolidon oder Tetrahydrofuran ist.

11. Verfahren nach Anspruch 10, wobei das wässrige Lösemittel Wasser oder Wasser gemischt mit einem C1 bis C4 Alkohol ist. 5 12. Verfahren nach Anspruch 11, wobei das wässrige Lösemittel Wasser oder Wasser gemischt mit 2- Propanol ist.

13. Verfahren nach Anspruch 1, wobei die wasserlösliche Base ausgewählt ist aus Natriumhydroxyd, Kaliumhydroxid, Lithiumhydroxid, Caesiumhydroxid oder Ammoniumhydroxid. 10 14. Verfahren nach Anspruch 13, wobei die Base ausgewählt ist aus Natriumhydroxid oder Kaliumhydroxid.

15. Verfahren nach Anspruch 5, wobei die Menge an Morphinan-6β-ol Verbindung der Formel (IIb) oder der Formel (IId) weniger als 0,20 % beträgt. 15 16. Verfahren nach Anspruch 5, wobei die Menge an Morphinan-6β-ol Verbindung der Formel (IIb) oder der Formel (IId) weniger als 0,10 % beträgt.

17. Verfahren nach Anspruch 5, wobei die Menge an Morphinan-6β-ol Verbindung der Formel (IIb) oder der Formel 20 (IId) weniger als 0,05 % beträgt.

18. Verfahren nach Anspruch 7, wobei die Verbindung der Formel (IIa) 6α-Noroxymorphol oder 6α-Nalbuphin ist.

19. Verfahren nach Anspruch 18, wobei die Verbindung der Formel (IIa) 6 α-Noroxymorphol ist und wobei das Verfahren 25 des Weiteren den Schritt des Reagierens des 6α-Noroxymorphols mit 3-Brom-1-Propen umfasst um 6α-Naloxol bereit zu stellen.

20. Verfahren nach Anspruch 19, des Weiteren umfassend den Schritt des Isolierens des 6 α-Naloxols.

30 Revendications

1. Procédé de production d’un composé morphinan-6α-ol de formule (IIa)

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et des sels pharmaceutiquement acceptables de celui-ci, comprenant l’hydrogénation d’un composé morphinan-6-one de formule (I) 50

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19 EP 2 328 900 B1

5

10

dans un solvant aqueux et une base soluble dans l’eau dans laquelle le solvant aqueux est choisi dans le groupe 15 constitué par l’eau et un mélange d’eau et d’un co- solvant miscible à l’eau en présence d’un catalyseur dans lequel ledit catalyseur est le platine ou l’oxyde de platine à un pH compris entre environ 11 et environ 14 pour fournir le composé de formule (IIa) ayant moins d’un pour cent d’un composé morphinan-6β-ol de formule (IIb)

20

25

30

dans laquelle 1 R est choisi parmi hydrogène, alkyle en C 1-C10, (cycloalkyl en C3-C6)alkyle en C1-C10, -C(O)-alkyle en C1-C10 ou -C(O)-O(alkyle en C1-C10); et 35 2 3 3 3 R est choisi parmi H, OR ou OC(O)R dans lequel R est choisi parmi hydrogène ou alkyle en C 1-C10.

2. Procédé selon la revendication 1, dans lequel le pH est compris entre environ 12,0 et environ 13,5.

1 3. Procédé selon la revendication 1, dans lequel R est choisi parmi H, alkyle en C 1-C6, ou (cycloalkyl en C 3-C6)alkyle 40 en C1-C6.

4. Procédé selon la revendication 3, dans lequel R 1 est choisi parmi hydrogène, méthyle, éthyle, propyle,

45

50 5. Procédé selon la revendication 1, dans lequel la quantité du composé morphinan- 6β-ol de formule (IIb) ou de formule (IId) est inférieure à 0,5 pour cent.

6. Procédé selon la revendication 1, dans lequel le composé de formule (I) est choisi dans le groupe constitué par l’hydromorphone, l’oxymorphone, la norhydromorphone, la noroxymorphone, la naltrexone et la nalbuphone. 55 7. Procédé selon la revendication 1, dans lequel le composé de formule (IIa) est choisi dans le groupe constitué par la 6α-7,8-dihydromorphine, le 6α-oxymorphol, le 6α-norhydromorphol, le 6α-noroxymorphol, le 6α-naltrexol et la 6α-nalbuphine.

20 EP 2 328 900 B1

8. Procédé selon la revendication 1, dans lequel l’hydrogénation est effectuée avec un donneur d’hydrogène choisi dans le groupe constitué par l’hydrogène gazeux, l’acide formique, l’hypophosphite de sodium, et les combinaisons de ceux-ci.

5 9. Procédé selon la revendication 8, dans lequel le donneur d’hydrogène est l’hydrogène gazeux.

10. Procédé selon la revendication 1, dans lequel le solvant aqueux est l’eau ou l’eau mélangée à un co- solvant miscible à l’eau choisi parmi un alcool en C1 à C4, le diméthylformamide, le diméthylacétamide, la N-méthylpyrrolidone ou le tétrahydrofurane. 10

11. Procédé selon la revendication 10, dans lequel le solvant aqueux est l’eau ou l’eau mélangée avec un alcool en C 1 à C4.

12. Procédé selon la revendication 11, dans lequel le solvant aqueux est l’eau ou l’eau mélangée avec du 2- propanol. 15 13. Procédé selon la revendication 1, dans lequel la base soluble dans l’eau est choisie parmi l’hydroxyde de sodium, l’hydroxyde de potassium, l’hydroxyde de lithium, l’hydroxyde de césium ou l’hydroxyde d’ammonium.

14. Procédé selon la revendication 13, dans lequel la base est choisie parmi l’hydroxyde de sodium ou l’hydroxyde de 20 potassium.

15. Procédé selon la revendication 5, dans lequel la quantité du composé morphinan- 6β-ol de formule (IIb) ou de formule (IId) est inférieure à 0,20 %.

25 16. Procédé selon la revendication 5, dans lequel la quantité du composé morphinan- 6β-ol de formule (IIb) ou de formule (IId) est inférieure à 0,10 %.

17. Procédé selon la revendication 5, dans lequel la quantité du composé morphinan- 6β-ol de formule (IIb) ou de formule (IId) est inférieure à 0,05 %. 30 18. Procédé selon la revendication 7, dans lequel le composé de formule (IIa) est leα -noroxymorphol6 ou la 6α- nalbuphine.

19. Procédé selon la revendication 18, dans lequel le composé de formule (IIa) est le 6 α-noroxymorphol et dans lequel 35 le procédé comprend en outre l’étape consistant à faire réagir le 6α-noroxymorphol avec du 3-bromo-1-propène pour fournir du 6α-naloxol.

20. Procédé selon la revendication 19, comprenant en outre l’étape consistant à isoler le 6α-naloxol.

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21 EP 2 328 900 B1

REFERENCES CITED IN THE DESCRIPTION

This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

Patent documents cited in the description

• US 6887999 B [0002] • US 5208338 A [0002] • US 5756745 A [0002] • US 5336483 A [0002] • WO 2007121114 A [0002] • US 3830819 A [0004]

Non-patent literature cited in the description

• SARGENT et al. Hydroxylated codeine derivatives. • BRINE et al. Ring C conformation of 6 β-naltrexol and Journal of Organic Chemistry, 1958, vol. 23, 6α-naltrexol. Evidence from Proton and Carbon-13 1247-1251 [0002] nuclear magnetic resonance.Journal of Organic • CURRIE et al. J. Chem. Soc., 1960, 773 [0002] Chemistry, 1976, vol. 41, 3445-3448 [0002] • BURKE ; RICE. Probes for narcotic receptor medi- • L.D. OLSEN et al. J. Med. Chem., 1990, vol. 33, ated phenomena. 11. Synthesis of 17-methyl-and 737-741 [0002] 17-cyclopropylmethyl-3,14-dihy- • G.A. BRINE et al. J. Org. Chem., 1976, vol. 41 (21), droxy-4,5α-epoxy-6β-fluoromorphinans (FOXY and 3445-3448 [0002] CYCLOFOXY) as models of opioid ligands suitable •LUTZR.E.; SMALL L. Reduction studies in the mor- for positron emission transaxial tomography. Hetero- phine series. X. Hydroxycodeinone. Journal of Or- cycles, 1985, vol. 23, 99-106 [0002] ganic Chemistry, 1939, vol. 4, 220-233 [0004]

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