WO2015095585A2 - Synthese de chlorhydrate d'oxycodone - Google Patents

Synthese de chlorhydrate d'oxycodone Download PDF

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Publication number
WO2015095585A2
WO2015095585A2 PCT/US2014/071264 US2014071264W WO2015095585A2 WO 2015095585 A2 WO2015095585 A2 WO 2015095585A2 US 2014071264 W US2014071264 W US 2014071264W WO 2015095585 A2 WO2015095585 A2 WO 2015095585A2
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WIPO (PCT)
Prior art keywords
oxycodone
sulfate
hydroxycodeinone
base
acid
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PCT/US2014/071264
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English (en)
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WO2015095585A3 (fr
WO2015095585A8 (fr
Inventor
Zinovy Itov
Vladimir F. KUZNETSOV
Iouri Voitsekhovski
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Cody Laboratories, Inc.
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Priority claimed from US14/132,910 external-priority patent/US10227354B2/en
Priority claimed from US14/132,825 external-priority patent/US8846923B1/en
Priority claimed from US14/132,737 external-priority patent/US9062062B1/en
Application filed by Cody Laboratories, Inc. filed Critical Cody Laboratories, Inc.
Priority to CA2934527A priority Critical patent/CA2934527A1/fr
Priority to CN201480075277.9A priority patent/CN106164078A/zh
Priority to EP14824727.3A priority patent/EP3083632A2/fr
Publication of WO2015095585A2 publication Critical patent/WO2015095585A2/fr
Publication of WO2015095585A3 publication Critical patent/WO2015095585A3/fr
Publication of WO2015095585A8 publication Critical patent/WO2015095585A8/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

  • Oxycodone hydrochloride is an opioid receptor agonist that is indicated for relief of moderate to severe pain. Preparation of oxycodone hydrochloride from thebaine through intermediate preparation of 14-hydroxycodeinine is a well-known technology that has been employed since 1916.
  • FIG. 1 shows a prior art conventional synthetic route for preparation of oxycodone hydrochloride by oxidation of thebaine to form 14-hydroxycodeinone (ABUK), reduction of 14-hydroxycodeinone to form oxycodone base, and conversion of the base to oxycodone hydrochloride.
  • a synthetic impurity, 7,8-dihydro-8,14- dihydroxycodeinone, (DHC) interconverts by hydration dehydration from/to 14- hydroxycodeinone.
  • Synthetic methods are provided for preparation of oxycodone hydrochloride with an improved impurity profile.
  • Thebaine is converted to 14-hydroxycodeinone sulfate intermediate to minimize a 7,8-dihydro-8,14-dihydroxycodeinone impurity.
  • Efficient methods for conversion of oxycodone base to oxycodone hydrochloride are provided to minimize 14-hydroxycodeinone impurity in the final product.
  • a method for preparation of oxycodone comprising exposing thebaine to hydrogen peroxide or peroxyacid and another organic acid in the presence of sodium hydrogen sulfate, sodium sulfate, potassium sulfate, potassium hydrogen sulfate and/or sulfuric acid in an aqueous reaction mixture to form 14-hydroxycodeinone sulfate; reducing the 14-hydroxycodeinone sulfate in the presence of a catalyst to form oxycodone base; and dissolving the oxycodone base in an aqueous organic acid to form an oxycodone organic acid salt.
  • the oxycodone organic acid salt is converted to oxycodone hydrochloride by adding hydrochloric acid or ammonium chloride to the oxycodone organic acid salt to form oxycodone hydrochloride.
  • the sodium hydrogen sulfate, sodium sulfate, potassium sulfate and/or potassium hydrogen sulfate is added to the aqueous reaction mixture prior to addition of the hydrogen peroxide or peroxyacid.
  • the another organic acid is formic acid.
  • the oxycodone organic acid salt is oxycodone acetate.
  • a method for preparing oxycodone comprising exposing thebaine to hydrogen peroxide or peroxyacid and another organic acid in the presence of sodium hydrogen sulfate, sodium sulfate, potassium sulfate, potassium hydrogen sulfate and/or sulfuric acid in an aqueous reaction mixture to form 14-hydroxycodeinone sulfate; reducing the 14-hydroxycodeinone sulfate in the presence of a catalyst to form oxycodone base; and dissolving the oxycodone base in an aqueous organic acid to form an oxycodone organic acid salt.
  • the method further comprises adding hydrochloric acid or ammonium chloride to the oxycodone organic acid salt to form oxycodone hydrochloride, wherein any 8,14- dihydroxy-7,8-dihydrocodeinone impurity present in the oxycodone base is not converted to 14-hydroxycodeinone.
  • a method for preparation of oxycodone hydrochloride comprising oxidizing thebaine to provide 14-hydroxycodeinone sulfate and further comprising isolating the 14-hydroxycodeinone sulfate from the aqueous reaction mixture to form isolated 14-hydroxycodeinone sulfate or a hydrate thereof.
  • the 14-hydroxycodeinone sulfate hydrate is selected from a hemihydrate, monohydrate, sesquihydrate, or dihydrate.
  • a method for providing oxycodone hydrochloride comprising reducing the isolated 14-hydroxycodeinone sulfate or a hydrate thereof in the presence of the catalyst to form oxycodone base.
  • the oxycodone base is purified to form purified oxycodone base.
  • the purified oxycodone base has not more than 0.10%, 0.05%, or 0.01% of a 8,14-dihydroxy-7,8-dihydrocodeinone (DHC, DHDHC) impurity.
  • a method for converting oxycodone base to oxycodone hydrochloride comprising dissolving oxycodone base in an aqueous organic acid.
  • the dissolving comprises complete or partial dissolution of the oxycodone base in the aqueous organic acid.
  • the aqueous organic acid is aqueous acetic acid.
  • the dissolving step is performed at a temperature within the range from about 0°C to about 70°C; about 0°C to about 60°C; about 0°C to about 50°C; or about 10°C to 40°C; or at ambient temperature.
  • the purified oxycodone hydrochloride has not more than 0.15%, 0.10%, 0.05%, or 0.01% of an 8,14-dihydroxy-7,8- dihydrocodeinone (DHC) impurity.
  • DHC 8,14-dihydroxy-7,8- dihydrocodeinone
  • methods comprise purifying the oxycodone hydrochloride by a method comprising crystallizing the oxycodone hydrochloride to form purified oxycodone hydrochloride.
  • the crystallizing is performed by addition of water and/or one or more water miscible organic solvents to the oxycodone hydrochloride to form the purified oxycodone hydrochloride.
  • the crystallizing is performed at a temperature range within about 0°C to about 30°C; or from about 5°C to about 15°C.
  • methods for purifying oxycodone hydrochloride comprising crystallizing to form purified oxycodone hydrochloride from water or a combination of water and one or more water miscible organic solvents selected from the group consisting of isopropyl alcohol, ethanol, methanol, methyl ethyl ketone and acetone.
  • the purified oxycodone hydrochloride has less than 0.01% 14-hydroxycodeinone; less than 0.001% 14-hydroxycodeinone; less than 0.0005%) 14-hydroxycodeinone; or less than 0.0002%> 14-hydroxycodeinone.
  • thebaine starting material is selected or obtained from concentrated poppy straw, anhydrous or raw thebaine alkaloid. In some embodiments, thebaine starting material is obtained from a commercial and/or synthetic source.
  • a method for preparation of 14- hydroxycodeinone sulfate or a hydrate thereof comprising exposing thebaine to hydrogen peroxide or peroxyacid and another organic acid in the presence of sodium hydrogen sulfate, sodium sulfate, potassium sulfate, potassium hydrogen sulfate and/or sulfuric acid in an aqueous reaction mixture; and isolating a precipitate of 14- hydroxycodeinone sulfate or a hydrate thereof from the reaction mixture.
  • the another organic acid is formic acid.
  • the 14- hydroxycodeinone sulfate has less than 0.05%>, 0.025%), or 0.01% of DHC impurity.
  • methods are provided for purifying 14- hydroxycodeinone sulfate by a method comprising recrystallization from an aqueous solvent.
  • a compound comprising 14- hydroxycodeinone sulfate or a hydrate thereof.
  • the isolated 14-hydroxycodeinone sulfate hydrate is a 14-hydroxycodeinone sulfate hemihydrate, monohydrate, sesquihydrate or dihydrate. 14-hydroxycodeinone hemisulfate monohydrate is provided.
  • the isolated 14-hydroxycodeinone sulfate or hydrate thereof exhibits not more than 0.05 %, 0.025%, or 0.01% DHC impurity level.
  • a method for preparation of oxycodone base from 14-hydroxycodeinone sulfate or a hydrate thereof comprising reducing the 14-hydroxycodeinone sulfate or hydrate thereof in the presence of a catalyst to form oxycodone base.
  • the oxycodone base is purified to form purified oxycodone base.
  • a method for preparation of oxycodone hydrochloride from oxycodone base comprising dissolving oxycodone base in an aqueous organic acid; and adding hydrochloric acid or ammonium chloride to the solution to form oxycodone hydrochloride.
  • the dissolving comprises complete or partial dissolution of the oxycodone base in the aqueous organic acid.
  • the aqueous organic acid is selected from tartaric acid, fumaric acid, trifluoroacetic acid, trichloroacetic acid, monochloroacetic acid, lactic acid, glycolic acid, and acetic acid.
  • the aqueous organic acid is aqueous acetic acid.
  • the oxycodone hydrochloride is crystallized by adding water and/or one or more water miscible organic solvents to the oxycodone hydrochloride to form purified oxycodone hydrochloride.
  • the crystallizing is performed at a temperature range within about 0°C to about 30°C; or at a temperature range of from about 5°C to about 35°C.
  • a method for preparation of oxycodone base comprising treating 14-hydroxycodeinone sulfate or a hydrate thereof with calcium acetate or barium acetate to prepare a 14-hydroxycodeinone acetate solution; and reducing the 14-hydroxycodeinone acetate solution to form oxycodone base.
  • a method for preparing oxycodone comprising exposing thebaine to hydrogen peroxide or peroxyacid and another organic acid in the presence of sodium hydrogen sulfate, sodium sulfate, potassium sulfate, potassium hydrogen sulfate and/or sulfuric acid in an aqueous reaction mixture to form 14-hydroxycodeinone sulfate; reducing the 14-hydroxycodeinone sulfate in the presence of a catalyst to form oxycodone base; and dissolving the oxycodone base in an aqueous organic acid to form an oxycodone organic acid salt.
  • the another organic acid is formic acid.
  • the method further comprises adding hydrochloric acid or ammonium chloride to the oxycodone organic acid salt to form oxycodone hydrochloride.
  • the exposing step comprises wherein the sodium hydrogen sulfate, sodium sulfate, potassium sulfate and/or potassium hydrogen sulfate is added to the aqueous reaction mixture prior to addition of the hydrogen peroxide or peroxyacid.
  • the reducing step employs a catalyst selected from the group consisting of palladium on active carbon (Pd/C), Pd/C/FeCl 3 , Pd/C/Fe(III) hydroxide or oxide, Pd/Al 2 0 3 , Pt/C, Pt/Al 2 0 3 , Pd/BaS0 4 , Raney Ni-catalyst,
  • a catalyst selected from the group consisting of palladium on active carbon (Pd/C), Pd/C/FeCl 3 , Pd/C/Fe(III) hydroxide or oxide, Pd/Al 2 0 3 , Pt/C, Pt/Al 2 0 3 , Pd/BaS0 4 , Raney Ni-catalyst,
  • a method for preparing oxycodone comprising: exposing thebaine to hydrogen peroxide or peroxyacid and another organic acid in the presence of sodium hydrogen sulfate, sodium sulfate, potassium sulfate, potassium hydrogen sulfate and/or sulfuric acid in an aqueous reaction mixture to form 14-hydroxycodeinone sulfate; isolating the 14-hydroxycodeinone sulfate from the aqueous reaction mixture to form isolated 14-hydroxycodeinone sulfate or a hydrate thereof; reducing the isolated 14-hydroxycodeinone sulfate in the presence of a catalyst to form oxycodone base; and dissolving the oxycodone base in an aqueous organic acid to form an oxycodone organic acid salt.
  • the method further comprises adding hydrochloric acid or ammonium chloride to the oxycodone organic acid salt to form oxycodone hydrochloride.
  • isolated 14-hydroxycodeinone sulfate hydrate is provided selected from a 14-hydroxycodeinone sulfate hemihydrate, a 14- hydroxycodeinone sulfate monohydrate, a 14-hydroxycodeinone sulfate sesquihydrate, or a 14-hydroxycodeinone sulfate dihydrate.
  • the isolated 14-hydroxycodeinone sulfate is selected from 14-hydroxycodeinone hemisulfate or 14-hydroxycodeinone monosulfate.
  • the isolated 14-hydroxycodeinone sulfate hydrate is 14-hydroxycodeinone hemisulfate dihydrate.
  • the reducing step comprises reducing the isolated the 14-hydroxycodeinone sulfate or a hydrate thereof in the presence of the catalyst to form the oxycodone base.
  • the method further comprises purifying the oxycodone base to form purified oxycodone base.
  • purified oxycodone base produced by a method provided herein has not more than 0.05% of a 8,14-dihydroxy-7,8-dihydrocodeinone.
  • the dissolving step comprises dissolving purified oxycodone base in the aqueous organic acid to form an oxycodone organic acid salt.
  • the dissolving comprises complete or partial dissolution of the oxycodone base in the aqueous organic acid.
  • the aqueous organic acid is selected from aqueous tartaric acid, aqueous fumaric acid, aqueous lactic acid, aqueous trifluoroacetic acid, aqueous trichloroacetic acid, aqueous glycolic acid, aqueous monochloroacetic acid, and aqueous acetic acid.
  • the oxycodone organic acid salt is oxycodone acetate.
  • the dissolving step is performed at a temperature within the range from about 0°C to about 70°C; 10°C to about 40°C; or at ambient temperature.
  • the method comprises crystallizing the oxycodone hydrochloride to form oxycodone hydrochloride.
  • the crystallizing is performed by addition of water and/or one or more water miscible organic solvents to the oxycodone hydrochloride to form purified oxycodone hydrochloride.
  • the crystallizing is performed at a temperature range within about 0°C to about 30°C; or from about 5°C to about 15°C.
  • the method comprises crystallizing oxycodone hydrochloride by addition of water and/or one or more water miscible organic solvents to the oxycodone hydrochloride wherein the one or more water miscible organic solvents is/are selected from the group consisting of isopropyl alcohol, ethanol, methanol, methyl ethyl ketone and acetone.
  • method provides purified oxycodone hydrochloride with less than 0.001% 14-hydroxycodeinone; or less than 0.0005% 14- hydroxycodeinone.
  • the method employs use of thebaine selected or obtained from synthetic thebaine, concentrated poppy straw, anhydrous or raw thebaine alkaloid.
  • a method for preparation of 14- hydroxycodeinone sulfate or a hydrate thereof comprising exposing thebaine to hydrogen peroxide or peroxyacid and another organic acid in the presence of sodium hydrogen sulfate, sodium sulfate, potassium sulfate, potassium hydrogen sulfate and/or sulfuric acid in an aqueous reaction mixture; and isolating a precipitate of 14- hydroxycodeinone sulfate or a hydrate thereof from the reaction mixture.
  • the another organic acid is formic acid.
  • the method provides 14-hydroxycodeinone sulfate that exhibits less than 0.05%, 0.025%, or 0.01 % of a 8,14-dihydroxy-7,8- dihydrocodeinone (DHC) impurity.
  • DHC 8,14-dihydroxy-7,8- dihydrocodeinone
  • the method further comprises purifying the 14- hydroxycodeinone sulfate or hydrate thereof.
  • the purifying comprises recrystallization of the 14-hydroxycodeinone sulfate or hydrate thereof from an aqueous solvent.
  • the recrystallized 14-hydroxycodeinone sulfate is selected from 14-hydroxycodeinone hemisulfate, 14-hydroxycodeinone hemisulfate monohydrate, 14-hydroxycodeinone hemisulfate dihydrate, 14-hydroxycodeinone sulfate sesquihydrate, 14-hydroxycodeinone sulfate_dihydrate, 14-hydroxycodeinone sulfate_mono hydrate, 14-hydroxycodeinone sulfate dihydrate, or 14-hydroxycodeinone monosulfate.
  • the exposing step is performed in the presence of sodium hydrogen sulfate, sodium sulfate, potassium sulfate, or potassium hydrogen sulfate.
  • isolated 14-hydroxycodeinone sulfate or a hydrate thereof is provided.
  • the isolated 14-hydroxycodeinone sulfate or hydrate thereof is obtained by exposing thebaine to hydrogen peroxide or peroxyacid and another organic acid in the presence of sodium hydrogen sulfate, sodium sulfate, potassium sulfate, potassium hydrogen sulfate and/or sulfuric acid in an aqueous reaction mixture.
  • the isolated 14-hydroxycodeinone sulfate or hydrate thereof is a 14-hydroxycodeinone hemisulfate or a hydrate thereof.
  • isolated 14-hydroxycodeinone sulfate hydrate is provided selected from a 14-hydroxycodeinone sulfate hemihydrate, 14- hydroxycodeinone sulfate monohydrate, 14-hydroxycodeinone sulfate sesquihydrate, or 14-hydroxycodeinone sulfate dihydrate.
  • isolated 14-hydroxycodeinone sulfate or hydrate thereof is provided having not more than 0.05% total 8,14-dihydroxy-7,8- dihydrocodeinone (DHC) impurity.
  • isolated 14-hydroxycodeinone sulfate or hydrate thereof is provided having less than 0.01 % of an 8,14-dihydroxy-7,8-dihydrocodeinone (DHC) impurity.
  • DHC 8,14-dihydroxy-7,8-dihydrocodeinone
  • a method for preparation of oxycodone from 14-hydroxycodeinone sulfate or a hydrate thereof comprising reducing the 14- hydroxycodeinone sulfate or hydrate thereof in the presence of a catalyst to form oxycodone base.
  • the method further comprises dissolving the oxycodone base in an aqueous organic acid to form an oxycodone organic acid salt.
  • the method further comprises adding hydrochloric acid or ammonium chloride to the oxycodone organic acid salt to form oxycodone
  • a catalyst for the reducing step is selected from the group consisting of palladium on active carbon (Pd/C), Pd/C/FeCl 3 , Pd/C/Fe(III) hydroxide or oxide, Pd/Al 2 0 3 , Pt/C, Pt/Al 2 0 3 , Pd/BaS0 4 , Raney Ni-catalyst, Urushibara Ni-catalyst, rhodium on active carbon, Raney nickel, ruthenium black, PtC"2, Pt/C and platinum black.
  • a method for purifying oxycodone base to form purified oxycodone base comprising crystallizing, recrystallizing and/or triturating the crude oxycodone base in water and/or one or more water miscible organic solvents.
  • a method for preparation of oxycodone base comprising treating 14-hydroxycodeinone sulfate or a hydrate thereof with calcium acetate or barium acetate to prepare a 14-hydroxycodeinone acetate solution; and reducing the 14-hydroxycodeinone acetate solution to form oxycodone base.
  • the method further comprises purifying the oxycodone base to form purified oxycodone base.
  • a method is provided for purifying oxycodone base comprising crystallizing, recrystallizing and/or triturating the crude oxycodone base in a solvent that is a mixture of water and one or more water miscible organic solvents.
  • a method for preparation of oxycodone hydrochloride from oxycodone base comprising dissolving oxycodone base in an aqueous organic acid solution to form an oxycodone organic acid salt; and adding hydrochloric acid or ammonium chloride to the oxycodone organic acid salt to form oxycodone hydrochloride.
  • the oxycodone organic acid salt is oxycodone acetate.
  • the dissolving step comprises complete or partial dissolution of the oxycodone base in the aqueous organic acid solution.
  • the aqueous organic acid solution is comprised of water and an organic acid selected from tartaric acid, fumaric acid, lactic acid, trifluoroacetic acid, trichloroacetic acid, monochloroacetic acid, glycolic acid, and acetic acid.
  • the dissolving step comprises complete or partial dissolution of the oxycodone base in aqueous organic acid solution comprising water and acetic acid.
  • the dissolving step is performed at a temperature within the range from about 0°C to about 70°C; about 10°C to about 40°C; or at ambient temperature.
  • a method comprising crystallizing oxycodone hydrochloride by adding water and/or one or more water miscible organic solvents to the oxycodone hydrochloride to form purified oxycodone hydrochloride.
  • the one or more water miscible organic solvents is/are selected from the group consisting of isopropyl alcohol, ethanol, methanol, methyl ethyl ketone and acetone.
  • the crystallizing step is performed at a temperature range within about 0°C to about 35°C; about 0°C to about 30°C; about 5°C to about 30°C;or from about 5°C to about 15°C.
  • methods are provided herein for preparation of oxycodone hydrochloride from oxycodone base wherein any 8,14-dihydroxy-7,8-dihydrocodeinone impurity present in the oxycodone base is not converted to 14-hydroxycodeinone.
  • methods are provided for obtaining purified oxycodone hydrochloride with not more than 0.001% 14-hydroxycodeinone.
  • the purified oxycodone hydrochloride has no more than 0.0005% 14-hydroxycodeinone.
  • the purified oxycodone hydrochloride has not more than 0.25 % 6-alpha oxycodol impurity.
  • the purified oxycodone hydrochloride has not more than 0.05%> of a 8,14-dihydroxy-7,8-dihydrocodeinone impurity.
  • FIG. 1 shows a prior art conventional synthetic route for preparation of oxycodone hydrochloride by oxidation of thebaine to form 14-hydroxycodeinone (ABUK), reduction of 14-hydroxycodeinone to form oxycodone base, and conversion of the base to oxycodone hydrochloride.
  • a synthetic impurity, 7,8-dihydro-8,14- dihydroxycodeinone, (DHC) interconverts by hydration/dehydration from/to 14- hydroxycodeinone.
  • FIG. 2 shows a synthetic route for preparation of 14-hydroxycodeinone sulfate by oxidation of thebaine and treatment with sodium hydrogen sulfate.
  • FIG. 3 shows a synthetic route for preparation of 14-hydroxycodeinone sulfate by oxidation of thebaine and treatment with potassium hydrogen sulfate.
  • FIG. 4 shows a method for purification of impure 14-hydroxycodeinone sulfate by neutralization to form ABUK base, then dissolution of the base in aqueous acetic acid and crystallization of 14-hydroxycodeinone as a sulfate salt.
  • FIG. 5 shows a synthetic route for preparation of oxycodone base from reduction of 14-hydroxycodeinone sulfate with formic acid over Pd/C-catalyst.
  • FIG. 6 shows methods for preparing oxycodone hydrochloride from 14- hydroxycodeinone sulfate.
  • FIG. 7 shows two methods for conversion of oxycodone base to oxycodone hydrochloride via oxycodone acetate and either HC1 or ammonium chloride.
  • FIG. 8 shows a synthetic route for conversion of oxycodone base to oxycodone hydrochloride.
  • FIG. 9 shows preparation of ABUK solution in acetic acid
  • FIG. 10 shows 1H NMR Spectrum of 14-hydroxycodeinone base.
  • FIG. 11 shows a 13 C NMR Spectrum of 14-hydroxycodeinone base.
  • Oxycodone hydrochloride is an opioid agonist compound that is valuable as an active pharmaceutical ingredient (API) and as a starting material in the preparation of the opioid antagonists naloxone and naltrexone.
  • API active pharmaceutical ingredient
  • Preparation of oxycodone hydrochloride from thebaine through intermediate preparation of 14-hydroxycodeinine is a well-known technology that has been known since 1916.
  • oxidation of thebaine provides intermediate 14-hydroxycodeinone ( ⁇ , ⁇ unsaturated ketone, ABUK), followed by reduction of the ABUK to provide oxycodone base, and finally conversion of oxycodone base provides oxycodone hydrochloride.
  • ABUK refers to 14- hydroxycodeinone.
  • DHC 8,14-dihydroxy-7,8- dihydrocodeinone
  • the DHC impurity can be carried though the process to the production of oxycodone base.
  • oxycodone free base to oxycodone hydrochloride using aqueous hydrochloric acid and heat
  • the DHC impurity can undergo acid-catalyzed dehydration to be converted into 14-hydroxycodeinone (ABUK).
  • ABUK 14-hydroxycodeinone
  • 6-oxycodol impurities (6a- and/or ⁇ -oxycodol isomers) can be present in oxycodone base, for example, due to over-reduction of ABUK.
  • oxycodol refers to 6- oxycodol (both 6a- and ⁇ -oxycodol isomers).
  • 6- oxycodol major isomer refers to 6a-oxycodol.
  • High ABUK content in oxycodone hydrochloride API can be explained by (1) insufficient reduction of ABUK (product-intermediate of the first synthetic step) to oxycodone base (OC-base) or (2) by conversion of residual amount of the impurity DHC in oxycodone base into ABUK, for example, by acid catalyzed dehydration, during the last step of oxycodone hydrochloride preparation.
  • ABUK 14-hydroxycodeinone
  • Many of the known 14-hydroxycodeinone (ABUK) preparation procedures provide a preparation of ABUK in the form of ABUK formate salt solution in the aqueous reaction mixture.
  • the reaction mixture in these cases is conventionally treated with ammonium or potassium or sodium hydroxides inducing the ABUK base precipitation.
  • Such isolated ABUK base has elevated DHC level (up to 0.5 - 2.0%) and its further usage as a starting material for the oxycodone preparation is not acceptable because elevated DHC levels in the ABUK base can lead to a high level of ABUK impurity in the final oxycodone hydrochloride product under standard reaction conditions.
  • methods are provided herein for conversion of thebaine to 14-hydroxycodeinone sulfate (ABUK sulfate) with minimal formation of the impurity DHC (0-250 ppm), and other impurities, at a conversion rate greater than 99%.
  • methods are provided for minimizing the amount of DHC in ABUK synthetic intermediate.
  • pure 14-hydroxycodeinone sulfate intermediate is converted to oxycodone base using a two-stage reduction that minimizes residual ABUK sulfate to undetectable levels; remarkably without significant formation of DHC or other impurities.
  • the ABUK sulfate is reduced directly to oxycodone without being converted back to its base form.
  • methods are provided to minimize production and/or presence of oxycodol and other impurities in the oxycodone base.
  • the disclosure provides methods for preparing oxycodone hydrochloride from oxycodone base without conversion of DHC to ABUK on the final step.
  • methods are provided for preparation of oxycodone hydrochloride that minimize or eliminate detectable DHC in oxycodone base.
  • methods for converting oxycodone base to oxycodone hydrochloride are provided that minimize or eliminate acid catalyzed dehydration of DHC to ABUK.
  • methods for converting oxycodone base to oxycodone hydrochloride that minimize acid-catalyzed dehydration of DHC to ABUK comprising dissolving the oxycodone base in an organic acid and water without heating prior to introduction of hydrochloric acid.
  • methods for converting oxycodone base to oxycodone hydrochloride that minimize acid-catalyzed dehydration of DHC to ABUK comprising dissolving the oxycodone base in an organic acid and water at ambient temperature prior to introduction of hydrochloric acid.
  • the organic acid is selected from tartaric acid, fumaric acid, lactic acid, trifluoroacetic acid, trichloroacetic acid, monochloroacetic acid, glycolic acid, and acetic acid.
  • the oxycodone base is dissolved or partially dissolved in organic acid and water, wherein the organic acid is acetic acid, prior to the introduction of HC1 for the conversion of oxycodone base to oxycodone HC1, as shown in FIG. 8.
  • synthetic methods are provided for the production of highly pure oxycodone hydrochloride API.
  • the overall process follows four main steps. An outline of the overall process comprising three or four main steps:
  • Step 1 Oxidation of CPS-ATA to form 14-Hydroxycodeinone Sulfate.
  • methods are provided to minimize the amount of DHC impurity in the 14-hydroxycodeinone (ABUK) intermediate.
  • DHC formation is minimized by preparing the ABUK intermediate as a sulfate salt.
  • the DHC impurity is further minimized by purification and/or isolation of the 14-hydroxycodeinone sulfate salt. The DHC impurity is undesirable because it can be carried through the process and be converted to ABUK in conventional preparation of oxycodone hydrochloride.
  • methods are provided for ABUK preparation as an ABUK sulfate salt form.
  • the ABUK sulfate is isolated.
  • the ABUK sulfate is isolated as a hydrate.
  • the ABUK sulfate is isolated in an anhydrous form.
  • the ABUK sulfate is isolated as a hemihydrate, monohydrate, sesquihydrate or dihydrate.
  • the ABUK sulfate is ABUK x 0.5H 2 SO 4 x 2H 2 0 (MW 398.42).
  • the ABUK sulfate form has not more than 300 ppm, not more than 150 ppm, not more than 100 ppm, not more than 75 ppm, not more than 50 ppm, not more than 25 ppm, or not more than 10 ppm of an 8,14-dihydroxy-7,8- dihydrocodeinone (DHC) impurity.
  • DHC 8,14-dihydroxy-7,8- dihydrocodeinone
  • the 14-hydroxycodeinone sulfate is purified by an aqueous treatment and recrystallization.
  • the ABUK sulfate is re-crystallized from water. In one experiment, recrystallization of impure ABUK sulfate (213 ppm DHC) from water provided ABUK sulfate with 24 ppm DHC in an 81% yield.
  • oxycodone hydrochloride from a thebaine component selected from synthetic thebaine, concentrated poppy straw, anhydrous or raw thebaine alkaloid (CPS-ATA), or thebaine from various other sources.
  • Thebaine component can be obtained from a commercial source and used directly or further isolated and/or purified prior to use.
  • Thebaine (paramorphine) can be obtained from opium poppies or related species including various strains of Papaver somniferum, P. orientate or P. bracteatum plants, for example, leaves, roots, pedicels, straw, chaff, head, pod, capsules, seeds or bled latex.
  • thebaine starting material is selected from any commercial or synthetic source.
  • poppy straw or concentrated poppy straw rich in thebaine is employed as an economical source of thebaine component.
  • the thebaine component is CPS-ATA.
  • CP A- ATA is used directly as the thebaine component.
  • methods are provided for preparation of 14- hydroxycodeinone (ABUK) sulfate from thebaine component.
  • thebaine component is, for example, CPS-ATA.
  • methods are provided for preparation of ABUK sulfate comprising mixing thebaine component, water, sodium hydrogen sulfate, formic acid and 30% hydrogen peroxide aqueous solution, and stirring of the prepared mixture at a temperature within the range of from about 50 - 80°C until a complete conversion of thebaine into ABUK is detected.
  • the oxidation reaction is monitored by HPLC. The visible sign of the reaction progress is a massive precipitation of ABUK sulfate from the reaction mixture.
  • reaction product is isolated by filtering off precipitated solid material, and product washing with water and acetone mixture, water or ammonium sulfate aqueous solution; followed by drying on filter.
  • the typical yield following washing with acetone/water mixture for example, 3/1 acetone water, is within the range of from about 70-75% of pure product.
  • the method for preparing ABUK sulfate from thebaine component comprises washing wet ABUK sulfate product with ammonium sulfate aqueous solution to prevent ABUK sulfate losses on washings.
  • cold 40%> ammonium sulfate aqueous solution is used in the washing step.
  • ABUK sulfate product washing on filter with 40% ammonium sulfate aqueous solution ((NH 4 ) 2 S0 4 ) is employed to increase yield to about 75-80%) and prevent product losses due to its high solubility in water or aqueous organic solvents, such as acetone/water mixtures.
  • some sulfate salts such as ammonium and sodium sulfate can be present in a minor amount in the ABUK sulfate product, the product is suitable for catalytic reduction for the preparation of oxycodone base.
  • the filtrate contains impure ABUK, DHC, salts, colored materials and other impurities.
  • methods for isolation of purified ABUK sulfate from this filtrate are provided.
  • Example 1 provides a representative 30-g scale oxidation process run at 60°C, for less than 6 hours for production of 14- hydroxycodeinone sulfate from thebaine.
  • Impure ABUK sulfate intermediate batches can be recycled by this process by neutralization with ammonium hydroxide of mother liquors of either an aqueous solution or impure ABUK sulfate intermediate batches.
  • the impure ABUK base can be purified using the crystallization of ABUK in form of sulfate salt that can be used for the oxycodone preparation.
  • a method for purifying oxycodone base comprising dissolving impure ABUK base in aqueous acetic acid, treating the solution with sulfate anion sources (sulfuric acid, sodium sulfate, sodium or potassium hydrogen sulfate), and crystallizing ABUK sulfate from the aqueous solution.
  • sulfate anion sources sulfuric acid, sodium sulfate, sodium or potassium hydrogen sulfate
  • a method for providing purified ABUK sulfate comprises neutralizing impure ABUK sulfate by addition of water and ammonium hydroxide to provide ABUK base; dissolving the water insoluble ABUK base in aqueous acetic acid to form ABUK acetate; crystallizing ABUK sulfate from water and sulfuric acid, sodium sulfate or potassium hydrogen sulfate; and isolating the purified ABUK sulfate.
  • Step 2 Reduction of 14-hydroxycodeinone Sulfate to crude Oxycodone base.
  • methods are provided for preparing crude oxycodone base with a minimal amount of ABUK and DHC to prevent ABUK formation on the last technological step - oxycodone HC1 preparation.
  • the highest limit of ABUK in the final product is set as 10 ppm.
  • the reduction step is a catalytical reduction of the ABUK sulfate carbon-carbon double bond with oxycodone formation.
  • the reduction can employ hydrogen gas or formic acid as reducing agents, as shown in FIG. 3.
  • Catalyst in both cases is a palladium on charcoal (Pd/C) wet catalyst (for example, 10% catalyst, LOD 50%).
  • Pd/C palladium on charcoal
  • oxycodol can occur in the reaction mixture in amount of about 1.5%.
  • oxycodol content can be 4 to 6%.
  • further methods are provided for the isolation and purification of oxycodone base and/or oxycodone hydrochloride in order to remove a significant portion of oxycodol impurity.
  • the limit of 6a-oxycodol in final oxycodone hydrochloride is set as 0.25%> by US
  • methods for reducing 14- hydroxycodeinone to oxycodone with minimal impurities, comprising mixing ABUK sulfate in water; reducing the ABUK sulfate with a catalyst and either hydrogen or a hydrogen transfer reagent; filtering off the catalyst with water and/or aqueous acetic acid; neutralizing to basic pH to form oxycodone base; and isolating the oxycodone base.
  • the pH is adjusted with ammonium hydroxide.
  • the pH is adjusted with ammonium hydroxide to from about pH 8.0 to about pH 10.5; or from about pH 8.5 to about pH 10.0.
  • the pH is adjusted with ammonium hydroxide to about pH 9.5.
  • the mixing step and/or reducing steps are performed under nitrogen or argon gas.
  • the reducing step is performed with a reducing catalyst selected from the group consisting of palladium on active carbon (Pd/C), Pd/C/FeCl 3 , Pd/C/Fe(III) hydroxide or oxide, Pd/Al 2 0 3 , Pt/C, Pt/Al 2 0 3 , Pd/BaS0 4 , Raney Ni-catalysts, Urushibara Ni-catalysts, rhodium on active carbon, Raney nickel, ruthenium black, Pt0 2 , Pt/C and platinum black.
  • a reducing catalyst selected from the group consisting of palladium on active carbon (Pd/C), Pd/C/FeCl 3 , Pd/C/Fe(III) hydroxide or oxide, Pd/Al 2 0 3 , Pt/C, Pt/Al 2 0 3 , Pd/BaS0 4 , Raney Ni-catalyst
  • the reducing catalyst is selected from 1 - 20% palladium on active carbon (Pd/C), Pd/C/FeCl 3 , Pd/C/Fe(III) hydroxide or oxide; 0.04 - 10% Pd/Al 2 0 3 , 5% Pt/C, 5% Pt/Al 2 0 3 , or 5% rhodium on active carbon.
  • the reducing step is performed with a palladium on carbon catalyst Pd/C catalyst selected from 2 %> Pd/C, 2.5 %> Pd/C, 3% Pd/C, 5% Pd/C, 10% Pd/C, or 5% Pd/BaS0 4 .
  • the reducing step is performed with a regenerable palladium, platinum, rhodium, nickel or ruthenium catalyst.
  • the catalyst may be either dry or in wet form with e.g. 50% water.
  • the catalyst is 10%> Pd/C (50%> L.O.D.).
  • the reducing catalyst is used in an amount from about 0.01 -5 wt%>, 0.02-3 wt%> or 0.03-1.6 wt%> with respect to the starting ABUK sulfate.
  • the reducing step is performed with a reducing catalyst as described herein and hydrogen.
  • the reducing step is performed with a reducing catalyst as described herein and a hydrogen transfer reagent.
  • the hydrogen transfer reagent is used as a hydrogen donor.
  • the hydrogen donor must correspond to the catalyst, therefore formic acid and hypophosphorous acid as well as the salts thereof, such as triethylammonium formate, tri-n-butylammonium formate, sodium formate, potassium formate and ammonium formate as well as sodium hypophosphite are used.
  • the reducing step employs a catalyst and a hydrogen transfer reagent that is formic acid.
  • a method for reducing 14- hydroxycodeinone sulfate to oxycodone base comprising exposing 14- hydroxycodeinone sulfate to a reducing catalyst and hydrogen and/or a hydrogen transfer agent at a temperature of less than 50°C. In some embodiments, the method is performed at less than 45°C. As demonstrated in the examples, the method for reducing 14-hydroxycodeinone sulfate to oxycodone base, even when performed without acetic acid as a co-solvent and without additional reduction treatment of the reaction mixture with formic acid at elevated temperature, surprisingly exhibited higher catalyst selectivity resulting in minimized oxycodol formation in the oxycodone base.
  • a method for reducing 14- hydroxycodeinone to oxycodone further comprising one or more catalytic reduction steps.
  • a method is provided with an additional catalytical reduction step with formic acid as a reducing agent.
  • the additional catalytical reduction step is performed without intermediate oxycodone base isolation.
  • the additional catalytical reduction step comprises adding formic acid and additional catalyst to the reaction mixture.
  • the additional catalytic reduction step is performed at 50-60°C for about one hour.
  • an additional catalytic reduction step is performed with intermediate oxycodone base isolation.
  • oxycodone crude is isolated from the initial reductive system performed with Pd/C-catalyst.
  • the additional reduction method further comprises isolating oxycodone base from the reaction mixture by adding ammonium hydroxide solution and filtering to obtain initial crude oxycodone base; converting the initial crude oxycodone base to its formate salt in aqueous solution and treating with formic acid over Pd/C-catalyst at around 50°C. In both cases, good quality crude oxycodone was prepared.
  • methods for preparing oxycodone acetate by conversion of 14-hydroxycodeinone sulfate to oxycodone acetate, comprising dissolving barium diacetate in aqueous acetic acid to form a solution;
  • the oxycodone acetate solution is treated with a base to provide oxycodone base.
  • the oxycodone acetate is treated with ammonium hydroxide to provide oxycodone base.
  • the reduction is performed in a solvent selected from one or more of water, acetic acid, aqueous acetic acid, aqueous formic acid, ethanol, or methanol.
  • Step 3 Purification of crude Oxycodone base.
  • oxycodone base crude is converted directly into oxycodone hydrochloride.
  • oxycodone base is purified prior to converting to oxycodone hydrochloride.
  • methods are provided for purifying crude oxycodone base to remove process impurities.
  • oxycodone base is purified by a process comprising crystallizing, recrystallizing or triturating the crude oxycodone base in a solvent.
  • methods for producing oxycodone hydrochloride comprise purifying oxycodone base by treating with an organic solvent.
  • the organic solvent is a water-miscible solvent selected from ethanol, acetone or isopropyl alcohol.
  • the organic solvent is a combination of a halogenated solvent and a water miscible solvent.
  • oxycodone base is dissolved in a halogenated solvent prior to adding one or more water miscible solvents.
  • the organic solvent is a combination of a water miscible solvent with a halogenated solvent, wherein the halogenated solvent is selected from chloroform, or dichloromethane.
  • the water miscible solvent is selected from any water miscible solvent known in the art.
  • the water miscible solvent is selected from one or more of methanol, ethanol, isopropyl alcohol, methyl ethyl ketone, acetone, ethylene glycol, propylene glycol, monomethyl- or monoethyl ethers of ethylene- or propylene glycols.
  • the organic solvent is selected from methanol or isopropyl alcohol.
  • the organic solvent is a mixture of methanol and isopropyl alcohol.
  • the organic solvent is isopropyl alcohol.
  • methods for oxycodone base purification comprising treating the crude oxycodone base with isopropyl alcohol to provide oxycodone base with reduced levels of impurities.
  • methods are provided for purifying crude oxycodone base to remove process impurities comprising crystallizing, recrystallizmg or triturating the crude oxycodone base in a solvent that is a mixture of one or more water miscible organic solvents.
  • methods for purifying crude oxycodone base to remove process impurities comprising crystallizing, recrystallizmg or triturating the crude oxycodone base in a solvent that is a mixture of water and one or more water miscible organic solvents in a ratio within from about 5 to 95 vol%, 10 to 70 vol%, 20 to 60 vol%, or 30 to 50 vol% with water.
  • the solvent for the oxycodone base purification is a mixture of one or more water miscible organic solvents at about 20 vol%, 30 vol%, 35 vol%, 45 vol% or 50 vol% water miscible organic solvents in water.
  • a method for purifying oxycodone base comprises treating oxycodone base with one or more organic solvents, or one or more organic solvents and water.
  • oxycodone base is purified in a water/ organic solvent system to economize on use of organic solvent.
  • oxycodone base is treated with a mixture of water and isopropyl alcohol; a mixture of water, isopropyl alcohol and propylene glycol; a mixture of water, isopropyl alcohol and methoxyethanol; or a mixture of water, isopropyl alcohol and ethylene glycol.
  • the method comprises treating oxycodone base with a mixture of water and isopropyl alcohol in a ratio of about 2: 1
  • the method comprises treating oxycodone base with a mixture of water/ isopropyl alcohol/propylene glycol in a ratio of about 6:2:3 (v/v). In some aspects, the method comprises treating oxycodone base with a mixture of water/ isopropyl alcohol/methoxyethanol in a ratio of about 6: 1 :3 (v/v).
  • a method for purifying crude oxycodone base comprising transferring isolated crude oxycodone base into a reaction vessel with isopropyl alcohol; and refluxing the oxycodone base with isopropyl alcohol to provides crystalline purified oxycodone base. The product is obtained by filtering, rinsing with IPA and drying to provide purified oxycodone base that is suitable for the oxycodone hydrochloride preparation step.
  • a method for purifying crude oxycodone base comprising completely dissolving crude oxycodone base in small volume of chloroform or chloroform/methanol mixture; diluting the mixture with isopropyl alcohol to form a homogenous mixture; distilling off the chloroform under nitrogen and precipitating the crystalline oxycodone base from isopropyl alcohol.
  • the crystalline oxycodone base is filtered, rinsed with isopropyl alcohol and dried to provide purified oxycodone base, suitable for the oxycodone hydrochloride preparation step.
  • methods are provided for preparing oxycodone base with not more than 0.25 %, 0.20 %, 0.15 %, 0.10 %, 0.05%, or 0.025% DHC.
  • oxycodone base crude comprising 0.0202%> DHC was obtained by reducing 14-hydroxycodeinone sulfate in water without any purification.
  • methods are provided for preparing oxycodone base with not more than 0.50 %, 0.25 %, 0.15 %, 0.10 %, total 6-oxycodol.
  • methods are provided for preparing oxycodone base with not more than 0.1%, 0.010 %, 0.005 %, 0.002 %, or 0.001% (less than 10 ppm) ABUK.
  • Step 4 Preparation and Crystallization of Oxycodone Hydrochloride.
  • Conventional conversion of oxycodone base to oxycodone HC1 using aqueous HC1 is typically performed at elevated temperatures, such as at a temperature greater than about 50°C, greater than about 55°C, greater than about 60°C, or at about 70°C up to 100°C, or higher.
  • methods are provided for minimizing ABUK formation due to residual DHC in oxycodone base in the last technological step of oxycodone HC1 preparation.
  • methods for converting oxycodone base to oxycodone hydrochloride comprising converting oxycodone base to oxycodone acetate, and exposing the oxycodone acetate to HC1.
  • a method for preparation of oxycodone hydrochloride from oxycodone base comprising dissolving oxycodone base in an aqueous organic acid; and adding hydrochloric acid or ammonium chloride to the solution to form oxycodone hydrochloride.
  • the dissolving comprises complete or partial dissolution of the oxycodone base in the aqueous organic acid.
  • the aqueous organic acid is selected from tartaric acid, fumaric acid, lactic acid, trifluoroacetic acid, trichloroacetic acid, monochloroacetic acid, glycolic acid, and acetic acid.
  • the aqueous organic acid is aqueous acetic acid.
  • methods for converting oxycodone base to oxycodone hydrochloride comprising dissolving oxycodone base in aqueous organic acid at a temperature below 50°C, below 40°C, or below 30°C, to form an oxycodone organic acid salt in situ, and exposing the oxycodone organic acid salt to HC1 or ammonium chloride.
  • the oxycodone organic acid salt is oxycodone acetate.
  • methods for converting oxycodone base to oxycodone hydrochloride comprising dissolving oxycodone base in aqueous acetic acid at a temperature below 50°C, below 40°C, or below 30°C, to form oxycodone acetate in situ, and exposing the oxycodone acetate to HC1 as shown in FIG. 8.
  • the oxycodone acetate is isolated or utilized in situ to form an oxycodone organic acid salt or an oxycodone inorganic acid salt.
  • the oxycodone inorganic acid salt is selected from oxycodone hydrochloride, hydrobromide, hydrofluoride, phosphate, sulfate, or nitrate.
  • the oxycodone inorganic acid salt is selected from oxycodone hydrochloride, oxycodone hydrobromide, or oxycodone sulfate.
  • the oxycodone inorganic acid salt is oxycodone hydrochloride.
  • the oxycodone organic acid salt is selected from organic acid salts such as terephthalate, citrate, lactate, glycolate, tartrate, maleate, fumarate, mandelate, acetate, dichloroacetate, trifluoroacetate, oxalate, formate, succinate, and the like; and amino acid salts such as aspartate, glutamate and the like.
  • the oxycodone organic acid salt is oxycodone acetate or oxycodone terephthalate. In some embodiments, the oxycodone organic acid salt is oxycodone acetate.
  • methods are provided for preparing oxycodone hydrochloride with not more than 200 ppm (0.02%); 150 ppm (0.015%); 100 ppm (0.01%); 75 ppm (0.0075%); 50 ppm (0.005%) or 25 ppm (0.0025%) 14- hydroxycodeinone.
  • oxycodone hydrochloride is provided with not more than 10 ppm, 5 ppm, 3 ppm, 2 ppm or 1 ppm 14-hydroxycodeinone.
  • FDA guidelines provide a limit of not more than 0.001% of API (10 parts per million (ppm)) as the acceptable level of 14-hydroxycodeinone impurity in oxycodone HCl.
  • methods are provided for preparing oxycodone HCl with not more than 0.01%, 0.0075%, 0.005%, 0.001%, 0.0005%, 0.0003%, 0.0002%, or 0.0001% 14-hydroxycodeinone.
  • methods are provided for preparing oxycodone hydrochloride with not more than 10 ppm, 5 ppm, 3 ppm, 2 ppm, or 1 ppm 14- hydroxycodeinone.
  • oxycodone hydrochloride is provided with not more than 10 ppm, 5 ppm, 3 ppm, 2 ppm, or 1 ppm 14-hydroxycodeinone impurity.
  • methods are provided for preparation of crystalline oxycodone hydrochloride (the final product) in order to minimize residual impurities including ABUK, oxycodol, and DHC.
  • the USP acceptance criteria for oxycodone hydrochloride is not more than 0.25%) 6-a Oxycodol.
  • methods are provided for preparation of oxycodone hydrochloride with not more than 0.25 %, 0.20 %, 0.15 %, 0.10 %, 0.05%, 0.02%), or 0.01%) 6-a Oxycodol impurity.
  • the USP acceptance criteria for oxycodone hydrochloride is not more than 0.15%) 7,8-dihydro-8 -14-dihydroxycodeinone.
  • methods are provided for preparing purified oxycodone hydrochloride with not more than 0.15%, 0.10%, 0.05%, or 0.01% of an 8,14-dihydroxy-7,8-dihydrocodeinone (DHC) impurity.
  • DHC 8,14-dihydroxy-7,8-dihydrocodeinone
  • methods for conversion of oxycodone base to oxycodone hydrochloride comprising dissolving the oxycodone base in aqueous acetic acid; followed by treating the oxycodone acetate in solution with ammonium chloride.
  • ammonium chloride one equivalent of ammonium chloride is employed. This method avoids both use of strong acid HC1 and use of elevated temperature and thus provides oxycodone hydrochloride with a minimal amount of ABUK impurity.
  • methods are provided for conversion of oxycodone base to oxycodone hydrochloride comprising dissolving or partially dissolving the oxycodone base in aqueous organic acid, so as to avoid elevated temperature.
  • methods are provided for conversion of oxycodone base to oxycodone hydrochloride comprising dissolving the oxycodone base in aqueous organic acid at a temperature less than 50°C, less than 45°C, less than 40°C, or preferably less than 30°C, or at ambient temperature.
  • methods for conversion of oxycodone base to oxycodone hydrochloride comprising dissolving the oxycodone base in aqueous acetic acid at not more than 50°C, 45°C, 40°C, 30°C, or at ambient temperature.
  • methods for conversion of oxycodone base to oxycodone hydrochloride comprising dissolving or partially dissolving the oxycodone base in aqueous organic acid, wherein the aqueous organic acid is present in greater than about 1.1, 1.2, 1.3, 1.4, 1.5, 2, 3-fold, or more, molar equivalents excess compared to mols of oxycodone base.
  • methods for conversion of oxycodone base to oxycodone hydrochloride comprising dissolving or partially dissolving the oxycodone base in aqueous organic acid, wherein the aqueous organic acid is present in about 1, or about 0.9, 0.8, 0.7, 0.5-fold, or less, molar equivalents compared to mols of oxycodone base.
  • a method for preparing oxycodone hydrochloride from 14-hydroxycodeinone sulfate comprising reducing the 14- hydroxycodeinone sulfate in the presence of a catalyst to form oxycodone base;
  • a method for preparation of oxycodone hydrochloride comprising forming oxycodone acetate from oxycodone base in situ, followed by treatment with an aqueous solution of hydrochloric acid or ammonium chloride, for example, as shown in FIG. 7.
  • preparation of oxycodone hydrochloride from purified oxycodone base comprises mixing purified oxycodone base, water and acetic acid until a clear or almost clear homogenous aqueous oxycodone acetate solution is obtained.
  • the oxycodone acetate in solution is treated with a small excess (15 - 20%) of concentrated hydrochloric acid at ambient temperature.
  • oxycodone hydrochloride crystallizes for about one hour, and then the crystallizing mixture is diluted with IPA or other organic water miscible solvent (MEK for example) using magnetic stirring. The product is filtered off, washed on filter with IPA and acetone, and then dried on filter.
  • the oxycodone hydrochloride product contains less than 10 ppm of 14-hydroxycodeinone.
  • a method for preparation of oxycodone hydrochloride from purified oxycodone base comprising generating oxycodone acetate in solution and treating with about one equivalent of ammonium chloride at ambient temperature to provide oxycodone hydrochloride.
  • a method for preventing or minimizing acid catalyzed dehydration of DHC to ABUK in the conversion of oxycodone base to oxycodone hydrochloride is provided.
  • the oxycodone base is dissolved without heating in acetic acid and water; then HC1 or ammonium chloride is added to effect conversion to oxycodone hydrochloride.
  • an organic solvent is added to crystallize oxycodone hydrochloride.
  • the organic solvent is selected from isopropyl alcohol, ethanol, methanol, acetone, or methyl ethyl ketone.
  • the conversion step is performed at a temperature between from about 0°C to about 50°C; at a temperature between from about 10°C to about 40°C; or at a temperature between from about 15°C to about 35°C. In some embodiments, the conversion step is performed at ambient temperature.
  • crystallization of oxycodone hydrochloride is provided by addition of water or water and a combination of one or more organic water miscible solvents.
  • the one or more organic water miscible solvents are selected from one or more of isopropyl alcohol, methyl ethyl ketone, and acetone.
  • crystallization of oxycodone hydrochloride is performed at a temperature between from about 0°C to about 50°C, between about 10°C to about 40°C; from about 15°C to about 35°C; or at about ambient temperature.
  • HPLC normalization method was an HPLC analysis method based on the assumption that area of all HPLC peaks equal 100%, where the highest oxycodone peak value is in the linear range of 1.00 - 1.50 units (absorbance units). DHC was evaluated using pH 8.5 mobile phase, ABUK was evaluated with pH 9.5 mobile phase. The typical sample concentration was around 0.3 - 2.0 mg/rnL, and an injection volume was 7 to 50 ⁇ . Generally, the normalization method was employed for the routine preparative work. Unless otherwise specified, HPLC values provided herein are obtained by the area Normalization method.
  • An R&D HPLC Assay method for quantification of ABUK was employed based on determination of HPLC response of exact concentration (amount) from a standard injection (typical standard concentration was 8.24 ⁇ g/mL, injection volume - 10 ⁇ ), and determination of HPLC response of oxycodone sample injection (typical concentration 30 - 40 mg/mL, injection volume is 50 ⁇ ) and further proper calculations based on AUC comparison.
  • a QC Method HPLC Assay was employed for quantification of ABUK in a sample based on comparison of area ABUK peak of the sample and the same of sample plus known amount of ABUK standard mixture.
  • the ABUK R&D Assay method was more sensitive than normalization method by factor around 450 (considering concentration and volume of injected analyte), but the normalization method was employed as more convenient for the routine preparative work.
  • Example 1 14-Hydroxycodeinone Sulfate Preparation from Thebaine.
  • ABUK sulfate and ABUK base samples were analyzed with HPLC.
  • HPLC data correlate with ABUK x O.5H 2 SO 4 x 2H 2 0 (molecular weight 398.42) as a molecular formula.
  • a 250 mL jacketed reactor was subsequently charged with thebaine (311.37 g/mol, 30.0 g, 96.35 mmol), solution of KHS0 4 (14.1 g, 100.44 mmol) in DI water (40 ml) and 97% formic acid (5.2 mL, 133.61 mmol).
  • the mixture was warmed to 30°C (Julabo thermostat) and stirred for 20 min to give yellow to light brown almost homogeneous pale solution.
  • Hydrogen peroxide (30%, 13.5 mL, 119.12 mmol) was added to the stirred reaction mixture at 30-31 °C over 25 minutes.
  • Example 5 Purification of 14-Hydroxycodeinone Sulfate by base formation.
  • ABUK base Lot G, 32.32 g (wet) was placed in 500-ml Erlenmeyer flask, mixed with 150 ml of water and 7.0 ml of acetic acid till a clear solution formed.
  • Example 7 Preparation of ABUK Sulfate from ABUK Base of Mother Liquors.
  • Example 8 Preparation of ABUK Sulfate from ABUK Base with sulfuric acid.
  • Example 9 Preparation of ABUK Solution in Acetic Acid and Its Hydrogenation to form Oxycodone Acetate.
  • the filtrate was transferred into 3-neck 250-mL RBF, purged with argon, mixed with Pd/C catalyst (0.74 g, 10%, 50% LOD) and hydrogen was introduced into the reaction mixture with a gas dispersion tube at 5°C at magnetic stirring. Additional Pd/C catalyst (0.84 g) was added after 2 hours of hydrogenation. After 6 hours of hydrogenation, formic acid (97%, 10 mL) was introduced into the reaction mixture. The reaction mixture was warmed gradually from 5 to 15°C overnight. Reaction progress was followed by HPLC, as shown in Table 7. [00197] The reaction mixture was purged with argon and stirred with Celite (3 g, 15 minutes). Filtering off Pd/C catalyst on filter with Celite cake provided almost colorless (yellow tint) solution containing oxycodone acetate. The reaction progress was followed by HPLC as shown in Table 7.
  • Oxycodone acetate solution was diluted with isopropanol (25 mL), cooled to ⁇ 10°C and neutralized at 10°C to 5°C with ammonium hydroxide (cone, ⁇ 30 mL until pH -9.5). Stirring continued for 10 minutes and precipitated solids were filtered off, washed on filter with water (20 mL, 2 x 50 mL, 10 mL) and dried on filter for 0.5 hours. The light gray wet material (22.29 g) was prepared. This material was dissolved in chloroform (150 mL), treated with sodium sulfate (anhydrous) for one hour.
  • Pd/C Catalyst was filtered off and ammonium hydroxide was used for the oxycodone base precipitation ( ⁇ 60 mL) at temperature less than 15°C. Precipitated product was washed with water (2 x 75 mL) and dried on filter giving 28.07 g of oxycodone base. The oxycodone base was transferred into 250-mL RBF with Pd/C catalyst (0.59 g) and water (120 mL). Formic acid (4.36 mL) was added (pH 2.1) and stirring continued for 45 minutes at 50 - 60°C.
  • reaction mixture was cooled to ambient temperature, catalyst was filtered off, and oxycodone base was isolated with ammonium hydroxide addition to the filtrate at temperature lower than 20°C. Drying on filter provided 29.51 g of the oxycodone base (2 nd crude, Lot O).
  • the oxycodone base (29.51 g, Lot O) was transferred into a 3-neck 250-mL RBF, dissolved in chloroform (-100 mL). The mixture was heated till the distillation started and IP A (totally 250 mL) was added portion- wise till temperature in vapors was stable at 88°C (1.5 hours). The mixture was allowed to cool to ambient temperature;
  • hydrochloride with less than 10 ppm, less than 5 ppm, less than 2 ppm, or less than 1 ppm, of 14-hydroxycodeinone (ABUK) in the final product.
  • Hydrochloric acid (6.94 g, 10.094 mmol/g, 70.09 mmol) was added portion-wise over 45 minutes: at the beginning - about 2.30 g (over ⁇ 4 minutes, the mixture became transparent, followed by a precipitation); the rest of the hydrochloric acid was added portion-wise (5 drops at once) over 40 minutes (rate of stirring was increase to 250 RPM after 30 minutes). The mixture was stirred for 0.5 hours at ambient temperature, 0.5 hours at ice-bath temperature, and cold IPA (0°C, 77 mL) was added over 25 minutes. Stirring continued for 0.5 hours, and the precipitated product was filtered off.
  • this method for conversion of oxycodone base to oxycodone hydrochloride does not promote acid catalyzed dehydration of DHC impurity to 14-hydroxycodeinone (ABUK); but rather the DHC remains in the mother liquor.
  • this method provides oxycodone hydrochloride with not more than 10 ppm 14-hydroxycodeinone.
  • oxycodone hydrochloride was provided without detectable 14-hydroxycodeinone (ABUK) by the HPLC normalization method, and with not more than 10 ppm 14-hydroxycodeinone level by QC Assay method.
  • Oxycodone hydrochloride was prepared from 14-hydroxycodeinone sulfate as shown in FIG. 5.
  • a mixture of ABUK hemisulfate dihydrate (20.0 g, Lot U lot, 50.20 mmol) and water (65 mL) was made in a 250-mL 3-neck RBF. This mixture was purged with argon and Pd/C catalyst (0.65 g, 10%, 50% LOD) was loaded into the flask. Hydrogen gas purged into the flask at ambient temperature for 5.25 hours and HPLC analysis indicated almost the end of reaction.
  • Oxycodone base was washed with water (3 x 40 mL) and dried on filter providing 12.57 g of dry oxycodone base crude, Lot V. This amount of oxycodone base crude was dissolved in chloroform (-50 mL, 250-ml 3-neck RBF), this solution was heated to boiling point and IP A (250 mL) was added gradually over 1 hour at boiling point of the mixture and then 150 mL of the solvent was distilled (at 58 - 82°C).
  • the catalyst was filtered off, washed with water (2 x 10 mL), pH of the filtrate was adjusted to 9, using ammonium hydroxide cone, aqueous solution. After one hour stirring, the product was filtered off, washed with water ( 2 x 20 mL) and dried on the filter to constant weight to give oxycodone free base as white powder - 8.8 g. (92.4% yield), lot Y.
  • oxycodone base purified (Lot P, 13.56 g, 43.0 mmol) was dissolved (in 80-mL beaker over 15 minutes) in the mixture of water (13 mL) and acetic acid (3.0 mL) at ambient temperature. Hydrochloric acid (10.41 mol/kg, 5.0 g or 51.6 mmol) was added to the solution over 5 minutes. Stirring was continued for another 40 minutes and IP A (55 mL) was added over 15 minutes. Stirring was continued for another 30 minutes.
  • Precipitated product was filtered off, washed on filter with IPA (2 x 20 ml) and acetone (2 x 20 mL), dried on filter providing 14.74 g oxycodone HC1 (39.86 mmol or 93% yield on OC base purified) - lot Q.
  • HPLC profile of the final product oxycodone hydrochloride, Lot Q, and the starting material, oxycodone base, Lot P, are shown in Table 13.
  • Two special oxycodone hydrochloride Lot Q HPLC analyses were performed using R&D and QC Assay methods.
  • Oxycodone HC1 Lot Q exhibited 14-hydroxycodeinone impurity by HPLC R&D laboratory method of 1.61 ppm, and QC laboratory method of 3.0 ppm.
  • Example 16 Evaluation of Oxycodone Hydrochloride with Improved Impurity Profile.
  • Oxycodone hydrochloride was prepared from oxycodone base purified by (a) dissolution of oxycodone as its acetate salt in water, by (b) conversion of the oxycodone acetate salt into its hydrochloric acid salt at ambient temperature by using either hydrochloric acid or ammonium chloride, as indicated, and by (c) crystallization of oxycodone hydrochloride as provided herein, as noted in Table 14.
  • PF is used to denote purification factor (in parenthesis) which refers to ratio of impurity content before and after preparation, purification and/or crystallization.
  • ND refers to not detected.
  • NA means not applicable.
  • Impurity Profile for oxycodone hydrochloride samples with not more than 10 ppm, or not more than 5 ppm, or not more than 3 ppm, or not more than 2 ppm, or not more than 1 ppm 14-hydroxycodeinone.
  • Oxycodone hydrochloride sample Lot BB impurity oxycodol major isomer was present at 0.0103%, and DHC was present at 3.84 ppm (R&D HPLC assay method).
  • ABUK was present at only 0.27 ppm (R&D HPLC assay method).
  • Lot EE oxycodone hydrochloride also exhibited a reduced impurity profile for DHC and oxycodol impurities with 2.64 ppm DHC impurity, and 0.0165% oxycodol, major isomer (R&D HPLC assay method).
  • Example 17 Oxycodone Crude Purification.
  • Oxycodone base crude Lot FF (21.76 g) was charged into 250-mL one-neck RBF with propylene glycol (38 mL), water (76 mL) and IPA (25 mL) mixture. The mixture was heated at reflux for 2 hours (115 - 133°C in the bath), cooled down to ambient temperature over 30 minutes and kept in the ice bath for 0.5 hours. The precipitated product was filtered off, washed with water twice (30 and 15 mL) and dried on filter till constant weight (20.96 g or 96.3% yield, Lot GG). Starting material and product was evaluated by HPLC as shown in Table 15.
  • Example 18 Oxycodone Crude Purification.
  • Oxycodone base crude (31.23 g, Lot FF) was charged into 500-mL one-neck RBF with IPA (20 mL), water (114 mL) and methoxyethanol (57 mL) mixture. The mixture was heated at reflux for 4.5 hours (110 - 115° in the bath), cooled down to ambient temperature over 30 minutes and kept in the ice bath for 0.5 hours. The precipitated product was filtered off, washed with water (50 mL and 30 mL) and dried on filter till constant weight (29.83 g or 95.5% yield, Lot II). Impurity profiles are shown in Table 16.
  • a 250 mL jacketed reactor was subsequently charged with thebaine (lot TCPS-132, Lot LL ,79% Assay Thebaine - 37.97 g, MW 311.37 g/mol; 96.35 mmol, 1 equivalent), solution of DI water (8.03 g) and 97% formic acid (5.72 g, 120.54 mmol, 1.25 equiv) and then sodium hydrogen sulfate (13.57 g, 98.28 mmol, 1.02 equiv. to thebaine). The mixture was stirred (125 RPM) at 20°C for 5 minutes to give a good stirrable mixture. Hydrogen peroxide (30%, 13.64 g, 1.25 equiv.
  • Example 20 Oxycodone Base Preparation to minimize Oxycodol formation.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des procédés de synthèse pour la préparation d'oxycodone et ses sels avec un profil d'impureté amélioré. La thébaïne est convertie en un intermédiaire de sulfate 14-hydroxycodéinone pour minimiser l'impureté de 7,8-dihydro-8,14-dihydroxycodéinone. L'invention concerne des procédés efficaces pour la conversion d'oxycodone basique en chlorhydrate d'oxycodone pour minimiser l'impureté de 14-hydroxycodéinone dans le produit final.
PCT/US2014/071264 2013-12-18 2014-12-18 Synthese de chlorhydrate d'oxycodone WO2015095585A2 (fr)

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CA2934527A CA2934527A1 (fr) 2013-12-18 2014-12-18 Synthese de chlorhydrate d'oxycodone
CN201480075277.9A CN106164078A (zh) 2013-12-18 2014-12-18 氧可酮盐酸盐的合成
EP14824727.3A EP3083632A2 (fr) 2013-12-18 2014-12-18 Synthese de chlorhydrate d'oxycodone

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US14/132,910 US10227354B2 (en) 2013-12-18 2013-12-18 Conversion of oxycodone base to oxycodone hydrochloride
US14/132,825 US8846923B1 (en) 2013-12-18 2013-12-18 Preparation of 14-hydroxycodeinone sulfate
US14/132,737 2013-12-18
US14/132,737 US9062062B1 (en) 2013-12-18 2013-12-18 Synthesis of oxycodone hydrochloride
US14/132,825 2013-12-18
US14/132,910 2013-12-18

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US9938285B2 (en) 2014-01-15 2018-04-10 Rhodes Technologies Process for improved oxymorphone synthesis
US10202396B2 (en) 2012-07-16 2019-02-12 Rhodes Technologies Process for improved opioid synthesis
US10316042B2 (en) 2012-07-16 2019-06-11 Rhodes Technologies Process for improved opioid synthesis

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AU2018287728B2 (en) * 2017-06-20 2021-10-28 Macfarlan Smith Limited Hydrogenation process for preparing oxycodone hydrochloride from 14-hydroxycodeinone

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US4795813A (en) 1981-08-17 1989-01-03 The Florida Board Of Regents On Behalf Of The Florida State University Synthesis of derivatives of codeine and other 3-O-alkylmorphines
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US4613668A (en) 1983-12-22 1986-09-23 The United States Of America As Represented By The Department Of Health And Human Services Short total synthesis or morphinan compounds which uses cyclization of a cycloalkylcarbonyl compound selected from cyclopropylcarbonyl and cyclobutylcarbonyl
US6723894B2 (en) 1996-07-11 2004-04-20 Tasmanian Alkaloids Pty. Ltd. Production of thebaine and oripavine
US8067597B2 (en) 2005-06-16 2011-11-29 Mallinckrodt Llc Synthetic route to 14-hydroxyl opiates through 1-halo-thebaine or analogs
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US10202396B2 (en) 2012-07-16 2019-02-12 Rhodes Technologies Process for improved opioid synthesis
US10316042B2 (en) 2012-07-16 2019-06-11 Rhodes Technologies Process for improved opioid synthesis
US11390627B2 (en) 2012-07-16 2022-07-19 Rhodes Technologies Process for improved opioid synthesis
JP2017502991A (ja) * 2014-01-15 2017-01-26 ローズ テクノロジーズ 改良されたオキシコドン合成のための方法
US9932348B2 (en) 2014-01-15 2018-04-03 Rhodes Technologies Process for improved oxycodone synthesis
US9938285B2 (en) 2014-01-15 2018-04-10 Rhodes Technologies Process for improved oxymorphone synthesis
US10189852B2 (en) 2014-01-15 2019-01-29 Rhodes Technologies Process for improved oxymorphone synthesis
US10428079B2 (en) 2014-01-15 2019-10-01 Rhodes Technologies Process for improved oxycodone synthesis
US10844072B2 (en) 2014-01-15 2020-11-24 Rhodes Technologies Process for improved oxycodone synthesis

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WO2015095585A8 (fr) 2016-02-04

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