JP2003342259A - Method for producing optically active cis-piperidine derivative - Google Patents
Method for producing optically active cis-piperidine derivativeInfo
- Publication number
- JP2003342259A JP2003342259A JP2002369405A JP2002369405A JP2003342259A JP 2003342259 A JP2003342259 A JP 2003342259A JP 2002369405 A JP2002369405 A JP 2002369405A JP 2002369405 A JP2002369405 A JP 2002369405A JP 2003342259 A JP2003342259 A JP 2003342259A
- Authority
- JP
- Japan
- Prior art keywords
- optically active
- group
- derivative
- amino
- tartaric acid
- 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.)
- Pending
Links
- 238000004519 manufacturing process Methods 0.000 title claims description 11
- 230000003287 optical effect Effects 0.000 claims abstract description 47
- 239000000203 mixture Substances 0.000 claims abstract description 29
- 238000000034 method Methods 0.000 claims abstract description 20
- 150000003862 amino acid derivatives Chemical class 0.000 claims abstract description 19
- 150000003892 tartrate salts Chemical class 0.000 claims abstract description 12
- PICQEJDBZKDWOD-AWEZNQCLSA-N (2s)-2-(benzenesulfonamido)-3-phenylpropanoic acid Chemical compound C([C@@H](C(=O)O)NS(=O)(=O)C=1C=CC=CC=1)C1=CC=CC=C1 PICQEJDBZKDWOD-AWEZNQCLSA-N 0.000 claims abstract description 6
- CCIUQRKCMXXTOI-UHFFFAOYSA-N 2,3-dihydroxy-2,3-bis(4-methoxybenzoyl)butanedioic acid Chemical compound C1=CC(OC)=CC=C1C(=O)C(O)(C(O)=O)C(O)(C(O)=O)C(=O)C1=CC=C(OC)C=C1 CCIUQRKCMXXTOI-UHFFFAOYSA-N 0.000 claims abstract description 4
- NTOIKDYVJIWVSU-UHFFFAOYSA-N 2,3-dihydroxy-2,3-bis(4-methylbenzoyl)butanedioic acid Chemical compound C1=CC(C)=CC=C1C(=O)C(O)(C(O)=O)C(O)(C(O)=O)C(=O)C1=CC=C(C)C=C1 NTOIKDYVJIWVSU-UHFFFAOYSA-N 0.000 claims abstract description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 48
- GFMAFYNUQDLPBP-QWRGUYRKSA-N (2s,3s)-2-phenylpiperidin-3-amine Chemical compound N[C@H]1CCCN[C@H]1C1=CC=CC=C1 GFMAFYNUQDLPBP-QWRGUYRKSA-N 0.000 claims description 28
- -1 2-methoxybenzoyl Chemical group 0.000 claims description 22
- 125000004432 carbon atom Chemical group C* 0.000 claims description 17
- 239000002904 solvent Substances 0.000 claims description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- 125000003118 aryl group Chemical group 0.000 claims description 11
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 10
- 150000001721 carbon Chemical group 0.000 claims description 10
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 125000002252 acyl group Chemical group 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- ICFOBMSVJMGIMX-HNNXBMFYSA-N (2s)-2-(benzylsulfonylamino)-3-phenylpropanoic acid Chemical compound C([C@@H](C(=O)O)NS(=O)(=O)CC=1C=CC=CC=1)C1=CC=CC=C1 ICFOBMSVJMGIMX-HNNXBMFYSA-N 0.000 claims description 5
- ZCOVHLPDAJWNFS-JTQLQIEISA-N (2s)-2-(benzylsulfonylamino)pentanedioic acid Chemical compound OC(=O)CC[C@@H](C(O)=O)NS(=O)(=O)CC1=CC=CC=C1 ZCOVHLPDAJWNFS-JTQLQIEISA-N 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- RBLNYXNJCNZJDD-VIFPVBQESA-N (2s)-2-(benzylsulfonylamino)butanedioic acid Chemical compound OC(=O)C[C@@H](C(O)=O)NS(=O)(=O)CC1=CC=CC=C1 RBLNYXNJCNZJDD-VIFPVBQESA-N 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- 238000005984 hydrogenation reaction Methods 0.000 claims description 4
- PJLOGZZDKDUMFU-VIFPVBQESA-N (2s)-2-(benzenesulfonamido)pentanedioic acid Chemical compound OC(=O)CC[C@@H](C(O)=O)NS(=O)(=O)C1=CC=CC=C1 PJLOGZZDKDUMFU-VIFPVBQESA-N 0.000 claims description 3
- WMJNKBXKYHXOHC-UHFFFAOYSA-N 2,3-dihydroxy-2,3-bis(2-methylbenzoyl)butanedioic acid Chemical compound CC1=CC=CC=C1C(=O)C(O)(C(O)=O)C(O)(C(O)=O)C(=O)C1=CC=CC=C1C WMJNKBXKYHXOHC-UHFFFAOYSA-N 0.000 claims description 3
- HYQFZIWQHXXBER-UHFFFAOYSA-N 2,3-dihydroxy-2,3-bis(3-methoxybenzoyl)butanedioic acid Chemical compound COC1=CC=CC(C(=O)C(O)(C(O)=O)C(O)(C(O)=O)C(=O)C=2C=C(OC)C=CC=2)=C1 HYQFZIWQHXXBER-UHFFFAOYSA-N 0.000 claims description 3
- QJBGCXNTFZBQJR-UHFFFAOYSA-N 2-(benzenesulfonamido)-2-phenylacetic acid Chemical compound C=1C=CC=CC=1C(C(=O)O)NS(=O)(=O)C1=CC=CC=C1 QJBGCXNTFZBQJR-UHFFFAOYSA-N 0.000 claims description 3
- GNKIIMLQXMFHLQ-UHFFFAOYSA-N 2-(benzylsulfonylamino)-2-phenylacetic acid Chemical compound C=1C=CC=CC=1C(C(=O)O)NS(=O)(=O)CC1=CC=CC=C1 GNKIIMLQXMFHLQ-UHFFFAOYSA-N 0.000 claims description 3
- KMGUEILFFWDGFV-UHFFFAOYSA-N 2-benzoyl-2-benzoyloxy-3-hydroxybutanedioic acid Chemical compound C=1C=CC=CC=1C(=O)C(C(C(O)=O)O)(C(O)=O)OC(=O)C1=CC=CC=C1 KMGUEILFFWDGFV-UHFFFAOYSA-N 0.000 claims description 3
- XTHJCITVHCRQRD-UHFFFAOYSA-N 2-phenylpyridin-3-amine Chemical compound NC1=CC=CN=C1C1=CC=CC=C1 XTHJCITVHCRQRD-UHFFFAOYSA-N 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- DJLTZJGULPLVOA-UHFFFAOYSA-N N-Benzoylaspartic acid Chemical compound OC(=O)CC(C(O)=O)NC(=O)C1=CC=CC=C1 DJLTZJGULPLVOA-UHFFFAOYSA-N 0.000 claims description 3
- NPKISZUVEBESJI-AWEZNQCLSA-N N-benzoyl-L-phenylalanine Chemical compound C([C@@H](C(=O)O)NC(=O)C=1C=CC=CC=1)C1=CC=CC=C1 NPKISZUVEBESJI-AWEZNQCLSA-N 0.000 claims description 3
- NPKISZUVEBESJI-UHFFFAOYSA-N Nalpha-benzoyl-L-phenylalanine Natural products C=1C=CC=CC=1C(=O)NC(C(=O)O)CC1=CC=CC=C1 NPKISZUVEBESJI-UHFFFAOYSA-N 0.000 claims description 3
- 230000007935 neutral effect Effects 0.000 claims description 3
- 150000003053 piperidines Chemical class 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- GAUDUMMZSVZLNU-QMMMGPOBSA-N (2s)-2-(benzenesulfonamido)butanedioic acid Chemical compound OC(=O)C[C@@H](C(O)=O)NS(=O)(=O)C1=CC=CC=C1 GAUDUMMZSVZLNU-QMMMGPOBSA-N 0.000 claims description 2
- LPJXPACOXRZCCP-VIFPVBQESA-N (2s)-2-benzamidopentanedioic acid Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)C1=CC=CC=C1 LPJXPACOXRZCCP-VIFPVBQESA-N 0.000 claims description 2
- ACDLFRQZDTZESK-UHFFFAOYSA-N 2-benzamido-2-phenylacetic acid Chemical compound C=1C=CC=CC=1C(C(=O)O)NC(=O)C1=CC=CC=C1 ACDLFRQZDTZESK-UHFFFAOYSA-N 0.000 claims description 2
- ZYPJGOCQEPYWIE-UHFFFAOYSA-N 4-amino-2,3-dihydroxy-4-oxobutanoic acid Chemical class NC(=O)C(O)C(O)C(O)=O ZYPJGOCQEPYWIE-UHFFFAOYSA-N 0.000 claims 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 claims description 2
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000000440 benzylamino group Chemical group [H]N(*)C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000003395 phenylethylamino group Chemical group [H]N(*)C([H])([H])C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- 239000011975 tartaric acid Substances 0.000 claims description 2
- DVMNOSBSAVUYEU-UHFFFAOYSA-N 2,3-dihydroxy-2,3-bis(3-methylbenzoyl)butanedioic acid Chemical compound CC1=CC=CC(C(=O)C(O)(C(O)=O)C(O)(C(O)=O)C(=O)C=2C=C(C)C=CC=2)=C1 DVMNOSBSAVUYEU-UHFFFAOYSA-N 0.000 claims 1
- XQDSIGDVDWFZPP-UHFFFAOYSA-N 2-phenylpiperidin-1-amine Chemical compound NN1CCCCC1C1=CC=CC=C1 XQDSIGDVDWFZPP-UHFFFAOYSA-N 0.000 claims 1
- 239000000126 substance Substances 0.000 abstract description 21
- 238000009776 industrial production Methods 0.000 abstract description 4
- 150000003839 salts Chemical class 0.000 description 49
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 34
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- 239000013078 crystal Substances 0.000 description 23
- GFMAFYNUQDLPBP-UHFFFAOYSA-N 2-phenylpiperidin-3-amine Chemical compound NC1CCCNC1C1=CC=CC=C1 GFMAFYNUQDLPBP-UHFFFAOYSA-N 0.000 description 22
- 239000003795 chemical substances by application Substances 0.000 description 16
- 238000003756 stirring Methods 0.000 description 14
- 238000004817 gas chromatography Methods 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 7
- 238000000926 separation method Methods 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- WGIAUTGOUJDVEI-UHFFFAOYSA-N 2-phenylpiperidine Chemical compound N1CCCCC1C1=CC=CC=C1 WGIAUTGOUJDVEI-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 239000007788 liquid Substances 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- VQGHOUODWALEFC-UHFFFAOYSA-N 2-phenylpyridine Chemical compound C1=CC=CC=C1C1=CC=CC=N1 VQGHOUODWALEFC-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 229960005261 aspartic acid Drugs 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- PICQEJDBZKDWOD-CQSZACIVSA-N (2r)-2-(benzenesulfonamido)-3-phenylpropanoic acid Chemical compound C([C@H](C(=O)O)NS(=O)(=O)C=1C=CC=CC=1)C1=CC=CC=C1 PICQEJDBZKDWOD-CQSZACIVSA-N 0.000 description 3
- MEQBJJUWDCYIAB-UHFFFAOYSA-N 2-chloropyridin-3-amine Chemical compound NC1=CC=CN=C1Cl MEQBJJUWDCYIAB-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 235000003704 aspartic acid Nutrition 0.000 description 3
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- UKQPNXSQGUFKPM-UHFFFAOYSA-N n-methyl-2-phenylpiperidin-3-amine Chemical compound CNC1CCCNC1C1=CC=CC=C1 UKQPNXSQGUFKPM-UHFFFAOYSA-N 0.000 description 3
- SYTBZMRGLBWNTM-SNVBAGLBSA-N (R)-flurbiprofen Chemical compound FC1=CC([C@H](C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-SNVBAGLBSA-N 0.000 description 2
- DVFMYDXKJZNVGI-UHFFFAOYSA-N 2,3-dihydroxy-2,3-bis(2-methoxybenzoyl)butanedioic acid Chemical compound COC1=CC=CC=C1C(=O)C(O)(C(O)=O)C(O)(C(O)=O)C(=O)C1=CC=CC=C1OC DVFMYDXKJZNVGI-UHFFFAOYSA-N 0.000 description 2
- GFMSRLFQVPVUHZ-UHFFFAOYSA-N 2-cyclohexylpiperidin-3-amine Chemical compound NC1CCCNC1C1CCCCC1 GFMSRLFQVPVUHZ-UHFFFAOYSA-N 0.000 description 2
- HHSOUQXZVNRLQM-UHFFFAOYSA-N CC1=CC(C(C(C(O)=O)(C2=CC=CC(C)=C2)O)(C(O)=O)O)=CC=C1 Chemical compound CC1=CC(C(C(C(O)=O)(C2=CC=CC(C)=C2)O)(C(O)=O)O)=CC=C1 HHSOUQXZVNRLQM-UHFFFAOYSA-N 0.000 description 2
- NSTPXGARCQOSAU-UHFFFAOYSA-N N-Formyl-Phenylalanine Natural products O=CNC(C(=O)O)CC1=CC=CC=C1 NSTPXGARCQOSAU-UHFFFAOYSA-N 0.000 description 2
- NSTPXGARCQOSAU-VIFPVBQESA-N N-formyl-L-phenylalanine Chemical compound O=CN[C@H](C(=O)O)CC1=CC=CC=C1 NSTPXGARCQOSAU-VIFPVBQESA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 229960005190 phenylalanine Drugs 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- DNISEZBAYYIQFB-PHDIDXHHSA-N (2r,3r)-2,3-diacetyloxybutanedioic acid Chemical compound CC(=O)O[C@@H](C(O)=O)[C@H](C(O)=O)OC(C)=O DNISEZBAYYIQFB-PHDIDXHHSA-N 0.000 description 1
- IWYDHOAUDWTVEP-ZETCQYMHSA-N (S)-mandelic acid Chemical compound OC(=O)[C@@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-ZETCQYMHSA-N 0.000 description 1
- LLSKXGRDUPMXLC-UHFFFAOYSA-N 1-phenylpiperidine Chemical compound C1CCCCN1C1=CC=CC=C1 LLSKXGRDUPMXLC-UHFFFAOYSA-N 0.000 description 1
- VOXXGUAZBWSUSS-UHFFFAOYSA-N 2,4,6-triphenyl-1,3,5,2,4,6-trioxatriborinane Chemical compound O1B(C=2C=CC=CC=2)OB(C=2C=CC=CC=2)OB1C1=CC=CC=C1 VOXXGUAZBWSUSS-UHFFFAOYSA-N 0.000 description 1
- CZHBLKINFJLTRU-UHFFFAOYSA-N 2-(3-ethyl-2-methylphenyl)piperidin-3-amine Chemical compound CCC1=CC=CC(C2C(CCCN2)N)=C1C CZHBLKINFJLTRU-UHFFFAOYSA-N 0.000 description 1
- PNDGHBKOLZNDRC-UHFFFAOYSA-N 2-(4-chlorophenyl)piperidin-3-amine Chemical compound NC1CCCNC1C1=CC=C(Cl)C=C1 PNDGHBKOLZNDRC-UHFFFAOYSA-N 0.000 description 1
- PXKWUKUIDAUOCI-UHFFFAOYSA-N 2-(4-methylphenyl)piperidin-3-amine Chemical compound C1=CC(C)=CC=C1C1C(N)CCCN1 PXKWUKUIDAUOCI-UHFFFAOYSA-N 0.000 description 1
- HUTHUTALXJNNRS-UHFFFAOYSA-N 2-cyclohexylpyridine Chemical compound C1CCCCC1C1=CC=CC=N1 HUTHUTALXJNNRS-UHFFFAOYSA-N 0.000 description 1
- AZTYHYHSDPMHRA-UHFFFAOYSA-N 2-formamido-2-phenylacetic acid Chemical compound O=CNC(C(=O)O)C1=CC=CC=C1 AZTYHYHSDPMHRA-UHFFFAOYSA-N 0.000 description 1
- MQUUQXIFCBBFDP-UHFFFAOYSA-N 2-formamidobutanedioic acid Chemical compound OC(=O)CC(C(O)=O)NC=O MQUUQXIFCBBFDP-UHFFFAOYSA-N 0.000 description 1
- ADZLWSMFHHHOBV-UHFFFAOYSA-N 2-formamidopentanedioic acid Chemical compound OC(=O)CCC(C(O)=O)NC=O ADZLWSMFHHHOBV-UHFFFAOYSA-N 0.000 description 1
- 125000001999 4-Methoxybenzoyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C(*)=O 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
- ZGUNAGUHMKGQNY-ZETCQYMHSA-N L-alpha-phenylglycine zwitterion Chemical compound OC(=O)[C@@H](N)C1=CC=CC=C1 ZGUNAGUHMKGQNY-ZETCQYMHSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical class OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- OTCCIMWXFLJLIA-UHFFFAOYSA-N N-acetyl-DL-aspartic acid Natural products CC(=O)NC(C(O)=O)CC(O)=O OTCCIMWXFLJLIA-UHFFFAOYSA-N 0.000 description 1
- VKDFZMMOLPIWQQ-VIFPVBQESA-N N-acetyl-L-alpha-phenylglycine Chemical compound CC(=O)N[C@H](C(O)=O)C1=CC=CC=C1 VKDFZMMOLPIWQQ-VIFPVBQESA-N 0.000 description 1
- OTCCIMWXFLJLIA-BYPYZUCNSA-N N-acetyl-L-aspartic acid Chemical compound CC(=O)N[C@H](C(O)=O)CC(O)=O OTCCIMWXFLJLIA-BYPYZUCNSA-N 0.000 description 1
- RFMMMVDNIPUKGG-YFKPBYRVSA-N N-acetyl-L-glutamic acid Chemical compound CC(=O)N[C@H](C(O)=O)CCC(O)=O RFMMMVDNIPUKGG-YFKPBYRVSA-N 0.000 description 1
- CBQJSKKFNMDLON-JTQLQIEISA-N N-acetyl-L-phenylalanine Chemical compound CC(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 CBQJSKKFNMDLON-JTQLQIEISA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 238000004807 desolvation Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- JVZRCNQLWOELDU-UHFFFAOYSA-N gamma-Phenylpyridine Natural products C1=CC=CC=C1C1=CC=NC=C1 JVZRCNQLWOELDU-UHFFFAOYSA-N 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000011268 mixed slurry Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- UXUMJCYFONDHKI-UHFFFAOYSA-N n,n-dimethyl-2-phenylpiperidin-3-amine Chemical compound CN(C)C1CCCNC1C1=CC=CC=C1 UXUMJCYFONDHKI-UHFFFAOYSA-N 0.000 description 1
- BBYOBISKKSFQGU-UHFFFAOYSA-N n-ethyl-2-phenylpiperidin-3-amine Chemical compound CCNC1CCCNC1C1=CC=CC=C1 BBYOBISKKSFQGU-UHFFFAOYSA-N 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 1
- 150000004885 piperazines Chemical class 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Landscapes
- Hydrogenated Pyridines (AREA)
Abstract
Description
【０００１】[0001]
【発明の属する技術分野】本発明は医薬またはその中間
体として有用な光学活性シスピペリジン誘導体の製造法
である。TECHNICAL FIELD The present invention relates to a method for producing an optically active cispiperidine derivative useful as a medicine or an intermediate thereof.
【０００２】[0002]
【従来の技術】光学活性シス３−アミノ−２−フェニル
ピペリジンを製造する方法として、光学活性マンデル酸
で光学分割する方法が知られている（特許文献１）。そ
の方法は優れた分割法であるが、分割溶液の濃度が薄
く、生産効率が悪い。また、高い化学純度で高い光学純
度の目的物を得るためには、さらに２回以上の再結晶精
製工程が必要であり、工業的製造法としては課題があ
る。2. Description of the Related Art As a method for producing optically active cis 3-amino-2-phenylpiperidine, a method of optically resolving with optically active mandelic acid is known (Patent Document 1). Although the method is an excellent resolution method, the concentration of the resolution solution is low and the production efficiency is poor. Further, in order to obtain a target product having high chemical purity and high optical purity, it is necessary to further perform the recrystallization purification step twice or more, which is a problem as an industrial production method.
【０００３】[0003]
【特許文献１】特表平８−５０７２９７号公報[Patent Document 1] Japanese Patent Publication No. 8-507297
【０００４】[0004]
【発明が解決しようとする課題】したがって、高い化学
純度で高い光学純度の光学活性シスピペリジン誘導体
を、効率的に生産できる工業的製造法が望まれていた。Therefore, there has been a demand for an industrial production method capable of efficiently producing an optically active cispiperidine derivative having high chemical purity and high optical purity.
【０００５】[0005]
【課題を解決するための手段】本発明者らは課題解決に
向けて鋭意検討した結果、本発明を完成させた。すなわ
ち、ラセミシスピペリジン誘導体を、光学活性酒石酸誘
導体または光学活性アミノ酸誘導体で光学分割すること
で、高い化学純度で高い光学純度の光学活性シスピペリ
ジン誘導体を効率的に生産できる工業的製造法を見いだ
した。Means for Solving the Problems The present inventors have completed the present invention as a result of intensive studies aimed at solving the problems. That is, the inventors have found an industrial production method capable of efficiently producing an optically active cispiperidine derivative with high chemical purity and high optical purity by optically resolving a racemic cispiperidine derivative with an optically active tartaric acid derivative or an optically active amino acid derivative. .
【０００６】本発明は、一般式（１）および一般式
（２）The present invention includes the general formula (1) and the general formula (2).
【０００７】[0007]
【化７】 [Chemical 7]
【０００８】（ここで、Ｒ１，Ｒ２は、水素、または炭
素数１〜６のアルキル基、Ｒ３は、水素、炭素数１〜６
のアルキル基、炭素数１〜６のアルコキシ基、またはハ
ロゲンを示し、ｎは０〜３の整数を意味する。）で表さ
れるシスピペリジン誘導体の混合物であるラセミシスピ
ペリジン誘導体を、光学活性酒石酸誘導体または光学活
性アミノ酸誘導体で光学分割することを特徴とする光学
活性シスピペリジン誘導体の製造法である。(Here, R 1 and R 2 are hydrogen or an alkyl group having 1 to 6 carbon atoms, R 3 is hydrogen, and 1 to 6 carbon atoms.
Represents an alkyl group, an alkoxy group having 1 to 6 carbon atoms, or halogen, and n means an integer of 0 to 3. ), A racemic cispiperidine derivative which is a mixture of cispiperidine derivatives is optically resolved with an optically active tartaric acid derivative or an optically active amino acid derivative.
【０００９】[0009]
【発明の実施の形態】本発明において出発原料として用
いられるラセミシスピペリジン誘導体とは前記一般式
（１）で表される化合物と一般式（２）で表される化合
物の混合物である。ここで、一般式（１）または一般式
（２）で表されるピペリジン誘導体には４種の光学異性
体が存在する。BEST MODE FOR CARRYING OUT THE INVENTION The racemic cispiperidine derivative used as a starting material in the present invention is a mixture of the compound represented by the general formula (1) and the compound represented by the general formula (2). Here, the piperidine derivative represented by the general formula (1) or the general formula (2) has four optical isomers.
【００１０】[0010]
【化８】 [Chemical 8]
【００１１】本発明のラセミシスピペリジン誘導体と
は、一般式（１）で表されるアミノ基とフェニル基がシ
ス配座である（２Ｓ，３Ｓ）体と、一般式（２）で表さ
れる（２Ｒ，３Ｒ）体の混合物を意味し、それらのいず
れか一方の存在量が他方より多くても２０％以下である
混合物、すなわち光学純度が２０％ｄ.ｅ.以下の混合物
を意味する。また、光学活性シスピペリジン誘導体と
は、いずれか一方の存在量が他方より８０％以上多い混
合物、すなわち光学純度が８０％ｄ.ｅ.以上の混合物を
意味する。シスピペリジン誘導体の具体例としては、シ
ス３−アミノ−２−フェニルピペリジン、シス３−メチ
ルアミノ−２−フェニルピペリジン、シス３−エチルア
ミノ−２−フェニルピペリジン、シス３−アミノ−２−
（４−メチルフェニル）ピペリジン、シス３−アミノ−
２−（４−クロロフェニル）ピペリジン、３−ジメチル
アミノ−２−フェニルピペリジン、シス３−アミノ−２
−（２，４−ジメチルフェニル）ピペリジン、シス３−
アミノ−２−（２−メチル−３−エチルフェニル）ピペ
リジン等が好ましく使用できるが、シス３−アミノ−２
−フェニルピペリジンが特に好ましい。これらシスピペ
リジン誘導体のラセミ体を光学分割剤を使用して分割す
る。The racemic cispiperidine derivative of the present invention is represented by the general formula (2) and the (2S, 3S) form in which the amino group and the phenyl group represented by the general formula (1) are in cis conformation. It means a mixture of (2R, 3R) isomers, and a mixture in which the abundance of one of them is 20% or less at the most, that is, a mixture having an optical purity of 20% de or less. Further, the optically active cispiperidine derivative means a mixture in which the amount of one of them is 80% or more higher than the other, that is, a mixture having an optical purity of 80% de or more. Specific examples of the cispiperidine derivative include cis 3-amino-2-phenylpiperidine, cis 3-methylamino-2-phenylpiperidine, cis 3-ethylamino-2-phenylpiperidine, cis 3-amino-2-
(4-methylphenyl) piperidine, cis 3-amino-
2- (4-chlorophenyl) piperidine, 3-dimethylamino-2-phenylpiperidine, cis-3-amino-2
-(2,4-Dimethylphenyl) piperidine, cis 3-
Amino-2- (2-methyl-3-ethylphenyl) piperidine and the like can be preferably used, but cis-3-amino-2
-Phenylpiperidine is especially preferred. The racemates of these cispiperidine derivatives are resolved using an optical resolving agent.
【００１２】ここで、原料のシスピペリジン誘導体はい
かなる方法で製造した物でも使用できるが、例えば下記
反応式に従って製造することができる。Here, the raw material cispiperidine derivative can be used by any method, for example, it can be produced according to the following reaction formula.
【００１３】[0013]
【化９】 [Chemical 9]
【００１４】すなわち、３−アミノ−２−クロルピリジ
ンとフェニルホウ酸を反応させて得た３−アミノ−２−
フェニルピリジンを、水素化触媒存在下で水素化するこ
とによって、ラセミシス３−アミノ−２−フェニルピぺ
リジンが得られる。ここで、中間体である３−アミノ−
２−フェニルピリジンを水素化触媒存在下で水素化する
と、得られる反応液中には２−フェニルピペリジン、３
−アミノ−２−シクロヘキシルピペリジン、あるいは３
−アミノ−２−シクロヘキシルピリジン等の塩基性成分
が多く含まれる。このような塩基性成分はシス３−アミ
ノ−２−フェニルピぺリジンと同じように挙動する。例
えば、反応液を塩基性にして有機溶媒を用いて抽出した
のち、有機溶媒層を濃縮すると、２−フェニルピペリジ
ン等の塩基性成分を多く含む化学純度の低いシス３−ア
ミノ−２−フェニルピぺリジンが得られる。また、この
化学純度の低いシス３−アミノ−２−フェニルピぺリジ
ンを原料に用いて、光学活性酸性化合物で光学分割する
と、得られる光学活性シス３−アミノ−２−フェニルピ
ぺリジンと光学活性酸性化合物との塩には２−フェニル
ピペリジン等の塩基性成分が混入してくるので、この塩
を更に精製処理しない限り、解塩して得られる目的とす
る光学活性シス３−アミノ−２−フェニルピぺリジンは
通常２−フェニルピペリジン等を多く含む低純度品であ
る。That is, 3-amino-2-chloropyridine obtained by reacting 3-amino-2-chloropyridine with phenylboric acid.
Hydrogenation of phenylpyridine in the presence of a hydrogenation catalyst gives racemic cis 3-amino-2-phenylpiperidine. Here, the intermediate 3-amino-
When 2-phenylpyridine is hydrogenated in the presence of a hydrogenation catalyst, 2-phenylpiperidine, 3
-Amino-2-cyclohexylpiperidine, or 3
A large amount of basic component such as -amino-2-cyclohexylpyridine is contained. Such basic components behave similarly to cis 3-amino-2-phenylpiperidine. For example, if the reaction solution is made basic and extracted with an organic solvent and then the organic solvent layer is concentrated, cis 3-amino-2-phenylpiper having a low chemical purity containing a large amount of basic components such as 2-phenylpiperidine. Lysine is obtained. When cis 3-amino-2-phenylpiperidine having a low chemical purity is used as a raw material and optically resolved with an optically active acidic compound, the obtained optically active cis 3-amino-2-phenylpiperidine and optically active acidic compound are obtained. Since a basic component such as 2-phenylpiperidine is mixed in the salt with the compound, the objective optically active cis 3-amino-2-phenylpipy obtained by desolvation is obtained unless the salt is further purified. Peridine is a low-purity product that usually contains a large amount of 2-phenylpiperidine and the like.
【００１５】本発明で使用する光学分割剤とは、Ｒ体、
またはＳ体の光学活性酒石酸誘導体や光学活性アミノ酸
誘導体を意味し、いずれか一方が９５％以上過剰の光学
活性体、すなわち光学純度が９５％ｅ．ｅ．以上である
ことが好ましい。また、Ｒ体を使用するか、Ｓ体を使用
するかは、目的とする光学活性シスピペリジン誘導体の
立体配座によって異なるので、目的に応じて選択すれば
よい。The optical resolving agent used in the present invention is R-form,
Alternatively, it means an S-form optically active tartaric acid derivative or an optically active amino acid derivative, one of which has an excess of 95% or more, that is, an optical purity of 95% e. e. The above is preferable. Further, whether to use the R-form or the S-form depends on the conformation of the objective optically active cispiperidine derivative, and therefore may be selected according to the purpose.
【００１６】光学分割剤として使用する光学活性酒石酸
誘導体とは一般式（３）The optically active tartaric acid derivative used as the optical resolving agent is represented by the general formula (3)
【００１７】[0017]
【化１０】 [Chemical 10]
【００１８】（ここで、Ｒ５は、芳香環が置換または無
置換のフェニルアミノ基、ベンジルアミノ基、またはフ
ェニルエチルアミノ基を示す。また、＊のついている炭
素原子が不斉中心であることを意味する。）で表される
光学活性酒石酸アミド誘導体または一般式（４）(Here, R 5 represents a phenylamino group, a benzylamino group, or a phenylethylamino group whose aromatic ring is substituted or unsubstituted. Further, the carbon atom with * is an asymmetric center. Or an optically active tartaric acid amide derivative represented by the general formula (4)
【００１９】[0019]
【化１１】 [Chemical 11]
【００２０】（ここで、Ｒ６は、炭素数１〜５のアルキ
ル基、または置換もしくは無置換のフェニル基もしくは
ベンジル基を示す。また、＊のついている炭素原子が不
斉中心であることを意味する。）で表される光学活性ジ
アシル酒石酸誘導体が好ましく使用できる。例えば、光
学活性４−クロルタルトラニル酸、光学活性４−ニトロ
タルトラニル酸、光学活性２，４−ジクロルタルトラニ
ル酸、光学活性ジアセチル酒石酸、光学活性ジベンゾイ
ル酒石酸、光学活性ジ（パラトルオイル）酒石酸、光学
活性ジ（メタトルオイル）酒石酸、光学活性ジ（オルソ
トルオイル）酒石酸、光学活性ジ（４−メトキシベンゾ
イル）酒石酸、光学活性ジ（３−メトキシベンゾイル）
酒石酸、光学活性ジ（２−メトキシベンゾイル）酒石酸
等が好ましく使用できるが、光学活性ジベンゾイル酒石
酸、光学活性ジ（パラトルオイル）酒石酸、光学活性ジ
（メタトルオイル）酒石酸、光学活性ジ（オルソトルオ
イル）酒石酸、光学活性ジ（４−メトキシベンゾイル）
酒石酸、光学活性ジ（３−メトキシベンゾイル）酒石
酸、光学活性ジ（２−メトキシベンゾイル）酒石酸等が
特に好ましい。(Here, R 6 represents an alkyl group having 1 to 5 carbon atoms, or a substituted or unsubstituted phenyl group or benzyl group. Also, the carbon atom with * is an asymmetric center. Means an optically active diacyl tartaric acid derivative. For example, optically active 4-chlorotartranylic acid, optically active 4-nitrotartranylic acid, optically active 2,4-dichlorotartranylic acid, optically active diacetyl tartaric acid, optically active dibenzoyl tartaric acid, optically active di (paratoluoyl) Tartaric acid, optically active di (metatoluyl) tartaric acid, optically active di (orthotoluoyl) tartaric acid, optically active di (4-methoxybenzoyl) tartaric acid, optically active di (3-methoxybenzoyl)
Tartaric acid, optically active di (2-methoxybenzoyl) tartaric acid and the like can be preferably used, but optically active dibenzoyl tartaric acid, optically active di (paratoluoyl) tartaric acid, optically active di (metatoluyl) tartaric acid, optically active di (orthotoluoyl) tartaric acid, Optically active di (4-methoxybenzoyl)
Tartaric acid, optically active di (3-methoxybenzoyl) tartaric acid, optically active di (2-methoxybenzoyl) tartaric acid and the like are particularly preferable.
【００２１】また、光学活性アミノ酸誘導体としては、
一般式（５）As the optically active amino acid derivative,
General formula (5)
【００２２】[0022]
【化１２】 [Chemical 12]
【００２３】（ここで、Ｒ７は、炭素数１〜６のアルキ
ル基、または置換もしくは無置換のフェニル基、ベンジ
ル基、もしくはフェニルエチル基を示し、Ｒ８は、炭素
数１〜５のアシル基、または芳香環が置換もしくは無置
換のベンゾイル基、ベンジルカルボニル基、ベンゼンス
ルホニル基、もしくはベンジルスルホニル基を示す。ま
た、＊のついている炭素原子が不斉中心であることを意
味する。）で表される光学活性中性アミノ酸誘導体、一
般式（６）(Here, R 7 represents an alkyl group having 1 to 6 carbon atoms, or a substituted or unsubstituted phenyl group, benzyl group, or phenylethyl group, and R 8 represents an acyl group having 1 to 5 carbon atoms. A group, or a benzoyl group, a benzylcarbonyl group, a benzenesulfonyl group, or a benzylsulfonyl group whose aromatic ring is substituted or unsubstituted, and means that the carbon atom with * is an asymmetric center. An optically active neutral amino acid derivative represented by the general formula (6)
【００２４】[0024]
【化１３】 [Chemical 13]
【００２５】（ここで、Ｒ９は、炭素数１〜５のアシル
基、または芳香環が置換もしくは無置換のベンゾイル
基、ベンジルカルボニル基、ベンゼンスルホニル基、も
しくはベンジルスルホニル基を示す。ｍは１〜３の整
数。また、＊のついている炭素原子が不斉中心であるこ
とを意味する。）で表される光学活性酸性アミノ酸誘導
体、または一般式（７）(Here, R 9 represents an acyl group having 1 to 5 carbon atoms, or a benzoyl group, a benzylcarbonyl group, a benzenesulfonyl group, or a benzylsulfonyl group whose aromatic ring is substituted or unsubstituted. M is 1 An integer of 3 to 3. Also, a carbon atom marked with * means an asymmetric center), or an optically active acidic amino acid derivative represented by the general formula (7).
【００２６】[0026]
【化１４】 [Chemical 14]
【００２７】（ここで、Ｒ１０は、炭素数１〜５のアシ
ル基、または芳香環が置換もしくは無置換のベンゾイル
基、ベンジルカルボニル基、ベンゼンスルホニル基、も
しくはベンジルスルホニル基を示す。ｌは１〜５の整
数。また、＊のついている炭素原子が不斉中心であるこ
とを意味する。）で表される光学活性塩基性アミノ酸誘
導体等が好ましく使用できる。(Here, R 10 represents an acyl group having 1 to 5 carbon atoms, or a benzoyl group having a substituted or unsubstituted aromatic ring, a benzylcarbonyl group, a benzenesulfonyl group, or a benzylsulfonyl group. L is 1 It is an integer from 5 to 5. Also, an optically active basic amino acid derivative represented by the meaning that the carbon atom with * is an asymmetric center is preferably used.
【００２８】ここで、一般式（５）において、Ｒ７がフ
ェニル基、またはベンジル基であり、Ｒ８が芳香環が置
換または無置換のベンゾイル基、ベンジルカルボニル
基、ベンゼンスルホニル基、またはベンジルスルホニル
基である光学活性中性アミノ酸誘導体、または、一般式
（６）において、Ｒ９が芳香環が置換または無置換のベ
ンゾイル基、ベンジルカルボニル基、ベンゼンスルホニ
ル基、またはベンジルスルホニル基である光学活性酸性
アミノ酸誘導体が好ましく使用できる。Here, in the general formula (5), R 7 is a phenyl group or a benzyl group, and R 8 is a benzoyl group having a substituted or unsubstituted aromatic ring, a benzylcarbonyl group, a benzenesulfonyl group, or a benzylsulfonyl group. Or an optically active neutral amino acid derivative of formula (6), wherein R 9 is a benzoyl group, a benzylcarbonyl group, a benzenesulfonyl group or a benzylsulfonyl group in which the aromatic ring is substituted or unsubstituted. Amino acid derivatives can be preferably used.
【００２９】例えば、光学活性Ｎ−ホルミルフェニルグ
リシン、光学活性Ｎ−アセチルフェニルグリシン、光学
活性Ｎ−ベンゾイルフェニルグリシン、光学活性Ｎ−ベ
ンゼンスルホニルフェニルグリシン、光学活性Ｎ−トル
エンスルホニルフェニルグリシン、光学活性Ｎ−ベンジ
ルスルホニルフェニルグリシン、光学活性Ｎ−ホルミル
フェニルアラニン、光学活性Ｎ−アセチルフェニルアラ
ニン、光学活性Ｎ−ベンゾイルフェニルアラニン、光学
活性Ｎ−ベンゼンスルホニルフェニルアラニン、光学活
性Ｎ−トルエンスルホニルフェニルアラニン、光学活性
Ｎ−ベンジルスルホニルフェニルアラニン、光学活性Ｎ
−ホルミルアスパラギン酸、光学活性Ｎ−アセチルアス
パラギン酸、光学活性Ｎ−ベンゾイルアスパラギン酸、
光学活性Ｎ−ベンゼンスルホニルアスパラギン酸、光学
活性Ｎ−トルエンスルホニルアスパラギン酸、光学活性
Ｎ−ベンジルスルホニルアスパラギン酸、光学活性Ｎ−
ホルミルグルタミン酸、光学活性Ｎ−アセチルグルタミ
ン酸、光学活性Ｎ−ベンゾイルグルタミン酸、光学活性
Ｎ−ベンゼンスルホニルグルタミン酸、光学活性Ｎ−ト
ルエンスルホニルグルタミン酸、光学活性Ｎ−ベンジル
スルホニルグルタミン酸等が好ましく、光学活性Ｎ−ト
ルエンスルホニルフェニルグリシン、光学活性Ｎ−ベン
ゼンスルホニルフェニルグリシン、光学活性Ｎ−ホルミ
ルフェニルアラニン、光学活性Ｎ−ベンゾイルフェニル
アラニン、光学活性Ｎ−ベンゼンスルホニルフェニルア
ラニン、光学活性Ｎ−トルエンスルホニルフェニルアラ
ニン、光学活性Ｎ−ベンゾイルアスパラギン酸、光学活
性Ｎ−ベンゼンスルホニルアスパラギン酸、光学活性Ｎ
−トルエンスルホニルアスパラギン酸、光学活性Ｎ−ベ
ンゼンスルホニルグルタミン酸、光学活性Ｎ−トルエン
スルホニルグルタミン酸が特に好ましい。For example, optically active N-formylphenylglycine, optically active N-acetylphenylglycine, optically active N-benzoylphenylglycine, optically active N-benzenesulfonylphenylglycine, optically active N-toluenesulfonylphenylglycine, optically active N. -Benzylsulfonylphenylglycine, optically active N-formylphenylalanine, optically active N-acetylphenylalanine, optically active N-benzoylphenylalanine, optically active N-benzenesulfonylphenylalanine, optically active N-toluenesulfonylphenylalanine, optically active N-benzylsulfonylphenylalanine , Optically active N
-Formyl aspartic acid, optically active N-acetyl aspartic acid, optically active N-benzoyl aspartic acid,
Optically active N-benzenesulfonylaspartic acid, optically active N-toluenesulfonylaspartic acid, optically active N-benzylsulfonylaspartic acid, optically active N-
Formylglutamic acid, optically active N-acetylglutamic acid, optically active N-benzoylglutamic acid, optically active N-benzenesulfonylglutamic acid, optically active N-toluenesulfonylglutamic acid, optically active N-benzylsulfonylglutamic acid and the like are preferable, and optically active N-toluenesulfonyl. Phenylglycine, optically active N-benzenesulfonylphenylglycine, optically active N-formylphenylalanine, optically active N-benzoylphenylalanine, optically active N-benzenesulfonylphenylalanine, optically active N-toluenesulfonylphenylalanine, optically active N-benzoylaspartic acid, Optically active N-benzenesulfonyl aspartic acid, optically active N
-Toluenesulfonyl aspartic acid, optically active N-benzenesulfonylglutamic acid, and optically active N-toluenesulfonylglutamic acid are particularly preferable.
【００３０】２−フェニルピペリジン、３−アミノ−２
−シクロヘキシルピペリジン、あるいは３−アミノ−２
−シクロヘキシルピリジン等の不純物を含む化学純度が
低いラセミシス３−アミノ−２−フェニルピペリジンを
光学分割する際には、上記の一般式（３）または一般式
（４）で表される光学活性酒石酸誘導体や一般式
（５）、一般式（６）、または一般式（７）で表される
光学活性アミノ酸誘導体のなかでも特に光学活性Ｎ−ベ
ンゼンスルホニルフェニルアラニンを光学分割剤として
用いると、高い化学純度で高い光学純度の光学活性シス
３−アミノ−２−フェニルピペリジンが得られるので特
に好ましい。2-phenylpiperidine, 3-amino-2
-Cyclohexylpiperidine, or 3-amino-2
When optically resolving racemic cis 3-amino-2-phenylpiperidine containing impurities such as cyclohexylpyridine and having a low chemical purity, an optically active tartaric acid derivative represented by the above general formula (3) or general formula (4) Among the optically active amino acid derivatives represented by Formula (5), Formula (6), or Formula (7), when optically active N-benzenesulfonylphenylalanine is used as an optical resolving agent, high chemical purity is obtained. It is particularly preferable because an optically active cis 3-amino-2-phenylpiperidine of high optical purity can be obtained.
【００３１】光学分割剤の使用量は、ラセミシスピペリ
ジン誘導体に対して０．８〜２．５倍モルが好ましく、
さらに好ましくは０．９〜２．０倍モルである。また、
分割剤に加えて、塩酸、硫酸等の無機酸類や光学不活性
体である酢酸やプロピオン酸を併用することもできる。
その場合には、光学分割剤の使用量を低減することがで
きる。The amount of the optical resolving agent used is preferably 0.8 to 2.5 times mol relative to the racemic cispiperidine derivative,
More preferably, it is 0.9 to 2.0 times mol. Also,
In addition to the resolving agent, inorganic acids such as hydrochloric acid and sulfuric acid, and acetic acid and propionic acid which are optically inactive substances can be used together.
In that case, the amount of the optical resolving agent used can be reduced.
【００３２】光学分割する際に使用する溶媒（以下「光
学分割溶媒」ともいう。）は、基質と反応しないことが
必要があり、原料のラセミシスピペリジン誘導体や分割
剤の種類によって異なるが、例えば水、炭素数１〜８の
アルコール類、アセトニトリル等のニトリル類、テトラ
ヒドロフラン等のエーテル類、酢酸エチル、酢酸イソプ
ロピル等のエステル類、クロロホルム等のハロゲン化物
等が好ましく使用できる。これらは、単独でも、あるい
は混合溶媒としても使用できるが、特に好ましくは水、
メタノール、エタノール、プロパノール、テトラヒドロ
フラン、アセトニトリル、酢酸エチル、またはこれらの
混合物である。The solvent used for optical resolution (hereinafter also referred to as "optical resolution solvent") must not react with the substrate, and it depends on the racemic cyspiperidine derivative as a raw material and the type of resolving agent. Water, alcohols having 1 to 8 carbon atoms, nitriles such as acetonitrile, ethers such as tetrahydrofuran, esters such as ethyl acetate and isopropyl acetate, and halides such as chloroform can be preferably used. These can be used alone or as a mixed solvent, but particularly preferably water,
It is methanol, ethanol, propanol, tetrahydrofuran, acetonitrile, ethyl acetate, or a mixture thereof.
【００３３】光学分割する際の温度は、原料のラセミシ
スピペリジン誘導体、分割剤、溶媒の種類によって異な
るが、通常は０℃から沸点以下の温度である。The temperature for the optical resolution varies depending on the kinds of the raw material racemic cispiperidine derivative, the resolving agent and the solvent, but it is usually from 0 ° C. to the boiling point or lower.
【００３４】光学分割の方法は、原料のラセミシスピペ
リジン誘導体、分割剤、および溶媒を仕込み、析出した
塩を濾過する方法が採用できる。この場合、一括仕込み
する方法、原料のラセミシスピペリジン誘導体と溶媒を
仕込んだ後に、攪拌しながら分割剤を入れる方法、逆に
溶媒と分割剤を仕込んだ後に、攪拌しながら原料のラセ
ミシスピペリジン誘導体を仕込む方法等があるが、原料
のラセミシスピペリジン誘導体、分割剤、溶媒の種類に
よって異なるので、最も適した方法を採用すればよい。
これらを仕込んだ後、昇温して溶解させるか、あるいは
スラリー状態で充分に平衡に到達させてから、徐々に降
温して、析出した結晶を濾過して単離する。母液の付着
による影響が大きい場合や、特に高い光学純度の製品を
生産する場合には、再度、溶媒を加えて溶解、あるいは
スラリー洗浄し、析出結晶を濾過することで、容易に光
学純度を高くすることができる。As a method of optical resolution, a method of charging a starting material racemic cispiperidine derivative, a resolving agent, and a solvent and filtering a precipitated salt can be adopted. In this case, the method of batch charging, the method of charging the starting material racemic cyspiperidine derivative and the solvent, and then the resolving agent while stirring, conversely after charging the solvent and the resolving agent, the starting material racemic cyspiperidine derivative while stirring There is a method of charging, but it depends on the kind of the racemic cyspiperidine derivative as the raw material, the resolving agent, and the solvent.
After these are charged, the temperature is raised to dissolve them, or after reaching a sufficient equilibrium in a slurry state, the temperature is gradually lowered, and the precipitated crystals are isolated by filtration. When the influence of mother liquor adhesion is large, or when a product with a particularly high optical purity is produced, it is possible to easily increase the optical purity by adding a solvent again to dissolve or wash the slurry and filter the precipitated crystals. can do.
【００３５】光学活性シスピペリジン誘導体を単離する
のは定法に従って実施できる。例えば、光学活性シスピ
ペリジン誘導体と分割剤の塩を水とトルエン中で攪拌し
ながらアルカリを添加して塩基性とすれば、トルエン層
に光学活性シスピペリジン誘導体が移行するので、トル
エン層を濃縮してから蒸留することで、高純度の光学活
性シスピペリジン誘導体を製造することができる。ま
た、塩基性水溶液中にある分割剤は回収・リサイクル使
用することもできる。本法によれば、高い光学純度の光
学活性シスピペリジン誘導体を効率よく生産できるだけ
でなく、分割剤を回収・リサイクルすることができるの
で、省資源的な製造法と云える。また、回収した不要の
光学異性体であるシスピペリジン誘導体をラセミ化・再
使用すれば、更に省資源的な製造法となる。Isolation of the optically active cispiperidine derivative can be performed according to a conventional method. For example, if the salt of the optically active cispiperidine derivative and the resolving agent is made basic by adding alkali with stirring in water and toluene, the optically active cispiperidine derivative migrates to the toluene layer, so the toluene layer is concentrated. By performing distillation after that, a highly pure optically active cispiperidine derivative can be produced. Further, the resolving agent in the basic aqueous solution can be recovered and recycled. According to this method, an optically active cispiperidine derivative having high optical purity can be efficiently produced, and a resolving agent can be recovered / recycled, which is a resource-saving production method. Further, if the recovered cispiperidine derivative which is an unnecessary optical isomer is racemized and reused, a more resource-saving production method can be obtained.
【００３６】[0036]
【実施例】以下、実施例により本発明をさらに詳細に説
明するが、本発明はこれに限定されるものではない。The present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto.
【００３７】なお、実施例において光学活性ピペラジン
誘導体の光学純度分析は、対象物によって異なるが、下
記の反応式により光学活性酒石酸誘導体無水物（東レ
（株）製品）と反応させて、光学活性酒石酸誘導体に誘
導してからＯＤＳカラムを装着したＨＰＬＣで実施し
た。In the examples, the optical purity analysis of the optically active piperazine derivative varies depending on the object, but it is reacted with the optically active tartaric acid derivative anhydride (product of Toray Industries, Inc.) according to the following reaction formula to obtain optically active tartaric acid. Derivatization was performed and then carried out by HPLC equipped with an ODS column.
【００３８】[0038]
【化１５】 [Chemical 15]
【００３９】光学純度計算法 (R,R)＞(S,S)の場合Optical Purity Calculation Method (R, R)> (S, S)
【００４０】[0040]
【数１】 [Equation 1]
【００４１】実施例１
温度計、コンデンサー、攪拌機を装着した容量３０００
ｍｌの反応容器に、トリフェニルフォスフィン１．０５
ｇ（４ミリモル）と酢酸パラジウム０．２２４ｇ（１ミ
リモル）、トルエン７５０ｍｌを仕込み、２０℃で１５
分間攪拌した。次いで、トリフェニルボロキシン９６．
８ｇ（０．９３３モル）、３−アミノ−２−クロロピリ
ジン１００．０ｇ（０．７７８モル）、２１％炭酸ナト
リウム水溶液９５０．０ｇ（１．９モル）を仕込んだ。
この混合スラリーを加温し、沸点下に４時間攪拌した。
反応液を室温まで冷却したのち、分液して水層を除去し
た。トルエン層を水２００ｇで洗浄したのち減圧下に濃
縮して３−アミノ−２−フェニルピリジンを得た。（純
度９７．０％）
得られた３−アミノ−２−フェニルピリジン２０ｇ、３
５％塩酸１００ｍｌ、水３００ｍｌ、および５％Ｐｔ／
Ｃ（５０％含水品）２０ｇを容量１０００ｍｌのガラス
製オートクレーブに仕込み、約３０℃で圧力０．３〜
０．４ＭＰａの水素雰囲気下に１３時間撹拌した。反応
終了後、濾過して触媒を除去した。濾液に４８％水酸化
ナトリウム水溶液を加えてｐＨを１２に調製したのち、
クロロホルム３００ｍｌを加えて抽出した。分液して水
層を除去したのち、クロロホルム層を濃縮して、油状の
ラセミシス３−アミノ−２−フェニルピペリジン１９．
４ｇを得た。化学純度は８２．４％であった。Example 1 Capacity 3000 equipped with a thermometer, condenser and stirrer
Add 1.05 of triphenylphosphine to the reaction vessel of ml.
g (4 mmol), 0.224 g (1 mmol) of palladium acetate and 750 ml of toluene were charged, and the mixture was stirred at 20 ° C. for 15 minutes.
Stir for minutes. Then triphenylboroxine 96.
8 g (0.933 mol), 3-amino-2-chloropyridine 100.0 g (0.778 mol), and 210.0% sodium carbonate aqueous solution 950.0 g (1.9 mol) were charged.
The mixed slurry was heated and stirred at the boiling point for 4 hours.
The reaction solution was cooled to room temperature and then separated to remove the aqueous layer. The toluene layer was washed with 200 g of water and then concentrated under reduced pressure to obtain 3-amino-2-phenylpyridine. (Purity 97.0%) 20 g of 3-amino-2-phenylpyridine obtained, 3
5% hydrochloric acid 100 ml, water 300 ml, and 5% Pt /
20 g of C (50% water-containing product) was charged into a glass autoclave having a capacity of 1000 ml, and the pressure was about 0.3 to 30 ° C.
The mixture was stirred under a hydrogen atmosphere of 0.4 MPa for 13 hours. After the reaction was completed, the catalyst was removed by filtration. After adjusting the pH to 12 by adding a 48% sodium hydroxide aqueous solution to the filtrate,
Chloroform (300 ml) was added for extraction. After separating and separating the aqueous layer, the chloroform layer was concentrated to give oily racemic cis 3-amino-2-phenylpiperidine 19.
4 g was obtained. The chemical purity was 82.4%.
【００４２】得られたラセミシス３−アミノ−２−フェ
ニルピペリジン５．７１ｇ（２６．７ミリモル）、Ｎ−
ベンゼンスルホニル−Ｌ−フェニルアラニン８．１６ｇ
（２６．７ミリモル）、およびメタノール２２．６ｇ
を、攪拌機、温度計、コンデンサーを装着した容量１０
０ｍｌのフラスコに仕込んだ。５０〜５５℃に加温し、
同温度下で１時間撹拌したのち、約２時間かけて２０℃
まで冷却した。析出した結晶を濾過したのち、乾燥して
５．３６ｇの塩を得た。塩中の３−アミノ−２−フェニ
ルピペリジンの含有率は３３．９％であり、（２Ｒ，３
Ｒ）体の光学純度は９３％ｄ．ｅ．であった。次いで、
この塩０．３ｇに、４８％水酸化ナトリウム水溶液０．
５ｇ、水１ｍｌ、およびクロロホルム５ｍｌを加えて、
室温下に撹拌して３−アミノ−２−フェニルピペリジン
を抽出した。分液後、クロロホルム層をガスクロマトグ
ラフィーに注入して分析したところ、溶媒ピークを除い
た３−アミノ−２−フェニルピペリジンの純度は９９．
４％であった。5.71 g (26.7 mmol) of the obtained racemic cis 3-amino-2-phenylpiperidine, N-
Benzenesulfonyl-L-phenylalanine 8.16 g
(26.7 mmol), and 22.6 g of methanol.
Equipped with a stirrer, thermometer, condenser
Charge to 0 ml flask. Warm to 50-55 ° C,
Stir at the same temperature for 1 hour, then at 20 ℃ for about 2 hours.
Cooled down. The precipitated crystals were filtered and dried to obtain 5.36 g of salt. The content of 3-amino-2-phenylpiperidine in the salt was 33.9%, and (2R, 3
R) has an optical purity of 93% d. e. Met. Then
0.3 g of this salt was added to a 48% aqueous sodium hydroxide solution.
Add 5 g, 1 ml of water, and 5 ml of chloroform,
The mixture was stirred at room temperature to extract 3-amino-2-phenylpiperidine. After liquid separation, the chloroform layer was injected into gas chromatography and analyzed, and the purity of 3-amino-2-phenylpiperidine excluding the solvent peak was 99.
It was 4%.
【００４３】実施例２
攪拌機、温度計、コンデンサーを装着した容量１００ｍ
ｌのフラスコに、実施例１で取得したラセミシス３−ア
ミノ−２−フェニルピペリジン５．７１ｇ（２６．７ミ
リモル）、Ｎ−ベンゼンスルホニル−Ｄ−フェニルアラ
ニン８．１６ｇ（２６．７ミリモル）、およびメタノー
ル２２．６ｇを仕込んだ。５０〜５５℃に加温し、同温
度下で１時間撹拌したのち、約２時間かけて２０℃まで
冷却した。析出した結晶を濾過したのち、乾燥して５．
３６ｇの塩を得た。塩中の３−アミノ−２−フェニルピ
ペリジンの含有率は３４．１％であり、（２Ｓ，３Ｓ）
体の光学純度は９２％ｄ．ｅ．であった。次いで、この
塩０．３ｇに、４８％水酸化ナトリウム水溶液０．５
ｇ、水１ｍｌ、およびクロロホルム５ｍｌを加えて、室
温下に撹拌して３−アミノ−２−フェニルピペリジンを
抽出した。分液後、クロロホルム層をガスクロマトグラ
フィーに注入して分析したところ、溶媒ピークを除いた
３−アミノ−２−フェニルピペリジンの純度は９９．３
％であった。Example 2 100 m capacity equipped with a stirrer, thermometer and condenser
In a 1-liter flask, 5.71 g (26.7 mmol) of racemic cis 3-amino-2-phenylpiperidine obtained in Example 1, 8.16 g (26.7 mmol) of N-benzenesulfonyl-D-phenylalanine, and methanol. 22.6 g was charged. The mixture was heated to 50 to 55 ° C, stirred at the same temperature for 1 hour, and then cooled to 20 ° C over about 2 hours. 4. The precipitated crystals are filtered and then dried to 5.
36 g of salt was obtained. The content of 3-amino-2-phenylpiperidine in the salt was 34.1%, (2S, 3S)
The optical purity of the body is 92% d. e. Met. Next, 0.3 g of this salt was added to 0.5% of a 48% sodium hydroxide aqueous solution.
g, water 1 ml, and chloroform 5 ml were added, and the mixture was stirred at room temperature to extract 3-amino-2-phenylpiperidine. After separation, the chloroform layer was injected into a gas chromatography and analyzed, and the purity of 3-amino-2-phenylpiperidine excluding the solvent peak was 99.3.
%Met.
【００４４】実施例３
攪拌機、温度計、コンデンサーを装着した容量１００ｍ
ｌのフラスコに、実施例１で取得したラセミシス３−ア
ミノ−２−フェニルピペリジン５．７１ｇ（２６．７ミ
リモル）、Ｎ−ベンゼンスルホニル−Ｄ−フェニルアラ
ニン５．７１ｇ（１８．７ミリモル）、およびメタノー
ル１４．１ｇを仕込んだ。５０〜５５℃に加温し、同温
度下で１時間撹拌したのち、約２時間かけて２０℃まで
冷却した。析出した結晶を濾過したのち、乾燥して４．
８９ｇの塩を得た。塩中の３−アミノ−２−フェニルピ
ペリジンの含有率は３４．３％であり、（２Ｓ，３Ｓ）
体の光学純度は９４％ｄ．ｅ．であった。次いで、この
塩０．３ｇに、４８％水酸化ナトリウム水溶液０．５
ｇ、水１ｍｌ、およびクロロホルム５ｍｌを加えて、室
温下に撹拌して３−アミノ−２−フェニルピペリジンを
抽出した。分液後、クロロホルム層をガスクロマトグラ
フィーに注入して分析したところ、溶媒ピークを除いた
３−アミノ−２−フェニルピペリジンの純度は９９．４
％であった。Example 3 100 m capacity equipped with a stirrer, thermometer and condenser
In a 1-liter flask, 5.71 g (26.7 mmol) of racemic cis 3-amino-2-phenylpiperidine obtained in Example 1, 5.71 g (18.7 mmol) of N-benzenesulfonyl-D-phenylalanine, and methanol. 14.1 g was charged. The mixture was heated to 50 to 55 ° C, stirred at the same temperature for 1 hour, and then cooled to 20 ° C over about 2 hours. The precipitated crystals are filtered, dried and then 4.
89 g of salt was obtained. The content of 3-amino-2-phenylpiperidine in the salt was 34.3%, (2S, 3S)
The optical purity of the body is 94% d. e. Met. Next, 0.3 g of this salt was added to 0.5% of a 48% sodium hydroxide aqueous solution.
g, water 1 ml, and chloroform 5 ml were added, and the mixture was stirred at room temperature to extract 3-amino-2-phenylpiperidine. After liquid separation, the chloroform layer was injected into gas chromatography and analyzed, and the purity of 3-amino-2-phenylpiperidine excluding the solvent peak was 99.4.
%Met.
【００４５】実施例４
攪拌機、温度計、コンデンサーを装着した容量１００ｍ
ｌのフラスコに、実施例１と同じ方法で取得した純度８
１．１％のラセミシス３−アミノ−２フェニル−ピペリ
ジン５．８０ｇ（２６．７ミリモル）、Ｎ−ベンゼンス
ルホニル−Ｄ−フェニルアラニン５．７１ｇ（１８．７
ミリモル）、酢酸０．４８ｇ（８．０ミリモル）、およ
びメタノール１４．１ｇを仕込んだ。５０〜５５℃に加
温し、同温度下で１時間撹拌したのち、約２時間かけて
２０℃まで冷却した。析出した結晶を濾過したのち、乾
燥して５．５１ｇの塩を得た。塩中の３−アミノ−２−
フェニルピペリジンの含有率は３５．７％であり、（２
Ｓ，３Ｓ）体の光学純度は９３％ｄ．ｅ．であった。次
いで、この塩０．３ｇに、４８％水酸化ナトリウム水溶
液０．５ｇ、水１ｍｌ、およびクロロホルム５ｍｌを加
えて、室温下に撹拌して３−アミノ−２−フェニルピペ
リジンを抽出した。分液後、クロロホルム層をガスクロ
マトグラフィーに注入して分析したところ、溶媒ピーク
を除いた３−アミノ−２−フェニルピペリジンの純度は
９９．２％であった。Example 4 100 m capacity equipped with a stirrer, thermometer and condenser
In a 1-liter flask, the purity of 8 obtained in the same manner as in Example 1
1.1% racemic cis 3-amino-2phenyl-piperidine 5.80 g (26.7 mmol), N-benzenesulfonyl-D-phenylalanine 5.71 g (18.7).
(Mmol), 0.48 g (8.0 mmol) of acetic acid, and 14.1 g of methanol. The mixture was heated to 50 to 55 ° C, stirred at the same temperature for 1 hour, and then cooled to 20 ° C over about 2 hours. The precipitated crystals were filtered and then dried to obtain 5.51 g of salt. 3-amino-2- in salt
The content rate of phenylpiperidine is 35.7%, and (2
The optical purity of the (S, 3S) form is 93% d. e. Met. Then, to 0.3 g of this salt, 0.5 g of 48% aqueous sodium hydroxide solution, 1 ml of water, and 5 ml of chloroform were added, and the mixture was stirred at room temperature to extract 3-amino-2-phenylpiperidine. After liquid separation, the chloroform layer was injected into gas chromatography and analyzed, and the purity of 3-amino-2-phenylpiperidine excluding the solvent peak was 99.2%.
【００４６】実施例５
攪拌機、温度計、コンデンサーを装着した容量１００ｍ
ｌのフラスコに、実施例１と同じ方法で取得した純度８
１．１％のラセミシス３−アミノ−２−フェニルピペリ
ジン５．８０ｇ（２６．７ミリモル）、Ｎ−ｐ−トルエ
ンスルホニル−Ｌ−フェニルアラニン８．５３ｇ（２
６．７ミリモル）、およびメタノール２２．６ｇを仕込
んだ。５０〜５５℃に加温し、同温度下で１時間撹拌し
たのち、約２時間かけて２０℃まで冷却した。析出した
結晶を濾過したのち、乾燥して４．７２ｇの塩を得た。
塩中の３−アミノ−２−フェニルピペリジンの含有率は
３１．４％であり、（２Ｓ，３Ｓ）体の光学純度は８０
％ｄ．ｅ．であった。次いで、この塩０．３ｇに、４８
％水酸化ナトリウム水溶液０．５ｇ、水１ｍｌ、および
クロロホルム５ｍｌを加えて、室温下に撹拌して３−ア
ミノ−２−フェニルピペリジンを抽出した。分液後、ク
ロロホルム層をガスクロマトグラフィーに注入して分析
したところ、溶媒ピークを除いた３−アミノ−２−フェ
ニルピペリジンの純度は９２．３％であった。Example 5 100 m capacity equipped with a stirrer, thermometer and condenser
In a 1-liter flask, the purity of 8 obtained in the same manner as in Example 1
1.1% racemic cis 3-amino-2-phenylpiperidine 5.80 g (26.7 mmol), Np-toluenesulfonyl-L-phenylalanine 8.53 g (2
(6.7 mmol), and 22.6 g of methanol were charged. The mixture was heated to 50 to 55 ° C, stirred at the same temperature for 1 hour, and then cooled to 20 ° C over about 2 hours. The precipitated crystals were filtered and dried to obtain 4.72 g of salt.
The content of 3-amino-2-phenylpiperidine in the salt was 31.4%, and the optical purity of the (2S, 3S) form was 80.
% D. e. Met. Then, to 0.3 g of this salt, 48
% Aqueous solution of sodium hydroxide (0.5 g), water (1 ml) and chloroform (5 ml) were added and the mixture was stirred at room temperature to extract 3-amino-2-phenylpiperidine. After liquid separation, the chloroform layer was injected into gas chromatography and analyzed, and the purity of 3-amino-2-phenylpiperidine excluding the solvent peak was 92.3%.
【００４７】実施例６
攪拌機、温度計、コンデンサーを装着した容量１００ｍ
ｌのフラスコに、実施例１と同じ方法で取得した純度８
１．１％のラセミシス３−アミノ−２−フェニルピペリ
ジン５．８０ｇ（２６．７ミリモル）、ジ（パラトルオ
イル）−Ｌ−酒石酸１０．３１ｇ（２６．７ミリモ
ル）、およびメタノール４８．０ｇを仕込んだ。５０〜
５５℃に加温し、同温度下で１時間撹拌したのち、約２
時間かけて２０℃まで冷却した。析出した結晶を濾過し
たのち、乾燥して７．４６ｇの塩を得た。塩中の３−ア
ミノ−２−フェニルピペリジンの含有率は２８．７％で
あり、（２Ｓ，３Ｓ）体の光学純度は９６％ｄ．ｅ．で
あった。次いで、この塩０．３ｇに、４８％水酸化ナト
リウム水溶液０．５ｇ、水１ｍｌ、およびクロロホルム
５ｍｌを加えて、室温下に撹拌して３−アミノ−２−フ
ェニルピペリジンを抽出した。分液後、クロロホルム層
をガスクロマトグラフィーに注入して分析したところ、
溶媒ピークを除いた３−アミノ−２−フェニルピペリジ
ンの純度は９４．７％であった。Example 6 100 m capacity equipped with a stirrer, thermometer and condenser
In a 1-liter flask, the purity of 8 obtained in the same manner as in Example 1
1.1% racemic cis 3-amino-2-phenylpiperidine 5.80 g (26.7 mmol), di (paratoluoyl) -L-tartaric acid 10.31 g (26.7 mmol), and methanol 48.0 g were charged. . 50-
After warming to 55 ° C and stirring at the same temperature for 1 hour, about 2
It cooled to 20 degreeC over time. The precipitated crystals were filtered and dried to obtain 7.46 g of salt. The content of 3-amino-2-phenylpiperidine in the salt was 28.7%, and the optical purity of the (2S, 3S) form was 96% d. e. Met. Then, to 0.3 g of this salt, 0.5 g of 48% aqueous sodium hydroxide solution, 1 ml of water, and 5 ml of chloroform were added, and the mixture was stirred at room temperature to extract 3-amino-2-phenylpiperidine. After liquid separation, the chloroform layer was injected into gas chromatography and analyzed,
The purity of 3-amino-2-phenylpiperidine excluding the solvent peak was 94.7%.
【００４８】実施例７
攪拌機、コンデンサー、温度計を装着した５０ｍｌの３
口フラスコに、メタノール１０ｍｌ、ラセミシス３−ア
ミノ−２−フェニルピペリジン１．８ｇ（１０ミリモ
ル）、ジ（４−メトキシベンゾイル）−Ｌ−酒石酸（東
レ（株）製品）４．２ｇ（１０ミリモル）を仕込み、６
０℃で攪拌して溶解させた。次いで攪拌しながら約１時
間で室温まで冷却し、更に２時間攪拌した。析出結晶を
濾過・乾燥して２．７ｇの塩を得た。塩としての収率は
４５％、光学純度は（２Ｓ，３Ｓ）体が５０．４％ｄ．
ｅ．であった。析出結晶を２０ｍｌのメタノールで再結
晶し、析出結晶を濾過・乾燥して１．８ｇの塩を得た。
塩としての収率は６５％、塩に含まれているシス３−ア
ミノ−２−フェニルピペリジンの光学純度は、（２Ｓ，
３Ｓ）体が９８．６％ｄ．ｅ．であった。Example 7 50 ml of 3 equipped with a stirrer, condenser and thermometer
10 ml of methanol, 1.8 g (10 mmol) of racemic cis 3-amino-2-phenylpiperidine, and 4.2 g (10 mmol) of di (4-methoxybenzoyl) -L-tartaric acid (product of Toray Industries, Inc.) were placed in a neck flask. Preparation, 6
It was dissolved by stirring at 0 ° C. Then, the mixture was cooled to room temperature with stirring for about 1 hour, and further stirred for 2 hours. The precipitated crystals were filtered and dried to obtain 2.7 g of salt. The yield as a salt was 45%, and the optical purity was 50.4% d.s. (2S, 3S).
e. Met. The precipitated crystals were recrystallized with 20 ml of methanol, and the precipitated crystals were filtered and dried to obtain 1.8 g of salt.
The yield as a salt is 65%, and the optical purity of cis 3-amino-2-phenylpiperidine contained in the salt is (2S,
3S) form is 98.6% d. e. Met.
【００４９】実施例８〜１１
２０ｍｌの栓付きサンプル瓶に、攪拌子、メタノール７
ｍｌ、下記の光学活性Ｌ−アスパラギン酸誘導体（５ミ
リモル）、ラセミシス−３−アミノ−２−フェニルピペ
リジン０．９ｇ（５ミリモル）を仕込み、５０℃で１０
分間加熱し、室温まで冷却して、更に２時間攪拌した。
析出した結晶を濾過・乾燥して、塩に含まれているシス
３−アミノ−２−フェニルピペリジンの光学純度を求め
た。結果を表１に示す。Examples 8 to 11 A stirring bottle and methanol 7 were placed in a 20 ml sample bottle with a stopper.
ml, the following optically active L-aspartic acid derivative (5 mmol), and 0.9 g (5 mmol) of racemic cis-3-amino-2-phenylpiperidine were charged, and the mixture was added at 10 ° C at 10 ° C.
Heat for 1 minute, cool to room temperature and stir for an additional 2 hours.
The precipitated crystals were filtered and dried to determine the optical purity of cis3-amino-2-phenylpiperidine contained in the salt. The results are shown in Table 1.
【００５０】[0050]
【化１６】 [Chemical 16]
【００５１】[0051]
【表１】 [Table 1]
【００５２】これらの析出結晶をメタノールで再結晶す
ることで、塩に含まれているシス３−アミノ−２−フェ
ニルピペリジンの光学純度が９８％ｄ．ｅ．以上の光学
活性３−アミノ−２−フェニルピペリジンを得た。By recrystallizing these precipitated crystals with methanol, the optical purity of cis 3-amino-2-phenylpiperidine contained in the salt was 98% d. e. The above optically active 3-amino-2-phenylpiperidine was obtained.
【００５３】実施例１２
攪拌機、コンデンサー、温度計を装着した５０ｍｌの３
口フラスコに、メタノール１０ｍｌ、ラセミシス３−ア
ミノ−２−フェニルピペリジン１．８ｇ（１０ミリモ
ル）、ジ（パラトルオイル）−Ｌ−酒石酸３．９ｇ（１
０ミリモル）を仕込み、６０℃で攪拌して溶解させた。
次いで攪拌しながら約１時間で室温まで冷却し、更に２
時間攪拌した。析出結晶を濾過・乾燥して２．５ｇの塩
を得た。塩としての収率は４５％、塩に含まれているシ
ス３−アミノ−２−フェニルピペリジンの光学純度は、
（２Ｓ，３Ｓ）体が８８．７％ｄ．ｅ．であった。析出
結晶を１０ｍｌのメタノールで再結晶し、析出結晶を濾
過・乾燥して２．３ｇの塩を得た。塩としての収率は９
１％、塩に含まれているシス３−アミノ−２−フェニル
ピペリジンの光学純度は（２Ｓ，３Ｓ）体が９９．３％
ｄ．ｅ．であった。Example 12 50 ml of 3 equipped with a stirrer, condenser and thermometer
In a necked flask, 10 ml of methanol, 1.8 g (10 mmol) of racemic cis 3-amino-2-phenylpiperidine, 3.9 g (1 of di (paratoluoyl) -L-tartaric acid.
(0 mmol) was charged and dissolved by stirring at 60 ° C.
Then, while stirring, the mixture was cooled to room temperature in about 1 hour, and further 2
Stir for hours. The precipitated crystals were filtered and dried to obtain 2.5 g of salt. The yield as a salt is 45%, and the optical purity of cis 3-amino-2-phenylpiperidine contained in the salt is
(2S, 3S) form is 88.7% d. e. Met. The precipitated crystals were recrystallized with 10 ml of methanol, and the precipitated crystals were filtered and dried to obtain 2.3 g of salt. Yield as salt is 9
1%, the optical purity of cis 3-amino-2-phenylpiperidine contained in the salt is 99.3% for the (2S, 3S) form.
d. e. Met.
【００５４】５０ｍｌの分液ロートに、析出結晶２．３
ｇとトルエン２０ｍｌを仕込み、更に５％水酸化ナトリ
ウム水溶液１０ｍｌを加えて良く震とうした。トルエン
層を分液し、水層を更に２０ｍｌのトルエンで抽出し
た。両トルエン層を合わせてエバポレータで濃縮し、
０．７ｇの濃縮物を得た。濃縮物中の（２Ｓ，３Ｓ）−
３−アミノ−２−フェニルピペリジンの化学純度は９
８．１％（溶媒ピークを除いたＧＣ分析純度）、光学純
度は９９．３％ｄ．ｅ．であった。Precipitated crystals 2.3 in a 50 ml separating funnel.
g and 20 ml of toluene were charged, 10 ml of 5% aqueous sodium hydroxide solution was added, and the mixture was shaken well. The toluene layer was separated, and the aqueous layer was further extracted with 20 ml of toluene. Both toluene layers were combined and concentrated with an evaporator,
0.7 g of concentrate was obtained. (2S, 3S) -in the concentrate
The chemical purity of 3-amino-2-phenylpiperidine is 9
8.1% (GC analysis purity excluding the solvent peak), optical purity 99.3% d. e. Met.
【００５５】実施例１３
ラセミシス３−アミノ−２−フェニルピペリジンをラセ
ミシス−３−メチルアミノ−２−フェニルピペリジンに
変えた以外は実施例７と同様にして光学分割し、析出結
晶を濾過・乾燥して２．７ｇの塩を得た。塩としての収
率は４５％、塩に含まれているシス３−メチルアミノ−
２−フェニルピペリジンの光学純度は、（２Ｓ，３Ｓ）
体が５０．４％ｄ．ｅ．であった。析出結晶を２０ｍｌ
のメタノールで再結晶し、析出結晶を濾過・乾燥して
１．８ｇの塩を得た。塩としての収率は６５％、塩に含
まれているシス３−メチルアミノ−２−フェニルピペリ
ジンの光学純度は、（２Ｓ，３Ｓ）体が９８．１％ｄ．
ｅ．であった。再度１０ｍｌのメタノールで再結晶し、
塩に含まれているシス３−メチルアミノ−２−フェニル
ピペリジンの光学純度が（２Ｓ，３Ｓ）体９９．７％
ｄ．ｅ．の結晶を得た。Example 13 Optical resolution was carried out in the same manner as in Example 7 except that racemic cis 3-amino-2-phenylpiperidine was changed to racemic cis-3-methylamino-2-phenylpiperidine, and the precipitated crystals were filtered and dried. To give 2.7 g of salt. The yield as a salt was 45%, and cis 3-methylamino- contained in the salt
The optical purity of 2-phenylpiperidine is (2S, 3S)
Body is 50.4% d. e. Met. 20 ml of precipitated crystals
Was recrystallized from methanol, and the precipitated crystals were filtered and dried to obtain 1.8 g of salt. The yield as a salt is 65%, and the optical purity of cis 3-methylamino-2-phenylpiperidine contained in the salt is 98.1% d.
e. Met. Recrystallize again with 10 ml of methanol,
The optical purity of cis 3-methylamino-2-phenylpiperidine contained in the salt is 99.7% of (2S, 3S) isomer.
d. e. Was obtained.
【００５６】実施例１４
２０ｍｌの栓付きサンプル瓶に、攪拌子、水７ｍｌ、光
学活性パラトルエンスルホニル−Ｌ−アスパラギン酸
１．４ｇ（５ミリモル）、ラセミシス−３−アミノ−２
−フェニルピペリジン０．９ｇ（５ミリモル）を仕込
み、５０℃で１０分間加熱し、室温まで冷却して、更に
２時間攪拌した。析出した結晶を濾過・乾燥して１．０
ｇの塩を得た。塩としての収率は４０．１％、塩中の
（２Ｓ，３Ｓ）体の光学純度は４５．２％ｄ．ｅ．であ
った。析出した結晶を水中で２回再結晶を行い、塩に含
まれている（２Ｓ，３Ｓ）−３−アミノ−２−フェニル
ピペリジンの光学純度が９９．１％ｄ．ｅ．の結晶を得
た。Example 14 In a 20 ml sample bottle with a stopper, a stirring bar, 7 ml of water, 1.4 g (5 mmol) of optically active paratoluenesulfonyl-L-aspartic acid, racemic cis-3-amino-2.
0.9 g (5 mmol) of -phenylpiperidine was charged, heated at 50 ° C for 10 minutes, cooled to room temperature, and further stirred for 2 hours. The precipitated crystals are filtered and dried to 1.0
g of salt was obtained. The yield as a salt was 40.1%, and the optical purity of the (2S, 3S) form in the salt was 45.2% d. e. Met. The precipitated crystals were recrystallized twice in water, and the optical purity of (2S, 3S) -3-amino-2-phenylpiperidine contained in the salt was 99.1% d.p. e. Was obtained.
【００５７】比較例１
攪拌機、温度計、コンデンサーを装着した容量１００ｍ
ｌのフラスコに、実施例１と同じ方法で取得した純度８
１．１％のラセミシス３−アミノ−２−フェニルピペリ
ジン５．８０ｇ（２６．７ミリモル）、Ｌ−マンデル酸
４．０６ｇ（２６．７ミリモル）、およびアセトニトリ
ル１４８．９を仕込んだ。５０〜５５℃に加温し、同温
度下で１時間撹拌したのち、約２時間かけて２０℃まで
冷却した。析出した結晶を濾過したのち、乾燥して３．
２１ｇの塩を得た。塩中の３−アミノ−２−フェニルピ
ペリジンの含有率は３４．９％であり、（２Ｓ，３Ｓ）
体の光学純度は５２％ｄ．ｅ．であった。次いで、この
塩０．３ｇに、４８％水酸化ナトリウム水溶液０．５
ｇ、水１ｍｌ、およびクロロホルム５ｍｌを加えて、室
温下に撹拌して３−アミノ−２−フェニルピペリジンを
抽出した。分液後、クロロホルム層をガスクロマトグラ
フィーに注入して分析したところ、溶媒ピークを除いた
３−アミノ−２−フェニルピペリジンの純度は９０．４
％であった。Comparative Example 1 100 m capacity equipped with a stirrer, thermometer and condenser
In a 1-liter flask, the purity of 8 obtained in the same manner as in Example 1
1.1% racemic cis 3-amino-2-phenylpiperidine 5.80 g (26.7 mmol), L-mandelic acid 4.06 g (26.7 mmol) and acetonitrile 148.9 were charged. The mixture was heated to 50 to 55 ° C, stirred at the same temperature for 1 hour, and then cooled to 20 ° C over about 2 hours. The precipitated crystals are filtered, dried and then 3.
21 g of salt was obtained. The content of 3-amino-2-phenylpiperidine in the salt was 34.9%, (2S, 3S)
The optical purity of the body is 52% d. e. Met. Next, 0.3 g of this salt was added to 0.5% of a 48% sodium hydroxide aqueous solution.
g, water 1 ml, and chloroform 5 ml were added, and the mixture was stirred at room temperature to extract 3-amino-2-phenylpiperidine. After separation, the chloroform layer was injected into a gas chromatography and analyzed, and the purity of 3-amino-2-phenylpiperidine excluding the solvent peak was 90.4.
%Met.
【００５８】[0058]
【発明の効果】本発明によれば、容易に高い光学純度の
光学活性シスピペリジン誘導体を製造することができ
る。INDUSTRIAL APPLICABILITY According to the present invention, an optically active cispiperidine derivative having high optical purity can be easily produced.
───────────────────────────────────────────────────── フロントページの続き Ｆターム(参考） 4C054 AA02 BB01 CC01 DD05 DD08 DD22 DD25 EE30 FF01 ─────────────────────────────────────────────────── ─── Continued front page F term (reference) 4C054 AA02 BB01 CC01 DD05 DD08 DD22 DD25 EE30 FF01
Claims (10)
アルキル基、Ｒ３は、水素、炭素数１〜６のアルキル
基、炭素数１〜６のアルコキシ基、またはハロゲンを示
し、ｎは０〜３の整数を意味する。）で表されるシスピ
ペリジン誘導体の混合物であるラセミシスピペリジン誘
導体を、光学活性酒石酸誘導体または光学活性アミノ酸
誘導体で光学分割することを特徴とする光学活性シスピ
ペリジン誘導体の製造法。1. A general formula (1) and a general formula (2): (Here, R 1 and R 2 are hydrogen or an alkyl group having 1 to 6 carbon atoms, R 3 is hydrogen, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, or halogen. , And n represents an integer of 0 to 3), wherein the racemic cispiperidine derivative, which is a mixture of cispiperidine derivatives represented by the formula, is optically resolved with an optically active tartaric acid derivative or an optically active amino acid derivative. Process for producing active cispiperidine derivative.
ルアミノ基、ベンジルアミノ基、またはフェニルエチル
アミノ基を示す。また、＊のついている炭素原子が不斉
中心であることを意味する。）で表される光学活性酒石
酸アミド誘導体または一般式（４） 【化３】 （ここで、Ｒ６は、炭素数１〜５のアルキル基、または
芳香環が置換もしくは無置換のフェニル基もしくはベン
ジル基を示す。また、＊のついている炭素原子が不斉中
心であることを意味する。）で表される光学活性ジアシ
ル酒石酸誘導体であることを特徴とする請求項１記載の
光学活性シスピペリジン誘導体の製造法。2. An optically active tartaric acid derivative has the general formula (3): (Here, R 5 represents a substituted or unsubstituted phenylamino group, a benzylamino group, or a phenylethylamino group. Also, the carbon atom with * is an asymmetric center. .) Or an optically active tartaric acid amide derivative represented by the general formula (4): (Here, R 6 represents an alkyl group having 1 to 5 carbon atoms, or a phenyl group or a benzyl group in which the aromatic ring is substituted or unsubstituted. Further, the carbon atom with * is an asymmetric center. The process for producing an optically active cispiperidine derivative according to claim 1, which is an optically active diacyl tartaric acid derivative represented by the formula (1).
ゾイル酒石酸、光学活性ジ（パラトルオイル）酒石酸、
光学活性ジ（メタトルオイル）酒石酸、光学活性ジ（オ
ルソトルオイル）酒石酸、光学活性ジ（４−メトキシベ
ンゾイル）酒石酸、光学活性ジ（３−メトキシベンゾイ
ル）酒石酸、および光学活性ジ（２−メトキシベンゾイ
ル）酒石酸からなる群から選ばれた１種であることを特
徴とする請求項２記載の光学活性シスピペリジン誘導体
の製造法。3. An optically active tartaric acid derivative is an optically active dibenzoyl tartaric acid, an optically active di (paratoluoyl) tartaric acid,
Optically active di (metatoluoyl) tartaric acid, Optically active di (orthotoluoyl) tartaric acid, Optically active di (4-methoxybenzoyl) tartaric acid, Optically active di (3-methoxybenzoyl) tartaric acid, and Optically active di (2-methoxybenzoyl) The method for producing an optically active cispiperidine derivative according to claim 2, wherein the method is one selected from the group consisting of tartaric acid.
置換もしくは無置換のフェニル基、ベンジル基、もしく
はフェニルエチル基を示し、Ｒ８は、炭素数１〜５のア
シル基、または芳香環が置換もしくは無置換のベンゾイ
ル基、ベンジルカルボニル基、ベンゼンスルホニル基、
もしくはベンジルスルホニル基を示す。また、＊のつい
ている炭素原子が不斉中心であることを意味する。）で
表される光学活性中性アミノ酸誘導体、一般式（６） 【化５】 （ここで、Ｒ９は、炭素数１〜５のアシル基、または芳
香環が置換もしくは無置換のベンゾイル基、ベンジルカ
ルボニル基、ベンゼンスルホニル基、もしくはベンジル
スルホニル基を示す。ｍは１〜３の整数。また、＊のつ
いている炭素原子が不斉中心であることを意味する。）
で表される光学活性酸性アミノ酸誘導体、または一般式
（７） 【化６】 （ここで、Ｒ１０は、炭素数１〜５のアシル基、または
芳香環が置換もしくは無置換のベンゾイル基、ベンジル
カルボニル基、ベンゼンスルホニル基、もしくはベンジ
ルスルホニル基を示す。ｌは１〜５の整数。また、＊の
ついている炭素原子が不斉中心であることを意味す
る。）で表される光学活性塩基性アミノ酸誘導体である
ことを特徴とする請求項１記載の光学活性シスピペリジ
ン誘導体の製造法。4. An optically active amino acid derivative is represented by the general formula (5): (Here, R 7 represents an alkyl group having 1 to 6 carbon atoms, or a substituted or unsubstituted phenyl group, benzyl group, or phenylethyl group, and R 8 is an acyl group having 1 to 5 carbon atoms, or Aromatic ring substituted or unsubstituted benzoyl group, benzylcarbonyl group, benzenesulfonyl group,
Alternatively, it represents a benzylsulfonyl group. Further, it means that the carbon atom with * is an asymmetric center. ) An optically active neutral amino acid derivative represented by the general formula (6): (Here, R 9 represents an acyl group having 1 to 5 carbon atoms, or a benzoyl group in which an aromatic ring is substituted or unsubstituted, a benzylcarbonyl group, a benzenesulfonyl group, or a benzylsulfonyl group. M is 1 to 3 An integer, and means that the carbon atom with * is an asymmetric center.)
An optically active acidic amino acid derivative represented by or a general formula (7): (Here, R 10 represents an acyl group having 1 to 5 carbon atoms, or a benzoyl group having a substituted or unsubstituted aromatic ring, a benzylcarbonyl group, a benzenesulfonyl group, or a benzylsulfonyl group. L is 1 to 5 An integer, and means that the carbon atom with * is an asymmetric center.) Is an optically active basic amino acid derivative, and the optically active cis-piperidine derivative according to claim 1, Manufacturing method.
またはベンジル基であり、Ｒ８が芳香環が置換または無
置換のベンゾイル基、ベンジルカルボニル基、ベンゼン
スルホニル基、またはベンジルスルホニル基であること
を特徴とする請求項４記載の光学活性シスピペリジン誘
導体の製造法。5. In the general formula (5), R 7 is a phenyl group or a benzyl group, and R 8 is a substituted or unsubstituted benzoyl group, a benzylcarbonyl group, a benzenesulfonyl group, or a benzylsulfonyl group. The method for producing an optically active cispiperidine derivative according to claim 4, wherein
換または無置換のベンゾイル基、ベンジルカルボニル
基、ベンゼンスルホニル基、またはベンジルスルホニル
基であることを特徴とする請求項４記載の光学活性シス
ピペリジン誘導体の製造法。6. The formula (6), wherein R 9 is a benzoyl group, a benzylcarbonyl group, a benzenesulfonyl group, or a benzylsulfonyl group whose aromatic ring is substituted or unsubstituted. Process for producing optically active cispiperidine derivative.
ベンゾイルフェニルグリシン、光学活性Ｎ−ベンゼンス
ルホニルフェニルグリシン、光学活性Ｎ−トルエンスル
ホニルフェニルグリシン、光学活性Ｎ−ベンジルスルホ
ニルフェニルグリシン、光学活性Ｎ−ベンゾイルフェニ
ルアラニン、光学活性Ｎ−ベンゼンスルホニルフェニル
アラニン、光学活性Ｎ−トルエンスルホニルフェニルア
ラニン、光学活性Ｎ−ベンジルスルホニルフェニルアラ
ニン、光学活性Ｎ−ベンゾイルアスパラギン酸、光学活
性Ｎ−ベンゼンスルホニルアスパラギン酸、光学活性Ｎ
−トルエンスルホニルアスパラギン酸、光学活性Ｎ−ベ
ンジルスルホニルアスパラギン酸、光学活性Ｎ−ベンゾ
イルグルタミン酸、光学活性Ｎ−ベンゼンスルホニルグ
ルタミン酸、光学活性Ｎ−トルエンスルホニルグルタミ
ン酸、光学活性Ｎ−ベンジルスルホニルグルタミン酸か
らなる群から選ばれた１種であることを特徴とする請求
項５または６記載の光学活性シスピペリジン誘導体の製
造法。7. An optically active amino acid derivative is an optically active N-
Benzoylphenylglycine, optically active N-benzenesulfonylphenylglycine, optically active N-toluenesulfonylphenylglycine, optically active N-benzylsulfonylphenylglycine, optically active N-benzoylphenylalanine, optically active N-benzenesulfonylphenylalanine, optically active N- Toluenesulfonylphenylalanine, optically active N-benzylsulfonylphenylalanine, optically active N-benzoylaspartic acid, optically active N-benzenesulfonylaspartic acid, optically active N
-Toluenesulfonylaspartic acid, optically active N-benzylsulfonylaspartic acid, optically active N-benzoylglutamic acid, optically active N-benzenesulfonylglutamic acid, optically active N-toluenesulfonylglutamic acid, optically active N-benzylsulfonylglutamic acid 7. The method for producing an optically active cispiperidine derivative according to claim 5, which is one of the above.
ベンゼンスルホニルフェニルアラニンであることを特徴
とする請求項５記載の光学活性シスピペリジン誘導体の
製造法。8. An optically active amino acid derivative is an optically active N-
It is benzenesulfonyl phenylalanine, The manufacturing method of the optically active cis piperidine derivative of Claim 5 characterized by the above-mentioned.
ール、プロパノール、テトラヒドロフラン、アセトニト
リル、酢酸エチルまたはこれらの混合物であることを特
徴とする請求項１〜８のいずれか１項記載の光学活性シ
スピペリジン誘導体の製造法。9. The optically active cis according to claim 1, wherein the optically resolving solvent is water, methanol, ethanol, propanol, tetrahydrofuran, acetonitrile, ethyl acetate or a mixture thereof. Process for producing piperidine derivative.
リジン誘導体が、３−アミノ−２−フェニルピリジンを
水素化触媒存在下で水素化して得られたラセミシス３−
アミノ−２−フェニルピぺリジンであり、光学活性シス
ピぺリジン誘導体が光学活性シス３−アミノ−２−フェ
ニルピぺリジンであることを特徴とする請求項１〜９の
いずれか１項記載の光学活性シスピぺリジン誘導体の製
造法。10. A racemic cis 3-compound obtained by hydrogenating 3-amino-2-phenylpyridine in the presence of a hydrogenation catalyst to obtain a racemic cispiperidine derivative represented by the general formula (1).
Amino-2-phenylpiperidine, and the optically active cis-piperidine derivative is optically active cis 3-amino-2-phenylpiperidine, The optical activity according to any one of claims 1 to 9, Process for producing cispiperidine derivative.
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| JP2002369405A JP2003342259A (en) | 2001-12-21 | 2002-12-20 | Method for producing optically active cis-piperidine derivative |
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| JP2001388633 | 2001-12-21 | ||
| JP2001-388633 | 2001-12-21 | ||
| JP2002-74160 | 2002-03-18 | ||
| JP2002074160 | 2002-03-18 | ||
| JP2002369405A JP2003342259A (en) | 2001-12-21 | 2002-12-20 | Method for producing optically active cis-piperidine derivative |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2012211174A (en) * | 2004-11-05 | 2012-11-01 | Boehringer Ingelheim Internatl Gmbh | Method for production of chiral 8-(3-amino-piperidin-1-yl)-xanthine |
| JP2021515029A (en) * | 2017-12-22 | 2021-06-17 | ジークフリート アクチェンゲゼルシャフトＳｉｅｇｆｒｉｅｄ Ａｇ | Separation of racemic nicotine enantiomer by addition of O, O'-disubstituted tartrate enantiomer |
| US11407730B2 (en) | 2017-12-22 | 2022-08-09 | Siegfried Ag | Preparation of racemic nicotine by reaction of ethyl nicotinate with N-vinylpyrrolidone in the presence of an alcoholate base and subsequent process steps |
-
2002
- 2002-12-20 JP JP2002369405A patent/JP2003342259A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2012211174A (en) * | 2004-11-05 | 2012-11-01 | Boehringer Ingelheim Internatl Gmbh | Method for production of chiral 8-(3-amino-piperidin-1-yl)-xanthine |
| JP2021515029A (en) * | 2017-12-22 | 2021-06-17 | ジークフリート アクチェンゲゼルシャフトＳｉｅｇｆｒｉｅｄ Ａｇ | Separation of racemic nicotine enantiomer by addition of O, O'-disubstituted tartrate enantiomer |
| JP7030208B2 (en) | 2017-12-22 | 2022-03-04 | ジークフリート アクチェンゲゼルシャフト | Separation of racemic nicotine enantiomer by addition of O, O'-disubstituted tartarate enantiomer |
| US11279685B2 (en) | 2017-12-22 | 2022-03-22 | Siegfried Ag | Enantiomeric separation of racemic nicotine by addition of an O,O″-disubstituted tartaric acid enantiomer |
| US11407730B2 (en) | 2017-12-22 | 2022-08-09 | Siegfried Ag | Preparation of racemic nicotine by reaction of ethyl nicotinate with N-vinylpyrrolidone in the presence of an alcoholate base and subsequent process steps |
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