TWI698431B - 製備具光學活性之貝前列素（Ｂｅｒａｐｒｏｓｔ）之方法 - Google Patents
製備具光學活性之貝前列素（Ｂｅｒａｐｒｏｓｔ）之方法 Download PDFInfo
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- TWI698431B TWI698431B TW106110689A TW106110689A TWI698431B TW I698431 B TWI698431 B TW I698431B TW 106110689 A TW106110689 A TW 106110689A TW 106110689 A TW106110689 A TW 106110689A TW I698431 B TWI698431 B TW I698431B
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- Prior art keywords
- acid
- beraprost
- formula
- ester
- chiral
- Prior art date
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- 229960002890 beraprost Drugs 0.000 title claims abstract description 57
- 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 abstract description 38
- 238000000034 method Methods 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title abstract description 8
- 230000007062 hydrolysis Effects 0.000 claims abstract description 7
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 7
- 239000002253 acid Substances 0.000 claims description 52
- 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 36
- 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
- 238000002425 crystallisation Methods 0.000 claims description 18
- 230000008025 crystallization Effects 0.000 claims description 18
- 239000000203 mixture Substances 0.000 claims description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 13
- -1 beraprost ester Chemical class 0.000 claims description 13
- 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 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 10
- 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 9
- 238000004587 chromatography analysis Methods 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 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
- 239000003480 eluent Substances 0.000 claims description 6
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- 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 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
- 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
- 150000007513 acids Chemical class 0.000 claims description 3
- 239000012069 chiral reagent Substances 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
- 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 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
- 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
- 229960002510 mandelic acid Drugs 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
- 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
- LSPHULWDVZXLIL-QUBYGPBYSA-N camphoric acid Chemical compound CC1(C)[C@H](C(O)=O)CC[C@]1(C)C(O)=O LSPHULWDVZXLIL-QUBYGPBYSA-N 0.000 claims 2
- LSPHULWDVZXLIL-UHFFFAOYSA-N Camphoric acid Natural products CC1(C)C(C(O)=O)CCC1(C)C(O)=O LSPHULWDVZXLIL-UHFFFAOYSA-N 0.000 claims 1
- 125000004432 carbon atom Chemical group C* 0.000 claims 1
- 238000000926 separation method Methods 0.000 abstract description 3
- 230000032050 esterification Effects 0.000 abstract 1
- 238000005886 esterification reaction Methods 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 16
- 150000001299 aldehydes Chemical class 0.000 description 13
- 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
- 239000013078 crystal Substances 0.000 description 9
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 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 5
- 239000012141 concentrate Substances 0.000 description 5
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 5
- 0 C*CCCc1cccc2c1O[C@](CC1O)[C@@]2[C@@]1C=CC([C@](C)CC#CC)O Chemical compound C*CCCc1cccc2c1O[C@](CC1O)[C@@]2[C@@]1C=CC([C@](C)CC#CC)O 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
- ZSWFCLXCOIISFI-UHFFFAOYSA-N cyclopentadiene Chemical group C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 description 4
- 125000004185 ester group Chemical group 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 239000002994 raw material 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
- 238000003756 stirring Methods 0.000 description 4
- 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
- 238000002441 X-ray diffraction Methods 0.000 description 3
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 150000002009 diols Chemical class 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 125000004043 oxo group Chemical group O=* 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
- 238000001228 spectrum Methods 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- DSSYKIVIOFKYAU-XCBNKYQSSA-N (R)-camphor Chemical compound C1C[C@@]2(C)C(=O)C[C@@H]1C2(C)C DSSYKIVIOFKYAU-XCBNKYQSSA-N 0.000 description 2
- PNWFXPGGROADNS-UHFFFAOYSA-N 1,2-dibromocyclopentene Chemical compound BrC1=C(Br)CCC1 PNWFXPGGROADNS-UHFFFAOYSA-N 0.000 description 2
- 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 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 241000723346 Cinnamomum camphora Species 0.000 description 2
- 239000007818 Grignard reagent Substances 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
- 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
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 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
- 229960000846 camphor Drugs 0.000 description 2
- 229930008380 camphor Natural products 0.000 description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 2
- VYLVYHXQOHJDJL-UHFFFAOYSA-K cerium trichloride Chemical compound Cl[Ce](Cl)Cl VYLVYHXQOHJDJL-UHFFFAOYSA-K 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 150000004795 grignard reagents Chemical class 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 238000005259 measurement Methods 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
- 125000002496 methyl group Chemical group [H]C([H])([H])* 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
- 208000002815 pulmonary hypertension Diseases 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
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-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
- CSJCEQXZVMIHRX-UHFFFAOYSA-N 2,3-dibenzyl-2,3-dihydroxybutanedioic acid Chemical compound C=1C=CC=CC=1CC(O)(C(O)=O)C(O)(C(=O)O)CC1=CC=CC=C1 CSJCEQXZVMIHRX-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
- MXYRECHYECATMB-UHFFFAOYSA-N 2-(benzylamino)-2-cyclohexylethanol Chemical compound C1CCCCC1C(CO)NCC1=CC=CC=C1 MXYRECHYECATMB-UHFFFAOYSA-N 0.000 description 1
- VADKRMSMGWJZCF-UHFFFAOYSA-N 2-bromophenol Chemical class OC1=CC=CC=C1Br VADKRMSMGWJZCF-UHFFFAOYSA-N 0.000 description 1
- UTNSTTZHNMPBEE-UHFFFAOYSA-N 2-chloro-2-hydroxy-2-phenylacetic acid Chemical compound OC(=O)C(O)(Cl)C1=CC=CC=C1 UTNSTTZHNMPBEE-UHFFFAOYSA-N 0.000 description 1
- YVZVHNPTRCHYEY-UHFFFAOYSA-N 2-methylhex-4-ynoic acid Chemical compound CC#CCC(C)C(O)=O YVZVHNPTRCHYEY-UHFFFAOYSA-N 0.000 description 1
- 229910004664 Cerium(III) chloride Inorganic materials 0.000 description 1
- 235000001258 Cinchona calisaya Nutrition 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
- 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
- 238000010478 Prins reaction Methods 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
- 150000001298 alcohols Chemical class 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
- 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 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
- 239000003054 catalyst Substances 0.000 description 1
- ZDQWVKDDJDIVAL-UHFFFAOYSA-N catecholborane Chemical compound C1=CC=C2O[B]OC2=C1 ZDQWVKDDJDIVAL-UHFFFAOYSA-N 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 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 1
- 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 1
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 1
- 239000012004 corey–bakshi–shibata catalyst Substances 0.000 description 1
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Abstract
本發明提供製備式I具有光學活性之貝前列素的新方法，其由外消旋貝前列素烷基酯開始透過水解、對映異構物酯化、製備二醯基-貝前列素酯非對映異構物及其分離與水解進行。
Description
本專利申請的發明主題為製備式I的具有光學活性(1α2/1)的貝前列素(beraprost)及其鹽的方法：
市售的貝前列素鈉用於治療外周動脈疾病(Drugs,2002,62,107-133)且自2007年起其也用於治療肺動脈高壓(PAH)(J.Am.Coll.Cardiol.,2004,43,56S-61S)。
考慮到其化學結構貝前列素鈉為外消旋化合物，其為四種異構物的混合物。
Toray公司合成貝前列素的原料為環戊二烯(2)。對環戊二烯進行溴化，使二溴環戊烯(3)與三溴苯酚反應。由所得化合物形成的Grignard試劑在CuI催化劑存在下轉化為外消旋三環(rac-5)*，通過Prins反應由所述外消旋三環(rac-5)*製備外消旋二羥基衍生物(rac-6)。兩個羥基通過縮醛(rac-7)保護，上部鏈通過甲醯基丙酸甲酯(8)構建並氫化，將縮醛保護基裂解，對兩個羥基進行選擇性保護，將伯羥基釋放並氧化為醛(rac-9)。下部鏈通過使用外消旋膦酸酯(10)進行Horner-Wadsworth-Emmon(HWE)反應來構建，將所得外消旋烯酮衍生物(rac-11)的酮基還原為羥基，分離異構物(rac-12)，將酯基水解並分離酸的鈉鹽(Tetrahedron,1999,55,2449-2474)(方案1)。
為了進一步應用於治療領域而有必要使最有效的形式即活性貝前列素(314-d BPS=1α2/1)以光學純形式獲得。
根據Toray公司公開的方法，光學活性貝前列素鈉(1α2/1)如下製備：使由外消旋三環(rac-5)獲得的Grignard試劑與二氧化碳反應且所獲得的粗外消旋酸用手性胺((+)-順式-N-苄基-2-(羥基甲基)環己胺)解析，獲得光學活性酸(14)(Tetrahedron Asymmetry,1999,10,4099-4105)。
通過Prins反應在光學活性酸(14)的雙鍵上形成羥基和羥基甲基，通過催化氫化反應除去溴基，對酸官能團進行酯化(15)，游離羥基用THP基團保護，將酯基還原為醇，然後氧化為醛(16)，上部鏈通過Wittig反應構建，將酸轉化為甲酯，然後除去THP基團(17)，使上部鏈中的雙鍵飽和，對羥基進行選擇性保護，釋放伯羥基，然後氧化為醛以獲得光學活性形式(9)即rac-9。使醛與手性膦酸酯(S-10)反應，通過已描述的化學步驟將其轉化為具有光學活性的貝前列素鈉異構物。製備全部四種貝前列素鈉異構物，但出版物既沒有公開鹽的製備，也沒有公開鹽的特徵(Heterocycles,2000,53,1085-1110)(方案2)。
為了製備手性膦酸酯(S-10)，用手性胺(奎寧、辛可尼丁、1-苄基氨基-2-羥基乙基-環己烷(順式-胺))(18)對外消旋的2-甲基-4-己炔酸(rac-18)進行解析(Tetrahedron Asymmetry,2000,11,2981-2989)(方案3)。
專利申請案WO2012/174407A1公開了光學活性貝前列素的製備。合成原料為具有光學活性的Corey-內酯(19)，其在幾個步驟中轉化為經保護的二氫呋喃衍生物(20)。脫羧和芳化後，使20與3-甲氧羰基吡喃-2-酮(21)進行由Lantanida催化(Eu(hfc)3)的Diels-Alder反應，獲得含有苯並呋喃環的中間體(22)(方案4)。
為了構建上部鏈，將22中的甲酯基團分兩步轉化為醛，由醛(23)及(1-重氮基-2-氧代丙基)-膦酸二甲酯(24)獲得乙炔衍生物(25)，使其與重氮乙酸乙酯(26)反應，最後通過催化氫化使三鍵飽和(27)(方案5)。
釋放經保護的二醇27中的伯羥基並氧化為醛，使醛28與S-10膦酸酯反應，烯酮29中的氧代基團用硼氫化鈉氯化鈰(III)試劑還原或在(R)-(+)-CBS催化劑存在下用兒茶酚硼烷或硼烷二甲基硫醚試劑進行選擇性還原以獲得(30)，由仲醇除去保護基，用氫氧化鈉在甲醇中的溶液將酯轉化為鈉鹽(方案6)。
鈉鹽的物理特徵尚未公開。
亦由活性貝前列素酸在乙酸乙酯中用氫氧化鉀在乙醇中的溶液製備鉀鹽。將鉀鹽從含水乙醇中重結晶。
專利申請案WO2013/040068A1所公開的方法的原料為光學活性環戊烯酮衍生物31，其用溴代苯酚衍生物32進行烷基化。使芳基醚33環化，對氧代基團進行還原，獲得醇(34)。仲羥基用乙醯基保護，對雙鍵進行由PdCl2催化的氧化轉化，獲得衍生物35。通過對雙鍵進行臭氧分解，然後與三苯基膦反應，獲得醛9(方案7)。
使醛9與具有光學活性的R-10膦酸酯反應，烯酮R-11中的氧代基團在(R)-CBS催化劑存在下用硼烷四氫呋喃試劑選擇性還原，然後將酯基水解，獲得貝前列素酸的α1/1異構物，其不是活性異構物。
所述專利要求保護經由上述化學步驟通過使用相應的膦酸酯對映異構物(S-10和R-10)來製備每種貝前列素酸異構物。
貝前列素鈉鹽的製備在說明書中沒有描述。
根據專利說明書WO2015/179427的方法的原料為手性鹵素衍生物35，其在幾個步驟中轉化為經保護的二醇36。對二醇36中的游離羥基進行氧化，獲得醛，然後使醛與手性膦酸酯S-10反應。
R1=甲基或乙基
R2=H或適於對醇進行保護的基團
在R2=H和R2=叔丁基二甲基甲矽烷基的情況下亦進行立體選擇性還原。將活性酯37水解為酸。將酸(固體泡沫狀物)轉化為結晶性鉀鹽。
本申請的主題為製備式I的光學活性貝前列素及其鹽的方法：
其特徵在於對式II的外消旋貝前列素酯進行水解：
其中R表示C1-4直鏈或支鏈烷基，對所得式III的外消旋貝前列素酸進行結晶：
對所得式IIIa和IIIb的貝前列素酸對映異構物進行酯化：
使所得式IVa和IVb的貝前列素酯對映異構物與手性酸或酸衍生物反應：
其中R’表示C1-4直鏈或支鏈烷基， 對所得式VIa和VIb的二醯基-貝前列素酯非對映異構物進行分離：
其中R’具有與上述相同的含義且R2是指含有手性碳原子的酸殘基， 對式VIa的貝前列素酯進行水解且將所得式I的光學活性貝前列素酸以結晶形式分離，按需轉化為其鹽。
根據本發明的較佳實施方案，式II化合物的水解在水混溶性有機溶劑中用無機鹼的水溶液進行，可使用醇(甲醇、乙醇、異丙醇)或水混溶性醚(乙醚、四氫呋喃、二噁烷)或其它水混溶性溶劑(例如乙腈)作為溶劑，可使用氫氧化鉀、氫氧化鈉作為無機鹼。
結晶在極性-非極性溶劑混合物中較佳在乙酸乙酯：己烷混合物中進行且重複進行結晶數次。
可使用手性酸或酸衍生物的光學純對映異構物作為手性試劑，所述手性酸或酸衍生物為例如蘋果酸、氨基酸、酒石酸或酒石酸衍生物(例如二苯甲醯基酒石酸)、樟腦酸或樟腦酸衍生物(例如樟腦磺酸)、薄荷基氧基乙酸、α-甲氧基苯基乙酸、α-甲氧基-α-三氟甲基苯基乙酸、2-苯基丙酸、扁桃酸或扁桃酸衍生物(例如氯扁桃酸、乙醯基-氯扁桃酸(較佳R-乙醯基-氯扁桃酸))。
根據本發明，通過層析法較佳通過常壓矽膠層析法對式VIa和VIb的非對映異構物進行分離。
層析法可使用多組分梯度混合物作為洗脫劑來進行。可使用飽和烴(戊烷、己烷、庚烷、異辛烷、環己烷、甲基環己烷)或芳族烴(甲苯)或鹵代烴(二 氯甲烷)作為非極性溶劑組分。可使用醇(甲醇、乙醇、異丙醇)、酯(乙酸甲酯、乙酸乙酯、乙酸異丙酯)、醚(乙醚、甲基叔丁基醚)或酮類(丙酮、甲基乙基酮、甲基異丁基酮)溶劑混合物作為極性組分。較佳可使用二氯甲烷：乙酸乙酯混合物作為洗脫劑。
根據本發明的較佳實施方案，將式I的光學活性貝前列素酸以結晶形式分離。結晶使用丙酮：水和二氯甲烷：二異丙醚：己烷溶劑來進行。按需要將式I的貝前列素酸轉化為其鹽。
本發明的較佳實施方案如下詳述。
所述方法的原料為外消旋貝前列素酯(rac-BP-酯，II)，其可根據本申請人的專利HU-227158B1或專利申請案WO2003/011849製備。
外消旋貝前列素酯為4種異構物的比例為約1：1的混合物。
異構物α2/1與α2/2和異構物α1/1與α1/2為對映異構物，而異構物α2/1與α1/1和異構物α2/2與α1/2為非對映異構物。
本案方法的基礎是具有不同物理特徵的非對映異構物可通過物理方法(例如結晶、層析法)分離。
然而，對映異構物的物理特徵是相同的，區別僅在於它們使線性偏振光的平面在相反的方向上旋轉。
對映異構物不可能通過簡單的物理方法分離，它們的分離需要手性輔助材料。
在本案方法中，首先對非對映異構物對進行分離。
出於該目的，將含有4種異構物的外消旋貝前列素酯(II)水解為含有4種異構物的外消旋貝前列素酸(II)。
貝前列素酸的非對映異構物通過重複進行結晶來分離。從己烷：乙酸乙酯溶劑混合物中進行結晶。
重複進行結晶後，外消旋貝前列素酸僅含有α2/1貝前列素酸及其α2/2對映異構物。
由於對映異構物的分離需要手性輔助材料，因此首先用碘甲烷對含有α2/1和α2/2對映異構物對的rac-貝前列素酸進行酯化，然後用手性酸即R-乙醯基-氯扁桃酸(V)對rac-貝前列素酯(α2/1和α2/2異構物)中的游離羥基進行酯化。
用手性酸酯化的二醯基-貝前列素酯非對映異構物可通過物理方法在本申請中通過層析法分離。
色譜分離使用二氯甲烷：乙酸乙酯溶劑混合物來進行。
層析法的主要級分為由活性貝前列素酯(IVa)與R-乙醯基-氯扁桃酸形成的二酯(二醯基-貝前列素酯(α2/1))。
對酯基進行水解，得到活性貝前列素酸(貝前列素酸(α2/1),I)。
可通過重複進行結晶將結晶性活性貝前列素酸的異構物雜質的量降低至滿足質量要求所確定的限度的值。
從丙酮-水和二氯甲烷：二異丙醚：己烷混合物中進行結晶。
可按需將活性結晶性貝前列素酸轉化為其鹽。
所述方法顯示在方案8中。
本發明通過以下實施例說明，但不使本案申請專利範圍限於實施例所描述的方案。
圖1：結晶性光學活性貝前列素酸的X射線衍射譜。
由外消旋貝前列素酯(rac-BP-酯)製備活性貝前列素鈉(1α2/1)
a.)rac-貝前列素酸
(1R*,2R*,3aS*,8bS*)-2,3,3a,8b-四氫-2-羥基-1-[(E,3S*,4RS)-3-羥基-4-甲基-1-辛烯-6-炔基]-1H-環戊並[b]苯並呋喃-5-丁酸
將400.0g rac-BP-酯溶解在1.5L四氫呋喃中，在室溫在惰性氣氛中在攪拌下向溶液中添加6L 0.5M氫氧化鈉溶液。水解結束時，將反應混合物用水稀釋並用甲基叔丁基醚洗滌。用1M硫酸氫鈉溶液將水溶液酸化至pH
3。將酸性水溶液用甲基叔丁基醚萃取。將合併的有機相用飽和鹽溶液洗滌至中性，用硫酸鈉乾燥並蒸發。將蒸發的濃縮物溶解在乙酸乙酯中並用己烷結晶。產率：290.0g(75%)。
b.)rac-貝前列素酸(α2/1和α2/2異構物)(rac-BP-酸(α2/1和α2/2異構物))
(1R*,2R*,3aS*,8bS*)-2,3,3a,8b-四氫-2-羥基-1-[(E,3S*,4S*)-3-羥基-4-甲基-1-辛烯-6-炔基]-1H-環戊並[b]苯並呋喃-5-丁酸
在50℃將290g rac-BP-酸溶解在2.9L乙酸乙酯中，將溶液冷卻至室溫且在攪拌下向其中添加2.9L己烷。大量晶體析出後，向混懸液中再添加1.45L己烷，然後將其冷卻至0-10℃並在該溫度攪拌15分鐘。濾出晶體並洗滌。將濾器過濾的濕晶體再次結晶。重複進行結晶直到通過HPLC確定rac-貝前列素酸(α1/1和α1/2異構物)的量降低至
0.5%。為了滿足所期望的質量要求而需要進行10次結晶。產率：82.0g(28.3%)。
c.)rac-貝前列素酯(α2/1和α2/2異構物)(rac-BP-酯(α2/1和α2/2異構物))
(1R*,2R*,3aS*,8bS*)-2,3,3a,8b-四氫-2-羥基-1-[(E,3S*,4S*)-3-羥基-4-甲基-1-辛烯-6-炔基]-1H-環戊並[b]苯並呋喃-5-丁酸甲酯
將82g rac-BP-酸(α2/1和α2/2異構物)溶解在410mL二甲基甲醯胺中，向其中添加49.8g碳酸鉀和25.6mL碘甲烷。將混合物在40℃攪拌直到實現所期望的轉化。反應完成時，將混合物倒在酸性水上並用甲苯萃取產物。將合併的有機相用1M碳酸氫鈉溶液、水和飽和鹽溶液洗滌，用硫酸鈉乾燥並蒸發。產率：84.0g(99.0%)。
d.)二醯基-貝前列素酯(α2/1異構物)(二醯基-BP-酯(α2/1))
(1R,2R,3aS,8bS)-2,3,3a,8b-四氫-2-[2R-乙醯氧基-2-(2-氯苯基)-乙醯氧基]-1-[(E,3S,4S)-3-[2R-乙醯氧基-2-(2-氯苯基)-乙醯氧基]-4-甲基-1-辛烯-6-炔基]-1H-環戊並[b]苯並呋喃-5-丁酸甲酯
在惰性氣氛中將84.0g rac-BP-酯(α2/1和α2/2異構物)溶解在1.68L二氯甲烷(DCM)中，向溶液中添加9.95g二甲基氨基吡啶(DMAP)和107.1g R-乙醯基-氯扁桃酸且攪拌混合物直到溶解。完全溶解後，將反應混合物冷卻至(-)-10℃且添加100.8g二環己基碳二亞胺(DCC)。在不冷卻的情況下攪拌反應混合物直到實現所期望的轉化。反應結束時，過量的二環己基碳二亞胺用1M鹽酸破壞，濾出析出的物質且用乙酸乙酯洗滌。將合併的有機相先後用1M碳酸氫鈉溶液和飽和鹽溶液洗滌，用硫酸鈉乾燥並蒸發。將蒸發的濃縮物在矽膠柱上使用二氯甲烷：乙酸乙酯=20：1和二氯甲烷：乙酸乙酯=5：1洗脫劑混合物進行色譜分離。二醯基-BP-酯(α2/1)異構物在二醯基-BP-酯(α2/2)異構物後洗脫。蒸發含有二醯基-BP-酯(α2/1)異構物的主要級分。產率：83.0g(48.9%)。
R-乙醯基-氯扁桃酸的製備
2R-乙醯氧基-2-(2-氯苯基)乙酸
在室溫在攪拌下將100g R-氯扁桃酸溶解在95mL乙酸酐中。完全溶解後，將反應混合物真空濃縮，向濃縮物中添加甲苯，然後真空蒸餾出甲苯。在室溫將蒸發的濃縮物溶解在二異丙醚和己烷的混合物中。攪拌溶液直到開始結晶，然後添加更多量的己烷。將混懸液冷卻至0℃以完成結晶。產率： 112.0g(91.4%)。
e.)貝前列素酸(α2/1異構物)(BP-酸(α2/1)
(1R,2R,3aS,8bS)-2,3,3a,8b-四氫-2-羥基-1-[(E,3S,4S)-3-羥基-4-甲基-1-辛烯-6-炔基]-1H-環戊並[b]苯並呋喃-5-丁酸
將83.0g二醯基-BP-酯(α2/1)溶解在1L甲醇中。向溶液中添加0.84L 1M氫氧化鈉溶液且攪拌混合物直到進行水解。反應結束時，真空除去甲醇。將濃縮的溶液用1M硫酸氫鈉溶液酸化並用乙酸乙酯萃取。將合併的有機相用飽和鹽溶液洗滌，用硫酸鈉乾燥並蒸發。將蒸發的濃縮物溶解在256mL丙酮中並在室溫用2.57L水結晶。濾出晶體且將濾器過濾的濕產物在35-40℃重複溶解在143mL丙酮中且在冷卻至室溫後，用1.43L水結晶。濾出晶體並乾燥。在40℃將乾燥的晶體混懸在70mL二氯甲烷和525mL二異丙醚的混合物中，攪拌10分鐘並緩慢冷卻至25℃。濾出沒有溶解的晶體。在室溫向濾液溶液中滴加約1L己烷，然後將晶體混懸液冷卻至0℃以完成結晶。濾出晶體，洗滌並乾燥。產率：30.0g(75.6%)。熔點：61-64℃。
結晶性光學活性貝前列素酸的X射線衍射譜(圖1所示)的特徵峰：
X射線衍射譜的測量條件：起始位置[°2θ]：2.0084
結束位置[°2θ]：39.9864
測量溫度[℃]：25.00
陽極材料：Cu
K-α1[
]：1.54060
K-α2[
]：1.54443
上述物質的DCS曲線顯示在圖1中。
DSC測量條件：儀器：METTLER TOLEDO DSC1 STARe系統
Starebasic V9.30
方法：起始溫度：150℃
結束溫度：250℃
加熱速度：10℃/min、5℃/min、2℃/min
重量：2-6mg
多孔氧化鋁坩堝(40μl)
Claims (14)
- 一種製備式I的光學活性貝前列素及其鹽的方法：
- 如請求項1所述的方法，其特徵在於使用醇或水混溶性醚作為有機溶劑。
- 如請求項2所述的方法，其特徵在於使用甲醇、乙醇、異丙醇、乙醚或四氫呋喃作為有機溶劑。
- 如請求項1所述的方法，其特徵在於使用氫氧化鈉、氫氧化鉀作為 無機鹼。
- 如請求項1所述的方法，其特徵在於結晶使用乙酸乙酯：己烷混合物來進行。
- 如請求項1所述的方法，其特徵在於重複進行結晶數次。
- 如請求項1所述的方法，其特徵在於可使用以下物質的光學純對映異構物作為手性酸：蘋果酸、氨基酸、酒石酸或酒石酸衍生物、樟腦酸或樟腦酸衍生物、薄荷基氧基乙酸、α-甲氧基苯基乙酸、α-甲氧基-α-三氟甲基苯基乙酸、2-苯基丙酸、扁桃酸或扁桃酸衍生物。
- 如請求項7所述的方法，其特徵在於使用呈R構型的乙醯基氯扁桃酸作為手性酸。
- 如請求項1所述的方法，其特徵在於通過層析法對式VIa和VIb的非對映異構物進行分離。
- 如請求項9所述的方法，其特徵在於使用常壓矽膠層析法。
- 如請求項9所述的方法，其特徵在於層析法使用多組分梯度洗脫劑來進行。
- 如請求項11所述的方法，其特徵在於使用含有非極性和極性組分的混合物作為洗脫劑。
- 如請求項12所述的方法，其特徵在於使用二氯甲烷：乙酸乙酯混合物作為洗脫劑。
- 如請求項1所述的方法，其特徵在於式I的光學活性貝前列素酸用丙酮：水和二氯甲烷：二異丙醚：己烷溶劑進行結晶。
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