WO2001096301A1 - Procedes de production de derive de piperidine racemique et de production de derive de piperidine a activite optique - Google Patents
Procedes de production de derive de piperidine racemique et de production de derive de piperidine a activite optique Download PDFInfo
- Publication number
- WO2001096301A1 WO2001096301A1 PCT/JP2001/004689 JP0104689W WO0196301A1 WO 2001096301 A1 WO2001096301 A1 WO 2001096301A1 JP 0104689 W JP0104689 W JP 0104689W WO 0196301 A1 WO0196301 A1 WO 0196301A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- optically active
- piperidine derivative
- producing
- acid
- Prior art date
Links
- 150000003053 piperidines Chemical class 0.000 title claims abstract description 70
- 238000000034 method Methods 0.000 title claims abstract description 28
- 239000002253 acid Chemical class 0.000 claims abstract description 27
- 150000003839 salts Chemical class 0.000 claims abstract description 26
- 239000003054 catalyst Substances 0.000 claims abstract description 23
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 22
- 239000001257 hydrogen Substances 0.000 claims abstract description 22
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 17
- 239000012298 atmosphere Substances 0.000 claims abstract description 5
- 230000003287 optical effect Effects 0.000 claims description 57
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 33
- 238000004519 manufacturing process Methods 0.000 claims description 27
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical group [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 26
- 125000000217 alkyl group Chemical group 0.000 claims description 21
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 19
- 125000004432 carbon atom Chemical group C* 0.000 claims description 17
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 13
- 229910052697 platinum Inorganic materials 0.000 claims description 13
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 12
- 239000003795 chemical substances by application Substances 0.000 claims description 11
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 10
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 8
- 125000005140 aralkylsulfonyl group Chemical group 0.000 claims description 7
- 125000002252 acyl group Chemical group 0.000 claims description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 230000000737 periodic effect Effects 0.000 claims description 5
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 4
- 229910052751 metal Inorganic materials 0.000 claims description 4
- 239000002184 metal Substances 0.000 claims 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 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
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 150000003892 tartrate salts Chemical class 0.000 claims description 3
- 230000001548 androgenic effect Effects 0.000 claims 1
- 125000004429 atom Chemical group 0.000 claims 1
- 239000000049 pigment Substances 0.000 claims 1
- 150000003222 pyridines Chemical class 0.000 claims 1
- 239000000243 solution Substances 0.000 description 30
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- 230000006340 racemization Effects 0.000 description 14
- 239000000706 filtrate Substances 0.000 description 12
- VTDIWMPYBAVEDY-UHFFFAOYSA-N 1-propylpiperidine Chemical compound CCCN1CCCCC1 VTDIWMPYBAVEDY-UHFFFAOYSA-N 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- GZVBVBMMNFIXGE-AWEZNQCLSA-N (3r)-3-(3-methylsulfonylphenyl)-1-propylpiperidine Chemical compound C1N(CCC)CCC[C@@H]1C1=CC=CC(S(C)(=O)=O)=C1 GZVBVBMMNFIXGE-AWEZNQCLSA-N 0.000 description 7
- GZVBVBMMNFIXGE-UHFFFAOYSA-N 3-(3-methylsulfonylphenyl)-1-propylpiperidine Chemical compound C1N(CCC)CCCC1C1=CC=CC(S(C)(=O)=O)=C1 GZVBVBMMNFIXGE-UHFFFAOYSA-N 0.000 description 7
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 229960001367 tartaric acid Drugs 0.000 description 6
- 235000002906 tartaric acid Nutrition 0.000 description 6
- 239000011975 tartaric acid Substances 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- 239000012456 homogeneous solution Substances 0.000 description 4
- 150000002431 hydrogen Chemical class 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 3
- 150000001735 carboxylic acids Chemical class 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- GZVBVBMMNFIXGE-CQSZACIVSA-N osu-6162 Chemical compound C1N(CCC)CCC[C@H]1C1=CC=CC(S(C)(=O)=O)=C1 GZVBVBMMNFIXGE-CQSZACIVSA-N 0.000 description 3
- 229910052703 rhodium Inorganic materials 0.000 description 3
- 239000010948 rhodium Substances 0.000 description 3
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 3
- 229910052707 ruthenium Inorganic materials 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 2
- KMVLMAUQHRUFDO-UHFFFAOYSA-N 3-(3-methylsulfonylphenyl)piperidine Chemical compound CS(=O)(=O)C1=CC=CC(C2CNCCC2)=C1 KMVLMAUQHRUFDO-UHFFFAOYSA-N 0.000 description 2
- 125000004208 3-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C([H])C(*)=C1[H] 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 239000007868 Raney catalyst Substances 0.000 description 2
- 235000011054 acetic acid Nutrition 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 229910017052 cobalt Inorganic materials 0.000 description 2
- 239000010941 cobalt Substances 0.000 description 2
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 2
- DIOQZVSQGTUSAI-UHFFFAOYSA-N decane Chemical compound CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 235000019260 propionic acid Nutrition 0.000 description 2
- 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 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- FOTRUJUPLHRVNU-MOGJOVFKSA-N (2s,3s)-2,3-bis[(4-methylbenzoyl)oxy]butanedioic acid;hydrate Chemical compound O.C1=CC(C)=CC=C1C(=O)O[C@H](C(O)=O)[C@@H](C(O)=O)OC(=O)C1=CC=C(C)C=C1 FOTRUJUPLHRVNU-MOGJOVFKSA-N 0.000 description 1
- DXDIHODZARUBLA-IODNYQNNSA-N (2s,3s)-2,3-dibenzoyloxybutanedioic acid;hydrate Chemical compound O.O([C@H](C(=O)O)[C@H](OC(=O)C=1C=CC=CC=1)C(O)=O)C(=O)C1=CC=CC=C1 DXDIHODZARUBLA-IODNYQNNSA-N 0.000 description 1
- 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 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- WIIZDUASENTRCP-UHFFFAOYSA-N 1-(3-methylsulfonylphenyl)piperidine Chemical compound CS(=O)(=O)C1=CC=CC(N2CCCCC2)=C1 WIIZDUASENTRCP-UHFFFAOYSA-N 0.000 description 1
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- WZFUQSJFWNHZHM-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)CC(=O)N1CC2=C(CC1)NN=N2 WZFUQSJFWNHZHM-UHFFFAOYSA-N 0.000 description 1
- -1 Ararukiru group Chemical group 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- FEWJPZIEWOKRBE-LWMBPPNESA-L D-tartrate(2-) Chemical compound [O-]C(=O)[C@@H](O)[C@H](O)C([O-])=O FEWJPZIEWOKRBE-LWMBPPNESA-L 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 239000010425 asbestos Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- VEIOBOXBGYWJIT-UHFFFAOYSA-N cyclohexane;methanol Chemical compound OC.OC.C1CCCCC1 VEIOBOXBGYWJIT-UHFFFAOYSA-N 0.000 description 1
- 229960001270 d- tartaric acid Drugs 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 238000011033 desalting Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- NTBIYBAYFBNTCD-KBPBESRZSA-N dibenzoyl (2s,3s)-2,3-dihydroxybutanedioate Chemical compound O=C([C@@H](O)[C@H](O)C(=O)OC(=O)C=1C=CC=CC=1)OC(=O)C1=CC=CC=C1 NTBIYBAYFBNTCD-KBPBESRZSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 150000002668 lysine derivatives Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229910052895 riebeckite Inorganic materials 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- UQDJGEHQDNVPGU-UHFFFAOYSA-N serine phosphoethanolamine Chemical compound [NH3+]CCOP([O-])(=O)OCC([NH3+])C([O-])=O UQDJGEHQDNVPGU-UHFFFAOYSA-N 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/24—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by sulfur atoms to which a second hetero atom is attached
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/582—Recycling of unreacted starting or intermediate materials
Definitions
- the present invention relates to general formula (1), general formula (2), and general formula (3) useful as a pharmaceutical or an intermediate thereof.
- R 1 represents a lower alkyl group having 1 to 4 carbon atoms, a phenyl group, and an aralkyl group
- R 2 , R 3 , and R 4 may be the same or different; and hydrogen, an alkyl group, a phenyl group , An aralkyl group, an alkoxycarbonyl group, an alkylsulfonyl group, an arylsulfonyl group, an aralkylsulfonyl group, and an acyl group
- R 5 is an alkyl group, a phenyl group, an aralkyl group, or an alkoxycarbonyl group.
- An object of the present invention is to provide a method for producing a racemic piperidine derivative by racemizing a palmar body.
- equation (6)
- optically active 3- [3- (methylsulfonyl) phenyl] _1 hydropropyl chloride of propylbiperidine is a useful compound as a Parkinson's disease drug.
- an optically active piperidine derivative its racemic form may be resolved by optical resolution, but the yield is theoretically 50% of that of the racemic form, which is insufficient for industrial production. . Therefore, if the unnecessary enantiomer can be racemized and recycled as a raw material for optical resolution, the optically active piperidine derivative can be theoretically produced at a yield close to 100%. Therefore, a method for producing a racemic piperidine derivative by racemizing an optically active piperidine derivative is an important technique.
- R 1 represents a lower alkyl group having 14 carbon atoms, a phenyl group, or an aralkyl group.
- R 2 , R 3 , and R 4 may be the same or different, and include hydrogen, an alkyl group, a phenyl group, an aralkyl group, an alkoxycarbonyl group, an alkylsulfonyl group, an arylsulfonyl group, and an aralkylsulfonyl.
- R 5 represents an alkyl group, a phenyl group, an aralkyl group, an alkoxycarbonyl group, an alkylsulfonyl group, an arylsulfonyl group, an aralkylsulfonyl group, or an acyl group.
- optically active 3- [3- (methylsulfonyl) phenyl] -1-propylpiperidine a method for derivatizing from optically active 3- (3-hydroxyphenyl) -1-propylpropylidine is used.
- racemic 3- [3- (methylsulfonyl) phenyl] piperidine was optically resolved using optically active tartaric acid, and then propionate.
- a method is known in which the compound is reacted with aldehyde and then reduced (Tetrahedron on Letters, Vol. 35, No. 48, 9063-9066).
- optically active 3- (3-hydroxyphenyl) -111-propylpiperidine
- the yield of optically active 3 -— [3- (methylsulfonyl) phenyl] _1-propylpiperidine is low.
- the method of optically resolving racemic 3-' [3- (methylsulfonyl) phenyl] piperidine using optically active tartaric acid and then derivatizing it can be obtained with low optical resolution yield.
- the optical purity of optically active 3- [3- (methylsulfonyl) phenyl] piperidine is also low.
- the present invention relates to a method of racemizing an optically active piperidine derivative of an optical antipode by-produced when obtaining an optically active piperidine derivative, and furthermore, a required optically active piperidine derivative or It is intended to provide a method for obtaining the acid salt.
- the configuration of the present invention is as follows.
- R 1 represents a lower alkyl group having 14 carbon atoms, a phenyl group, and an aralkyl group
- R 2 R 3 R 4 may be the same or different, and include hydrogen, an alkyl group, a phenyl group, and an aralkyl group
- R 5 represents an alkyl group, a phenyl group, an aralkyl group, an alkoxycarbonyl group, an alkylsulfonyl group, or an arylsulfonyl group. Group, an aralkylsulfonyl group, and an acyl group.
- a method for producing a racemic piperidine derivative which comprises reacting an optically active piperidine derivative represented by any of the above in a hydrogen atmosphere in the presence of a reduction catalyst.
- R 1 represents a lower alkyl group having 1 to 4 carbon atoms
- R 4 represents an alkylsulfonyl group having 1 to 4 carbon atoms.
- the optically active piperidine derivative has the formula (6)
- racemic piperidine derivative according to any one of the above (1) to (5) which is an optically active 3- [3- (methylsulfonyl) phenyl] 111-bipropylperidine represented by the formula: Production method.
- a method for producing an optically active piperidine derivative or an acid salt thereof, comprising optically resolving the racemic piperidine derivative obtained by the method according to any one of the above (1) to (6).
- Optically active 0, O'-diacyl tartaric acid derivative has the following general formula (7)
- R 6 and R 7 represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 3 carbon atoms, an alkoxyl group having 1 to 3 carbon atoms, or a nitro group, and are different even if R 6 and R 7 are the same.
- the method for producing an optically active pyrididine derivative or an acid salt thereof according to the above (7) which is represented by the following formula:
- R 6 is a hydrogen atom
- R 7 is a hydrogen atom, a methyl group or a methoxy group.
- optically active 0, O'-diaciltartaric acid is any of optically active dibenzoyltartaric acid, optically active di-P-toluoyltartaric acid, and optically active dianisyltartaric acid.
- optically active piperidine derivative used as a starting material in the present invention
- general formula (1) general formula (2)
- R 1 represents a lower alkyl group having 1 to 4 carbon atoms, a phenyl group, and an aralkyl group
- R 2 , R 3 , and R 4 may be the same or different
- hydrogen an alkyl group, a phenyl group group, Ararukiru group, an alkoxycarbonyl group, an alkylsulfonyl group, an Arirusuruhoniru group, ⁇ Lal kill sulfonyl group and Ashiru group
- R 5 is an alkyl group, phenyl group, Ararukiru group, alkoxycarbonyl group, Arukirusu Ruhoniru , An arylsulfonyl group, an aralkylsulfonyl group, and an acyl group.
- optically active piperidine derivative represented by the general formula (1) . : or (2) is racemized, and furthermore, the optical system represented by the following general formula (4) or (5) It can be more preferably applied when racemizing an active piperidine derivative.
- R 1 represents a lower alkyl group having 1 to 4 carbon atoms
- R 4 represents an alkylsulfonyl group having 1 to 4 carbon atoms.
- the optically active piperidine derivative means a piperidine derivative in which one optical isomer is contained more than the other optical isomer, and is substantially a piperidine having an optical intensity of 30% e.e. or more.
- the racemic piperidine derivative is a piberidine derivative having an optical purity lower than that of the raw material, and substantially means a piperidine derivative having an optical purity of less than 30% e.e.
- the racemization of the present invention can be carried out in a solvent-free system, but is preferably carried out in an inert organic solvent.
- hydrocarbons such as benzene, toluene, xylene, hexane, octane, decane, cyclohexane; methanol, ethanol, propanol, isopropanol, butanol, isobutanol, t-butanol, etc.
- Alcohols such as ethyl ether, isopropyl ether, butyr ether, isoptyl ether, tetrahydrofuran, dioxane, etc.
- Monoters or a mixed solvent thereof can be used as a reaction solvent. Further, those solvents may contain water.
- the amount of the solvent used is not particularly limited, but is preferably within 50 times the volume of the substrate from an economical viewpoint.
- the reduction catalyst used in the present invention is preferably a catalyst containing a noble metal of Group VIII of the periodic table, such as nickel, cobalt, ruthenium, rhodium, palladium, or platinum, and more preferably a catalyst containing platinum.
- a noble metal of Group VIII of the periodic table such as nickel, cobalt, ruthenium, rhodium, palladium, or platinum
- the form is not particularly limited, and examples thereof include Raney catalysts such as Raney nickel and Raney cobalt, and those in which ruthenium, rhodium, palladium, platinum and the like are supported on activated carbon, alumina, asbestos and the like.
- These catalysts can be used alone or as a mixture of two or more kinds, and the amount of use is not limited. However, it is preferably 0.1 to 0.5 times by weight based on the optically active piperidine derivative. .
- the reaction is preferably performed at a temperature of at least 100, more preferably at least 150, and the hydrogen pressure used is preferably at least 0.2 MPa.
- the time required for racemization depends on the reaction temperature, hydrogen pressure, type of catalyst, or the amount of catalyst used, but usually ends in 5 to 40 hours.
- the target racemized racemic piperidine derivative can be obtained by, after the completion of the reaction, concentrating the filtrate from which the catalyst has been removed by filtration.
- the racemic piperidine derivative thus obtained can be used as a raw material for diastereomeric monosalt resolution.
- optical resolving agent used in the present invention is selected from optically active ⁇ , O'-diacyltartaric acid, and its D-form and L-form can be used properly according to the purpose.
- optically active ⁇ , .0 'diacyl tartaric acid is represented by the following general formula (7)
- R 6 and R 7 represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 3 carbon atoms, an alkoxyl group having 1 to 3 carbon atoms, or a nitro group, and are different even if R 6 and R 7 are the same. May be used.
- R 6, R 7 is a hydrogen atom, a methyl group
- R 6 is A compound in which R 7 is a hydrogen atom, a methyl group, or a methoxy group can be used.
- Specific examples include optically active dibenzoyltartaric acid, optically active di-p_toluoyltartaric acid, optically active dianisyltartaric acid, and hydrates thereof.
- optically active tartaric acid derivatives can be easily synthesized from optically active tartaric acid by a known method.
- racemic piperidine derivative used as a raw material not only a mixture containing equal amounts of S-form and R-form but also a mixture containing at least one optical isomer in equal amounts or the like can be used.
- the optical activity of 0, ⁇ '-diasyl tartaric acid is increased by contacting the racemic piperidine derivative with 0.4 to 1.5 moles, preferably 0.7 to 1.2 moles, of diacetate in a solvent. Make salt.
- organic carboxylic acids such as formic acid, acetic acid and propionic acid may coexist.
- the amount of the organic carboxylic acid used is 0.8 to 1.5 mol, preferably 0.9 to 1.2 mol, per 1 mol of the racemic piperidine derivative together with the optical resolving agent.
- the solvent used here may be any solvent as long as neither the piperidine derivative nor the optical resolving agent is chemically changed in the solution and one diastereomer salt is precipitated.
- water alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, and tert-butanol; ketones such as acetone and methyl ethyl ketone; and acetonitrile , Tetrahydrofuran, 1,4-dioxane, 1,3-dioxola
- Organic solvents such as benzene, black form, and black benzene, or a mixed solvent thereof can be used.
- the racemic piperidine derivative and the optical resolution agent may be added to the solvent at once, or they may be added sequentially.
- organic carboxylic acids may be added at once, or they may be added sequentially. The order in which they are added is not particularly limited.
- the temperature at which the sparingly soluble diastereomer salt is precipitated from the solution may be in the range of the freezing point to the boiling point of the solvent used, and can be appropriately selected according to the purpose.
- Crystals of the sparingly soluble diastereomer salt can be easily separated by ordinary solid-liquid separation methods such as filtration and centrifugation.
- the crystals of the sparingly soluble diastereomer salt can be subjected to a recrystallization operation or a rinsing operation to obtain the desired high-purity diastereomer salt.
- the diastereomer salt thus obtained is subjected to desalting by an appropriate method, whereby the optically active piperidine derivative and the optical resolving agent can be separated and collected.
- a generally known method that is, a method of treating with an acid or alkali in an aqueous solvent, a method of using an ion exchange resin, or the like can be applied.
- a method of treating with an acid or alkali in an aqueous solvent a method of using an ion exchange resin, or the like
- diastereomeric monosalt is salted by adding an aqueous solution of sodium hydroxide or the like in water and then extracted with an organic solvent such as isopropyl ether, the piperidine derivative is extracted into the organic layer.
- the desired optically active piperidine derivative can be obtained by concentrating the liquid.
- a mineral acid such as hydrochloric acid or sulfuric acid is added to the aqueous layer from which the piperidine derivative has been removed to adjust the pH to 1-2, and then the precipitated optical resolving agent is separated by filtration, or an organic solvent such as dichloromethane.
- the optical resolving agent can be recovered by extraction.
- the optically active piperidine derivative thus obtained is allowed to react with a mineral acid such as hydrochloric acid or sulfuric acid or an organic acid such as formic acid, acetic acid or propionic acid. Therefore, an acid salt of a piperidine derivative can be obtained.
- optically active 3- [3- (methylsulfonyl) phenyl] -111-propylpiperidine obtained by the present invention is useful as a pharmaceutical.
- the optical purity of 3- [3- (methylsulfonyl) phenyl] -1-propylpiperidine obtained in the examples was determined by the following method.
- 3- [3- (Methylsulfonyl) phenyl] — 1-propylpiperidine 8 to 1 Omg is dissolved in 1-Om1 n-hexane solution containing 25% ethanol, and 201 of the solution is dissolved in HPLC. Injected and analyzed.
- the column temperature was about 25, the flow rate was 0.60 ml / i, and the detection was performed by UV (266 nm).
- (R) -3- [3- (Methylsulfonyl) phenyl] 1-1-propylpiperidine is 24.5 minutes
- (S) -3- [3- (Methylsulfonyl) phenyl]-1-propylpiperidine is 2 6. Detected in 1 minute.
- racemic 3- [3- (methylsulfonyl) phenyl] -1-propylpiperidine obtained by the method of Example 4 1-l02 g (purity 92.8%, 36. 3 mmol), 15.06 g (40.4 mmol) of dibenzoyl-D-tartaric acid monohydrate and 85 ml of acetonitrile, and stirred at about 30 to form a homogeneous solution.
- a racemic piperidine derivative can be efficiently obtained by an industrially practicable method, and by using the optical resolution agent of the present invention, an optically active piperidine derivative or an acid salt thereof can be obtained. It can be obtained with high optical purity and high yield. These can be used as medicines or their intermediates.
Description
Claims
Priority Applications (2)
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EP01934516A EP1295873A4 (en) | 2000-06-14 | 2001-06-04 | METHODS OF PRODUCING RACEMIC PIPERIDINE DERIVATIVE AND PRODUCING OPTICALLY ACTIVE PIPERIDINE DERIVATIVE |
US10/296,772 US6962998B2 (en) | 2000-06-14 | 2001-06-04 | Processes for producing racemic piperidine derivative and for producing optically active piperidine derivative |
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JP2000178117 | 2000-06-14 | ||
JP2000-178117 | 2000-06-14 | ||
JP2000-282512 | 2000-09-18 | ||
JP2000282512 | 2000-09-18 |
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WO2001096301A1 true WO2001096301A1 (fr) | 2001-12-20 |
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PCT/JP2001/004689 WO2001096301A1 (fr) | 2000-06-14 | 2001-06-04 | Procedes de production de derive de piperidine racemique et de production de derive de piperidine a activite optique |
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US (1) | US6962998B2 (ja) |
EP (1) | EP1295873A4 (ja) |
WO (1) | WO2001096301A1 (ja) |
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US11925637B2 (en) | 2015-08-21 | 2024-03-12 | Srx Cardio, Llc | Phenylpiperazine proprotein convertase subtilisin/kexin type 9 (PCSK9) modulators and their use |
US11944619B2 (en) | 2015-08-21 | 2024-04-02 | Srx Cardio, Llc | Phenylalanine small organic compounds to directly modulate PCSK9 protein activity |
US11945782B2 (en) | 2015-08-21 | 2024-04-02 | Srx Cardio, Llc | Composition and methods of use of tetrahydroisoquinoline small molecules to bind and modulate PCSK9 protein activity |
US11891369B2 (en) | 2016-02-23 | 2024-02-06 | Srx Cardio, Llc | Compounds for binding proprotein convertase subtilisin/kexin type 9 |
US10155000B2 (en) | 2016-06-10 | 2018-12-18 | Boehringer Ingelheim International Gmbh | Medical use of pharmaceutical combination or composition |
Also Published As
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EP1295873A4 (en) | 2004-05-19 |
EP1295873A1 (en) | 2003-03-26 |
US20030130313A1 (en) | 2003-07-10 |
US6962998B2 (en) | 2005-11-08 |
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