PT1404642E - Processo para a preparação de derivados do ácido 7-amino sin 3,5-dihidroxi heptanoico, intermediários respectivos e métodos para a sua preparação - Google Patents
Processo para a preparação de derivados do ácido 7-amino sin 3,5-dihidroxi heptanoico, intermediários respectivos e métodos para a sua preparação Download PDFInfo
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- PT1404642E PT1404642E PT02764615T PT02764615T PT1404642E PT 1404642 E PT1404642 E PT 1404642E PT 02764615 T PT02764615 T PT 02764615T PT 02764615 T PT02764615 T PT 02764615T PT 1404642 E PT1404642 E PT 1404642E
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- 238000000034 method Methods 0.000 title claims description 40
- 238000002360 preparation method Methods 0.000 title claims description 31
- 230000008569 process Effects 0.000 title claims description 27
- 239000000543 intermediate Substances 0.000 title description 11
- PDBMVYIMAMQDCW-UHFFFAOYSA-N 3,5-dihydroxyheptanoic acid Chemical class CCC(O)CC(O)CC(O)=O PDBMVYIMAMQDCW-UHFFFAOYSA-N 0.000 title description 2
- -1 phenyloxy Chemical group 0.000 claims description 245
- 150000001875 compounds Chemical class 0.000 claims description 101
- 125000006239 protecting group Chemical group 0.000 claims description 60
- 238000006243 chemical reaction Methods 0.000 claims description 49
- 239000000203 mixture Substances 0.000 claims description 40
- 239000001257 hydrogen Substances 0.000 claims description 38
- 229910052739 hydrogen Inorganic materials 0.000 claims description 38
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 34
- 150000001408 amides Chemical group 0.000 claims description 25
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 25
- 239000002253 acid Substances 0.000 claims description 22
- 125000000217 alkyl group Chemical group 0.000 claims description 21
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 15
- 239000003054 catalyst Substances 0.000 claims description 14
- 125000004432 carbon atom Chemical group C* 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- 239000002585 base Substances 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 8
- 230000009467 reduction Effects 0.000 claims description 8
- 238000006722 reduction reaction Methods 0.000 claims description 8
- 125000004423 acyloxy group Chemical group 0.000 claims description 7
- 229910052751 metal Inorganic materials 0.000 claims description 7
- 239000002184 metal Substances 0.000 claims description 7
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 claims description 6
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 claims description 6
- 229960005370 atorvastatin Drugs 0.000 claims description 6
- 125000001589 carboacyl group Chemical group 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 5
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 5
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 125000006413 ring segment Chemical group 0.000 claims description 5
- 125000003282 alkyl amino group Chemical group 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 238000011917 diastereoselective reduction Methods 0.000 claims description 4
- UEGPKNKPLBYCNK-UHFFFAOYSA-L magnesium acetate Chemical group [Mg+2].CC([O-])=O.CC([O-])=O UEGPKNKPLBYCNK-UHFFFAOYSA-L 0.000 claims description 4
- 235000011285 magnesium acetate Nutrition 0.000 claims description 4
- 239000011654 magnesium acetate Substances 0.000 claims description 4
- 229940069446 magnesium acetate Drugs 0.000 claims description 4
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 3
- 229910052783 alkali metal Inorganic materials 0.000 claims description 3
- 125000004104 aryloxy group Chemical group 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 159000000003 magnesium salts Chemical group 0.000 claims description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 3
- 229910052760 oxygen Chemical group 0.000 claims description 3
- 239000001301 oxygen Chemical group 0.000 claims description 3
- 229910052697 platinum Inorganic materials 0.000 claims description 3
- 229910052707 ruthenium Inorganic materials 0.000 claims description 3
- 239000012279 sodium borohydride Substances 0.000 claims description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 claims description 2
- RDVHGEJCYQSYNF-UHFFFAOYSA-N OC.CCB(CC)CC Chemical compound OC.CCB(CC)CC RDVHGEJCYQSYNF-UHFFFAOYSA-N 0.000 claims description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- FAFYLCKQPJOORN-UHFFFAOYSA-N diethylborane Chemical compound CCBCC FAFYLCKQPJOORN-UHFFFAOYSA-N 0.000 claims description 2
- 125000005842 heteroatom Chemical group 0.000 claims description 2
- 125000005844 heterocyclyloxy group Chemical group 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 239000011593 sulfur Chemical group 0.000 claims description 2
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 9
- 230000001476 alcoholic effect Effects 0.000 claims 1
- 150000001340 alkali metals Chemical class 0.000 claims 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims 1
- 125000004429 atom Chemical group 0.000 claims 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 claims 1
- 125000005030 pyridylthio group Chemical group N1=C(C=CC=C1)S* 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 45
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 42
- 239000002904 solvent Substances 0.000 description 40
- 239000000243 solution Substances 0.000 description 38
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 31
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 30
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 30
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 26
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 22
- 238000001704 evaporation Methods 0.000 description 22
- 238000005160 1H NMR spectroscopy Methods 0.000 description 21
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 21
- 239000012074 organic phase Substances 0.000 description 21
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 20
- 230000008020 evaporation Effects 0.000 description 20
- 102000004190 Enzymes Human genes 0.000 description 17
- 108090000790 Enzymes Proteins 0.000 description 17
- 150000003254 radicals Chemical class 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- 238000005481 NMR spectroscopy Methods 0.000 description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 14
- 229940088598 enzyme Drugs 0.000 description 12
- 108090000371 Esterases Proteins 0.000 description 11
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 10
- 150000003839 salts Chemical class 0.000 description 10
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 10
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 8
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 8
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- 241000208199 Buxus sempervirens Species 0.000 description 7
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- 125000000654 isopropylidene group Chemical group C(C)(C)=* 0.000 description 7
- 229910052938 sodium sulfate Inorganic materials 0.000 description 7
- 235000011152 sodium sulphate Nutrition 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- BWLUMTFWVZZZND-UHFFFAOYSA-N Dibenzylamine Chemical compound C=1C=CC=CC=1CNCC1=CC=CC=C1 BWLUMTFWVZZZND-UHFFFAOYSA-N 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 6
- 239000000460 chlorine Substances 0.000 description 6
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 6
- 239000008363 phosphate buffer Substances 0.000 description 6
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 5
- 108090000317 Chymotrypsin Proteins 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- 239000011942 biocatalyst Substances 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000011575 calcium Substances 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 229960002376 chymotrypsin Drugs 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 238000005984 hydrogenation reaction Methods 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000002243 precursor Substances 0.000 description 5
- 238000010561 standard procedure Methods 0.000 description 5
- OIHWWYAGPIJOLJ-UHFFFAOYSA-N 2,4-diethyl-3-hydroxypentanedioic acid Chemical compound C(C)C(C(=O)O)C(C(C(=O)O)CC)O OIHWWYAGPIJOLJ-UHFFFAOYSA-N 0.000 description 4
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 4
- 229910021529 ammonia Inorganic materials 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 150000004292 cyclic ethers Chemical class 0.000 description 4
- 239000012153 distilled water Substances 0.000 description 4
- 150000002170 ethers Chemical class 0.000 description 4
- 239000007789 gas Substances 0.000 description 4
- 150000008282 halocarbons Chemical class 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 125000001183 hydrocarbyl group Chemical group 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
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- 239000012071 phase Substances 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
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- 229910002027 silica gel Inorganic materials 0.000 description 4
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- 238000003756 stirring Methods 0.000 description 4
- 125000000547 substituted alkyl group Chemical group 0.000 description 4
- FEAIJEPIONZIPN-RXMQYKEDSA-N (2R)-2-(2-methoxyacetyl)oxypentanedioic acid Chemical compound COCC(=O)O[C@@H](C(=O)O)CCC(=O)O FEAIJEPIONZIPN-RXMQYKEDSA-N 0.000 description 3
- SHAHPWSYJFYMRX-GDLCADMTSA-N (2S)-2-(4-{[(1R,2S)-2-hydroxycyclopentyl]methyl}phenyl)propanoic acid Chemical compound C1=CC([C@@H](C(O)=O)C)=CC=C1C[C@@H]1[C@@H](O)CCC1 SHAHPWSYJFYMRX-GDLCADMTSA-N 0.000 description 3
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 3
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
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- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 102000004157 Hydrolases Human genes 0.000 description 3
- 108090000604 Hydrolases Proteins 0.000 description 3
- 102000004286 Hydroxymethylglutaryl CoA Reductases Human genes 0.000 description 3
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- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
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- 239000004365 Protease Substances 0.000 description 3
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- 239000007983 Tris buffer Substances 0.000 description 3
- 125000003342 alkenyl group Chemical group 0.000 description 3
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- 108010027597 alpha-chymotrypsin Proteins 0.000 description 3
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- 150000008064 anhydrides Chemical class 0.000 description 3
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- 125000004122 cyclic group Chemical group 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
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- 235000019341 magnesium sulphate Nutrition 0.000 description 3
- 125000004092 methylthiomethyl group Chemical group [H]C([H])([H])SC([H])([H])* 0.000 description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N n-propyl alcohol Natural products CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 3
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- 238000010992 reflux Methods 0.000 description 3
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- 239000000126 substance Substances 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- 125000000453 2,2,2-trichloroethyl group Chemical group [H]C([H])(*)C(Cl)(Cl)Cl 0.000 description 2
- HEWZVZIVELJPQZ-UHFFFAOYSA-N 2,2-dimethoxypropane Chemical compound COC(C)(C)OC HEWZVZIVELJPQZ-UHFFFAOYSA-N 0.000 description 2
- 125000003821 2-(trimethylsilyl)ethoxymethyl group Chemical group [H]C([H])([H])[Si](C([H])([H])[H])(C([H])([H])[H])C([H])([H])C(OC([H])([H])[*])([H])[H] 0.000 description 2
- 125000002774 3,4-dimethoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C(OC([H])([H])[H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000006281 4-bromobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Br)C([H])([H])* 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
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- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
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- 125000006216 methylsulfinyl group Chemical group [H]C([H])([H])S(*)=O 0.000 description 1
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- 230000000737 periodic effect Effects 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 1
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- 239000011148 porous material Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 239000000047 product Substances 0.000 description 1
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- BPRHUIZQVSMCRT-VEUZHWNKSA-N rosuvastatin Chemical compound CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC(O)=O BPRHUIZQVSMCRT-VEUZHWNKSA-N 0.000 description 1
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- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
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- 238000007086 side reaction Methods 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
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- 238000004611 spectroscopical analysis Methods 0.000 description 1
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- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 description 1
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- 108010031354 thermitase Proteins 0.000 description 1
- HFRXJVQOXRXOPP-UHFFFAOYSA-N thionyl bromide Chemical compound BrS(Br)=O HFRXJVQOXRXOPP-UHFFFAOYSA-N 0.000 description 1
- 125000005413 thiopyridyl group Chemical group 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 125000005208 trialkylammonium group Chemical group 0.000 description 1
- LALRXNPLTWZJIJ-UHFFFAOYSA-N triethylborane Chemical compound CCB(CC)CC LALRXNPLTWZJIJ-UHFFFAOYSA-N 0.000 description 1
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- RIOQSEWOXXDEQQ-UHFFFAOYSA-O triphenylphosphanium Chemical compound C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-O 0.000 description 1
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Classifications
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- 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
- C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/72—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms
- C07C235/74—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of a saturated carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/30—Preparation of optical isomers
- C07C227/32—Preparation of optical isomers by stereospecific synthesis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/22—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated the carbon skeleton being further substituted by oxygen atoms
-
- 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
- C07C235/04—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 being acyclic and saturated
- C07C235/06—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 being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/67—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/67—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids
- C07C69/716—Esters of keto-carboxylic acids or aldehydo-carboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
- C07C69/732—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids of unsaturated hydroxy carboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
- C07C69/738—Esters of keto-carboxylic acids or aldehydo-carboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P7/00—Preparation of oxygen-containing organic compounds
- C12P7/62—Carboxylic acid esters
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Wood Science & Technology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Zoology (AREA)
- Biotechnology (AREA)
- Microbiology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP01810670 | 2001-07-06 |
Publications (1)
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|---|---|
| PT1404642E true PT1404642E (pt) | 2010-03-29 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PT02764615T PT1404642E (pt) | 2001-07-06 | 2002-07-02 | Processo para a preparação de derivados do ácido 7-amino sin 3,5-dihidroxi heptanoico, intermediários respectivos e métodos para a sua preparação |
Country Status (17)
| Country | Link |
|---|---|
| US (3) | US7420078B2 (enExample) |
| EP (2) | EP2161250A1 (enExample) |
| JP (1) | JP2004533479A (enExample) |
| KR (2) | KR20040017277A (enExample) |
| CN (2) | CN101880227A (enExample) |
| AR (3) | AR034735A1 (enExample) |
| AU (1) | AU2002354701B2 (enExample) |
| BR (1) | BR0210842A (enExample) |
| CA (1) | CA2448917A1 (enExample) |
| CZ (1) | CZ2004150A3 (enExample) |
| ES (1) | ES2340260T3 (enExample) |
| HR (1) | HRPK20040119B3 (enExample) |
| HU (1) | HUP0401145A3 (enExample) |
| IL (3) | IL159050A0 (enExample) |
| PL (1) | PL366392A1 (enExample) |
| PT (1) | PT1404642E (enExample) |
| WO (1) | WO2003004450A1 (enExample) |
Families Citing this family (25)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6101484A (en) | 1999-03-31 | 2000-08-08 | Mercata, Inc. | Dynamic market equilibrium management system, process and article of manufacture |
| WO2002057229A1 (en) | 2001-01-19 | 2002-07-25 | Biocon India Limited | FORM V CRYSTALLINE [R-(R*,R*)]-2-(4-FLUOROPHENYL)-ß,$G(D)-DIHYDROXY-5-(1-METHYLETHYL)-3-PHENYL-4-[(PHENYLAMINO)CARBONYL]-1H-PYRROLE-1- HEPTANOIC ACID HEMI CALCIUM SALT. (ATORVASTATIN) |
| CA2448917A1 (en) | 2001-07-06 | 2003-01-16 | Reinhold Ohrlein | Process for the preparation of intermediates useful in the synthesis of statin derivatives especially 7-amino 3,5-dihydroxy heptanoic acid derivatives, and intermediates thereof |
| KR100888408B1 (ko) | 2001-07-13 | 2009-03-13 | 아스트라제네카 유케이 리미티드 | 아미노피리미딘 화합물의 제조 방법 |
| US7361772B2 (en) | 2001-08-16 | 2008-04-22 | Biocon Limited | Process for the production of atorvastatin calcium |
| EP1485343B1 (en) | 2002-03-18 | 2009-12-23 | Biocon Limited | Amorphous hmg-coa reductase inhibitors of desired particle size |
| US7179942B2 (en) | 2002-07-05 | 2007-02-20 | Bicon Limited | Halo-substituted active methylene compounds |
| AU2003295684A1 (en) * | 2002-11-15 | 2004-06-15 | Teva Pharmaceutical Industries Ltd. | Synthesis of 3,5-dihydroxy-7-pyrrol-1-yl heptanoic acids |
| ES2323366T3 (es) | 2003-04-22 | 2009-07-14 | Biocon Limited | Procedimiento novedoso para la reduccion estereoselectiva de beta-cetoesteres. |
| WO2005026107A1 (en) | 2003-09-18 | 2005-03-24 | Biocon Limited | Novel process for the preparation of tert-butyl 6-cyano-5-hydroxy-3-oxohexanoate |
| GB0428328D0 (en) | 2004-12-24 | 2005-02-02 | Astrazeneca Uk Ltd | Chemical process |
| WO2007034909A1 (ja) * | 2005-09-22 | 2007-03-29 | Kaneka Corporation | （３ｒ，５ｒ）－７－アミノ－３，５－ジヒドロキシヘプタン酸誘導体の製造法 |
| KR20100080432A (ko) * | 2008-12-29 | 2010-07-08 | 한미약품 주식회사 | 스타틴 화합물의 신규 제조방법 및 이에 사용되는 벤조티아졸릴 술폰 화합물 |
| WO2012034958A1 (en) * | 2010-09-16 | 2012-03-22 | Dsm Sinochem Pharmaceuticals Netherlands B.V. | Esters of hexanoic acids as intermediates for the preparation of atorvastatin |
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| CN104230879B (zh) * | 2014-08-15 | 2016-08-24 | 新发药业有限公司 | 一种2-((4r, 6s)-6-甲酰基-2,2-二取代基-1,3-二氧六环-4-基)乙酸酯制备方法 |
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| US4677211A (en) * | 1984-06-29 | 1987-06-30 | Sandoz Pharmaceuticals Corp. | Preparation of lactones |
| US4950775A (en) * | 1985-10-11 | 1990-08-21 | University Of California | Antihypercholesterolemic compounds and synthesis thereof |
| US5003080A (en) | 1988-02-22 | 1991-03-26 | Warner-Lambert Company | Process for trans-6-(2-(substituted-pyrrol-1-yl)alkyl)pryan-2-one inhibitors of cholesterol synthesis |
| IT1226726B (it) * | 1988-07-29 | 1991-02-05 | Zambon Spa | Composti attivi come inibitori della biosintesi del colesterolo. |
| US5196440A (en) * | 1988-07-29 | 1993-03-23 | Zambon Group S.P.A. | Compounds active as inhibitors of the cholesterol biosynthesis |
| IT1224795B (it) * | 1988-12-01 | 1990-10-24 | Sigma Tau Ind Farmaceuti | Uso dell'acetil d-carnitina nel trattamento terapeutico del glaucoma e composizioni farmaceutiche utili in tale trattamento |
| IT1237792B (it) | 1989-12-21 | 1993-06-17 | Zambon Spa | Composti attivi come inibitori dell'enzima hmg-coa reduttasi |
| US5155251A (en) | 1991-10-11 | 1992-10-13 | Warner-Lambert Company | Process for the synthesis of (5R)-1,1-dimethylethyl-6-cyano-5-hydroxy-3-oxo-hexanoate |
| JP3652394B2 (ja) | 1995-01-27 | 2005-05-25 | 高砂香料工業株式会社 | Ｎ−置換−７−アミノ−５−ヒドロキシ−３−オキソヘプタン酸誘導体およびその製造法 |
| CN1217930C (zh) | 2000-05-26 | 2005-09-07 | 西巴特殊化学品控股有限公司 | 吲哚衍生物的制备方法和该方法的中间体 |
| HUP0401014A2 (hu) | 2001-07-06 | 2004-08-30 | Teva Pharmaceutical Industries Ltd. | Eljárás 7-amino-szin-3,5-dihidroxi-heptánsavszármazékok előállítására, 6-ciano-szin-3,5-dihidroxi-hexánsav származékokon keresztül |
| US7317123B2 (en) | 2001-07-06 | 2008-01-08 | Teva Pharmaceutical Industries, Ltd | Process for preparation of 7-amino syn 3,5-dihydroxy heptanoic acid derivatives, intermediates thereof and methods for their preparation |
| CA2448917A1 (en) | 2001-07-06 | 2003-01-16 | Reinhold Ohrlein | Process for the preparation of intermediates useful in the synthesis of statin derivatives especially 7-amino 3,5-dihydroxy heptanoic acid derivatives, and intermediates thereof |
-
2002
- 2002-07-02 CA CA002448917A patent/CA2448917A1/en not_active Abandoned
- 2002-07-02 WO PCT/EP2002/007307 patent/WO2003004450A1/en not_active Ceased
- 2002-07-02 CN CN201010004468XA patent/CN101880227A/zh active Pending
- 2002-07-02 IL IL15905002A patent/IL159050A0/xx not_active IP Right Cessation
- 2002-07-02 JP JP2003510418A patent/JP2004533479A/ja active Pending
- 2002-07-02 EP EP09176993A patent/EP2161250A1/en not_active Withdrawn
- 2002-07-02 KR KR20047000160A patent/KR20040017277A/ko not_active Withdrawn
- 2002-07-02 HU HU0401145A patent/HUP0401145A3/hu unknown
- 2002-07-02 BR BR0210842-9A patent/BR0210842A/pt not_active IP Right Cessation
- 2002-07-02 EP EP02782448A patent/EP1404639A1/en not_active Withdrawn
- 2002-07-02 AU AU2002354701A patent/AU2002354701B2/en not_active Ceased
- 2002-07-02 US US10/482,463 patent/US7420078B2/en not_active Expired - Fee Related
- 2002-07-02 HR HR20040119A patent/HRPK20040119B3/xx not_active IP Right Cessation
- 2002-07-02 CZ CZ2004150A patent/CZ2004150A3/cs unknown
- 2002-07-02 KR KR20047000163A patent/KR20040017278A/ko not_active Withdrawn
- 2002-07-02 ES ES02764615T patent/ES2340260T3/es not_active Expired - Lifetime
- 2002-07-02 CN CNA028135342A patent/CN1610657A/zh active Pending
- 2002-07-02 PT PT02764615T patent/PT1404642E/pt unknown
- 2002-07-02 PL PL02366392A patent/PL366392A1/xx not_active Application Discontinuation
- 2002-07-05 AR ARP020102537A patent/AR034735A1/es not_active Application Discontinuation
- 2002-07-05 AR ARP020102535A patent/AR034733A1/es unknown
- 2002-07-05 AR ARP020102536A patent/AR034734A1/es not_active Application Discontinuation
-
2008
- 2008-07-24 US US12/220,390 patent/US7855302B2/en not_active Expired - Fee Related
-
2010
- 2010-11-04 US US12/939,401 patent/US8026383B2/en not_active Expired - Fee Related
-
2011
- 2011-07-19 IL IL214165A patent/IL214165A0/en unknown
- 2011-07-19 IL IL214164A patent/IL214164A0/en unknown
Also Published As
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|---|---|
| CZ2004150A3 (cs) | 2004-09-15 |
| US20080312466A1 (en) | 2008-12-18 |
| AR034735A1 (es) | 2004-03-17 |
| AR034734A1 (es) | 2004-03-17 |
| IL159050A0 (en) | 2004-05-12 |
| ES2340260T3 (es) | 2010-06-01 |
| US8026383B2 (en) | 2011-09-27 |
| WO2003004450A1 (en) | 2003-01-16 |
| CN1610657A (zh) | 2005-04-27 |
| US20110046411A1 (en) | 2011-02-24 |
| KR20040017277A (ko) | 2004-02-26 |
| HRP20040119A2 (en) | 2005-04-30 |
| BR0210842A (pt) | 2004-07-13 |
| AR034733A1 (es) | 2004-03-17 |
| HUP0401145A3 (en) | 2008-08-28 |
| CA2448917A1 (en) | 2003-01-16 |
| US20040186313A1 (en) | 2004-09-23 |
| KR20040017278A (ko) | 2004-02-26 |
| CN101880227A (zh) | 2010-11-10 |
| US7855302B2 (en) | 2010-12-21 |
| AU2002354701B2 (en) | 2007-11-22 |
| IL214164A0 (en) | 2011-08-31 |
| IL214165A0 (en) | 2011-08-31 |
| HUP0401145A2 (hu) | 2004-09-28 |
| EP1404639A1 (en) | 2004-04-07 |
| HRPK20040119B3 (en) | 2006-07-31 |
| EP2161250A1 (en) | 2010-03-10 |
| PL366392A1 (en) | 2005-01-24 |
| JP2004533479A (ja) | 2004-11-04 |
| US7420078B2 (en) | 2008-09-02 |
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