CN106414376B - 获得光学活性吡吲哚对映异构体及其盐的方法 - Google Patents
获得光学活性吡吲哚对映异构体及其盐的方法 Download PDFInfo
- Publication number
- CN106414376B CN106414376B CN201480078731.6A CN201480078731A CN106414376B CN 106414376 B CN106414376 B CN 106414376B CN 201480078731 A CN201480078731 A CN 201480078731A CN 106414376 B CN106414376 B CN 106414376B
- Authority
- CN
- China
- Prior art keywords
- pirlindole
- acid
- compound obtained
- salt
- free alkali
- 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.)
- Active
Links
- 229950002220 pirlindole Drugs 0.000 title claims abstract description 153
- 150000003839 salts Chemical class 0.000 title claims abstract description 43
- 238000000034 method Methods 0.000 title claims abstract description 42
- IWVRVEIKCBFZNF-UHFFFAOYSA-N LSM-1636 Chemical compound C1CNC2CCCC3=C2N1C1=CC=C(C)C=C13 IWVRVEIKCBFZNF-UHFFFAOYSA-N 0.000 title claims abstract description 20
- 230000003287 optical effect Effects 0.000 title claims abstract description 8
- 239000003513 alkali Substances 0.000 claims abstract description 32
- 239000003814 drug Substances 0.000 claims abstract description 6
- 229940079593 drug Drugs 0.000 claims abstract description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 42
- 239000002253 acid Substances 0.000 claims description 40
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 26
- 239000003960 organic solvent Substances 0.000 claims description 19
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 18
- 150000001875 compounds Chemical class 0.000 claims description 17
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 13
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 12
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 claims description 12
- 235000019441 ethanol Nutrition 0.000 claims description 12
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 10
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 10
- 229940043265 methyl isobutyl ketone Drugs 0.000 claims description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 238000005660 chlorination reaction Methods 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 9
- IWYDHOAUDWTVEP-SSDOTTSWSA-M (R)-mandelate Chemical compound [O-]C(=O)[C@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-SSDOTTSWSA-M 0.000 claims description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 7
- 239000003125 aqueous solvent Substances 0.000 claims description 7
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 6
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical group COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 claims description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 6
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 6
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 claims description 6
- IWYDHOAUDWTVEP-SSDOTTSWSA-N (R)-mandelic acid Chemical compound OC(=O)[C@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-SSDOTTSWSA-N 0.000 claims description 5
- IWYDHOAUDWTVEP-ZETCQYMHSA-M (S)-mandelate Chemical compound [O-]C(=O)[C@@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-ZETCQYMHSA-M 0.000 claims description 5
- 239000012458 free base Substances 0.000 claims description 5
- IWYDHOAUDWTVEP-ZETCQYMHSA-N (S)-mandelic acid Chemical compound OC(=O)[C@@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-ZETCQYMHSA-N 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- 238000004090 dissolution Methods 0.000 claims description 4
- 230000001376 precipitating effect Effects 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- 239000000725 suspension Substances 0.000 claims description 4
- LSPHULWDVZXLIL-LDWIPMOCSA-N (?)-Camphoric acid Chemical compound CC1(C)[C@@H](C(O)=O)CC[C@@]1(C)C(O)=O LSPHULWDVZXLIL-LDWIPMOCSA-N 0.000 claims description 3
- BJEPYKJPYRNKOW-UWTATZPHSA-N (R)-malic acid Chemical compound OC(=O)[C@H](O)CC(O)=O BJEPYKJPYRNKOW-UWTATZPHSA-N 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical class ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 3
- LSPHULWDVZXLIL-QUBYGPBYSA-N camphoric acid Chemical compound CC1(C)[C@H](C(O)=O)CC[C@]1(C)C(O)=O LSPHULWDVZXLIL-QUBYGPBYSA-N 0.000 claims description 3
- 229960001760 dimethyl sulfoxide Drugs 0.000 claims description 3
- 238000000638 solvent extraction Methods 0.000 claims description 3
- 238000013507 mapping Methods 0.000 claims description 2
- QSLPNSWXUQHVLP-UHFFFAOYSA-N $l^{1}-sulfanylmethane Chemical compound [S]C QSLPNSWXUQHVLP-UHFFFAOYSA-N 0.000 claims 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims 2
- 244000248349 Citrus limon Species 0.000 claims 2
- 235000005979 Citrus limon Nutrition 0.000 claims 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims 2
- 229910052794 bromium Inorganic materials 0.000 claims 2
- 229910052739 hydrogen Inorganic materials 0.000 claims 2
- 239000001257 hydrogen Substances 0.000 claims 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims 2
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 claims 1
- RDRCCJPEJDWSRJ-UHFFFAOYSA-N pyridine;1h-pyrrole Chemical compound C=1C=CNC=1.C1=CC=NC=C1 RDRCCJPEJDWSRJ-UHFFFAOYSA-N 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- 238000004296 chiral HPLC Methods 0.000 description 12
- 238000001035 drying Methods 0.000 description 11
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 9
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 7
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 7
- 206010013786 Dry skin Diseases 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 239000008367 deionised water Substances 0.000 description 5
- 229910021641 deionized water Inorganic materials 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 229910052938 sodium sulfate Inorganic materials 0.000 description 5
- 235000011152 sodium sulphate Nutrition 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- 230000005526 G1 to G0 transition Effects 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 238000005194 fractionation Methods 0.000 description 3
- 238000004811 liquid chromatography Methods 0.000 description 3
- UTEFBSAVJNEPTR-RGEXLXHISA-N loprazolam Chemical compound C1CN(C)CCN1\C=C/1C(=O)N2C3=CC=C([N+]([O-])=O)C=C3C(C=3C(=CC=CC=3)Cl)=NCC2=N\1 UTEFBSAVJNEPTR-RGEXLXHISA-N 0.000 description 3
- 229960003019 loprazolam Drugs 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- UOCLXMDMGBRAIB-UHFFFAOYSA-N 1,1,1-trichloroethane Chemical class CC(Cl)(Cl)Cl UOCLXMDMGBRAIB-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- -1 Hemisulphate Chemical compound 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- WNLRTRBMVRJNCN-UHFFFAOYSA-L adipate(2-) Chemical compound [O-]C(=O)CCCCC([O-])=O WNLRTRBMVRJNCN-UHFFFAOYSA-L 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 229960004543 anhydrous citric acid Drugs 0.000 description 2
- 229940077388 benzenesulfonate Drugs 0.000 description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- VFNGKCDDZUSWLR-UHFFFAOYSA-L disulfate(2-) Chemical compound [O-]S(=O)(=O)OS([O-])(=O)=O VFNGKCDDZUSWLR-UHFFFAOYSA-L 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 229930195712 glutamate Natural products 0.000 description 2
- 150000002475 indoles Chemical class 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 230000006340 racemization Effects 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 229950004288 tosilate Drugs 0.000 description 2
- 238000007738 vacuum evaporation Methods 0.000 description 2
- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 description 1
- DSSYKIVIOFKYAU-XCBNKYQSSA-N (R)-camphor Chemical compound C1C[C@@]2(C)C(=O)C[C@@H]1C2(C)C DSSYKIVIOFKYAU-XCBNKYQSSA-N 0.000 description 1
- 229940080296 2-naphthalenesulfonate Drugs 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical class OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 241000723346 Cinnamomum camphora Species 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 229940091512 Monoamine oxidase A inhibitor Drugs 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229920002230 Pectic acid Polymers 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 208000030961 allergic reaction Diseases 0.000 description 1
- AEMOLEFTQBMNLQ-BKBMJHBISA-N alpha-D-galacturonic acid Chemical compound O[C@H]1O[C@H](C(O)=O)[C@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-BKBMJHBISA-N 0.000 description 1
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000001509 aspartic acid derivatives Chemical class 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- SXDBWCPKPHAZSM-UHFFFAOYSA-N bromic acid Chemical compound OBr(=O)=O SXDBWCPKPHAZSM-UHFFFAOYSA-N 0.000 description 1
- 229960000846 camphor Drugs 0.000 description 1
- 229930008380 camphor Natural products 0.000 description 1
- 229950005953 camsilate Drugs 0.000 description 1
- 150000001716 carbazoles Chemical class 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229960004106 citric acid Drugs 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-M heptanoate Chemical compound CCCCCCC([O-])=O MNWFXJYAOYHMED-UHFFFAOYSA-M 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-M hexanoate Chemical compound CCCCCC([O-])=O FUZZWVXGSFPDMH-UHFFFAOYSA-M 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-M naphthalene-2-sulfonate Chemical compound C1=CC=CC2=CC(S(=O)(=O)[O-])=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-M 0.000 description 1
- 229960002715 nicotine Drugs 0.000 description 1
- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- JRKICGRDRMAZLK-UHFFFAOYSA-L peroxydisulfate Chemical compound [O-]S(=O)(=O)OOS([O-])(=O)=O JRKICGRDRMAZLK-UHFFFAOYSA-L 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229940075930 picrate Drugs 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000004237 preparative chromatography Methods 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 150000003335 secondary amines Chemical group 0.000 description 1
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000010977 unit operation Methods 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/06—Peri-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B57/00—Separation of optically-active compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Indole Compounds (AREA)
Abstract
本发明提供一种获得光学活性吡吲哚对映异构体的新方法,其处于游离碱的形式或者处于药学上可接受的盐的形式。本发明所获得的产物是对映异构体纯的,并且可用作药物。
Description
技术领域
本发明涉及一种获得光学活性吡吲哚对映异构体的方法,其处于游离碱形式或者处于药学上可接受的盐形式。
本发明的光学活性吡吲哚对映异构体是(R)-吡吲哚和(S)-吡吲哚。
本发明所获得的产品是对映异构体纯,并且可用作药物。
背景技术
吡吲哚,2,3,3a,4,5,6-六氢-1H-8-甲基-吡嗪[3,2,1-j,k]咔唑是一种式I的四环化合物:
吡吲哚是可逆的单胺氧化酶A抑制剂,目前用作抑郁症治疗药物中。
吡吲哚具有非对称的碳原子,这意味着存在两种对映异构体:(S)-吡吲哚和(R)-吡吲哚。
现有技术教导了几种用于对映异构体分离吡吲哚的方法。例如Ceccato等人的TheJournal of Pharmaceutical and Biomedical Analysis,18(1998)605-614,“Enantiomeric separation of pirlindole by liquid chromatography usingdifferent types of chiral stationary phases”公开了通过液相色谱法(LC),使用三种不同的手性固定相来分离吡吲哚对映异构体。
此外,Chiap等人的The Journal of Pharmaceutical and Biomedical Analysis27(2002)447-455,“Automated determination of pirlindole enantiomers in plasmaby on-line coupling of a pre-column packed with restricted access material toa chiral liquid chromatographic column”公开了将用于样品清洁的受限获取的材料填充的预备柱连接到含有纤维素基手性固定相的柱上,来分离和定量分析对映异构体。
根据现有技术,Chirality 11:261-266(1999),全部通过用光学活性酸选择性结晶来获得吡吲哚的对映异构体的努力都失败了,并且使用衍生技术结合制备性色谱法,仅仅可能获得实验室规模(几克)的盐酸盐。
现有技术公开的方法的特性局限于一种明确的方式,它以工业或者半工业规模来实施,这归因于必需使用大规模的色谱法来分离,这使得所述方法非常昂贵,难以实施和再现性差。
因此本领域需要寻找一种新方法,其是可行的,并且易于工业应用,来获得处于它的游离碱形式或者作为药学上可接受的盐的吡吲哚的对映异构体。
发明内容
根据本发明,(R)-吡吲哚和(S)-吡吲哚可以以游离碱形式或者药学上可接受的盐的形式来获得,不同于现有技术的教导:用光学活性酸来结晶游离碱形式的(外消旋)-吡吲哚,并且随后使得它作为游离碱或者作为药学上可接受的盐来产生。
所以本发明的一个目标是一种获得游离碱形式或者药学上可接受的盐形式的光学活性(R)-和(S)-吡吲哚对映异构体的方法,特征在于通过用光学活性酸结晶游离碱形式的(外消旋)-吡吲哚来进行拆分。
该光学活性吡吲哚对映异构体是对映异构体纯(S)-吡吲哚或者(R)-吡吲哚。
所以本发明的另一目标是一种方法,特征在于包含下面的步骤:
i)将(外消旋)-吡吲哚盐酸盐溶解在水性溶剂中,随后用氯化的溶剂随后萃取,并且完全除去溶剂来获得处于游离碱形式的(外消旋)-吡吲哚;
ii)将步骤i)所获得的(外消旋)-吡吲哚溶解在有机溶剂中,随后加入光学活性酸用于拆分;
iii)将ii)中形成的悬浮液搅拌15min至2h,同时发生非对映异构体盐沉淀;
iv)过滤所获得的非对映异构体盐和通过悬浮在有机溶剂中来纯化它,以获得处于药学上可接受的盐的形式的,用光学活性酸形成的(S)-吡吲哚或者(R)-吡吲哚对映异构体;和任选的,
v)通过将步骤iv)获得的产物溶解在水性溶剂中,随后用氯化的溶剂萃取和完全除去溶剂,来获得作为游离碱的对映异构体纯(S)-吡吲哚和/或(R)-吡吲哚;和进一步任选的,
vi)如下来获得处于药学上可接受的酸加成盐形式的S)-吡吲哚或者(R)-吡吲哚:用药学上可接受的酸对步骤v)所获得的处于游离碱形式的对映异构体纯(S)-吡吲哚和/或(R)-吡吲哚进行成盐,来形成(S)-吡吲哚或者(R)-吡吲哚对映异构体的药学上可接受的酸加成盐。
同样本发明的另一目标是一种前述的方法,其中步骤ii)所用的光学活性酸选自:(R)-扁桃酸,(R)-(+)-α-甲氧基-α-三氟苯基乙酸,(1R,3S)-(+)-樟脑酸,D(+)-苹果酸,(S)-扁桃酸,(S)-(-)-α-甲氧基-α-三氟苯基乙酸,(1S,3R)-(+)-樟脑酸或者L(-)-苹果酸。
同样本发明的另一目标是一种前述方法,其中步骤ii)和iv)所用的有机溶剂选自:甲醇,乙醇,丙醇,1-丁醇,2-丁醇,叔丁醇,2-丁酮,丙酮,乙基甲基酮,甲基异丁基酮,二甲基亚砜,1,2-二氯乙烷,二乙基醚,二甲基醚,二甲基甲酰胺,甲基叔丁基醚,2-丙醇,吡啶,甲苯,二甲苯或者其任意比例的混合物。
另外,本发明的另一目标是前述方法,特征在于所获得的化合物是对映异构体纯(S)-吡吲哚(R)-扁桃酸盐,(R)-吡吲哚(S)-扁桃酸盐,(S)-吡吲哚氢溴酸盐,(R)-吡吲哚氢溴酸盐,(S)-吡吲哚柠檬酸盐,(R)-吡吲哚柠檬酸盐,(S)-吡吲哚甲磺酸盐,(R)-吡吲哚甲磺酸盐,(R)-吡吲哚(R)-(+)-α-甲氧基-α-三氟苯基乙酸盐和(S)-吡吲哚R)-(+)-α-甲氧基-α-三氟苯基乙酸盐。
具体实施方式
根据本发明,(R)-吡吲哚和(S)-吡吲哚可以以游离碱形式或者药学上可接受的盐的形式来获得,不同于现有技术的教导:用光学活性酸来结晶游离碱形式的(外消旋)-吡吲哚,并且随后使得它作为游离碱或者作为药学上可接受的盐来产生。
更具体的,根据本发明,游离碱形式或者药学上可接受的盐形式的(R)-吡吲哚和(S)-吡吲哚可以如下来获得:用光学活性酸在有机溶剂中结晶游离碱形式的(外消旋)-吡吲哚,和任选的,它随后用药学上可接受的酸进行盐化来形成药学上可接受的盐。
申请人已经发现在某些具体加工条件下,确实可以进行外消旋非对映异构体吡吲哚的拆分。
上述基本加工条件包括预先分离外消旋吡吲哚(不使用它时,令人惊讶的不可能进行有效拆分),在加入光学活性酸之后的搅拌时间(其必须专门控制来避免外消旋化)和用于光学活性酸的加入阶段和纯化的有机溶剂的具体类型。
申请人已经发现对于短期搅拌来说,在将光学活性酸加入游离碱形式的(外消旋)-吡吲哚中之后,拆分是无效的,和对于较长时间的搅拌来说,发生外消旋化。
作为一个通用规则,搅拌进行15分钟至2小时的时间。优选搅拌进行30分钟至1小时的时间。
申请人还已经发现用于光学活性酸加成阶段(拆分)和纯化的具体有机溶剂的选择是相当重要的,因为其显著影响了拆分方法的效率和产率。
本发明的方法首次获得了这样量的游离碱或者药学上可接受的盐形式的(R)-吡吲哚和(S)-吡吲哚,其能够进行临床前和临床研究,另外其是这样的方法,其容易以工业规模使用,这不同于本领域已知的方法。
该吡吲哚分子具有仲胺基团,其具有碱性属性和因此可以形成酸加成盐,其是药学上可接受的盐。
本发明所述的方法允许获得处于它的游离碱形式和药学上可接受的盐形式二者的(R)-吡吲哚和(S)-吡吲哚。
在本发明中,当通过手性光谱法所计算的对映异构体纯度等于或者大于97%时,它被认为是对映异构体纯的。
本发明的方法当从(外消旋)-吡吲哚盐酸盐开始时,包含下面的步骤:
i)将(外消旋)-吡吲哚盐酸盐溶解在水性溶剂中,随后用氯化的溶剂随后萃取,并且完全除去溶剂来获得处于游离碱形式的(外消旋)-吡吲哚;
ii)将步骤i)所获得的(外消旋)-吡吲哚溶解在有机溶剂中,随后加入光学活性酸用于拆分;
iii)将ii)中形成的悬浮液搅拌15min至2h,同时发生非对映异构体盐沉淀;
iv)过滤所获得的非对映异构体盐和通过悬浮在有机溶剂中来纯化它,以获得处于药学上可接受的盐的形式的,用光学活性酸形成的(S)-吡吲哚或者(R)-吡吲哚对映异构体;
除了详细的方法步骤,和在打算获得的产物是作为游离碱或者作为合适的有机酸和无机酸的药学上可接受的酸加成盐的(S)-吡吲哚或者(R)-吡吲哚对映异构体的情况中,所述的方法涉及任选的至少一种下面的步骤:
v)通过将步骤iv)获得的产物溶解在水性溶剂中,随后用氯化的溶剂萃取和完全除去溶剂,来获得作为游离碱的对映异构体纯(S)-吡吲哚和/或(R)-吡吲哚;和
vi)如下来获得处于药学上可接受的酸加成盐形式的S)-吡吲哚或者(R)-吡吲哚:用药学上可接受的酸对步骤v)所获得的处于游离碱形式的对映异构体纯(S)-吡吲哚和/或(R)-吡吲哚进行成盐。
所进行的单元操作,所获得的产率,不存在困难条件的步骤(例如高温)和特别是不需要使用色谱法来分离使得这种方法特别适于工业使用,并且其是独特的和与现有技术相比是不同的。
在本发明中,术语“药学上可接受的盐”指的是那些盐,其处于合理的医学评价范围内,适用于与人体和低等动物的组织和器官接触,不表现出毒性,刺激,过敏反应等,并且是与合理的益处/风险比一致的。药学上可接受的盐包括用有机酸和无机酸所形成的那些药学上可接受的酸加成盐和根据本发明,用光学活性酸形成的那些药学上可接受的盐。
代表性的酸加成盐包括但不限于乙酸盐,己二酸盐,藻酸盐,柠檬酸盐,天冬氨酸盐,苯甲酸盐,苯磺酸盐,硫酸氢盐,丁酸盐,樟脑酸盐,樟脑磺酸盐,二葡糖酸盐,富马酸盐,甘油磷酸盐,半硫酸盐,庚酸盐,己酸盐,富马酸盐,盐酸盐,氢溴酸盐,氢碘酸,2-羟基乙烷磺酸盐(羟乙基磺酸盐),乳酸盐,马来酸盐,甲烷磺酸盐,烟碱酸盐,2-萘磺酸盐,草酸盐,扑酸盐,果胶酸盐,过硫酸盐,3-苯基丙酸盐,苦味酸盐,戊酸盐,丙酸盐,琥珀酸盐,酒石酸盐,硫代氰酸盐,磷酸盐,谷氨酸盐,碳酸氢盐,对甲苯磺酸盐和十一碳酸盐。
可以用于与本发明的化合物形成药学上可接受的酸加成盐的酸的非限定性例子包括无机酸例如盐酸,氢溴酸(HBR),硫酸和磷酸和有机酸例如柠檬酸,无水柠檬酸,扁桃酸,琥珀酸和甲烷磺酸。
在本发明中,“光学活性酸”包括(S)-扁桃酸,(R)-扁桃酸,(R)-(+)-α-甲氧基-α-三氟苯基乙酸,(S)-(-)-α-甲氧基-α-三氟苯基乙酸,(1S,3R)-(-)-樟脑酸,(1R,3S)-(+)-樟脑酸,L-(-)-苹果酸,D-(+)-苹果酸,或者类似的本领域公知的光学活性酸。
在本发明中,术语“水性溶剂”指的是水或者水与其他有机溶剂的混合物,在其中水是主要组分,即,水的存在量不低于95%(v/v)。
在本发明中,术语“有机溶剂”指的是通常用于有机化学中的溶剂或者其任意比例的混合物。
用于本发明方法的步骤ii)和iv)的有机溶剂的非限定性例子选自:甲醇,乙醇,丙醇,1-丁醇,2-丁醇,叔丁醇,2-丁酮,丙酮,乙基甲基酮,甲基异丁基酮,二甲基亚砜,1,2-二氯乙烷,二乙基醚,二甲基醚,二甲基甲酰胺,甲基叔丁基醚,2-丙醇,吡啶,甲苯,二甲苯等等,及其任意比例的混合物。
优选的是下面的溶剂:乙醇,甲醇,1-丁醇,2-丁醇,叔丁醇,丙酮,甲乙酮和异丙醇以及任意比例的混合物,例如异丙醇/丙酮(1:1),乙醇/丙酮(1:1),乙醇/甲基异丁基酮(1:1)和乙醇/1-丁醇(1:4)。
在本发明中,术语“氯化的溶剂”表示氯仿,二氯甲烷,二氯甲烷,三氯甲烷或者四氯化碳,或者其任意比例的混合物。
根据本发明所获得的化合物是:
(S)-吡吲哚(S)-扁桃酸盐;
(S)-吡吲哚(R)-扁桃酸盐;
(S)-吡吲哚(R)-(+)-α-甲氧基-α-三氟苯基乙酸盐;
(R)-吡吲哚氢溴酸;
(R)-吡吲哚甲磺酸盐;
(S)-吡吲哚柠檬酸盐;
(R)-吡吲哚柠檬酸盐;
(R)-吡吲哚(游离碱);
(S)-吡吲哚(游离碱);
通过本发明的方法可获得的其他化合物的例子是:
(S)-吡吲哚氢溴酸
(S)-吡吲哚甲磺酸盐
(S)-吡吲哚苯磺酸盐
(R)-吡吲哚对甲苯磺酸盐
(S)-吡吲哚硫酸氢盐
(R)-吡吲哚草酸盐
(R)-吡吲哚马来酸盐
(S)-吡吲哚乙酸盐
(S)-吡吲哚谷氨酸酯
(S)-吡吲哚乳酸盐
(R)-吡吲哚己二酸盐
(R)-吡吲哚苯甲酸盐
(S)-吡吲哚苹果酸盐
实施例
下面的实施例目的是说明本发明,并且不应当解释为对其进行限制。
实施例1
(R)-吡吲哚(S)-扁桃酸盐
在室温将100g(0.38mol)的(R,S)-吡吲哚盐酸盐溶解在16L去离子水中。向该溶液中加入42.4g(0.4mol)的无水碳酸钠,并且将内容物搅拌1h。
将上面的溶液用3x4L的二氯甲烷萃取,并且将合并的有机相在硫酸钠上干燥和在真空下蒸发干燥。
向该浓缩物中加入2L丙酮。
在搅拌下向上面的溶液中加入27.6g(0.18mol)的(S)-扁桃酸在150ml丙酮中的溶液。
搅拌持续45分钟。
将沉淀的产物过滤,用2x100mL丙酮清洗和在真空下在35℃-45℃干燥。
将上面的产物悬浮于乙醇(250mL)中,随后过滤和在真空下在35℃-45℃干燥,产生48.5g(0.13mol)的(R)-吡吲哚(S)-扁桃酸盐(产率=68%)。手性HPLC(对映异构体纯度=98.2%)。
实施例2
(S)-吡吲哚(R)-扁桃酸盐
使用与实施例1相同的程序(除了手性酸加入后的搅拌时间是60min之外),由100g(0.38mol)的(R,S)-吡吲哚盐酸盐开始和使用27.6g(0.18mol)的(R)-扁桃酸,产生了45.6g(0.12mol)的(S)-吡吲哚(R)-扁桃酸盐(产率=63%)。手性HPLC(对映异构体纯度=98.7%)。
实施例3
(S)-吡吲哚(R)-扁桃酸盐
使用与实施例1相同的程序,除了将异丙醇/丙酮(1:1)的混合物用作有机溶剂和手性酸加入后的搅拌时间是35min之外,由10g(0.038mol)的(R,S)-吡吲哚盐酸盐开始和使用2.8g(0.018mol)的(R)-扁桃酸,产生了4.1g(0.011mol)的(S)-吡吲哚(R)-扁桃酸盐(产率=57.9%)。手性HPLC(对映异构体纯度=98.1%)。
实施例4
(S)-吡吲哚(R)-(+)-α-甲氧基-α-三氟苯基乙酸盐
使用与实施例1相同的程序,除了将乙醇/丙酮(1:1)的混合物用作有机溶剂,手性酸加入后的搅拌时间是55min和作为光学活性酸,使用(R)-(+)-α-甲氧基-α-三氟苯基乙酸(8.3g)(0.018mol)之外,由10g(0.038mol)的(R,S)-吡吲哚盐酸盐开始,产生了4.8g(0.010mol)的(S)-吡吲哚(R)-(+)-α-甲氧基-α-三氟苯基乙酸盐(产率=52.6%)。手性HPLC(对映异构体纯度=97.7%)。
实施例5
(R)-吡吲哚氢溴酸
将实施例1所获得的产物(10g,0.027mol)溶解在550ml去离子水中。将水相用3x300ml的氯仿萃取。将合并的有机相在硫酸钠上干燥,在真空下蒸发干燥和加入200ml丙酮。
在搅拌下向上面的溶液中加入6ml的HBr溶液(48%水溶液)(0.04mol)。
将该干燥的沉淀产物过滤,用2x10ml丙酮清洗和在真空下在35℃-45℃干燥。
将上面的产物悬浮于乙醇/甲基异丁基酮(1:1)(250mL)中,随后过滤和在真空下在35℃-45℃干燥,产生了6.5g(0.021mol)的(R)-吡吲哚氢溴酸(产率=77.8%)。手性HPLC(对映异构体纯度=97.9%)。
实施例6
(R)-吡吲哚柠檬酸盐
将实施例1所获得的产物(10g,0.027mol)溶解在550ml去离子水中。将水相用3x300ml的三氯乙烷萃取。将合并的有机相在硫酸钠上干燥,在真空下蒸发干燥和加入200ml丙酮。
在搅拌下向上面的溶液中加入7.7g无水柠檬酸(0.04mol)。
将该干燥的沉淀产物过滤,用2x10ml丙酮清洗和在真空下在35℃-45℃干燥。
将上面的产物悬浮于乙醇/1-丁醇(1:4)(250mL)中,随后过滤和在真空下在35℃-45℃干燥,产生了9.2g(0.020mol)的(R)-吡吲哚柠檬酸盐(产率=74.1%)。手性HPLC(对映异构体纯度=97.6%)。
实施例7
(R)-吡吲哚甲磺酸盐
由实施例1所获得的10g的(R)-吡吲哚(S)-扁桃酸盐开始和依照实施例5所述的程序,使用甲烷磺酸作为药物可接受的酸,获得了7.4g(0.023mol)的(R)-吡吲哚甲磺酸盐(产率=85.2%)。手性HPLC(对映异构体纯度=98.0%)。
实施例8
(S)-吡吲哚氢溴酸
由实施例2所获得的10g的(S)-吡吲哚(R)-扁桃酸盐开始,使用氢溴酸作为药物可接受的酸和依照实施例6所述的程序,获得了7.4g(0.024mol)的(S)-吡吲哚氢溴酸(产率=88.9%)。手性HPLC(对映异构体纯度=98.2%)。
实施例9
(S)-吡吲哚甲磺酸盐
由实施例2所获得的10g的(S)-吡吲哚(R)-扁桃酸盐开始和依照实施例6所述的程序,使用甲烷磺酸作为药物可接受的酸,获得了6.8g(0.021mol)的(S)-吡吲哚甲磺酸盐(产率=77.8%)。手性HPLC(对映异构体纯度=98.0%)。
实施例10
(S)-吡吲哚柠檬酸盐
由实施例2所获得的10g的(S)-吡吲哚的(R)-扁桃酸盐开始和依照实施例6所述的程序,使用柠檬酸作为药物可接受的酸,获得了9.5g(0.021mol)的(R)-吡吲哚柠檬酸盐(产率=77.8%)。手性HPLC(对映异构体纯度=98.5%)。
实施例11
(R)-吡吲哚(游离碱)
将实施例1所获得的产物(2g,0.005mol)溶解在110ml去离子水中。将水相用3x75ml二氯甲烷萃取。将合并的有机相在硫酸钠上干燥,在真空下蒸发,直到完全除去溶剂,并且在0℃/5℃放置一整夜。发生了结晶。获得了1.1g(0.0049mol)的((R)-吡吲哚(游离碱)(产率=98%)。手性HPLC(对映异构体纯度=98.3%)。
实施例12
(S)-吡吲哚(游离碱)
将实施例2所获得的产物(2g,0.005mol)溶解在110ml去离子水中。将水相用3x75ml的三氯乙烷萃取。将合并的有机相在硫酸钠上干燥,在真空下蒸发,直到完全除去溶剂,并且在0℃/5℃放置一整夜。发生了结晶。获得了1.1g(0.0049mol)的(S)-吡吲哚(游离碱)(产率=98%)。手性HPLC(对映异构体纯度=97.8%)。
Claims (16)
1.获得处于游离碱的形式或者处于药学上可接受的盐的形式的光学活性吡吲哚对映异构体的方法,特征在于通过用光学活性酸结晶游离碱形式的(外消旋)-吡吲哚来进行拆分,其中所述方法包含:
以游离碱形式分离(外消旋)-吡吲哚;
将所述(外消旋)-吡吲哚溶解在有机溶剂中,所述有机溶剂选自以下有机溶剂构成的组:甲醇、乙醇、丙醇、1-丁醇、2-丁醇、叔丁醇、2-丁酮、丙酮、乙基甲基酮、甲基异丁基酮、二甲基亚砜、1,2-二氯乙烷、二乙基醚、二甲基醚、二甲基甲酰胺、甲基叔丁基醚、2-丙醇、吡啶、甲苯、二甲苯或者其任意比例的混合物;
加入所述光学活性酸;
搅拌悬浮液15min至2h;
并且在纯化中使用选自所述相同的组的有机溶剂。
2.根据权利要求1的方法,特征在于该光学活性吡吲哚对映异构体是对映异构体纯(S)-吡吲哚或者(R)-吡吲哚。
3.根据权利要求1和2任一项的方法,特征在于包含下面的步骤:
i)将(外消旋)-吡吲哚盐酸盐溶解在水性溶剂中,随后用氯化的溶剂随后萃取,并且完全除去溶剂来获得处于游离碱形式的(外消旋)-吡吲哚;
ii)将步骤i)所获得的(外消旋)-吡吲哚溶解在所述有机溶剂中,随后加入光学活性酸用于拆分;
iii)将ii)中形成的悬浮液搅拌15min至2h,同时发生非对映异构体盐沉淀;
iv)过滤所获得的非对映异构体盐和通过悬浮在所述有机溶剂中来纯化它,以获得处于药学上可接受的盐的形式的,用光学活性酸形成的(S)-吡吲哚或者(R)-吡吲哚对映异构体;和任选的,
v)通过将步骤iv)获得的产物溶解在水性溶剂中,随后用氯化的溶剂萃取和完全除去溶剂,来获得作为游离碱的对映异构体纯(S)-吡吲哚和/或(R)-吡吲哚;和任选的,
vi)如下来获得处于药学上可接受的酸加成盐形式的S)-吡吲哚或者(R)-吡吲哚:用药学上可接受的酸对步骤v)所获得的处于游离碱形式的对映异构体纯(S)-吡吲哚和/或(R)-吡吲哚进行成盐,来形成(S)-吡吲哚或者(R)-吡吲哚对映异构体的药学上可接受的酸加成盐
其中,所述氯化的溶剂选自:二氯甲烷、三氯甲烷或者四氯化碳,或者其任意比例的混合物。
4.根据权利要求3的方法,其中步骤ii)所用的光学活性酸选自:(R)-扁桃酸、(R)-(+)-α-甲氧基-α-三氟苯基乙酸、(1R,3S)-(+)-樟脑酸、D(+)-苹果酸、(S)-扁桃酸、(S)-(-)-α-甲氧基-α-三氟苯基乙酸、(1S,3R)-(+)-樟脑酸或者L(-)-苹果酸。
5.根据权利要求4的方法,特征在于所获得的化合物是作为(R)-扁桃酸盐的对映异构体纯(S)-吡吲哚。
6.根据权利要求4的方法,特征在于所获得的化合物是作为(S)-扁桃酸盐的对映异构体纯(R)-吡吲哚。
7.根据权利要求4的方法,特征在于所获得的化合物是对映异构体纯(S)-吡吲哚氢溴酸盐。
8.根据权利要求4的方法,特征在于所获得的化合物是对映异构体纯(R)-吡吲哚氢溴酸盐。
9.根据权利要求4的方法,特征在于所获得的化合物是对映异构体纯(S)-吡吲哚柠檬酸盐。
10.根据权利要求4的方法,特征在于所获得的化合物是对映异构体纯(R)-吡吲哚柠檬酸盐。
11.根据权利要求4的方法,特征在于所获得的化合物是对映异构体纯(S)-吡吲哚甲磺酸盐。
12.根据权利要求4的方法,特征在于所获得的化合物是对映异构体纯(R)-吡吲哚甲磺酸盐。
13.根据权利要求4的方法,特征在于所获得的化合物是对映异构体纯(R)-吡吲哚R)-(+)-α-甲氧基-α-三氟苯基乙酸盐。
14.根据权利要求4的方法,特征在于所获得的化合物是对映异构体纯(S)-吡吲哚R)-(+)-α-甲氧基-α-三氟苯基乙酸盐。
15.根据权利要求1的方法,特征在于所获得的化合物是处于游离碱形式的对映异构体纯(R)-吡吲哚。
16.根据权利要求1的方法,特征在于所获得的化合物是处于游离碱形式的对映异构体纯(S)-吡吲哚。
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/PT2014/000027 WO2015171003A1 (en) | 2014-05-09 | 2014-05-09 | Process for obtaining optically active pirlindole enantiomers and salts thereof |
Publications (2)
Publication Number | Publication Date |
---|---|
CN106414376A CN106414376A (zh) | 2017-02-15 |
CN106414376B true CN106414376B (zh) | 2019-06-07 |
Family
ID=50819929
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201480078731.6A Active CN106414376B (zh) | 2014-05-09 | 2014-05-09 | 获得光学活性吡吲哚对映异构体及其盐的方法 |
Country Status (30)
Country | Link |
---|---|
US (1) | US9682986B2 (zh) |
EP (1) | EP3140265B1 (zh) |
JP (1) | JP6516769B2 (zh) |
KR (1) | KR102258709B1 (zh) |
CN (1) | CN106414376B (zh) |
AU (1) | AU2014393488C1 (zh) |
BR (1) | BR112016025918B1 (zh) |
CA (1) | CA2948604C (zh) |
CY (1) | CY1122367T1 (zh) |
DK (1) | DK3140265T3 (zh) |
EC (1) | ECSP16086217A (zh) |
ES (1) | ES2753403T3 (zh) |
HR (1) | HRP20192029T1 (zh) |
HU (1) | HUE046437T2 (zh) |
IL (1) | IL248853B (zh) |
LT (1) | LT3140265T (zh) |
MA (1) | MA39449A1 (zh) |
MX (1) | MX357918B (zh) |
NZ (1) | NZ726129A (zh) |
PH (1) | PH12016502234B1 (zh) |
PL (1) | PL3140265T3 (zh) |
PT (1) | PT3140265T (zh) |
RS (1) | RS59499B1 (zh) |
RU (1) | RU2666731C2 (zh) |
SA (1) | SA516380265B1 (zh) |
SI (1) | SI3140265T1 (zh) |
TN (1) | TN2016000496A1 (zh) |
UA (1) | UA118696C2 (zh) |
WO (1) | WO2015171003A1 (zh) |
ZA (1) | ZA201607722B (zh) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
UA118587C2 (uk) * | 2014-05-09 | 2019-02-11 | Текнімеді Сос'Єдаді Текніку-Медісінал С.А. | Фармацевтично прийнятні солі енантіомерів пірліндолу для застосування в медицині |
AU2014393488C1 (en) | 2014-05-09 | 2020-07-16 | Tecnimede Sociedade Tecnico-Medicinal S.A. | Process for obtaining optically active pirlindole enantiomers and salts thereof |
EP3392251A1 (en) | 2017-04-21 | 2018-10-24 | Tecnimede-Sociedade Tecnico-Medicinal, S.A. | Process for the preparation of pirlindole enantiomers and its salts |
EP3392250A1 (en) | 2017-04-21 | 2018-10-24 | Tecnimede-Sociedade Tecnico-Medicinal, S.A. | Process for the preparation of piperazine ring for the synthesis of pyrazinocarbazole derivatives |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
RU2281085C2 (ru) * | 2004-05-25 | 2006-08-10 | Закрытое акционерное общество "Мастерлек" | Антидепрессивные лекарственные средства для парентерального применения на основе сульфонатных солей пирлиндола |
AU2014393488C1 (en) | 2014-05-09 | 2020-07-16 | Tecnimede Sociedade Tecnico-Medicinal S.A. | Process for obtaining optically active pirlindole enantiomers and salts thereof |
-
2014
- 2014-05-09 AU AU2014393488A patent/AU2014393488C1/en active Active
- 2014-05-09 MX MX2016014703A patent/MX357918B/es active IP Right Grant
- 2014-05-09 RS RS20191433A patent/RS59499B1/sr unknown
- 2014-05-09 US US15/309,906 patent/US9682986B2/en active Active
- 2014-05-09 SI SI201431386T patent/SI3140265T1/sl unknown
- 2014-05-09 HU HUE14726442A patent/HUE046437T2/hu unknown
- 2014-05-09 MA MA39449A patent/MA39449A1/fr unknown
- 2014-05-09 WO PCT/PT2014/000027 patent/WO2015171003A1/en active Application Filing
- 2014-05-09 NZ NZ726129A patent/NZ726129A/en unknown
- 2014-05-09 RU RU2016148181A patent/RU2666731C2/ru active
- 2014-05-09 CN CN201480078731.6A patent/CN106414376B/zh active Active
- 2014-05-09 JP JP2016567540A patent/JP6516769B2/ja active Active
- 2014-05-09 DK DK14726442T patent/DK3140265T3/da active
- 2014-05-09 TN TN2016000496A patent/TN2016000496A1/en unknown
- 2014-05-09 LT LT14726442T patent/LT3140265T/lt unknown
- 2014-05-09 UA UAA201611334A patent/UA118696C2/uk unknown
- 2014-05-09 CA CA2948604A patent/CA2948604C/en active Active
- 2014-05-09 ES ES14726442T patent/ES2753403T3/es active Active
- 2014-05-09 PL PL14726442T patent/PL3140265T3/pl unknown
- 2014-05-09 EP EP14726442.8A patent/EP3140265B1/en active Active
- 2014-05-09 PT PT147264428T patent/PT3140265T/pt unknown
- 2014-05-09 BR BR112016025918-1A patent/BR112016025918B1/pt active IP Right Grant
- 2014-05-09 KR KR1020167031371A patent/KR102258709B1/ko active IP Right Grant
-
2016
- 2016-11-09 EC ECIEPI201686217A patent/ECSP16086217A/es unknown
- 2016-11-09 PH PH12016502234A patent/PH12016502234B1/en unknown
- 2016-11-09 IL IL248853A patent/IL248853B/en active IP Right Grant
- 2016-11-09 ZA ZA2016/07722A patent/ZA201607722B/en unknown
- 2016-11-09 SA SA516380265A patent/SA516380265B1/ar unknown
-
2019
- 2019-11-08 HR HRP20192029TT patent/HRP20192029T1/hr unknown
- 2019-11-13 CY CY20191101194T patent/CY1122367T1/el unknown
Non-Patent Citations (3)
Title |
---|
Automated determination of pirlindole enantiomers in plasma by on-line coupling of a pre-column packed with restricted access material to a chiral liquid chromatographic column;P. Chiap等;《Journal of Pharmaceutical and Biomedical Analysis》;20021231;第27卷;第447-445页 |
Effective Resolution of Racemic Pirlindole at the Preparative Scale;PASCAL DE TULLIO等;《CHIRALITY》;19990329;第11卷(第4期);第261-266页 |
First Preparative Enantiomer Resolution of Pirlindole,a Potent Antidepressant Drug;Pascal de Tullio等;《HELVETICA CHIMICA ACTA》;19981231;第81卷(第3-4期);第539-547页 |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN106414376B (zh) | 获得光学活性吡吲哚对映异构体及其盐的方法 | |
CN101711236B (zh) | 表现出改善的心血管副作用特性的多巴胺受体稳定剂/调节剂的n-氧化物和/或二-n-氧化物衍生物 | |
CN102089296A (zh) | 高化学纯度埃索美拉唑钠的制备方法和埃索美拉唑的新晶型 | |
TW201200512A (en) | A crystalline form of (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride monohydrate | |
NZ585944A (en) | A process for preparation of stable amorphous R-(+)-lansoprazole | |
CN110423200A (zh) | 一种提高盐酸特比萘芬纯度的制备方法 | |
CN106413713B (zh) | 用作药物的吡吲哚对映异构体的药学上可接受的盐 | |
CN103804200B (zh) | 雷沙吉兰及其类似物的制备方法 | |
EP2094674A1 (en) | A salt of 3-benzyl-2-methyl-2,3,3a,4,5,6,7,7a-octahydrobenzo[d]isoxazol-4-one | |
Hu et al. | Resolutions of sibutramine with enantiopure tartaric acid derivatives: chiral discrimination mechanism | |
CN108822077A (zh) | 一种r-硫辛酸胆碱酯卤化物的精制方法 | |
US7067700B2 (en) | Process for preparing sertraline hydrochloride polymorphic form II | |
WO2015145163A1 (en) | Process for the manufacture of s-(+)-flurbiprofen | |
CN104402815A (zh) | 磷酸哌喹杂质的控制方法 | |
CN111689956B (zh) | 一种含有季铵基团的奎宁类化合物的拆分方法 | |
JP2007513936A (ja) | ネフォパムの分割のための方法 | |
WO2016142165A1 (en) | Improved process for the optical purification of esomeprazole | |
CN107501261A (zh) | 1‑芳基‑1H‑吡啶[3,4‑b]吲哚‑3‑羧酸甲酯的手性拆分 | |
WO2008107777A2 (en) | Improved method for the preparation of desloratadine with reduced levels of organic solvents |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |