CA2202911A1 - Process for separating enantiomers from a racemic mixture - Google Patents
Process for separating enantiomers from a racemic mixtureInfo
- Publication number
- CA2202911A1 CA2202911A1 CA002202911A CA2202911A CA2202911A1 CA 2202911 A1 CA2202911 A1 CA 2202911A1 CA 002202911 A CA002202911 A CA 002202911A CA 2202911 A CA2202911 A CA 2202911A CA 2202911 A1 CA2202911 A1 CA 2202911A1
- Authority
- CA
- Canada
- Prior art keywords
- gel forming
- process according
- particles
- separated
- liquid
- 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.)
- Abandoned
Links
- 238000000034 method Methods 0.000 title claims abstract description 48
- 239000000203 mixture Substances 0.000 title claims abstract description 45
- 230000008569 process Effects 0.000 title claims abstract description 41
- 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 title claims abstract description 19
- 239000007788 liquid Substances 0.000 claims abstract description 42
- 239000002245 particle Substances 0.000 claims abstract description 35
- -1 polypropylene Polymers 0.000 claims abstract description 29
- 239000000126 substance Substances 0.000 claims abstract description 26
- 239000002671 adjuvant Substances 0.000 claims abstract description 22
- 238000000605 extraction Methods 0.000 claims abstract description 19
- 239000011148 porous material Substances 0.000 claims abstract description 13
- 239000012982 microporous membrane Substances 0.000 claims abstract description 9
- 239000004743 Polypropylene Substances 0.000 claims abstract description 8
- 229920001155 polypropylene Polymers 0.000 claims abstract description 8
- 239000012528 membrane Substances 0.000 claims description 23
- 239000002904 solvent Substances 0.000 claims description 23
- 239000000835 fiber Substances 0.000 claims description 16
- 229920000642 polymer Polymers 0.000 claims description 10
- 229920000344 molecularly imprinted polymer Polymers 0.000 claims description 8
- 230000002209 hydrophobic effect Effects 0.000 claims description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 230000008859 change Effects 0.000 claims description 3
- 238000010348 incorporation Methods 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 238000002425 crystallisation Methods 0.000 claims description 2
- 238000001704 evaporation Methods 0.000 claims description 2
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- 239000000463 material Substances 0.000 abstract description 7
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 30
- 239000000499 gel Substances 0.000 description 30
- 229920002678 cellulose Polymers 0.000 description 16
- 239000001913 cellulose Substances 0.000 description 14
- 235000010980 cellulose Nutrition 0.000 description 14
- RCJRILMVFLGCJY-UHFFFAOYSA-N 4-phenyl-1,3-dioxane Chemical compound O1COCCC1C1=CC=CC=C1 RCJRILMVFLGCJY-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 239000006185 dispersion Substances 0.000 description 7
- 239000012071 phase Substances 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- YQEZLKZALYSWHR-UHFFFAOYSA-N Ketamine Chemical compound C=1C=CC=C(Cl)C=1C1(NC)CCCCC1=O YQEZLKZALYSWHR-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 238000000926 separation method Methods 0.000 description 6
- 229920002284 Cellulose triacetate Polymers 0.000 description 5
- NNLVGZFZQQXQNW-ADJNRHBOSA-N [(2r,3r,4s,5r,6s)-4,5-diacetyloxy-3-[(2s,3r,4s,5r,6r)-3,4,5-triacetyloxy-6-(acetyloxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6s)-4,5,6-triacetyloxy-2-(acetyloxymethyl)oxan-3-yl]oxyoxan-2-yl]methyl acetate Chemical compound O([C@@H]1O[C@@H]([C@H]([C@H](OC(C)=O)[C@H]1OC(C)=O)O[C@H]1[C@@H]([C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](COC(C)=O)O1)OC(C)=O)COC(=O)C)[C@@H]1[C@@H](COC(C)=O)O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O NNLVGZFZQQXQNW-ADJNRHBOSA-N 0.000 description 5
- ATTZFSUZZUNHBP-UHFFFAOYSA-N Piperonyl sulfoxide Chemical compound CCCCCCCCS(=O)C(C)CC1=CC=C2OCOC2=C1 ATTZFSUZZUNHBP-UHFFFAOYSA-N 0.000 description 4
- 230000002349 favourable effect Effects 0.000 description 4
- 238000004382 potting Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 239000004721 Polyphenylene oxide Substances 0.000 description 3
- 239000003463 adsorbent Substances 0.000 description 3
- 230000001476 alcoholic effect Effects 0.000 description 3
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 3
- 235000001014 amino acid Nutrition 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 229960003299 ketamine Drugs 0.000 description 3
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 description 3
- 229960000991 ketoprofen Drugs 0.000 description 3
- 239000000178 monomer Substances 0.000 description 3
- ADIMAYPTOBDMTL-UHFFFAOYSA-N oxazepam Chemical compound C12=CC(Cl)=CC=C2NC(=O)C(O)N=C1C1=CC=CC=C1 ADIMAYPTOBDMTL-UHFFFAOYSA-N 0.000 description 3
- 229960004535 oxazepam Drugs 0.000 description 3
- 230000008929 regeneration Effects 0.000 description 3
- 238000011069 regeneration method Methods 0.000 description 3
- 230000008961 swelling Effects 0.000 description 3
- 229920001169 thermoplastic Polymers 0.000 description 3
- XHXUANMFYXWVNG-ADEWGFFLSA-N (-)-Menthyl acetate Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(C)=O XHXUANMFYXWVNG-ADEWGFFLSA-N 0.000 description 2
- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 description 2
- YQEZLKZALYSWHR-ZDUSSCGKSA-N (S)-ketamine Chemical compound C=1C=CC=C(Cl)C=1[C@@]1(NC)CCCCC1=O YQEZLKZALYSWHR-ZDUSSCGKSA-N 0.000 description 2
- SGTNSNPWRIOYBX-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 SGTNSNPWRIOYBX-UHFFFAOYSA-N 0.000 description 2
- FSVJFNAIGNNGKK-UHFFFAOYSA-N 2-[cyclohexyl(oxo)methyl]-3,6,7,11b-tetrahydro-1H-pyrazino[2,1-a]isoquinolin-4-one Chemical compound C1C(C2=CC=CC=C2CC2)N2C(=O)CN1C(=O)C1CCCCC1 FSVJFNAIGNNGKK-UHFFFAOYSA-N 0.000 description 2
- SVTBMSDMJJWYQN-UHFFFAOYSA-N 2-methylpentane-2,4-diol Chemical compound CC(O)CC(C)(C)O SVTBMSDMJJWYQN-UHFFFAOYSA-N 0.000 description 2
- PECYZEOJVXMISF-UHFFFAOYSA-N 3-aminoalanine Chemical compound [NH3+]CC(N)C([O-])=O PECYZEOJVXMISF-UHFFFAOYSA-N 0.000 description 2
- 229920000856 Amylose Polymers 0.000 description 2
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 229920000858 Cyclodextrin Polymers 0.000 description 2
- SRBFZHDQGSBBOR-IOVATXLUSA-N D-xylopyranose Chemical compound O[C@@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-IOVATXLUSA-N 0.000 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 description 2
- 239000004593 Epoxy Substances 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 230000005526 G1 to G0 transition Effects 0.000 description 2
- 101000800807 Homo sapiens Tumor necrosis factor alpha-induced protein 8 Proteins 0.000 description 2
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 2
- PWWVAXIEGOYWEE-UHFFFAOYSA-N Isophenergan Chemical compound C1=CC=C2N(CC(C)N(C)C)C3=CC=CC=C3SC2=C1 PWWVAXIEGOYWEE-UHFFFAOYSA-N 0.000 description 2
- 241001267704 Oxyphanes Species 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- 102100033649 Tumor necrosis factor alpha-induced protein 8 Human genes 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 239000000739 antihistaminic agent Substances 0.000 description 2
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 description 2
- 229940049706 benzodiazepine Drugs 0.000 description 2
- 150000001557 benzodiazepines Chemical class 0.000 description 2
- ISAOCJYIOMOJEB-UHFFFAOYSA-N benzoin Chemical compound C=1C=CC=CC=1C(O)C(=O)C1=CC=CC=C1 ISAOCJYIOMOJEB-UHFFFAOYSA-N 0.000 description 2
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- SOYKEARSMXGVTM-UHFFFAOYSA-N chlorphenamine Chemical compound C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Cl)C=C1 SOYKEARSMXGVTM-UHFFFAOYSA-N 0.000 description 2
- 229960003291 chlorphenamine Drugs 0.000 description 2
- 238000005345 coagulation Methods 0.000 description 2
- 230000015271 coagulation Effects 0.000 description 2
- ZPUCINDJVBIVPJ-LJISPDSOSA-N cocaine Chemical compound O([C@H]1C[C@@H]2CC[C@@H](N2C)[C@H]1C(=O)OC)C(=O)C1=CC=CC=C1 ZPUCINDJVBIVPJ-LJISPDSOSA-N 0.000 description 2
- VRSRXLJTYQVOHC-YEJXKQKISA-N corydaline Chemical compound C=1([C@H]2[C@H]3C)C=C(OC)C(OC)=CC=1CCN2CC1=C3C=CC(OC)=C1OC VRSRXLJTYQVOHC-YEJXKQKISA-N 0.000 description 2
- 239000003431 cross linking reagent Substances 0.000 description 2
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 235000013870 dimethyl polysiloxane Nutrition 0.000 description 2
- 238000006073 displacement reaction Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000007863 gel particle Substances 0.000 description 2
- QNVRIHYSUZMSGM-UHFFFAOYSA-N hexan-2-ol Chemical compound CCCCC(C)O QNVRIHYSUZMSGM-UHFFFAOYSA-N 0.000 description 2
- 229960001680 ibuprofen Drugs 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 2
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 2
- SERHXTVXHNVDKA-UHFFFAOYSA-N pantolactone Chemical compound CC1(C)COC(=O)C1O SERHXTVXHNVDKA-UHFFFAOYSA-N 0.000 description 2
- JYVLIDXNZAXMDK-UHFFFAOYSA-N pentan-2-ol Chemical compound CCCC(C)O JYVLIDXNZAXMDK-UHFFFAOYSA-N 0.000 description 2
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 description 2
- 229920003229 poly(methyl methacrylate) Polymers 0.000 description 2
- 229920000570 polyether Polymers 0.000 description 2
- 239000004926 polymethyl methacrylate Substances 0.000 description 2
- 229920002635 polyurethane Polymers 0.000 description 2
- 239000004814 polyurethane Substances 0.000 description 2
- 229960002957 praziquantel Drugs 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 229960003910 promethazine Drugs 0.000 description 2
- 230000000717 retained effect Effects 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 230000001360 synchronised effect Effects 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
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- 229960005080 warfarin Drugs 0.000 description 2
- PJVWKTKQMONHTI-UHFFFAOYSA-N warfarin Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 PJVWKTKQMONHTI-UHFFFAOYSA-N 0.000 description 2
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- XWTYSIMOBUGWOL-UHFFFAOYSA-N (+-)-Terbutaline Chemical compound CC(C)(C)NCC(O)C1=CC(O)=CC(O)=C1 XWTYSIMOBUGWOL-UHFFFAOYSA-N 0.000 description 1
- FMCGSUUBYTWNDP-ONGXEEELSA-N (1R,2S)-2-(dimethylamino)-1-phenyl-1-propanol Chemical compound CN(C)[C@@H](C)[C@H](O)C1=CC=CC=C1 FMCGSUUBYTWNDP-ONGXEEELSA-N 0.000 description 1
- VCVOSERVUCJNPR-RFZPGFLSSA-N (1r,2r)-cyclopentane-1,2-diol Chemical compound O[C@@H]1CCC[C@H]1O VCVOSERVUCJNPR-RFZPGFLSSA-N 0.000 description 1
- AAIBYZBZXNWTPP-NWDGAFQWSA-N (1r,2s)-2-phenylcyclohexan-1-ol Chemical compound O[C@@H]1CCCC[C@H]1C1=CC=CC=C1 AAIBYZBZXNWTPP-NWDGAFQWSA-N 0.000 description 1
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical group O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
- BUJAGSGYPOAWEI-SECBINFHSA-N (2r)-2-amino-n-(2,6-dimethylphenyl)propanamide Chemical compound C[C@@H](N)C(=O)NC1=C(C)C=CC=C1C BUJAGSGYPOAWEI-SECBINFHSA-N 0.000 description 1
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- VPSSPAXIFBTOHY-LURJTMIESA-N (2s)-2-amino-4-methylpentan-1-ol Chemical compound CC(C)C[C@H](N)CO VPSSPAXIFBTOHY-LURJTMIESA-N 0.000 description 1
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- LJRDOKAZOAKLDU-UDXJMMFXSA-N (2s,3s,4r,5r,6r)-5-amino-2-(aminomethyl)-6-[(2r,3s,4r,5s)-5-[(1r,2r,3s,5r,6s)-3,5-diamino-2-[(2s,3r,4r,5s,6r)-3-amino-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-6-hydroxycyclohexyl]oxy-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl]oxyoxane-3,4-diol;sulfuric ac Chemical compound OS(O)(=O)=O.N[C@@H]1[C@@H](O)[C@H](O)[C@H](CN)O[C@@H]1O[C@H]1[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](N)C[C@@H](N)[C@@H]2O)O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)N)O[C@@H]1CO LJRDOKAZOAKLDU-UDXJMMFXSA-N 0.000 description 1
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- MXUCIEHYJYRTLT-UHFFFAOYSA-N 1,2-dihydroacenaphthylen-1-ol Chemical compound C1=CC(C(O)C2)=C3C2=CC=CC3=C1 MXUCIEHYJYRTLT-UHFFFAOYSA-N 0.000 description 1
- KDVFAMTXJXDPAO-UHFFFAOYSA-N 1,3-di(anthracen-9-yl)butan-1-ol Chemical compound C1=CC=C2C(C(CC(O)C=3C4=CC=CC=C4C=C4C=CC=CC4=3)C)=C(C=CC=C3)C3=CC2=C1 KDVFAMTXJXDPAO-UHFFFAOYSA-N 0.000 description 1
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- PWMWNFMRSKOCEY-UHFFFAOYSA-N 1-Phenyl-1,2-ethanediol Chemical compound OCC(O)C1=CC=CC=C1 PWMWNFMRSKOCEY-UHFFFAOYSA-N 0.000 description 1
- HXKKHQJGJAFBHI-UHFFFAOYSA-N 1-aminopropan-2-ol Chemical compound CC(O)CN HXKKHQJGJAFBHI-UHFFFAOYSA-N 0.000 description 1
- LEBVLXFERQHONN-UHFFFAOYSA-N 1-butyl-N-(2,6-dimethylphenyl)piperidine-2-carboxamide Chemical compound CCCCN1CCCCC1C(=O)NC1=C(C)C=CC=C1C LEBVLXFERQHONN-UHFFFAOYSA-N 0.000 description 1
- HJVFIQKBLPQQDY-UHFFFAOYSA-N 1-ethyl-2-(4-hydroxyphenyl)-3-methyl-1h-inden-5-ol Chemical compound CC=1C2=CC(O)=CC=C2C(CC)C=1C1=CC=C(O)C=C1 HJVFIQKBLPQQDY-UHFFFAOYSA-N 0.000 description 1
- BBOUFHMHCBZYJJ-UHFFFAOYSA-N 1-ethyl-2-(4-hydroxyphenyl)-3-methyl-3h-inden-5-ol Chemical compound CC1C2=CC(O)=CC=C2C(CC)=C1C1=CC=C(O)C=C1 BBOUFHMHCBZYJJ-UHFFFAOYSA-N 0.000 description 1
- RTCUCQWIICFPOD-UHFFFAOYSA-N 1-naphthalen-1-ylethanamine Chemical compound C1=CC=C2C(C(N)C)=CC=CC2=C1 RTCUCQWIICFPOD-UHFFFAOYSA-N 0.000 description 1
- CDRQOYRPWJULJN-UHFFFAOYSA-N 1-naphthalen-1-ylethanol Chemical compound C1=CC=C2C(C(O)C)=CC=CC2=C1 CDRQOYRPWJULJN-UHFFFAOYSA-N 0.000 description 1
- DVWQNBIUTWDZMW-UHFFFAOYSA-N 1-naphthalen-1-ylnaphthalen-2-ol Chemical compound C1=CC=C2C(C3=C4C=CC=CC4=CC=C3O)=CC=CC2=C1 DVWQNBIUTWDZMW-UHFFFAOYSA-N 0.000 description 1
- WAPNOHKVXSQRPX-UHFFFAOYSA-N 1-phenylethanol Chemical compound CC(O)C1=CC=CC=C1 WAPNOHKVXSQRPX-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D61/00—Processes of separation using semi-permeable membranes, e.g. dialysis, osmosis or ultrafiltration; Apparatus, accessories or auxiliary operations specially adapted therefor
- B01D61/24—Dialysis ; Membrane extraction
- B01D61/246—Membrane extraction
- B01D61/2461—Membrane extraction comprising multiple membrane extraction steps
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D61/00—Processes of separation using semi-permeable membranes, e.g. dialysis, osmosis or ultrafiltration; Apparatus, accessories or auxiliary operations specially adapted therefor
- B01D61/007—Separation by stereostructure, steric separation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B57/00—Separation of optically-active compounds
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Water Supply & Treatment (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Health & Medical Sciences (AREA)
- Urology & Nephrology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Proposed is a process for separating enantiomers from a racemic mixture by countercurrent extraction using at least two substances, one of them a liquid in which the racemic mixture to be separated is present, the other containing a chiral adjuvant which is combined with or part of a gel forming substance in the form of discrete particles in a liquid separated from the countercurrently flowing liquid containing the racemate to be separated by a microporous membrane having a pore size such that the pores can no longer be penetrated by the gel forming particles separated on conclusion of the extraction, followed by the setting free therefrom of one of the enantiomers under the influence of a stimulus, after which the particles are re-incorporated into the extracting process if so desired. During the extraction process the gel forming material preferably is in the swollen state, taking the form of discrete particles, and flows through a microporous membrane preferably made of polypropylene.
Description
W O 96/1189~ PCT~EP95/04063 PROCESS FOR SEPARATING ENANTIOMERS FROM A RACEMIC MIXTURE
The invention pertains to a process for separating enantiomers from a racemic mixture by countercurrent extraction using at least two substances, one of them a liquid in which the racemic mixture to be separated is present, the other containing a chiral adjuvant.
Such a process has earlier been proposed in WO 94/07814. The process disclosed therein specifies the countercurrent extraction of a racemic mixture using at least two liquids at least one of which is chiral or contains a chiral adjuvant, said liquids being wholly miscible and separated from each other by a phase with which they are immiscible.
The separating, immiscible phase can be incorporated into a solid carrier which may be porous or not, preferably in the form of a hollow fibre.
It has been found that most racemic mixtures can be separated very effectively by the process disclosed in said document, providing that the racemate is not only readily soluble in the extracting liquids, but also in the phase which separates these liquids and is immiscible therewith. Examples of substances which cannot be separated by the known process, or can be separated only with great difficulty, are chiral substances which do not have a functional group, such as an amino group, keto group, ester or hydroxyl group, as well as certain aromatics.
There is need for a separating technique giving the same result with fewer separating steps also when the only chiral adjuvant available for separating a racemic mixture is one which results in a very narrow coefficient of distribution, so that a large number of separating steps is required to attain a high degree of purity.
.
Accordingly, there is practical need for a process for separating racemic mixtures which can be separated by the known technique only with difficulty.
SU8STITUTE SHEET (RULE 26) The invention now provides a process by which said need can be satisfied for the most part.
The invention is characterised in that in the process of the known type mentioned in the opening paragraph ~he chiral adjuvant is combined with o ~ t of a gel forming substance in the form of ~ .s~C4~
discret~ ticles in a 1iquid separated from the countercurrently flowing liquid containing the racemate to be separated by a microporous membrane having a pore size such that the pores can no longer be penetrated by the gel forming particles separated on conclusion of the extraction, followed by the setting free therefrom of one of the enantiomers under the influence of a stimulus, after which the particles are re-incorporated into the extracting process if so desired.
It should be noted that the use of a chiral adjuvant combined with a gel-forming substance in the form of discrete particles for separating a racemic mixture from a liquid is known in itself from an article by Masakazu Negawa and Fumihiko Shoji in J. Chromatog. 590 (1992), 113-117.
In it the use is described of a simulated moving bed adsorption (SMBA) technique to optical resolution using eight columns packed with chiral stationary phases. Although, in theory, the authors make mention of a real countercurrent process in which the gel forming stationary phase continuously moves in a direction opposite to that in which the racemate liquid moves, the only practical embodiment used is a simulated moving bed.
A major advantage of the now proposed process is that the liquid containing the racemic mixture need no longer be separated from the chiral adjuvant-containing phase by a phase immiscible therewith, - enabling a much more rapid exchange than was possible with the known process.
A~NDED SHEET
IPEA~P
CA 022029ll l997-04-l6 W O 96/11894 PCT~EP95/04063 A further advantage of the now proposed process is that because the chiral adjuvant is combined with or part of the gel forming substance, its separation, and that of the enantiomer extracted therewith, can be simplified significantly. The chiral adjuvant may be covalently bonded to the gel forming substance in that case. Another possibility is that the chiral adjuvant is a gel forming substance in the form of a molecularly imprinted polymer (MIP) prepared against one of the enantiomers to be separated.
In order to prevent the gel forming particles from penetrating the pores of the membrane during the extracting process, they are in the swollen state. The enantiomer incorporated into them during the extraction is set free again by using a stimulus. This stimulus may take the form of a change in temperature, in pH, in salt concentration, electric or magnetic field, and/or solvent composition.
After having been released from the gel forming particles, the enantiomer is generally extracted and, if so desired, purified further by evaporation of the extracting agent and/or crystallisation.
The gel forming substance is present in the form of discrete particles. These particles may be of 50 nm to 300 ym in size, though particles of a larger size also qualify. When larger particles are employed, preference is given to an embodiment in which the gel forming substance no longer comprises the entire particle but is provided on a carrier and physically, preferably covalently, bonded thereto. In such a process favourable results can be attained both when the gel forming substance is provided in the pores of a carrier and when it is provided on its surface. The carriers can be of either inorganic or organic material. Examples of inorganic carriers are ~-alumina, y-alumina, carbon, ceramic material, or combinations thereof such as alumina on a porous carbon carrier. Examples of porous organic carriers based on organic polymers have been described in detail in US-A-4 247 498 and US-A-4 519 909.
SU~STITUTE SHEET (RULE 26) W O96/1189~ PCT/EP95/04063 When particles having a comparatively high specific weight are used, the force of gravity can be employed to effect countercurrent flow in relation to the liquid flowing in the opposite direction.
The porous membrane to be used in the process according to the invention preferably has the largest possible pores, with the proviso that their maximum size is selected such that the pores are just too small to be penetrated by the swollen particles.
When employing a porous membrane preference is given to the use of a membrane having the same polarity as the extracting liquid. More particularly, when the polarity of the extracting liquid does not correspond to the membrane's, favourable results can be attained usir,g a process in which the membrane, depending on whether the liquid flowing around it has polar or apolar properties, is rendered hydrophilic or hydrophobic by the chemical route, say, by grafting with an acrylate compound.
However, preference is given to a process in which the membrane, depending on whether the liquid flowing around it has polar or apolar properties, is rendered hydrophilic or hydrophobic by physical modification, for instance by treatment with a surface-active compound.
In another embodiment the liquid flowing around the microporous membrane is tailored to the polarity of the membrane by the incorporation of a small amount of a compound compatible with the membrane. Thus when a porous membrane based on polypropylene is used, very favourable results are attained by incorporating 0,1 to 5 wt.% of n-hexane into the alcoholic extracting liquid.
Both non-thermoplastic polymers, such as cuprophane, cellulose acetate, cellulose triacetate, cellulose nitrate, polytetrafluorethylene, polyacrylonitrile or (regenerated) cellulose, SUBSTITUTE SHEE~RULE 26) , PCT~P95/0~063 and thermoplastic materials, such as polyolefins, condensation polymers, oxidation polymers, and mixtures thereof can be employed when making the membranes to be used according to the invention.
Examples of suitable polymers to make membranes from are low-pressure and high-pressure polyethylene, polypropylene, polystyrene, polyvinyl chloride, polyvinylidene chloride, acrylonitrile-butadiene-styrene-terpolymer, styrene-acrylonitrile-copolymer, styrene-butadiene-copolymer, poly(4-methyl-pentene-1), polybutene, polyvinyl butyral, chlorinated polyethylene, polyvinyl acetate, polyvinyl alcohol, polymethyl methacrylate, polymethyl acrylate, polyimide, polyvinyl disulphide, polyphenylene oxide, polyethylene terephthalate, polybutylene terephthalate, polyaramid, copolyetheresters based on butylene terephthalate and polyethylene oxide glycol having a molecular weight in the range of 800 to 6000, polyamide 6, polyamide 6,6, polyamide 11, polyamide 12, polycarbonate, polyether urea, polypiperazine, polypiperazine amide, polyvinyl pyrrolidone, polyether sulphone, polysulphone, and the polydimethyl siloxanes (PDMS).
The preparation of microporous membranes from thermoplastic polymers has been described in, int. al., US-A-4 098 901. For the preparation of hollow fibre membranes from thermoplastic polymers reference may be had to US-A-4 564 488.
Highly favourable results can be obtained using a polypropylene hollow fibre membrane.
The hollow fibre membranes are commonly arranged in a hollow fibre module. The gel forming particles will then flow through the hollow fibres as a rule, while the racemic mixture flows around them. In contrast to the separating processes disclosed in W0 94/07814, n generally only one chiral adjuvant is used in the process according to the present invention. Of course, it is still possible to make use of a symmetrical system such as described in the aforesaid document, SUBSTITUTE SHEET (RULE 26) ~CR 2'31 R
though in that case two gel forming substances which differ only in terms of discrimination by the chiral adjuvant have to be available.
Generally, there will be selected a m~croporous membrane of minimal thickness, commonly in the range of 0,1 ~m to 1 mm, with ~reference being given to a membrane thickness in the range of 1 ~m to 00 ~m.
According to the invention, there will always be at least one gel forming substance which is chiral in itself, is covalently bonded to a chiral adjuvant, or is a molecularly imprinted polymer (MrP) prepared against one of the enantiomers to be separated.
The liquid employed as a solvent for the racemate to be separated is one which is capable of swelling the gel forming substance. Generally speaking, the person skilled in the art will know which solvent or combination of solvents to select.
The chiral adjuvant is incorporated into or part of the sel forming material. As a gel forming material which is chiral in itself may be mentioned cellulose triacetate. Another example is a gel forming polyester into the polymer chain of which, say, a chiral diol or dicarboxylic acid has been incorporated. Alternatively, the gel forming material can be combined with a chiral adjuvant.
New synthetic routes to optically active monomers and polymers are disclosed by Kevin D. Belfield et al. in TRIP Vol. 3, No. 6 (June 1995), 180-185. The following compounds, including their salts and derivatives, are eligible for incorporation into the gel forming material as chiral adjuvant:
1-aminoethyl phosphonic acid, 2-bromopropionic acid, lactic acid, epichlorohydrin, serine, 2,3-diaminopropionic acid, propylene oxide, alaninol, 1-amino-2-propanol, aspartic acid, malic acid, tartaric acid, 5-(hydroxymethyl)-2-pyrrolidinone, proline, cis-3-hydroxyproline, trans-1,2-cyclopentane diol, 2-methyl butyric 4h~NDED ~.Y~
r PCT~EP95/0~063 t acid, a-hydroxyisovaleric acid, methyl-3-hydroxybutyrate, methyl B-hydroxyisobutyrate, arabinose, lyxose, ribose, xylose, prolinol, alanine ethyl ester, norvaline, vali ne, methionine, penicillamine, methionine sulphoxide, 2-pentanol, 2,4-pentane diol, arabitol, 2-methyl-1-butylamine, valinol, 1,2-diaminocyclohexane, a-methylbenzylamine, 1-amino-2-(methoxymethyl)pyrrolidine, lysine, arginine, 2-hexanol, 2-methyl-2,4-pentane diol, leucinol, 2-fluorophenyl alanine, 3-fluorophenyl alanine, 5-fluorotryptophan, 5-hydroxytryptophan, 2-benzyloxy-1,3,4-butane triol, isopropyl noradrenaline, 1-(1-naphthyl)ethanol, 1-(1-naphthyl)ethylamine, trans-2-phenyl-1-cyclohexanol, thyroxine, menthyl acetate, N-(3,5-dinitrobenzoyl)-a-phenyl-glycine, N-methyl ephedrine, 3,5-dinitro-N-(1-phenylethyl)-benzamide, and ~,a-diphenyl prolinol.
The process according to the invention permits the separation of racemates of the most widely varying nature. The racemates may be compounds of the pharmacon group, as well as synthons, aromatics, and flavourings, or pesticides.
Although, according to the invention, a very wide variety of chiral, gel forming materials is eligible for use in separating an even wider variety of racemic mixtures, the use of certain combinations of chiral, gel forming materials and racemic mixtures to be separated is greatly preferred. Especially eligible are those chiral polymers which display a strong interaction with the racemic substances to be separated. Such strong interaction may be due to hydrogen bridging or Coulomb and/or Van der Waals forces, but may also be due to, e.g., the fact that one of the enantiomers to be separated is more readily incorporated into a cavity of the chiral, gel forming polymer. This situation not only occurs with polymers like the cellulose esters of the type disclosed in US-A-5 066 793, but is also applicable to molecularly imprinted polymers (MIPs). MIPs are prepared, according to Nicholls et al., Trends Biochem. Sci. 13 (1995), 47-51, by mixing a Sl~STlTUTE SHEET (RUEE 26) W O 96/1189~
PCT~EP95/01063 monomer or monomer mixture judiciously selected to ensure chemical functionality complementary to that of the imprint species with the imprint molecule in the presence of a suitable cross-linking agent.
The complementarily interacting functionalities form predictable solution structures, which, after polymerisation and extraction of the imprint species, always results in longer retention times for the imprinted enantiomer. This effect is reflected by the differing binding affinities of enantiomers at MIP recognition sites.
Good results are obtained when as MIP use is made of a copolymer of methacrylic acid and ethylene glycol dimethacrylate prepared according to a method disclosed by 0. Ramstrom et al., Tetrahedron: Asymmetry 5 (1994), 649-656.
Examples of finely particulate cellulose esters of aromatic or aromatic-aliphatic carboxylic acids in the form of substantially spherical, partially crystalline particles having an average diameter of 1 to 200 ~m and a specific surface area of 10 to 300 m2/g are disclosed in US-A-5 066 793. Specifically mentioned are cellulose tribenzoate, cellulose tri(paramethylbenzoate), cellulose tri(m-methylbenzoate), cellulose tricinnamate, o-methylbenzoyl cellulose, p-ethylbenzoyl cellulose, p-chlorobenzoyl cellulose, and m-chlorobenzoyl cellulose.
Another group of optically active adsorbents is disclosed in US-A-5 347 042. They are derived from sulphur-containing amino acids which in combination with specific ester and amide radicals, in particular with sterically bulky and rigid ester or amide radicals, lead to optically active adsorbents. The cross-linked polymers are preferably in the form of small particles. The degree of swelling of the particles can be adjusted by customary methods through the nature and the amount of the cross-linking agents, e.g., 1,6-hexane diol diacrylate and 1,2-ethylene glycol diacrylate. The adsorbents are particularly suitable for the separation of amino acids, SUB~TITUTE SHEET tRUEE 26~
-W 096/1189~
PCT~EP9~/04063 hexahydrocarbazole derivatives, such as 3-r-(4-fluorophenylsulphonamido)-9-(2-carboxyethyl)-1,2,3,4,4a,9a-hexahydrocarbazole, benzodiazepines, such as oxazepam, arylpropionic acids and their amides, such as ketoprofen and ibuprofenamide.
For instance, the following chiral, gel forming substances can be employed with advantage in separating the racemic mixtures below:
A gel forming epoxy resin or polyurethane into which cyclodextrine, more particularly ~-cyclodextrine, has been incorporated, for separating a racemic mixture of:
antihistaminics of the diphenyl alkylamine type such as bromopheniramin; methyl mandelate; indole alkaloids; chlormezanon, rolipram, triazoline; succinimides such as methsuximide and phensuximide; hydantoins such as mephenytoin; aminoglutethimide;
ketoprofen; calcium channel blockers such as nimodipin and verapamil; methyl phenidate; chlortalidone; glutethimide;
thalidomide; etaqualon, and methaqualon; steroids such as indenestrol A, indenestrol B, and norgesterol; insecticides such as EPN, salithion, and 3-phenoxybenzyl chrysanthemate;
praziquantel.
Derivatives of microcrystalline cellulose I, such as:
a) cellulose triacetate for separating a racemic mixture of:
~-butyrolactone, ketamin, cyanofenfos, dihydro-3-hydroxy-4,4-dimethyl-2(3H)-furanone, 4-hydroxy-2-cyclo-pentenone, 4-phenyl-1,3-dioxane, ~-fenyl-~-valerolactone, quinazolinone, 1-(9-anthryl)-2,2,2-trifluoroethanol; mandelic amide, praziquantel, trans-2,3-diphenyl oxirane.
b) cellulose tribenzoate for separating a racemic mixture of:
1-acenaphthenol, 2-acetoxy-1-phenyl propane, benzyl methyl SU~STITUTE SHEET (RULE 26) W 096/1189~ PCT~P95/0~063 sulphoxide, 1-butynyl-3-benzoate, 1-decalon, 1,3-diacetoxybutane, dibenzoyloxyalkane derivatives, methyl phenyl sulphoxide, naproanilide, 4-phenyl-1,3-dioxane, 1-phenyl ethanol, 1-phenyl propanol.
c) cellulose trisphenyl carbamate for separating a racemic mixture of:
acephate, alboatrin, benzoin, benzoin ethyl ether, benzyl vinyl tolyl sulphoxide, catechim, corylbulbine, corydaline, 2-cyclopenten-1-on-4-acetic ester, 1,3-di(9-anthryl)butanol, 2,2'-dihydroxy-6,6'-dimethyl biphenyl, DIOP, guaifenesine, a- ( 1-hydroxyethyl)naphthalene, isofenfos, isoprothiolane sulphoxide, ~-lactam, laudanosine, oxazepam, 2-phenyl cyclohexanone, 2-phenyl propionic acid, phosphinoxide, sulphilimine, sulphoxide, tetrahydrocrysamine, tetrahydropalmatine, thalictravine, warfarin.
Biopolymers such as albumin and acid ~-glycoprotein for separating a racemic mixture of:
~-blocking drugs; local anaesthetics such as bupivacaine and prilocaine; benzodiazepines such as oxazepam; disopyramide and tocainide; anti-coagulants such as warfarin; NSAIDs such as ibuprofen, fenoprofen, and naproxen; atropine, clidinium, mepenzolate, oxyphencyclidine; antineoplastic alkylating agents such as cyclophosphamide; verapamil; histamine antagonists such as chlorpheniramine, bromodiphenhydramine, promethazine; mianserin;
doxylamine; cocaine, butorphanol, methadon, propoxyphene, and pentazocine; ephedrine and pseudo-ephedrine, catecholamines such as dobutamine; terbutaline; phenmetrazine.
Amylose gels such as amylose carbamate for separating a racemic mixture of:
chlorpheniramine, dihydropyridine, dimethothiazine, NSAIDs such as SUI~STITUTE SHEET (RULE 26~
W 096/1189~
flurbiprofen, ketoprofen, and ibuprofen, methyl succinimic acid, 5-norbornene, p-cyclophane, 2-phenyl butyric acid, 1-phenyl-1,2-ethane diol, porphyrin, promethazine, sulindac methyl ester, thiaprofenic acid, 1,1,1-trichloro-2-hetanol, 4-acetoxy-2-azetidine, afloqualone, 2-chloro-2-butanone, 2-cyano-4-phenyl butyric acid, ethiazide, ofloxazine methyl ester.
Gels based on polymethyl methacrylate for separating a racemic mixture of:
binaphtol and tocopherol.
Gels based on polyurethanes modified with tartaric acid, mandelic acid or amino acid derivatives for separating ethanolamines such as ~-sympathicomimetics and ~-sympatnicolytics, amino ac, ds, and arylpropionic acids.
Gels based on polyacrylamide modified with D-glucosamine for separating a racemic mixture of amino acids.
The process according to the invention may be carried out by means of a single countercurrent extraction, but preferably takes place using a number of extracting units connected in series. Preference will be given to an embodiment utilising hollow fibre membranes whose maximum pore size is a fraction smaller than the smallest diameter of the swollen gel particles. Best results are obtained by convection in macroporous polymer modules operated in the closed shell and closed lumen mode.
The invention will be further illustrated with reference to the following examples, in which it is shown, int. al., that with the process according to the invention a purity in excess of 99% can be obtained when separating a mixture of two enantiomers. In addition, a number of figures have been included to further elucidate the SUBSTITUTE SHEET (RULE 26) PCT~EP95/0~063 invention.
Needless to say, the unlimitative examples are submitted for a better understanding of the invention only.
Fig.1 shows the hollow fibre module assembly used in the experiment described in Example II
Fig.2 shows the hollow fibre module assembly used in the experiment described in Example V
Fig.3 shows the hollow fibre module assembly used in the experiment described in Example VI.
In Fig. 1, the aforementioned hollow fibre module consists of a tubular case 1 connected at both ends via a thread to a socket 7 or an end cap 8. The case 1 is partially filled in longitudinal direction with hollow fibres 4, of which the hollow ends open into the epoxy pottings 5 and 6. The hollow cap 8 above said pottings is provided with connections 9 and 10, through which the suspension is kept in constant movement via pump 23. Cap 8 is further connected, via a tube and pump 12, to vessel 11, which contains a suspension kept in constant motion with magnetic bar 13.
During the experiment the suspension passes from vessel 11 via pump 12, cap 8, fibres 4, socket 7, fibres 4a, cap 8a, and pump 14 into vessel 15. The solvent in vessel 16 passes, via pump 17, to the shell side of fibres 4a, side connection 2a, and pump 18 to the shell side of fibres 4 and pump 19, to end in vessel 20.
The solution of the racemic mixture in vessel 22 is fed, via pump 21, to socket 7.
Fig. 2 shows a set-up of eight modules. Each module consists of a 254 mm long glass tube with two side connections. The inside diameter of each glass tube is 10 mm, the effective length between the side connections 200 mm. Each module contains 300 hollow fibres of Oxyphan SU~STITUTE SHEET (RULE 26) CA 022029ll l997-04-l6 W 096/1189~
PCT~EP9~/04063 Ox-pp5045/02.01. The inside diameter of each fibre is 280 ~m and the outside diameter 380 ~m. The fibres are bundled in the form of mats.
During the experiment the solvent passed from vessel 1 via pump 5 and the lumen side entrance 10a into module case 9a and left said case via connection 12a. The solvent passed the lumen of the other seven modules in an analogous manner to end up in vessel 2 via pump 6.
The suspension in vessel 3 passed, via pump 7 and shell side connection 13h, to the shell side connection of module 9h to leave via the shell side connection 11h. Then the suspension passed the shell of the other seven modules in an analogous manner to end in vessel 4 via pump 8.
e Fig. 3 shows a set-up of eight modules of the same type as those of Fig. 2. The magnetically stirred suspension in vessel 1 is recirculated via pumps 2, 4, 5, and 6 to pass the solvent regeneration modules 9a and 9b, the stripper modules 9c and 9d, the extraction modules 9e and 9f, and the washing modules 99 and 9h, respectively.
The cleaned suspension is returned via pump 8 to end in vessel 1.
The cleaned solvent leaves cap 19 and flows, via pump 20, to the solvent supply vessel 10. The dissolved racemic mixture in vessel 22 is fed to the system via pump 21.
A solution of the less well retained enantiomer is collected in vessel 17, use being made of a difference in flow rate between the metering pumps 16 and 18. A solution of the more strongly retained enantiomer is collected in a similar way in vessel 14, use being made of a difference in flow rate between the metering pumps 13 and 15.
Example I
On a racemic mixture of R- and S-ketamine.HCl it was first determined at room temperature how much more S-configuration than R-configuration was incorporated into a suspension of swollen cellulose triacetate (CTA-I) particles. The CTA-I (ex Fluka) was composed of a sieve SU~ST~TlTE SH~ET (RULE 26) -CA 022029ll l997-04-l6 W O 96/11894 PCT/EP95/0~063 fraction of particles - in the non-swollen state - of 15-25 ym. After swelling in 70C ethanol there was obtained, after cooling and decanting, a suspension of swollen particles having a volume at room temperature of 25 ml/10 9.
Ten suspensions were prepared, each containing abcut 250 mg of swollen CTA-I partic1es and about 750 mg of a sodium carbonate neutralised alcoholic solution containing approximately 1 mg of ketamine.HCl/ml (90, 96, and 100% ethanol, and 90, 96, and 100% 2-propanol, respectively).
After about 5 minutes of shaking at room temperature the suspensions were left to settle. After filtration of the aforementioned liquid through a filter with a pore size of O,S ym, the concentration of ketamine enantiomer was determined on the filtrate using capillary zone electrophoresis. In the analysis the alcoholic solutions used to prepare the suspensions were taken as external standards to calculate the ketamine enantiomer content in the filtrate.
In the table below ket.HCl stands for ketamine.HCl, ETOH represents ethanol, and IPA stands for 2-propanol.
Table 1 sample ket.HCl Na~CO~ ETOH IPA water Na~HPO4 volume no. mg mg g g g g (0,1 M) ml 1. 1,12 0,22 0,750 - - - 0,95 2. 0,98 0,20 - 0,751 - - 0,96 3. 1,14 0,22 0,765 - 0,043 - 1,01 4. 0,99 0,20 - 0,761 0,044 - 1,01 5. 1,11 0,22 0,748 - 0,081 - 1,02 6. 0,98 0,20 - 0,754 0,089 - 1,05 7. 1,11 0,22 0,749 - - 0,050 1,00 8. 0,98 0,20 - 0,751 - 0,059 1,01 9. 1,21 0,24 0,812 - - 0,111 1,13 10. 0,97 0,20 - 0,750 - 0,080 1,03 The standard solutions contain 1,17 9 of ket.HCl/ml ETOH and 1,02 9 of ket.HCl/ml IPA, respectively. The measured quantities of R- and S-SU~$TITUTE S~EET (RULE 26) W 096/11894 PCT~P9~10~063 enantiomer in the liquid phase and the calculated amounts of R- and S-enantiomer in the CTA-I phase are listed in Table 2.
Table 2 sample measured in liquid calculated in CTA-I
nr. R S R S
mg mg mg mg 1. 0,45 0,51 0,11 0,05 2. 0,37 0,41 0,12 0,08 3. 0,51 0,56 0,06 0,01 4. 0,44 0,47 0,06 0,03 5. 0,46 0,51 0,10 0,05 6. 0,43 0,46 0,05 0,03 7. 0,37 Q 46 Q,19 0,09 8. 0,31 0,38 0,18 0,10 9. 0,37 0,47 0,23 0,14 10. 0,33 0,41 0,15 0,08 Example II
A racemic mixture of R- and S-ketamine.HCl was separated using two hollow fibre modules 1 and la having an inner diameter of 23 mm and a length of 155 mm, which were connected in series. Each module contained 2100 porous polypropylene fibres of 240 ~m inner diameter.
Prior to the start of the passage of dispersion, the apparatus was filled with solvent and de-aerated on the shell side by the application of a vacuum. The solvent in question was a mixture composed of 96% of ethanol and 4% of an 0,01 M Na2HP04 solution in water. The dispersion of gel particles was composed of CTA-I particles having the same dimensions as in Example I.
~ In order to prevent the hollow fibres becoming clogged through coagulation of the particles, the dispersion was subjected to ultrasonic vibration. For the same reason the modules were arranged vertically and the dispersion was passed through the modules from the top downwards. Further, there were two membrane pumps 23 and 24 to SUBSTITUTE S~EETtRULE 2~
-W O96/11894 PCT~EP95/01063 16 ~
ensure that the dispersion was kept in motion over the potting and to create a pulsed flow in the lumen. After 80 minutes the amount of solids was reduced from about 11,1 wt.% to about 8 wt.%. The concentration of the feed in the channel connected to the lumen of the two modules was 1 g/100 ml for the first 30 minutes. After 50 minutes a feed of a different composition was employed, which also contained salt used for neutralising. This solution contained 1 g/100 ml of ketamine.NaCl. After 87 minutes the apparatus was flushed with ethanol. The measurement data, compiled by sampling and analysing every 5 minutes, is listed in the table below. eeR % refers to the percentage of enantiomeric excess, which when defined for an (R)-enantiomer reads: eeR % = (CR-cS)/(cR+cR)x100%, wherein cR is the concentration of the (R)-enantiomer in mg/ml.
SU~STITUTE SHEET (RULE 2~) PCT~P95/04063 Table 3 0\O a~
aJ ~r o\O ~ C ~ I_ CO ~ O ~ ~O O W ~D W C~
I O O ~I O _ C~J O--I O--~ ~ ^ ^ ^ ^ ^ ^
3 o ~ _ ~ ~ _ ~ _ _ I _ - _ _ ~ ~ ~ ~ w 0 ~ w w ,3 ~ ~
-05 ~D n ~ ~ w ~t 0 ~ W ~ W ~D _ ~ . o o o o o o o o I o o o o o o o o o o o o o ~n E ~ 0 ~0 ~ w c ~ ~:) w C~
C~ ~ ~ C~J-- ~ O ~ ô ~ ô ~ o ~ _ ô _ _ _ ô _ _ _ ,_ ~ E
~ E r . ~ UO C~ L~ D ~ W C~ D 0 Ln .~ ~ C 1~ _ _~ ô ~ ô ô ô ô ô ô ô ô o ô ô ~
, ~ _, _ r-~ _, ~ _ _ _ _ ~ _ ~
~ aJ ~ c~J
E "l E Ln l_ Ln ~ J c O o~ D c~l D 0 ~ J ^ c~
._ o ~ ^ - ^ .` ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ O
=~ ~
O 0 ~ 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 O
t3 E E
O ~ C ~ ~ ~ ~1- ~ ~ ~ ~t ~ ~r ~ ~ e~ ~ ~t n~
v~
~ cJ
O
._ O Ln O u~ O Ln O Ln O ~ O Ln O Ln O ~ O ~ O O _ CA 022029ll l997-04-l6 W O96/1189~ PCT~EP9~/04063 Example III
In a manner analogous to that disclosed in Example I it was determined on a racemic mixture of 4-phenyl-1,3-dioxan at room temperature how much more (-)-configuration than (+)-configuration was incorporated into a suspension of swollen cellulose triacetate (CTA-I) particles.
The eluent used was 96% ethanol. The sample of the suspension was composed of 1 9 of CTA-I and 7 9 of 96% ethanol in which 1,16 mg/ml of (~)-4-phenyl-1,3-dioxan had been dissolved. After one hour of shaking at room temperature the suspension was left to settle.
For identification of the enantiomer and determination of the concentration use was made of an analytic column filled with CTA-I and the information provided in an article by R.M. Wolf and E. Francotte in J. Chem. Soc. Perkin Trans. II (1988), 893-901.
After one hour the upper liquid contained 0,43 mg/ml of (+)-4-phenyl-1,3-dioxan and 0,26 mg/ml of (-)-4-phenyl-1,3-dioxan.
Example IV
The experiment of Example III was repeated, except that this time the gel forming chiral adjuvant used was tribenzoyl cellulose, which was obtained in accordance with the synthesis specifications in K.H.
Rimboeck, J. of Chromatography 351 (1986), 346-350. It was found that the affinity of tribenzoyl cellulose was opposite to that of CTA-I, resulting in the concentrations in the liquid and the gel phase being inversely distributed. The sample of the suspension was composed of 1,0 9 of tribenzoyl cellulose (CTB) and 7 9 of 96~ ethanol in which 1,16 mg/ml of (+)-4-phenyl-1,3-dioxan had been dissolved.
After one hour the upper liquid contained 0,37 mg/ml of (+)-4-phenyl-1,3-dioxan and 0,40 mg/ml of (-)-4-phenyl-1,3-dioxan.
SUBSTITUTE SHEET (RULE 26) WO 96/11894 PCT/EP95/0,1063 Example V
J
The example below shows that it is possible to separate a 50/50 mixture of enantiomers of 4-phenyl-1,3-dioxan by subjecting it to countercurrent separation using a set-up of hollow fibre modules such as depicted in Fig. 2. The column indicated with the reference numerals 9a, 9b, 9c, 9d, 9e, 9f, 99, and 9h in that case represents 8 hollow fibre modules connected in series. The hollow fibre modules had an inner diameter of 10 mm and an effective length of 200 mm. Each glass module contained 300 porous polypropylene fibres with an inner and an outer diameter of 280 and 380 ~m, respectively (Oxyphan ox-pp5045/02.01) in an epoxy potting. The hollow fibres were bundled on a knitting machine at one stitch per centimeter. The fluid streams were pumped from vessel 1 (solvent) and vessel 3 (suspension) through the shell and the lumen in the modules with the aid of four membrane pumps with back pressure valves mounted at the ends of the separating column. The pair of pumps 5 and 6 in the lumen stream was coupled to give a simultaneous membrane stroke in the pumps and create a pulsed flow in the lumen. The pair of pumps 7 and 8 in the shell stream was synchronised in the same way. The displacement of liquid on the lumen side was alternated 20 times per minute with the displacement of suspension on the shell side. The air bubbles were expelled by recirculation of the solvent via a buffer vessel and recirculation of the suspension via a second buffer vessel. The amount of liquid in each of the buffer vessels during the recirculation was kept constant.
Where necessary, the difference in delivery capacity of the synchronised pumps was reduced by adjusting the pumps' stroke volume.
The liquid used for separating the racemate of (+)-4-phenyl-1,3-dioxan was made up of 96% ethanol. The separation was carried out using a suspension of CTA-I of the same proportions as indicated in Example I.
The suspension was composed of a mixture of 100 g of CTA-I in 700 9 of ethanol-water mixture (96+4).
SU~STITUTE SHEET (RUEE 26) W O 96/1189~
In order to prevent clogging through coagulation of the particles, the suspension was subjected to ultrasonic vibration and sieved. For the same reason the modules were arranged vertically and the dispersion was passed through the modules from the top downwards. Settling of the suspension was counteracted by pulsing the movement in the tubes and the modules.
The extraction process was started by adding 1 g of racemate of 4-phenyl-1,3-dioxan to the suspension of the aforementioned composition. The measurement data, compiled by sampling and analysing every 5 minutes, is listed in Table 4. ee+ % refers to the percentage of enantiomeric excess, which when defined for a (+)-enantiomer reads:
ee+ % = (c+-c-)/(c++c-)x100%, wherein c+ is the concentration of the (+)-enantiomer in mg/ml.
S~STtTUT~ S~tEET (RUL~ 2~) WO 96/1189~ PCT/EP95/04063 Table 4 ~, sample flow through enantiomer after lumen (solvent) concentration excess minutes or m~/ml m~/ml ee+ %
shell (dispersion) 4-phenyl-1 ,3-dioxan (+) (-) 0 lumen13,875 0,022 0,060 shell11,014 0,223 0,249 -5,51 lumen14,080 shell10,538 0,184 0,222 -9,33 ~ 25 lumen14,000 0,158 0,157 0,17 shell10,299 0,221 0,242 -4,47 lumen13,989 0,159 0,182 -6,68 shell10,044 0,227 0,254 -5,66 lumen13,929 0,159 0,158 0,38 shell10,031 0,227 0,274 -9,38 lumen13,914 0,157 0,154 1,16 shell10,137 0,228 0,252 -5,19 lumen13,833 0,154 0,150 1,21 shell 9,995 0,217 0,264 -9,74 lumen13,612 0,152 0,146 2,23 shell10,013 0,228 0,255 -5,71 lumen13,849 0,153 0,139 4,60 shell10,045 0,228 0,254 -5,30 lumen13,878 0,152 0,153 -0,33 100 shell 9,857 0,219 0,266 -9,62 105 lumen13,747 0,145 0,139 2,08 110 shell 9,912 0,234 0,260 -5,15 Example VI
In the example below it is demonstrated that an enantiomers mixture can be separated into the (+)- and (-)-constituents with a set-up such as depicted schematically in Fig. 3. In this set-up, the suspension of vessel 1 is recirculated, being first passed, via pump 2, through the shell of the two solvent regeneration modules 9a and 9b, where the remainder of one of the enantiomers is removed from the solvent flowing through the lumen. Next, the flow of suspension is passed through the shell of the two extraction modules 9c and 9d, the stripper modules 9e and 9f, and the washing modules 99 and 9h. From S~3STITUTE StlEET (RULE 26) W O96/11894 PCTAEP9~104063 there the virtually enantiomer-free suspension is passed to vessel 1.
The virtually enantiomer-free solvent is passed from vessel 10, via pump 11, through the lumen of the washing modules 9h and 9g, where the suspension containing one of the enantiomers is washed such that practically all of the enantiomer absorbed by the chiral adjuvant is re-released, before ending up in vessel 14, from where a portion is passed countercurrently through the lumen of the stripper modules 9f and 9e. In between the stripper modules 9e and 9f and the extraction modules 9c and 9d the racemic mixture of vessel 22 is dosed using pump 21. From 9c the lumen flow is passed, via pump 16, into vessel 17, from where because of a difference in pump discharge between the pumps 16 and 18 a portion of the liquid is passed into the lumen of the solvent regeneration modules 9b and qa.
Complete separation of the racemic mixture is obtained by setting the flow ratios in the extraction and stripper modules using the equilibrium data of Example III and the design procedure disclosed by Giuseppe Storti et al. in Ind. Eng. Chem. Res. 34, 288-301 (1995).
The mean flow rate of the suspension in the scheme depicted in Fig. 3 is kept constant and equal in each module by an alternating pump action similar to that described in Example V. The solid flow rate can be calculated from the suspension flow rate.
The mean flow rate of the liquid is set per module section, and the differences in liquid flow rate between sections are compensated for by the solvent, raffinate, feed, and extract streams. Net liquid flow rates are calculated from the countercurrent suspension flow rate and the liquid flow rate. The net liquid flow rate and the solid flow rate are the parameters used in the aforementioned design procedure.
A module section can be used as a washer, stripper, extractor or solvent regenerator by adjusting a flow rate ratio within a specified range.
The system disclosed in Examples III and V, with a mean flow rate for SUBSTITUTE SHEET ~RULE 26) W O 96/11894 PCT~P95/04063 the suspension of 10 ml/min, will require the following typical mean liquid flow rates: 28 ml/min of liquid for the washing modules, 13,9 ml/min for the stripper modules, 14,1 ml/min for the extraction modules, and 4 ml/min for the amount of regenerated solvent. The resulting streams of the raffinate, feed, and extract are: 14,1 ml/min, 0,2 ml/min, and 10,2 ml/min, respectively.
ITUTE SHEET (RVLE 2
The invention pertains to a process for separating enantiomers from a racemic mixture by countercurrent extraction using at least two substances, one of them a liquid in which the racemic mixture to be separated is present, the other containing a chiral adjuvant.
Such a process has earlier been proposed in WO 94/07814. The process disclosed therein specifies the countercurrent extraction of a racemic mixture using at least two liquids at least one of which is chiral or contains a chiral adjuvant, said liquids being wholly miscible and separated from each other by a phase with which they are immiscible.
The separating, immiscible phase can be incorporated into a solid carrier which may be porous or not, preferably in the form of a hollow fibre.
It has been found that most racemic mixtures can be separated very effectively by the process disclosed in said document, providing that the racemate is not only readily soluble in the extracting liquids, but also in the phase which separates these liquids and is immiscible therewith. Examples of substances which cannot be separated by the known process, or can be separated only with great difficulty, are chiral substances which do not have a functional group, such as an amino group, keto group, ester or hydroxyl group, as well as certain aromatics.
There is need for a separating technique giving the same result with fewer separating steps also when the only chiral adjuvant available for separating a racemic mixture is one which results in a very narrow coefficient of distribution, so that a large number of separating steps is required to attain a high degree of purity.
.
Accordingly, there is practical need for a process for separating racemic mixtures which can be separated by the known technique only with difficulty.
SU8STITUTE SHEET (RULE 26) The invention now provides a process by which said need can be satisfied for the most part.
The invention is characterised in that in the process of the known type mentioned in the opening paragraph ~he chiral adjuvant is combined with o ~ t of a gel forming substance in the form of ~ .s~C4~
discret~ ticles in a 1iquid separated from the countercurrently flowing liquid containing the racemate to be separated by a microporous membrane having a pore size such that the pores can no longer be penetrated by the gel forming particles separated on conclusion of the extraction, followed by the setting free therefrom of one of the enantiomers under the influence of a stimulus, after which the particles are re-incorporated into the extracting process if so desired.
It should be noted that the use of a chiral adjuvant combined with a gel-forming substance in the form of discrete particles for separating a racemic mixture from a liquid is known in itself from an article by Masakazu Negawa and Fumihiko Shoji in J. Chromatog. 590 (1992), 113-117.
In it the use is described of a simulated moving bed adsorption (SMBA) technique to optical resolution using eight columns packed with chiral stationary phases. Although, in theory, the authors make mention of a real countercurrent process in which the gel forming stationary phase continuously moves in a direction opposite to that in which the racemate liquid moves, the only practical embodiment used is a simulated moving bed.
A major advantage of the now proposed process is that the liquid containing the racemic mixture need no longer be separated from the chiral adjuvant-containing phase by a phase immiscible therewith, - enabling a much more rapid exchange than was possible with the known process.
A~NDED SHEET
IPEA~P
CA 022029ll l997-04-l6 W O 96/11894 PCT~EP95/04063 A further advantage of the now proposed process is that because the chiral adjuvant is combined with or part of the gel forming substance, its separation, and that of the enantiomer extracted therewith, can be simplified significantly. The chiral adjuvant may be covalently bonded to the gel forming substance in that case. Another possibility is that the chiral adjuvant is a gel forming substance in the form of a molecularly imprinted polymer (MIP) prepared against one of the enantiomers to be separated.
In order to prevent the gel forming particles from penetrating the pores of the membrane during the extracting process, they are in the swollen state. The enantiomer incorporated into them during the extraction is set free again by using a stimulus. This stimulus may take the form of a change in temperature, in pH, in salt concentration, electric or magnetic field, and/or solvent composition.
After having been released from the gel forming particles, the enantiomer is generally extracted and, if so desired, purified further by evaporation of the extracting agent and/or crystallisation.
The gel forming substance is present in the form of discrete particles. These particles may be of 50 nm to 300 ym in size, though particles of a larger size also qualify. When larger particles are employed, preference is given to an embodiment in which the gel forming substance no longer comprises the entire particle but is provided on a carrier and physically, preferably covalently, bonded thereto. In such a process favourable results can be attained both when the gel forming substance is provided in the pores of a carrier and when it is provided on its surface. The carriers can be of either inorganic or organic material. Examples of inorganic carriers are ~-alumina, y-alumina, carbon, ceramic material, or combinations thereof such as alumina on a porous carbon carrier. Examples of porous organic carriers based on organic polymers have been described in detail in US-A-4 247 498 and US-A-4 519 909.
SU~STITUTE SHEET (RULE 26) W O96/1189~ PCT/EP95/04063 When particles having a comparatively high specific weight are used, the force of gravity can be employed to effect countercurrent flow in relation to the liquid flowing in the opposite direction.
The porous membrane to be used in the process according to the invention preferably has the largest possible pores, with the proviso that their maximum size is selected such that the pores are just too small to be penetrated by the swollen particles.
When employing a porous membrane preference is given to the use of a membrane having the same polarity as the extracting liquid. More particularly, when the polarity of the extracting liquid does not correspond to the membrane's, favourable results can be attained usir,g a process in which the membrane, depending on whether the liquid flowing around it has polar or apolar properties, is rendered hydrophilic or hydrophobic by the chemical route, say, by grafting with an acrylate compound.
However, preference is given to a process in which the membrane, depending on whether the liquid flowing around it has polar or apolar properties, is rendered hydrophilic or hydrophobic by physical modification, for instance by treatment with a surface-active compound.
In another embodiment the liquid flowing around the microporous membrane is tailored to the polarity of the membrane by the incorporation of a small amount of a compound compatible with the membrane. Thus when a porous membrane based on polypropylene is used, very favourable results are attained by incorporating 0,1 to 5 wt.% of n-hexane into the alcoholic extracting liquid.
Both non-thermoplastic polymers, such as cuprophane, cellulose acetate, cellulose triacetate, cellulose nitrate, polytetrafluorethylene, polyacrylonitrile or (regenerated) cellulose, SUBSTITUTE SHEE~RULE 26) , PCT~P95/0~063 and thermoplastic materials, such as polyolefins, condensation polymers, oxidation polymers, and mixtures thereof can be employed when making the membranes to be used according to the invention.
Examples of suitable polymers to make membranes from are low-pressure and high-pressure polyethylene, polypropylene, polystyrene, polyvinyl chloride, polyvinylidene chloride, acrylonitrile-butadiene-styrene-terpolymer, styrene-acrylonitrile-copolymer, styrene-butadiene-copolymer, poly(4-methyl-pentene-1), polybutene, polyvinyl butyral, chlorinated polyethylene, polyvinyl acetate, polyvinyl alcohol, polymethyl methacrylate, polymethyl acrylate, polyimide, polyvinyl disulphide, polyphenylene oxide, polyethylene terephthalate, polybutylene terephthalate, polyaramid, copolyetheresters based on butylene terephthalate and polyethylene oxide glycol having a molecular weight in the range of 800 to 6000, polyamide 6, polyamide 6,6, polyamide 11, polyamide 12, polycarbonate, polyether urea, polypiperazine, polypiperazine amide, polyvinyl pyrrolidone, polyether sulphone, polysulphone, and the polydimethyl siloxanes (PDMS).
The preparation of microporous membranes from thermoplastic polymers has been described in, int. al., US-A-4 098 901. For the preparation of hollow fibre membranes from thermoplastic polymers reference may be had to US-A-4 564 488.
Highly favourable results can be obtained using a polypropylene hollow fibre membrane.
The hollow fibre membranes are commonly arranged in a hollow fibre module. The gel forming particles will then flow through the hollow fibres as a rule, while the racemic mixture flows around them. In contrast to the separating processes disclosed in W0 94/07814, n generally only one chiral adjuvant is used in the process according to the present invention. Of course, it is still possible to make use of a symmetrical system such as described in the aforesaid document, SUBSTITUTE SHEET (RULE 26) ~CR 2'31 R
though in that case two gel forming substances which differ only in terms of discrimination by the chiral adjuvant have to be available.
Generally, there will be selected a m~croporous membrane of minimal thickness, commonly in the range of 0,1 ~m to 1 mm, with ~reference being given to a membrane thickness in the range of 1 ~m to 00 ~m.
According to the invention, there will always be at least one gel forming substance which is chiral in itself, is covalently bonded to a chiral adjuvant, or is a molecularly imprinted polymer (MrP) prepared against one of the enantiomers to be separated.
The liquid employed as a solvent for the racemate to be separated is one which is capable of swelling the gel forming substance. Generally speaking, the person skilled in the art will know which solvent or combination of solvents to select.
The chiral adjuvant is incorporated into or part of the sel forming material. As a gel forming material which is chiral in itself may be mentioned cellulose triacetate. Another example is a gel forming polyester into the polymer chain of which, say, a chiral diol or dicarboxylic acid has been incorporated. Alternatively, the gel forming material can be combined with a chiral adjuvant.
New synthetic routes to optically active monomers and polymers are disclosed by Kevin D. Belfield et al. in TRIP Vol. 3, No. 6 (June 1995), 180-185. The following compounds, including their salts and derivatives, are eligible for incorporation into the gel forming material as chiral adjuvant:
1-aminoethyl phosphonic acid, 2-bromopropionic acid, lactic acid, epichlorohydrin, serine, 2,3-diaminopropionic acid, propylene oxide, alaninol, 1-amino-2-propanol, aspartic acid, malic acid, tartaric acid, 5-(hydroxymethyl)-2-pyrrolidinone, proline, cis-3-hydroxyproline, trans-1,2-cyclopentane diol, 2-methyl butyric 4h~NDED ~.Y~
r PCT~EP95/0~063 t acid, a-hydroxyisovaleric acid, methyl-3-hydroxybutyrate, methyl B-hydroxyisobutyrate, arabinose, lyxose, ribose, xylose, prolinol, alanine ethyl ester, norvaline, vali ne, methionine, penicillamine, methionine sulphoxide, 2-pentanol, 2,4-pentane diol, arabitol, 2-methyl-1-butylamine, valinol, 1,2-diaminocyclohexane, a-methylbenzylamine, 1-amino-2-(methoxymethyl)pyrrolidine, lysine, arginine, 2-hexanol, 2-methyl-2,4-pentane diol, leucinol, 2-fluorophenyl alanine, 3-fluorophenyl alanine, 5-fluorotryptophan, 5-hydroxytryptophan, 2-benzyloxy-1,3,4-butane triol, isopropyl noradrenaline, 1-(1-naphthyl)ethanol, 1-(1-naphthyl)ethylamine, trans-2-phenyl-1-cyclohexanol, thyroxine, menthyl acetate, N-(3,5-dinitrobenzoyl)-a-phenyl-glycine, N-methyl ephedrine, 3,5-dinitro-N-(1-phenylethyl)-benzamide, and ~,a-diphenyl prolinol.
The process according to the invention permits the separation of racemates of the most widely varying nature. The racemates may be compounds of the pharmacon group, as well as synthons, aromatics, and flavourings, or pesticides.
Although, according to the invention, a very wide variety of chiral, gel forming materials is eligible for use in separating an even wider variety of racemic mixtures, the use of certain combinations of chiral, gel forming materials and racemic mixtures to be separated is greatly preferred. Especially eligible are those chiral polymers which display a strong interaction with the racemic substances to be separated. Such strong interaction may be due to hydrogen bridging or Coulomb and/or Van der Waals forces, but may also be due to, e.g., the fact that one of the enantiomers to be separated is more readily incorporated into a cavity of the chiral, gel forming polymer. This situation not only occurs with polymers like the cellulose esters of the type disclosed in US-A-5 066 793, but is also applicable to molecularly imprinted polymers (MIPs). MIPs are prepared, according to Nicholls et al., Trends Biochem. Sci. 13 (1995), 47-51, by mixing a Sl~STlTUTE SHEET (RUEE 26) W O 96/1189~
PCT~EP95/01063 monomer or monomer mixture judiciously selected to ensure chemical functionality complementary to that of the imprint species with the imprint molecule in the presence of a suitable cross-linking agent.
The complementarily interacting functionalities form predictable solution structures, which, after polymerisation and extraction of the imprint species, always results in longer retention times for the imprinted enantiomer. This effect is reflected by the differing binding affinities of enantiomers at MIP recognition sites.
Good results are obtained when as MIP use is made of a copolymer of methacrylic acid and ethylene glycol dimethacrylate prepared according to a method disclosed by 0. Ramstrom et al., Tetrahedron: Asymmetry 5 (1994), 649-656.
Examples of finely particulate cellulose esters of aromatic or aromatic-aliphatic carboxylic acids in the form of substantially spherical, partially crystalline particles having an average diameter of 1 to 200 ~m and a specific surface area of 10 to 300 m2/g are disclosed in US-A-5 066 793. Specifically mentioned are cellulose tribenzoate, cellulose tri(paramethylbenzoate), cellulose tri(m-methylbenzoate), cellulose tricinnamate, o-methylbenzoyl cellulose, p-ethylbenzoyl cellulose, p-chlorobenzoyl cellulose, and m-chlorobenzoyl cellulose.
Another group of optically active adsorbents is disclosed in US-A-5 347 042. They are derived from sulphur-containing amino acids which in combination with specific ester and amide radicals, in particular with sterically bulky and rigid ester or amide radicals, lead to optically active adsorbents. The cross-linked polymers are preferably in the form of small particles. The degree of swelling of the particles can be adjusted by customary methods through the nature and the amount of the cross-linking agents, e.g., 1,6-hexane diol diacrylate and 1,2-ethylene glycol diacrylate. The adsorbents are particularly suitable for the separation of amino acids, SUB~TITUTE SHEET tRUEE 26~
-W 096/1189~
PCT~EP9~/04063 hexahydrocarbazole derivatives, such as 3-r-(4-fluorophenylsulphonamido)-9-(2-carboxyethyl)-1,2,3,4,4a,9a-hexahydrocarbazole, benzodiazepines, such as oxazepam, arylpropionic acids and their amides, such as ketoprofen and ibuprofenamide.
For instance, the following chiral, gel forming substances can be employed with advantage in separating the racemic mixtures below:
A gel forming epoxy resin or polyurethane into which cyclodextrine, more particularly ~-cyclodextrine, has been incorporated, for separating a racemic mixture of:
antihistaminics of the diphenyl alkylamine type such as bromopheniramin; methyl mandelate; indole alkaloids; chlormezanon, rolipram, triazoline; succinimides such as methsuximide and phensuximide; hydantoins such as mephenytoin; aminoglutethimide;
ketoprofen; calcium channel blockers such as nimodipin and verapamil; methyl phenidate; chlortalidone; glutethimide;
thalidomide; etaqualon, and methaqualon; steroids such as indenestrol A, indenestrol B, and norgesterol; insecticides such as EPN, salithion, and 3-phenoxybenzyl chrysanthemate;
praziquantel.
Derivatives of microcrystalline cellulose I, such as:
a) cellulose triacetate for separating a racemic mixture of:
~-butyrolactone, ketamin, cyanofenfos, dihydro-3-hydroxy-4,4-dimethyl-2(3H)-furanone, 4-hydroxy-2-cyclo-pentenone, 4-phenyl-1,3-dioxane, ~-fenyl-~-valerolactone, quinazolinone, 1-(9-anthryl)-2,2,2-trifluoroethanol; mandelic amide, praziquantel, trans-2,3-diphenyl oxirane.
b) cellulose tribenzoate for separating a racemic mixture of:
1-acenaphthenol, 2-acetoxy-1-phenyl propane, benzyl methyl SU~STITUTE SHEET (RULE 26) W 096/1189~ PCT~P95/0~063 sulphoxide, 1-butynyl-3-benzoate, 1-decalon, 1,3-diacetoxybutane, dibenzoyloxyalkane derivatives, methyl phenyl sulphoxide, naproanilide, 4-phenyl-1,3-dioxane, 1-phenyl ethanol, 1-phenyl propanol.
c) cellulose trisphenyl carbamate for separating a racemic mixture of:
acephate, alboatrin, benzoin, benzoin ethyl ether, benzyl vinyl tolyl sulphoxide, catechim, corylbulbine, corydaline, 2-cyclopenten-1-on-4-acetic ester, 1,3-di(9-anthryl)butanol, 2,2'-dihydroxy-6,6'-dimethyl biphenyl, DIOP, guaifenesine, a- ( 1-hydroxyethyl)naphthalene, isofenfos, isoprothiolane sulphoxide, ~-lactam, laudanosine, oxazepam, 2-phenyl cyclohexanone, 2-phenyl propionic acid, phosphinoxide, sulphilimine, sulphoxide, tetrahydrocrysamine, tetrahydropalmatine, thalictravine, warfarin.
Biopolymers such as albumin and acid ~-glycoprotein for separating a racemic mixture of:
~-blocking drugs; local anaesthetics such as bupivacaine and prilocaine; benzodiazepines such as oxazepam; disopyramide and tocainide; anti-coagulants such as warfarin; NSAIDs such as ibuprofen, fenoprofen, and naproxen; atropine, clidinium, mepenzolate, oxyphencyclidine; antineoplastic alkylating agents such as cyclophosphamide; verapamil; histamine antagonists such as chlorpheniramine, bromodiphenhydramine, promethazine; mianserin;
doxylamine; cocaine, butorphanol, methadon, propoxyphene, and pentazocine; ephedrine and pseudo-ephedrine, catecholamines such as dobutamine; terbutaline; phenmetrazine.
Amylose gels such as amylose carbamate for separating a racemic mixture of:
chlorpheniramine, dihydropyridine, dimethothiazine, NSAIDs such as SUI~STITUTE SHEET (RULE 26~
W 096/1189~
flurbiprofen, ketoprofen, and ibuprofen, methyl succinimic acid, 5-norbornene, p-cyclophane, 2-phenyl butyric acid, 1-phenyl-1,2-ethane diol, porphyrin, promethazine, sulindac methyl ester, thiaprofenic acid, 1,1,1-trichloro-2-hetanol, 4-acetoxy-2-azetidine, afloqualone, 2-chloro-2-butanone, 2-cyano-4-phenyl butyric acid, ethiazide, ofloxazine methyl ester.
Gels based on polymethyl methacrylate for separating a racemic mixture of:
binaphtol and tocopherol.
Gels based on polyurethanes modified with tartaric acid, mandelic acid or amino acid derivatives for separating ethanolamines such as ~-sympathicomimetics and ~-sympatnicolytics, amino ac, ds, and arylpropionic acids.
Gels based on polyacrylamide modified with D-glucosamine for separating a racemic mixture of amino acids.
The process according to the invention may be carried out by means of a single countercurrent extraction, but preferably takes place using a number of extracting units connected in series. Preference will be given to an embodiment utilising hollow fibre membranes whose maximum pore size is a fraction smaller than the smallest diameter of the swollen gel particles. Best results are obtained by convection in macroporous polymer modules operated in the closed shell and closed lumen mode.
The invention will be further illustrated with reference to the following examples, in which it is shown, int. al., that with the process according to the invention a purity in excess of 99% can be obtained when separating a mixture of two enantiomers. In addition, a number of figures have been included to further elucidate the SUBSTITUTE SHEET (RULE 26) PCT~EP95/0~063 invention.
Needless to say, the unlimitative examples are submitted for a better understanding of the invention only.
Fig.1 shows the hollow fibre module assembly used in the experiment described in Example II
Fig.2 shows the hollow fibre module assembly used in the experiment described in Example V
Fig.3 shows the hollow fibre module assembly used in the experiment described in Example VI.
In Fig. 1, the aforementioned hollow fibre module consists of a tubular case 1 connected at both ends via a thread to a socket 7 or an end cap 8. The case 1 is partially filled in longitudinal direction with hollow fibres 4, of which the hollow ends open into the epoxy pottings 5 and 6. The hollow cap 8 above said pottings is provided with connections 9 and 10, through which the suspension is kept in constant movement via pump 23. Cap 8 is further connected, via a tube and pump 12, to vessel 11, which contains a suspension kept in constant motion with magnetic bar 13.
During the experiment the suspension passes from vessel 11 via pump 12, cap 8, fibres 4, socket 7, fibres 4a, cap 8a, and pump 14 into vessel 15. The solvent in vessel 16 passes, via pump 17, to the shell side of fibres 4a, side connection 2a, and pump 18 to the shell side of fibres 4 and pump 19, to end in vessel 20.
The solution of the racemic mixture in vessel 22 is fed, via pump 21, to socket 7.
Fig. 2 shows a set-up of eight modules. Each module consists of a 254 mm long glass tube with two side connections. The inside diameter of each glass tube is 10 mm, the effective length between the side connections 200 mm. Each module contains 300 hollow fibres of Oxyphan SU~STITUTE SHEET (RULE 26) CA 022029ll l997-04-l6 W 096/1189~
PCT~EP9~/04063 Ox-pp5045/02.01. The inside diameter of each fibre is 280 ~m and the outside diameter 380 ~m. The fibres are bundled in the form of mats.
During the experiment the solvent passed from vessel 1 via pump 5 and the lumen side entrance 10a into module case 9a and left said case via connection 12a. The solvent passed the lumen of the other seven modules in an analogous manner to end up in vessel 2 via pump 6.
The suspension in vessel 3 passed, via pump 7 and shell side connection 13h, to the shell side connection of module 9h to leave via the shell side connection 11h. Then the suspension passed the shell of the other seven modules in an analogous manner to end in vessel 4 via pump 8.
e Fig. 3 shows a set-up of eight modules of the same type as those of Fig. 2. The magnetically stirred suspension in vessel 1 is recirculated via pumps 2, 4, 5, and 6 to pass the solvent regeneration modules 9a and 9b, the stripper modules 9c and 9d, the extraction modules 9e and 9f, and the washing modules 99 and 9h, respectively.
The cleaned suspension is returned via pump 8 to end in vessel 1.
The cleaned solvent leaves cap 19 and flows, via pump 20, to the solvent supply vessel 10. The dissolved racemic mixture in vessel 22 is fed to the system via pump 21.
A solution of the less well retained enantiomer is collected in vessel 17, use being made of a difference in flow rate between the metering pumps 16 and 18. A solution of the more strongly retained enantiomer is collected in a similar way in vessel 14, use being made of a difference in flow rate between the metering pumps 13 and 15.
Example I
On a racemic mixture of R- and S-ketamine.HCl it was first determined at room temperature how much more S-configuration than R-configuration was incorporated into a suspension of swollen cellulose triacetate (CTA-I) particles. The CTA-I (ex Fluka) was composed of a sieve SU~ST~TlTE SH~ET (RULE 26) -CA 022029ll l997-04-l6 W O 96/11894 PCT/EP95/0~063 fraction of particles - in the non-swollen state - of 15-25 ym. After swelling in 70C ethanol there was obtained, after cooling and decanting, a suspension of swollen particles having a volume at room temperature of 25 ml/10 9.
Ten suspensions were prepared, each containing abcut 250 mg of swollen CTA-I partic1es and about 750 mg of a sodium carbonate neutralised alcoholic solution containing approximately 1 mg of ketamine.HCl/ml (90, 96, and 100% ethanol, and 90, 96, and 100% 2-propanol, respectively).
After about 5 minutes of shaking at room temperature the suspensions were left to settle. After filtration of the aforementioned liquid through a filter with a pore size of O,S ym, the concentration of ketamine enantiomer was determined on the filtrate using capillary zone electrophoresis. In the analysis the alcoholic solutions used to prepare the suspensions were taken as external standards to calculate the ketamine enantiomer content in the filtrate.
In the table below ket.HCl stands for ketamine.HCl, ETOH represents ethanol, and IPA stands for 2-propanol.
Table 1 sample ket.HCl Na~CO~ ETOH IPA water Na~HPO4 volume no. mg mg g g g g (0,1 M) ml 1. 1,12 0,22 0,750 - - - 0,95 2. 0,98 0,20 - 0,751 - - 0,96 3. 1,14 0,22 0,765 - 0,043 - 1,01 4. 0,99 0,20 - 0,761 0,044 - 1,01 5. 1,11 0,22 0,748 - 0,081 - 1,02 6. 0,98 0,20 - 0,754 0,089 - 1,05 7. 1,11 0,22 0,749 - - 0,050 1,00 8. 0,98 0,20 - 0,751 - 0,059 1,01 9. 1,21 0,24 0,812 - - 0,111 1,13 10. 0,97 0,20 - 0,750 - 0,080 1,03 The standard solutions contain 1,17 9 of ket.HCl/ml ETOH and 1,02 9 of ket.HCl/ml IPA, respectively. The measured quantities of R- and S-SU~$TITUTE S~EET (RULE 26) W 096/11894 PCT~P9~10~063 enantiomer in the liquid phase and the calculated amounts of R- and S-enantiomer in the CTA-I phase are listed in Table 2.
Table 2 sample measured in liquid calculated in CTA-I
nr. R S R S
mg mg mg mg 1. 0,45 0,51 0,11 0,05 2. 0,37 0,41 0,12 0,08 3. 0,51 0,56 0,06 0,01 4. 0,44 0,47 0,06 0,03 5. 0,46 0,51 0,10 0,05 6. 0,43 0,46 0,05 0,03 7. 0,37 Q 46 Q,19 0,09 8. 0,31 0,38 0,18 0,10 9. 0,37 0,47 0,23 0,14 10. 0,33 0,41 0,15 0,08 Example II
A racemic mixture of R- and S-ketamine.HCl was separated using two hollow fibre modules 1 and la having an inner diameter of 23 mm and a length of 155 mm, which were connected in series. Each module contained 2100 porous polypropylene fibres of 240 ~m inner diameter.
Prior to the start of the passage of dispersion, the apparatus was filled with solvent and de-aerated on the shell side by the application of a vacuum. The solvent in question was a mixture composed of 96% of ethanol and 4% of an 0,01 M Na2HP04 solution in water. The dispersion of gel particles was composed of CTA-I particles having the same dimensions as in Example I.
~ In order to prevent the hollow fibres becoming clogged through coagulation of the particles, the dispersion was subjected to ultrasonic vibration. For the same reason the modules were arranged vertically and the dispersion was passed through the modules from the top downwards. Further, there were two membrane pumps 23 and 24 to SUBSTITUTE S~EETtRULE 2~
-W O96/11894 PCT~EP95/01063 16 ~
ensure that the dispersion was kept in motion over the potting and to create a pulsed flow in the lumen. After 80 minutes the amount of solids was reduced from about 11,1 wt.% to about 8 wt.%. The concentration of the feed in the channel connected to the lumen of the two modules was 1 g/100 ml for the first 30 minutes. After 50 minutes a feed of a different composition was employed, which also contained salt used for neutralising. This solution contained 1 g/100 ml of ketamine.NaCl. After 87 minutes the apparatus was flushed with ethanol. The measurement data, compiled by sampling and analysing every 5 minutes, is listed in the table below. eeR % refers to the percentage of enantiomeric excess, which when defined for an (R)-enantiomer reads: eeR % = (CR-cS)/(cR+cR)x100%, wherein cR is the concentration of the (R)-enantiomer in mg/ml.
SU~STITUTE SHEET (RULE 2~) PCT~P95/04063 Table 3 0\O a~
aJ ~r o\O ~ C ~ I_ CO ~ O ~ ~O O W ~D W C~
I O O ~I O _ C~J O--I O--~ ~ ^ ^ ^ ^ ^ ^
3 o ~ _ ~ ~ _ ~ _ _ I _ - _ _ ~ ~ ~ ~ w 0 ~ w w ,3 ~ ~
-05 ~D n ~ ~ w ~t 0 ~ W ~ W ~D _ ~ . o o o o o o o o I o o o o o o o o o o o o o ~n E ~ 0 ~0 ~ w c ~ ~:) w C~
C~ ~ ~ C~J-- ~ O ~ ô ~ ô ~ o ~ _ ô _ _ _ ô _ _ _ ,_ ~ E
~ E r . ~ UO C~ L~ D ~ W C~ D 0 Ln .~ ~ C 1~ _ _~ ô ~ ô ô ô ô ô ô ô ô o ô ô ~
, ~ _, _ r-~ _, ~ _ _ _ _ ~ _ ~
~ aJ ~ c~J
E "l E Ln l_ Ln ~ J c O o~ D c~l D 0 ~ J ^ c~
._ o ~ ^ - ^ .` ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ O
=~ ~
O 0 ~ 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 O
t3 E E
O ~ C ~ ~ ~ ~1- ~ ~ ~ ~t ~ ~r ~ ~ e~ ~ ~t n~
v~
~ cJ
O
._ O Ln O u~ O Ln O Ln O ~ O Ln O Ln O ~ O ~ O O _ CA 022029ll l997-04-l6 W O96/1189~ PCT~EP9~/04063 Example III
In a manner analogous to that disclosed in Example I it was determined on a racemic mixture of 4-phenyl-1,3-dioxan at room temperature how much more (-)-configuration than (+)-configuration was incorporated into a suspension of swollen cellulose triacetate (CTA-I) particles.
The eluent used was 96% ethanol. The sample of the suspension was composed of 1 9 of CTA-I and 7 9 of 96% ethanol in which 1,16 mg/ml of (~)-4-phenyl-1,3-dioxan had been dissolved. After one hour of shaking at room temperature the suspension was left to settle.
For identification of the enantiomer and determination of the concentration use was made of an analytic column filled with CTA-I and the information provided in an article by R.M. Wolf and E. Francotte in J. Chem. Soc. Perkin Trans. II (1988), 893-901.
After one hour the upper liquid contained 0,43 mg/ml of (+)-4-phenyl-1,3-dioxan and 0,26 mg/ml of (-)-4-phenyl-1,3-dioxan.
Example IV
The experiment of Example III was repeated, except that this time the gel forming chiral adjuvant used was tribenzoyl cellulose, which was obtained in accordance with the synthesis specifications in K.H.
Rimboeck, J. of Chromatography 351 (1986), 346-350. It was found that the affinity of tribenzoyl cellulose was opposite to that of CTA-I, resulting in the concentrations in the liquid and the gel phase being inversely distributed. The sample of the suspension was composed of 1,0 9 of tribenzoyl cellulose (CTB) and 7 9 of 96~ ethanol in which 1,16 mg/ml of (+)-4-phenyl-1,3-dioxan had been dissolved.
After one hour the upper liquid contained 0,37 mg/ml of (+)-4-phenyl-1,3-dioxan and 0,40 mg/ml of (-)-4-phenyl-1,3-dioxan.
SUBSTITUTE SHEET (RULE 26) WO 96/11894 PCT/EP95/0,1063 Example V
J
The example below shows that it is possible to separate a 50/50 mixture of enantiomers of 4-phenyl-1,3-dioxan by subjecting it to countercurrent separation using a set-up of hollow fibre modules such as depicted in Fig. 2. The column indicated with the reference numerals 9a, 9b, 9c, 9d, 9e, 9f, 99, and 9h in that case represents 8 hollow fibre modules connected in series. The hollow fibre modules had an inner diameter of 10 mm and an effective length of 200 mm. Each glass module contained 300 porous polypropylene fibres with an inner and an outer diameter of 280 and 380 ~m, respectively (Oxyphan ox-pp5045/02.01) in an epoxy potting. The hollow fibres were bundled on a knitting machine at one stitch per centimeter. The fluid streams were pumped from vessel 1 (solvent) and vessel 3 (suspension) through the shell and the lumen in the modules with the aid of four membrane pumps with back pressure valves mounted at the ends of the separating column. The pair of pumps 5 and 6 in the lumen stream was coupled to give a simultaneous membrane stroke in the pumps and create a pulsed flow in the lumen. The pair of pumps 7 and 8 in the shell stream was synchronised in the same way. The displacement of liquid on the lumen side was alternated 20 times per minute with the displacement of suspension on the shell side. The air bubbles were expelled by recirculation of the solvent via a buffer vessel and recirculation of the suspension via a second buffer vessel. The amount of liquid in each of the buffer vessels during the recirculation was kept constant.
Where necessary, the difference in delivery capacity of the synchronised pumps was reduced by adjusting the pumps' stroke volume.
The liquid used for separating the racemate of (+)-4-phenyl-1,3-dioxan was made up of 96% ethanol. The separation was carried out using a suspension of CTA-I of the same proportions as indicated in Example I.
The suspension was composed of a mixture of 100 g of CTA-I in 700 9 of ethanol-water mixture (96+4).
SU~STITUTE SHEET (RUEE 26) W O 96/1189~
In order to prevent clogging through coagulation of the particles, the suspension was subjected to ultrasonic vibration and sieved. For the same reason the modules were arranged vertically and the dispersion was passed through the modules from the top downwards. Settling of the suspension was counteracted by pulsing the movement in the tubes and the modules.
The extraction process was started by adding 1 g of racemate of 4-phenyl-1,3-dioxan to the suspension of the aforementioned composition. The measurement data, compiled by sampling and analysing every 5 minutes, is listed in Table 4. ee+ % refers to the percentage of enantiomeric excess, which when defined for a (+)-enantiomer reads:
ee+ % = (c+-c-)/(c++c-)x100%, wherein c+ is the concentration of the (+)-enantiomer in mg/ml.
S~STtTUT~ S~tEET (RUL~ 2~) WO 96/1189~ PCT/EP95/04063 Table 4 ~, sample flow through enantiomer after lumen (solvent) concentration excess minutes or m~/ml m~/ml ee+ %
shell (dispersion) 4-phenyl-1 ,3-dioxan (+) (-) 0 lumen13,875 0,022 0,060 shell11,014 0,223 0,249 -5,51 lumen14,080 shell10,538 0,184 0,222 -9,33 ~ 25 lumen14,000 0,158 0,157 0,17 shell10,299 0,221 0,242 -4,47 lumen13,989 0,159 0,182 -6,68 shell10,044 0,227 0,254 -5,66 lumen13,929 0,159 0,158 0,38 shell10,031 0,227 0,274 -9,38 lumen13,914 0,157 0,154 1,16 shell10,137 0,228 0,252 -5,19 lumen13,833 0,154 0,150 1,21 shell 9,995 0,217 0,264 -9,74 lumen13,612 0,152 0,146 2,23 shell10,013 0,228 0,255 -5,71 lumen13,849 0,153 0,139 4,60 shell10,045 0,228 0,254 -5,30 lumen13,878 0,152 0,153 -0,33 100 shell 9,857 0,219 0,266 -9,62 105 lumen13,747 0,145 0,139 2,08 110 shell 9,912 0,234 0,260 -5,15 Example VI
In the example below it is demonstrated that an enantiomers mixture can be separated into the (+)- and (-)-constituents with a set-up such as depicted schematically in Fig. 3. In this set-up, the suspension of vessel 1 is recirculated, being first passed, via pump 2, through the shell of the two solvent regeneration modules 9a and 9b, where the remainder of one of the enantiomers is removed from the solvent flowing through the lumen. Next, the flow of suspension is passed through the shell of the two extraction modules 9c and 9d, the stripper modules 9e and 9f, and the washing modules 99 and 9h. From S~3STITUTE StlEET (RULE 26) W O96/11894 PCTAEP9~104063 there the virtually enantiomer-free suspension is passed to vessel 1.
The virtually enantiomer-free solvent is passed from vessel 10, via pump 11, through the lumen of the washing modules 9h and 9g, where the suspension containing one of the enantiomers is washed such that practically all of the enantiomer absorbed by the chiral adjuvant is re-released, before ending up in vessel 14, from where a portion is passed countercurrently through the lumen of the stripper modules 9f and 9e. In between the stripper modules 9e and 9f and the extraction modules 9c and 9d the racemic mixture of vessel 22 is dosed using pump 21. From 9c the lumen flow is passed, via pump 16, into vessel 17, from where because of a difference in pump discharge between the pumps 16 and 18 a portion of the liquid is passed into the lumen of the solvent regeneration modules 9b and qa.
Complete separation of the racemic mixture is obtained by setting the flow ratios in the extraction and stripper modules using the equilibrium data of Example III and the design procedure disclosed by Giuseppe Storti et al. in Ind. Eng. Chem. Res. 34, 288-301 (1995).
The mean flow rate of the suspension in the scheme depicted in Fig. 3 is kept constant and equal in each module by an alternating pump action similar to that described in Example V. The solid flow rate can be calculated from the suspension flow rate.
The mean flow rate of the liquid is set per module section, and the differences in liquid flow rate between sections are compensated for by the solvent, raffinate, feed, and extract streams. Net liquid flow rates are calculated from the countercurrent suspension flow rate and the liquid flow rate. The net liquid flow rate and the solid flow rate are the parameters used in the aforementioned design procedure.
A module section can be used as a washer, stripper, extractor or solvent regenerator by adjusting a flow rate ratio within a specified range.
The system disclosed in Examples III and V, with a mean flow rate for SUBSTITUTE SHEET ~RULE 26) W O 96/11894 PCT~P95/04063 the suspension of 10 ml/min, will require the following typical mean liquid flow rates: 28 ml/min of liquid for the washing modules, 13,9 ml/min for the stripper modules, 14,1 ml/min for the extraction modules, and 4 ml/min for the amount of regenerated solvent. The resulting streams of the raffinate, feed, and extract are: 14,1 ml/min, 0,2 ml/min, and 10,2 ml/min, respectively.
ITUTE SHEET (RVLE 2
Claims (13)
1. A process for separating enantiomers from a racemic mixture by countercurrent extraction using at least two substances, one of them a liquid in which the racemic mixture to be separated is present, the other containing a chiral adjuvant, characterised in that the chiral adjuvant is a gel forming substance or is combined with or forms part of a gel forming substance in the form of discrete swollen particles in a liquid separated from the countercurrently flowing liquid containing the racemate to be separated by a microporous membrane having a pore size such that the pores can no longer be penetrated by the gel forming particles separated on conclusion of the extraction, followed by the setting free therefrom of one of the enantiomers under the influence of a stimulus, after which the particles are re-incorporated into the extracting process if so desired.
2. A process according to claim 1, characterised in that after it has been released from the gel forming particles, the enantiomer is purified by extraction and, optionally, evaporation of the extracting agent and/or crystallisation.
3. A process according to claim 1, characterised in that the chiral adjuvant is covalently bonded to the gel forming substance.
4. A process according to claim 1, characterised in that the chiral adjuvant is a gel forming substance in the form of a molecularly imprinted polymer (MIP) prepared against one of the enantiomers to be separated.
5. A process according to claim 1, characterised in that during the extraction the gel forming particles are in the swollen state.
6. A process according to claim 1, characterised in that the stimulus with which one of the extracted enantiomers is set free from the gel forming particles takes the form of a change in temperature, a change in pH, in salt concentration, electric or magnetic field, and/or solvent composition.
7. A process according to claim 1, characterised in that the gel forming particles are provided in the pores of a carrier or on its surface.
8. A process according to claim 7, characterised in that the carrier is composed of porous polymer particles.
9. A process according to claim 1, characterised in that the microporous membrane is composed of microporous polypropylene.
10. A process according to claim 1, characterised in that the microporous membrane is in the form of a hollow fibre.
11. A process according to claim 9, characterised in that the liquid flowing around the microporous polypropylene is tailored to the polarity of the membrane by the incorporation of 0,1 to 5 wt. % of n-hexane.
12. A process according to claim 1, characterised in that depending on whether the liquid flowing around it has polar or apolar properties, the microporous membrane is rendered hydrophilic or hydrophobic by the chemical route.
13. A process according to claim 1, characterised in that depending on whether the liquid flowing around it has polar or apolar properties, the microporous membrane is rendered hydrophilic or hydrophobic by physical modification, for instance by treatment with a surface-active compound.
Applications Claiming Priority (2)
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NL9401705 | 1994-10-17 | ||
NL9401705 | 1994-10-17 |
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CA2202911A1 true CA2202911A1 (en) | 1996-04-25 |
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CA002202911A Abandoned CA2202911A1 (en) | 1994-10-17 | 1995-10-16 | Process for separating enantiomers from a racemic mixture |
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EP (1) | EP0787116A1 (en) |
JP (1) | JPH10507192A (en) |
AU (1) | AU3842795A (en) |
CA (1) | CA2202911A1 (en) |
WO (1) | WO1996011894A1 (en) |
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BRPI0002693B8 (en) * | 2000-06-19 | 2021-05-25 | Cristalia Produtos Quim Farmaceuticos Ltda | process for obtaining the enantiomers of ketamine and its pharmaceutically acceptable salts |
US9809706B2 (en) | 2013-08-30 | 2017-11-07 | Council Of Scientific & Industrial Research | Racemic drug resolution using polymer supported chiral selector |
US20160332962A1 (en) | 2015-05-13 | 2016-11-17 | Janssen Pharmaceutica Nv | (s)-csa salt of s-ketamine, (r)-csa salt of s-ketamine and processes for the preparation of s-ketamine |
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JPS59166502A (en) * | 1983-03-10 | 1984-09-19 | Daicel Chem Ind Ltd | Separating agent |
GB2233248A (en) * | 1989-06-07 | 1991-01-09 | Aligena Ag | Enantiomer enrichment by membrane processes |
US5080795A (en) * | 1990-05-23 | 1992-01-14 | Research Corporation Technologies, Inc. | Supported chiral liquid membrane for the separation of enantiomers |
ATE148443T1 (en) * | 1992-10-07 | 1997-02-15 | Akzo Nobel Nv | METHOD FOR SEPARATING ENANTIOMERS FROM A RACEMIX MIXTURE |
-
1995
- 1995-10-16 CA CA002202911A patent/CA2202911A1/en not_active Abandoned
- 1995-10-16 WO PCT/EP1995/004063 patent/WO1996011894A1/en not_active Application Discontinuation
- 1995-10-16 AU AU38427/95A patent/AU3842795A/en not_active Abandoned
- 1995-10-16 JP JP8512950A patent/JPH10507192A/en active Pending
- 1995-10-16 EP EP95936506A patent/EP0787116A1/en not_active Withdrawn
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WO1996011894A1 (en) | 1996-04-25 |
JPH10507192A (en) | 1998-07-14 |
AU3842795A (en) | 1996-05-06 |
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