WO2016187522A1 - Procédé de préparation d'oxymorphone sous forme de base libre - Google Patents

Procédé de préparation d'oxymorphone sous forme de base libre Download PDF

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Publication number
WO2016187522A1
WO2016187522A1 PCT/US2016/033494 US2016033494W WO2016187522A1 WO 2016187522 A1 WO2016187522 A1 WO 2016187522A1 US 2016033494 W US2016033494 W US 2016033494W WO 2016187522 A1 WO2016187522 A1 WO 2016187522A1
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amount
hydroxymorphinone
oxymorphone
range
water
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PCT/US2016/033494
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English (en)
Inventor
Timothy Samuel BAILEY
Paul Jonathan NICHOLS
Joshua S. SASINE
Ulrich Weigl
Aarti L. JOSHI
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Noramco, Inc.
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Publication of WO2016187522A1 publication Critical patent/WO2016187522A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
    • C07D489/06—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: with a hetero atom directly attached in position 14
    • C07D489/08—Oxygen atom

Definitions

  • the present invention is directed to a process for the preparation oxymorphone freebase, comprising hydrogenation of 14-hydroxymorphinone in DMF, to yield oxymorphone freebase, preferably oxymorphone freebase of improved appearance, purity and / or yield.
  • the present invention is further directed to oxymorphone freebase with improved impurity profile.
  • the present invention is further directed to an HPLC or UPLC system or method for analysis of opioid compounds, including for example, determining purity and measuring the presence and amount of impurities.
  • Oxymorphone hydrochloride also known as 4,5-epoxy-3, 14-dihydroxy- 17-methyl-(5a)-morphinan-6-one hydrochloride (1 : 1 ), or 14- hydroxydihydromorphinone, (d 7 H 2 oCIN0 4 , MW 337.80) is a semi-synthetic opioid analgesic.
  • the chemical structure of oxymorphone hydrochloride is shown below
  • Oxymorphone HCI is indicated for the relief of moderate to severe pain. Oxymorphone HCI is also indicated as a pre-operative medication to alleviate apprehension, maintain anesthesia and as an obstetric analgesic. Additionally, oxymorphone HCI may be used to alleviate pain in patients with dyspnea associated with acute left ventricular failure and pulmonary edema.
  • WANG, P.X., et al., in US Patent No. 8,217, 175 describe a process for the preparation of oxymorphone from oripavine, wherein the process aims to limit production of 1 , 1 '-dimer impurities such as 2,2-bis-oxymorphone.
  • oxymorphone hydrochloride including but not limited to oxymorphone freebase, 14-hydroxymorphinone, etc.
  • the present invention is directed to a process for the preparation of oxymorphone freebase comprising
  • a hydrogenating agent preferably hydrogen gas in the presence of Pd/C
  • ethylenediaminetetracetic acid disodium salt optionally in the presence of a proton source (preferably in the presence of a proton source, more preferably dibasic potassium phosphate); in dimethylformamide (DMF);
  • the present invention is directed to a process for the preparation of oxymorphone freebase comprising the steps of
  • the present invention is directed to a process for the preparation of oxymorphone freebase comprising the steps of
  • the present invention is further directed to a process for the preparation of a pharmaceutically acceptable salt of oxymorphone (preferably an HCI salt of oxymorphone), comprising
  • the present invention is further directed to a process for the preparation of oxymorphone freebase, comprising
  • STEP 2 reacting 14-hydroxymorphinone with a hydrogenating agent (preferably hydrogen gas in the presence of Pd/C); optionally in the presence of ethylenediaminetetracetic acid disodium salt; optionally in the presence of a proton source (preferably in the presence of a proton source, more preferably dibasic potassium phosphate); in dimethylformamide (DMF); to yield
  • a hydrogenating agent preferably hydrogen gas in the presence of Pd/C
  • ethylenediaminetetracetic acid disodium salt optionally in the presence of a proton source (preferably in the presence of a proton source, more preferably dibasic potassium phosphate); in dimethylformamide (DMF);
  • STEP 3 reacting the oxymorphone base with an acid (preferably hydrochloric acid), to yield the corresponding oxymorphone acid addition salt.
  • the present invention is further directed to a process for the preparation of oxymorphone freebase, comprising
  • STEP 2 reacting 14-hydroxymorphinone with a hydrogenating agent (preferably hydrogen gas in the presence of Pd/C); optionally in the presence of ethylenediaminetetracetic acid disodium salt; optionally in the presence of a proton source (preferably in the presence of a proton source, more preferably dibasic potassium phosphate); in dimethylformamide (DMF); to yield
  • a hydrogenating agent preferably hydrogen gas in the presence of Pd/C
  • ethylenediaminetetracetic acid disodium salt optionally in the presence of a proton source (preferably in the presence of a proton source, more preferably dibasic potassium phosphate); in dimethylformamide (DMF);
  • STEP 3 reacting the oxymorphone base with an acid (preferably hydrochloric acid), to yield the corresponding oxymorphone acid addition salt.
  • the present invention is further directed to any process for the synthesi of oxymorphone or a pharmaceutically acceptable salt thereof or for the synthesis of an intermediate useful in the synthesis of oxymorphone or a pharmaceutically acceptable salt thereof, as described herein.
  • the present invention is further directed to a product prepared according to any of the processes described herein.
  • the present invention is directed to oxymorphone freebase or oxymorphone hydrochloride of improved impurity profile (improved purity) as described hereinafter.
  • the present invention is further directed to HPLC and UPLC system(s) and method(s) for analyzing an opioid compound (including, but not limited to natural opioid compounds, synthetic opioid compounds, opioid derivatives, etc.) or pharmaceutically acceptable salts thereof.
  • an opioid compound including, but not limited to natural opioid compounds, synthetic opioid compounds, opioid derivatives, etc.
  • the HPLC and UPLC methods are used to determine the purity of the opioid compound.
  • the HPLC or UPLC method(s) are used to determine the impurity profile of an opioid compound or derivative thereof.
  • the HPLC or UPLC system(s)/method(s) are used to determine the impurity profile of opioid compounds including, but are not limited to oxymorphone, oxycodone, hydrocodone, hydromorphone, buprenorphine, morphine, codeine, benzhydrocodone and pharmaceutically acceptable salts thereof (preferably oxymorphone, oxycodone, hydrocodone,
  • the HPLC or UPLC system(s)/method(s) for analyzing an opioid compound are as described in Example 7, Example 8, Example 9 or Example 10, which follow hereinafter.
  • the present invention is directed to an HPLC or UPLC system for analyzing the purity or impurity profile of an opioid compound comprising
  • the HPLC or UPLC system further comprises a detector capable of emitting a wavelength suitable for detecting compounds (e.g., the opioid compounds) undergoing analysis.
  • a detector capable of emitting a wavelength suitable for detecting compounds (e.g., the opioid compounds) undergoing analysis.
  • the present invention is directed to HPLC and UPLC system for analyzing an opioid compound (preferably analyzing the purity and / or impurity profile of an opioid compound) comprising
  • a column temperature in the range of from about 40°C to about 75°C (for example 40°C, 68°C or 75°C);
  • a detector suitable for emitting a detection wavelength preferably in the range of from about 280 nm to about 285 nm (for example at 280 nm or about 284nm);
  • a flow rate adjuster suitable for adjusting the flow rate of the mobile phases and run time of the analysis, preferably in the range of from about about 0.65 mL/min to about 0.70 mL/min (for example about 0.60 mL/min or about 0.65 mL/min) and the run time in the range of from about 5 min to about 1 hour, preferably a run time in the range of from about 5 min to about 30 min (for example about 9 min, about 10 min or about 30 min);
  • Mobile Phase A is a mixed phosphate buffer in water or an ammonium formate buffer in water; preferably wherein the pH of the mixed phosphate buffer in water has a pH ranging from about pH8 to about pH9, preferably, in the range of from about pH 8.2 to about pH 8.6, for example, in the range of from about pH 8.3 to about pH8.4; and/or preferably wherein the pH of the ammonium formate buffer in water has a pH ranging from about pH 9 to about pH 10, more preferably in the range of about pH 9.4 to about pH 9.8, for example a pH of about 9.6; and wherein Mobile Phase B is acetonitrile, and further wherein at least one of the mobile phases has (or is buffered to have) a pH equal to or within 0.5 units of the pK of the opioid compound to be analyzed.
  • the pH of at least one of the mobile phase is (or is buffered to be) less than the pK of the opioid compound to be analyzed by no more than 0.5 units
  • the present invention is directed to HPLC and UPLC method(s) for analyzing an opioid compound (preferably analyzing the purity and / or impurity profile of an opioid compound) comprising the steps of:
  • Mobile Phase A is a mixed phosphate buffer in water or an ammonium formate buffer in water; preferably wherein the pH of the mixed phosphate buffer in water has a pH ranging from about pH 8 to about pH 9, preferably, in the range of from about pH 8.2 to about pH 8.6, for example, in the range of from about pH8.3 to about pH 8.4; and/or preferably wherein the pH of the ammonium formate buffer in water has a pH ranging from about pH 9 to about pH 10, more preferably in the range of about pH 9.4 to about pH 9.8, for example a pH of about 9.6; and wherein Mobile Phase B is acetonitrile; and preferably wherein the pH of Mobile Phase A is (or buffered to be) is equal to or within 0.5 units of the pKa of the opioid compound; and
  • the present invention relates to an HPLC or UPLC method for analyzing the purity or impurity profile of an opioid compound comprising the steps of:
  • Mobile Phase A is a mixed phosphate buffer in water or an ammonium formate buffer in water; wherein the pH of the mixed phosphate buffer in water is in the range of from about pH 8 to about pH 9; and wherein the pH of the ammonium formate buffer in water is preferably in the range of from about pH 9 to about pH 10; and wherein Mobile Phase B is acetonitrile; and further wherein the Mobile Phase A and the Mobile Phase B are applied with a Mobile Phase gradient selected to separate the opioid compound peaks from the impurity peaks.
  • the present invention is directed to HPLC and UPLC method(s) for analyzing an opioid compound (preferably analyzing the purity and / or impurity profile of an opioid compound) comprising the steps of:
  • a run time in the range of from about 5 min to about 1 hour, preferably a run time in the range of from about 5 min to about 30 min (for example about 9 min, about 10 min or about 30 min);
  • Mobile Phase A is a mixed phosphate buffer in water or an ammonium formate buffer in water; preferably wherein the pH of the mixed phosphate buffer in water has a pH ranging from about pH8 to about pH 9, preferably, in the range of from about pH 8.2 to about pH 8.6, for example, in the range of from about pH 8.3 to about pH 8.4; and/or preferably wherein the pH of the ammonium formate buffer in water has a pH ranging from about pH 9 to about pH 10, more preferably in the range of about pH 9.4 to about pH 9.8, for example a pH of about 9.6; and wherein Mobile Phase B is acetonitrile; and wherein the pH of Mobile Phase A is (or buffered to be) equal to or within 0.5 units of the pKa of the opioid compound;
  • the Mobile Phase gradient of the above methods is selected from the group of Gradient Timetables consisting of Gradient Timetable A
  • Gradient able A is preferred for oxymorphone and pharmaceutically acceptable salts thereof (for example HCI salts);
  • the present invention is directed to process(es) for the preparation of oxymorphone freebase comprising reacting 14-hydroxymorphinone with a suitably selected hydrogenating agent (preferably hydrogen gas in the presence of Pd/C); in the presence of ethylenediaminetetracetic acid disodium salt; optionally in the presence of a proton source (preferably in the presence of a proton source, preferably in the presence of dibasic potassium phosphate); in dimethylformamide (DMF); as described in more detail hereinafter.
  • a suitably selected hydrogenating agent preferably hydrogen gas in the presence of Pd/C
  • ethylenediaminetetracetic acid disodium salt optionally in the presence of a proton source (preferably in the presence of a proton source, preferably in the presence of dibasic potassium phosphate); in dimethylformamide (DMF); as described in more detail hereinafter.
  • the present invention is further directed to process(es) for the preparation of oxymorphone freebase from CPS oripavine or theb
  • the present invention is further directed to process(es) for the preparation of oxymorphone hydrochloride, as described in more detail hereinafter.
  • the present invention is further directed to process(es) for the preparation of 14-hydroxymorphinone, as described in more detail hereinafter.
  • the present invention is further directed to HPLC and UPLC
  • the HPLC and UPLC systems/methods are used to determine the purity of the opioid compound.
  • the HPLC or UPLC system (s)/method(s) are used to determine the impurity profile of an opioid compound or derivative thereof.
  • the HPLC or UPLC system (s)/method(s) are used to determine the impurity profile of opioid compounds selected from the group consisting of oxymorphone, oxycodone, hydrocodone, hydromorphone, buprenorphine, morphine, codeine,
  • the HPLC or UPLC system(s)/method(s) are used to determine the impurity profile of opioid compounds selected from the group consisting of oxymorphone, oxymorphone HCI, oxycodone, oxycodone HCI, hydrocodone, hydrocodone bitartrate and benzhydrocodone.
  • select mobile phases are eluted through an HPLC or UPLC column at an applied Mobile Phase gradient selected to achieve separation between the peaks of the opioid compound and any synthesis impurities.
  • At least one mobile phase is eluted through the HPLC or UPLC column and, preferably, at least one mobile phase is selected to be a buffer (or comprise a buffer); wherein the pH of that at least one of the mobile phase is equal to or within 0.5 units of the pK of the opioid compound (which is to be analyzed).
  • At least one mobile phase is a mixed phosphate buffer in water (preferably deionized water); wherein the pH of the mixed phosphate buffer is preferably in the range of from about pH 8 to about pH 9, preferably in the range of from about pH 8.2 to about pH 8.6, more preferably in the range of from about pH 8.3 to about pH 8.4; or an ammonium formate buffer in water; wherein the pH of the ammonium formate buffer is preferably in the range of from about pH 9 to about pH 10, more preferably in the range of from about pH 9.4 to about pH 9.8, more preferably pH 9.6.
  • the pH of the mixed phosphate buffer is preferably in the range of from about pH 8 to about pH 9, preferably in the range of from about pH 8.2 to about pH 8.6, more preferably in the range of from about pH 8.3 to about pH 8.4; or an ammonium formate buffer in water; wherein the pH of the ammonium formate buffer is preferably in the range of from about pH 9 to about pH 10, more preferably in the range of from about pH 9.
  • the present invention is directed to process(es) for the preparation of oxymorphone freebase or oxymorphone hydrochloride, wherein the product is isolated as a solid, and wherein the wt % of impurities (for example organic impurities or inorganic impurities or both), as measured by an HPLC or UPLC method that sufficiently separates the opioid compound from impurities, preferably the HPLC or UPLC system(s)/method(s) described herein, is less than about 10 wt% (preferably less than about 5 wt%, more preferably less than about 2 wt%, more preferably less than about 1 wt%, more preferably less than about 0.075 wt%, more preferably less than about 0.05 wt%, more preferably less than about 0.04%, more preferably less than about 0.03%, more preferably less than about 0.02%, more preferably less than about 0.01 %).
  • the wt% of impurities is below the ICH
  • the present invention is directed to process(es) for the preparation of oxymorphone freebase or oxymorphone hydrochloride, wherein the appearance / color of the isolated solid is white, off white or slight yellow.
  • the present invention is further directed to a product prepared according to any of the processes as described herein.
  • the present invention is directed to a product prepared according to any of the processes described herein, wherein the wt% of impurities in the product, as measured by an HPLC or UPLC method that sufficiently separates the opioid compound from impurities, preferably the HPLC or UPLC system(s)/method(s) described herein, is less than about 10 wt%, preferably less than about 5 wt%, more preferably less than about 2 wt%, more preferably less than about 1 wt%, more preferably less than about 0.075 wt%, more preferably less than about 0.05 wt%%, more preferably less than about 0.04%, more preferably less than about 0.03%, more preferably less than about 0.02%, more preferably less than about 0.01 %.
  • the present invention is directed to
  • oxymorphone freebase including, but not limited to oxymorphone freebase prepared according to any of the process(es) described herein.
  • oxymorphone hydrochloride including, but not limited to oxymorphone hydrochloride prepared according to any of the process(es) described herein); wherein the purity of the oxymorphone freebase or oxymorphone
  • hydrochloride as measured by an HPLC or UPLC method that sufficiently separates the opioid compound from impurities, preferably the HPLC or UPLC system(s)/method(s) described herein, is in the range of from about 95% to about 100%, or any amount or range therein, preferably, the purity is at least about 97.5%, more preferably at least about 98%, preferably at least 98.1 %, more preferably at least 98.2%, more preferably at least 98.3%, more preferably at least 98.4%, more preferably at least 98.5%, more preferably at least 98.6%, more preferably at least 98.7%, more preferably at least 98.8%, more preferably at least 98.9%, more preferably at least 99%, more preferably at least 99.1 %, more preferably at least 99.2%, more preferably at least 99.3%, more preferably at least 99.4%, more preferably at least 99.5%, more preferably at least 99.6%, more preferably at least 99.7%
  • the present invention is directed to a product prepared according to any of the processes described herein (preferably, oxymorphone freebase or oxymorphone hydrochloride), wherein the individual wt% of one or more (preferably one to two, more preferably one to four) of the following impurities (a) 14-hydroxymorphinone, (b) 14-hydroxy- dihydromorphine (a), (c) 8-hydroxyoxymorphone, (d) hydromorphone and / or 2,2-bis-oxymorphone is, as measured by an HPLC or UPLC method that sufficiently separates the opioid compound from such impurities, preferably the HPLC or UPLC system(s)/method(s) described herein, individually less than or equal to about 0.5 wt %, preferably less than about 0.3 wt%, more preferably less than about 0.2 wt %, more preferably less than about 0.1 wt%, more preferably less than about 0.05 wt%, most preferably in an amount below the ICH Reporting Thre
  • the present invention is directed to a product prepared according to any of the processes described herein (preferably, oxymorphone freebase or oxymorphone hydrochloride), wherein the sum total wt% of one or more (preferably one to two, more preferably one to four) of the following impurities (a) 14-hydroxymorphinone, (b) 14-hydroxy- dihydromorphine (a), (c) 8-hydroxyoxymorphone, (d) hydromorphone, and / or 2,2-bis-oxymorphone is, as measured by an HPLC or UPLC method that sufficiently separates the opioid compound from such impurities, preferably the HPLC or UPLC system(s)/method(s) described herein, less than or equal to about 2.0 wt %, preferably less than about 1 .5 wt%, more preferably less than about 1 .0 wt %, more preferably less than about 0.5 wt%, more preferably less than about 0.25 wt% more preferably less than about 0.1 wt
  • the present invention is directed to a product prepared according to any of the processes described herein (preferably, oxymorphone freebase or oxymorphone hydrochloride), wherein the individual wt% of one or more (preferably one to two, more preferably one to four, more preferably one to six, more preferably one to eight) of the following impurities (a) oxymorphone-/V-oxide, (b) 8-hydroxyoxymorphone, (c) hydromorphone, (d) 14-hydroxymorphinone, (e) 14-hydroxydihydromorphine (a), (f) oxycodone, (g) 2,2-bis-oxymorphone, and / or (h) any other individual unspecified or unidentified impurity is, as measured by an HPLC or UPLC method that sufficiently separates the opioid compound from such impurities, preferably the HPLC or UPLC system(s)/method(s) described herein, individually less than or equal to about 0.5 wt %, preferably less than about 0.3
  • the present invention is directed to a product prepared according to any of the processes described herein (preferably, oxymorphone freebase or oxymorphone hydrochloride), wherein the sum total wt% of one or more (preferably one to two, more preferably one to four, more preferably one to six, more preferably one to eight) of the following impurities (a) oxymorphone-/V-oxide, (b) 8-hydroxyoxymorphone, (c) hydromorphone, (d) 14-hydroxymorphinone, (e) 14-hydroxydihydromorphine (a), (f) oxycodone, (g) 2,2-bis-oxymorphone, and / or (h) any other individual unspecified or unidentified impurity is, as measured by an HPLC or UPLC method that sufficiently separates the opioid compound from such impurities, preferably the HPLC or UPLC system(s)/method(s) described herein, less than or equal to about 2.0 wt %, preferably less than about 1 .5
  • the process(es) of the present invention provide a means of preparing oxymorphone freebase or oxymorphone hydrochloride at higher throughput (faster reaction time / faster cycle time), reduced cost and / or with higher product quality, as determined by for example color / appearance, % impurities, % organic impurities, % inorganic impurities, etc.
  • the present invention is directed to process(es) for the preparation of oxymorphone or pharmaceutically acceptable salts thereof, wherein the hydrogenation of 14-hydroxymorphinone in DMF
  • (dimethylformamide) provides a means of removing (and purging) impurities from the oxymorphone product.
  • the present invention is directed to process(es) for the preparation of oxymorphone or
  • opioid compound when referring to compounds which may be analyzed using the HPLC and / or UPLC systems/methods disclosed herein, include natural opioids, synthetic opioids and opioid derivatives.
  • the opioid compound is selected from the group consisting of morphine, codeine, oxymorphone, oxycodone, hydrocodone, hydromorphone, buprenorphine, benzhydrocodone, and pharmaceutically acceptable salts thereof.
  • the opioid compound is selected from the group consisting of oxymorphone, oxycodone, hydrocodone, hydromorphone and pharmaceutically acceptable salts thereof. More preferably, the opioid compound is selected from the group consisting of oxymorphone, oxycodone and pharmaceutically acceptable salts thereof.
  • the compounds according to the present invention may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention.
  • the enantiomer is present at an enantiomeric excess of greater than or equal to about 80%, more preferably, at an enantiomeric excess of greater than or equal to about 90%, more preferably still, at an enantiomeric excess of greater than or equal to about 95%, more preferably still, at an enantiomeric excess of greater than or equal to about 98%, most preferably, at an enantiomeric excess of greater than or equal to about 99%.
  • the diastereomer is present at an diastereomeric excess of greater than or equal to about 80%, more preferably, at an diastereomeric excess of greater than or equal to about 90%, more preferably still, at an diastereomeric excess of greater than or equal to about 95%, more preferably still, at an diastereomeric excess of greater than or equal to about 98%, most preferably, at an diastereomeric excess of greater than or equal to about 99%.
  • crystalline forms for the compounds of the present invention may exist as polymorphs and as such are intended to be included in the present invention.
  • some of the compounds of the present invention may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.
  • any element shall comprise all isotopes and isotopic mixtures of said element, either naturally occurring or synthetically produced, either with natural abundance or in an isotopically enriched form.
  • a reference to hydrogen includes within its scope 1 H, 2 H (D), and 3 H (T).
  • references to carbon and oxygen include within their scope respectively 12 C, 13 C and 14 C and 16 0 and 18 0.
  • the isotopes may be radioactive or non-radioactive.
  • Radiolabelled compounds of formula (I) may comprise a radioactive isotope selected from the group of 3 H, 11 C, 18 F, 122 l, 123 l, 125 l, 131 1, 75 Br, 76 Br, 77 Br and 82 Br.
  • the radioactive isotope is selected from the group of 3 H, 11 C and 18 F.
  • isolated form shall mean that the compound is present in a form which is separate from any solid mixture with another compound(s), solvent system or biological environment.
  • the present invention is directed to process(es) for the preparation of oxymorphone freebase or oxymorphone hydrochloride in an isolated form.
  • the term "substantially free of a corresponding salt form(s)" when used to described the compound of formula (I) shall mean that mole percent of the corresponding salt form(s) in the isolated base of formula (I) is less than about 5 mole percent, preferably less than about 2 mole percent, more preferably, less than about 0.5 mole percent, most preferably less than about 0.1 mole percent.
  • the present invention is directed to process(es) for the preparation of oxymorphone freebase in a form which is substantially free of corresponding salt form(s).
  • reaction step(s) is performed under suitable conditions, according to known methods, to provide the desired product.
  • a reagent or reagent class/type e.g. base, solvent, etc.
  • the individual reagents are independently selected for each reaction step and may be the same of different from each other.
  • the organic or inorganic base selected for the first step may be the same or different than the organic or inorganic base of the second step.
  • reaction step of the present invention may be carried out in a variety of solvents or solvent systems, said reaction step may also be carried out in a mixture of the suitable solvents or solvent systems.
  • first and second reaction or process steps may be run in the same solvent or solvent system; or alternatively may be run in different solvents or solvent systems following solvent exchange, which may be completed according to known methods.
  • reaction or process step(s) as herein described (or claimed) are allowed to proceed for a sufficient period of time until the reaction is complete, as determined by any method known to one skilled in the art, for example, chromatography (e.g. HPLC, TLC, etc.).
  • chromatography e.g. HPLC, TLC, etc.
  • a "completed reaction or process step” shall mean that the reaction mixture contains a significantly diminished amount of the starting material(s) / reagent(s) and a significantly increased amount of the desired product(s), as compared to the amounts of each present at the beginning of the reaction.
  • the amount of staring material remaining in the reaction mixture upon completion of the reaction or process step is less than about 50 mole %, more preferably less than about 25 mole %, more preferably less than about 20 mole %, more preferably, less than about 15 mole %, more preferably less than about 10 mole %, more preferably less than about 5 mole %, more preferably less than about 2 mole %.
  • the amount of any desired reaction product, present in the reaction mixture, upon completion of the reaction or process step is greater than about 50 mole %, more preferably greater than about 75 mole %, more preferably greater than about 80 mole %, more preferably, greater than about 85 mole %, more preferably greater than about 90 mole %, more preferably greater than about 95 mole %, more preferably greater than about 98 mole %.
  • any of the processes for preparation of the compounds of the present invention it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991 .
  • the protecting groups may be removed at a convenient subsequent stage using methods known from the art.
  • the processes for the preparation of the compounds according to the invention give rise to mixture of stereoisomers
  • these isomers may be separated by conventional techniques such as preparative chromatography.
  • the compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution.
  • the compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-D-tartaric acid and/or (+)-di-p-toluoyl-L-tartaric acid followed by fractional crystallization and regeneration of the free base.
  • the compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.
  • chiral HPLC against a standard may be used to determine percent enantiomeric excess (%ee).
  • the enantiomeric excess may be calculated as follows
  • the salts of the compounds of this invention refer to non-toxic "pharmaceutically acceptable salts.”
  • Other salts may, however, be useful in the preparation of compounds according to this invention or of their pharmaceutically acceptable salts.
  • Suitable pharmaceutically acceptable salts of the compounds include acid addition salts which may, for example, be formed by mixing a solution of the compound with a solution of a
  • suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g., sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed with suitable organic ligands, e.g., quaternary ammonium salts.
  • representative pharmaceutically acceptable salts include, but are not limited to, the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride,
  • acids which may be used in the preparation of pharmaceutically acceptable salts include, but are not limited to, the following: acids including acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, (+)-camphoric acid, camphorsulfonic acid, (+)- (1 S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1 ,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucoronic
  • bases which may be used in the preparation of pharmaceutically acceptable salts include, but are not limited to, the following: bases including ammonia, L-arginine, benethamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)- ethanol, ethanolamine, ethylenediamine, /V-methyl-glucamine, hydrabamine, 1 H-imidazole, L-lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassium hydroxide, 1 -(2-hydroxyethyl)-pyrrolidine, secondary amine, sodium hydroxide, triethanolamine, tromethamine and zinc hydroxide.
  • bases including ammonia, L-arginine, benethamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)- ethanol
  • the present invention is directed to a process for the preparation of oxymorphone freebase comprising hydrogenation of 14-hydroxymorphinone in DMF, as
  • a suitably selected hydrogenating agent preferably hydrogen gas
  • a suitably selected catalyst such as Pd/C catalyst, and the like
  • a suitably selected proton source such as dibasic potassium phosphate, and the like
  • a suitably selected metal scavenger such as EDTA, and the like
  • 14-hydroxymorphinone is dissolved in DMF; wherein the DMF is present in any amount sufficient to dissolve the 14- hydroxymorphinone; preferably, the DMF is present in an amount in the range of from about 1 L/kg to about 10 L/kg (relative to the amount (mass) of 14- hydroxymorphinone), or any amount or range therein, more preferably in an amount in the range of from about 1 L/kg to about 5 L/kg, more preferably in an amount in the range of from about 2 L/kg to about 6 L/kg, more preferably in an amount in the range of from about 2 L/kg to about 4 L/kg, more preferably in an amount in the range of from about 2.3 L/kg to about 4 L/kg, more preferably in an amount in the range of from about 2.5 L/kg to about 3.5 L/kg, more preferably in an amount of about 3 L/Kg;
  • the hydrogen gas is preferably present at a pressure in the range of from about 10 psi to about 75 psi, more preferably at a pressure in the range of from about 20 psi to about 50 psi, or any amount or range therein, more preferably at a pressure in the range of from about 30 psi to about 50 psi, more preferably at a pressure in the range of from about 30 psi to about 40 psi, more preferably at a pressure of about 35 psi;
  • a suitably selected catalyst such as Pd/C, and the like, for example 5% Pd/C, 10%Pd/C, and the like, preferably 5% Pd/C;
  • the catalyst is preferably present in an amount in the range of from about 0.5 wt% to about 2 wt% (relative to the amount (weight) of 14- hydroxymorphinone), or any amount or range therein, more preferably present in an amount in the range of from about 1 wt% to about 2 wt %, more preferably in an amount in the range of from about 1 .5 wt% to about 2 wt%, more preferably in an amount of about 1 .8 wt%;
  • a suitably selected proton source such as dibasic potassium phosphate, monobasic potassium phosphate, phosphoric acid, and the like, preferably dibasic potassium phosphate; wherein the proton source is preferably present in an amount in the range of from about 0.001 kg/kg to about 0.05 kg/kg (relative to the amount (weight) of 14- hydroxymorphinone), or any amount or range therein, more preferably in an amount in the range of from about 0.001 kg/kg to about 0.02 kg/kg, more preferably in an amount in the range of from about 0.001 kg/kg to about 0.015 kg/kg, more preferably in an amount of about 0.01 kg/kg;
  • a suitably selected proton source such as dibasic potassium phosphate, monobasic potassium phosphate, phosphoric acid, and the like, preferably dibasic potassium phosphate;
  • the proton source is preferably present in an amount in the range of from about 0.001 kg/kg to about 0.05 kg/kg (relative
  • a suitably selected metal scavenger such as a suitably selected carboxylic acid (such as EDTA, and the like), a sulfonic acid (such as propylsulfonic acid, and the like), an amine (such as tris-(2- aminoethyl)amino, and the like) or a thiol (such as 1 -propanethiol, and the like), optionally on a solid support, preferably EDTA; wherein the metal scavenger is present in an amount in the range of from about 0.001 kg/kg to about 0.05 kg/kg (relative to the amount of 14-hydroxymorphinone), or any amount or range therein, more preferably in an amount in the range of from about 0.01 kg/kg to about 0.04 kg/kg, more preferably in an amount in the range of from about 0.01 kg/kg to about 0.03 kg/kg, more preferably in an amount of about 0.02 kg/kg;
  • a suitably selected carboxylic acid such as
  • a temperature greater than about room temperature preferably at a temperature in the range of from about 20°C to about 50°C, or any temperature or range therein, more preferably at a temperature in the range of from about 25°C to about 45°C, more preferably at a temperature in the range of from about 30°C to about 40°C, more preferably at a temperature of about 35°C; to yield oxymorphone as its corresponding freebase.
  • the amount of DMF is sufficient to at least partially dissolve the 14-hydroxymorphinone.
  • the mixture comprising the oxymorphone freebase is filtered to remove the catalyst; and the filtercake rinsed with DMF.
  • the oxymorphone freebase is isolated, for example according to known methods.
  • sodium hydrosulfite to improve color or appearance; wherein the sodium hydrosulfite is added in an amount in the range of from about 0.001 kg/kg to about 0.05 kg/kg (relative to the amount (weight) of 14-hydroxymorphinone), or any amount or range therein, preferably in an amount in the range of from about 0.005 kg/kg to about 0.03 kg/kg, more preferably in an amount in the range of from about 0.008 kg/kg to about 0.02 kg/kg, more preferably in an amount of about 0.01 kg/kg.
  • the oxymorphone freebase is then preferably precipitated from the reaction mixture by addition of water; wherein the water is added in an amount in the range of from about 6 L/kg to about 12 L/kg (relative to the amount (weight) of 14-hydroxymorphinone), or any amount or range therein, more preferably, in an amount in the range of from about 8 L/kg to about 12 L/kg, more preferably, in an amount in the range of from about 10 L/kg;
  • the temperature of the reaction mixture is preferably controlled to a temperature less than about 40°C (for example, by jacket temperature, rate of addition of water, etc.), preferably the temperature of the reaction mixture is controlled to a temperature in the range of from about 10°C to about 30°C, or any temperature or range therein, more preferably, the temperature of the reaction mixture is controlled to a temperature in the range of from about 20°C to about 35°C, more preferably, more preferably the temperature of the reaction mixture is controlled to a temperature in the range of from about 30°C to about 35°C.
  • the temperature of the reaction mixture is allowed to increase with the generated exotherm. More preferably, the temperature of the reaction mixture is allowed to increase to a temperature of less than about 50°C, preferably to a temperature less than about 40°C, preferably to a temperature in the range of from about 30°C to about 35°C.
  • the oxymorphone freebase is then preferably isolated, for example, by further cooling the reaction mixture to a temperature less than about 35°C, preferably to a temperature in the range of from about 10°C to about 30°C, or any temperature or range therein, more preferably to a temperature in the range of from about 15°C to about 25°C, more preferably to a temperature of about 20°C, and filtered; followed by optional washing of the filtercake with a suitably selected solvent such as water.
  • the filtercake (comprising the isolated oxymorphone freebase) is dried
  • the present invention is directed to a product
  • the amount (e.g. wt%) of 2,2'-bis-oxymorphone impurity present in the product is, as measured by an HPLC or UPLC method that sufficiently separates the opioid compound from impurities, preferably the HPLC or UPLC system(s)/method(s) described herein, less than or equal to about 0.5 wt%, preferably less than about 0.3 wt%, more preferably less than about 0.2 wt%, more preferably less than about 0.1 wt%, more preferably less than about 0.05 wt%.
  • the present invention is directed to a product
  • the amount (e.g. wt%) of 14-hydroxy-dihydromorphine (a) impurity present in the product is, as measured by an HPLC or UPLC method that sufficiently separates the opioid compound from impurities, preferably the HPLC or UPLC system(s)/method(s) described herein, less than or equal to about 0.5 wt%, preferably less than about 0.3 wt%, more preferably less than about 0.2 wt%, more preferably less than about 0.1 wt%, more preferably less than about 0.05 wt%.
  • the present invention is directed to a product
  • the amount (e.g. wt%) of 8-hydroxyoxymorphone impurity present in the product is, as measured by an HPLC or UPLC method that sufficiently separates the opioid compound from impurities, preferably the HPLC or UPLC system(s)/method(s) described herein, less than or equal to about 0.5 wt%, preferably less than about 0.3 wt%, more preferably less than about 0.2 wt%, more preferably less than about 0.1 wt%, more preferably less than about 0.05 wt%.
  • 14-hydroxymorphinone is prepared according to known methods, for example as described in more detail in Scheme 2, which follows hereinafter.
  • 14-hydroxymorphinone may be prepared from thebaine, according to for example, the process as described in Example 4, which follows hereinafter.
  • the present invention is further directed to a two-step process for the preparation of oxymorphone freebase, as described in more detail in Scheme 2 below.
  • Step 2 Hydrogenation of 14-Hvdroxymorphinone to Oxymorphone Freebase
  • CPS concentrated poppy straw
  • CPS oripavine is dissolved in a mixture of water and a suitably selected peroxyacid forming agent (an agent which, when mixed with hydrogen peroxide will form the corresponding peroxyacid in situ), such as a suitably selected carboxylic acid, a suitably selected carboxylic anhydride or a suitably selected acyl halide, preferably a suitably selected carboxylic acid, as formic acid, acetic acid, propionic acid, and the like, more preferably formic acid, more preferably 90% to 98% formic acid, more preferably 90% formic acid or 98% formic acid;
  • a suitably selected peroxyacid forming agent an agent which, when mixed with hydrogen peroxide will form the corresponding peroxyacid in situ
  • a suitably selected carboxylic acid such as a suitably selected carboxylic acid, a suitably selected carboxylic anhydride or a suitably selected acyl halide, preferably a suitably selected carboxylic acid, as formic acid, acetic
  • the water preferably the total amount of water present during the reaction
  • the water is present in an amount in the range of from about 0.1 kg/kg to about 5 kg/kg (relative to the amount (weight) of CPS oripavine), or any amount or range therein, preferably, in an amount in the range of from about 0.25 kg/kg to about 3 kg/kg, more preferably, in an amount in the range of from about 0.5 kg/kg to about 2 kg/kg, more preferably in an amount in the range of from about 0.8 kg/kg to about 2 kg/kg, more preferably in an amount in the range of from about 1 kg/kg to about 2 kg/kg, more preferably in an amount in the range of from about 1 .4 kg/kg to about 1 .8 kg/kg, more preferably in an amount of about 1 .6 kg/kg; (in an example, the amount of water present in the reaction is in the range of from about 1 .4 L/kg to about 1 .6 L/kg relative to the amount of CPS oripavine);
  • the peroxyacid forming agent preferably the carboxylic acid (preferably 90% formic acid or 98% formic acid), is present in an amount in the range of from about 0.1 kg/kg to about 2 kg/kg (relative to the amount (weight) of CPS oripavine), or any amount or range therein, preferably, in an amount in the range of from about 0.25 kg/kg to about 1 .8 kg/kg, more preferably, in an amount in the range of from about 0.5 kg/kg to about 1 .5 kg/kg, more preferably in an amount in the range of from about 0.75 kg/kg to about 1 .25 kg/kg, more preferably in an amount in the range of from about 0.9 kg/kg to about 1 .2 kg/kg, more preferably in an amount in the range of from about 1 .0 kg/kg to about 1 .1 kg/kg, more preferably in the amount of about 1 .04 kg/kg; (in an example, the peroxyacid forming agent is a 90% formic acid, present
  • (preferably carboxylic acid) is preferably in a range of from about 2:1 to about 1 : 1 , more preferably in a range of from about 1 .8: 1 to about 1 .4: 1 , more preferably in a ratio of about 1 .6: 1 .
  • the total amount of water used in the reaction step described above shall include the water added to dissolve the CPS oripavine and any water which is present in the peroxyacid forming agent (preferably the carboxylic acid).
  • the peroxyacid forming agent is formic acid and the formic acid is added as 90% formic acid
  • the total amount of water shall include the amount of water present in the formic acid plus the amount of water added directly to dissolve the CPS oripavine.
  • the resulting mixture is preferably stirred at a temperature in the range of from about room temperature to about 40°C, preferably at a temperature in the range of from about 30°C to about 40°C, and optionally filtered to remove any insoluble matter.
  • the resulting filtrate is then preferably cooled to about 20°C (or to room temperature) prior to the next addition.
  • a suitably selected metal scavenger such as a suitably selected carboxylic acid (such as EDTA, and the like), a sulfonic acid (such as propyl sulfonic acid, and the like), an amine (such as tris-(2-aminoethyl)amine, and the like) or a thiol (such as 1 -propanethiol, and the like), optionally on a solid support, preferably EDTA; wherein the metal scavenger is present in an amount in the range of from about 0.001 kg/kg to about 0.05 kg/kg (relative to the amount (weight) of CPS oripavine), or any amount or range therein, preferably in an amount in the range of from about 0.01 kg/kg to about 0.03 kg/kg, more preferably in an amount in the range of from about 0.018 kg/kg to about 0.22 kg/kg, more preferably in an amount of
  • a suitably selected carboxylic acid such as EDTA,
  • a suitably selected peroxide such as hydrogen peroxide, a suitably selected peroxyacid salt (such as sodium peroxide, and the like), and the like, preferably about 30% hydrogen peroxide (for example, hydrogen peroxide in the range of about 30% to about 35%, preferably hydrogen peroxide in the range of about 30% to about 32%); wherein the peroxide is present in an amount in the range of from about 0.5 to about 3 molar equivalents (relative to the moles of CPS oripavine), or any amount or range therein, preferably in an amount in the range of about 0.75 to about 2.0 molar equivalents, more preferably in an amount in the range of about 0.9 to about 1 .5 molar equivalents, more preferably, in an amount in the range of from about 1 .0 to about 1 .2 molar equivalents, more preferably in an amount in the range of from about 1 .05 to about 1
  • a suitably selected peroxide such as hydrogen peroxide, a suitably selected peroxy
  • the temperature of the reaction mixture is maintained in the range of from about 20°C to about 25°C (by for example, jacket temperature control, rate of peroxide addition, etc.); and then added a suitably selected acid such as sulfuric acid (to catalyze the peroxyacid formation), and the like; wherein the acid is present in an amount in the range of from about 0.25 to about 0.75 molar equivalents (relative to the moles of CPS oripavine), or any amount or range therein, preferably in an amount in the range of from about 0.4 to about 0.6 molar equivalents, more preferably in an amount of about 0.5 molar equivalents; (preferably, in an embodiment, an amount in the range of from about 0.13 kg/kg to about 0.20 kg/kg (relative to the amount (weight) of CPS oripavine); (in an example, sulfuric acid is added in an amount in the range of from about 0.07 to about 0.1 1 L/kg, relative to the amount of CPS ori
  • the temperature of the reaction mixture is preferably maintained below about 45°C (for example in the range of from about 20°C to about 45°C), more preferably, at a temperature less than about 35°C, more preferably at a temperature less than about 30°C (for example, at a
  • the temperature of the reaction, the amount of hydrogen peroxide, the amount of sulfuric acid and / or the amount of water are selected to maximize yield of the desired product, while minimizing the production of impurities and / or by-products.
  • the amount of hydrogen peroxide added to the reaction mixture is less than or equal to about 1 .2 molar equivalents (relative to the moles of CPS oripavine).
  • the amount of sulfuric acid added to the reaction mixture is less than or equal to about 0.6 molar equivalents (relative to the moles of CPS oripavine).
  • the temperature of the reaction mixture is maintained at less than or equal to about 30°C, preferably at a temperature in the range of from about 20°C to about 25°C, or any amount or range therein.
  • the oxidation reaction of the first step of the process(es) of the present invention may alternatively be completed using a pre-formed peroxyacid such as mCPBA, performic acid, peracetic acid, and the like; rather than forming the peroxyacid in situ, as described above.
  • a pre-formed peroxyacid such as mCPBA, performic acid, peracetic acid, and the like
  • some commercially available peroxyacids such as for example, peracetic acid
  • the oxidation reaction of the first step of the process(es) of the present invention, as described above is preferably stopped at the optimal point (e.g. at the point at which the target conversion amount or starting material consumption amount is reached), based on continuous or periodic testing (e.g. HPLC or other assay method) of the reaction mixture / product stream.
  • the 14-hydroxymorphinone is preferably isolated as a solid, according to known methods, for example by filtration.
  • the reaction mixture comprising the 14-hydroxymorphinone product is quenched by addition of a suitably selected peroxide neutralizer such as sodium sulfite, sodium bis-sulfite, and the like, preferably sodium sulfite, more preferably aqueous sodium sulfite; wherein the peroxide neutralizer is preferably present in an amount sufficient to quench any remaining peroxyacid, preferably in an amount in the range of from about 0.01 to about 0.5 molar equivalents (relative to the moles of CPS oripavine), or any amount or range therein, more preferably, in an amount in the range of from about 0.05 to about 0.25 molar equivalents, more preferably in an amount in the range of from about 0.05 to about 0.15 molar equivalents, more preferably in an amount in the range of from about 0.05 to about 0.1 molar equivalents, more preferably in an amount of about 0.08 molar equivalents (in an example, the peroxide neutralizer is added
  • the temperature of the reaction mixture is preferably maintained at a temperature less than about 30°C, more preferably, the temperature is maintained in the range of from about 15°C to about 25°C, more preferably, the temperature is maintained in the range of from about 20°C to about 25°C (for example, by controlling addition rate).
  • the amount of peroxide neutralizer (for example sodium sulfite) added to the reaction mixture is an amount sufficient to neutralize any excess peroxide or peroxyacid present in the reaction mixture.
  • the amount of peroxide neutralizer preferably sodium sulfite
  • the amount of peroxide neutralizer is the minimum amount necessary to neutralize any peroxyacid or peroxide remaining in the reaction mixture, the amount of which may be calculated from the excess peroxide initially charged (added) to the reaction mixture.
  • the presence or absence of residual peroxide or peroxyacid may be determined by methods know in the art, for example by testing with colorimetric strips.
  • water is added in an amount in the range of from about 1 to about 10 kilograms (relative to one kilogram of CPS oripavine), or any amount or range therein, preferably in an amount in the range of from about 2 to about 8 kilograms, more preferably in an amount in the range of from about 3 to about 6.5 kilograms, more preferably in an amount in the range of from about 4 to about 6 kilograms, more preferably, in an amount of about 5 kilograms.
  • the 14-hydroxymorphinone is then preferably precipitated by addition of a suitably selected organic amine base such as TEA (triethylamine), TMA (trimethylamine), DIPEA (diisopropylethylamine), pyridine, and the like, preferably, TEA; wherein the organic amine base is added in an amount sufficient to adjust the pH of the reaction mixture to a pH sufficient to precipitate 14-hydroxymorphinone, preferably, the organic amine base is added in an amount sufficient to adjust the pH of the reaction mixture to a pH in the range of from about pH 8 to about pH 10, or any pH or pH range therein, more preferably, to a pH in the range of from about pH 8.5 to about pH 9.5, more preferably, to a pH in the range of from about pH 8.6 to about pH 9.2, more preferably to a pH of about pH 8.9;
  • TEA triethylamine
  • TMA trimethylamine
  • DIPEA diisopropylethylamine
  • the temperature of the reaction mixture is maintained below about 50°C (for example, by controlling jacket temperature, the addition rate of the organic amine base, etc.), more preferably, the temperature is maintained below about 40°C, more preferably the temperature is maintained in the range of from about 10°C to about 40°C, more preferably, the temperature is maintained in the range of from about 15°C to about 35°C, more preferably, the temperature is maintained in the range of from about 20°C to about 32°C, more preferably the
  • temperature in maintained in the range of from about 20°C to about 25°C.
  • 14-hydroxymorphinone is preferably isolated as a solid.
  • the 14-hydroxymorphinone is isolated according to known methods, for example, by filtration and with optional drying, and / or optional washing of the filtercake with water and a suitably selected organic solvent, for example a suitably selected alcohol, such as isopropanol, n-butanol, ethanol, and the like, preferably isopropanol.
  • a suitably selected organic solvent for example a suitably selected alcohol, such as isopropanol, n-butanol, ethanol, and the like, preferably isopropanol.
  • the isolated 14-hydroxymorphinone is washed with water, in an amount in the range of from about 1 to about 10 kilograms water (relative to one kilogram of CPS oripavine), or any amount or range therein, preferably in an amount in the range of from about 1 to about 5 kilograms water, more preferably in an amount in the range of from about 1 to about 3 kilograms water, more preferably in an amount of about 2 kilograms water.
  • the 14-hydroxymorphinone is washed with isopropanol (IPA), in an amount in the range of from about 1 to about 4 liters (relative to one kilogram CPS oripavine), or any amount or range therein, preferably in an amount in the range of from about 1 to about 2 liters, more preferably in an amount of about 1 .3 liters.
  • IPA isopropanol
  • the 14-hydroxymorphinone is washed with a suitably selected organic solvent such an alcohol, preferably isopropanol or dried, for example under elevated temperature and / or vacuum conditions to yield a solid with a water content of less than about 10%, as measured by Karl-Fischer (KF), preferably to a water content of less than about 5%, more preferably to a water content of less than about 3%, more preferably to a water content of less than about 2%, more preferably to a water content less than about 1 %.
  • a suitably selected organic solvent such an alcohol, preferably isopropanol or dried, for example under elevated temperature and / or vacuum conditions to yield a solid with a water content of less than about 10%, as measured by Karl-Fischer (KF), preferably to a water content of less than about 5%, more preferably to a water content of less than about 3%, more preferably to a water content of less than about 2%, more preferably to a water content less than about 1 %.
  • the oxidation described in 1 above proceeds according to the following steps:
  • CPS oripavine is charged to the vessel to yield a reaction mixture; and stirring initiated to dissolve the CPS oripavine; iv. EDTA is added to the reaction mixture;
  • reaction mixture is heated to a temperature in the range of from about room temperature to about 40°C;
  • the reaction mixture is stirred at a temperature less than about 28°C; wherein the reaction mixture is stirred until the reaction is deemed complete (preferably until HPLC assay sampling indicates consumption of greater than about 95%, preferably greater than or equal to about 98%, more preferably greater than or equal to about 99%, of the original charge of CPS oripavine or conversion of greater than about 95%, preferably greater than or equal to about 98%, more preferably greater than or equal to about 99%, of the original charge of CPS oripavine to 14- hydroxymorphinone);
  • reaction is quenched by addition of aqueous sodium sulfite; x. 14-hydroxymorphinone is precipitated (and optionally isolated) by addition of an organic amine base.
  • the oxidation described in step 1 above proceeds according to the following steps: i. Water is charged to a reaction vessel; wherein the water is added in an amount of about 1 .5 kg/kg (relative to the mass of CPS oripavine)
  • ii. formic acid is added to the reaction mixture; wherein the formic acid is added in an amount of about 1 .13 kg/kg (relative to the mass of CPS oripavine);
  • CPS is charged to the vessel and stirring initiated to dissolve the CPS oripavine;
  • EDTA is added to the reaction mixture; wherein the EDTA is
  • the reaction mixture is heated to a temperature of about 35°C; vi. hydrogen peroxide is added to the reaction mixture; wherein the hydrogen peroxide is added in an amount of about 1 .14 molar equivalents (relative to the moles of CPS oripavine);
  • sulfuric acid is added in an amount of about 0.17 kg/kg (relative to the mass of CPS oripavine);
  • the reaction mixture is stirred at a temperature less than about 28°C, until HPLC assay sampling indicates consumption of greater than about 95% (preferably greater than or equal to about 98%, more preferably greater than or equal to about 99%) of the original charge of CPS oripavine or conversion of greater than about 9% (preferably greater than or equal to about 98%, more preferably greater than or equal to about 99%) of the original charge of CPS oripavine to 14-hydroxymorphinone;
  • aqueous sodium sulfite is added to the reaction mixture; wherein the aqueous sodium sulfite is added in an amount sufficient to quench the reaction (i.e. to neutralize any remaining peroxyacid);
  • x. 14-hydroxymorphinone is precipitated by addition of an TEA; wherein the TEA is added in an amount sufficient to raise the pH of the reaction mixture to a pH of about 8.5.
  • xi. 14-hydroxymorphinone is isolated by filtration.
  • 14- hydroxymorphinone (preferably prepared as described in Step 1 above) is dissolved in DMF (dimethylformamide) and then reacted with a suitably selected hydrogenating agent, preferably hydrogen gas; in the presence of a suitably selected catalyst such as Pd/C catalyst, and the like; in the presence of a suitably selected proton source such as dibasic potassium phosphate, and the like; and optionally in the presence of a suitably selected metal scavenger such as EDTA, and the like; to yield oxymorphone freebase.
  • a suitably selected hydrogenating agent preferably hydrogen gas
  • a suitably selected catalyst such as Pd/C catalyst, and the like
  • a suitably selected proton source such as dibasic potassium phosphate, and the like
  • a suitably selected metal scavenger such as EDTA, and the like
  • 14-hydroxymorphinone is dissolved in DMF; wherein the DMF is present in any amount sufficient to dissolve the 14- hydroxymorphinone; preferably, the DMF is present in an amount in the range of from about 1 L/kg to about 10 L/kg (relative to the amount (mass) of 14- hydroxymorphinone), or any amount or range therein, more preferably in an amount in the range of from about 1 L/kg to about 5 L/kg, more preferably in an amount in the range of from about 2 L/kg to about 6 L/kg, more preferably in an amount in the range of from about 2 L/kg to about 4 L/kg, more preferably in an amount in the range of from about 2.3 L/kg to about 4 L/kg, more preferably in an amount in the range of from about 2.5 L/kg to about 3.5 L/kg, more preferably in an amount of about 3 L/Kg;
  • the hydrogen gas is preferably present at a pressure in the range of from about 10 psi to about 75 psi, more preferably at a pressure in the range of from about 20 psi to about 50 psi, or any amount or range therein, more preferably at a pressure in the range of from about 30 psi to about 50 psi, more preferably at a pressure in the range of from about 30 psi to about 40 psi, more preferably at a pressure of about 35 psi;
  • a suitably selected catalyst such as Pd/C, and the like, for example 5% Pd/C, 10%Pd/C, and the like, preferably 5% Pd/C;
  • the catalyst is preferably present in an amount in the range of from about 0.5 wt% to about 2 wt% (relative to the amount (weight) of 14- hydroxymorphinone), or any amount or range therein, more preferably present in an amount in the range of from about 1 wt% to about 2 wt %, more preferably in an amount in the range of from about 1 .5 wt% to about 2 wt%, more preferably in an amount of about 1 .8 wt%;
  • a suitably selected proton source such as dibasic potassium phosphate, monobasic potassium phosphate, phosphoric acid, and the like, preferably dibasic potassium phosphate or monobasic potassium phosphate, more preferably dibasic potassium phosphate; wherein the proton source is preferably present in an amount in the range of from about 0.001 kg/kg to about 0.05 kg/kg (relative to the amount (weight) of 14- hydroxymorphinone), or any amount or range therein, more preferably in an amount in the range of from about 0.001 kg/kg to about 0.02 kg/kg, more preferably in an amount in the range of from about 0.001 kg/kg to about 0.015 kg/kg, more preferably, in an amount of about 0.01 kg/kg;
  • a suitably selected proton source such as dibasic potassium phosphate, monobasic potassium phosphate, phosphoric acid, and the like, preferably dibasic potassium phosphate or monobasic potassium phosphate, more preferably dibasic potassium
  • a suitably selected metal scavenger such as a suitably selected carboxylic acid (such as EDTA, and the like), a sulfonic acid (such as propylsulfonic acid, and the like), an amine (such as tris-(2- aminoethyl)amine, and the like) or a thiol (such as 1 -propanethiol, and the like), optionally on a solid support, preferably EDTA; wherein the metal scavenger is present in an amount in the range of from about 0.001 kg/kg to about 0.05 kg/kg (relative to the amount of 14-hydroxymorphinone), or any amount or range therein, more preferably in an amount in the range of from about 0.01 kg/kg to about 0.04 kg/kg, more preferably in an amount in the range of from about 0.01 kg/kg to about 0.03 kg/kg, more preferably in an amount of about 0.02 kg/kg;
  • a suitably selected carboxylic acid such as EDTA
  • a temperature greater than about room temperature preferably at a temperature in the range of from about 20°C to about 50°C, or any temperature or range therein, more preferably at a temperature in the range of from about 25°C to about 45°C, more preferably at a temperature in the range of from about 30°C to about 40°C, more preferably at a temperature of about 35°C; to yield oxymorphone as its corresponding freebase.
  • the amount of DMF is sufficient to at least partially dissolve the 14-hydroxymorphinone.
  • One skilled in the art may theorize that the addition of a greater amount of catalyst may result in increased rate of reaction. However, for the
  • the mixture comprising the oxymorphone freebase is filtered to remove the catalyst; and the filtercake rinsed with DMF.
  • the oxymorphone freebase is isolated, for example according to known methods.
  • sodium hydrosulfite to improve color or appearance; wherein the sodium hydrosulfite is added in an amount in the range of from about 0.001 kg/kg to about 0.05 kg/kg (relative to the amount (weight) of 14-hydroxymorphinone), or any amount or range therein, preferably in an amount in the range of from about 0.005 kg/kg to about 0.03 kg/kg, more preferably in an amount in the range of from about 0.008 kg/kg to about 0.02 kg/kg, more preferably in an amount of about 0.01 kg/kg.
  • the oxymorphone freebase is then preferably precipitated from the reaction mixture by addition of water; wherein the water is added in an amount in the range of from about 6 L/kg to about 12 L/kg (relative to the amount (weight) of 14-hydroxymorphinone), or any amount or range therein, more preferably, in an amount in the range of from about 8 L/kg to about 12 L/kg, more preferably, in an amount in the range of from about 10 L/kg;
  • the temperature of the reaction mixture is preferably controlled to a temperature less than about 40°C (for example, by jacket temperature, rate of addition of water, etc.), more preferably the temperature is controlled to a temperature in the range of from about 10°C to about 37°C, or any temperature or range therein, more preferably, the temperature is controlled to a temperature in the range of from about 20°C to about 35°C, more preferably, the temperature is controlled to a temperature in the range of about 30°C to about 35°C.
  • the temperature of the reaction mixture is allowed to increase with the generated exotherm. More preferably, the temperature of the reaction mixture is allowed to increase to a temperature of less than about 50°C, preferably to a temperature less than about 40°C, preferably to a temperature in the range of from about 30°C to about 35°C.
  • the oxymorphone freebase is then preferably isolated, for example, by further cooling the reaction mixture to a temperature less than about 35°C, preferably to a temperature in the range of from about 10°C to about 30°C, or any temperature or range therein, more preferably to a temperature in the range of from about 15°C to about 25°C, more preferably to a temperature of about 20°C, and filtered; followed by optional washing of the filtercake with a suitably selected solvent such as water.
  • the filtercake (comprising the isolated oxymorphone freebase) is dried, optionally under a temperature greater than room temperature and / or under reduced pressure.
  • step 2 the reduction of 14- hydroxymorphinone described in step 2 above proceeds according to the following steps:
  • VI H 2 gas is introduced into the reaction vessel at 35 psi and 35°C to effect hydrogenation of the 14-hydroxymorphinone; wherein the hydrogenation is continued until the reaction is deemed complete (preferably until HPLC assay sampling indicates consumption of greater than about 95%, preferably greater than or equal to about 98%, more preferably greater than or equal to about 99% of the original charge or conversion of greater than about 95%, preferably greater than or equal to about 98%, more preferably greater than or equal to about 99% of the original charge of 14- hydroxymorphinone to oxymorphone freebase); to yield oxymorphone freebase;
  • reaction mixture comprising the oxymorphone freebase is filtered to remove the catalyst
  • the oxymorphone freebase precipitate optionally isolated by filtration and optionally dried.
  • step 2 the reduction of 14- hydroxymorphinone described in step 2 above proceeds according to the following steps:
  • EDTA is charged to the vessel; wherein the EDTA is added in an amount of about 0.02 kg/kg (relative to the mass of 14- hydroxymorphinone);
  • dibasic potassium phosphate is charged to the vessel; wherein the dibasic potassium phosphate is added in an amount of about 0.01 kg/kg (relative to the mass of 14-hydroxymorphinone);
  • DMF is charged to the vessel; wherein the DMF is added in an amount of about 3 L/kg (relative to the mass of 14- hydroxymorphinone);
  • v. 5% Pd/C catalyst is charged to the vessel; wherein the catalyst is added in an amount of about 0.018 kg/kg (relative to the mass of 14-hydroxymorphinone);
  • H 2 gas is introduced into the reaction vessel at 35 psi and 35°C to effect hydrogenation of the 14-hydroxymorphinone; wherein the hydrogenation is continued until the HPLC assay sampling indicates consumption of greater than about 95% (preferably greater than or equal to about 98%, more preferably greater than or equal to about 99%) of the original charge of 14- hydroxymorphinone or conversion of greater than about 95% (preferably greater than or equal to about 98%, more preferably greater than or equal to about 99% of the original charge of 14- hydroxymorphinone to oxymorphone freebase; to yield oxymorphone freebase;
  • reaction mixture is filtered to remove the catalyst; sodium hydrosulfite is added to the filtrate; wherein the sodium hydrosulfite is added in an amount of about 0.01 kg/kg (relative to the mass of 14-hydroxymorphinone);
  • water is added to the filtrate; wherein the water is added in an amount of about 10 L/kg (relative to the mass of 14- hydroxymorphinone); to yield oxymorphone freebase as a precipitate;
  • the oxymorphone freebase precipitate is optionally isolated by filtration and optionally dried.
  • the present invention is directed to a process for the hydrogenation of 14-hydroxymorphinone to oxymorphone freebase, wherein the yield of the oxymorphone freebase (product) is greater than about 80%, preferably greater than about 85%, more preferably greater than about 88%, for example, in the range of from about 80% to about 100%, more preferably, in the range of from about 88% to about 92%, more preferably, about 90%.
  • the oxymorphone freebase is reacted with a suitably selected acid, preferably HCI, to yield the corresponding acid addition salt, preferably the corresponding pharmaceutically acceptable salt.
  • a suitably selected acid preferably HCI
  • the oxymorphone freebase is dissolved in a mixture of water and a suitably selected alcohol, such as ethanol, methanol, and the like, preferably ethanol; with heating to a temperature of about 50°C; to the reaction mixture is then added hydrochloric acid (HCI); wherein the amount of HCI added is sufficient to adjust the pH of the resulting mixture to about pH 1 ; and the resulting mixture heated to a temperature of about 50°C; to yield oxymorphone hydrochloride.
  • a suitably selected alcohol such as ethanol, methanol, and the like, preferably ethanol
  • reaction mixture comprising oxymorphone hydrochloride is optionally charged with powdered activated carbon and filtered.
  • reaction mixture comprising oxymorphone hydrochloride (or the filtrate following treatment with activated carbon and filtration) is then added isopropanol; wherein the isopropanol has been heated to about 50°C.
  • the resulting mixture is then cooled, preferably to a temperature of less than about room temperature, more preferably to about 20°C; to yield a precipitate of oxymorphone hydrochloride.
  • the reaction mixture comprising oxymorphone hydrochloride is seeded with the desired crystalline form of oxymorphone hydrochloride.
  • the oxymorphone hydrochloride is preferably isolated and dried according to known methods, for example, by cooling filtration, with optional washing of the filtercake with a suitable selected, cooled solvent, for example isopropanol at 20°C.
  • the isolated oxymorphone hydrochloride is preferably dried (optionally under vacuum) in the presence of water.
  • Step 1 wherein CPS oripavine is oxidized to 14-hydroxymorphinone
  • organic impurities such as 8-hydroxyoxymorphone and / or 2,2-bis-oxymorphone.
  • any residual (unreacted) CPS oripavine would be expected to convert to the undesired organic impurity
  • 14-hydroxymorphinone is isolated as a solid (by addition of an organic amine base) and any residual peroxide is either decomposed (by reacting with for example, aqueous sodium sulfite) or removed during isolation, thereby limiting (preferably minimizing) the formation of 8-hydroxyoxymorphone and / or 2,2'-bis-oxymorphone. Further, isolation of 14-hydroxymorphinone reduces the amount of residual (unreacted) CPS oripavine which is present in the reaction mixture, thereby limiting the amount of hydromorphone (an organic impurity) which is produced.
  • Step 2 wherein 14- hydroxymorphinone is hydrogenated to oxymorphone free base
  • acidic solvent can lead to the formation of the undesired organic impurity 14- hydroxydihydromorphine (a).
  • 14- hydroxymorphinone is dissolved in for example, dimethylformamide, without the addition of acid thereby limiting (preferably minimizing) the formation of 14- hydroxydihydromorphine (a).
  • At least one advantage of the process(es) of the present invention is a decrease in the amount of organic impurities present in the final isolated oxymorphone freebase product.
  • CPS oripavine is dissolved in acidic water and the oxymorphone is precipitated using sodium hydroxide, resulting in the formation of inorganic salts as byproducts.
  • 14-hydroxymorphinone is isolated as a solid using an organic amine base, for example triethylamine, and the hydrogenation of 14-hydroxymorphinone is carried out in DMF and the oxymorphone freebase is precipitated from water, without the need for additional acid or base, resulting in a decrease in the formation of inorganic salts (impurities)remaining in the final oxymorphone freebase product.
  • organic amine base for example triethylamine
  • synthesis products are listed as having been isolated as a residue. It will be understood by one of ordinary skill in the art that the term “residue” does not limit the physical state in which the product was isolated and may include, for example, a solid, an oil, a foam, a gum, a syrup, and the like.
  • Examples 1 -4 describe recipes / procedures for the synthesis of the title compounds.
  • One or more batches of the said compounds were prepared according to the recipes / procedures as described below.
  • the physical properties (e.g. MS + , 1 H NMR, etc.) listed at the end of the synthesis descriptions below are the physical properties measured for a representative sample of the prepared compound, from a batch prepared according to the described procedure and/or are a range of measured values from multiple batches run according to the procedure as described.
  • CPS oripavine (contained wt.), water (1 .0 kg/kg relative to oripavine), and formic acid (98%, 1 .04 kg/kg relative to oripavine) were charged to a reactor.
  • the resulting suspension was agitated, heated to a temperature in the range of 30-40°C, and held for 30-60 minutes.
  • the resulting mixture was filtered while maintaining temperature in the range of 30-40°C, to remove any insoluble matter.
  • the filtercake was washed with water (0.6 L/kg relative to oripavine). The water wash was added to the filtrate and the combined mixture added to a reactor.
  • EDTA ethylenediaminetetraacetic acid, 0.02 molar equivalents relative to oripavine
  • Hydrogen peroxide (30%, 1 .08 molar equivalents relative to starting CPS oripavine) was dosed to the reaction solution over 30-
  • Triethylamine was added to attain a pH of 8.6-9.2, while maintaining the temperature at 20-32°C, to precipitate the product.
  • the resulting slurry was cooled to 20-25°C and held for a minimum of 60 minutes.
  • the product 14- Hydroxymorphinone, 14-HM
  • the wet product was dried at a temperature in the range of 35-45°C, under vacuum with a slight air sweep. Typical yield (based on multiple runs of this reaction step) was in the range of 85-90%.
  • 14-Hydroxymorphinone 14-HM
  • dimethylformamide 14-HM
  • EDTA ethylenediaminetetraacetic acid
  • potassium phosphate dibasic 0.01 kg/kg relative to 14-HM
  • Pd/C 5%, 0.01 1 kg/kg relative to 14-HM
  • CPS oripavine 200 g, contained
  • water (200 mL) water (200 mL), and formic acid (98%, 170 mL) were charged to a reactor.
  • the suspension was agitated, heated to 37.3°C, and held for 52 minutes.
  • the reaction was filtered to remove any insoluble matter.
  • the filtercake was washed with water (120 mL).
  • the water wash was added to the filtrate and the combined mixture added to a reactor.
  • Ethylenediaminetetraacetic acid (EDTA, 3.94 g) was charged into the reactor and the solution was cooled to 21 .5°C.
  • Hydrogen peroxide (30%, 82.44 g) was dosed to the reaction solution over 62 minutes.
  • the product (14-HM) was filtered and washed with water (200 mL), then washed with isopropanol (260 mL). The wet product was dried at ⁇ 50°C under vacuum with a slight air sweep. The 14- HM yield was 85%.
  • Residue On Ignition (%) 15 0.00 0.01 Residual Organic Solvent (DMF) 761 Residual Organic Solvent (TEA) ND Residual Organic Solvent (IPA) ND
  • a reactor vessel was purged with nitrogen.
  • CPS oripavine 250-350kg
  • water (1 .4-1 .8 L/kg relative to oripavine
  • formic acid 90%, 1 .1 -1 .22 kg/kg relative to oripavine
  • EDTA ethylenediaminetetraacetic acid
  • the pH of the reaction mixture was adjusted to a pH in the range of 8.2-8.7 (by addition of triethylamine), and the reaction mixture held with stirring at this pH for about 15 minutes.
  • the pH was further adjusted to a final pH in the range of pH 8.6-9.2 (by addition of triethylamine), and the reaction mixture held, with agitation of an additional 1 -23 hours to yield 14-hydroxymorphinone as a precipitate.
  • the precipitate was isolated by centrifuge, the wet cake washed with water (81 -85 kg) and isopropanol (81 -85 kg) and dried at 35-45°C under 25" hg vacuum.
  • 14-Hydroxymorphinone 14-HM 200-315 kg
  • ethylenediaminetetraacetic acid EDTA, 0.02 kg/kg relative to 14-HM
  • potassium phosphate dibasic (0.01 kg/kg relative to 14-HM)
  • Nitrogen gas was added to inert the reactor.
  • Dimethylformamide (DMF, 2.3-4 L/kg relative to 14-HM) was then added and the reaction mixture agitated for 25-30 min.
  • Pd/C (5%, 0.01 -0.02 kg/kg relative to 14-HM) catalyst was charged to a
  • reaction mixture was hydrogenated at a temperature in the range of 25-45°C and at a hydrogen pressure in the range of 30-40 psi until the reaction was deemed "complete" (about 2 hours), with total time determined by an in-process test to attain a level of not less than (NLT) 99.5% w/w of oxymorphone freebase to 14-hydroxymorphinone.
  • NLT not less than
  • dimethylformamide (DMF, 1 -2 L/kg relative to 14-HM). Nitrogen gas was added to inert the reactor. Sodium hydrosulfite (0.01 kg/kg relative to 14-HM) was charged, nitrogen gas added to inert the reactor, followed by addition of water (9.5-10.5 L/kg (relative to 14-HM) at 20-30°C. The reaction mixture cooled to a temperature in the range of 15-25°C and held at this temperature for 1 -15 hours. Addition of water resulted in the precipitation of the
  • Nitrobenzene (water content 0.34% KF, 275 g) was added into a 350 ml_ reaction. The jacket temperature was increased to 1 15°C and 25 mg were distilled. Water (0.327 g) was added to set the water content to 0.27 wt%.
  • the resulting suspension was then slowly cooled to -5°C over about 2 hours, then stirred at -5°C for 60 min, then filtered and the filter cake washed with acetone (2x20 g, precooled to -5°C).
  • the wet cake was charged into the reactor, suspended in water (376 g) and acetic acid (14 g).
  • the pH of the reaction mixture was adjusted to a pH in the range of 4-8-5.0 with triethylamine.
  • the mixture was stirred until an almost clear, slightly turbid solution was formed.
  • activated carbon NORIT CN1 2.5 g
  • the mixture stirred at 25°C for 1 -2 hours and filtered.
  • the filter residue was washed with water (2x25 g).
  • CPS oripavine also known as 6,7,8, 14-tetradehydro-4, 5a-epoxy- 6-methoxy-17-methylmorphinan-3-ol
  • CELITE which is introduced into the reaction with the CPS
  • CPS Oripavine in a mixture with CELITE
  • water and 90% w/w or 98% w/w formic acid are charged to a reactor vessel.
  • the suspension is agitated and heated to 30-40°C.
  • the slurry is held at this temperature for 30-60 minutes and then cooled to 20-25°C.
  • Ethylenediaminetetraacetic acid (EDTA, 0.02 molar equivalents relative to Oripavine) is charged into the reactor.
  • a charge of hydrogen peroxide is dosed to the Oripavine solution over 30-60 minutes, while maintaining a reaction temperature of 20-25°C.
  • Sulfuric acid (95-98%) is added after the addition of hydrogen peroxide.
  • Sulfuric acid is charged into the reactor at a rate that maintains a temperature below 25°C.
  • the reaction mixture is stirred for approximately 12-14 hours with an in-process test to attain a level of NLT (not less than) 99.5 % w/w (equal to approximately 98 Area%) of product.
  • the mixture is quenched with aqueous sodium sulfite solution at a rate that maintains a temperature of 20-25°C, over 20-30 minutes.
  • the reaction slurry is agitated for approximately 30 minutes and diluted with water.
  • reaction mixture is heated to 40-45°C to dissolve the product, leaving the insoluble CELITE to be filtered as hot filtration to ensure product solubility in the reaction mixture. After CELITE filtration, the reaction mixture is cooled to room temperature.
  • the product (14-Hydroxymorphone) is precipitated with the addition of triethylamine to the desired pH in the range of 8.6 to 9.2.
  • the batch is precipitated with the addition of triethylamine to the desired pH in the range of 8.6 to 9.2.
  • Example 6 Prophetic Example
  • CPS oripavine also known as 6,7,8, 14-tetradehydro-4, 5a-epoxy- 6-methoxy-17-methylmorphinan-3-ol
  • CELITE which is introduced into the reaction with the CPS
  • CPS Oripavine in a mixture with CELITE
  • water and 90% w/w or 98% w/w formic acid are charged to a reactor vessel.
  • the suspension is agitated and heated to 30-40°C.
  • the slurry is held at this temperature for 30-60 minutes and then cooled to 20-25°C.
  • Ethylenediaminetetraacetic acid (EDTA, 0.02 molar equivalents relative to Oripavine) is charged into the reactor.
  • a charge of hydrogen peroxide is dosed to the Oripavine solution over 30-60 minutes, while maintaining a reaction temperature of 20-2 °C.
  • Sulfuric acid (95-98%) is added after the addition of hydrogen peroxide.
  • the mixture is quenched with aqueous sodium sulfite solution at a rate that maintains a temperature of 20-25°C, over 20-30 minutes.
  • the reaction slurry is agitated for approximately 30 minutes.
  • the reaction mixture is heated to 45-50°C to dissolve the product, leaving the insoluble CELITE to be filtered as hot filtration to ensure product solubility in the reaction mixture.
  • CELITE filtration the reaction mixture is cooled to room temperature and diluted with water and product precipitation is followed.
  • the product (14-HM) is precipitated with the addition of triethylamine to the desired pH in the range of 8.6 to 9.2.
  • the batch temperature is maintained below 30°C through both jacket temperature control and controlled addition of the triethylamine.
  • the reaction slurry is held at room temperature for 30 to 60 minutes, and is then filtered.
  • the cake is washed with water and isopropanol.
  • the wet product is dried at 50°C under vacuum with a slight air sweep.
  • the product (14-Hydroxymorphone) is taken forward into further reaction steps, as desired.
  • the HPLC and UPLC methods of the present invention may be run on any suitably HPLC or UPLC system.
  • Suitably examples include but are not limited to UPLC Waters H-Call, Agilent 1290, Agilent 1 100, Agilent 1200, Agilent 1260, Water Alliance 2695, and the like.
  • At least one mobile phase is a buffer such as a mixed phosphate buffer in deionized water, an ammonium formate buffer in water or equivalent; wherein the pH of the buffer is controlled to effect separation of the product and impurity peaks.
  • the buffer is a mixed phophate buffer in water
  • the pH of the buffer is adjusted and / or controlled by the ratio of the mono-potassium phophate and di-potassium phosphate salts dissolved in the water.
  • Product impurity profiles were determined using a Water Acquity UPLC system and the following parameters: (a) Column: Waters Acquity UPLC or equivalent equipped with a BEH C18, 100 x 2.1 mm, 1 .7 m (PART #186002352) column or equivalent, preferably with a Waters Column Stabilized (PART
  • Mobile Phase A was 10 mM mixed phosphate buffer in deionized water prepared by mixing 0.050 ⁇ 0.005 g potassium dihydrogen phosphate (KH 2 P0 4 ) and 1 .678 ⁇ 0.025 g dipotassium hydrogen phosphate (K 2 HP0 4 ) in 1000 mL of HPLC Grade water and sonicating the resulting mixture to ensure that the buffer salts are dissolved. After dissolution, pH of the mobile phase is measured to confirm that it is in the range of pH 8.3-8.4.
  • Mobile Phase B was HPLC Grade (or purer) acetonitrile. Retention times for selected products and impurities using the method described above, and Gradient Table 2 were as listed in Table 3, below.
  • Product impurity profiles may be determined using a Water Acquity UPLC system and the following parameters: (a) Column: Waters XBridge HPLC C18, 10 150 x 3.0 mm, 3.5 ⁇ (PART #186003028) column or equivalent; (b) Injection Volume: 7.5 ⁇ _; (c) Column Temperature: 68°C; (d) Detector Wavelength: 284 mm; (e) Flow Rate: 0.6 mL/min; (f) Run Time: 30 Min; and using the Gradient Timetable in Table 4, below.
  • Mobile Phase A was 10 mM mixed phosphate buffer in deionized water prepared by mixing 0.050 ⁇ 0.005 g potassium dihydrogen phosphate (KH 2 P0 4 ) 5 and 1 .678 ⁇ 0.025 g dipotassium hydrogen phosphate (K 2 HP0 4 ) in 1000 mL of HPLC Grade water and sonicating the resulting mixture to ensure that the buffer salts are dissolved. After dissolution, pH of the mobile phase is measured to confirm that it is in the range of pH 8.3-8.4.
  • Mobile Phase B was HPLC Grade (or purer) acetonitrile.
  • Example 8 The method as described in Example 8 is also useful for the analysis of benzhydrocodone.
  • Product impurity profiles may be determined using a Water Acquity UPLC system and the following parameters: (a) Column: Waters Acquity UPLC BEH C18, 100 x 2.1 mm, 1 .7 ⁇ (PART #186002352) column or equivalent, preferably with a Waters Column Stabilized (PART #205000489); (b) Injection Volume: 1 .6 ⁇ _; (c) Column Temperature: 68°C; (d) Detector Wavelength: 284 mm; (e) Flow Rate: 0.60 mL/min; (I) Run Time: 9 Min; and using the Gradient Timetable in Table 6, below.
  • Mobile Phase A was 10 mM mixed phosphate buffer in deionized water prepared by mixing 0.050 ⁇ 0.005 g potassium dihydrogen phosphate (KH 2 P0 4 ) 5 and 1 .678 ⁇ 0.025 g dipotassium hydrogen phosphate (K 2 HP0 4 ) in 1000 mL of HPLC Grade water and sonicating the resulting mixture to ensure that the buffer salts are dissolved. After dissolution, pH of the mobile phase is measured to confirm that it is in the range of pH 8.3-8.4.
  • Mobile Phase B was HPLC Grade (or purer) acetonitrile.
  • Product impurity profiles may be determined using a Water Acquity UPLC system and the following parameters: (a) Column: Waters XBridge Shield RP18 , 150 x 3.0 mm, 3.5 ⁇ (PART #186003041 ) column or equivalent; (b) Injection Volume: 5 ⁇ ; (c) Column Temperature: 40°C; (d) Detector Wavelength: 284 mm; (e) Flow Rate: 0.65 mL/min; (I) Run Time: 30 Min; and using the Gradient Timetable in Table 8, below.
  • Mobile Phase A was 1 .32g/L ammonium formate, pH 9.6 adjusted with ammonium hydroxie, prepared by dissolving 1 .32 ⁇ 0.01 g of ammonium formate in 1 L of water and mixing thoroughly. Mobile Phase A was then filtered through a pre-conditioned Mobile Phase Filtration Cartridge (3M EmporeTM SDB-XC, PN2240 or 3M EmporeTM SDB-RPS Extraction Disk Cartridge PN2241 ). After filtering, the pH of Mobile Phase A was adjusted to pH 9.6 by addition of 28% ammonium hydroxide, as needed. (NOTE: Mobile Phase A may alternatively be the mixed phosphate buffer in deionized water as described in Examples 7-9 above)
  • Mobile Phase B was HPLC Grade (or purer) acetonitrile.

Abstract

La présente invention concerne un procédé de préparation d'oxymorphone sous forme de base libre, comprenant l'hydrogénation d'une 14-hydroxymorphinone dans du DMF pour obtenir l'oxymorphone sous forme de base libre, de préférence une oxymorphone sous forme de base libre ayant un aspect, une pureté et/ou un rendement améliorés. Une oxymorphone sous forme de base libre ayant un profil d'impuretés amélioré est en outre décrite. La présente invention concerne en outre un système/procédé HPLC ou UPLC pour l'analyse des composés opioïdes.
PCT/US2016/033494 2015-05-20 2016-05-20 Procédé de préparation d'oxymorphone sous forme de base libre WO2016187522A1 (fr)

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