PT1812399E - Intermediários opiato e métodos de síntese - Google Patents
Intermediários opiato e métodos de síntese Download PDFInfo
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- PT1812399E PT1812399E PT05812329T PT05812329T PT1812399E PT 1812399 E PT1812399 E PT 1812399E PT 05812329 T PT05812329 T PT 05812329T PT 05812329 T PT05812329 T PT 05812329T PT 1812399 E PT1812399 E PT 1812399E
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- 238000000034 method Methods 0.000 title claims abstract description 65
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 26
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 25
- 229940127240 opiate Drugs 0.000 title claims abstract description 25
- 239000000543 intermediate Substances 0.000 title abstract description 14
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 76
- 125000003118 aryl group Chemical group 0.000 claims abstract description 67
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 54
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 50
- 239000000203 mixture Substances 0.000 claims abstract description 49
- 125000002252 acyl group Chemical group 0.000 claims abstract description 37
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 21
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 21
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims abstract description 20
- 229940124530 sulfonamide Drugs 0.000 claims abstract description 19
- 150000003456 sulfonamides Chemical class 0.000 claims abstract description 18
- 150000001875 compounds Chemical class 0.000 claims description 126
- 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 42
- 239000002904 solvent Substances 0.000 claims description 32
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 31
- -1 phosphorus halide Chemical class 0.000 claims description 31
- 238000006243 chemical reaction Methods 0.000 claims description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- 239000002253 acid Substances 0.000 claims description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 15
- 235000019253 formic acid Nutrition 0.000 claims description 15
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 14
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 14
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-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
- 239000003638 chemical reducing agent Substances 0.000 claims description 14
- 238000007363 ring formation reaction Methods 0.000 claims description 14
- 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 14
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 11
- 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 10
- 150000003461 sulfonyl halides Chemical class 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- 150000004820 halides Chemical class 0.000 claims description 9
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 claims description 9
- 229910052698 phosphorus Inorganic materials 0.000 claims description 9
- 239000011574 phosphorus Substances 0.000 claims description 9
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 9
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 7
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 7
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 7
- 238000006460 hydrolysis reaction Methods 0.000 claims description 7
- 230000003301 hydrolyzing effect Effects 0.000 claims description 7
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 7
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- 150000004675 formic acid derivatives Chemical class 0.000 claims description 6
- 230000007062 hydrolysis Effects 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
- 239000002841 Lewis acid Substances 0.000 claims description 5
- 150000002466 imines Chemical class 0.000 claims description 5
- 150000007517 lewis acids Chemical class 0.000 claims description 5
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 5
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 229910052703 rhodium Inorganic materials 0.000 claims description 3
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 claims 6
- 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 4
- 239000012279 sodium borohydride Substances 0.000 claims 2
- 229910000033 sodium borohydride Inorganic materials 0.000 claims 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 239000011737 fluorine Substances 0.000 claims 1
- 230000002140 halogenating effect Effects 0.000 claims 1
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 claims 1
- 238000006467 substitution reaction Methods 0.000 abstract description 4
- 150000003809 morphinane derivatives Chemical class 0.000 abstract 1
- 239000007787 solid Substances 0.000 description 27
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 24
- 239000000243 solution Substances 0.000 description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 22
- 238000006722 reduction reaction Methods 0.000 description 21
- 238000002360 preparation method Methods 0.000 description 19
- 230000009467 reduction Effects 0.000 description 18
- 239000000047 product Substances 0.000 description 17
- 239000002585 base Substances 0.000 description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- 229910021529 ammonia Inorganic materials 0.000 description 12
- 239000012044 organic layer Substances 0.000 description 11
- 150000001412 amines Chemical class 0.000 description 10
- 238000004821 distillation Methods 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- 229910052751 metal Inorganic materials 0.000 description 9
- 239000002184 metal Substances 0.000 description 9
- 239000011734 sodium Substances 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
- 229910052736 halogen Inorganic materials 0.000 description 8
- 150000002367 halogens Chemical class 0.000 description 8
- 239000010410 layer Substances 0.000 description 8
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical class 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 8
- 238000010992 reflux Methods 0.000 description 8
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 229910052783 alkali metal Inorganic materials 0.000 description 6
- 150000001340 alkali metals Chemical class 0.000 description 6
- 238000004090 dissolution Methods 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 229910052708 sodium Inorganic materials 0.000 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 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-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
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 229960005181 morphine Drugs 0.000 description 4
- 235000009566 rice Nutrition 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 3
- 239000005695 Ammonium acetate Substances 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
- 230000002378 acidificating effect Effects 0.000 description 3
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 3
- 150000008041 alkali metal carbonates Chemical class 0.000 description 3
- 235000019257 ammonium acetate Nutrition 0.000 description 3
- 229940043376 ammonium acetate Drugs 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
- 238000005695 dehalogenation reaction Methods 0.000 description 3
- 239000000706 filtrate Substances 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
- 229910052700 potassium Inorganic materials 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 230000008707 rearrangement Effects 0.000 description 3
- 239000003039 volatile agent Substances 0.000 description 3
- 238000006027 Birch reduction reaction Methods 0.000 description 2
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 2
- 239000008001 CAPS buffer Substances 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
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-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
- SEQKRHFRPICQDD-UHFFFAOYSA-N N-tris(hydroxymethyl)methylglycine Chemical compound OCC(CO)(CO)[NH2+]CC([O-])=O SEQKRHFRPICQDD-UHFFFAOYSA-N 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
- 229910006124 SOCl2 Inorganic materials 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 235000011089 carbon dioxide Nutrition 0.000 description 2
- YCIMNLLNPGFGHC-UHFFFAOYSA-N catechol Chemical compound OC1=CC=CC=C1O YCIMNLLNPGFGHC-UHFFFAOYSA-N 0.000 description 2
- 238000005660 chlorination reaction Methods 0.000 description 2
- MGNZXYYWBUKAII-UHFFFAOYSA-N cyclohexa-1,3-diene Chemical compound C1CC=CC=C1 MGNZXYYWBUKAII-UHFFFAOYSA-N 0.000 description 2
- UVJHQYIOXKWHFD-UHFFFAOYSA-N cyclohexa-1,4-diene Chemical compound C1C=CCC=C1 UVJHQYIOXKWHFD-UHFFFAOYSA-N 0.000 description 2
- 238000005906 dihydroxylation reaction Methods 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
- 238000006116 polymerization reaction Methods 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 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
- IMSQRCLWJIAQPA-WIQPZXRYSA-N (1r)-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-WIQPZXRYSA-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
- LBYNOXVFIMUWQJ-TYZXPVIJSA-N (1r)-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-TYZXPVIJSA-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
- SOTVOFUDLASMBF-MRXNPFEDSA-N (1r)-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-MRXNPFEDSA-N 0.000 description 1
- 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 1
- 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 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
- IMSQRCLWJIAQPA-UHFFFAOYSA-N 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)=C1CC1C2C=CC(=O)CC2CCN1 IMSQRCLWJIAQPA-UHFFFAOYSA-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
- 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
- SOTVOFUDLASMBF-UHFFFAOYSA-N 1-[(2-fluoro-4,5-dihydroxyphenyl)methyl]-6-methoxy-3,4,5,8-tetrahydro-1h-isoquinoline-2-carbaldehyde Chemical compound C1C(OC)=CCC2=C1CCN(C=O)C2CC1=CC(O)=C(O)C=C1F SOTVOFUDLASMBF-UHFFFAOYSA-N 0.000 description 1
- ZQXCQTAELHSNAT-UHFFFAOYSA-N 1-chloro-3-nitro-5-(trifluoromethyl)benzene Chemical compound [O-][N+](=O)C1=CC(Cl)=CC(C(F)(F)F)=C1 ZQXCQTAELHSNAT-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
- 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
- PFMTUKBCMGQIAX-OAHLLOKOSA-N 4-chloro-5-[[(1r)-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=C1Cl PFMTUKBCMGQIAX-OAHLLOKOSA-N 0.000 description 1
- PFMTUKBCMGQIAX-HNNXBMFYSA-N 4-chloro-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=C1Cl PFMTUKBCMGQIAX-HNNXBMFYSA-N 0.000 description 1
- 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 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-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
- 108010006464 Hemolysin Proteins Proteins 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
- 229910020667 PBr3 Inorganic materials 0.000 description 1
- 239000007990 PIPES buffer Substances 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 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
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001336 alkenes Chemical group 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000011260 aqueous acid Substances 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 239000007998 bicine buffer Substances 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 239000000872 buffer Substances 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
- 238000011109 contamination Methods 0.000 description 1
- 239000006184 cosolvent Substances 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
- 239000003228 hemolysin Substances 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- AHAREKHAZNPPMI-UHFFFAOYSA-N hexa-1,3-diene Chemical class CCC=CC=C AHAREKHAZNPPMI-UHFFFAOYSA-N 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 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
- 229930014626 natural product Natural products 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 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
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 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
- 238000006257 total synthesis reaction Methods 0.000 description 1
- 239000001226 triphosphate Substances 0.000 description 1
- 235000011178 triphosphate Nutrition 0.000 description 1
- 125000002264 triphosphate group Chemical group [H]OP(=O)(O[H])OP(=O)(O[H])OP(=O)(O[H])O* 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 (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US62539704P | 2004-11-04 | 2004-11-04 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| PT1812399E true PT1812399E (pt) | 2010-02-03 |
Family
ID=35695757
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PT05812329T PT1812399E (pt) | 2004-11-04 | 2005-10-21 | Intermediários opiato e métodos de síntese |
Country Status (13)
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101638387A (zh) * | 2006-12-12 | 2010-02-03 | 马林克罗特公司 | 由1,2,3,4-四氢异喹啉制备六氢异喹啉的方法 |
| 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 |
| DE1150095B (de) | 1960-01-07 | 1963-06-12 | Bayer Ag | Verfahren zur Herstellung von organischen Ammoniumverbindungen |
| 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 (cg-RX-API-DMAC10.html) | 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 |
| 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 |
| 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 |
| 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 |
| AU679765B2 (en) | 1993-06-22 | 1997-07-10 | Abbott Gmbh & Co. Kg | Isoquinoline derivatives as therapeutic agents |
| 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 |
| DE60042585D1 (de) | 2000-02-29 | 2009-09-03 | Univ Firenze | 3-Aza-6,8-dioxabicycloÄ3.2.1Üoctane und Analoga sowie diese enthaltende kombinatorische Bibliotheken |
| 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 AU AU2005305210A patent/AU2005305210B2/en not_active Expired
- 2005-10-21 MX MX2007005194A patent/MX2007005194A/es active IP Right Grant
- 2005-10-21 DE DE602005018092T patent/DE602005018092D1/de not_active Expired - Lifetime
- 2005-10-21 CA CA002585698A patent/CA2585698A1/en not_active Abandoned
- 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 CN CNA2005800376856A patent/CN101052622A/zh active Pending
- 2005-10-21 AT AT05812329T patent/ATE450513T1/de active
- 2005-10-21 EP EP05812329A patent/EP1812399B1/en 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 WO PCT/US2005/038140 patent/WO2006052430A2/en not_active Ceased
- 2005-10-21 PL PL05812329T patent/PL1812399T3/pl unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CN101052622A (zh) | 2007-10-10 |
| PL1812399T3 (pl) | 2010-05-31 |
| WO2006052430A2 (en) | 2006-05-18 |
| CA2585698A1 (en) | 2006-05-18 |
| US20080097100A1 (en) | 2008-04-24 |
| WO2006052430A3 (en) | 2006-08-24 |
| ATE450513T1 (de) | 2009-12-15 |
| JP2008518910A (ja) | 2008-06-05 |
| DE602005018092D1 (de) | 2010-01-14 |
| US7834184B2 (en) | 2010-11-16 |
| MX2007005194A (es) | 2007-06-20 |
| EP1812399A2 (en) | 2007-08-01 |
| ES2336131T3 (es) | 2010-04-08 |
| AU2005305210A1 (en) | 2006-05-18 |
| AU2005305210B2 (en) | 2012-01-19 |
| EP1812399B1 (en) | 2009-12-02 |
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