CA2934527A1 - Synthesis of oxycodone hydrochloride - Google Patents

Synthesis of oxycodone hydrochloride Download PDF

Info

Publication number: CA2934527A1
Authority: CA; Canada
Prior art keywords: oxycodone; sulfate; hydroxycodeinone; base; acid
Prior art date: 2013-12-18
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.): Abandoned

Application number

CA2934527A

Other languages

English (en)

French (fr)

Inventor

Zinovy Itov

Vladimir F. Kuznetsov

Iouri Voitsekhovski

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Cody Laboratories Inc

Original Assignee

Cody Laboratories Inc

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

2013-12-18

Filing date

2014-12-18

Publication date

2015-06-25

2013-12-18 Priority claimed from US14/132,737 external-priority patent/US9062062B1/en

2013-12-18 Priority claimed from US14/132,825 external-priority patent/US8846923B1/en

2013-12-18 Priority claimed from US14/132,910 external-priority patent/US10227354B2/en

2014-12-18 Application filed by Cody Laboratories Inc filed Critical Cody Laboratories Inc

2015-06-25 Publication of CA2934527A1 publication Critical patent/CA2934527A1/en

Status Abandoned legal-status Critical Current

Links

BQNSLJQRJAJITR-UHFFFAOYSA-N 1,1,2-trichloro-1,2-difluoroethane Chemical compound FC(Cl)C(F)(Cl)Cl BQNSLJQRJAJITR-UHFFFAOYSA-N 0.000 title claims abstract description 181
229960003617 oxycodone hydrochloride Drugs 0.000 title claims abstract description 181
230000015572 biosynthetic process Effects 0.000 title description 16
238000003786 synthesis reaction Methods 0.000 title description 3
229960002085 oxycodone Drugs 0.000 claims abstract description 352
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 claims abstract description 314
238000000034 method Methods 0.000 claims abstract description 233
WQRROQFAVLFQDK-RKXJKUSZSA-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;sulfuric acid Chemical compound OS(O)(=O)=O.O=C([C@@H]1O2)C=C[C@@]3(O)[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4C WQRROQFAVLFQDK-RKXJKUSZSA-N 0.000 claims abstract description 101
239000012535 impurity Substances 0.000 claims abstract description 95
238000002360 preparation method Methods 0.000 claims abstract description 83
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 82
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 81
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 abstract description 62
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 abstract description 62
229930003945 thebaine Natural products 0.000 claims abstract description 61
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 141
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 136
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 118
BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 82
239000000203 mixture Substances 0.000 claims description 82
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 75
239000003054 catalyst Substances 0.000 claims description 70
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 65
150000007524 organic acids Chemical class 0.000 claims description 64
NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 53
239000011541 reaction mixture Substances 0.000 claims description 52
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 51
-1 oxycodone organic acid salt Chemical class 0.000 claims description 45
OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 41
235000019253 formic acid Nutrition 0.000 claims description 41
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 39
239000003960 organic solvent Substances 0.000 claims description 35
MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 34
NZZWLZFHCRDHAZ-XFWGSAIBSA-N [(4r,4as,7ar,12bs)-9-methoxy-3-methyl-7-oxo-2,4,5,6,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-4a-yl] acetate Chemical group O=C([C@@H]1O2)CC[C@@]3(OC(C)=O)[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4C NZZWLZFHCRDHAZ-XFWGSAIBSA-N 0.000 claims description 34
QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 31
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 30
ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 29
235000019270 ammonium chloride Nutrition 0.000 claims description 26
239000002904 solvent Substances 0.000 claims description 25
BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 24
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 21
CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 claims description 21
229910000343 potassium bisulfate Inorganic materials 0.000 claims description 21
229910052938 sodium sulfate Inorganic materials 0.000 claims description 21
235000011152 sodium sulphate Nutrition 0.000 claims description 21
229910000342 sodium bisulfate Inorganic materials 0.000 claims description 20
229960000240 hydrocodone Drugs 0.000 claims description 18
WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 claims description 18
VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 15
229910052799 carbon Inorganic materials 0.000 claims description 15
OTYBMLCTZGSZBG-UHFFFAOYSA-L potassium sulfate Chemical compound [K+].[K+].[O-]S([O-])(=O)=O OTYBMLCTZGSZBG-UHFFFAOYSA-L 0.000 claims description 15
229910052939 potassium sulfate Inorganic materials 0.000 claims description 15
235000011151 potassium sulphates Nutrition 0.000 claims description 15
AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 claims description 14
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 14
238000004090 dissolution Methods 0.000 claims description 14
JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 14
150000004965 peroxy acids Chemical class 0.000 claims description 13
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 12
TZCXTZWJZNENPQ-UHFFFAOYSA-L barium sulfate Chemical compound [Ba+2].[O-]S([O-])(=O)=O TZCXTZWJZNENPQ-UHFFFAOYSA-L 0.000 claims description 12
IGUAHHYADOOLFE-PCHTVJFHSA-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;sulfuric acid;hydrate Chemical compound O.OS(O)(=O)=O.O=C([C@@H]1O2)C=C[C@@]3(O)[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4C IGUAHHYADOOLFE-PCHTVJFHSA-N 0.000 claims description 10
229910052763 palladium Inorganic materials 0.000 claims description 10
VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 9
240000001090 Papaver somniferum Species 0.000 claims description 8
238000001953 recrystallisation Methods 0.000 claims description 8
FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 7
GXYBPZAOEFQVCC-ZCOBFMRZSA-N O.O.OS(O)(=O)=O.COc1ccc2C[C@H]3N(C)CC[C@@]45[C@@H](Oc1c24)C(=O)C=C[C@@]35O Chemical compound O.O.OS(O)(=O)=O.COc1ccc2C[C@H]3N(C)CC[C@@]45[C@@H](Oc1c24)C(=O)C=C[C@@]35O GXYBPZAOEFQVCC-ZCOBFMRZSA-N 0.000 claims description 7
235000008753 Papaver somniferum Nutrition 0.000 claims description 7
FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 7
FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 claims description 7
239000001530 fumaric acid Substances 0.000 claims description 7
239000004310 lactic acid Substances 0.000 claims description 7
235000014655 lactic acid Nutrition 0.000 claims description 7
229910052697 platinum Inorganic materials 0.000 claims description 7
239000010948 rhodium Substances 0.000 claims description 7
229910052703 rhodium Inorganic materials 0.000 claims description 7
MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims description 7
239000010902 straw Substances 0.000 claims description 7
235000002906 tartaric acid Nutrition 0.000 claims description 7
239000011975 tartaric acid Substances 0.000 claims description 7
YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 claims description 7
KEXMNUOCYTVKIA-RKXJKUSZSA-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;acetic acid Chemical compound CC(O)=O.O=C([C@@H]1O2)C=C[C@@]3(O)[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4C KEXMNUOCYTVKIA-RKXJKUSZSA-N 0.000 claims description 6
VTLYFUHAOXGGBS-UHFFFAOYSA-N Fe3+ Chemical compound [Fe+3] VTLYFUHAOXGGBS-UHFFFAOYSA-N 0.000 claims description 6
KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 6
235000011087 fumaric acid Nutrition 0.000 claims description 6
XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 6
DUIFSYZSLBRPRG-PUQZGPAZSA-N O.S(=O)(=O)(O)O.O[C@@]12C=CC([C@H]3[C@]14C=1C(=C(C=CC1C[C@H]2N(C)CC4)OC)O3)=O.O.O.O[C@@]34C=CC([C@H]2[C@]31C=3C(=C(C=CC3C[C@H]4N(C)CC1)OC)O2)=O.S(=O)(=O)(O)O Chemical compound O.S(=O)(=O)(O)O.O[C@@]12C=CC([C@H]3[C@]14C=1C(=C(C=CC1C[C@H]2N(C)CC4)OC)O3)=O.O.O.O[C@@]34C=CC([C@H]2[C@]31C=3C(=C(C=CC3C[C@H]4N(C)CC1)OC)O2)=O.S(=O)(=O)(O)O DUIFSYZSLBRPRG-PUQZGPAZSA-N 0.000 claims description 5
239000007868 Raney catalyst Substances 0.000 claims description 5
229910000564 Raney nickel Inorganic materials 0.000 claims description 5
ITHZDDVSAWDQPZ-UHFFFAOYSA-L barium acetate Chemical compound [Ba+2].CC([O-])=O.CC([O-])=O ITHZDDVSAWDQPZ-UHFFFAOYSA-L 0.000 claims description 5
ZLSOEGVSXYPCHL-UHFFFAOYSA-N sulfuric acid;tetrahydrate Chemical compound O.O.O.O.OS(O)(=O)=O ZLSOEGVSXYPCHL-UHFFFAOYSA-N 0.000 claims description 5
FQXXSQDCDRQNQE-WRGHYRGKSA-N (4r,12bs)-7,9-dimethoxy-3-methyl-2,4,7a,13-tetrahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline Chemical compound C([C@@H](N(CC1)C)C2=CC=C3OC)C4=CC=C(OC)C5=C4[C@@]21C3O5 FQXXSQDCDRQNQE-WRGHYRGKSA-N 0.000 claims description 4
VCSZKSHWUBFOOE-UHFFFAOYSA-N dioxidanium;sulfate Chemical compound O.O.OS(O)(=O)=O VCSZKSHWUBFOOE-UHFFFAOYSA-N 0.000 claims description 4
239000002244 precipitate Substances 0.000 claims description 4
239000003125 aqueous solvent Substances 0.000 claims description 3
VSGNNIFQASZAOI-UHFFFAOYSA-L calcium acetate Chemical compound [Ca+2].CC([O-])=O.CC([O-])=O VSGNNIFQASZAOI-UHFFFAOYSA-L 0.000 claims description 3
239000001639 calcium acetate Substances 0.000 claims description 3
235000011092 calcium acetate Nutrition 0.000 claims description 3
229960005147 calcium acetate Drugs 0.000 claims description 3
LHTAJTFGGUDLRH-QMVVXIJUSA-N (4r,4as,7s,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 O[C@H]([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4C LHTAJTFGGUDLRH-QMVVXIJUSA-N 0.000 claims description 2
PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 claims 4
229910052593 corundum Inorganic materials 0.000 claims 4
229910001845 yogo sapphire Inorganic materials 0.000 claims 4
229910021578 Iron(III) chloride Inorganic materials 0.000 claims 2
229910019020 PtO2 Inorganic materials 0.000 claims 2
NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims 2
YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 claims 2
RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims 2
FWFGVMYFCODZRD-UHFFFAOYSA-N oxidanium;hydrogen sulfate Chemical compound O.OS(O)(=O)=O FWFGVMYFCODZRD-UHFFFAOYSA-N 0.000 claims 1
TXKRWVMEUQBFSO-UHFFFAOYSA-N sulfuric acid;trihydrate Chemical compound O.O.O.OS(O)(=O)=O TXKRWVMEUQBFSO-UHFFFAOYSA-N 0.000 claims 1
238000006243 chemical reaction Methods 0.000 abstract description 61
239000012467 final product Substances 0.000 abstract description 12
150000003839 salts Chemical class 0.000 abstract description 5
238000010189 synthetic method Methods 0.000 abstract description 5
239000002585 base Substances 0.000 description 259
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XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 12
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NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 8
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XYYVYLMBEZUESM-CMKMFDCUSA-N codeinone Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=CC(=O)[C@@H]1OC1=C2C3=CC=C1OC XYYVYLMBEZUESM-CMKMFDCUSA-N 0.000 description 6
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HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical class [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 4
229910000147 aluminium phosphate Inorganic materials 0.000 description 4
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238000011002 quantification Methods 0.000 description 4
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XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 3
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
238000002835 absorbance Methods 0.000 description 3
239000007795 chemical reaction product Substances 0.000 description 3
150000004683 dihydrates Chemical class 0.000 description 3
150000004682 monohydrates Chemical class 0.000 description 3
238000006386 neutralization reaction Methods 0.000 description 3
QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
101150041968 CDC13 gene Proteins 0.000 description 2
238000005481 NMR spectroscopy Methods 0.000 description 2
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
238000010521 absorption reaction Methods 0.000 description 2
159000000021 acetate salts Chemical class 0.000 description 2
238000009835 boiling Methods 0.000 description 2
239000006227 byproduct Substances 0.000 description 2
238000004364 calculation method Methods 0.000 description 2
150000001875 compounds Chemical class 0.000 description 2
239000006184 cosolvent Substances 0.000 description 2
239000006185 dispersion Substances 0.000 description 2
230000000694 effects Effects 0.000 description 2
238000005516 engineering process Methods 0.000 description 2
238000011156 evaluation Methods 0.000 description 2
150000004675 formic acid derivatives Chemical class 0.000 description 2
239000012458 free base Substances 0.000 description 2
230000036571 hydration Effects 0.000 description 2
238000006703 hydration reaction Methods 0.000 description 2
239000000852 hydrogen donor Substances 0.000 description 2
150000002500 ions Chemical class 0.000 description 2
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
238000011005 laboratory method Methods 0.000 description 2
238000010907 mechanical stirring Methods 0.000 description 2
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
230000003472 neutralizing effect Effects 0.000 description 2
229910052757 nitrogen Inorganic materials 0.000 description 2
239000003402 opiate agonist Substances 0.000 description 2
OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 2
238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 2
239000012047 saturated solution Substances 0.000 description 2
235000011121 sodium hydroxide Nutrition 0.000 description 2
239000011343 solid material Substances 0.000 description 2
239000012258 stirred mixture Substances 0.000 description 2
DYHDRNAXUHIHMW-KFIKYVJASA-N (4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,4,7a,13-tetrahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-one Chemical compound COc1ccc2C[C@H]3N(C)CC[C@@]45[C@@H](Oc1c24)C(=O)C=C[C@@]35O.COc1ccc2C[C@H]3N(C)CC[C@@]45[C@@H](Oc1c24)C(=O)C=C[C@@]35O DYHDRNAXUHIHMW-KFIKYVJASA-N 0.000 description 1
SJNBSBNGJYPSBY-RKXJKUSZSA-N (4r,4as,7ar,12bs)-4a-hydroxy-9-methoxy-3-methyl-2,4,5,6,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7-one;hydrobromide Chemical compound Br.O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4C SJNBSBNGJYPSBY-RKXJKUSZSA-N 0.000 description 1
BTEYIHUKHHAVAN-KDKWOIFOSA-N (4r,4as,7ar,12bs)-4a-hydroxy-9-methoxy-3-methyl-2,4,5,6,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7-one;terephthalic acid Chemical compound OC(=O)C1=CC=C(C(O)=O)C=C1.O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4C.O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4C BTEYIHUKHHAVAN-KDKWOIFOSA-N 0.000 description 1
238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
KWSLGOVYXMQPPX-UHFFFAOYSA-N 5-[3-(trifluoromethyl)phenyl]-2h-tetrazole Chemical compound FC(F)(F)C1=CC=CC(C2=NNN=N2)=C1 KWSLGOVYXMQPPX-UHFFFAOYSA-N 0.000 description 1
QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical class CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 1
BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
AEMRFAOFKBGASW-UHFFFAOYSA-M Glycolate Chemical compound OCC([O-])=O AEMRFAOFKBGASW-UHFFFAOYSA-M 0.000 description 1
CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
238000003109 Karl Fischer titration Methods 0.000 description 1
CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
229910002651 NO3 Inorganic materials 0.000 description 1
NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
229940121954 Opioid receptor agonist Drugs 0.000 description 1
MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
229910019142 PO4 Inorganic materials 0.000 description 1
241001596485 Papaver bracteatum Species 0.000 description 1
ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
239000004280 Sodium formate Substances 0.000 description 1
DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
LLRZWSLBLGNDFM-XFKAJCMBSA-N [(4R,4aS,7aR,12bS)-9-methoxy-3-methyl-7-oxo-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-4a-yl] hydrogen sulfate Chemical compound S(=O)(=O)(O)O[C@@]12CCC([C@H]3[C@]11C=4C(=C(C=CC=4C[C@H]2N(C)CC1)OC)O3)=O LLRZWSLBLGNDFM-XFKAJCMBSA-N 0.000 description 1
150000007513 acids Chemical class 0.000 description 1
229940024606 amino acid Drugs 0.000 description 1
VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
239000012491 analyte Substances 0.000 description 1
229940009098 aspartate Drugs 0.000 description 1
230000008033 biological extinction Effects 0.000 description 1
239000002775 capsule Substances 0.000 description 1
238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
238000012512 characterization method Methods 0.000 description 1
239000003795 chemical substances by application Substances 0.000 description 1
238000010959 commercial synthesis reaction Methods 0.000 description 1
239000000306 component Substances 0.000 description 1
238000012937 correction Methods 0.000 description 1
239000012043 crude product Substances 0.000 description 1
239000013078 crystal Substances 0.000 description 1
238000001514 detection method Methods 0.000 description 1
SWXVUIWOUIDPGS-UHFFFAOYSA-N diacetone alcohol Natural products CC(=O)CC(C)(C)O SWXVUIWOUIDPGS-UHFFFAOYSA-N 0.000 description 1
229940120124 dichloroacetate Drugs 0.000 description 1
JXTHNDFMNIQAHM-UHFFFAOYSA-N dichloroacetic acid Chemical compound OC(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-N 0.000 description 1
238000007865 diluting Methods 0.000 description 1
230000003292 diminished effect Effects 0.000 description 1
238000004821 distillation Methods 0.000 description 1
229940079593 drug Drugs 0.000 description 1
239000003814 drug Substances 0.000 description 1
238000010828 elution Methods 0.000 description 1
229930195712 glutamate Natural products 0.000 description 1
239000008241 heterogeneous mixture Substances 0.000 description 1
239000008240 homogeneous mixture Substances 0.000 description 1
230000001939 inductive effect Effects 0.000 description 1
239000011261 inert gas Substances 0.000 description 1
150000002576 ketones Chemical class 0.000 description 1
239000004816 latex Substances 0.000 description 1
229920000126 latex Polymers 0.000 description 1
230000014759 maintenance of location Effects 0.000 description 1
VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
238000012544 monitoring process Methods 0.000 description 1
JFRPUDPEFYDFJM-UHFFFAOYSA-N n,n-dibutylbutan-1-amine;formic acid Chemical compound OC=O.CCCCN(CCCC)CCCC JFRPUDPEFYDFJM-UHFFFAOYSA-N 0.000 description 1
UZHSEJADLWPNLE-GRGSLBFTSA-N naloxone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(O)C2=C5[C@@]13CCN4CC=C UZHSEJADLWPNLE-GRGSLBFTSA-N 0.000 description 1
229960004127 naloxone Drugs 0.000 description 1
DQCKKXVULJGBQN-XFWGSAIBSA-N naltrexone Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CCC5=O)O)CC1)O)CC1CC1 DQCKKXVULJGBQN-XFWGSAIBSA-N 0.000 description 1
229960003086 naltrexone Drugs 0.000 description 1
239000003887 narcotic antagonist Substances 0.000 description 1
229910052759 nickel Inorganic materials 0.000 description 1
238000010899 nucleation Methods 0.000 description 1
230000001590 oxidative effect Effects 0.000 description 1
229960004004 oxycodone terephthalate Drugs 0.000 description 1
235000006502 papoula Nutrition 0.000 description 1
239000007793 ph indicator Substances 0.000 description 1
NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
239000010452 phosphate Substances 0.000 description 1
ACVYVLVWPXVTIT-UHFFFAOYSA-N phosphinic acid Chemical compound O[PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-N 0.000 description 1
239000011591 potassium Substances 0.000 description 1
229910052700 potassium Inorganic materials 0.000 description 1
WFIZEGIEIOHZCP-UHFFFAOYSA-M potassium formate Chemical compound [K+].[O-]C=O WFIZEGIEIOHZCP-UHFFFAOYSA-M 0.000 description 1
235000011118 potassium hydroxide Nutrition 0.000 description 1
230000001376 precipitating effect Effects 0.000 description 1
239000002243 precursor Substances 0.000 description 1
238000010926 purge Methods 0.000 description 1
239000000376 reactant Substances 0.000 description 1
238000004007 reversed phase HPLC Methods 0.000 description 1
229910052707 ruthenium Inorganic materials 0.000 description 1
239000012266 salt solution Substances 0.000 description 1
238000006748 scratching Methods 0.000 description 1
230000002393 scratching effect Effects 0.000 description 1
238000007086 side reaction Methods 0.000 description 1
239000011734 sodium Substances 0.000 description 1
BBMHARZCALWXSL-UHFFFAOYSA-M sodium dihydrogenphosphate monohydrate Chemical compound O.[Na+].OP(O)([O-])=O BBMHARZCALWXSL-UHFFFAOYSA-M 0.000 description 1
HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 description 1
235000019254 sodium formate Nutrition 0.000 description 1
229910001379 sodium hypophosphite Inorganic materials 0.000 description 1
239000012265 solid product Substances 0.000 description 1
241000894007 species Species 0.000 description 1
239000012899 standard injection Substances 0.000 description 1
239000000126 substance Substances 0.000 description 1
KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
239000000725 suspension Substances 0.000 description 1
229940095064 tartrate Drugs 0.000 description 1
KKEYFWRCBNTPAC-UHFFFAOYSA-L terephthalate(2-) Chemical compound [O-]C(=O)C1=CC=C(C([O-])=O)C=C1 KKEYFWRCBNTPAC-UHFFFAOYSA-L 0.000 description 1
PTMFUWGXPRYYMC-UHFFFAOYSA-N triethylazanium;formate Chemical compound OC=O.CCN(CC)CC PTMFUWGXPRYYMC-UHFFFAOYSA-N 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

Landscapes

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

CA2934527A 2013-12-18 2014-12-18 Synthesis of oxycodone hydrochloride Abandoned CA2934527A1 (en)

Applications Claiming Priority (7)

Application Number	Priority Date	Filing Date	Title
US14/132,825		2013-12-18
US14/132,737 US9062062B1 (en)	2013-12-18	2013-12-18	Synthesis of oxycodone hydrochloride
US14/132,825 US8846923B1 (en)	2013-12-18	2013-12-18	Preparation of 14-hydroxycodeinone sulfate
US14/132,910		2013-12-18
US14/132,910 US10227354B2 (en)	2013-12-18	2013-12-18	Conversion of oxycodone base to oxycodone hydrochloride
US14/132,737		2013-12-18
PCT/US2014/071264 WO2015095585A2 (en)	2013-12-18	2014-12-18	Sysnthesis of oxycodone hydrochloride

Publications (1)

Publication Number	Publication Date
CA2934527A1 true CA2934527A1 (en)	2015-06-25

Family

ID=52293289

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
CA2934527A Abandoned CA2934527A1 (en)	2013-12-18	2014-12-18	Synthesis of oxycodone hydrochloride

Country Status (4)

Country	Link
EP (1)	EP3083632A2 (zh)
CN (1)	CN106164078A (zh)
CA (1)	CA2934527A1 (zh)
WO (1)	WO2015095585A2 (zh)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
AR091779A1 (es)	2012-07-16	2015-02-25	Rhodes Technologies	Procedimiento para la sintesis mejorada de opioides
KR101946103B1 (ko)	2012-07-16	2019-02-08	로드스 테크놀로지즈	개선된 오피오이드 합성을 위한 방법
MX2016009125A (es)	2014-01-15	2017-02-02	Rhodes Tech	Proceso para la sintesis mejorada de oximorfona.
US9932348B2 (en)	2014-01-15	2018-04-03	Rhodes Technologies	Process for improved oxycodone synthesis
US10941154B2 (en) *	2017-06-20	2021-03-09	Johnson Matthey Public Limited Company	Hydrogenation process for preparing oxycodone hydrochloride from 14-hydroxycodeinone

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* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
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
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
US6067749A (en)	1996-07-11	2000-05-30	Tasmanian Alkaloids Pty. Ltd.	Papaver somniferum strain with high concentration of thebaine and oripavine
SK286087B6 (sk) *	2004-08-18	2008-03-05	Zentiva, A. S.	Spôsob prípravy oxykodonu
GB0421149D0 (en) *	2004-09-23	2004-10-27	Johnson Matthey Plc	Preparation of oxycodone
MX2007015789A (es)	2005-06-16	2008-02-15	Mallinckrodt Inc	Nueva ruta de sintesis para opiatos de 14-hidroxilo a traves de 1-halo-tebaina o analogos.
EP2377866B1 (en) *	2010-03-23	2014-02-26	Siegfried AG	Preparation of low impurity opiates in a continuous flow reactor
AR091779A1 (es) *	2012-07-16	2015-02-25	Rhodes Technologies	Procedimiento para la sintesis mejorada de opioides

2014
- 2014-12-18 CN CN201480075277.9A patent/CN106164078A/zh active Pending
- 2014-12-18 EP EP14824727.3A patent/EP3083632A2/en not_active Withdrawn
- 2014-12-18 CA CA2934527A patent/CA2934527A1/en not_active Abandoned
- 2014-12-18 WO PCT/US2014/071264 patent/WO2015095585A2/en active Application Filing

Also Published As

Publication number	Publication date
WO2015095585A2 (en)	2015-06-25
WO2015095585A8 (en)	2016-02-04
WO2015095585A3 (en)	2015-08-13
CN106164078A (zh)	2016-11-23
EP3083632A2 (en)	2016-10-26

Publication	Publication Date	Title
US9233972B2 (en)	2016-01-12	Preparation of 14-hydroxycodeinone sulfate
US9062062B1 (en)	2015-06-23	Synthesis of oxycodone hydrochloride
US8134002B2 (en)	2012-03-13	Process for preparing oxymorphone
RU2401270C2 (ru)	2010-10-10	Способ очистки соединений нороксиморфона
US9487532B2 (en)	2016-11-08	Process for preparing oxymorphone, naltrexone, and buprenorphine
AU2011231748B2 (en)	2013-11-14	Preparation of low impurity opiates in a continuous flow reactor
CA2934527A1 (en)	2015-06-25	Synthesis of oxycodone hydrochloride
US10227354B2 (en)	2019-03-12	Conversion of oxycodone base to oxycodone hydrochloride
EP1658293B1 (en)	2006-12-13	A method of preparation of oxycodone
US9657029B2 (en)	2017-05-23	Method of preparing oxymorphone
JP6215399B2 (ja)	2017-10-18	ナルトレキソンの製造方法
WO2006005112A1 (en)	2006-01-19	Process for the synthesis of hydromorphone
EP2480555B1 (en)	2015-11-11	Methods for producing hydrocodone, hydromorphone or a derivative thereof
CA2747331C (en)	2018-01-23	Process for making a crystalline zilpaterol salt
EP3186256B1 (en)	2023-02-22	Improved process for making 14-hydroxycodeinone
EP2970320B1 (en)	2020-10-28	Morphine sulfate methanolic solvate, processes for making same and related compositions and methods for treating pain
WO2024184270A1 (en)	2024-09-12	Novel process for synthesizing opioid derivatives
WO2004078700A1 (en)	2004-09-16	3,3-diarylpropylamine derivatives and processes for isolation thereof
KR20100044486A (ko)	2010-04-30	암로디핀 니코티네이트의 신규 결정형 및 이의 제조방법
EP3252055A1 (en)	2017-12-06	Process for obtaining 3,14-diacetyloxymorphone from oripavine
SG189369A1 (en)	2013-05-31	Method for the manufacturing of naltrexone

Legal Events

Date	Code	Title	Description
2021-05-04	FZDE	Discontinued	Effective date: 20210309
2022-05-05	FZDE	Discontinued	Effective date: 20210309