JP6925366B2 - 光学活性なベラプロストの製造方法 - Google Patents
光学活性なベラプロストの製造方法 Download PDFInfo
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- JP6925366B2 JP6925366B2 JP2018552171A JP2018552171A JP6925366B2 JP 6925366 B2 JP6925366 B2 JP 6925366B2 JP 2018552171 A JP2018552171 A JP 2018552171A JP 2018552171 A JP2018552171 A JP 2018552171A JP 6925366 B2 JP6925366 B2 JP 6925366B2
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- Prior art keywords
- acid
- beraprost
- formula
- optically active
- ester
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 229960002890 beraprost Drugs 0.000 title claims description 48
- CTPOHARTNNSRSR-APJZLKAGSA-N beraprost Chemical compound O([C@H]1C[C@@H](O)[C@@H]([C@@H]21)/C=C/[C@@H](O)C(C)CC#CC)C1=C2C=CC=C1CCCC(O)=O CTPOHARTNNSRSR-APJZLKAGSA-N 0.000 title claims description 33
- 238000004519 manufacturing process Methods 0.000 title claims description 10
- 239000002253 acid Substances 0.000 claims description 57
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 42
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 39
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 33
- 238000000034 method Methods 0.000 claims description 33
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- 239000000203 mixture Substances 0.000 claims description 18
- 238000002425 crystallisation Methods 0.000 claims description 17
- 230000008025 crystallization Effects 0.000 claims description 17
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- -1 Beraprost ester enantiomers Chemical class 0.000 claims description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 11
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 150000002148 esters Chemical class 0.000 claims description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 238000004587 chromatography analysis Methods 0.000 claims description 6
- 239000003480 eluent Substances 0.000 claims description 6
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 5
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 5
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 claims description 5
- 229960002510 mandelic acid Drugs 0.000 claims description 5
- 238000002441 X-ray diffraction Methods 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 150000007529 inorganic bases Chemical class 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 238000001228 spectrum Methods 0.000 claims description 4
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 3
- 239000012069 chiral reagent Substances 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 3
- 239000012454 non-polar solvent Substances 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 2
- MXWRMAVYGKENFI-UHFFFAOYSA-N 2-(2-acetylphenyl)-2-chloro-2-hydroxyacetic acid Chemical compound C(C)(=O)C1=C(C(C(=O)O)(O)Cl)C=CC=C1 MXWRMAVYGKENFI-UHFFFAOYSA-N 0.000 claims description 2
- DIWVBIXQCNRCFE-UHFFFAOYSA-N DL-alpha-Methoxyphenylacetic acid Chemical compound COC(C(O)=O)C1=CC=CC=C1 DIWVBIXQCNRCFE-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 2
- 235000001014 amino acid Nutrition 0.000 claims description 2
- 150000001413 amino acids Chemical class 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 230000032050 esterification Effects 0.000 claims description 2
- 238000005886 esterification reaction Methods 0.000 claims description 2
- YPGCWEMNNLXISK-UHFFFAOYSA-N hydratropic acid Chemical compound OC(=O)C(C)C1=CC=CC=C1 YPGCWEMNNLXISK-UHFFFAOYSA-N 0.000 claims description 2
- 239000001630 malic acid Substances 0.000 claims description 2
- 235000011090 malic acid Nutrition 0.000 claims description 2
- 238000002844 melting Methods 0.000 claims description 2
- 230000008018 melting Effects 0.000 claims description 2
- JJYKJUXBWFATTE-UHFFFAOYSA-N mosher's acid Chemical compound COC(C(O)=O)(C(F)(F)F)C1=CC=CC=C1 JJYKJUXBWFATTE-UHFFFAOYSA-N 0.000 claims description 2
- 239000002798 polar solvent Substances 0.000 claims description 2
- 238000010898 silica gel chromatography Methods 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- 239000011975 tartaric acid Substances 0.000 claims description 2
- 150000003892 tartrate salts Chemical class 0.000 claims description 2
- 150000007513 acids Chemical class 0.000 claims 1
- 125000004432 carbon atom Chemical group C* 0.000 claims 1
- 150000002170 ethers Chemical class 0.000 claims 1
- 239000000243 solution Substances 0.000 description 14
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 12
- 150000001299 aldehydes Chemical class 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 9
- 239000013078 crystal Substances 0.000 description 9
- 0 *C[C@@]1[C@]2c(cccc3C=O)c3O[C@]2C[C@@]1* Chemical compound *C[C@@]1[C@]2c(cccc3C=O)c3O[C@]2C[C@@]1* 0.000 description 8
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 6
- YTCZZXIRLARSET-VJRSQJMHSA-M beraprost sodium Chemical compound [Na+].O([C@H]1C[C@@H](O)[C@@H]([C@@H]21)/C=C/[C@@H](O)C(C)CC#CC)C1=C2C=CC=C1CCCC([O-])=O YTCZZXIRLARSET-VJRSQJMHSA-M 0.000 description 6
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 239000012141 concentrate Substances 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- MXWRMAVYGKENFI-JTQLQIEISA-N (2R)-2-(2-acetylphenyl)-2-chloro-2-hydroxyacetic acid Chemical compound C(C)(=O)C1=C([C@@](C(=O)O)(O)Cl)C=CC=C1 MXWRMAVYGKENFI-JTQLQIEISA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- ZSWFCLXCOIISFI-UHFFFAOYSA-N cyclopentadiene Chemical compound C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 description 4
- 125000004185 ester group Chemical group 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000012266 salt solution Substances 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-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
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 238000000113 differential scanning calorimetry Methods 0.000 description 3
- 150000002009 diols Chemical class 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 125000004043 oxo group Chemical group O=* 0.000 description 3
- 230000000704 physical effect Effects 0.000 description 3
- 238000000053 physical method Methods 0.000 description 3
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 3
- 159000000000 sodium salts Chemical class 0.000 description 3
- 239000011877 solvent mixture Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- SQHSJJGGWYIFCD-UHFFFAOYSA-N (e)-1-diazonio-1-dimethoxyphosphorylprop-1-en-2-olate Chemical compound COP(=O)(OC)C(\[N+]#N)=C(\C)[O-] SQHSJJGGWYIFCD-UHFFFAOYSA-N 0.000 description 2
- PNWFXPGGROADNS-UHFFFAOYSA-N 1,2-dibromocyclopentene Chemical compound BrC1=C(Br)CCC1 PNWFXPGGROADNS-UHFFFAOYSA-N 0.000 description 2
- MXYRECHYECATMB-UHFFFAOYSA-N 2-(benzylamino)-2-cyclohexylethanol Chemical compound C1CCCCC1C(CO)NCC1=CC=CC=C1 MXYRECHYECATMB-UHFFFAOYSA-N 0.000 description 2
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 2
- XBYGDAGWXPBGNY-UHFFFAOYSA-N 4-(1-benzofuran-5-yl)butanoic acid Chemical compound OC(=O)CCCC1=CC=C2OC=CC2=C1 XBYGDAGWXPBGNY-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 238000006130 Horner-Wadsworth-Emmons olefination reaction Methods 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 102000002397 Kinins Human genes 0.000 description 2
- 108010093008 Kinins Proteins 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical class OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 2
- 206010064911 Pulmonary arterial hypertension Diseases 0.000 description 2
- 150000000475 acetylene derivatives Chemical class 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 2
- KMPWYEUPVWOPIM-KODHJQJWSA-N cinchonidine Chemical compound C1=CC=C2C([C@H]([C@H]3[N@]4CC[C@H]([C@H](C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-KODHJQJWSA-N 0.000 description 2
- KMPWYEUPVWOPIM-UHFFFAOYSA-N cinchonidine Natural products C1=CC=C2C(C(C3N4CCC(C(C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-UHFFFAOYSA-N 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- GJVZWOMUTYNUCE-UHFFFAOYSA-N methyl 2-oxopyran-3-carboxylate Chemical compound COC(=O)C1=CC=COC1=O GJVZWOMUTYNUCE-UHFFFAOYSA-N 0.000 description 2
- UNFHYDYRCYLZJT-UHFFFAOYSA-N methyl 4-(1-benzofuran-5-yl)butanoate Chemical compound COC(=O)CCCC1=CC=C2OC=CC2=C1 UNFHYDYRCYLZJT-UHFFFAOYSA-N 0.000 description 2
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 2
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 2
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- UTNSTTZHNMPBEE-QMMMGPOBSA-N (2r)-2-chloro-2-hydroxy-2-phenylacetic acid Chemical compound OC(=O)[C@](O)(Cl)C1=CC=CC=C1 UTNSTTZHNMPBEE-QMMMGPOBSA-N 0.000 description 1
- VMKAFJQFKBASMU-QGZVFWFLSA-N (r)-2-methyl-cbs-oxazaborolidine Chemical compound C([C@@H]12)CCN1B(C)OC2(C=1C=CC=CC=1)C1=CC=CC=C1 VMKAFJQFKBASMU-QGZVFWFLSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical group C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 description 1
- BSWWXRFVMJHFBN-UHFFFAOYSA-N 2,4,6-tribromophenol Chemical compound OC1=C(Br)C=C(Br)C=C1Br BSWWXRFVMJHFBN-UHFFFAOYSA-N 0.000 description 1
- KMGUEILFFWDGFV-UHFFFAOYSA-N 2-benzoyl-2-benzoyloxy-3-hydroxybutanedioic acid Chemical compound C=1C=CC=CC=1C(=O)C(C(C(O)=O)O)(C(O)=O)OC(=O)C1=CC=CC=C1 KMGUEILFFWDGFV-UHFFFAOYSA-N 0.000 description 1
- VADKRMSMGWJZCF-UHFFFAOYSA-N 2-bromophenol Chemical class OC1=CC=CC=C1Br VADKRMSMGWJZCF-UHFFFAOYSA-N 0.000 description 1
- CTPOHARTNNSRSR-DIWPNRAGSA-N CC(CC#CC)[C@@H](/C=C/C1[C@H]2c3cccc(CCCC(O)=O)c3O[C@H]2C[C@H]1O)O Chemical compound CC(CC#CC)[C@@H](/C=C/C1[C@H]2c3cccc(CCCC(O)=O)c3O[C@H]2C[C@H]1O)O CTPOHARTNNSRSR-DIWPNRAGSA-N 0.000 description 1
- KJJSQLNNCPOREA-DMHWIWMTSA-N C[C@@H](CC#CC)C(/C=C/[C@H]1[C@@H]2c(cccc3CCCC(OC)=O)c3O[C@@H]2C[C@@H]1O)O Chemical compound C[C@@H](CC#CC)C(/C=C/[C@H]1[C@@H]2c(cccc3CCCC(OC)=O)c3O[C@@H]2C[C@@H]1O)O KJJSQLNNCPOREA-DMHWIWMTSA-N 0.000 description 1
- CTPOHARTNNSRSR-NOQAJONNSA-N C[C@@H](CC#CC)[C@@H](/C=C/[C@@H]1[C@H]2c(cccc3CCCC(O)=O)c3O[C@H]2C[C@H]1O)O Chemical compound C[C@@H](CC#CC)[C@@H](/C=C/[C@@H]1[C@H]2c(cccc3CCCC(O)=O)c3O[C@H]2C[C@H]1O)O CTPOHARTNNSRSR-NOQAJONNSA-N 0.000 description 1
- KJJSQLNNCPOREA-VIWJKOKZSA-N C[C@@H](CC#CC)[C@@H](/C=C/[C@@H]1[C@H]2c(cccc3CCCC(OC)=O)c3O[C@H]2C[C@H]1O)O Chemical compound C[C@@H](CC#CC)[C@@H](/C=C/[C@@H]1[C@H]2c(cccc3CCCC(OC)=O)c3O[C@H]2C[C@H]1O)O KJJSQLNNCPOREA-VIWJKOKZSA-N 0.000 description 1
- RCHAOWGXGUAHBE-KWUSUBJKSA-N C[C@H](CC#CC)C(/C=C/[C@H]1C2C(CCC=C3CCCC(O)=O)=C3OC2CC1C)O Chemical compound C[C@H](CC#CC)C(/C=C/[C@H]1C2C(CCC=C3CCCC(O)=O)=C3OC2CC1C)O RCHAOWGXGUAHBE-KWUSUBJKSA-N 0.000 description 1
- CTPOHARTNNSRSR-HYCREKKDSA-N C[C@H](CC#CC)C(/C=C/[C@H]1[C@@H]2c(cccc3CCCC(O)=O)c3O[C@@H]2C[C@@H]1O)O Chemical compound C[C@H](CC#CC)C(/C=C/[C@H]1[C@@H]2c(cccc3CCCC(O)=O)c3O[C@@H]2C[C@@H]1O)O CTPOHARTNNSRSR-HYCREKKDSA-N 0.000 description 1
- KJJSQLNNCPOREA-ADSYAEIHSA-N C[C@H](CC#CC)C(/C=C/[C@H]1[C@@H]2c(cccc3CCCC(OC)=O)c3O[C@@H]2C[C@@H]1O)O Chemical compound C[C@H](CC#CC)C(/C=C/[C@H]1[C@@H]2c(cccc3CCCC(OC)=O)c3O[C@@H]2C[C@@H]1O)O KJJSQLNNCPOREA-ADSYAEIHSA-N 0.000 description 1
- KJJSQLNNCPOREA-VYWODAIRSA-N C[C@H](CC#CC)[C@@H](/C=C/[C@@H]1[C@H]2c(cccc3CCCC(OC)=O)c3O[C@H]2C[C@H]1O)O Chemical compound C[C@H](CC#CC)[C@@H](/C=C/[C@@H]1[C@H]2c(cccc3CCCC(OC)=O)c3O[C@H]2C[C@H]1O)O KJJSQLNNCPOREA-VYWODAIRSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- BZKFMUIJRXWWQK-UHFFFAOYSA-N Cyclopentenone Chemical class O=C1CCC=C1 BZKFMUIJRXWWQK-UHFFFAOYSA-N 0.000 description 1
- 102100021202 Desmocollin-1 Human genes 0.000 description 1
- 238000005698 Diels-Alder reaction Methods 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- 101000968043 Homo sapiens Desmocollin-1 Proteins 0.000 description 1
- 101000880960 Homo sapiens Desmocollin-3 Proteins 0.000 description 1
- NHTMVDHEPJAVLT-UHFFFAOYSA-N Isooctane Chemical compound CC(C)CC(C)(C)C NHTMVDHEPJAVLT-UHFFFAOYSA-N 0.000 description 1
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 1
- 101150003085 Pdcl gene Proteins 0.000 description 1
- 208000005764 Peripheral Arterial Disease Diseases 0.000 description 1
- 208000030831 Peripheral arterial occlusive disease Diseases 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 238000007239 Wittig reaction Methods 0.000 description 1
- BRQFIORUNWWNBM-ZIAGYGMSSA-N [(1s,2r)-2-(benzylamino)cyclohexyl]methanol Chemical compound OC[C@H]1CCCC[C@H]1NCC1=CC=CC=C1 BRQFIORUNWWNBM-ZIAGYGMSSA-N 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 239000010405 anode material Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 238000005899 aromatization reaction Methods 0.000 description 1
- 150000008378 aryl ethers Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 description 1
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- ZDQWVKDDJDIVAL-UHFFFAOYSA-N catecholborane Chemical compound C1=CC=C2O[B]OC2=C1 ZDQWVKDDJDIVAL-UHFFFAOYSA-N 0.000 description 1
- XQTIWNLDFPPCIU-UHFFFAOYSA-N cerium(3+) Chemical compound [Ce+3] XQTIWNLDFPPCIU-UHFFFAOYSA-N 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012004 corey–bakshi–shibata catalyst Substances 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 150000005690 diesters Chemical class 0.000 description 1
- 125000004852 dihydrofuranyl group Chemical class O1C(CC=C1)* 0.000 description 1
- JVSWJIKNEAIKJW-UHFFFAOYSA-N dimethyl-hexane Natural products CCCCCC(C)C JVSWJIKNEAIKJW-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- YVPJCJLMRRTDMQ-UHFFFAOYSA-N ethyl diazoacetate Chemical compound CCOC(=O)C=[N+]=[N-] YVPJCJLMRRTDMQ-UHFFFAOYSA-N 0.000 description 1
- VGLKHVQPWGFXEG-NCJHBDPTSA-K europium(3+);(1z)-2,2,3,3,4,4,4-heptafluoro-1-(4,7,7-trimethyl-3-oxo-2-bicyclo[2.2.1]heptanylidene)butan-1-olate Chemical compound [Eu+3].C1CC2(C)C(=O)\C(=C(/[O-])C(F)(F)C(F)(F)C(F)(F)F)C1C2(C)C.C1CC2(C)C(=O)\C(=C(/[O-])C(F)(F)C(F)(F)C(F)(F)F)C1C2(C)C.C1CC2(C)C(=O)\C(=C(/[O-])C(F)(F)C(F)(F)C(F)(F)F)C1C2(C)C VGLKHVQPWGFXEG-NCJHBDPTSA-K 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-M isovalerate Chemical compound CC(C)CC([O-])=O GWYFCOCPABKNJV-UHFFFAOYSA-M 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 125000004492 methyl ester group Chemical group 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- GYNNXHKOJHMOHS-UHFFFAOYSA-N methyl-cycloheptane Natural products CC1CCCCCC1 GYNNXHKOJHMOHS-UHFFFAOYSA-N 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 238000005949 ozonolysis reaction Methods 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 150000003333 secondary alcohols Chemical class 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000008259 solid foam Substances 0.000 description 1
- 238000011916 stereoselective reduction Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229960001367 tartaric acid Drugs 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
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
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- 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
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- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
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- A—HUMAN NECESSITIES
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Description
活性なベラプロスト酸から、エタノール中の水酸化カリウムを用いて酢酸エチル中でカリウム塩も製造した。カリウム塩は水性エタノールから再結晶させた。
然しながら、エナンチオマーの物理的特性は同一であり、唯一の違いは、直線偏光の平面を反対方向に回転することである。
単純な物理的方法によるエナンチオマーの分離は、不可能である、というのは、それらの分離には、キラル補助物質が必要であるからである。
この目的のために、異性体4種を含有するラセミ体ベラプロストエステル(II)を、異性体4種を含有するラセミ体ベラプロスト酸(II)に加水分解する。
ベラプロスト酸のジアステレオマーを、繰り返し結晶化することにより分離する。結晶化は、ヘキサン:酢酸エチル溶媒混合物から行う。
キラル酸でエステル化したジアシル−ベラプロストエステルジアステレオマーは、もう既に、物理的方法、本発明の場合はクロマトグラフィーにより、分離し得る。
クロマトグラフィー分離は、ジクロロメタン:酢酸エチル溶媒混合物を使用して実行する。
活性があり、結晶性のベラプロスト酸は、所望により、その塩に変換しても良い。
この工程をスキーマ8で実証した。
a) rac −ベラプロスト酸
(1R*、2R*、3aS*、8bS*)−2,3,3a、8b−テトラヒドロ−2−ヒドロキシ−1−[(E、3S*、4RS)−3−ヒドロキシ−4−メチル−1−オクテン−6−インイル]−1H−シクロペンタ[b]ベンゾフラン−5−ブタン酸
収量:290.0g(75%)。
(1R*、2R*、3aS*、8bS*)−2,3,3a、8b−テトラヒドロ−2−ヒドロキシ−1−[(E、3S*、4S*)−3−ヒドロキシ−4−メチル−1−オクテン−6−インイル]−1H−シクロペンタ[b]ベンゾフラン−5−ブタン酸
フィルター上の湿潤結晶を再び結晶化させた。
結晶化は、HPLCで測定して、rac−ベラプロスト酸(α1/1及びα1/2異性体)の量が≦0.5%に減少するまで繰り返した。
要求される品質要件を実現するには、10回の結晶化を必要とした。
収量:82.0g(28.3%)
(1R*、2R*、3aS*、8bS*)−2,3,3a、8b−テトラヒドロ−2−ヒドロキシ−1−[(E、3S*、4S*)−3−ヒドロキシ−4−メチル−1−オクテン−6−インイル]−1H−シクロペンタ[b]ベンゾフラン−5−ブタン酸メチルエステル
収量:84.0g(99.0%)。
(1R、2R、3aS、8bS)−2,3,3a、8b−テトラヒドロ−2−[2R−アセトキシ−2−(2−クロロフェニル)−アセトキシ]−1−[(E、3S、4S)−3−[2R−アセトキシ−2−(2−クロロフェニル)−アセトキシ]−4−メチル−1−オクテン−6−インイル]−1H−シクロペンタ[b]ベンゾフラン−5−ブタン酸メチルエステル
収量:83.0g(48.9%)。
2R−アセトキシ−2−(2−クロロフェニル)酢酸
蒸発させた濃縮物をジイソプロピルエーテルとヘキサンとの混合物に室温で溶解させた。その溶液を結晶化が開始するまで撹拌し、次に更なる量のヘキサンを加えた。懸濁液を0℃に冷却して結晶化を完了させた。
収量:112.0g(91.4%)。
(1R、2R、3aS、8bS)−2,3,3a、8b−テトラヒドロ−2−ヒドロキシ−1−[(E、3S、4S)−3−ヒドロキシ−4−メチル−1−オクテン−6−インイル]−1H−シクロペンタ[b]ベンゾフラン−5−ブタン酸
蒸発した濃縮物をアセトン256mL中に溶解し、室温下、水2.57Lで結晶化させた。結晶を濾別し、フィルター上の湿潤生成物をアセトン143mL中、35〜40℃で繰り返し溶解させ、室温に冷却した後、水1.43Lで結晶化させた。その結晶を濾別し、乾燥させた。
その濾液にヘキサン凡そ1Lを室温下で滴加し、次いで結晶懸濁液を0℃に冷却して結晶化を完了させた。結晶を濾別し、洗浄し、乾燥させた。
収量:30.0g、(75.6%)、融点:61〜64℃
°2θ 相対強度(%)
6.1532 100.00
7.1324 51.49
12.2637 94.90
16.0125 82.22
19.1605 61.64
19.3288 82.45
19.4872 53.29
機器:
METTLER TOLEDO DSC1 STAReシステム
Stare basic V9.30
開始温度:150℃
終了温度:250℃
加熱速度:10℃/分、5℃/分、2℃/分
重量:2〜6mg
有孔アルミナポット(40μl)
Claims (20)
- 下記式Iの光学的に活性なベラプロスト及びその塩の製造方法であって、
IIIのラセミ体ベラプロスト酸を
得られたジアシル−ベラプロストエステルジアステレオマー、VIa及びVIb、
を意味する、を分離し、式VIaのベラプロストエステルを加水分解し、次に、得られた式Iの光学活性なベラプロスト酸を、結晶化し、かつ、所望により、その塩に変換することを特徴とする、前記の製造方法。 - 式IIの化合物の加水分解を、水混和性有機溶媒中、無機塩基の水溶液を用いて実施することを特徴とする、請求項1に記載の方法。
- 有機溶媒としてのアルコール類又は水混和性エーテル類を適用することを特徴とする請求項2に記載の方法。
- 有機溶媒としてのメタノール、エタノール,イソプロパノール、ジエチルエーテル又はテトラヒドロフランを適用することを特徴とする請求項3に記載の方法。
- 無機塩基として、水酸化ナトリウム、水酸化カリウムを適用することを特徴とする請求項2に記載の方法。
- 結晶化を極性・無極性溶媒混合物中で実施することを特徴とする請求項1に記載の方法。
- 酢酸エチル:ヘキサン混合物を用いて結晶化を実施することを特徴とする請求項6に記載の方法。
- 結晶化を数回繰り返すことを特徴とする、請求項1に記載の方法。
- キラルな試薬として、キラル酸又はその誘導体を適用することを特徴とする、請求項1に記載の方法。
- キラルな酸として、リンゴ酸、アミノ酸又は 酒石酸若しくは酒石酸誘導体、樟脳酸若しくは樟脳酸誘導体、メンチルオキシ酢酸、α−メトキシフェニル酢酸、α−メトキシ−α−トリフルオロメチルフェニル酢酸、2−フェニルプロピオン酸、マンデル酸若しくはマンデル酸誘導体の光学的に純粋なエナンチオマーを適用し得る請求項9に記載の方法。
- キラルな酸として、R−配置アセチル−クロロマンデル酸の光学的に純粋なエナンチオマーを適用し得る請求項10に記載の方法。
- 一般式VIa及びVIbのジアステレオマーをクロマトグラフィー法により分離することを特徴とする、請求項1に記載の方法。
- 大気圧シリカゲルクロマトグラフィーを適用することを特徴とする請求項12に記載の方法。
- 多成分勾配溶離液を用いてクロマトグラフィーを実施することを特徴とする請求項12に記載の方法。
- 溶離剤として、無極性成分及び極性成分を含む混合物を適用することを特徴とする請求項12に記載の方法。
- 溶離剤として、ジクロロメタン:酢酸エチルの混合物を適用することを特徴とする請求項15に記載の方法。
- 式Iの光学的に活性なベラプロスト酸を結晶形態で単離することを特徴とする、請求項1に記載の方法。
- 式Iの光学的に活性なベラプロスト酸をアセトン:水、及びジクロロメタン:ジイソプロピルエーテル:ヘキサン溶媒で結晶化することを特徴とする請求項17に記載の方法。
- 前記方法により製造した式Iの光学的に活性なベラプロスト酸の融点が61〜64℃で
あることを特徴とする、請求項17に記載の方法。 - 前記方法により製造した式Iの光学的に活性なベラプロスト酸のX線回折スペクトルの特性ピークが下記
°2θ 相対強度(%)
6.1532 100.00
7.1324 51.49
12.2637 94.90
16.0125 82.22
19.1605 61.64
19.3288 82.45
19.4872 53.29
であることを特徴とする、請求項17に記載の方法。
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HU1600232A HU231080B1 (hu) | 2016-04-05 | 2016-04-05 | Eljárás optikailag aktív Beraprost előállítására |
HUP1600232 | 2016-04-05 | ||
PCT/EP2017/057582 WO2017174439A1 (en) | 2016-04-05 | 2017-03-30 | Process for the preparation of optically active beraprost |
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US10577340B1 (en) * | 2018-11-26 | 2020-03-03 | Chirogate International Inc. | Beraprost-314d crystals and methods for preparation thereof |
US10577341B1 (en) | 2018-11-26 | 2020-03-03 | Chirogate International Inc. | Beraprost-314d monohydrate crystals and methods for preparation thereof |
CN111087284A (zh) * | 2019-12-27 | 2020-05-01 | 安庆润科生物医药科技有限公司 | 一种贝前列环素中间体的制备方法 |
CN113493430A (zh) * | 2020-03-19 | 2021-10-12 | 上海时莱生物技术有限公司 | 一种贝前列素及其盐的中间体及其制备方法 |
US11884640B2 (en) | 2021-06-02 | 2024-01-30 | Chirogate International Inc. | Processes and intermediates for the preparations of benzoprostacyclin analogues and benzoprostacyclin analogues prepared therefrom |
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HU227158B1 (en) | 2001-07-30 | 2010-09-28 | Chinoin Gyogyszer Es Vegyeszet | Production of beraprost ester by selective reduction |
HU227157B1 (en) | 2001-07-30 | 2010-09-28 | Chinoin Gyogyszer Es Vegyeszet | Production of beraprost ester by selective oxidation |
WO2008058766A1 (en) * | 2006-11-16 | 2008-05-22 | Bayer Schering Pharma Aktiengesellschaft | Ep2 and ep4 agonists as agents for the treatment of influenza a viral infection |
CN103717585B (zh) * | 2011-06-16 | 2015-11-25 | 琅歌生物技术股份有限公司 | 贝前列素的生产方法 |
US9388154B2 (en) | 2011-09-12 | 2016-07-12 | Lund Biotechnology PBC | Process for preparing synthetic prostacyclins |
CA2906528A1 (en) * | 2013-03-15 | 2014-09-25 | Gemmus Pharma Inc. | Beraprost isomer as an agent for the treatment of viral infection |
EP2978313B1 (en) | 2013-03-25 | 2018-02-21 | United Therapeutics Corporation | Process of making prostacyclin compounds with linker thiol and pegylated forms |
US10005753B2 (en) | 2014-05-20 | 2018-06-26 | Lung Biotechnology Pbc | Methods for producing beraprost and its derivatives |
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US20190062295A1 (en) | 2019-02-28 |
ES2925739T3 (es) | 2022-10-19 |
TWI698431B (zh) | 2020-07-11 |
HU231080B1 (hu) | 2020-07-28 |
EP3440065B1 (en) | 2022-06-08 |
CN109219601A (zh) | 2019-01-15 |
JP2019513729A (ja) | 2019-05-30 |
KR102373051B1 (ko) | 2022-03-11 |
EP3440065A1 (en) | 2019-02-13 |
WO2017174439A1 (en) | 2017-10-12 |
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US10421737B2 (en) | 2019-09-24 |
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