WO2012003468A1 - Process for the synthesis and purification of oxycodone - Google Patents
Process for the synthesis and purification of oxycodone Download PDFInfo
- Publication number
- WO2012003468A1 WO2012003468A1 PCT/US2011/042834 US2011042834W WO2012003468A1 WO 2012003468 A1 WO2012003468 A1 WO 2012003468A1 US 2011042834 W US2011042834 W US 2011042834W WO 2012003468 A1 WO2012003468 A1 WO 2012003468A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- hydroxycodeinone
- oxycodone
- ppm
- dihydroxy
- dihydrocodeinone
- Prior art date
Links
- BRUQQQPBMZOVGD-XFKAJCMBSA-N Oxycodone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4C BRUQQQPBMZOVGD-XFKAJCMBSA-N 0.000 title claims abstract description 148
- 229960002085 oxycodone Drugs 0.000 title claims abstract description 142
- 238000000034 method Methods 0.000 title claims abstract description 85
- 230000008569 process Effects 0.000 title description 22
- 230000015572 biosynthetic process Effects 0.000 title description 14
- 238000000746 purification Methods 0.000 title description 10
- 238000003786 synthesis reaction Methods 0.000 title description 4
- YYCRAERBSFHMPL-XFKAJCMBSA-N (4r,4as,7ar,12bs)-4a-hydroxy-9-methoxy-3-methyl-2,4,7a,13-tetrahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7-one Chemical compound O=C([C@@H]1O2)C=C[C@@]3(O)[C@]4([H])N(C)CC[C@]13C1=C2C(OC)=CC=C1C4 YYCRAERBSFHMPL-XFKAJCMBSA-N 0.000 claims abstract description 136
- YYCRAERBSFHMPL-UHFFFAOYSA-N 14beta-Hydroxycodeinone Natural products O1C2C(=O)C=CC3(O)C4CC5=CC=C(OC)C1=C5C23CCN4C YYCRAERBSFHMPL-UHFFFAOYSA-N 0.000 claims abstract description 136
- 229960000240 hydrocodone Drugs 0.000 claims abstract description 70
- YPZPXTZKBNWUTF-QMVVXIJUSA-N (4r,4as,7s,7ar,12bs)-9-methoxy-3-methyl-1,2,4,7,7a,13-hexahydro-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diol Chemical compound O[C@H]([C@@H]1O2)C=C[C@@]3(O)[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4C YPZPXTZKBNWUTF-QMVVXIJUSA-N 0.000 claims abstract description 38
- YPZPXTZKBNWUTF-UHFFFAOYSA-N 14beta-Hydroxy-codein Natural products O1C2C(O)C=CC3(O)C4CC5=CC=C(OC)C1=C5C23CCN4C YPZPXTZKBNWUTF-UHFFFAOYSA-N 0.000 claims abstract description 38
- 230000008707 rearrangement Effects 0.000 claims abstract description 21
- 230000009467 reduction Effects 0.000 claims abstract description 15
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 66
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 63
- 239000000203 mixture Substances 0.000 claims description 61
- 239000002585 base Substances 0.000 claims description 54
- 239000000243 solution Substances 0.000 claims description 53
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 41
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 38
- 239000012458 free base Substances 0.000 claims description 32
- 239000003054 catalyst Substances 0.000 claims description 26
- 239000012535 impurity Substances 0.000 claims description 23
- BQNSLJQRJAJITR-UHFFFAOYSA-N 1,1,2-trichloro-1,2-difluoroethane Chemical group FC(Cl)C(F)(Cl)Cl BQNSLJQRJAJITR-UHFFFAOYSA-N 0.000 claims description 18
- 229960003617 oxycodone hydrochloride Drugs 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 16
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 15
- 239000007787 solid Substances 0.000 claims description 12
- 239000003960 organic solvent Substances 0.000 claims description 10
- 239000011734 sodium Substances 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 229910052751 metal Inorganic materials 0.000 claims description 7
- 239000002184 metal Substances 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 238000007254 oxidation reaction Methods 0.000 claims description 6
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims description 6
- 239000012279 sodium borohydride Substances 0.000 claims description 6
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 5
- 239000003153 chemical reaction reagent Substances 0.000 claims description 5
- 230000003647 oxidation Effects 0.000 claims description 5
- 239000010948 rhodium Substances 0.000 claims description 5
- 229910052708 sodium Inorganic materials 0.000 claims description 5
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 4
- FQXXSQDCDRQNQE-UHFFFAOYSA-N markiertes Thebain Natural products COC1=CC=C2C(N(CC3)C)CC4=CC=C(OC)C5=C4C23C1O5 FQXXSQDCDRQNQE-UHFFFAOYSA-N 0.000 claims description 4
- 229930003945 thebaine Natural products 0.000 claims description 4
- FQXXSQDCDRQNQE-VMDGZTHMSA-N thebaine Chemical compound C([C@@H](N(CC1)C)C2=CC=C3OC)C4=CC=C(OC)C5=C4[C@@]21[C@H]3O5 FQXXSQDCDRQNQE-VMDGZTHMSA-N 0.000 claims description 4
- 239000008366 buffered solution Substances 0.000 claims description 3
- 229910052703 rhodium Inorganic materials 0.000 claims description 3
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 2
- 239000003446 ligand Substances 0.000 claims description 2
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 2
- 229910052707 ruthenium Inorganic materials 0.000 claims description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims 6
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 claims 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims 4
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims 2
- 150000004678 hydrides Chemical class 0.000 claims 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims 2
- 229940011051 isopropyl acetate Drugs 0.000 claims 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims 2
- MUZQPDBAOYKNLO-RKXJKUSZSA-N oxycodone hydrochloride Chemical compound [H+].[Cl-].O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4C MUZQPDBAOYKNLO-RKXJKUSZSA-N 0.000 claims 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims 2
- 239000008096 xylene Substances 0.000 claims 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims 1
- 150000002431 hydrogen Chemical class 0.000 claims 1
- 239000002243 precursor Substances 0.000 abstract description 10
- 150000004072 triols Chemical class 0.000 abstract description 10
- 125000000468 ketone group Chemical group 0.000 abstract description 4
- XSTXAVWGXDQKEL-UHFFFAOYSA-N Trichloroethylene Chemical compound ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 abstract description 2
- 239000000356 contaminant Substances 0.000 abstract description 2
- 238000002407 reforming Methods 0.000 abstract 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 36
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 34
- 150000002009 diols Chemical class 0.000 description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 24
- 238000005984 hydrogenation reaction Methods 0.000 description 22
- 229910001868 water Inorganic materials 0.000 description 22
- 238000006243 chemical reaction Methods 0.000 description 19
- 238000004128 high performance liquid chromatography Methods 0.000 description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- 239000000047 product Substances 0.000 description 16
- 229910052757 nitrogen Inorganic materials 0.000 description 15
- 239000000523 sample Substances 0.000 description 13
- 239000002002 slurry Substances 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- 238000005755 formation reaction Methods 0.000 description 12
- 238000013459 approach Methods 0.000 description 9
- 239000007789 gas Substances 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- 238000004458 analytical method Methods 0.000 description 8
- 230000018044 dehydration Effects 0.000 description 8
- 238000006297 dehydration reaction Methods 0.000 description 8
- 150000002576 ketones Chemical class 0.000 description 8
- 239000010410 layer Substances 0.000 description 8
- 239000002253 acid Substances 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 231100000024 genotoxic Toxicity 0.000 description 6
- 230000001738 genotoxic effect Effects 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- -1 and in some cases Chemical compound 0.000 description 5
- LHTAJTFGGUDLRH-LIAWFRAQSA-N (4R,4aS,7aR,12bS)-9-methoxy-3-methyl-1,2,4,5,6,7,7a,13-octahydro-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diol Chemical compound OC([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4C LHTAJTFGGUDLRH-LIAWFRAQSA-N 0.000 description 4
- 238000013019 agitation Methods 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- 229910001873 dinitrogen Inorganic materials 0.000 description 4
- 230000014759 maintenance of location Effects 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 239000012488 sample solution Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
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- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 3
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 3
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 3
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- 125000000746 allylic group Chemical group 0.000 description 3
- 235000019257 ammonium acetate Nutrition 0.000 description 3
- 229940043376 ammonium acetate Drugs 0.000 description 3
- 239000001273 butane Substances 0.000 description 3
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 3
- OROGSEYTTFOCAN-DNJOTXNNSA-N codeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC OROGSEYTTFOCAN-DNJOTXNNSA-N 0.000 description 3
- OROGSEYTTFOCAN-UHFFFAOYSA-N hydrocodone Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OC OROGSEYTTFOCAN-UHFFFAOYSA-N 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 description 3
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- 239000002244 precipitate Substances 0.000 description 3
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- BRUQQQPBMZOVGD-DILQNVEWSA-N CN(CCC12c3c(C4)ccc(OC)c3O[C@H]1C(CC1)=O)C4[C@@]21O Chemical compound CN(CCC12c3c(C4)ccc(OC)c3O[C@H]1C(CC1)=O)C4[C@@]21O BRUQQQPBMZOVGD-DILQNVEWSA-N 0.000 description 2
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- 230000006518 acidic stress Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 229960004126 codeine Drugs 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
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- XYYVYLMBEZUESM-UHFFFAOYSA-N dihydrocodeine Natural products C1C(N(CCC234)C)C2C=CC(=O)C3OC2=C4C1=CC=C2OC XYYVYLMBEZUESM-UHFFFAOYSA-N 0.000 description 2
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- 239000006228 supernatant Substances 0.000 description 1
- 238000012876 topography Methods 0.000 description 1
- LLPOLZWFYMWNKH-UHFFFAOYSA-N trans-dihydrocodeinone Natural products C1C(N(CCC234)C)C2CCC(=O)C3OC2=C4C1=CC=C2OC LLPOLZWFYMWNKH-UHFFFAOYSA-N 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 239000011995 wilkinson's catalyst Substances 0.000 description 1
- UTODFRQBVUVYOB-UHFFFAOYSA-P wilkinson's catalyst Chemical compound [Cl-].C1=CC=CC=C1P(C=1C=CC=CC=1)(C=1C=CC=CC=1)[Rh+](P(C=1C=CC=CC=1)(C=1C=CC=CC=1)C=1C=CC=CC=1)P(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 UTODFRQBVUVYOB-UHFFFAOYSA-P 0.000 description 1
Classifications
-
- 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 isomeric 8,14-dihydroxy- 7,8-dihydrocodeinone diols are understood to be unstable such that, during conversion of the oxycodone free base to oxycodone hydrochloride, they undergo acid-catalyzed dehydration to form the 14-hydroxycodeinone ABUK impurity.
- Weiss teaches that 8, 14- dihydroxy-7,8-dihydrocodeinone can be recrystallized from hot 2N HC1 if the treatment is rapid, but also reports that treatment in "dilute acid ( 1 : 1) in a boiling water bath for 20 minutes" converts the dihydroxy species to 14-hydroxycodeinone.
- the peak at RRT 0.91 was identified as the 8 ⁇ diol. Exposure of a mixture of the two species to acid showed a correlation between the loss of the RRT 0.82 peak with the growth of 14- hydroxycodeinone over a 20 hour period. The peak at RRT 0.91 degraded little under the same conditions over the 20 hour period. On the basis of this study and in view of Baldwin's assertions, the peak at RRT 0.82 was assigned as the 8a diol for the purposes of developing the invention.
- the 1,2 sulfite adducts hydrolyze to the ketone; however, the 1,4 adduct derived from 14-hydroxycodeinone remains intact and confers water solubility.
- the oxycodone precipitates or may be preferentially extracted into organic solvent and the adducted 14-hydroxycodeinone remains in the aqueous mixture.
- the Shafer approach differs in emphasizing the formation of the 1,4 adduct of 14- hydroxycodeinone and does not explicitly rely upon selective 1,2 hydrolysis to recover and separate the oxycodone from the water-soluble 1,4 adduct.
- the alpha diol of 8,14-dihydroxy-7,8- dihydrocodeinone can be present in up to 1,000 ppm in oxycodone base, and that the beta diol can be present at even higher levels.
- the approaches outlined above have the potential to actively create and contaminate oxycodone hydrochloride with over 1,000 ppm of the undesired, purportedly genotoxic, impurity then require measures to rigorously remove the impurity.
- measures to destroy diol precursors may not proceed exhaustively as noted, for example, in Example 3 of U.S. Patent No. 7,129,248 of Chapman et al., where a cautionary note appears that purified oxycodone salt must be handled with care to avoid dehydrating remaining diols to reform 14-hydroxycodeinone and contaminate the product.
- the above approaches include the conversion of the diols to 14- hydroxycodeinone in the presence of oxycodone free base.
- a variety of chemical approaches are used to remove the 14-hydroxycodeinone, especially during conversion of the oxycodone free base to oxycodone hydrochloride.
- the above approaches include the formation of 14-hydroxycodeinone - the actual ABUK impurity one is trying to eliminate - during the formation and in the presence of oxycodone, and in some cases, oxycodone hydrochloride. Accordingly, new methods of producing oxycodone and its salts with low levels of impurities, including ABUK, would be beneficial.
- Schemes 1 and 2 An exemplary sequence of steps according to preferred embodiments of the invention is shown in Schemes 1 and 2. As shown, after oxidation and reduction steps, a rearrangement step for producing oxycodone free base is used to significantly reduce or eliminate impurities, including especially ABUK, prior to converting the oxycodone free base to its salt. Also described are several optional purification steps, and a salt formation step.
- the ketone of 14-hydroxycodeinone is reduced to form 14- hydroxycodeine and, as a consequence of the reduction, the ketones of the two isomers of 8,14-dihydroxy-7,8-dihydrocodeinone are also reduced, creating related 8,14-dihydroxy- 7,8-dihydrocodein-6-ol isomers, or triols. Only traces of the two isomers of the diols remain and these are purged when the oxycodone base is purified prior to salt formation.
- 14-hydroxycodeine is rearranged to oxycodone in a reaction whereby the 6-hydroxyl group is oxidized and the 7,8 double bond is reduced. Because the two isomers of 8,14-dihydroxy-7,8-dihydrocodein-6-ol do not have the allylic C6, C7, C8 topography contained within 14-hydroxycodeine, they do not participate in the rearrangement. The triols are observed in the resulting oxycodone. The triols also do not appear to interfere and therefore cannot convert to 14-hydroxycodeinone. In this sense, they are inert with regard to conversion to either 14-hydroxycodeinone or oxycodone.
- the triols are far more polar than oxycodone and can potentially be separated from oxycodone by precipitating the oxycodone from a polar solvent or solvent mixture, or by extracting oxycodone into a suitable organic solvent. Notwithstanding, even if some of the triols were to remain with oxycodone, these species lack the purportedly genotoxic alpha, beta unsaturated ketone, cannot generate it, and do not fall under FDA alert compound status. When the resulting oxycodone base is converted to the hydrochloride salt, the active, alpha diol is not present and any traces of the triols are incapable of generating 14-hydroxycodeinone, so the salt can be produced without risk of regenerating that impurity.
- Oxidation of thebaine to 14-hydroxycodeinone may be performed by any means known in the art, for example as described in U.S. Patent Application Publication No. 2006/01 1 1383 to Casner et al.
- Reduction of 14-hydroxycodeinone to 14- hydroxycodeine may involve any method known in the art for reducing ketone groups of alpha, beta unsaturated ketones, with sodium borohydride being one example as described below.
- Suitable catalysts for Step 3 of Scheme 1 include any of a variety of ligand- complexed metal catalyst, including such catalysts wherein the ligand is a phosphine and the metal is rhodium or ruthenium. Wilkinson's catalyst and analogs thereof are generally suitable. Specific examples of suitable catalysts are disclosed in U.S. Patent No. 7,323,565 and U.S. Patent No. 7,321,038 to Wang et al. One suitable catalyst is shown below, the preparation and use of which is detailed in the Examples herein.
- the new route to oxycodone enjoys several advantages over the aforementioned routes as per Chapman, Shafer, Buehler, and Cox.
- the process converts known precursors of the purportedly genotoxic 14-hydroxycodeinone to triol species that are incapable of giving rise to this impurity. This conversion may be performed concurrently with the conversion of 14-hydroxycodeinone to 14-hydroxycodeine (i.e., before converting the 14-hydroxycodeine to oxycodone).
- the 14-hydroxycodeine may be isolated as a solid or extracted into a suitable organic solvent, either approach allowing the opportunity to purge these triols a full chemical stage before oxycodone is formed.
- the 14- hydroxycodeine may be treated with sodium weta-bisulfite as per Rappoport et al., J. Amer. Chem. Soc. 89:8, 1967, 1942-1947, 1 or similar species as a means to remove any remaining traces of 14-hydroxycodeinone or of the ketone-containing diols.
- the 14-hydroxycodeine may be treated with resin-supported borohydride to remove any trace amounts of 14-hydroxycodeinone.
- residual 14-hydroxycodeine may be treated with organic thiol species to selectively form water-soluble or resin bound derivatives of any remains 14- hydroxycodeinone such that 14-hydroxycodeine may be produced free of 14- hydroxycodeinone.
- the incorporation of treatments using weta-bisulfite-related or thiol-type species 14-hydroxycodeine substantially free of residual 14-hydroxycodeinone and of the two diols can be produced.
- any trace amounts of 14-hydroxycodeinone in 14-hydroxycodeine are carried through the rearrangement step and removed from the oxycodone base by catalytic hydrogenation in an organic solvent.
- diols that are potential precursors to 14-hydroxycodeinone are not converted to that compound, but instead are converted to species that are incapable of giving rise to 14-hydroxycodeinone.
- the drug entity is not actively contaminated with the purportedly genotoxic impurity one is also trying to remove.
- 14-hydroxycodeinone is both the undesired, purportedly genotoxic species and the penultimate intermediate common to most traditional syntheses of oxycodone.
- Conventional synthesis routes rely upon hydrogenation of 14- hydroxycodeinone to form oxycodone, and the hydrogenation may often be left incomplete such that large amounts of 14-hydroxycodeinone - 1,000-5,000 ppm - are carried forward directly into the isolated oxycodone. See, e.g. U.S. Patent No. 7,674,800, Examples 2 and 3) .
- the aforementioned approaches may thus be burdened by the need to overcome this reservoir of 14-hydroxycodeinone carried forward along with that formed by forced dehydration of the diols.
- the new process converts 14-hydroxycodeinone to a new, non-ketone intermediate (i.e., 14-hydroxycodeine) with zero or low single digit ppm levels of remaining 14-hydroxycodeinone. Should non-zero levels of 14-hydroxycodeinone remain, these can be removed as described above using weta-bisulfite or organic thiol agents. Alternatively, 14-hydroxycodeinone can be removed from oxycodone base by catalytic hydrogenation in an organic solvent or a mixture of solvents.
- the new route employs what is believed to be a novel rearrangement of a C- 14 oxidized codeine-like entity to oxycodone.
- codeine oxidized codeine-like entity
- hydrocodone hydrocodone
- 14- hydroxycodeine the intermediate in the new process disclosed here, is a "bisallylic" entity to the extent that the 7,8 double bond and 14-hydroxylic moiety constitute a second allylic function.
- the lack of reports of metal-catalyzed rearrangements of C-14 hydroxyl analogues of codeine to form the 6-ketone function suggests that those skilled in the art would not expect this to be a particularly productive, or even probable, reaction.
- 14-hydroxycodeinone The reduction of 14-hydroxycodeinone to 14-hydroxycodeine is expected to entirely convert the diols to the triols.
- 14-hydroxycodeine containing ca. 0-50 ppm of 14- hydroxycodeinone will undergo a metal catalyzed rearrangement to form oxycodone base with about 45-350 ppm of 14-hydroxycodeinone.
- LC/MS analysis indicates that the presumed active diol, 8a, 14-dihydroxy-7,8-dihydrocodeinone, may be present at up to 16 ppm while 8p, 14-dihydroxy-7,8-dihydrocodeinone may be present, with two other species having molecular weights matching the triols, at up to about 1 10 ppm.
- the very low levels of 14-hydroxycodeinone observed in oxycodone formed by the current invention are, however, in sharp contrast to the high levels found in oxycodone produced by the aforementioned processes, as noted above, which may contain 1 ,000-5,000 ppm of 14-hydroxycodeinone, and the potential for more due to the 1000 ppm or more of each of the diol precursors to 14-hydroxycodeinone, i.e., 8a,14- dihydroxy-7,8-dihydrocodeinone and 8p,14-dihydroxy-7,8-dihydrocodeinone.
- Oxycodone base prepared by the new process containing ca. 0-350 ppm of 14-hydroxycodeinone, can be rendered virtually free of this impurity by following a purification process such as the sodium weto-bisulfite procedure described by Rappoport et al., J. Amer. Chem. Soc. 89:8, 1967, 1942-1947. This affords an oxycodone free base having undetectable (or, at most, very low) levels of 14-hydroxycodeinone. Alternatively, one may reduce the residual 14-hydroxycodeinone to levels under 5 ppm by catalytic hydrogenation using a palladium on carbon catalyst in an organic solvent or solvent mixture.
- the hydrogenation may be run at about 13-50 psi and at temperatures from about room temperature (e.g., 18°C) to about 40°C.
- Suitable catalysts include, but are not limited to, 5% and 10% palladium on carbon.
- Suitable solvents include alcohols, chlorinated solvents, or mixtures thereof.
- crude oxycodone base containing traces of 14- hydroxycodeine may be purified by hydrogenation as described above, and used as a solution after catalyst filtration to form and isolate oxycodone HCI salt having less than 5 ppm of residual 14-hydroxycodeinone.
- the new process does not require breaking down the diol precursors to form 14-hydroxycodeinone in the presence of oxycodone.
- care is required when handling the HCI salt from the base in the route described there due to the possible presence of unconverted diol precursors.
- Bis(norbornadiene)rhodium (I) tetrafluoroborate 70 mg, 0.19 mmol
- l,4-bis(diphenylphosphino)butane 80 mg, 0.19 mmol
- the solution of the catalyst was transferred to the solution of 14-hydroxycodeine via cannula.
- the combined solution was heated at 50 °C for 90 minutes.
- a small sample was taken for an in-process test to confirm the reaction completion.
- the reaction mixture was cooled to 0-5 °C for 2 hours, and the product was filtered off and washed with 10 ml cold 2-propanol.
- Resin supported borohydride (0.15g) was added to the solution and it was stirred for 24 h at 55 °C. A small sample was taken for the in process test to confirm the removal of 14-hydroxycodeinone. The mixture was then filtered through 45 ⁇ filter under nitrogen blanket into a 100 ml 4 necked round bottom flask, equipped with condenser and a gas sparging tube, gas outlet, and a thermometer. The solution was deoxygenated by sparging nitrogen gas through it while stirring, for use in Example 4.
- Bis(norbornadiene)rhodium (I) tetrafluoroborate 70 mg, 0.19 mmol
- l,4-bis(diphenylphosphino)butane 80 mg, 0.19 mmol
- the solution of the catalyst was transferred to the solution of 14-hydroxycodeine from Example 3 via cannula.
- the combined solution was heated at 50 °C for 90 minutes. Oxycodone free base precipitated from the reaction mixture and a thick slurry formed. A small sample was taken for an in- process test to confirm the reaction completion.
- the reaction mixture was cooled to 0-5 °C for 2 hours and the product was filtered off, washed with 10 ml cold 2-propanol.
- 14-Hvdroxycodeinone 14-Hvdroxycodeine 14-Hydroxycodeinone (25.0g wet, 22.225g dry weight, 70.93mmol) was combined with 178mL methylene chloride and 13mL methanol under nitrogen in a round bottomed flask equipped with a thermometer and a solution resulted. The batch was cooled to 0-5 °C in an ice bath. Sodium borohydride (3.44g, 90.93mmol) was added in one portion. The mixture was stirred at 0-5°C for 7 hours and then allowed to warm up to ambient temperature and stirred for 17 hours.
- the excess sodium borohydride was quenched with l lOmL of 2.4N hydrochloric acid at 0-5°C.
- the two phase mixture was stirred at 0-5°C for 30 min.
- the layers were settled and separated.
- the upper aqueous layer was separated from the lower organic layer.
- the organic layer was washed with 15mL of 2.4N hydrochloric acid.
- the aqueous layers were combined and the pH was adjusted to 9.5 with the addition of 30 mL of 25% sodium hydroxide solution at ⁇ 10°C. There was no precipitate formed in the beginning at 10°C.
- the ice/water bath was then removed and the batch was stirred at ambient temperature.
- reaction mixture was cooled to 0-5 °C for 2 hours and the product was filtered off, and the filter cake washed with cold ethanol (10 mL x 2).
- Example 13 Hot Acid Stress Test of Oxycodone Hydrochloride from Example 1 1
- Example 14 Dry Heat Stress Test of Oxycodone Hydrochloride from Example 1 1
- Mobile Phase A Weigh ⁇ 0.77 ( ⁇ 0.03) g of Ammonium Acetate into a suitable mobile phase bottle, dissolve with 950 mL of deionized water, add 25 mL of Acetonitrile and 25 mL of MeOH to the container. Mix well and degas.
- Mobile Phase B Weigh ⁇ 0.77 ( ⁇ 0.03) g of Ammonium Acetate into a suitable mobile phase bottle, dissolve with 100 mL of deionized water, add 450 mL of Acetonitrile and 450 mL of MeOH to the container. Mix well and degas.
- the RRT of the inert diol (MS signal) relevant to the saturated Oxycodone (UV signal) is NMT O.95.
- Figure 1 shows a typical chromatogram using 0.2% TFA H 2 0 as Blank:
- Figure 2 shows a typical chromatogram using a Resolution Solution (10 PPM ABUK
- Figure 3 shows a typical chromatogram using a Resolution Solution (10 PPM ⁇ -Diol
- Figure 4 shows a typical chromatogram using a Sample Solution (Containing ⁇ 3 PPM of 14-Hy droxy Codeinone)
- Figure 5 shows a typical chromatogram using a Sample Solution (Containing ⁇ 30 PPM of ⁇ -Diol)
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Abstract
Description
Claims
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JP2013518764A JP5988272B2 (en) | 2010-07-02 | 2011-07-01 | Oxycodone synthesis and purification process |
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WO2014013311A1 (en) * | 2012-07-16 | 2014-01-23 | Rhodes Technologies | Process for improved opioid synthesis |
US8822687B2 (en) | 2004-03-30 | 2014-09-02 | Purdue Pharma L.P. | 8a,14-dihydroxy-7,8-dihydrocodeinone |
US8846923B1 (en) | 2013-12-18 | 2014-09-30 | Cody Laboratories, Inc. | Preparation of 14-hydroxycodeinone sulfate |
WO2015011474A1 (en) * | 2013-07-24 | 2015-01-29 | Cambrex Karlskoga Ab | Preparation of saturated ketone morphinan compounds by catalytic isomerisation |
US9062062B1 (en) | 2013-12-18 | 2015-06-23 | Cody Laboratories, Inc. | Synthesis of oxycodone hydrochloride |
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Families Citing this family (3)
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AU2011274361B2 (en) * | 2010-07-02 | 2014-09-18 | Macfarlan Smith Limited | Process for the synthesis and purification of oxycodone |
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Citations (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050124811A1 (en) * | 2002-11-11 | 2005-06-09 | Wang Peter X. | Method for the catalytic production of hydrocodone and hydromorphone |
WO2006019364A1 (en) * | 2004-08-18 | 2006-02-23 | Zentiva, A.S. | A method of preparation of oxycodone |
US20060111383A1 (en) | 2004-09-23 | 2006-05-25 | Casner Michael L | Preparation of oxycodone |
US7129248B2 (en) | 2004-03-30 | 2006-10-31 | Euro-Celtique, S.A. | Process for preparing oxycodone hydrochloride having less than 25 ppm 14-hydroxycodeinone |
WO2006138020A2 (en) * | 2005-06-16 | 2006-12-28 | Mallinckrodt Inc. | A synthetic route to 14-hydroxyl opiates through 1-halo-thebaine or analogs |
WO2007062184A2 (en) * | 2005-11-22 | 2007-05-31 | Controlled Chemicals, Inc. | Processes for reducing contaminating michael acceptor levels in oxycodone and other compositions |
WO2007103105A2 (en) | 2006-03-02 | 2007-09-13 | Mallinckrodt Inc. | Processes for preparing morphinan-6-one products with low levels of alpha, beta-unsaturated ketone compounds |
US7323565B2 (en) | 2002-11-11 | 2008-01-29 | Mallinckrodt Inc. | Method for the catalytic production of hydrocodone and hydromorphone |
WO2008070656A2 (en) | 2006-12-04 | 2008-06-12 | Noramco, Inc | Process for reducing impurities in oxycodone base |
WO2008070658A1 (en) | 2006-12-04 | 2008-06-12 | Noramco, Inc. | Process for preparing oxycodone having reduced levels of 14-hydroxycodeinone |
Family Cites Families (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE296916C (en) | ||||
US6067749A (en) | 1996-07-11 | 2000-05-30 | Tasmanian Alkaloids Pty. Ltd. | Papaver somniferum strain with high concentration of thebaine and oripavine |
US5869669A (en) | 1996-07-26 | 1999-02-09 | Penick Corporation | Preparation of 14-hydroxynormorphinones from normorphinone dienol acylates |
GB9616253D0 (en) * | 1996-08-01 | 1996-09-11 | Johnson Matthey Plc | Preparation of narcotic analgesics |
ES2121554B1 (en) | 1996-12-23 | 1999-06-16 | Univ Santiago Compostela | PROCEDURE FOR OBTAINING 14-HYDROXIMOFINONES BY PHOTOOXIDATION OF MORPHINE ALKALOIDS WITH ALCOXIDIENIC SYSTEM IN RING C. |
GB9713703D0 (en) | 1997-06-30 | 1997-09-03 | Johnson Matthey Plc | Preparation of opiates |
US6177567B1 (en) | 1999-10-15 | 2001-01-23 | Boehringer Ingelheim Chemicals, Inc. | Method for preparing oxycodone |
WO2004016618A1 (en) | 2002-08-15 | 2004-02-26 | Noramco, Inc. | Oxycodone-hydrochloride polymorhs |
MXPA05005781A (en) | 2002-11-29 | 2005-12-12 | Forest Laboratories | Combination of ibuprofen and oxycodone for acute pain relief. |
US6864370B1 (en) | 2003-06-05 | 2005-03-08 | Zhaiwei Lin | Process for manufacturing oxycodone |
CN1914210A (en) * | 2004-05-13 | 2007-02-14 | 马林克罗特公司 | Method for the catalytic production of hydrocodone and hydromorphone |
MX2009010931A (en) | 2007-04-16 | 2009-10-29 | Mallinckrodt Inc | Novel opiate reduction utilizing catalytic hydrogen transfer reaction. |
AU2011274361B2 (en) * | 2010-07-02 | 2014-09-18 | Macfarlan Smith Limited | Process for the synthesis and purification of oxycodone |
-
2011
- 2011-07-01 AU AU2011274361A patent/AU2011274361B2/en active Active
- 2011-07-01 WO PCT/US2011/042834 patent/WO2012003468A1/en active Application Filing
- 2011-07-01 PL PL11738337T patent/PL2588481T3/en unknown
- 2011-07-01 CA CA2804101A patent/CA2804101C/en active Active
- 2011-07-01 EP EP11738337.2A patent/EP2588481B1/en active Active
- 2011-07-01 ES ES11738337.2T patent/ES2659168T3/en active Active
- 2011-07-01 US US13/175,537 patent/US8703950B2/en active Active
- 2011-07-01 GB GB1301533.4A patent/GB2495062A/en not_active Withdrawn
- 2011-07-01 JP JP2013518764A patent/JP5988272B2/en active Active
-
2014
- 2014-03-21 US US14/221,818 patent/US20140206871A1/en not_active Abandoned
Patent Citations (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050124811A1 (en) * | 2002-11-11 | 2005-06-09 | Wang Peter X. | Method for the catalytic production of hydrocodone and hydromorphone |
US7323565B2 (en) | 2002-11-11 | 2008-01-29 | Mallinckrodt Inc. | Method for the catalytic production of hydrocodone and hydromorphone |
US7321038B2 (en) | 2002-11-11 | 2008-01-22 | Mallinckrodt Inc. | Method for the catalytic production of hydrocodone and hydromorphone |
US7129248B2 (en) | 2004-03-30 | 2006-10-31 | Euro-Celtique, S.A. | Process for preparing oxycodone hydrochloride having less than 25 ppm 14-hydroxycodeinone |
US7674800B2 (en) | 2004-03-30 | 2010-03-09 | Purdue Pharma L.P. | Oxycodone hydrochloride having less than 25 PPM 14-hydroxycodeinone |
US7683072B2 (en) | 2004-03-30 | 2010-03-23 | Purdue Pharma L.P. | Oxycodone hydrochloride having less than 25 ppm 14-hydroxycodeinone |
WO2006019364A1 (en) * | 2004-08-18 | 2006-02-23 | Zentiva, A.S. | A method of preparation of oxycodone |
US7153966B2 (en) | 2004-09-23 | 2006-12-26 | Johnson Matthey Public Limited Company | Preparation of oxycodone |
US20060111383A1 (en) | 2004-09-23 | 2006-05-25 | Casner Michael L | Preparation of oxycodone |
WO2006138020A2 (en) * | 2005-06-16 | 2006-12-28 | Mallinckrodt Inc. | A synthetic route to 14-hydroxyl opiates through 1-halo-thebaine or analogs |
WO2007062184A2 (en) * | 2005-11-22 | 2007-05-31 | Controlled Chemicals, Inc. | Processes for reducing contaminating michael acceptor levels in oxycodone and other compositions |
US20070149559A1 (en) | 2005-11-22 | 2007-06-28 | Controlled Chemicals, Inc. | Process for reducing contaminating Michael acceptor levels in oxycodone and other compositions |
WO2007103105A2 (en) | 2006-03-02 | 2007-09-13 | Mallinckrodt Inc. | Processes for preparing morphinan-6-one products with low levels of alpha, beta-unsaturated ketone compounds |
WO2008070656A2 (en) | 2006-12-04 | 2008-06-12 | Noramco, Inc | Process for reducing impurities in oxycodone base |
WO2008070658A1 (en) | 2006-12-04 | 2008-06-12 | Noramco, Inc. | Process for preparing oxycodone having reduced levels of 14-hydroxycodeinone |
Non-Patent Citations (4)
Title |
---|
CURRIE A C ET AL: "SOME REACTIONS OF 14-HYDROXYCODEINE", JOURNAL OF THE CHEMICAL SOCIETY. ABSTRACTS,, 1 January 1960 (1960-01-01), pages 773 - 781, XP008035133, ISSN: 0590-9791 * |
PROSKA, ARCH. PHARM. PHARM. MED. CHEM., vol. 332, 1999, pages 369 - 70 |
RAPPOPORT ET AL., J. AMER. CHEM. SOC., vol. 89, 1967, pages 1942 - 1947 |
WEISS, J., ORG. CHEM., vol. 22, no. 11, 1957, pages 1505 - 08 |
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CA2804101A1 (en) | 2012-01-05 |
AU2011274361A1 (en) | 2013-01-31 |
EP2588481B1 (en) | 2017-11-15 |
US20140206871A1 (en) | 2014-07-24 |
CA2804101C (en) | 2021-01-19 |
US8703950B2 (en) | 2014-04-22 |
GB2495062A (en) | 2013-03-27 |
EP2588481A1 (en) | 2013-05-08 |
AU2011274361B2 (en) | 2014-09-18 |
ES2659168T3 (en) | 2018-03-14 |
JP5988272B2 (en) | 2016-09-07 |
US20120259118A1 (en) | 2012-10-11 |
JP2013531678A (en) | 2013-08-08 |
GB201301533D0 (en) | 2013-03-13 |
PL2588481T3 (en) | 2018-05-30 |
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