CA2585698A1 - Opiate intermediates and methods of synthesis - Google Patents
Opiate intermediates and methods of synthesis Download PDFInfo
- Publication number
- CA2585698A1 CA2585698A1 CA002585698A CA2585698A CA2585698A1 CA 2585698 A1 CA2585698 A1 CA 2585698A1 CA 002585698 A CA002585698 A CA 002585698A CA 2585698 A CA2585698 A CA 2585698A CA 2585698 A1 CA2585698 A1 CA 2585698A1
- Authority
- CA
- Canada
- Prior art keywords
- formula
- compound
- alkyl
- aryl
- group
- Prior art date
- 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
Links
- 238000000034 method Methods 0.000 title claims abstract description 64
- 229940127240 opiate Drugs 0.000 title claims abstract description 26
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 26
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 25
- 239000000543 intermediate Substances 0.000 title abstract description 13
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 68
- 239000000203 mixture Substances 0.000 claims abstract description 68
- 125000003118 aryl group Chemical group 0.000 claims abstract description 62
- 125000002252 acyl group Chemical group 0.000 claims abstract description 50
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 50
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 46
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims abstract description 17
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 17
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 15
- 229940124530 sulfonamide Drugs 0.000 claims abstract description 15
- 150000003456 sulfonamides Chemical class 0.000 claims abstract description 15
- 150000001875 compounds Chemical class 0.000 claims description 110
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 60
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 43
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 37
- -1 phosphorous halide Chemical class 0.000 claims description 33
- 239000002904 solvent Substances 0.000 claims description 32
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- 235000019253 formic acid Nutrition 0.000 claims description 18
- 239000002253 acid Substances 0.000 claims description 17
- 238000006243 chemical reaction Methods 0.000 claims description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- 239000003638 chemical reducing agent Substances 0.000 claims description 14
- 238000007363 ring formation reaction Methods 0.000 claims description 13
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 11
- 150000004820 halides Chemical class 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 9
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 9
- 150000003461 sulfonyl halides Chemical class 0.000 claims description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 8
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 8
- 239000012279 sodium borohydride Substances 0.000 claims description 8
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 8
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 8
- 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 6
- 150000004675 formic acid derivatives Chemical class 0.000 claims description 6
- 229910052741 iridium Inorganic materials 0.000 claims description 6
- 229910052763 palladium Inorganic materials 0.000 claims description 6
- 229910052697 platinum Inorganic materials 0.000 claims description 6
- 229910052707 ruthenium Inorganic materials 0.000 claims description 6
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 150000002466 imines Chemical class 0.000 claims description 5
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 5
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims description 5
- 229910019213 POCl3 Inorganic materials 0.000 claims description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 4
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 4
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 4
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 4
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 3
- NIRCAUPPZAUKDX-UHFFFAOYSA-N 5-benzyl-2-[[4-(3-chlorophenyl)piperazin-1-yl]methyl]-6-methylpyridazin-3-one Chemical compound O=C1C=C(CC=2C=CC=CC=2)C(C)=NN1CN(CC1)CCN1C1=CC=CC(Cl)=C1 NIRCAUPPZAUKDX-UHFFFAOYSA-N 0.000 claims description 2
- 239000002841 Lewis acid Substances 0.000 claims description 2
- 229910019201 POBr3 Inorganic materials 0.000 claims description 2
- 229910006121 SOBr2 Inorganic materials 0.000 claims description 2
- 150000007517 lewis acids Chemical class 0.000 claims description 2
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 claims description 2
- UXCDUFKZSUBXGM-UHFFFAOYSA-N phosphoric tribromide Chemical compound BrP(Br)(Br)=O UXCDUFKZSUBXGM-UHFFFAOYSA-N 0.000 claims description 2
- HFRXJVQOXRXOPP-UHFFFAOYSA-N thionyl bromide Chemical compound BrS(Br)=O HFRXJVQOXRXOPP-UHFFFAOYSA-N 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims 8
- 241000352333 Amegilla alpha Species 0.000 claims 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 claims 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical group ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims 2
- LXFQSRIDYRFTJW-UHFFFAOYSA-N 2,4,6-trimethylbenzenesulfonic acid Chemical compound CC1=CC(C)=C(S(O)(=O)=O)C(C)=C1 LXFQSRIDYRFTJW-UHFFFAOYSA-N 0.000 claims 1
- 229910006124 SOCl2 Inorganic materials 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 claims 1
- 230000002140 halogenating effect Effects 0.000 claims 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims 1
- 238000006467 substitution reaction Methods 0.000 abstract description 4
- 150000003809 morphinane derivatives Chemical class 0.000 abstract 1
- 229910001868 water Inorganic materials 0.000 description 35
- 239000007787 solid Substances 0.000 description 28
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 26
- 238000006722 reduction reaction Methods 0.000 description 23
- 239000000243 solution Substances 0.000 description 21
- 238000002360 preparation method Methods 0.000 description 20
- 238000010992 reflux Methods 0.000 description 20
- 239000000047 product Substances 0.000 description 16
- 239000002585 base Substances 0.000 description 15
- 230000002829 reductive effect Effects 0.000 description 15
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 229910021529 ammonia Inorganic materials 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- 239000012044 organic layer Substances 0.000 description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 150000002367 halogens Chemical class 0.000 description 10
- 238000004821 distillation Methods 0.000 description 9
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 239000013078 crystal Substances 0.000 description 8
- 229910052751 metal Inorganic materials 0.000 description 8
- 239000002184 metal Substances 0.000 description 8
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 7
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 7
- 150000001412 amines Chemical class 0.000 description 6
- YCIMNLLNPGFGHC-UHFFFAOYSA-N catechol Chemical compound OC1=CC=CC=C1O YCIMNLLNPGFGHC-UHFFFAOYSA-N 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 description 6
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 5
- 239000003513 alkali Substances 0.000 description 5
- 229910052783 alkali metal Inorganic materials 0.000 description 5
- 150000001340 alkali metals Chemical class 0.000 description 5
- 235000011114 ammonium hydroxide Nutrition 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 5
- INAXVFBXDYWQFN-XHSDSOJGSA-N morphinan Chemical class C1C2=CC=CC=C2[C@]23CCCC[C@H]3[C@@H]1NCC2 INAXVFBXDYWQFN-XHSDSOJGSA-N 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 4
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 4
- 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 description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 4
- 241000209094 Oryza Species 0.000 description 4
- 235000007164 Oryza sativa Nutrition 0.000 description 4
- 150000001491 aromatic compounds Chemical class 0.000 description 4
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 235000009566 rice Nutrition 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- 229910052791 calcium Inorganic materials 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- MGNZXYYWBUKAII-UHFFFAOYSA-N cyclohexa-1,3-diene Chemical compound C1CC=CC=C1 MGNZXYYWBUKAII-UHFFFAOYSA-N 0.000 description 3
- 238000005695 dehalogenation reaction Methods 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 229910052744 lithium Inorganic materials 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 235000011007 phosphoric acid Nutrition 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 230000008707 rearrangement Effects 0.000 description 3
- 238000006798 ring closing metathesis reaction Methods 0.000 description 3
- IMSQRCLWJIAQPA-ASYNLNLVSA-N (1s)-1-[(2-chloro-4,5-dihydroxyphenyl)methyl]-2,3,4,4a,5,8a-hexahydro-1h-isoquinolin-6-one Chemical compound C1=C(O)C(O)=CC(Cl)=C1C[C@H]1C2C=CC(=O)CC2CCN1 IMSQRCLWJIAQPA-ASYNLNLVSA-N 0.000 description 2
- JNQSIOPTNRZXBD-AWEZNQCLSA-N (1s)-1-[(2-chloro-4,5-dihydroxyphenyl)methyl]-2,3,4,5,7,8-hexahydro-1h-isoquinolin-6-one Chemical compound C1=C(O)C(O)=CC(Cl)=C1C[C@H]1C(CCC(=O)C2)=C2CCN1 JNQSIOPTNRZXBD-AWEZNQCLSA-N 0.000 description 2
- LBYNOXVFIMUWQJ-PYMCNQPYSA-N (1s)-1-[(2-chloro-4,5-dihydroxyphenyl)methyl]-2,3,4,7,8,8a-hexahydro-1h-isoquinolin-6-one Chemical compound C1=C(O)C(O)=CC(Cl)=C1C[C@H]1C2CCC(=O)C=C2CCN1 LBYNOXVFIMUWQJ-PYMCNQPYSA-N 0.000 description 2
- FICJQAXYUWAVFO-KHXKVGHRSA-N (1s)-1-[(2-chloro-4,5-dihydroxyphenyl)methyl]-6-oxo-1,3,4,4a,5,8a-hexahydroisoquinoline-2-carbaldehyde Chemical compound C1=C(O)C(O)=CC(Cl)=C1C[C@@H]1N(C=O)CCC2CC(=O)C=CC21 FICJQAXYUWAVFO-KHXKVGHRSA-N 0.000 description 2
- NWUTYCNWNYQFPC-HNNXBMFYSA-N (1s)-1-[(2-chloro-4,5-dihydroxyphenyl)methyl]-6-oxo-1,3,4,5,7,8-hexahydroisoquinoline-2-carbaldehyde Chemical compound C1=C(O)C(O)=CC(Cl)=C1C[C@H]1C(CCC(=O)C2)=C2CCN1C=O NWUTYCNWNYQFPC-HNNXBMFYSA-N 0.000 description 2
- SOTVOFUDLASMBF-INIZCTEOSA-N (1s)-1-[(2-fluoro-4,5-dihydroxyphenyl)methyl]-6-methoxy-3,4,5,8-tetrahydro-1h-isoquinoline-2-carbaldehyde Chemical compound C([C@@H]1N(C=O)CCC2=C1CC=C(C2)OC)C1=CC(O)=C(O)C=C1F SOTVOFUDLASMBF-INIZCTEOSA-N 0.000 description 2
- ARDAIVOLIZJAQV-HNNXBMFYSA-N 4-fluoro-5-[[(1s)-6-methoxy-1,2,3,4,5,8-hexahydroisoquinolin-1-yl]methyl]benzene-1,2-diol Chemical compound C([C@@H]1NCCC2=C1CC=C(C2)OC)C1=CC(O)=C(O)C=C1F ARDAIVOLIZJAQV-HNNXBMFYSA-N 0.000 description 2
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 2
- 239000005695 Ammonium acetate Substances 0.000 description 2
- 229910015845 BBr3 Inorganic materials 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 2
- SEQKRHFRPICQDD-UHFFFAOYSA-N N-tris(hydroxymethyl)methylglycine Chemical compound OCC(CO)(CO)[NH2+]CC([O-])=O SEQKRHFRPICQDD-UHFFFAOYSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 235000019257 ammonium acetate Nutrition 0.000 description 2
- 229940043376 ammonium acetate Drugs 0.000 description 2
- 239000000908 ammonium hydroxide Substances 0.000 description 2
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 2
- 238000005660 chlorination reaction Methods 0.000 description 2
- 239000006184 cosolvent Substances 0.000 description 2
- UVJHQYIOXKWHFD-UHFFFAOYSA-N cyclohexa-1,4-diene Chemical compound C1C=CCC=C1 UVJHQYIOXKWHFD-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 2
- 235000021317 phosphate Nutrition 0.000 description 2
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 2
- 238000006116 polymerization reaction Methods 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 2
- 239000003039 volatile agent Substances 0.000 description 2
- BQJCRHHNABKAKU-XKUOQXLYSA-N (-)-Morphine Natural products O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@H]3CC5=CC=C4O BQJCRHHNABKAKU-XKUOQXLYSA-N 0.000 description 1
- JNQSIOPTNRZXBD-CQSZACIVSA-N (1r)-1-[(2-chloro-4,5-dihydroxyphenyl)methyl]-2,3,4,5,7,8-hexahydro-1h-isoquinolin-6-one Chemical compound C1=C(O)C(O)=CC(Cl)=C1C[C@@H]1C(CCC(=O)C2)=C2CCN1 JNQSIOPTNRZXBD-CQSZACIVSA-N 0.000 description 1
- NWUTYCNWNYQFPC-OAHLLOKOSA-N (1r)-1-[(2-chloro-4,5-dihydroxyphenyl)methyl]-6-oxo-1,3,4,5,7,8-hexahydroisoquinoline-2-carbaldehyde Chemical compound C1=C(O)C(O)=CC(Cl)=C1C[C@@H]1C(CCC(=O)C2)=C2CCN1C=O NWUTYCNWNYQFPC-OAHLLOKOSA-N 0.000 description 1
- JXGVXCZADZNAMJ-NSHDSACASA-N (2s)-1-phenylmethoxycarbonylpyrrolidine-2-carboxylic acid Chemical compound OC(=O)[C@@H]1CCCN1C(=O)OCC1=CC=CC=C1 JXGVXCZADZNAMJ-NSHDSACASA-N 0.000 description 1
- JNQSIOPTNRZXBD-UHFFFAOYSA-N 1-[(2-chloro-4,5-dihydroxyphenyl)methyl]-2,3,4,5,7,8-hexahydro-1h-isoquinolin-6-one Chemical compound C1=C(O)C(O)=CC(Cl)=C1CC1C(CCC(=O)C2)=C2CCN1 JNQSIOPTNRZXBD-UHFFFAOYSA-N 0.000 description 1
- LBYNOXVFIMUWQJ-UHFFFAOYSA-N 1-[(2-chloro-4,5-dihydroxyphenyl)methyl]-2,3,4,7,8,8a-hexahydro-1h-isoquinolin-6-one Chemical compound C1=C(O)C(O)=CC(Cl)=C1CC1C2CCC(=O)C=C2CCN1 LBYNOXVFIMUWQJ-UHFFFAOYSA-N 0.000 description 1
- FICJQAXYUWAVFO-UHFFFAOYSA-N 1-[(2-chloro-4,5-dihydroxyphenyl)methyl]-6-oxo-1,3,4,4a,5,8a-hexahydroisoquinoline-2-carbaldehyde Chemical compound C1=C(O)C(O)=CC(Cl)=C1CC1N(C=O)CCC2CC(=O)C=CC21 FICJQAXYUWAVFO-UHFFFAOYSA-N 0.000 description 1
- JMKSEQQMVVMPFE-UHFFFAOYSA-N 1-[(2-chloro-4,5-dihydroxyphenyl)methyl]-6-oxo-1,3,4,7,8,8a-hexahydroisoquinoline-2-carbaldehyde Chemical compound C1=C(O)C(O)=CC(Cl)=C1CC1N(C=O)CCC2=CC(=O)CCC21 JMKSEQQMVVMPFE-UHFFFAOYSA-N 0.000 description 1
- IHPYMWDTONKSCO-UHFFFAOYSA-N 2,2'-piperazine-1,4-diylbisethanesulfonic acid Chemical compound OS(=O)(=O)CCN1CCN(CCS(O)(=O)=O)CC1 IHPYMWDTONKSCO-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- INEWUCPYEUEQTN-UHFFFAOYSA-N 3-(cyclohexylamino)-2-hydroxy-1-propanesulfonic acid Chemical compound OS(=O)(=O)CC(O)CNC1CCCCC1 INEWUCPYEUEQTN-UHFFFAOYSA-N 0.000 description 1
- PFMTUKBCMGQIAX-UHFFFAOYSA-N 4-chloro-5-[(6-methoxy-1,2,3,4,5,8-hexahydroisoquinolin-1-yl)methyl]benzene-1,2-diol Chemical compound C1C(OC)=CCC2=C1CCNC2CC1=CC(O)=C(O)C=C1Cl PFMTUKBCMGQIAX-UHFFFAOYSA-N 0.000 description 1
- ARDAIVOLIZJAQV-UHFFFAOYSA-N 4-fluoro-5-[(6-methoxy-1,2,3,4,5,8-hexahydroisoquinolin-1-yl)methyl]benzene-1,2-diol Chemical compound C1C(OC)=CCC2=C1CCNC2CC1=CC(O)=C(O)C=C1F ARDAIVOLIZJAQV-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 238000006027 Birch reduction reaction Methods 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 239000008001 CAPS buffer Substances 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- OWXMKDGYPWMGEB-UHFFFAOYSA-N HEPPS Chemical compound OCCN1CCN(CCCS(O)(=O)=O)CC1 OWXMKDGYPWMGEB-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 239000007987 MES buffer Substances 0.000 description 1
- 239000007993 MOPS buffer Substances 0.000 description 1
- FSVCELGFZIQNCK-UHFFFAOYSA-N N,N-bis(2-hydroxyethyl)glycine Chemical compound OCCN(CCO)CC(O)=O FSVCELGFZIQNCK-UHFFFAOYSA-N 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- 229910020667 PBr3 Inorganic materials 0.000 description 1
- 239000007990 PIPES buffer Substances 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- UZMAPBJVXOGOFT-UHFFFAOYSA-N Syringetin Natural products COC1=C(O)C(OC)=CC(C2=C(C(=O)C3=C(O)C=C(O)C=C3O2)O)=C1 UZMAPBJVXOGOFT-UHFFFAOYSA-N 0.000 description 1
- 239000007997 Tricine buffer Substances 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 208000034953 Twin anemia-polycythemia sequence Diseases 0.000 description 1
- MUCRYNWJQNHDJH-OADIDDRXSA-N Ursonic acid Chemical compound C1CC(=O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CC[C@@H](C)[C@H](C)[C@H]5C4=CC[C@@H]3[C@]21C MUCRYNWJQNHDJH-OADIDDRXSA-N 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 150000001266 acyl halides Chemical class 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000011260 aqueous acid Substances 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 125000001743 benzylic group Chemical group 0.000 description 1
- 239000007998 bicine buffer Substances 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 229960004424 carbon dioxide Drugs 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cis-cyclohexene Natural products C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 description 1
- 125000004850 cyclobutylmethyl group Chemical group C1(CCC1)C* 0.000 description 1
- KCFYHBSOLOXZIF-UHFFFAOYSA-N dihydrochrysin Natural products COC1=C(O)C(OC)=CC(C2OC3=CC(O)=CC(O)=C3C(=O)C2)=C1 KCFYHBSOLOXZIF-UHFFFAOYSA-N 0.000 description 1
- 150000002009 diols Chemical class 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N ethyl formate Chemical compound CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229930013053 morphinan alkaloid Natural products 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- IPNPIHIZVLFAFP-UHFFFAOYSA-N phosphorus tribromide Chemical compound BrP(Br)Br IPNPIHIZVLFAFP-UHFFFAOYSA-N 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000002128 sulfonyl halide group Chemical group 0.000 description 1
- UWYZHKAOTLEWKK-UHFFFAOYSA-N tetrahydro-isoquinoline Natural products C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical class C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical class N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
- C07C235/34—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
- C07D217/18—Aralkyl radicals
- C07D217/20—Aralkyl radicals with oxygen atoms directly attached to the aromatic ring of said aralkyl radical, e.g. papaverine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/22—Bridged ring systems
- C07D221/28—Morphinans
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
- Vacuum Packaging (AREA)
- Saccharide Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US62539704P | 2004-11-04 | 2004-11-04 | |
| US60/625,397 | 2004-11-04 | ||
| PCT/US2005/038140 WO2006052430A2 (en) | 2004-11-04 | 2005-10-21 | Opiate intermediates and methods of synthesis |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2585698A1 true CA2585698A1 (en) | 2006-05-18 |
Family
ID=35695757
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002585698A Abandoned CA2585698A1 (en) | 2004-11-04 | 2005-10-21 | Opiate intermediates and methods of synthesis |
Country Status (13)
| Country | Link |
|---|---|
| US (1) | US7834184B2 (enExample) |
| EP (1) | EP1812399B1 (enExample) |
| JP (1) | JP2008518910A (enExample) |
| CN (1) | CN101052622A (enExample) |
| AT (1) | ATE450513T1 (enExample) |
| AU (1) | AU2005305210B2 (enExample) |
| CA (1) | CA2585698A1 (enExample) |
| DE (1) | DE602005018092D1 (enExample) |
| ES (1) | ES2336131T3 (enExample) |
| MX (1) | MX2007005194A (enExample) |
| PL (1) | PL1812399T3 (enExample) |
| PT (1) | PT1812399E (enExample) |
| WO (1) | WO2006052430A2 (enExample) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MX2009006008A (es) * | 2006-12-12 | 2009-06-16 | Mallinckrodt Inc | Preparacion de hexahidroisoquinolinas a partir de dihidroisoquinolinas. |
| US8829020B2 (en) | 2009-07-16 | 2014-09-09 | Mallinckrodt Llc | Compounds and compositions for use in phototherapy and in treatment of ocular neovascular disease and cancers |
| WO2011038169A2 (en) | 2009-09-24 | 2011-03-31 | Mallinckrodt Inc. | One-pot preparation of hexahydroisoquinolines from amides |
| CN108383788A (zh) * | 2018-03-27 | 2018-08-10 | 合肥医工医药有限公司 | 一种二甲啡烷异构体的制备方法 |
Family Cites Families (32)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB685748A (en) | 1949-10-14 | 1953-01-07 | Hoffmann La Roche | Improvements in or relating to isoquinoline derivatives |
| DE1138765B (de) | 1954-12-28 | 1962-10-31 | Farmaceutici Italia | Verfahren zur Herstellung der Kaffeesaeureester der Chinasaeure |
| DE1154268B (de) | 1960-01-07 | 1963-09-12 | Bayer Ag | Die Verhuetung der elektrostatischen Aufladung bei synthetischen Hochpolymeren |
| US3438989A (en) | 1967-03-10 | 1969-04-15 | Warner Lambert Pharmaceutical | Process for the production of ( ) dihydrothebainone |
| US3862327A (en) | 1967-11-01 | 1975-01-21 | Uniroyal Inc | Substituted phenylethyl sulfites useful for controlling mites |
| FR2015566A1 (enExample) | 1968-08-13 | 1970-04-30 | Basf Ag | |
| US3922285A (en) | 1971-03-26 | 1975-11-25 | Hoffmann La Roche | Process for the methylenation of catechols |
| US3914233A (en) | 1972-10-20 | 1975-10-21 | Hoffmann La Roche | 4-Hydroxy-N-substituted morphinan derivatives |
| HU182087B (en) | 1980-01-15 | 1983-12-28 | Mta Kiserleti Orvostudomanyi K | Process for preparing an active substance for the selective inhibition of the multiplication of normal cells and of cells in myeloide leukemia |
| US4727146A (en) | 1980-07-03 | 1988-02-23 | The United States Of America As Represented By The Department Of Health And Human Services | Synthesis of chiral 1-benzyl-1,2,3,4-tetra-hydroisoquinolines by asymmetric reduction |
| US4410700A (en) * | 1980-07-03 | 1983-10-18 | The United States Of America As Represented By The Department Of Health And Human Services | Preparation of chiral 1-benzyl-1,2,3,4-tetrahydroisoquinolines by optical resolution |
| US4368326A (en) * | 1980-07-03 | 1983-01-11 | Rice Kenner C | Short total synthesis of dihydrothebainone, dihydrocodeinone, and nordihydroccodeinone |
| US4521601A (en) | 1981-05-20 | 1985-06-04 | The United States Of America As Represented By The Department Of Health & Human Services | Practical total synthesis unnatural enantiomers of opium-derived morphinans |
| US4514569A (en) | 1982-01-28 | 1985-04-30 | Hendrickson James B | Synthesis of 1-substituted isoquinolines |
| US4452601A (en) | 1982-03-19 | 1984-06-05 | Celanese Corporation | Process for the thermal stabilization of acrylic fibers and films |
| 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 |
| US4727504A (en) * | 1984-07-05 | 1988-02-23 | The Charles Stark Draper Laboratory, Inc. | Interference canceller and signal quantizer |
| US4737504A (en) | 1986-07-25 | 1988-04-12 | Ohio State University Research Foundation | 5-fluoro-and 8-fluoro-trimetoquinol compounds and the processes for their preparation |
| US5668285A (en) | 1986-10-31 | 1997-09-16 | The United States Of America As Represented By The Department Of Health And Human Services | Total synthesis of northebaine, normophine, noroxymorphone enantiomers and derivatives via N-Nor intermediates |
| US5023342A (en) | 1988-05-26 | 1991-06-11 | Massachusetts Institute Of Technology | Cyclic sulfate compounds |
| US5189200A (en) | 1990-12-21 | 1993-02-23 | Sepracor, Inc. | Process for the stereoselective transformation of a diol to an alcohol |
| GB9127306D0 (en) | 1991-12-23 | 1992-02-19 | Boots Co Plc | Therapeutic agents |
| JPH06247935A (ja) | 1993-02-25 | 1994-09-06 | Banyu Pharmaceut Co Ltd | ６，７−ジアルコキシ−３，４−ジヒドロイソキノリン−８−オール類、その製造法及び該化合物を用いた６，７−ジアルコキシ−１，２，３，４−テトラヒドロイソキノリン−８−オール類の製造法 |
| US5445164A (en) | 1993-05-11 | 1995-08-29 | Gynetech, Inc. | Cervical tissue sampling device |
| BR9406897A (pt) | 1993-06-22 | 1996-03-26 | Knoll Ag | Compostos de tetraidroisoquinolina composiçoes farmaceuticas processo de analgesia ou de tratamento de psicoses doença de parkinson sindrome de leschnyan distúrbio da falta de atençao ou danos cognitivos ou na supressao da dependencia de drogas ou discinesia tardia e uso de um composto |
| US5869697A (en) | 1994-05-02 | 1999-02-09 | Council Of Scientific & Industrial Research | Process for preparing diltiazem |
| US6043253A (en) | 1998-03-03 | 2000-03-28 | Merck & Co., Inc. | Fused piperidine substituted arylsulfonamides as β3-agonists |
| KR100295740B1 (ko) | 1998-09-17 | 2001-11-05 | 박영구 | N-치환된-하이드록시고리화알킬아민유도체의제조방법 |
| EP1130022B1 (en) | 2000-02-29 | 2009-07-22 | Universita Degli Studi di Firenze | 3-Aza-6,8-dioxabicyclo[3.2.1]octanes and analogues and combinatorial libraries containing them |
| US6593341B2 (en) | 2001-03-29 | 2003-07-15 | Molecular Design International, Inc. | β3-adrenoreceptor agonists, agonist compositions and methods of making and using the same |
| US6818766B2 (en) | 2002-10-02 | 2004-11-16 | Synthon Bv | Process for making bicalutamide and intermediates thereof |
| US6596734B1 (en) | 2002-10-11 | 2003-07-22 | Molecular Design International, Inc. | Tetrahydroisoquinoline compounds for use as β3-adrenoreceptor agonists |
-
2005
- 2005-10-21 CA CA002585698A patent/CA2585698A1/en not_active Abandoned
- 2005-10-21 AT AT05812329T patent/ATE450513T1/de active
- 2005-10-21 MX MX2007005194A patent/MX2007005194A/es active IP Right Grant
- 2005-10-21 PL PL05812329T patent/PL1812399T3/pl unknown
- 2005-10-21 WO PCT/US2005/038140 patent/WO2006052430A2/en not_active Ceased
- 2005-10-21 CN CNA2005800376856A patent/CN101052622A/zh active Pending
- 2005-10-21 EP EP05812329A patent/EP1812399B1/en not_active Expired - Lifetime
- 2005-10-21 DE DE602005018092T patent/DE602005018092D1/de not_active Expired - Lifetime
- 2005-10-21 US US11/718,263 patent/US7834184B2/en active Active
- 2005-10-21 ES ES05812329T patent/ES2336131T3/es not_active Expired - Lifetime
- 2005-10-21 PT PT05812329T patent/PT1812399E/pt unknown
- 2005-10-21 JP JP2007539018A patent/JP2008518910A/ja not_active Withdrawn
- 2005-10-21 AU AU2005305210A patent/AU2005305210B2/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| DE602005018092D1 (de) | 2010-01-14 |
| WO2006052430A3 (en) | 2006-08-24 |
| MX2007005194A (es) | 2007-06-20 |
| EP1812399A2 (en) | 2007-08-01 |
| US7834184B2 (en) | 2010-11-16 |
| EP1812399B1 (en) | 2009-12-02 |
| JP2008518910A (ja) | 2008-06-05 |
| AU2005305210B2 (en) | 2012-01-19 |
| AU2005305210A1 (en) | 2006-05-18 |
| CN101052622A (zh) | 2007-10-10 |
| PT1812399E (pt) | 2010-02-03 |
| WO2006052430A2 (en) | 2006-05-18 |
| PL1812399T3 (pl) | 2010-05-31 |
| US20080097100A1 (en) | 2008-04-24 |
| ATE450513T1 (de) | 2009-12-15 |
| ES2336131T3 (es) | 2010-04-08 |
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