TW310321B - - Google Patents
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- TW310321B TW310321B TW081107537A TW81107537A TW310321B TW 310321 B TW310321 B TW 310321B TW 081107537 A TW081107537 A TW 081107537A TW 81107537 A TW81107537 A TW 81107537A TW 310321 B TW310321 B TW 310321B
- Authority
- TW
- Taiwan
- Prior art keywords
- formula
- compound
- liters
- preparation
- pentyl
- Prior art date
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- 238000002360 preparation method Methods 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 11
- 150000001875 compounds Chemical class 0.000 claims description 67
- 239000000203 mixture Substances 0.000 claims description 29
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 22
- -1 4-carboxybutyl Chemical group 0.000 claims description 18
- 238000004519 manufacturing process Methods 0.000 claims description 13
- 239000002904 solvent Substances 0.000 claims description 10
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 7
- 239000000126 substance Substances 0.000 claims description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 6
- PXGPLTODNUVGFL-BRIYLRKRSA-N (E,Z)-(1R,2R,3R,5S)-7-(3,5-Dihydroxy-2-((3S)-(3-hydroxy-1-octenyl))cyclopentyl)-5-heptenoic acid Chemical compound CCCCC[C@H](O)C=C[C@H]1[C@H](O)C[C@H](O)[C@@H]1CC=CCCCC(O)=O PXGPLTODNUVGFL-BRIYLRKRSA-N 0.000 claims description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 3
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 3
- 238000005984 hydrogenation reaction Methods 0.000 claims description 3
- 229910052744 lithium Inorganic materials 0.000 claims description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- OTYBMLCTZGSZBG-UHFFFAOYSA-L potassium sulfate Chemical compound [K+].[K+].[O-]S([O-])(=O)=O OTYBMLCTZGSZBG-UHFFFAOYSA-L 0.000 claims description 2
- 229910052939 potassium sulfate Inorganic materials 0.000 claims description 2
- 239000001120 potassium sulphate Substances 0.000 claims description 2
- 235000011151 potassium sulphates Nutrition 0.000 claims description 2
- 125000006239 protecting group Chemical group 0.000 claims description 2
- 101000692466 Bos taurus Prostaglandin F synthase 2 Proteins 0.000 claims 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims 1
- 230000029936 alkylation Effects 0.000 claims 1
- 238000005804 alkylation reaction Methods 0.000 claims 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 claims 1
- CZZYITDELCSZES-UHFFFAOYSA-N diphenylmethane Chemical compound C=1C=CC=CC=1CC1=CC=CC=C1 CZZYITDELCSZES-UHFFFAOYSA-N 0.000 claims 1
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 claims 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 claims 1
- DPLVEEXVKBWGHE-UHFFFAOYSA-N potassium sulfide Chemical group [S-2].[K+].[K+] DPLVEEXVKBWGHE-UHFFFAOYSA-N 0.000 claims 1
- 238000001953 recrystallisation Methods 0.000 claims 1
- 159000000000 sodium salts Chemical class 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 claims 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 abstract description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 2
- 229920006395 saturated elastomer Polymers 0.000 abstract description 2
- 125000000217 alkyl group Chemical group 0.000 abstract 1
- 125000004122 cyclic group Chemical group 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 93
- 239000000243 solution Substances 0.000 description 48
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 42
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 24
- 125000003118 aryl group Chemical group 0.000 description 15
- 239000000047 product Substances 0.000 description 15
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 239000012267 brine Substances 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- 239000002244 precipitate Substances 0.000 description 9
- 239000000741 silica gel Substances 0.000 description 9
- 229910002027 silica gel Inorganic materials 0.000 description 9
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 8
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 7
- 238000002844 melting Methods 0.000 description 7
- 230000008018 melting Effects 0.000 description 7
- 238000012544 monitoring process Methods 0.000 description 7
- 229910052938 sodium sulfate Inorganic materials 0.000 description 7
- 235000011152 sodium sulphate Nutrition 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000007789 gas Substances 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 239000000499 gel Substances 0.000 description 4
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 4
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 4
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 4
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 4
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 4
- 239000011800 void material Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 3
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 230000002079 cooperative effect Effects 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000002329 infrared spectrum Methods 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 150000003180 prostaglandins Chemical class 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- WDYVUKGVKRZQNM-UHFFFAOYSA-N 6-phosphonohexylphosphonic acid Chemical compound OP(O)(=O)CCCCCCP(O)(O)=O WDYVUKGVKRZQNM-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- UEZVMMHDMIWARA-UHFFFAOYSA-N Metaphosphoric acid Chemical compound OP(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 229910052797 bismuth Inorganic materials 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000011259 mixed solution Substances 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
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 229920001296 polysiloxane Polymers 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 229910052710 silicon Inorganic materials 0.000 description 2
- 239000010703 silicon Substances 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 235000010288 sodium nitrite Nutrition 0.000 description 2
- 230000003595 spectral effect Effects 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- OTZGYUUQQRXJMY-UHFFFAOYSA-N $l^{2}-bismuthanylidenesilicon Chemical compound [Bi]=[Si] OTZGYUUQQRXJMY-UHFFFAOYSA-N 0.000 description 1
- IYLGZMTXKJYONK-ACLXAEORSA-N (12s,15r)-15-hydroxy-11,16-dioxo-15,20-dihydrosenecionan-12-yl acetate Chemical compound O1C(=O)[C@](CC)(O)C[C@@H](C)[C@](C)(OC(C)=O)C(=O)OCC2=CCN3[C@H]2[C@H]1CC3 IYLGZMTXKJYONK-ACLXAEORSA-N 0.000 description 1
- ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical group CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 description 1
- XSDLSEOIVCVTQZ-UHFFFAOYSA-N 2h-cyclopenta[b]furan Chemical compound C1=CC2=CCOC2=C1 XSDLSEOIVCVTQZ-UHFFFAOYSA-N 0.000 description 1
- MLMQPDHYNJCQAO-UHFFFAOYSA-N 3,3-dimethylbutyric acid Chemical compound CC(C)(C)CC(O)=O MLMQPDHYNJCQAO-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 102000040350 B family Human genes 0.000 description 1
- 108091072128 B family Proteins 0.000 description 1
- SCEQOUNDRXZZQR-UHFFFAOYSA-N C1(=CC=CC=C1)[Yb] Chemical class C1(=CC=CC=C1)[Yb] SCEQOUNDRXZZQR-UHFFFAOYSA-N 0.000 description 1
- 241001164374 Calyx Species 0.000 description 1
- 241000282461 Canis lupus Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 244000241257 Cucumis melo Species 0.000 description 1
- 235000015510 Cucumis melo subsp melo Nutrition 0.000 description 1
- 229910052692 Dysprosium Inorganic materials 0.000 description 1
- 241000234435 Lilium Species 0.000 description 1
- 239000012448 Lithium borohydride Substances 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical group CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 235000014676 Phragmites communis Nutrition 0.000 description 1
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N Propene Chemical group CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- KBMHVBCZMGFDJM-UHFFFAOYSA-N S(=O)(=O)(O)O.[Kr] Chemical compound S(=O)(=O)(O)O.[Kr] KBMHVBCZMGFDJM-UHFFFAOYSA-N 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical class [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 1
- 206010041349 Somnolence Diseases 0.000 description 1
- 244000062793 Sorghum vulgare Species 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- XSTXAVWGXDQKEL-UHFFFAOYSA-N Trichloroethylene Chemical compound ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 description 1
- FJJCIZWZNKZHII-UHFFFAOYSA-N [4,6-bis(cyanoamino)-1,3,5-triazin-2-yl]cyanamide Chemical compound N#CNC1=NC(NC#N)=NC(NC#N)=N1 FJJCIZWZNKZHII-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical compound [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 125000001231 benzoyloxy group Chemical group C(C1=CC=CC=C1)(=O)O* 0.000 description 1
- 150000001621 bismuth Chemical class 0.000 description 1
- JCXGWMGPZLAOME-UHFFFAOYSA-N bismuth atom Chemical compound [Bi] JCXGWMGPZLAOME-UHFFFAOYSA-N 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 210000005252 bulbus oculi Anatomy 0.000 description 1
- 235000014121 butter Nutrition 0.000 description 1
- CSMMKMOVLRCJAW-UHFFFAOYSA-L butylaluminum(2+);difluoride Chemical compound [F-].[F-].CCCC[Al+2] CSMMKMOVLRCJAW-UHFFFAOYSA-L 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229910052792 caesium Inorganic materials 0.000 description 1
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 description 1
- BRPQOXSCLDDYGP-UHFFFAOYSA-N calcium oxide Chemical compound [O-2].[Ca+2] BRPQOXSCLDDYGP-UHFFFAOYSA-N 0.000 description 1
- 239000000292 calcium oxide Substances 0.000 description 1
- ODINCKMPIJJUCX-UHFFFAOYSA-N calcium oxide Inorganic materials [Ca]=O ODINCKMPIJJUCX-UHFFFAOYSA-N 0.000 description 1
- 239000013043 chemical agent Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 235000019504 cigarettes Nutrition 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000010779 crude oil Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- UMQKCVIQVNOKLY-UHFFFAOYSA-N cyclohex-5-ene-1,2,4-trione Chemical compound O=C1CC(=O)C(=O)C=C1 UMQKCVIQVNOKLY-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- KBQHZAAAGSGFKK-UHFFFAOYSA-N dysprosium atom Chemical compound [Dy] KBQHZAAAGSGFKK-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 210000001508 eye Anatomy 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000002309 gasification Methods 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 229910052746 lanthanum Inorganic materials 0.000 description 1
- FZLIPJUXYLNCLC-UHFFFAOYSA-N lanthanum atom Chemical compound [La] FZLIPJUXYLNCLC-UHFFFAOYSA-N 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 235000019713 millet Nutrition 0.000 description 1
- 238000005065 mining Methods 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 235000012149 noodles Nutrition 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- 229960005222 phenazone Drugs 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- CUQOHAYJWVTKDE-UHFFFAOYSA-N potassium;butan-1-olate Chemical compound [K+].CCCC[O-] CUQOHAYJWVTKDE-UHFFFAOYSA-N 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- IYLGZMTXKJYONK-UHFFFAOYSA-N ruwenine Natural products O1C(=O)C(CC)(O)CC(C)C(C)(OC(C)=O)C(=O)OCC2=CCN3C2C1CC3 IYLGZMTXKJYONK-UHFFFAOYSA-N 0.000 description 1
- 238000005464 sample preparation method Methods 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- BHZOKUMUHVTPBX-UHFFFAOYSA-M sodium acetic acid acetate Chemical class [Na+].CC(O)=O.CC([O-])=O BHZOKUMUHVTPBX-UHFFFAOYSA-M 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- HYHCSLBZRBJJCH-UHFFFAOYSA-M sodium hydrosulfide Chemical compound [Na+].[SH-] HYHCSLBZRBJJCH-UHFFFAOYSA-M 0.000 description 1
- KKCBUQHMOMHUOY-UHFFFAOYSA-N sodium oxide Chemical compound [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 description 1
- 229910001948 sodium oxide Inorganic materials 0.000 description 1
- QGMRQYFBGABWDR-UHFFFAOYSA-N sodium;5-ethyl-5-pentan-2-yl-1,3-diazinane-2,4,6-trione Chemical compound [Na+].CCCC(C)C1(CC)C(=O)NC(=O)NC1=O QGMRQYFBGABWDR-UHFFFAOYSA-N 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 210000004243 sweat Anatomy 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical group CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- FIQMHBFVRAXMOP-UHFFFAOYSA-N triphenylphosphane oxide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
- C07D307/935—Not further condensed cyclopenta [b] furans or hydrogenated cyclopenta [b] furans
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- 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
-
- 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
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Ophthalmology & Optometry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Furan Compounds (AREA)
- Catalysts (AREA)
- Physical Or Chemical Processes And Apparatus (AREA)
- Emergency Lowering Means (AREA)
Description
s^〇32i 經濟部屮央楳準局κχ工消#合作杜印Μ 五、發明説明(1) 本鉍明係關於通式(I)所示13,μ —二氫—15 (R17 苯基一 18,19,20 —三原P G F 2 α酯之新製法: ΟΗ '
⑴ 其中R代表飽和或不飽和直_、支鍵或環型烷基或 苯基或苄基。 已知有許多***素衍生物局部使用時,卽用於處埋 靑光眼時,可以減少眼球內的緊張(昆歐洲專利公告0170258 和0 25 3094號)。具有特殊翁益效采的***漸衍生物, 載於公告之PCT專利申請案W〇9〇/〇 25 5 3號。由此證 明以式(I)化合物特別有利。式(丨)化合物的合成方法, 已載於上述PCT申請案內 本發明之因的,在於提供一植改良合成方法,可以良 好產率、大最、並以所需純度,也淹式u )化合物。 _ 获驶叫"厂以砰純丨cn彳μα淹_製丨1丨武(丨)化丨>物,1丨.汰 垃將式(W)化合物之側鏈上的緘基遍_ :
(VII) 所得式(VU 之 3, 3a,4,5,6} 6a —六氫——2 —氧代—4„_ 〔5 —苯基一· 3*(K)—翔基戊一-1 丨戈基〕一5 —( 4 ’- 笨基苯甲縫氧基)一2 Η —環戊〔b〕吵啸: t紙张反度遑用中《困家楳毕(CNS> T4规格(210x297公鼇} HI. 7. 20,00)»^ ill) 先 間 A ;V 而 之 卞 項 I')- >n' % s^〇32l 84· 7U 年 fl u 二 r: :iiy
Λ β Π G 五、#明説明(2)
〇 (VI) 藉加氮轉化成式(V)之3,3a,4»5»6»6a —六氮一2 —氧 代—4 —〔5* —苯基一3 f (R )—翔基一I1 —戊基〕一5·— (f 一苯基笨甲酾氧基)一2Η —環戊〔b〕呋喃:
(V)
將式(V )化合物還原成式(IV)之3, 3a,4,5,6,6a—六 氣~ 2—翔甚一4 一( 5 ’ 一^基一3’(R) —翔基一1匕戊基〕一 5—( 4f—苯基苯甲醯氧基)-2 Η —環戊〔b〕咲喃: QH
(IV) ih 先 WI 而 之 if. * Ψ 4 訂 線 經濟部屮央梂準>PJA工消费合作社印Μ 自式(IV)化合物除去保護基*得式(ΙίΙ)之3, 3a· 4,5,6,
6 a —六截一2 »5 —二翔基一4—〔 5’笨基一3* fR) —控基 —1,一戊基〕一2H —環戊Cb〕呋喃: OH
(III) 本紙》尺度遑《中《«家«準(CHS) f 4规格(210X297公;》) — 5 —- HI. 7. W.OOOiMH) Λ (> Η 6 五、發明説明(3) 再將式(H )化合物•使用4 一羧丁基三笨基阁化鱗轉化成 基一18 ·〗9.?0—三原 PGF2a:
式(Π ) Z 13.14 —二靜‘ 一15 i R ) — 17 — COOH
(ΪΪ) 經濟部十央標準"Jcxx消赀合作社印製 最後,以通式K — X—之化合物,其中R意義同上,而X 爲鹵素、硫酸酯、甲磺醯基、甲苯磺麵基,或任何適當基 將式(Π)化合物轉變成通式U )所示13 ,14--二氫一15(R) —17~-笨基一18,19>20—三原一以】?'2«_。 式(祖)化合物是由苯基鏞鹽扣3, 3a, 4, 5, 6, 6a -六氫一2 ~氧代一4 — ( 5,.-苯基一 3 氧戊一1 ’ 一唏基) —5—( 4 ’一苯基苯甲醯氧基)一· 2H —瓔戊〔b〕〇々喃製 成,後者爲已知***素中間物,可例如依照美國專利 3 7 7845 0號製得。其他反應劑均市上有售。 式(1)化合物還原成式(W)化合物》可用特別是前 列腺素化學文獻上所知適於將烯_還原的任何已知化學劑 進行,例如使用三次丁基硼化鋰或氫湖化納〔J. AT". Chem. Soc. 8616 (1972k J. Am. Chem. Soc. 106, 6717 U984) j。 式(VO化合物之轉變成式(V)物質,HJ在加氫常用觸媒 存在下Μ施,例如碳上鈀或碳上鍩,以碳上鈀爲佳,最好 是在鹸或納鹽,例如Μ*氧化納或亞硝酸納存在卜爲之。 式(111 )化合物轉變成式(II)化合物,是使用Witting 反應中常用的任何組合條件(_、溶劑等)進行。醎以氨 ifi 間 η 而 之 注 急 f 項 % Η 線
本紙張尺度遑用中《國家標率(CNS)f 4規格(210x237公藿》—I HI. 7. 20,0ίΗ)^ (II) s^〇S2i Λ ftn c 五、發明説明(4) 驻納、特丁酸鉀、鉍化納成Γ丛师爲作,洁剤"ί ίΠ :::乙二 醇二甲醚、DMS〇、DMF或四mMc喃。k: (V)化合物轉嬤成 式(IV)化合物,隨後由式(IV)化合物轉變成式(III)產品: 亦可不必單離式(F)化合物*就在適當選定條件F達成。 凡精於此道之士均知,式(11一 1)扣通式U )之化合物可 含有其他取代物,而本發明所請求之方法仍能進行《所以; 此等反應顯然都在本案範幽內》 茲綜合本發明方法的進程如F:
OPPB
(VII)
OH 經濟部屮央標準局β工消伢合作杜印51
OPPB (IV)
OH 1紙張尺度適用中《 B家摞準<CNS>Ή規格(2】0X297公Λ) _ 7 Η\. 7. :^ί),0()〇*;/< ΠΙ) 31Q321 84 7. 2 五、發明説明(δ) Λ 6 it 6
⑴ 茲以如下非限制性實施例詳述本發明方法如F : (請先n/Jiliw-一之·:一必秤項外艰艿本A) 經濟部屮央梂準而只工消奸合作社印製 賁施例1 製造 3 , 3 a , 4 , δ , 6,6 a —六氫一 2 --氧代一4 —ί 5 ’ —笨基~ 3—氧代‘一戊一 1 ·一烯基)一 5 —ί 4匕笨基笨甲酴 氧基)一2Η—瑷戊Cb〕H夫喃〔式(W )化合物〕 無水甲苯(110毫升)內含3a*4,5,6,6 a —六愚 一2 —氧代一4 —羥甲基一5— ( 4 ·—苯基苯甲醯氧基)一 2H —環戊〔b〕呋喃(18克,51毫莫耳)之溶液,冷却至 18 1C,再加無水二甲亞*風內含二瑣己基碳化二亞胺(18克, 83毫莫耳)和1克分子量磷鹸液(8毫升,8毫莫耳)之 溶液β反應混合物在連續冷却下,維持溫度於25C以下· 30分鐘後•於反混合物間隔30分鐘添加下列反臁劑: 在二甲亞職内之1 Μ磷酸液(4毫升);在二甲亞观 內的二瓚己基碳化二亞胺(9克,41毫莫耳)和1 Μ磷酸 液(5毫升) 其次,反饞混合物在20 — 22 *€_拌2小時。闻時,三 -· 本《張尺Α遑用中国國家«率(CHS) Τ4规格(2丨0x29?公藿> 81. 7. 'iO.dOOifc (II) Λ 6 Η β 五、發明説明(6 ) 苯基一(4 —笨基— 3—氧丁基)一峨化鎭(2 / . 3克,50毫 莫耳),和甲苯(250毫升)内& MM氧化鈣溶液(10毫 升)*在45 1C搅掸90分Μ ;再將所得溶液毎次用》〇毫升45 一 50 Ό水洗三次,丨·至中性,再減應肖溶液除去甲苯(45 毫升)β殘餘溶液加於其他反應混合物,其速率便溫度不 超過30 t: » 2小時後,溶液加熱至35 t: ·再經1小時,添 加溶人水(30毫升丼的濃麵酸(4毫升)*又搅拌.1小時ϋ 過濾除去沉澱物,應液用甲苯洗淨,合併後,甲苯溶液用 水洗(150毫升),用鹽水(30毫升)洗4次,在無水硫 酸納上乾燥•再蒸發至350毫升/ 上述溶液送至含矽凝膠(135克)和甲苯的管柱,‘使 用甲笨和乙酸乙酯5 : 1混合物洗提。溶液蒸發後,得深棕 色固體(21克),溶人沸騰甲醇(《40毫升)內》溶液冷 却至〇€後·將沉澱物過濂•以冷甲酵(30毫升)洗淨* 產品在室溫乾燥,得式(I)之標的產品,爲内色物質,牽 率 12。0 克(48. 7 % ),融點 1 29-1 30*C ’ 〔a〕D=—145 (c二1,乙酸乙嗰)° 寅施例2 製造 3, 3a,4,5,6,6a--六氫一2—氧代一4--( 5,一 苯蕋一3 —氧代一戊一P烯基j^ o - ( 4 * ψ it % 基)—2H—環戊〔b〕呋喃〔式(1)化合物〕 (a )於甲苯(1 6 5 公升)內含 3,3 a,4,5,6 , 6 a — 六氣一 2 —^氧代一4 翔,甲基-5 '•— ( ^ --苯基笨甲酿氧基) —2 Η ~環戊〔b〕呋喃(27公斤)冷却至17'€之溶液,加 ^紙張尺度遑用中《«家螵零(CHS)T4規格(210X29?公波)一3 【./.先閱讀评而之注急卞項4美荈-ί IV * 經濟部屮央標準局!S:工消伢合作杜印製 81. 7 •-Ό,ΟΟΟίΐ,. (iij Λ 6 η β 經濟»'||'屮火標準Ass工消赀合作杜印製 五、發明説明(7) 1 Μ二甲亞难U DMSO)內的二環己基碳化二亞胺(DCC) (27公斤)和磷酸(12公升)* 60分鐘後,反勝混合物溫 度維持在25X:以F 〇以60分鐘間刚按F列順序*於反應混 合物添加下列反應劑:在1M DiViSC)內的磷酸(6公升), DCC ( 13.5公斤),在1 M DMiSO内的磷酸(6公 斤)。反應混合物在20 -- 25*C父搅捭7小時(T L C監控)。 TLC Rf = 0.32 (矽凝膠,AcOKt :中笨) (矽凝膠,f|» -AcOEt-AcOH = 30:15:2) Cb)三苯基一2 —氧代一4 —苯基丁基碘化鳞(38.4 公斤)、氫氧化鉀(5公斤)*在水(105公升)*甲笨 (210公升)和二氣甲烷(9〇公升)內,激烈攬拌3小時, 然後加氣化納(5公斤)。將有機W分離,用鹽水(3 X 113公升)洗,在硫酸納上乾爍,眞空濃縮至70公升,此 溶液添加於本實施例(a )部份所述方法製成之溶液,其速 率使反應混合物的溜度不超過25 C 7小時後,溶液冷却 至18 C ( TL C監控)。添加水(45公升)中含濃鹽酸(6 公升)的溶液*混合物搅拌1小時。過_除去沉澱物,用 甲苯洗淨(2 X45公升+2 X23公升)有機腊用水(225 公升)和镧木(.4 X 45公升)淨洗,水溶液用甲呆(2 X ' 23公升+ 1 X 30公升)萃収,收集心概射,在峋酸辦(1δ J ii,轉㈣85公;]_ 公升)上乾燥•過應•用甲¥ ( 2 X 15公/1- ) ϋΓ^Ιΐΰϊί' 醇(240公升),冷却至Οχ:,過濾,用甲酵:甲苯9 : 1 (49公升)和甲醇(98 + 60公升)洗淨*得白色結晶產品, 融點 1 29 —130 t:(產率 19· 4 公斤,52 · 7 % ),〔《〕€ >n 先 間 ifi ίΐ 而 之 Λ 項 /'i m r. .線 紙張尺度逍用中β 家《半(CHS) 規格(210X297公 «I. 7. 20,0()()¾ (11) 86. 5. 8
Λ (» n (I 反、發明説明(8) 二一116° ( C = 1 · 26,C Π 3 CN ) « (α ) 10 =- 144° (C = 1,乙酸乙酯)。 實施例3 製造 3,3a,4, 5, 6,6a —六氬一2 —氣代一4 —〔5* — 苯基一3 , (R) —翔戊一I ' — '1$ Μ ) ~ ~ 〇 - - - ( 4 —苯基苯中 _氧基)一2Η--環戊〔b〕呋喃〔式(VP化合物〕 裝· 四氫呋喃內含1 »〇4M三次丁基氫棚化鋰(418毫升, 0.434莫耳)的溶液與無水二***(420毫升)的混合物, 冷却至1 30 t:。式(\1)化合物(200克)溶入四氫呋喃( 1000毫升)和二***(900毫升)內,冷却至一1 30 t:, 在1分鐘內加於上述氫硼化鋰溶液。5分鐘後*將反應混 合物傾人含水(5。5公升),2M硫酸納溶液(250毫升) 和鹽水(500毫升)的混合液內,在室溫携拌15分鐘。溶 液接續以水(2公升)、乙酸乙議(1公升)和鹽水(2 X 200毫升)洗淨,在無水硫酸納上乾燥,減壓蒸發。所 得液體殘渣送至含矽凝膠(5公斤)的管柱。用含二氯甲 烷和乙酸乙酯的7 : 1混合物洗提後,所得產品由乙酸乙 酯(80毫升)、二異丙醚(160毫升)相己烷(8〇毫升) 經濟部十央標¥^工消费合作社印51 的混合液再結晶*得白色結晶性之標的式(W)化合物( 69.7 克),融點 129 --1 30 1,〇〕p = - 108。(c=l, 乙酸乙酯)。 實施例4 製造 3,3a,4,5,o,6a 六氣 2 氧代— —苯蕋一a ’( R )—抨戊一1,一烯某〕-5 — ( 4,一架 基苯甲醣氧基)一2H —瑣戊〔b〕呋喃(,式(W )化合物〕 本紙ΛΛ度逡用中《«家«爭(CNS>f4規格(210x297公- u ^ϊφ32ι Λ 6 η 6 五、發明説丨丨』丨(9) 於甲酵(4.5公升)和氯仿(200公升)內含式(VD烯 _ 1; _( 19.3公斤)而冷坪至—3至5 的楷捭懸溶液•加氫 砸化鈉(2.38公斤)(TLC監控)。將反應混合物傾入水 (20公升)中.接精加濃鹽酸(12.6公升)。混合物在矽 凝膠(奶公斤)上乾燥、過_ ·川氯仿洗浄(60 + 30公汁)。 有機層濃縮至60公升•在二管柱上層析。二管柱均充塡矽 凝_( 1 35公斤)和甲笨(300公升)。接續使用申苯: Ac〇Et 660公升:133公升+ ( 250公升:Ϊ50公升)· 以及AcOEt 25〇公升爲二管柱的洗,提液。分部V ί 410公 升)眞空濃縮至筘公升。於殘渣加二異丙_( 90公升)·冷 却至0 Ό / — 5 X: *攪拌[小時。將臼色結晶性產品過濾· 用DIPE—AcOEt 3: 1 ( 16公升)洗浄。產率7.38公斤(38 % ) ° TLC :Rf = 〇·5 (矽凝膠;AcOEt ) · 0·36 (AcOEt :己烷 1 : 1 ) *〔《〕= 一101.59。( C = 0.69· CH3 CN ) 〇 〔a〕g° = -1〇9。( C =1,乙酸乙酯)a ff施例5 ^ ‘ 也^ 3 » 3¾ « 4 » 5 » 6 » 6a —六氣一2 —代 一 4 一〔 5 1 —笨 經濟部屮央標準而0工消#合作社印$1 ji二( R )-一羥基一1 I —戊基〕一 5 — ( 4,一笨某笨甲醯氧 U — 2 Η —環戊〔b〕呋喃〔式(V)化合物〕 於18 — 20 t:乙酵(2公升)內含3.3a,4.5,6,6a —六 鉍一2 —氧代一4 一〔 5,一笨站—3,( R )—秤戊一 Γ 一烯#:〕 —5 — ( 4 , —苯基笨甲醯氧基)—2H _環戊〔b〕映喃(7〇克, U4毫莫耳)的溶液,添加碳上鈀觸媒(7.〇克)和亞硝 酸鈉(3.5克· 50牽莫耳)在水(丨㈤毫升)中的懸浮液。 混合物在5巴壓力的氫內攢捭90分錄•再將觸媒除•加 本紙诋尺A4用中a«家《準(CHS)T4規格(210X297公;St) — 12 — Hi. 7, 20,000^(11) 經濟部屮火梂準局=3:工消伢合作杜印31 五、發明説明(10) 1 Μ鹽酸溶液(耽毫升)*混合物在室溫攪拌1小時*減 壓除去溶劑後,所得油狀殘渣溶人乙酸乙酯(川〇毫升〕 內》水相用乙酸乙_( 200毫升)萃取二次〃合併乙酸乙 酯溶液用鹽水萃取(2 X则毫升)β在無水硫酸納..h乾燥 和溶劑蒸發後,得標的式(V)化合物,呈油狀殘镝,產率 95%,Rf値0.23 (展開系統爲己烷/乙酸乙酯1 : 1 ), 〔= —66° ( C = 1,乙酸乙酷)。 I R譜(取自Zeiss Specord Μ —80型光譜計)( KBr, y> cm-1 ) : 3500((顶)》3080 3020 ( CH 芳香 族),2 940,2860 ( C Η 脂昉族),1 7 70,:! 71 〇 ( C =0),1610,1 500(芳播族環振 _),1290,1 190, 1 1 00 ( C — Ο — C ),850 (對位取代芳香族)* 7 5 0,70 0 (單取代芳香族 實施例6 製造 3,3a,4,5,6,6a —六 Μ — 2 —氧代.一 4 -- C 5 '— 笨基苯
f酵萼蓋」二AH=里迖lbJ α喃〔式(V)化合物〕 於15 —20 1C無水乙醇(200公升)内豸式(VI)化合物 (7 · 2公斤)的溶液,添加水(30公汁)屮含10 % P d /C ( 1· 4公厅)和亞g丨酸納(0· 7 2公斤)的懸游液〇溶液在祕 氛幽(1 200肋1.)卜—攪拌3小時(丁[(:監控)。加2 1^ HC1 ( 10 &公升),在室瀰搅拌1小時。暹濾除去觸媒, 用無水乙_( 20公升)洗淨。眞空除去溶劑至50公升。所 .I 得油溶人甲苯(14 0公汁)內•以15 % _水洗浄(3 x邓公 升)。水相用甲采·( ?〇公升)洗淨。合併有機翠収液•分別在 I -----Ί-ΙΓΓ HIIIIIITTI..........................1 π ΤΙΙΙΓ _ _ 广~1 Γ~--- ' II II III II··· I I t紙張尺度遑用+ «國家楳畢(CNS)<P4規格(2WX297公t)
Hi. 7 ?Ι),()()〇ΪΜΙΙ) 訂, 13 ίί· f η Λ 6 Π 6 經濟部屮央梂準局EX工消奸合作社印51 五、發明説明(ιι) 硫酸納(10公斤)和碳酸氫納(〇»5公斤)上乾燥、過濾。 沉澱物用甲苯(30公升)洗淨。眞空^除去溶劑*得殘渣( t 90公升)*直接用於次一步驟。殘渣含式(V)化合物( 7.03 公斤 * 96.7%)。融點爲 74 — 75 C 實施例7 製造 8,3a, 4,5,6, 6 a -六鐘)一2 —~ 經基一4 —〔 5 ’ ~苯甚一3 * ( R )—翔基~~ 1 f —戊:基2 ~~ 5 — C 4;」-―苯某 笨甲醯氧基)一2H 一環戊〔b〕fl夫喃〔式(IV〕化合物〕. 3,3 a,4,.5,6:,6 a —六蠢一2 ~·氧代 ~~ 4. — [ 5 '—苯 華3 ’(. R )—翔基~ 1 * —~戊基〕-—5 — ( 4 ’ 一笨基笨甲 醯氧基)一2Η—環戊〔b〕μ夫喃(65. 7克,135毫莫耳) 溶人無水四氫呋喃(3 3 0毫升)後,在-65 t:和一75 t:間之 溫度滴加無水己烷溶液(150毫升)內之二與丁基Μ化鋁 (150毫升,297毫莫耳)。反應混合物攪拌1〇分鐘後* 溶液傾人水(1公升)和2 Μ硫酸氫納溶液(500毫升) 之混合液內*攙拌30分鐘。溶液用乙酸乙酯(1公升十2 X 500毫升),合併有機相用鹽水(2 X 2〇〇毫升)洗 淨。有機相減壓蒸發後,得標的式(IV)產品,爲無色汕 狀殘渣,不必精製卽可用於次一步驟,K f = 0 · 2 5 (笨/ 乙酸乙酯1 : 1)。融點爲87— 90X:。 實施例8 製備 3,3a,4 >5,6,6:a--六懿一-2 —釋基 ~~ 4 —〔 δ , —苯基一3 F (R j —羥基一1 戊棊〕——-5— ( 4,一苯基 苤里遵氧基j —2H—環戊〔b〕呋喃〔式(]V)化合物〕
卜紙》尺A逍用中《國家樣率(CNS) f 4規格(210x29/公釐> 一 M «I. 7. 20,Q〇ih'k (II)
五、發明説明(12)
Th 先 間 1Ϊ 而 之 意 項 % λ h 線 將無水甲笨(31公升)內含二異丁基氫化鋁(D1BAL )( 9.1公斤)的溶液.添加於—72/— 80<€甲笨(70公升)內含 式(V)化合物(6.8公斤)之攪拌液* 1小時(TLC監控) 後•加乙酸乙酯(5公升)·檫着加1M硫酸氫鈉(240公 升)。將有機層分離•在硫酸納f 9公斤)上乾燥•過濾* 用甲笨:ACOEt ( 5公升:5公升)洗淨。水層用AcOEt (3 X35公升)洗淨。收集有機層,在硫酸鈉(9公斤) 上乾燥•過濾,用Φ苯:AcOEt i : 1 ( 40公升)洗淨。收 集有機層·加甲笨(100公升)和Η乙胺(1>·5公汁)·將 三元醇安定。Ξ元瞧溶液在充塡於甲笨(60公升)上的矽 凝膠(34公斤)上層析•分別使用甲笨:AcOEt ( 400 公升)和AcOEt ί 560公升)爲洗提液·按下列頓序收 集下述分部:分部I ( 50公什),分部U和!(各400公 升)、分別F ( 230公升)。分部ffl富有所需產品,溶劑 在眞空內除去。於殘渣(20公升)加二異丙醚(DIPE)
(65么升)*冷却至0 。形成固體物質*過狼,用Di PE :AcOE t 3 : 1洗浄ί 2 X K)公升)·得白色結晶產品· 經濟部十央梂準局=5工消#合作社印33. 產率(2.8公斤·63.1% )。使用過量DIBAL除去ΡΡΒ· 而式(V)化合物還原成式(IV)化合物。融點爲87 — 90C。 實施例9 製造 3 , 3a · 4 , 5.6,6 a --六氫 一 2 —羥基 一 4 —〔 ft , -¾基 3 | ( R ) —羥基一1 1 —戊基〕一2 Η —瓔戊ί b〕映喃〔式(JI ) 化合物〕 含 3,3 a . 4 . 5 · 6,6 a —六氧一 2 —翔基一 4 一〔 5 · — 笨基 本紙5民尺庠遑用中明黷家«半(CHS>f4规格⑵0X297公釐)—】5 一 8!. !. 20,000¾ (II) Λ β Η (ί 五、發明説明(I3) 一 3 ' ( R )—羥基一1' 一戊基〕一5 — ( 4 ’ 一笨甚笨甲醯氧基) —2H—瓒戊〔b〕卩1:喃(65.2克* 嘈莫丨)、碳哮 W C 1 9.0 ιΑ* * 133.4 -¾¾ ί| ) fiH|i|^ ( ;{;{〇 ) ^ fr 物•在40 — 45 t:搅挣5小時.洱冷却罕0 T: ·徐餘添加1 n 磷酸液調節pH俯至7 — 8。沉澱物渦濾後,濾液用水萃 収(2 X 70 丨)·丨丨ί以丨丨丨酌(30 M/丨.)和水2 : 1祉介液 洗二次。 於濾液添加鹽水•並以乙酸乙酯萃取(4 X 2 5 0薄升) 後•合併有機相用鹽水洗淨、乾燥、和減爾蒸發。所得固 體溶入60 X:乙酸乙酯(_毫升)內•於溶液加二異內醚( 丨00毫升)·冷却至室溫,再徐徐加己院(200毫升)。混 合物在0 Ό攪拌後*將結晶性沉殿物過濾•用二異內酸和 乙酸乙酯的2: 1混合物(各30毫升)洗二次.乾燥•得白 色結晶性讎的式(1丨丨)化合物(35 · 9 3克· 87.90 % ).融 點 103 — 1061C ’〔α〕ι> = —... 47。((: = 1 ·乙酸乙_ )。 IR 譜(取自 Zeiss Specoird Μ-80 ρ 光譜計)(KBr, 經濟部屮央梂準局κτ工消合作杜印製 9 cm-1 ) : 338 0 ( OH ) * 3030 ( C Η芳香族).298 U , 2960· 2920. 2860 ( CH 脂肪族)· i6U0, 159〇· 157 0. 1 500 (芳香族環振動、1090 ( C 〇 —C ) · ΐ〇〇0 〔C 一0 —(Η)〕. 750. 700 (單取代芳香族)《 .
4 —NMR 譜(肷自 Bruker WP 80 裝置·( DC 13 TMS 標準 S ppm) : 7.23 ( s ·5Η.芳香舞 Η ) · ft.64. 5.51 (d · 1H,3—H)»4.63 ( m . 1H. I —H.),3.9(> ( 1H , 7 - H ) · 3.60 ί lli . 3 ' -H ) 〇 本紙》尺度遑用 + 國國家«率(CNS)T4規格(21(1X297公t} — 16 — KI/7. 20,000^(11) ^20321 84, 7; Λ 6 Η 6 經濟部-5-央樣準局Η工消$:合作杜印3i 五、發明説明(14) 產品爲技型(exo )和橋型(endo )異媾物的1 : 1混‘合物〇 實施例10 擊造 13.14 —一 懲· 一 15 ( R ) —U —笨基一访.19 · 20 — 三原一 PGF2a〔式(π)化合物Ί 取4 —羧丁基Ξ呆基溴化鐄(147.2克· 332毫莫耳) 和特丁酵化鉀(186克· 1沾〇毫英耳)·添加於四g卩夹喃 ί 500 毫升)內含 3, 3a.4· 5,6,6a -六氧一 2. 5 — 二翔基 一 4 一〔 5’ 一苯基一3’(R) —羥基一 1 ’ —戊基"j _2Π—環戊 〔b〕呋喃(33.9克· 110·7毫莫耳)〔式(ffl)化合物〕 之溶液•溶液冷却至一25X:。混合物先在.2〇 »再於〇 C攪枠共計6小時•添加2 Μ硫酸氪納水溶液調節pH至 8 — 9 ·減壓蒸餾除去四氫b夫喃。殘渣加水(2〇〇奄什) 後•混合物冷却至室溫•將沉澱物過璩•以碳酸氫鈉飽和 溶液(各200毫升)洗二次•再用水(各咖毫升)洗二次。 合併水相用二氣甲院.(各150毫升)洗二次.·使用硫酸氣 鈉溶液調節pH値至3 — 4 ,再以乙酸乙_ (各5〇〇毫升) 萃収二次。合併乙酸乙酯相用鹽水(各丨㈤毫升)洗二次, 並蒸绒。濃稠懸浮g與丙酮t iflfl毫汁)振搖丨〇分鐘•將 沉澱物過濾•用之40: 25 (容匱比)混合液(各丨〇n 毫升)洗六次.濾液在減壓下蒸發•得攘的式(丑)化合物, 爲油質殘渣•產率85%,不用精製即可轉懸成式(化合物。 實施例11 製造 13.14 — 一寧一17 —苯基一18 · 19 · 20 — ΞΞ 原- PG F 2 cr 〔式(B )化合物〕 (請先閱jft背而之;i息菸項rhJvni^ t Γ 本紙》尺 A 遑《 + «家«攀(CHS>f4 规格(210X297 公:— 17 H1. 7, 2〇(〇〇〇^ (H) 經濟部屮央楳準局CX工消"合作社印製 五、發明説明U5)' 於THF ( 40公升)內含4 —羧丁基三笨基溴化锬( 5.72公斤)的攙拌懸浮液,在0 — 3 C氮流下加丁醇化 鉀(4· 49公斤),在室溫搅拌20分鐘β於所得紅橙$溶 液*在一 15/— 10C,添加THF ( 8公升)內的式(瓜) 化合物(1· 23公斤),混合物搛拌4 — 7小時(TLC監 控)❶反應混合物用水(25公升)稀釋,用甲苯(25公升) 洗淨*將有機相分麵。水層以氯仿(3 X 6公升)洗淨* ‘ 用2 Μ硫激氫轳(15公升)酸化,以AcOEt ( 18公升和 22 X 6公歼)接縯萃取《有機靥以15 %氯化納溶液(2 X 6公升)洗淨,在硫酸納(0.4公斤)上乾燥*過攄。沉 澱物用AcOEt (4公升)洗二次。在眞空內除去溶劑, 漿液與DIPE :丙_2 : 1 ( 18公升)振搖,使三苯基氧 化磷副產品結晶析出*過d除去,用[ΕΠΡΕ :丙爾1 : 1 (4 X 3公升)洗淨。有機曆在興^縮*得式(Π)化 合物,不經單離*卽直接用於次一步_ » 實施例12 製造 13 >14 —二簕一15 ( R )—17—苯基一18,19 ,20 — 三原一PGF2«異丙酯〔式U )化合物〕 於實施例10所得2 0 0毫升二甲基甲醯胺內含粗製13, 14 —二氫一15 ( R ) —17 —苯基一18,19 ^20 —三原一-PGF2a (50.64克,】10. 7莫耳)之溶液,添加無水碳酸鉀( 22.95克)和興内碘(37 . 55克* 221.4毫莫耳)後· 混合物在50 X:攪拌5小時,冉將反廳混合物傾人水(900 毫升)·2Μ硫酸氫納溶液(i20毫升)和乙酸乙酯( «I, 7. ?0,00〇ίΜ (!|) 經濟部十央榀準:ΤΑ工消件合作社印Μ 五、發明説明(16) 500毫升)的混合物。水相以另外乙酸乙酯(&00毫升) 萃取。合併乙酸乙_接續以2 %氣化鋰溶液(2 X 500毫 升)、飽扣碳酸氫納溶液(]〇0_升)和鹽水(2 X 200毫 升)洗淨*乾燥,乙酸乙_在滅_ F蒸Μ »油質残渣在含 矽凝膠C 1公斤)的管柱上層析,使用二氣甲烷扣異内_ 20 : 1混合物爲洗提液,再於矽凝膠(900克)上層析, 使用乙酸乙fig Μ丨己烷1 : 1混合物爲洗捉液,蒸驶後,得 無色油狀標的式(I )化合橡(16克),R f =0.4 2 (二 異丙醚/ 丙_/水 40 : 25: 1 ) * 〇〕D =十 34 0 ( c = 1, 乙腈)° Ϊ R譜(取自Zeiss Specord M-80型光譜計),使 用NaCl片材間之液膜法(cm-1) : 3400 ( OH),3060 (CH 芳香族),2990,2930,2860 ( (JH 丨丨旨昉族), 17 30 (C= 〇 ),1600, 1&00 (芳香族環振動)1U0 ( C — O —C ),750,700 (単取代芳香族)〇 lH — NMR 譜(取自 Brukei: AC 400 裝置,CDCi 3 , TMS 内標準,5 ppm ):7· 24 ( s,5H,芳香族H ),6,44 ( dd,lH, 6-H ) 5.41 C dd , 1 Η , 5—Η ) . 4.99 ( m,1 Η , 内_ ), 4-17 ( s 1 Η, 9 Η) » 3.94 ( (m,1 Η、15—Η ) 〇 賞施例13 製造 13,14--二氫一17— 笨基一18,19,2t)~二 fe —PGF 2“ 異丙酯〔.通式U)化合物,其中K爲興:内甚〕 > 1 Η , I! ----- Η 3-66 本紙》疋度遑和中國國家楳毕(CHS)T4規格(210X297公ft) _ ^ 81. 7. 20,()()0¾ (II) ............................................................................................物♦螭丨.丨 ιι ih 先 IVJ ih 背 之 f 磧 ι'ί- Λ:1 % 裝 線 ^10321 Λ (; Η β 經濟部屮失標準i.JA工消伢合作杜.''I'li 五、發明説明(17) 於溶人LMViF ( 6公升)内之式(丨丨)料丨媸品,加破酸鉀 (1 . 24公斤)和異内賴(1 . 1 5公开)》混合在5 -- 7小 時內加溫至45 — 50 €,完成反臟(TL C監控)。混合物用 £ . 水(2。8公升)稀櫸,以〗iVl ( B公升J酸化至1出 2 3。水層以A c ()1£ t :己烷3 : 2 ( :i X 9公升)萃収, 有機相經水洗(2 X 4公升),在硫i讀納(1 . 5公斤)丨: 乾燥,過Μ。沉澱物用A c < j E: t ( 2 X〖.5公升.)洗_, 眞空內濃縮,提供標的化合物,爲淡棕色汕。粗Μ汕(2. ? 公斤)矽凝膠經管柱層析二次。 粗製油溶人1:>丨Ρ :内喇:丨:1 ( 6公汁)内*在矽鉍 膠(70公斤)上敁析,使W L>丨Ρ Ε :内酬:]:1 ( 1 200公 升)爲洗提液,按K列順序收集五分邰:分別爲!( 2 8 0 公升),II (50公汁),Hi ( 10公升),IV ( 2 7 0公汁) 和V ( 70公升)。分别j IV含產品的主嬰部份(TL C監控), 在眞空內濃縮。所辩油溶人二Μ屮烷(6公升)内,在矽 凝膠(20公斤)上丨trf析*使用梯度洗提,接||这二Μ Ψ火完 (20公升),以及二氣屮规:與内_ 40 :(61。5公汁), 30 : 1 ( 20 . 7公升)相5 : 1 ( 60公汁)°按卜述順序收 集/£分邰:分別爲I ( 1 2厂公汗),丨丨(().5公升), Μ ( 〇。5公升.),IV ( ί2公_汁)111 V ( 5公汁〕。分部純 度以TLC祁HPLC硏究。設视分邰丨V爲純物。溶_在眞 空内除去,帶黄油以活性炭(υ. 11公斤)在與内_ ( 6 2 公升)内處埋,過铯,以舆内_( 2 X ϋ · δΰ公升)洗淨。 .濟押I/h丨)4空(0. 2巴)内,於40 m:除上,ίί/松的化ίΐ :,:»n>L間:λ.·ιι*τ·?->^;ν'ν: 本紙張尺度遑用十《«家採率(〇奶)^規格(2丨0父297公款)——;?0 HI 7. ^(),0()0¾ (II) 經濟部中央標準i'JH工消许合作杜.'ι'5ί 五、發明説明(18) 物,爲無色純物,略帶舆色之油,淹率(Ο . 96公斤,55 · 5% )。 實施例14 製造 3, Sa , 4 » 5, 6 , 6a .六氫-—2 }—5 —二抨基…-4 — 〔5 ,--苯基一3 / ( HJ --裡基一1 ,-.…iJcji .....Η-繼戌 〔b〕μΑ;喃〔式(I)化合物.) ' · 収無水甲苯(82毫升)内含3 » 3a s 4,H ti a ---A 1¾-- 2 -—氧代--4 --- L. 5 ’ --采―基…3 ' (K)…朽彳-.¾ -〜1 …戊 基〕-一 5 — ( 4 '—笨基笨甲醯氣基一 2 Η —環戊〔b〕炚η南 (6.8克,14毫莫珲)之溶液,冷却至一 80 t:,在冷却中 滴加溶入無水甲笨(31毫升)内之二舆丨基氫化鋁(9. 1 克,64毫莫坏)。反應混合物在一/0 扣一80 C Μ之溫度 攪拌,直至反腦完全(約1小時)。再將反疆混合物傾人 1 Μ硫酸氫納溶液(204毫汁)内,擬拌45分鐘,分相後, 水相內剩餘的產品萃取人乙酸乙酯內。合併後,有機相在 無水硫酸納上乾燥,丙移至矽凝膠(34兑)⑴中:(60 β 汁)Μ成的管杻。標的產品以Ψ: Η丨乙酸乙酯的浞合物洗 從。含純庵敁的分邰蒸狻辛科Ιι·ί U 2i) Ά ^)[ * .Ψί,ν. ΐϋ! JU 二異内醚(65鐘升)結品。所以畦敁坩.::與内ftl H丨乙酸乙 _的混合物洗淨*得標的式(1丨1)化合物(2 · 8兑),_| 點 103 - 106 C 〇 本紙張尺度遑用中《國家螵毕(CNS)f 4規格(210X297公釐)_.. 2\ H I. 7. 211,()()0¾ (II) 5¾
Η 3 式II之化合物
IR 操作條件: 儀器 範圍 樣品製法 光譜編號 ZEISS SPECORD M-80 4000 - 400 cm*1 膜式 6399 表1 I R光譜之指定 波長(cm_1) 4ta frn Ab 3400 vOH 3000 vCH 芳香族 2940 vCH 脂肪族 2860 -2650 OH(COOH) 1700 vC=0 1600 芳香族環振動 1560 1500 750 單取代芳香族 700 甲4(2】0 X 297公釐) 式Π之化合物 IH NMR 操作條件: 儀器 BRUKER AC-400 溶劑 CDCL3 光譜編號 2806 表2 Η* NMR光if之指定 信號(Sppm) 指定 質子數 偶合 7.36.6.97m 芳香族-Η 5 5.47m 6·Η 1 3J*11.6Hz 5.34 m 5-Η 1 4.74 b ΟΗ 4 4.13 b 9·Η 1 3.93 b 11-Η 1 3.6G m 15·Η 1 2.76 m 17-Ha 1 2.63 m 17-Hb 1 2.311 2.Η2 2 2.23 m 7.Η2 2 2.11 q 4-Η2 2 1.89.1.32 m 3-Η2ι8·Η(10^Η2 12·Η,13·Η2·14·Η2 16Η2 12 見圖2 ΟΗ 甲4(2】 ΟΧ 297公釐)
Claims (2)
- AT B7CT 1)7 中绩專丨,1範圓(修正本) 1. ~ 嵇通式 ΓΙ )所示 13 · 14 ·~•二骶—15 ( R ) _17 —苯基 叫8 · 19 . 20 —三原PG F 2 α酯頫之製法·其中r代表胞和或不 飽和直鏈或支鏈Ct —7 烷基一 OH八 ~~ 八/(XOR-in ^ 製法包拮將式(1)化合物之側鏈上的氧基還原 〇 (I)(VII) 所得式 ί ΎΙ)之 3.3a»4.5.6,6a —六彰一 2 — 氧代一 4 —〔 5 一笨基一3'(R)—羥基戊一1·—烯基〕一5 —(,一苯基苯 甲醯氧基)一—環戊〔b〕呋喃:經濟郎屮失標半^w工消费合作杜印製 _ (VI) _ OH 藉加氫轉化成式fV)之3.3a, 4. 5.6.6a —六氫一 2 —氧代 一 4 一〔 5’一苯基一 3’(R) —羥基一 1 ’ 一戊基〕—5 — ί · 4 1 — 笨基笨甲醯氧基)一211 —環戊〔b )呋喃 〇OPPB 0H (V) ........................-…:::..:1 ...............汊..............................打........严.................*?. f背面之注惫事項再填寫夂W; 本紙張尺度適用t« «家楳平(CNS),P4规格(210x297公祛> 一 22 310321 A< B7 CT [)7 屮二ί專H«LM將式(V)化合物還原成式(IV)之3. 3a . 4, 6 .6a —六_:—2 —羥甚一4 —〔 5 , —苯基一 3 , ( R )—羥基一 1 ’一戊丛:〕 一 5 —( 4’一笨基苯甲酿氧基)珊戊〔1>〕卩夫喃' :ίΟΡΡΒ OH (IV) 自式(IV)化合物除去保護基*得式(ffl)之3,3a. 4 ·5,6. 6a —六热一 2,5— 二 1¾丨站一4 一〔 5’一笨基一 3 (R)—拽鉴. —1 ’ 一戊基〕一2 Η —環戊〔b〕卩夫喃:(III) S將式(HI)化合物•使用4 —羧丁基Ξ苯基_化鏡轉化成 式(Π )之 13 .14 —二氫一15ί ΙΟ —17 --苯基一j8 · 19 , ?0— Ξ 原 PGF2«: • K. 郎t k Ιί Ψ ii 消 Λ·^.iiM印(II) 最後* W通式R — X —之化合物其中K总義同!_ :,而X 爲鹵索、硫酸酯、Φ磁_甚、Φ笨硪醯基,或任何適常摄 將式(丨丨)化合物轉變成诚式(I )所示丨3 ,丨4 —二g —is ( R ) 一 17 — 笨基一18 · 19,?0 — Ξ 原一 PGF 2 c» _ 敏奔。 本从度47丨丨t W W家«?屮(CNS),「4从!格(210x21)7公;« ) — ^ V. 叫1柳w Λ: *10321 c? ______1)7 ___ 六、中綺專彳ISLii)
- 2. SD中請專利範幽第1項之製法·包括使用三^^-基 敏硼化鋰或氯硼化鈉,將式(V«)化合物還k者。 3·δη中請專利範圍第1項之製法•包括在碳上鈀_媒 存在下*將式(ΥΙ )化合物加鎮者。 4. 6D中請專利範幽第1項之製法·包括在鈉鹽存在下. 將式(V[)化合物加氫者。 5. 如中諕專利範圍第1項之製法•包,括使用二異丁基 紐化錦•將式(V )烯酬化合物還原成式(权)烯醵化合物 者0 6. 如中請專利範圍第i項之製法•包括使用臟_鉀和 fp醇之混合物•自式(IV )化合物除去4 —笨基笨甲醯氣莊 保護基者。 7·如ΦΜ專利簕國第1項之製法•乜括令式(m)化合 物块i 4 —羧丁基三苯基滇化鱗•在財型溶劑內的特丁_化 鉀存在下反應者。 8.如申請專利範:® Μ 1項之製法.包括在衡_溶劑内 的摄酸鉀存在下•以興內-基碘將式(丨〖)的PGF 2«衍生物 烷化者。 a/mH請專利範画绾1項之魁法·包括在丨:〗式(1)化 合物開始的合成過程Φ ·將式(VI】(v)和(1|〗)化合物單轆 (分離)·必要時,利用再結晶加以精製者。 10.如Φ請堪利範腿第〗項之製法•仞括使用Φ苯內之 二與丁基氫化鋰·進行式(V)化合物之還原•並0所得式 (IV)烯_化合物除去4 —苯基笨甲醞氧基保護基者。 本紙it X度遴W十《 W家你i(i (CHS) |丨,4姒格(2ΙΟχ297公;ίί) 一找 A 7 B? C? D7 六、中锖Ψ HfeM 11·式(Dl) Ss.sad.s.eja-4 —〔 5’一呆·基 一 3 ' ( R )—邦基一1 ς氫一2,5 —二羥基一 戊基〕一2Η—繼戊〔b] μ夫喃。 12. 式(IV )之 3. 3 a . 4 · 5,6 . 6 a —六©— 2 —辨.基一4 —〔5 1 —笨基一 3 · ( 1〇 —羥基一 I * —戊鋥〕一5 — ( 4 —笨基笨 Φ醯氧基)一 2H —椴戊〔b〕卩大喃》 13. 式(V )之 3 . 3a , 4 , 5 . 6 * 6a —六 g — 2 —氧代一4 一 〔51—笨基一3(( R )—羥基一1,一戊基〕一5 —( 4 —笨基 苯ψ醯氧基)一;m—環戊〔b〕呋喃。 綺^^:^计而之:/£息事項再^_'"^.盯 ί'ίΐ 郎 t k \$ Π 工 «' /s. 杜 印 ii -1· 本紙》尺度適坩中國國家橾#(CNS)甲4塊格(210X297公梦)
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HU912092A HU212570B (en) | 1991-06-24 | 1991-06-24 | Process for producing 13,14-dihydro-15(r)-17-phenyl-18,19,20-trinor-pgf2alfa-isopropylester |
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US (1) | US5466833A (zh) |
EP (1) | EP0544899B1 (zh) |
JP (1) | JP2635213B2 (zh) |
KR (1) | KR0163022B1 (zh) |
CN (1) | CN1035764C (zh) |
AT (1) | ATE127450T1 (zh) |
AU (1) | AU656994B2 (zh) |
BG (1) | BG61261B1 (zh) |
CZ (1) | CZ287168B6 (zh) |
DE (1) | DE69204627T2 (zh) |
DK (1) | DK0544899T3 (zh) |
ES (1) | ES2078055T3 (zh) |
FI (1) | FI104895B (zh) |
GR (1) | GR3017874T3 (zh) |
HU (1) | HU212570B (zh) |
IE (1) | IE71645B1 (zh) |
IL (1) | IL102280A (zh) |
PL (1) | PL170728B1 (zh) |
RO (1) | RO117323B1 (zh) |
RU (1) | RU2099325C1 (zh) |
TW (1) | TW310321B (zh) |
UA (1) | UA39864C2 (zh) |
WO (1) | WO1993000329A1 (zh) |
Families Citing this family (23)
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US5510383A (en) † | 1993-08-03 | 1996-04-23 | Alcon Laboratories, Inc. | Use of cloprostenol, fluprostenol and their salts and esters to treat glaucoma and ocular hypertension |
US6294563B1 (en) | 1994-10-27 | 2001-09-25 | Allergan Sales, Inc. | Combinations of prostaglandins and brimonidine or derivatives thereof |
US6225348B1 (en) | 1998-08-20 | 2001-05-01 | Alfred W. Paulsen | Method of treating macular degeneration with a prostaglandin derivative |
IL134241A (en) | 2000-01-27 | 2006-06-11 | Finetech Pharmaceutical Ltd | Process for the preparation of latanoprost |
IL143477A (en) | 2001-05-31 | 2009-07-20 | Finetech Pharmaceutical Ltd | Process for the preparation of 17-phenyl-18,19,20-trinor-pgf2?? and its derivatives |
GB0112699D0 (en) * | 2001-05-24 | 2001-07-18 | Resolution Chemicals Ltd | Process for the preparation of prostglandins and analogues thereof |
US20110065129A1 (en) * | 2001-07-27 | 2011-03-17 | Lowe Derek B | Indane acetic acid derivatives and their use as pharmaceutical agents, intermediates, and method of preparation |
US20050119262A1 (en) * | 2003-08-21 | 2005-06-02 | Pharmacia Corporation | Method for preventing or treating an optic neuropathy with a cox-2 inhibitor and an intraocular pressure reducing agent |
ITRM20050231A1 (it) * | 2005-05-13 | 2006-11-14 | Technopharma Sa | Procedimento per la sintesi di derivati delle prostaglandine f. |
US7511168B2 (en) | 2006-01-18 | 2009-03-31 | Shih-Yi Wei | Processes and intermediates for the preparations of prostaglandins |
US8546114B2 (en) | 2006-01-18 | 2013-10-01 | Chirogate International Inc. | Processes for the preparation of optically active cyclopentenones and cyclopentenones prepared therefrom |
JP2008037782A (ja) * | 2006-08-04 | 2008-02-21 | Daiichi Fine Chemical Co Ltd | プロスタグランジン誘導体の製造方法 |
US7642370B2 (en) | 2006-08-07 | 2010-01-05 | Daiichi Fine Chemical Co., Ltd. | Method for preparing prostaglandin derivative |
IT1392492B1 (it) | 2008-12-24 | 2012-03-09 | Ind Chimica Srl | Processo per la purificazione del latanoprost, analogo sintetico della prostaglandina pgf2alfa. |
SI2523669T1 (sl) * | 2010-01-11 | 2017-05-31 | Inotek Pharmaceuticals Corporation | Kombinacija, komplet in metoda za zmanjšanje intraokularnega tlaka |
BR112012023749A2 (pt) | 2010-03-26 | 2016-08-23 | Inotek Pharmaceuticals Corp | método para reduzir a pressão intraocular em humanos utilizando n6-ciclopentiladenosina (cpa), derivados de cpa ou pró-fármacos desses |
EP2495235B1 (en) | 2011-03-04 | 2015-08-05 | Newchem S.p.A. | Process for the synthesis of prostaglandins and intermediates thereof |
PT2723714T (pt) | 2011-06-02 | 2017-08-18 | Chinoin Zrt | Novos processos para a preparação de amidas de prostaglandina |
HU231203B1 (hu) * | 2011-12-21 | 2021-10-28 | CHINOIN Gyógyszer és Vegyészeti Termékek Gyára Zrt. | Új eljárás travoprost előállítására |
KR20140128974A (ko) | 2012-01-26 | 2014-11-06 | 이노텍 파마슈티컬스 코포레이션 | ((2r,3s,4r,5r)-5-(6-(시클로펜틸아미노)-9h-퓨린-9-일)-3,4-디히드록시테트라히드로푸란-2-일) 메틸 니트레이트의 무수 다형체들 및 이들의 제조 방법들 |
HU230744B1 (hu) * | 2012-11-30 | 2018-01-29 | CHINOIN Gyógyszer és Vegyészeti Termékek Gyára Zrt. | Új eljárás travoprost előállítására |
SG11201506882YA (en) | 2013-03-15 | 2015-09-29 | Inotek Pharmaceuticals Corp | Ophthalmic formulations |
HU231214B1 (hu) * | 2014-03-13 | 2021-11-29 | CHINOIN Gyógyszer és Vegyészeti Termékek Gyára Zrt. | Új eljárás nagytisztaságú prosztaglandinok előállítására |
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BE786251A (fr) * | 1971-07-14 | 1973-01-15 | Ici Ltd | Nouveaux derives du cyclopentane |
US3971826A (en) * | 1972-07-13 | 1976-07-27 | Pfizer Inc. | 15-Substituted-ω-pentanorprostaglandins |
EP0569046B1 (en) * | 1988-09-06 | 2002-11-13 | Pharmacia Aktiebolag | Prostaglandin derivatives for the treatment of glaucoma or ocular hypertension |
-
1991
- 1991-06-24 HU HU912092A patent/HU212570B/hu unknown
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1992
- 1992-06-19 ES ES92915265T patent/ES2078055T3/es not_active Expired - Lifetime
- 1992-06-19 WO PCT/HU1992/000025 patent/WO1993000329A1/en active IP Right Grant
- 1992-06-19 UA UA94010047A patent/UA39864C2/uk unknown
- 1992-06-19 EP EP92915265A patent/EP0544899B1/en not_active Expired - Lifetime
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- 1992-06-19 AU AU22629/92A patent/AU656994B2/en not_active Expired
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- 1992-06-19 RU RU9393004874A patent/RU2099325C1/ru active
- 1992-06-19 AT AT92915265T patent/ATE127450T1/de active
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1993
- 1993-02-22 FI FI930773A patent/FI104895B/fi not_active IP Right Cessation
- 1993-02-23 BG BG97471A patent/BG61261B1/bg unknown
- 1993-02-24 CZ CZ1993271A patent/CZ287168B6/cs not_active IP Right Cessation
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1994
- 1994-10-06 US US08/319,327 patent/US5466833A/en not_active Expired - Lifetime
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1995
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Also Published As
Publication number | Publication date |
---|---|
HU212570B (en) | 1996-08-29 |
EP0544899A1 (en) | 1993-06-09 |
US5466833A (en) | 1995-11-14 |
AU2262992A (en) | 1993-01-25 |
HU912092D0 (en) | 1991-12-30 |
PL298127A1 (en) | 1994-01-24 |
CN1072408A (zh) | 1993-05-26 |
PL170728B1 (pl) | 1997-01-31 |
IE71645B1 (en) | 1997-02-26 |
DE69204627D1 (de) | 1995-10-12 |
GR3017874T3 (en) | 1996-01-31 |
IE922026A1 (en) | 1992-12-30 |
CZ287168B6 (en) | 2000-10-11 |
EP0544899B1 (en) | 1995-09-06 |
CZ27193A3 (en) | 1993-10-13 |
JP2635213B2 (ja) | 1997-07-30 |
ATE127450T1 (de) | 1995-09-15 |
JPH06500804A (ja) | 1994-01-27 |
WO1993000329A1 (en) | 1993-01-07 |
ES2078055T3 (es) | 1995-12-01 |
FI104895B (fi) | 2000-04-28 |
AU656994B2 (en) | 1995-02-23 |
IL102280A (en) | 1998-02-08 |
BG97471A (bg) | 1994-03-24 |
FI930773A (fi) | 1993-02-22 |
HUT62561A (en) | 1993-05-28 |
RU2099325C1 (ru) | 1997-12-20 |
FI930773A0 (fi) | 1993-02-22 |
DE69204627T2 (de) | 1996-05-02 |
BG61261B1 (en) | 1997-04-30 |
CN1035764C (zh) | 1997-09-03 |
DK0544899T3 (da) | 1995-10-23 |
UA39864C2 (uk) | 2001-07-16 |
KR0163022B1 (ko) | 1999-01-15 |
RO117323B1 (ro) | 2002-01-30 |
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