WO1999062877A1 - Procede de production d'un derive de prostaglandine purifie - Google Patents
Procede de production d'un derive de prostaglandine purifie Download PDFInfo
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- WO1999062877A1 WO1999062877A1 PCT/JP1999/002975 JP9902975W WO9962877A1 WO 1999062877 A1 WO1999062877 A1 WO 1999062877A1 JP 9902975 W JP9902975 W JP 9902975W WO 9962877 A1 WO9962877 A1 WO 9962877A1
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- Prior art keywords
- group
- compound
- nitrogen
- alkyl group
- atom
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 25
- 150000003180 prostaglandins Chemical class 0.000 title claims abstract description 9
- -1 alkyl lithium Chemical compound 0.000 claims abstract description 102
- 150000001336 alkenes Chemical class 0.000 claims abstract description 26
- 239000000376 reactant Substances 0.000 claims abstract description 23
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims abstract description 20
- 229910052802 copper Inorganic materials 0.000 claims abstract description 19
- 239000010949 copper Substances 0.000 claims abstract description 19
- BZKFMUIJRXWWQK-UHFFFAOYSA-N Cyclopentenone Chemical compound O=C1CCC=C1 BZKFMUIJRXWWQK-UHFFFAOYSA-N 0.000 claims abstract description 13
- 150000001244 carboxylic acid anhydrides Chemical class 0.000 claims abstract description 11
- 230000009471 action Effects 0.000 claims abstract description 8
- 229910052744 lithium Inorganic materials 0.000 claims abstract description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 46
- 150000001875 compounds Chemical class 0.000 claims description 34
- 125000005842 heteroatom Chemical group 0.000 claims description 25
- 239000007795 chemical reaction product Substances 0.000 claims description 18
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 18
- 150000008064 anhydrides Chemical class 0.000 claims description 15
- 238000004519 manufacturing process Methods 0.000 claims description 14
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 13
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 10
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 7
- 238000007259 addition reaction Methods 0.000 claims description 6
- 125000003342 alkenyl group Chemical group 0.000 claims description 6
- 125000000304 alkynyl group Chemical group 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 6
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 6
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 5
- 229910052740 iodine Inorganic materials 0.000 claims description 5
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 claims description 5
- UMGDCJDMYOKAJW-UHFFFAOYSA-N aminothiocarboxamide Natural products NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims description 4
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 4
- 238000010511 deprotection reaction Methods 0.000 claims description 4
- 125000005678 ethenylene group Chemical group [H]C([*:1])=C([H])[*:2] 0.000 claims description 4
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 229910019142 PO4 Inorganic materials 0.000 claims description 3
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- 239000010452 phosphate Substances 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 150000001491 aromatic compounds Chemical class 0.000 claims description 2
- 150000002391 heterocyclic compounds Chemical class 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
- 239000006227 byproduct Substances 0.000 abstract description 5
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical group N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 18
- 125000004432 carbon atom Chemical group C* 0.000 description 15
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 125000002252 acyl group Chemical group 0.000 description 11
- 125000006239 protecting group Chemical group 0.000 description 11
- 150000002148 esters Chemical class 0.000 description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 10
- 239000007810 chemical reaction solvent Substances 0.000 description 9
- 239000003814 drug Substances 0.000 description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 9
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- 239000002960 lipid emulsion Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- PTCGDEVVHUXTMP-UHFFFAOYSA-N flutolanil Chemical compound CC(C)OC1=CC=CC(NC(=O)C=2C(=CC=CC=2)C(F)(F)F)=C1 PTCGDEVVHUXTMP-UHFFFAOYSA-N 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 150000002903 organophosphorus compounds Chemical class 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- JILHZKWLEAKYRC-UHFFFAOYSA-N 1-methoxy-2,2-dimethylpropane Chemical group COCC(C)(C)C JILHZKWLEAKYRC-UHFFFAOYSA-N 0.000 description 3
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 125000004104 aryloxy group Chemical group 0.000 description 3
- YHASWHZGWUONAO-UHFFFAOYSA-N butanoyl butanoate Chemical compound CCCC(=O)OC(=O)CCC YHASWHZGWUONAO-UHFFFAOYSA-N 0.000 description 3
- 150000001721 carbon Chemical group 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 125000001153 fluoro group Chemical group F* 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 239000012442 inert solvent Substances 0.000 description 3
- 150000002632 lipids Chemical class 0.000 description 3
- 150000002898 organic sulfur compounds Chemical class 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- NKJOXAZJBOMXID-UHFFFAOYSA-N 1,1'-Oxybisoctane Chemical compound CCCCCCCCOCCCCCCCC NKJOXAZJBOMXID-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 2
- ITQTTZVARXURQS-UHFFFAOYSA-N 3-methylpyridine Chemical compound CC1=CC=CN=C1 ITQTTZVARXURQS-UHFFFAOYSA-N 0.000 description 2
- FKNQCJSGGFJEIZ-UHFFFAOYSA-N 4-methylpyridine Chemical compound CC1=CC=NC=C1 FKNQCJSGGFJEIZ-UHFFFAOYSA-N 0.000 description 2
- 206010002383 Angina Pectoris Diseases 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- 206010003210 Arteriosclerosis Diseases 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 2
- AFBPFSWMIHJQDM-UHFFFAOYSA-N N-methylaniline Chemical compound CNC1=CC=CC=C1 AFBPFSWMIHJQDM-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 2
- 206010000210 abortion Diseases 0.000 description 2
- 231100000176 abortion Toxicity 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 208000011775 arteriosclerosis disease Diseases 0.000 description 2
- 125000003710 aryl alkyl group Chemical group 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 208000000718 duodenal ulcer Diseases 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 208000037805 labour Diseases 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 2
- 208000010125 myocardial infarction Diseases 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 230000001766 physiological effect Effects 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- CYSGHNMQYZDMIA-UHFFFAOYSA-N 1,3-Dimethyl-2-imidazolidinon Chemical compound CN1CCN(C)C1=O CYSGHNMQYZDMIA-UHFFFAOYSA-N 0.000 description 1
- AHHIHXWGQDPOMM-UHFFFAOYSA-N 1-o-(3-oxo-3-trimethylsilyloxypropanoyl) 3-o-trimethylsilyl propanedioate Chemical compound C[Si](C)(C)OC(=O)CC(=O)OC(=O)CC(=O)O[Si](C)(C)C AHHIHXWGQDPOMM-UHFFFAOYSA-N 0.000 description 1
- 125000004343 1-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C([H])([H])[H] 0.000 description 1
- WBIBUCGCVLAPQG-UHFFFAOYSA-N 2-(2-pyridin-2-ylethyl)pyridine Chemical compound C=1C=CC=NC=1CCC1=CC=CC=N1 WBIBUCGCVLAPQG-UHFFFAOYSA-N 0.000 description 1
- UHPWYBATPHCMGD-UHFFFAOYSA-N 2-(3-pyridin-2-ylpropyl)pyridine Chemical compound C=1C=CC=NC=1CCCC1=CC=CC=N1 UHPWYBATPHCMGD-UHFFFAOYSA-N 0.000 description 1
- JVYGSYTXAREMJK-UHFFFAOYSA-N 2-(pyridin-2-ylmethyl)pyridine Chemical compound C=1C=CC=NC=1CC1=CC=CC=N1 JVYGSYTXAREMJK-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 description 1
- 125000000143 2-carboxyethyl group Chemical group [H]OC(=O)C([H])([H])C([H])([H])* 0.000 description 1
- NRGGMCIBEHEAIL-UHFFFAOYSA-N 2-ethylpyridine Chemical compound CCC1=CC=CC=N1 NRGGMCIBEHEAIL-UHFFFAOYSA-N 0.000 description 1
- 125000006040 2-hexenyl group Chemical group 0.000 description 1
- ICPWFHKNYYRBSZ-UHFFFAOYSA-N 2-methoxypropanoic acid Chemical compound COC(C)C(O)=O ICPWFHKNYYRBSZ-UHFFFAOYSA-N 0.000 description 1
- OAHBLNOHPOWVLP-UHFFFAOYSA-N 2-methoxypropanoyl 2-methoxypropanoate Chemical compound COC(C)C(=O)OC(=O)C(C)OC OAHBLNOHPOWVLP-UHFFFAOYSA-N 0.000 description 1
- 125000003229 2-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000006024 2-pentenyl group Chemical group 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- XBQNHQYPRSJJLQ-UHFFFAOYSA-N 2-trimethylsilyloxypropanoyl 2-trimethylsilyloxypropanoate Chemical compound C[Si](C)(C)OC(C)C(=O)OC(=O)C(C)O[Si](C)(C)C XBQNHQYPRSJJLQ-UHFFFAOYSA-N 0.000 description 1
- KDRCYHFOWYXCBB-UHFFFAOYSA-N 2-trimethylsilyloxypropanoyl chloride Chemical compound ClC(=O)C(C)O[Si](C)(C)C KDRCYHFOWYXCBB-UHFFFAOYSA-N 0.000 description 1
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 description 1
- NLSIURXGEOLJPO-UHFFFAOYSA-N 3-methoxypropanoyl 3-methoxypropanoate Chemical compound COCCC(=O)OC(=O)CCOC NLSIURXGEOLJPO-UHFFFAOYSA-N 0.000 description 1
- JSMDUOFOPDSKIQ-UHFFFAOYSA-N 3-methoxypropanoyl chloride Chemical compound COCCC(Cl)=O JSMDUOFOPDSKIQ-UHFFFAOYSA-N 0.000 description 1
- LFCUTSBIPDVUCF-UHFFFAOYSA-N 3-o-(3-ethoxy-3-oxopropanoyl) 1-o-ethyl propanedioate Chemical compound CCOC(=O)CC(=O)OC(=O)CC(=O)OCC LFCUTSBIPDVUCF-UHFFFAOYSA-N 0.000 description 1
- PEECHUVSNVZQRY-UHFFFAOYSA-N 3-o-(3-methoxy-3-oxopropanoyl) 1-o-methyl propanedioate Chemical compound COC(=O)CC(=O)OC(=O)CC(=O)OC PEECHUVSNVZQRY-UHFFFAOYSA-N 0.000 description 1
- YGPAEIRNVVIPHA-UHFFFAOYSA-N 3-trimethylsilyloxybutanoyl 3-trimethylsilyloxybutanoate Chemical compound C[Si](C)(C)OC(C)CC(=O)OC(=O)CC(C)O[Si](C)(C)C YGPAEIRNVVIPHA-UHFFFAOYSA-N 0.000 description 1
- MTZWYIDCIJKPQV-UHFFFAOYSA-N 4,4-difluorooctane Chemical compound CCCCC(F)(F)CCC MTZWYIDCIJKPQV-UHFFFAOYSA-N 0.000 description 1
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- 101100084421 Caenorhabditis elegans pros-1 gene Proteins 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
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- 206010061218 Inflammation Diseases 0.000 description 1
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- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical group CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- XTUVJUMINZSXGF-UHFFFAOYSA-N N-methylcyclohexylamine Chemical compound CNC1CCCCC1 XTUVJUMINZSXGF-UHFFFAOYSA-N 0.000 description 1
- PAMIQIKDUOTOBW-UHFFFAOYSA-N N-methylcyclohexylamine Natural products CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- BHWRMAMIMNCWIV-UHFFFAOYSA-N [2-(dimethylamino)acetyl] 2-(dimethylamino)acetate Chemical compound CN(C)CC(=O)OC(=O)CN(C)C BHWRMAMIMNCWIV-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 125000002723 alicyclic group Chemical group 0.000 description 1
- 125000005107 alkyl diaryl silyl group Chemical group 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 1
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 1
- 235000011130 ammonium sulphate Nutrition 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 description 1
- XTKDAFGWCDAMPY-UHFFFAOYSA-N azaperone Chemical compound C1=CC(F)=CC=C1C(=O)CCCN1CCN(C=2N=CC=CC=2)CC1 XTKDAFGWCDAMPY-UHFFFAOYSA-N 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- DVECBJCOGJRVPX-UHFFFAOYSA-N butyryl chloride Chemical compound CCCC(Cl)=O DVECBJCOGJRVPX-UHFFFAOYSA-N 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 239000013522 chelant Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 125000004651 chloromethoxy group Chemical group ClCO* 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 150000001880 copper compounds Chemical class 0.000 description 1
- ORYJCHVFAFAXME-UHFFFAOYSA-N copper(1+);tributylphosphane Chemical compound [Cu+].CCCCP(CCCC)CCCC ORYJCHVFAFAXME-UHFFFAOYSA-N 0.000 description 1
- UKSFURGLGLVJNV-UHFFFAOYSA-M copper(1+);tributylphosphane;iodide Chemical compound I[Cu].CCCCP(CCCC)CCCC UKSFURGLGLVJNV-UHFFFAOYSA-M 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000001120 cytoprotective effect Effects 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 230000001882 diuretic effect Effects 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000004993 emission spectroscopy Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- KWFADUNOPOSMIJ-UHFFFAOYSA-N ethyl 3-chloro-3-oxopropanoate Chemical compound CCOC(=O)CC(Cl)=O KWFADUNOPOSMIJ-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000010419 fine particle Substances 0.000 description 1
- 230000027119 gastric acid secretion Effects 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000009616 inductively coupled plasma Methods 0.000 description 1
- 230000004054 inflammatory process Effects 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
- 239000000463 material Substances 0.000 description 1
- UTBCRHAMJFMIIR-UHFFFAOYSA-N methyl 3-chloro-3-oxopropanoate Chemical compound COC(=O)CC(Cl)=O UTBCRHAMJFMIIR-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- XTAZYLNFDRKIHJ-UHFFFAOYSA-N n,n-dioctyloctan-1-amine Chemical compound CCCCCCCCN(CCCCCCCC)CCCCCCCC XTAZYLNFDRKIHJ-UHFFFAOYSA-N 0.000 description 1
- ROZPNEGZBIUWBX-UHFFFAOYSA-N n-[bis(diethylamino)phosphoryl]-n-ethylethanamine Chemical compound CCN(CC)P(=O)(N(CC)CC)N(CC)CC ROZPNEGZBIUWBX-UHFFFAOYSA-N 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 125000005359 phenoxyalkyl group Chemical group 0.000 description 1
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- WGJJROVFWIXTPA-OALUTQOASA-N prostanoic acid Chemical compound CCCCCCCC[C@H]1CCC[C@@H]1CCCCCCC(O)=O WGJJROVFWIXTPA-OALUTQOASA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 1
- 230000016160 smooth muscle contraction Effects 0.000 description 1
- BHZOKUMUHVTPBX-UHFFFAOYSA-M sodium acetic acid acetate Chemical compound [Na+].CC(O)=O.CC([O-])=O BHZOKUMUHVTPBX-UHFFFAOYSA-M 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- 125000001302 tertiary amino group Chemical group 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- 125000005106 triarylsilyl group Chemical group 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- RKBCYCFRFCNLTO-UHFFFAOYSA-N triisopropylamine Chemical compound CC(C)N(C(C)C)C(C)C RKBCYCFRFCNLTO-UHFFFAOYSA-N 0.000 description 1
- NNSQSOXDXSJIRM-UHFFFAOYSA-N trimethylsilyl 3-chloro-3-oxopropanoate Chemical compound C[Si](C)(C)OC(=O)CC(Cl)=O NNSQSOXDXSJIRM-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000000304 vasodilatating effect Effects 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
- C07C405/0008—Analogues having the carboxyl group in the side-chains replaced by other functional groups
- C07C405/0016—Analogues having the carboxyl group in the side-chains replaced by other functional groups containing only hydroxy, etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
Definitions
- the present invention relates to a method for producing a purified prostaglandin derivative.
- Prostaglandins (hereinafter, the broth tag run Gin referred to as PG) are, PGE i to 1 96 0 year, PGE 2, PGE 3, PGF , a, the six structures of PGF 2 alpha and P GF 3 a Since the decision, PG analogs have been discovered one after another, and their physiological effects have been revealed one after another. Specifically, various physiological activities such as platelet aggregation inhibitory action, vasodilatory blood pressure lowering action, gastric acid secretion inhibitory action, smooth muscle contraction action, cytoprotective action, and diuretic action have been clarified. It has also been shown that PGs are a group of compounds that are effective in treating or preventing myocardial infarction, angina, arteriosclerosis, hypertension, duodenal ulcer, labor induction, and abortion.
- PGs are the typical local hormones, hormones that are made locally when needed and act locally. From this, it has been proposed that these PG-related drugs require a drug release system (drug delivery system) that takes into account the properties as an otacoid and the chemical properties.
- the drug release system is a system that improves drugs that have the drawbacks of being ineffective when administered systemically and exhibiting strong systemic side effects.
- LM Lipid's microsphere
- This LM is actually considered to be emulsified fine particles of lipids containing PGs, and is also called a fat emulsion.
- fat emulsion-PG refers to an emulsion of lipids containing PGs and the like.
- lipid emulsion in which PGE is encapsulated in LM with a diameter of 2 / zm-PGE is a target therapeutic agent that has high stability in vivo and has a stronger vasodilator effect and platelet aggregation inhibitory effect than PGE alone.
- S im, A.., E ta 1., Arzneim-Forsch / Drug Res., 1206-1209, 1986 is a target therapeutic agent that has high stability in vivo and has a stronger vasodilator effect and platelet aggregation inhibitory effect than PGE alone.
- PGE and esters have no activity, and PGE and esters show activity as PGE by cleavage of ester bond by esterase in the living body (this is called PGE.
- PGE PGE
- esters were used.
- the platelet aggregation inhibitory effect was used as an indicator of the activity of PGE and esters.
- the stability of the lipid emulsion in blood was evaluated by measuring the release of PGE and esters from LM when incubated in an isotonic salt. As a result, the storage stability and effectiveness of the LM preparations of PGE and esters were confirmed.
- the present invention has been made in order to solve the above-mentioned problem.
- the alkene represented by the following formula (1) is converted into the following formula (2) Is added to the cyclopentenone represented by the formula to form an adduct, and then the carboxylic acid halide represented by the following formula (3) and the carboxylic acid represented by the following formula (4)
- the reaction product After reacting an anhydride or a carboxylic acid mixed anhydride represented by the following formula (5) to obtain a reaction product containing a prostaglandin derivative represented by the following formula (6), the reaction product And a method for producing a purified prostaglandin derivative.
- R 1 is an alkanol group or an alkanol group containing a hetero atom in the alkyl group.
- R 2 an alkyl group or an alkyl group containing a hetero atom.
- R 3 and R 4 each independently represent a hydroxyl-protecting group or a hydrogen atom.
- R 5 an alkyl group, a substituted alkyl group, a cycloalkyl group, a substituted cycloalkyl group, an alkenyl group, or an alkynyl group.
- R 6 is an alkanol group or an alkanol group containing a hetero atom in the alkyl group part, and is different from R 1 .
- X 1 an iodine atom or a trialkyltin group.
- X 2 a halogen atom.
- Alkenes represented by the formula (1) (hereinafter, alkenes (1)) will be described. The same applies to other compounds.
- X 1 represents an iodine atom or a trialkyltin group.
- a triptyltin group is preferable.
- X 1 is preferably an iodine atom.
- R 4 in the alkene (1) is a protecting group for a hydroxyl group or a hydrogen atom.
- the protecting group for the hydroxyl group the protecting group described by Greene et al. (Protective Groups in Organic Synthesis, John Wiley & Sons, 1981) can be used.
- the hydroxyl-protecting group is preferably an acyl group (for example, an alkanol group containing a lower alkyl group, preferably an acetyl group or the like; or an acyl group containing an aromatic ring, preferably a benzoyl group).
- trialkylsilyl group for example, trimethylsilyl group, t-butyldimethylsilyl group
- triarylsilyl group alkyldiarylsilyl group
- aryloxy group Preferred are a rudialkylsilyl group, an aralkyl group (for example, a benzyl group), and a tetrahydrobiranyl group.
- R 5 in the alkene (1) is an alkyl group, a substituted alkyl group, a cycloalkyl group, a substituted cycloalkyl group, an alkenyl group, or an alkynyl group.
- R 5 is an alkyl group, preferably a linear or branched al Kill group having 3 to 8 carbon atoms.
- alkyl group include a butyl group, a pentyl group, a hexyl group, a 2-methylhexyl group, a heptyl group and an octyl group.
- R 5 is a substituted alkyl group, a linear or branched unsubstituted alkyl group having 3 to 8 carbon atoms in which at least one hydrogen atom has been substituted with a monovalent substituent, or A group in which a divalent hetero atom (for example, an etheric oxygen atom, a thioetheric sulfur atom, or the like) is inserted between carbon-carbon bonds of the group is preferable.
- the monovalent substituent in the substituted alkyl group is preferably a halogen atom, a halogenated alkyl group, an aryl group, a halogenated aryl group, an aryloxy group, or a halogenated aryloxy group.
- R 5 as the substituted alkyl group is a halogenated alkyl group (for example, a monohalogenated alkyl group, a dihalogenated alkyl group, etc.), an arylalkyl group, a (halogenated arylyl) alkyl group, a phenoxyalkyl group, (Halogenated phenoxy) alkyl group and the like are preferable, and in particular, 1-fluoropentyl group, 1,1-difluoropentyl group, 1-fluoro-2-methylhexyl group, phenoxymethyl group, 2-chlorophenoxymethyl group, and 3-chlorophenoxy group
- a cimethyl group, a 4-chlorophenoxymethyl group, a 1-phenylethyl group or a 2-phenylethyl group is preferred, and a phenoxymethyl group, a chloromethyloxy group or a phenylethyl group is particularly preferred.
- the ring portion is preferably a cycloalkyl group having 3 to 8 carbon atoms.
- the cycloalkyl group may be a cycloalkyl group having an alkyl group bonded to a ring portion, and examples of the alkyl group include a linear or branched alkyl group having 1 to 8 carbon atoms.
- cycloalkyl group examples include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a 3-methylcyclopentyl group, a 3-ethylcyclopentyl group, a cyclohexyl group, a 4-methylcyclohexyl group, a cycloheptyl group, and And the like.
- R 5 is a substituted cycloalkyl group
- a group in which at least one hydrogen atom of the cycloalkyl group is substituted is preferable.
- a substituent a halogen atom is preferred.
- the ring portion of the substituted cycloalkyl group preferably has 3 to 8 carbon atoms.
- Specific examples of the substituted cycloalkyl group include a 2-fluorocyclopropyl group, a 3-fluorocyclobutyl group, a 3-chlorocyclobutyl group, a 3-fluorocyclopentyl group and a 3-chloro group. Cyclopentyl group, (cyclo or fluoro) cyclohexyl Group, (black or fluoro) cycloheptyl group, (black or fluoro) cyclooctyl group and the like.
- R 5 is an alkenyl group, preferably a linear or branched ⁇ alkenyl group having 3 to 8 carbon atoms.
- alkenyl group include a 2-butenyl group, a 2-pentenyl group, a 2-hexenyl group, a 1-methyl-2-hexenyl group, a 2-heptyl group, a 2-octyl group and a 2-methyl group. 4 One-butenyl group and the like.
- R 5 is an alkynyl group, preferably a linear or branched ⁇ Rukiniru group having 3 to 8 carbon atoms.
- alkynyl group include a 2-butynyl group, a 2-pentynyl group, a 2-hexynyl group, a 1-methyl-3-pentynyl group, a 1-methyl-3-hexynyl group, and a 1-methyl-3-heptulyl. And the like.
- the stereochemistry of the carbon atom may be mixed they even be R.
- alkene (1) in which X 1 is an iodine atom include the following compounds.
- alkene (1) in which X 1 is a trialkyltin group include the following compounds.
- alkyl lithium t-butyl lithium is preferable.
- the amount of alkyllithium is preferably 0.5 to 10 moles, more preferably 1 to 2 moles, based on the alkene (1).
- a trialkylphosphine-copper (I) complex is preferable, and a tri (n-butyl) phosphine-copper (I) complex is particularly preferable.
- the amount of the organic copper reactant is preferably from 0.2 to 4 equivalents, particularly preferably from 0.5 to 2 equivalents, based on the alkene (1).
- An organic phosphorus compound or an organic sulfur compound may be added to the reaction system for the purpose of improving the solubility of the organic copper reactant.
- trialkylphosphine is preferable, and tri (n-butyl) phosphine is preferred. Is preferred.
- organic sulfur compound dimethyl sulfide, getyl sulfide, and difuninyl sulfide are preferable.
- the amount of the organic phosphorus compound or the organic sulfur compound is preferably 0.8 to 1.2 times equivalent to the organic copper reactant.
- an alkene (1) is added to cyclopentenone (2) under the action of an alkyllithium and an organocopper reactant.
- R 2 in the formula (2) is an alkyl group
- an alkyl group having 1 to 8 carbon atoms is preferable, and an alkyl group having 1 to 5 carbon atoms is particularly preferable.
- the alkyl group may be linear or branched.
- R 2 is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, n-hexyl, or n-heptyl
- particularly preferred are a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, and an n-pentyl group.
- R 2 is an alkyl group containing a hetero atom
- a group in which at least one hydrogen atom of the alkyl group is substituted with a monovalent group containing a hetero atom is preferable.
- the monovalent group containing a hetero atom a monovalent group composed of a hydroxyl group, an alkoxy group, a carboxyl group, an amino group, a carbamoyl group, or the like, or a monovalent group containing these, is preferred.
- the alkyl group portion of the alkyl group containing a hetero atom may be linear or branched.
- R 2 which is an alkyl group containing a hetero atom, includes 2-methoxyl, 3-methoxypropyl, 2-hydroxyl, 3-hydroxypropyl, carboxymethyl, and 2-carboxyethyl.
- R 2 is preferably an alkyl group containing a hetero atom, more preferably an alkyl group having 1 to 8 carbon atoms, and particularly preferably an alkyl group having 1 to 5 carbon atoms. .
- R 3 in the formula (2) represents a hydroxyl-protecting group or a hydrogen atom, and the same groups as R 4 are preferable as the hydroxyl-protecting group.
- R 3 and R 4 are the same but different You may use it.
- the double bond may be a trans double bond or a cis double bond, and a trans double bond is preferred.
- Cyclopentenone (2) includes prostanoic acid There is an asymmetric carbon atom at position 11 in the carbon atom number of PG having the basic skeleton of PG, but the absolute configuration is not particularly limited.
- an alkylene (1) is reacted with cyclopentenone (2) under the action of an alkyllithium and an organocopper reactant to form an adduct.
- the amount of the alkene (1) is preferably 0.5 to 10 times the molar amount of the cyclopentenone (2).
- the addition reaction is considered to proceed by the following mechanism. That is, the alkene (1) is lithiated by reacting with the alkyl lithium, and becomes a 1-lithioalkene in which one X 1 in the alkene (1) is substituted with -Li. Then, by reacting the 1-lithioalkenes with the organocopper reactant, an organocopper in which the terminal Li of the 1-lithioalkenes is complexed with a copper atom is produced. Next, it is considered that this organocopper undergoes 1,4-conjugate addition to cyclopentenone (2) to form an adduct.
- the reaction is preferably performed in the presence of an inert solvent.
- an inert solvent an aprotic solvent is preferable, and hexane, heptane, cyclohexane, dimethyl ether, getyl ether, dioctyl ether, t- butyl methyl ether, tetrahydrofuran, and 1,4-dioxane And the like, and particularly preferred is tetrahydrofuran or getyl ether.
- the amount is preferably 1 to 500 times, more preferably 10 to 100 times the weight of the alkene (1).
- the reaction temperature of the addition reaction is preferably from 195 ° C to 150 ° C, particularly preferably from 178 ° C to 120 ° C. Further, the reaction time is preferably 0.1 to 20 hours.
- the adduct obtained by the addition reaction may be isolated if necessary. _ It is preferable to use the compound directly in the next reaction (hereinafter, also referred to as the second step) without removing the additive.
- the adduct is reacted with a carboxylic acid halide (3), a carboxylic acid anhydride (4), or a carboxylic acid mixed anhydride (5) to obtain a PG derivative (6).
- the amount of carboxylic acid halide (3), carboxylic acid anhydride (4), or carboxylic acid mixed anhydride (5) should be 0.5 to 50 times the molar amount of cyclopentenone (2). preferable.
- the conditions of the method known for known compounds having a similar skeleton Sih, et al., J. Am. Chem. Soc., 110, 3588, 1988
- R 1 in the carboxylic acid halide (3), the carboxylic acid anhydride (4), or the carboxylic acid mixed anhydride (5) is an alkanoyl group or an alkynyl group containing a hetero atom in the alkyl group.
- R 1 is an alkanoyl group
- an alkanoyl group having 2 to 6 carbon atoms is preferable, and an alkanoyl group having 2 to 4 carbon atoms is particularly preferable.
- an acetyl group, a propionyl group, an isopropionyl group, or a butanol group is preferable. Is preferred.
- the alkanoyl group in which R 1 contains a hetero atom in the alkyl group portion (hereinafter referred to as a substituted alkanoyl group)
- at least one hydrogen atom in the alkyl group portion is substituted with a monovalent group containing a hetero atom.
- Preferred substituted aryl groups are preferred.
- the monovalent group containing a hetero atom is preferably a hydroxyl group, an alkoxy group, a carboxyl group, an amino group, or a rubamoyl group, or a monovalent group containing these groups.
- R 1 is an alkanoyl group
- the following embodiments are preferred. That is, acetic anhydride or butyric anhydride is preferable as the carboxylic anhydride (4).
- R 6 in the carboxylic acid mixed adult anhydride (5) is Arukanoiru group, or a Arukanoiru group containing heteroatoms in the alkyl moiety, and the R 'are different groups, specific examples of R 1 Alkanoyl groups similar to certain groups are preferred.
- a mixed acid anhydride of vivaric acid acetate (a compound in which R 1 is an acetyl group and R 6 is a vivaloyl group) or a mixed anhydride of vivaric acid butyrate (R 1 is a butylyl group) And a compound in which R 6 is a bivaloyl group).
- X 2 in the carboxylic acid halide (3) is preferably a chlorine atom. Lide or butyric acid chloride is preferred.
- R 1 is an alkanoyl group containing a hetero atom
- carboxylic acid halide (3) or carboxylic acid anhydride (4) is preferable, and 2-methoxypropionic acid anhydride and 2-methoxypropionic acid are particularly preferable.
- reaction solvent a non-proton solvent is preferable.
- reaction solvent hexane, heptane, cyclohexane, dimethyl ether, getyl ether, octyl ether, t-butyl methyl ether, tetrahydrofuran, and 1,4-dioxane are preferable.
- tetrahydrofuran and getyl ether are preferable.
- One or more reaction solvents can be used.
- the amount of the reaction solvent is preferably 1 to 500 times the weight of the alkene (1).
- the reaction temperature of the above reaction is in the range of ⁇ 78 ° C. to about solvent reflux, and is preferably ⁇ 78 ° C. to a temperature around room temperature.
- the reaction time is preferably 0.5 to 48 hours.
- R 1 , R 2 , R 5 and Q in the formula (6) have the same meaning as described above, and the preferred embodiments are also the same.
- R 3 and R 4 are a protecting group for a hydroxyl group or a hydrogen atom.
- a PG derivative (6) useful as a medicament is that both R 3 and R 4 are water —In the case where R 3 and Z or R ⁇ are hydroxyl-protecting groups, they are preferably treated with a nitrogen-containing compound without deprotection.
- the PG derivative (6) in which R 3 and Z or are hydroxyl-protecting groups is represented by the formula (6a).
- R 1, R 2, R 5 , Q the same meanings as defined above.
- R 3 ° and R 4 ° each represents a hydroxyl-protecting group or a hydrogen atom, and one of them is a hydroxyl-protecting group.
- R 3 ° and R 4 ° are each a protecting group for a hydroxyl group include the same groups as when R 3 is a protecting group for a hydroxyl group.
- the PG derivative (6) or the compound represented by the formula (6a) has asymmetric carbon atoms at positions 11, 12, and 15 and thus has various stereoisomers.
- the present invention may be any of the PG derivatives or a mixture thereof.
- reaction product containing the PG derivative (6) obtained by the above reaction is treated with a nitrogen-containing compound.
- nitrogen-containing compound examples include an organic carboxylic acid amide compound, an organic thiourea compound, an organic phosphite triamide compound, an organic phosphate triamide compound, an organic amine compound, or an aromatic compound having a nitrogen atom as a hetero atom. Heterocyclic compounds are preferred.
- organic carboxylic acid amide compound examples include N, N-dimethylformamide, N, N-dimethylacetamide, perea, 1,3-dimethylperia, 1,1,3,3-tetramethylperia, or 1,3-Dimethyl-2-imidazolidinone is preferred.
- organic thiocyanate compound thiourea, 1,3-dimethyl-2-thiorea, 1,1,3,3-tetramethyl-2-thiorea, and the like are preferable.
- organic phosphite triamide compound hexamethyl phosphite triamide, hexethyl phosphite triamide and the like are preferable.
- organic phosphoric acid triamide compound hexamethyl phosphoric acid triamide, hexethyl phosphoric acid triamide and the like are preferable.
- the organic amine compound is an organic amine compound having a primary, secondary, or tertiary amino group, and the group bonded to the amino group is a linear aliphatic group, a branched aliphatic group, or an alicyclic group.
- a formula hydrocarbon group or an aromatic hydrocarbon group is preferred.
- organic amine compounds include trimethylamine, triethylamine, triisopropylamine, tributylamine, trioctylamine, cyclohexylamine, pyrrolidine, piperidine, and N-methylcyclohexylamine, aniline, N-methylaniline, N, N-dimethylaniline is preferred.
- aromatic heterocyclic compound having a nitrogen atom as a hetero atom a pyridine compound or a pyrimidine compound is preferable, and a compound represented by the following formula (7) is particularly preferable.
- R 7 and R 8 each independently represents a hydrogen atom or an alkyl group.
- Y 1 and Y 2 each independently represent a nitrogen atom or CH. However, Y 1 to which R 7 is bonded is C, and Y 2 to which R 8 is bonded is C.
- n an integer from 0 to 5.
- n an integer from 0 to 3.
- R 7 is an alkyl group
- an alkyl group having 1 to 5 carbon atoms is preferable, and a methyl group, an ethyl group, a propyl group, and the like are particularly preferable.
- Examples of the compound represented by the formula (7) include pyridine, 2-methylpyridine, 3-methylpyridine, 4-methylpyridine, 2-ethylpyridine, and biviridyl (for example, For example, 2,2'-biviridyl), bis (2-pyridyl) methane, 1,2-bis (2-pyridyl) ethane, 1,3-bis (2-pyridyl) propane, 6,6'-bis ( 2-methylpyridyl) and 2,2 * -bis (4-methylpyridyl).
- biviridyl for example, For example, 2,2'-biviridyl
- bis (2-pyridyl) methane 1,2-bis (2-pyridyl) ethane
- 1,3-bis (2-pyridyl) propane 1,3-bis (2-pyridyl) propane
- 6,6'-bis 2-methylpyridyl
- 2,2 * -bis (4-methylpyridyl 2,2 * -bis (4-methylpyri
- an aromatic heterocyclic compound having a nitrogen atom as a hetero atom is preferable, and a compound represented by the formula (7) is particularly preferable.
- the nitrogen-containing compound is a crude reaction product immediately after reacting the carboxylic acid halide (3), carboxylic anhydride (4), or carboxylic acid mixed anhydride (5), or the reaction crude product.
- a conventional purification means eg, filtration, column chromatography, etc.
- the method includes the steps of mixing the impurities in the reaction product, particularly the organic copper reaction used in the reaction.
- By-products derived from the agent or the organocopper reactant can be removed. It is considered that the removal is due to the formation of a chelate by the nitrogen-containing compound and the organic copper reactant and by-product.
- It is already known in the literature D. Purdie and AFWells, J. Chem. Soc., 1503, 1936.
- nitrogen-containing compounds and organocopper compounds form chelates, but this is applied to purification methods. This is a feature of the present invention. In the purification method, only unnecessary impurities can be efficiently removed without adversely affecting the production of the target compound.
- the amount of the nitrogen-containing compound is preferably 1 to 100 times the mol of the organocopper reactant used in the reaction.
- the temperature for treating the nitrogen-containing compound is preferably from ⁇ 20 ° C. to about room temperature, and the stirring time for stirring is preferably from 0.1 to 24 hours. It is preferable that the reaction product after the reaction with the nitrogen-containing compound is distilled off the reaction solvent and the like, and then purified by ordinary purification means (for example, silica gel chromatography). Ordinary purification means can sufficiently reduce the amount of the organocopper reactant or by-products derived from the organocopper reactant in the target compound.
- a purified PG derivative (6) is obtained.
- the copper content with respect to the purified PG derivative (6) can be reduced to about 0 to about 100 ppm.
- the purified PG derivative has R 3 and / or R
- a deprotection reaction may be carried out, if necessary, after the action of the nitrogen-containing compound.
- the deprotection reaction can be performed by a known method.
- a deprotected product (6b) purified by the method described in a book by Greene et al. (Protective Groups in Organic Synthesis, John Wiley & Sons, 1981) is obtained.
- R 31 , R 41 : R 31 is R 3 respectively.
- R 41 is a group corresponding to R 4 °, and each is independently a hydroxyl protecting group or a hydrogen atom, and R 3 ° corresponding to the hydroxyl protecting group, R 31 corresponding to R 4 °, At least one of R 4 ′ is a hydrogen atom, and R 31 and R 41 corresponding to hydrogen atoms R 3 and R 4 are hydrogen atoms.
- the purified PG derivative (6) obtained by the method of the present invention is a highly pure compound from which the organic copper reactant used in the reaction or impurities derived from the reactant has been efficiently removed.
- Examples of the PG derivative (6) include the following compounds.
- R 1 and R 2 are butyl groups, and R 3 and A compound in which R 4 is a hydrogen atom, Q is an ethylene group, and R 5 is an ⁇ -pentyl group.
- the purified PG derivative obtained according to the present invention can be used as it is or as a pharmaceutical composition containing it.
- the PG derivative is effective for treating or preventing myocardial infarction, angina, arteriosclerosis, hypertension, duodenal ulcer, labor induction, abortion, etc. It can be used as an agent.
- the present invention will be described specifically with reference to Examples, but the present invention is not limited thereto.
- the copper content was measured by inductively coupled plasma emission spectroscopy.
- Butyric anhydride (1.12 ml, 6.83 mmol) was added dropwise to the adduct at 0 ° C, and the mixture was stirred at 0 ° C to room temperature for 2 hours. After pouring into a saturated aqueous solution of ammonium sulfate (43 ml) and separating from the organic layer, the aqueous layer was extracted with ether (21 ml), and the combined organic layers were dried over anhydrous magnesium sulfate to obtain a reaction product ( Copper content in the reaction product 1-3%). After filtration of the reaction product, 2,2′-biviridyl (2.06 g, 13.2 mmol) was added and stirred for 5 minutes.
- a PG derivative having a protecting group 700 mg, 0.99 mmol was dissolved in acetate nitrile (8.32 ml), and a 46% aqueous solution of hydrofluoric acid (2.62 ml) was dissolved at 0 ° C. ) And stirred at the same temperature for 1 hour.
- the reaction solution was poured into a mixture of a 20% aqueous potassium carbonate solution (29 ml) and methylene chloride (5.9 ml), separated from the organic layer, and the aqueous layer was extracted with methylene chloride (7.75 ml) and combined.
- the organic layer was dried and filtered with anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
- Example 2 Purified methyl 9-acetoxy 11 ⁇ , 15-bis (t-butyldimethylsiloxy) pros-butane-8,13 E-Gen-11- ore Synthesis example
- Example 1 (4 R) — t-Butyldimethylsiloxy 2 -— (6-butoxycarbonylhexyl) -12-cyclopentene—instead of 1-one, (4R) —t-butyldimethylsiloxy-2 -— (6-meth)
- the same reaction was carried out using 2-cyclopentene-11-one and acetic anhydride instead of butyric anhydride, and methyl 9-acetoxy-11 ⁇ , 15S-bis (t Butyldimethylsiloxy) Prostar 8,13 E-gen-11 was obtained (copper content 5 ppm).
- Example 1 was carried out in the same manner as in Example 1 except that the step of adding 2,2'-biviridyl (2.06 g, 13.2 mmol) and stirring for 5 minutes was omitted.
- the copper content in the final compound was 26 ppm.
- a copper compound derived from an organic copper reactant used for a skeleton forming reaction can be efficiently removed by a simple method. Since the copper content in the obtained PG derivative (Formula 6) can be extremely small, the PG derivative (Formula 6) can be used as it is as a raw material for pharmaceuticals.
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Description
Claims
Priority Applications (4)
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JP2000552089A JP4386581B2 (ja) | 1998-06-04 | 1999-06-03 | 精製されたプロスタグランジン誘導体の製造方法 |
DE69939826T DE69939826D1 (de) | 1998-06-04 | 1999-06-03 | Verfahren zur herstellung eines gereinigten prostaglandin-derivats |
US09/701,388 US6632958B1 (en) | 1998-06-04 | 1999-06-03 | Process for producing a purified prostaglandin derivative |
EP99923891A EP1085012B1 (en) | 1998-06-04 | 1999-06-03 | Process for producing a purified prostaglandin derivative |
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JP15643898 | 1998-06-04 | ||
JP10/156438 | 1998-06-04 |
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WO1999062877A1 true WO1999062877A1 (fr) | 1999-12-09 |
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PCT/JP1999/002975 WO1999062877A1 (fr) | 1998-06-04 | 1999-06-03 | Procede de production d'un derive de prostaglandine purifie |
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US (1) | US6632958B1 (ja) |
EP (1) | EP1085012B1 (ja) |
JP (1) | JP4386581B2 (ja) |
DE (1) | DE69939826D1 (ja) |
ES (1) | ES2315013T3 (ja) |
WO (1) | WO1999062877A1 (ja) |
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CN102050771A (zh) * | 2009-11-05 | 2011-05-11 | 沈阳万爱普利德医药科技有限公司 | 一个一种前列腺素衍生物的制造方法 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
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JPS5839660A (ja) * | 1981-08-27 | 1983-03-08 | マイルス・ラボラトリ−ス・インコ−ポレ−テツド | プロスタグランジンc−9のエノ−ルアシレ−ト同族体 |
JPH0859607A (ja) * | 1994-08-22 | 1996-03-05 | Teijin Ltd | プロスタグランジンe1 類の製造法、及びその合成中間体 |
JPH08119934A (ja) * | 1994-10-21 | 1996-05-14 | Teijin Ltd | プロスタグランジン類およびその製造法 |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
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IT1162731B (it) * | 1979-04-10 | 1987-04-01 | Lepetit Spa | 16-metil-16-metossi-5,6-diidro-prosta-glandine della serie e1 ad attivita'antisecretoria |
US5194670A (en) * | 1989-10-16 | 1993-03-16 | Yutaka Mizushima, Asahi Glass Company Ltd. | Emulsion of lipid containing a prostaglandin analogue |
JP2602964B2 (ja) * | 1989-10-16 | 1997-04-23 | 裕 水島 | プロスタグランジン類縁体およびその脂肪乳剤 |
JPH11158120A (ja) | 1997-11-27 | 1999-06-15 | Asahi Glass Co Ltd | シクロペンテン誘導体の製造方法 |
-
1999
- 1999-06-03 WO PCT/JP1999/002975 patent/WO1999062877A1/ja active Application Filing
- 1999-06-03 ES ES99923891T patent/ES2315013T3/es not_active Expired - Lifetime
- 1999-06-03 DE DE69939826T patent/DE69939826D1/de not_active Expired - Fee Related
- 1999-06-03 JP JP2000552089A patent/JP4386581B2/ja not_active Expired - Fee Related
- 1999-06-03 US US09/701,388 patent/US6632958B1/en not_active Expired - Fee Related
- 1999-06-03 EP EP99923891A patent/EP1085012B1/en not_active Expired - Lifetime
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5839660A (ja) * | 1981-08-27 | 1983-03-08 | マイルス・ラボラトリ−ス・インコ−ポレ−テツド | プロスタグランジンc−9のエノ−ルアシレ−ト同族体 |
JPH0859607A (ja) * | 1994-08-22 | 1996-03-05 | Teijin Ltd | プロスタグランジンe1 類の製造法、及びその合成中間体 |
JPH08119934A (ja) * | 1994-10-21 | 1996-05-14 | Teijin Ltd | プロスタグランジン類およびその製造法 |
Non-Patent Citations (1)
Title |
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See also references of EP1085012A4 * |
Also Published As
Publication number | Publication date |
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EP1085012A4 (en) | 2002-08-14 |
US6632958B1 (en) | 2003-10-14 |
EP1085012B1 (en) | 2008-10-29 |
ES2315013T3 (es) | 2009-03-16 |
DE69939826D1 (de) | 2008-12-11 |
JP4386581B2 (ja) | 2009-12-16 |
EP1085012A1 (en) | 2001-03-21 |
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