JP6695235B2 - A method for producing (4-hydroxy) -1-piperidinoalkylcarboxylic acid ester, and 4- [4-[(4- Method for producing chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoic acid. - Google Patents
A method for producing (4-hydroxy) -1-piperidinoalkylcarboxylic acid ester, and 4- [4-[(4- Method for producing chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoic acid. Download PDFInfo
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- JP6695235B2 JP6695235B2 JP2016156286A JP2016156286A JP6695235B2 JP 6695235 B2 JP6695235 B2 JP 6695235B2 JP 2016156286 A JP2016156286 A JP 2016156286A JP 2016156286 A JP2016156286 A JP 2016156286A JP 6695235 B2 JP6695235 B2 JP 6695235B2
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- 239000002253 acid Substances 0.000 title claims description 61
- 238000004519 manufacturing process Methods 0.000 title claims description 50
- 150000002148 esters Chemical class 0.000 title claims description 34
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 title description 4
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 title description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 title description 2
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 title description 2
- 125000000068 chlorophenyl group Chemical group 0.000 title 1
- 239000003054 catalyst Substances 0.000 claims description 46
- 239000001257 hydrogen Substances 0.000 claims description 33
- 229910052739 hydrogen Inorganic materials 0.000 claims description 33
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 31
- 125000004494 ethyl ester group Chemical group 0.000 claims description 27
- GCNTZFIIOFTKIY-UHFFFAOYSA-N 4-hydroxypyridine Chemical compound OC1=CC=NC=C1 GCNTZFIIOFTKIY-UHFFFAOYSA-N 0.000 claims description 21
- YWGDOWXRIALTES-UHFFFAOYSA-N bepotastine Chemical compound C1CN(CCCC(=O)O)CCC1OC(C=1N=CC=CC=1)C1=CC=C(Cl)C=C1 YWGDOWXRIALTES-UHFFFAOYSA-N 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 125000005843 halogen group Chemical group 0.000 claims description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims description 7
- 125000004185 ester group Chemical group 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 description 58
- 238000000034 method Methods 0.000 description 20
- -1 (Halogenated alkyl carboxylic acid ester Chemical class 0.000 description 19
- YWGDOWXRIALTES-NRFANRHFSA-N bepotastine Chemical compound C1CN(CCCC(=O)O)CCC1O[C@H](C=1N=CC=CC=1)C1=CC=C(Cl)C=C1 YWGDOWXRIALTES-NRFANRHFSA-N 0.000 description 17
- 229960002071 bepotastine Drugs 0.000 description 17
- 239000007810 chemical reaction solvent Substances 0.000 description 17
- 239000002585 base Substances 0.000 description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- 238000006722 reduction reaction Methods 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 150000001875 compounds Chemical class 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 230000003197 catalytic effect Effects 0.000 description 9
- 239000002994 raw material Substances 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- 239000000203 mixture Substances 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- MXCDYLMZERSLGO-UHFFFAOYSA-N C(C)OC(CCC(N1CCCCC1)O)=O Chemical compound C(C)OC(CCC(N1CCCCC1)O)=O MXCDYLMZERSLGO-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
- 238000004809 thin layer chromatography Methods 0.000 description 6
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Substances [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 5
- HDOWRFHMPULYOA-UHFFFAOYSA-N piperidin-4-ol Chemical compound OC1CCNCC1 HDOWRFHMPULYOA-UHFFFAOYSA-N 0.000 description 5
- 230000009257 reactivity Effects 0.000 description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- 238000010531 catalytic reduction reaction Methods 0.000 description 4
- 230000008034 disappearance Effects 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 4
- 238000005956 quaternization reaction Methods 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- 0 *CCCN(CC1)CCC1OC(c1ccc(*)cc1)c1ccccn1 Chemical compound *CCCN(CC1)CCC1OC(c1ccc(*)cc1)c1ccccn1 0.000 description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 3
- 229910000564 Raney nickel Inorganic materials 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 125000001309 chloro group Chemical group Cl* 0.000 description 3
- XBPOBCXHALHJFP-UHFFFAOYSA-N ethyl 4-bromobutanoate Chemical compound CCOC(=O)CCCBr XBPOBCXHALHJFP-UHFFFAOYSA-N 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 235000011181 potassium carbonates Nutrition 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 150000003839 salts Chemical group 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- KHXSJSBQIWAIEG-UHFFFAOYSA-N (4-chlorophenyl)-pyridin-2-ylmethanone Chemical compound C1=CC(Cl)=CC=C1C(=O)C1=CC=CC=N1 KHXSJSBQIWAIEG-UHFFFAOYSA-N 0.000 description 2
- JJOZASAAOCISAR-UHFFFAOYSA-N 2-[chloro-(4-chlorophenyl)methyl]pyridine Chemical compound C=1C=CC=NC=1C(Cl)C1=CC=C(Cl)C=C1 JJOZASAAOCISAR-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 239000011865 Pt-based catalyst Substances 0.000 description 2
- 239000007868 Raney catalyst Substances 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-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
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 239000012670 alkaline solution Substances 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 2
- 150000004679 hydroxides Chemical class 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 229910052806 inorganic carbonate Inorganic materials 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 238000005580 one pot reaction Methods 0.000 description 2
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- XSVWMIMFDMJQRL-UHFFFAOYSA-N 2-[(4-chlorophenyl)methyl]pyridine Chemical compound C1=CC(Cl)=CC=C1CC1=CC=CC=N1 XSVWMIMFDMJQRL-UHFFFAOYSA-N 0.000 description 1
- HGUQRHAFHQJTGR-UHFFFAOYSA-N 2-[4-[(4-chlorophenyl)-pyridin-2-ylmethoxy]piperidin-1-yl]butanoic acid Chemical compound ClC1=CC=C(C=C1)C(OC1CCN(CC1)C(C(=O)O)CC)C1=NC=CC=C1 HGUQRHAFHQJTGR-UHFFFAOYSA-N 0.000 description 1
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 206010024769 Local reaction Diseases 0.000 description 1
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 229910019020 PtO2 Inorganic materials 0.000 description 1
- 239000004280 Sodium formate Substances 0.000 description 1
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
- 230000003266 anti-allergic effect Effects 0.000 description 1
- 230000001387 anti-histamine Effects 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- LYQFWZFBNBDLEO-UHFFFAOYSA-M caesium bromide Chemical compound [Br-].[Cs+] LYQFWZFBNBDLEO-UHFFFAOYSA-M 0.000 description 1
- XQPRBTXUXXVTKB-UHFFFAOYSA-M caesium iodide Chemical compound [I-].[Cs+] XQPRBTXUXXVTKB-UHFFFAOYSA-M 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 1
- 238000007257 deesterification reaction Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000006266 etherification reaction Methods 0.000 description 1
- XIMFCGSNSKXPBO-UHFFFAOYSA-N ethyl 2-bromobutanoate Chemical compound CCOC(=O)C(Br)CC XIMFCGSNSKXPBO-UHFFFAOYSA-N 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 150000004675 formic acid derivatives Chemical class 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 150000002366 halogen compounds Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 1
- 229910052808 lithium carbonate Inorganic materials 0.000 description 1
- 229910000032 lithium hydrogen carbonate Inorganic materials 0.000 description 1
- HQRPHMAXFVUBJX-UHFFFAOYSA-M lithium;hydrogen carbonate Chemical compound [Li+].OC([O-])=O HQRPHMAXFVUBJX-UHFFFAOYSA-M 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 150000002736 metal compounds Chemical class 0.000 description 1
- AMUCTDNDAXEAOW-UHFFFAOYSA-M methyl(trioctyl)azanium;iodide Chemical compound [I-].CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC AMUCTDNDAXEAOW-UHFFFAOYSA-M 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- ZDHURYWHEBEGHO-UHFFFAOYSA-N potassiopotassium Chemical compound [K].[K] ZDHURYWHEBEGHO-UHFFFAOYSA-N 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229960003975 potassium Drugs 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 description 1
- 235000019254 sodium formate Nutrition 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 150000003459 sulfonic acid esters Chemical class 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- 239000011995 wilkinson's catalyst Substances 0.000 description 1
- UTODFRQBVUVYOB-UHFFFAOYSA-P wilkinson's catalyst Chemical compound [Cl-].C1=CC=CC=C1P(C=1C=CC=CC=1)(C=1C=CC=CC=1)[Rh+](P(C=1C=CC=CC=1)(C=1C=CC=CC=1)C=1C=CC=CC=1)P(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 UTODFRQBVUVYOB-UHFFFAOYSA-P 0.000 description 1
Landscapes
- Hydrogenated Pyridines (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Description
本発明は、ベポタスチンの製造原料として用いられる（４−ヒドロキシ）−１−ピペリジノアルキルカルボン酸エステルの新規な製造方法、及び該製造方法で得られた（４−ヒドロキシ）−１−ピペリジノブタン酸エチルエステルを用いたベポタスチンの製造方法に関する。 The present invention provides a novel method for producing (4-hydroxy) -1-piperidinoalkylcarboxylic acid ester used as a raw material for producing bepotastine, and (4-hydroxy) -1-piperidinobutanoic acid obtained by the production method. The present invention relates to a method for producing bepotastine using ethyl ester.
４−［４−［（４−クロロフェニル）（２−ピリジル）メトキシ］ピペリジノ］ブタン酸（以下、「ベポタスチン」とも言う。）は、以下の構造を持ち、周知の抗ヒスタミン活性及び抗アレルギー活性を有する治療薬である。ベポタスチンは下記式のとおり、ベンゼンスルホン酸塩として用いられている。 4- [4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoic acid (hereinafter, also referred to as “bepotastine”) has the following structure and has well-known antihistamine activity and antiallergic activity. It is a therapeutic drug. Bepotastine is used as a benzene sulfonate as shown in the formula below.
前記ベポタスチンは、以下の合成経路で製造する方法が知られている（特許文献１参照）。 A method for producing the above bepotastine by the following synthetic route is known (see Patent Document 1).
このような治療薬として有用なベポタスチンは、光学異性体を有するが、特に有用であるのは（Ｓ）型異性体であると言われており、その効率的な製造方法が検討されている。例えば特許文献２では、以下の合成経路で示されるとおり、（４−クロロフェニル）−２−ピリジニルメタノンを不斉還元した後に、（４−ヒドロキシ）−１−ピペリジノブチル酸エチルエステルの金属アルコラートを反応させることにより、ベポタスチンの（Ｓ）型異性体のフリー体を製造する方法が示されている。 Bepotastine, which is useful as such a therapeutic agent, has an optical isomer, and it is said that the (S) -type isomer is particularly useful, and an efficient production method thereof has been investigated. For example, in Patent Document 2, as shown in the following synthetic route, after asymmetric reduction of (4-chlorophenyl) -2-pyridinylmethanone, a metal alcoholate of (4-hydroxy) -1-piperidinobutyric acid ethyl ester is obtained. Has been shown to produce a free form of the (S) -type isomer of bepotastine.
上記特許文献２記載の方法は、（４−クロロフェニル）−２−ピリジニルメタノンから誘導されるスルホン酸エステル体と（４−ヒドロキシ）−１−ピペリジノブタン酸エチルエステルとの反応によってベポタスチンを得るものであり、ベポタスチンの効率的な製造方法であり、該合成経路において、（４−ヒドロキシ）−１−ピペリジノブタン酸エチルエステルは重要な原料である。この（４−ヒドロキシ）−１−ピペリジノブタン酸エチルエステルを含む、（４−ヒドロキシ）−１−ピペリジノアルキル酸エチルエステルの製造方法としては、塩基の存在下４−ヒドロキシピペリジンと、ブロモアルキル酸エチルエステルとの反応によって製造されるが、４−ヒドロキシピペリジンが比較的高価であること、上記反応による収率の点で尚改善の余地があり、工業的に効率的な製造方法が望まれていた。 According to the method described in Patent Document 2, bepotastine is obtained by the reaction between a sulfonic acid ester derivative derived from (4-chlorophenyl) -2-pyridinylmethanone and (4-hydroxy) -1-piperidinobutanoic acid ethyl ester. It is an efficient method for producing bepotastine, and (4-hydroxy) -1-piperidinobutanoic acid ethyl ester is an important raw material in the synthetic route. The production method of (4-hydroxy) -1-piperidinoalkyl acid ethyl ester containing this (4-hydroxy) -1-piperidinobutanoic acid ethyl ester is as follows: 4-hydroxypiperidine and bromoalkyl acid in the presence of a base. Although it is produced by a reaction with ethyl ester, 4-hydroxypiperidine is relatively expensive, and there is still room for improvement in the yield of the above reaction, and an industrially efficient production method is desired. It was
従って本発明の目的は、（４−ヒドロキシ）−１−ピペリジノアルキル酸エチルエステルを安価な原料を用いてより簡便な方法で製造する方法を提供することである。 Therefore, an object of the present invention is to provide a method for producing (4-hydroxy) -1-piperidinoalkyl acid ethyl ester by a simpler method using inexpensive raw materials.
本発明者らは、上記課題を解決するため鋭意研究を行った。ブロモアルキル酸エチルエステルと反応させる基質として窒素原子の反応性が高いピリジンに着目し、４−ヒドロキシピリジンとハロゲン化アルキル酸エチルエステルとの反応を検討した結果、塩基を存在させることなく、上記反応が選択的に進行することを確認した。そこで、さらに、得られた４−ヒドロキシ−１−ピリジノアルキル酸エチルエステルの接触水素還元についても検討を行った結果、驚くべきことに特定の触媒の存在下で水添圧力及び反応温度を下げることが可能であること、さらに、４−ヒドロキシピリジンと、ハロゲン化アルキル酸エチルエステルとを触媒及び水素の存在下反応させることで、一段階の反応より、目的物である（４−ヒドロキシ）−１−ピペリジノアルキル酸エチルエステルが高収率で得られることを見出し、本発明を完成させるに至った。 The present inventors have conducted intensive research to solve the above problems. As a substrate to be reacted with bromoalkyl acid ethyl ester, the reaction of 4-hydroxypyridine and halogenated alkyl acid ethyl ester was examined, focusing on pyridine having a high reactivity of nitrogen atom. As a result, the above reaction was performed without the presence of a base. Was confirmed to proceed selectively. Therefore, as a result of further investigation on catalytic hydrogen reduction of the obtained 4-hydroxy-1-pyridinoalkyl acid ethyl ester, surprisingly, the hydrogenation pressure and the reaction temperature were lowered in the presence of a specific catalyst. Furthermore, by reacting 4-hydroxypyridine with a halogenated alkyl acid ethyl ester in the presence of a catalyst and hydrogen, the target compound (4-hydroxy)- The inventors have found that 1-piperidinoalkyl acid ethyl ester can be obtained in high yield, and have completed the present invention.
すなわち、本発明は、
４−ヒドロキシピリジンと、下記式（１）
That is, the present invention is
4-hydroxypyridine and the following formula (1)
（式中Ｘはハロゲン原子、Ｒは炭素数１〜３のアルキル基、ａは１〜５の整数である）
で示されるハロゲン化アルキルカルボン酸エステルとを触媒及び水素の存在下反応させて、下記式（２）
(In the formula, X is a halogen atom, R is an alkyl group having 1 to 3 carbon atoms, and a is an integer of 1 to 5)
A halogenated alkylcarboxylic acid ester represented by the formula (2) below is reacted in the presence of a catalyst and hydrogen.
（式中、Ｒおよびａは前記式（１）におけるものと同義である）
で示される（４−ヒドロキシ）−１−ピペリジノアルキルカルボン酸エステルを得ることを特徴とする、（４−ヒドロキシ）−１−ピペリジノアルキルカルボン酸エステルの製造方法である。
(In the formula, R and a have the same meanings as in the formula (1))
The method for producing a (4-hydroxy) -1-piperidinoalkylcarboxylic acid ester is characterized by obtaining a (4-hydroxy) -1-piperidinoalkylcarboxylic acid ester represented by
本発明においては、さらに以下の態様が好適に採り得る。
１）前記式２におけるＲが炭素数２のアルキル基、及びａが３であること。
２）請求項１における触媒がＮｉ系触媒であること。
In the present invention, the following aspects can be preferably adopted.
1) R in the above formula 2 is an alkyl group having 2 carbon atoms, and a is 3.
2) The catalyst according to claim 1 is a Ni-based catalyst.
さらに本発明の別の発明は、上記製造方法で（４−ヒドロキシ）−１−ピペリジノブタン酸エチルエステルを得、次いで、得られた（４−ヒドロキシ）−１−ピペリジノブタン酸エチルエステルと、（３）
Still another invention of the present invention is to obtain (4-hydroxy) -1-piperidinobutanoic acid ethyl ester by the above production method , and then obtain the obtained (4-hydroxy) -1-piperidinobutanoic acid ethyl ester , and (3).
（式中、Ｘはハロゲン原子または活性エステル基である）
とを塩基の存在下反応させることを特徴とする、４−［４−［（４−クロロフェニル）（２−ピリジル）メトキシ］ピペリジノ］ブタン酸の製造方法である。
(In the formula, X is a halogen atom or an active ester group)
Is a reaction method in the presence of a base, which is a method for producing 4- [4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoic acid.
本発明の方法によれば、比較的安価な４−ヒドロキシピリジンを用いて、一段階の反応で、高収率で効率良く（４−ヒドロキシ）−１−ピペリジノアルキルカルボン酸エステルを得ることができる。 According to the method of the present invention, a relatively inexpensive 4-hydroxypyridine is used to obtain a (4-hydroxy) -1-piperidinoalkylcarboxylic acid ester efficiently in a high yield in a one-step reaction. You can
さらに本発明で得られた（４−ヒドロキシ）−１−ピペリジノアルキルカルボン酸エステルを用いることにより、ベポタスチンを容易に製造することも可能である。 Furthermore, by using the (4-hydroxy) -1-piperidinoalkylcarboxylic acid ester obtained in the present invention, bepotastine can be easily produced.
本発明の製造方法は、４−ヒドロキシピリジンと、ハロゲン化アルキルカルボン酸エステルとを触媒及び水素の存在下反応させることが特徴である。この方法により、一段階の反応で、高収率で、（４−ヒドロキシ）−１−ピペリジノアルキルカルボン酸エステルを得ることができる。本発明の方法によって、高収率で（４−ヒドロキシ）−１−ピペリジノアルキルカルボン酸エステルを得られる理由について詳細は明らかではないが、本発明者らは、以下のように推測している。即ち、本発明の製造方法では、ピリジン環の接触水素還元反応と、ピリジン環の窒素原子へのアルキルカルボン酸エステルの付加反応（４級化反応）の２つの反応が考えられる。一般に水素を用いた接触水素還元反応と４級塩の形成反応とを比べると、反応速度は４級塩化反応の方が早い。このため本発明の製造方法においては、（４−ヒドロキシ）−１−ピリジニウムアルキルカルボン酸エステルが中間体として生成した後、接触水素還元反応により目的の（４−ヒドロキシ）−１−ピペリジノアルキルカルボン酸エステルが製造されていると考えられる。ここで、４−ヒドロキシピリジンにおけるハロゲン化アルキルカルボン酸エステルの反応点としては、ピリジン環の窒素原子の他に、水酸基が考えられるが、ピリジン環の窒素原子の反応性が高いために、水酸基を保護することなく、選択的に４級化反応が進行するものと推測される。さらに、ピリジン環が４級化されることで、ピリジン環の電子密度が低くなり、ピリジン環の還元反応性が向上するため、高収率でピリジン環の接触水素還元反応も進行するものと推測される。
以下、本発明の製造方法について詳述する。
The production method of the present invention is characterized by reacting 4-hydroxypyridine with a halogenated alkylcarboxylic acid ester in the presence of a catalyst and hydrogen. According to this method, the (4-hydroxy) -1-piperidinoalkylcarboxylic acid ester can be obtained in a high yield in a one-step reaction. The reason why the method of the present invention makes it possible to obtain (4-hydroxy) -1-piperidinoalkylcarboxylic acid ester in high yield is not clear, but the present inventors speculate as follows. There is. That is, in the production method of the present invention, two reactions, a catalytic hydrogen reduction reaction of a pyridine ring and an addition reaction (quaternization reaction) of an alkylcarboxylic acid ester to a nitrogen atom of the pyridine ring, can be considered. Generally, when the catalytic hydrogen reduction reaction using hydrogen is compared with the quaternary salt forming reaction, the reaction rate of the quaternary chlorination reaction is faster. Therefore, in the production method of the present invention, after the (4-hydroxy) -1-pyridinium alkylcarboxylic acid ester is produced as an intermediate, the desired (4-hydroxy) -1-piperidinoalkyl is obtained by catalytic hydrogen reduction reaction. It is believed that the carboxylic acid ester is produced. Here, as the reaction point of the halogenated alkylcarboxylic acid ester in 4-hydroxypyridine, a hydroxyl group may be considered in addition to the nitrogen atom of the pyridine ring, but since the reactivity of the nitrogen atom of the pyridine ring is high, the hydroxyl group is It is presumed that the quaternization reaction proceeds selectively without protection. Furthermore, it is assumed that the quaternization of the pyridine ring lowers the electron density of the pyridine ring and improves the reduction reactivity of the pyridine ring, so that the catalytic hydrogen reduction reaction of the pyridine ring also proceeds at high yield. To be done.
Hereinafter, the manufacturing method of the present invention will be described in detail.
（ハロゲン化アルキルカルボン酸エステル）
本発明の製造方法に用いるハロゲン化アルキルカルボン酸エステルは、
下記式（１）
(Halogenated alkyl carboxylic acid ester)
The halogenated alkylcarboxylic acid ester used in the production method of the present invention is
Formula (1) below
（式中Ｘはハロゲン原子、Ｒは炭素数１〜３のアルキル基、ａは１〜５の整数である）
で示される。
(In the formula, X is a halogen atom, R is an alkyl group having 1 to 3 carbon atoms, and a is an integer of 1 to 5)
Indicated by.
上記式（１）中、Ｘはハロゲン原子であり、具体的には、フッ素原子、塩素原子、臭素原子、ヨウ素原子が挙げられるが、工業的な入手のし易さ、反応性の点から、臭素原子、又はヨウ素原子が好ましい。また、式中Ｒは炭素数１〜３のアルキル基であり、具体的には、メチル基、エチル基、プロピル基等が挙げられる。中でも、工業的な入手のし易さ、後工程の反応（脱エステル化）のし易さ等を考慮すると、Ｒはメチル基又はエチル基であることが好ましい。またａは１〜５の整数であるが、反応の進行しやすさから２〜３が好ましい。上記ハロゲン化アルキルカルボン酸エステルの中でも、ベポタスチン製造において用いられる点から、Ｘが臭素原子、Ｒがエチル基、ａが３である、ブロモブチル酸エチルエステルを用いることが特に好ましい。 In the above formula (1), X is a halogen atom, and specific examples thereof include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom, but from the viewpoint of industrial availability and reactivity, A bromine atom or an iodine atom is preferable. Further, in the formula, R is an alkyl group having 1 to 3 carbon atoms, and specific examples thereof include a methyl group, an ethyl group, a propyl group and the like. Of these, R is preferably a methyl group or an ethyl group in consideration of industrial availability, reaction in the subsequent step (deesterification), and the like. Further, a is an integer of 1 to 5, but is preferably 2 to 3 from the viewpoint of easy reaction progress. Among the halogenated alkylcarboxylic acid esters, it is particularly preferable to use bromobutyric acid ethyl ester in which X is a bromine atom, R is an ethyl group, and a is 3 from the viewpoint of being used in the production of bepotastine.
上記ハロゲン化アルキルカルボン酸エステルの使用量は、４−ヒドロキシピリジンと反応させるために十分な量を用いれば良く、特に制限されるものではない。反応収率の点、或いは精製が容易であるとの観点から４−ヒドロキシピリジン１モルに対して、前記ハロゲン化アルキルカルボン酸エステルを０．８〜５モル使用することが好ましく、さらに１〜２モル使用することが好ましい。 The amount of the halogenated alkylcarboxylic acid ester used is not particularly limited as long as it is sufficient to react with 4-hydroxypyridine. From the viewpoint of reaction yield or from the viewpoint of easy purification, it is preferable to use 0.8 to 5 mol of the halogenated alkylcarboxylic acid ester, and further 1 to 2 mol, relative to 1 mol of 4-hydroxypyridine. It is preferable to use mol.
（触媒）
本発明の製造方法における触媒とは、接触水素還元触媒である。接触水素還元触媒を具体的に例示すると、ラネーニッケル等のＮｉ系；Ｐｄ／Ｃ等のＰｄ系；ＰｔＯ２、Ｐｔ／Ｃ等のＰｔ系；Ｒｕ／Ｃ等のＲｕ系等の不均一系接触還元触媒、ウイルキンソン触媒等の金属と配位子との錯体を用いた均一系接触還元触媒を挙げることが出来る。これらの中でも安価で収率も高いことから不均一系接触還元触媒が好ましく、特に価格の点からＮｉ系触媒、さらにはラネーニッケルが特に好ましい。これらの触媒は一種類でも複数の触媒を組み合わせて使用しても良いが、工業的に優位な点から一種類の触媒を用いることが好ましい。
(catalyst)
The catalyst in the production method of the present invention is a catalytic hydrogen reduction catalyst. Specific examples of the catalytic hydrogen reduction catalysts are Ni-based catalysts such as Raney nickel; Pd-based catalysts such as Pd / C; Pt-based catalysts such as PtO2, Pt / C; Ru-based catalysts such as Ru / C. , A homogeneous catalytic reduction catalyst using a complex of a metal and a ligand such as Wilkinson's catalyst. Among these, a heterogeneous catalytic reduction catalyst is preferable because it is inexpensive and has a high yield, and a Ni-based catalyst and Raney nickel are particularly preferable in terms of cost. These catalysts may be used alone or in combination of a plurality of catalysts, but it is preferable to use one kind of catalyst from the viewpoint of industrial advantage.
触媒の使用量は、接触水素還元反応が十分に進行する程度使用すれば良く、特に制限されるものではない。反応収率の観点から４−ヒドロキシピリジン１質量部に対して、触媒を０．００１〜１質量部使用することが好ましく、さらに０．０１〜０．２質量部使用することが好ましい。 The amount of the catalyst used is not particularly limited as long as the catalytic hydrogen reduction reaction is sufficiently advanced. From the viewpoint of reaction yield, it is preferable to use 0.001 to 1 part by mass, and more preferably 0.01 to 0.2 part by mass of catalyst with respect to 1 part by mass of 4-hydroxypyridine.
（水素）
本発明の製造方法では、水素の存在下で製造を行う。この時に水素源としては、反応系に直接水素を供給する他に、触媒の存在下において分解して水素を発生させる化合物を存在させて反応系で水素を発生させるものであってよい。触媒の存在下において水素を発生させる化合物として具体的には、ギ酸アンモニウム、ギ酸ナトリウム等のギ酸塩等が挙げられる。
(hydrogen)
In the production method of the present invention, production is performed in the presence of hydrogen. At this time, as the hydrogen source, in addition to directly supplying hydrogen to the reaction system, a compound that decomposes to generate hydrogen in the presence of a catalyst may be present to generate hydrogen in the reaction system. Specific examples of compounds that generate hydrogen in the presence of a catalyst include formate salts such as ammonium formate and sodium formate.
接触還元反応時の圧力は、特に制限されるものではなく用いる触媒によって適宜選択すればよい。例えば触媒として、Ｎｉ系触媒を用いた場合には反応促進の観点から好ましくは９．８×１０５〜９．８×１０６Ｐａの範囲で、特に好ましくは２．９×１０６〜４．９×１０６Ｐａの範囲で製造を行うことが好ましい。また、触媒としてＰｄ系触媒を用いた場合には反応促進の観点から好ましくは９．８×１０４〜４．９×１０６Ｐａの範囲で、特に好ましくは２．９×１０５〜２．０×１０６Ｐａの範囲で製造を行うことが好ましい。或いは、触媒としてＰｔ系触媒を用いた場合には反応促進の観点から好ましくは９．８×１０４〜４．９×１０６Ｐａの範囲で、特に好ましくは９．８×１０４〜９．８×１０５Ｐａの範囲で製造を行うことが好ましい。 The pressure during the catalytic reduction reaction is not particularly limited and may be appropriately selected depending on the catalyst used. For example, when a Ni-based catalyst is used as the catalyst, it is preferably in the range of 9.8 × 10 5 to 9.8 × 10 6 Pa, particularly preferably 2.9 × 10 6 to 4. It is preferable to carry out the production in the range of 9 × 10 6 Pa. When a Pd-based catalyst is used as the catalyst, it is preferably in the range of 9.8 × 10 4 to 4.9 × 10 6 Pa, and particularly preferably 2.9 × 10 5 to 2. The production is preferably performed in the range of 0 × 10 6 Pa. Alternatively, when a Pt-based catalyst is used as the catalyst, it is preferably in the range of 9.8 × 10 4 to 4.9 × 10 6 Pa, and particularly preferably 9.8 × 10 4 to 9. It is preferable to carry out the production in the range of 8 × 10 5 Pa.
また、触媒の存在下において分解して水素を発生させる化合物を用いる場合には、４−ヒドロキシピリジン１モルに対して、１〜１００モルの水素が発生するように該化合物を用いれば良い。 When a compound that decomposes to generate hydrogen in the presence of a catalyst is used, the compound may be used so that 1 to 100 mol of hydrogen is generated with respect to 1 mol of 4-hydroxypyridine.
（反応溶媒）
本発明の製造方法においては、溶媒を用いずに反応を行うことも可能であるが、局所的な反応を抑制し、反応を円滑に進めるために反応溶媒を用いることが好ましい。本発明の製造方法に用いる反応溶媒としては、接触水素還元反応に一般に用いられる溶媒を用いることが出来る。例示すれば、メタノール、エタノール、プロピルアルコール、イソプロピルアルコール、シロクヘキサノール等のアルコール類；ヘキサン、ペプタン、シクロヘキサン等の脂肪族炭化水素類；酢酸、ジオキサン、水等を挙げることができる。これら溶媒は、単独溶媒であっても、複数の溶媒の混合物であってもよい。
(Reaction solvent)
In the production method of the present invention, it is possible to carry out the reaction without using a solvent, but it is preferable to use a reaction solvent in order to suppress the local reaction and allow the reaction to proceed smoothly. As the reaction solvent used in the production method of the present invention, a solvent generally used in the catalytic hydrogen reduction reaction can be used. Examples include alcohols such as methanol, ethanol, propyl alcohol, isopropyl alcohol, and cyclohexanol; aliphatic hydrocarbons such as hexane, peptane, and cyclohexane; acetic acid, dioxane, water, and the like. These solvents may be a single solvent or a mixture of a plurality of solvents.
反応溶媒の使用量は、反応が進行するに十分な量を用いれば良く、特に制限されるものではない。反応収率の点、或いは操作性の観点から、４−ヒドロキシピリジン１質量部に対して、溶媒を１〜１００質量部使用することが好ましく、さらに５〜２０質量部使用することが好ましい。 The amount of the reaction solvent used is not particularly limited as long as it is an amount sufficient for the reaction to proceed. From the viewpoint of reaction yield or operability, the solvent is preferably used in an amount of 1 to 100 parts by mass, more preferably 5 to 20 parts by mass, relative to 1 part by mass of 4-hydroxypyridine.
（その他の添加剤）
本発明において、前記４級化反応が遅い場合には、ハロゲン化アルキルカルボン酸エステルの反応性を向上させる目的でハロゲン化合物を添加することができる。具体的には、臭化カリウム、臭化セシウム、ヨウ化ナトリウム、ヨウ化カリウム、ヨウ化セシウム等の無機塩、テトラブチルアンモニウムヨージド、トリオクチルメチルアンモニウムヨージド等のアンモニウムカチオンを有する塩等を挙げることができる。また前記接触還元反応を促進させるためには、酸、アルカリ、無機金属化合物等の助触媒を適宜添加することが出来る。
(Other additives)
In the present invention, when the quaternization reaction is slow, a halogen compound can be added for the purpose of improving the reactivity of the halogenated alkylcarboxylic acid ester. Specifically, inorganic salts such as potassium bromide, cesium bromide, sodium iodide, potassium iodide, cesium iodide, salts having an ammonium cation such as tetrabutylammonium iodide, trioctylmethylammonium iodide, etc. Can be mentioned. Further, in order to promote the catalytic reduction reaction, a cocatalyst such as an acid, an alkali or an inorganic metal compound can be added as appropriate.
（反応条件）
本発明の製造方法では、４−ヒドロキシピリジンと、前記ハロゲン化アルキルカルボン酸エステルとを触媒及び水素の存在下反応させる。反応方法については、触媒及び水素の存在下、４−ヒドロキシピリジンと前記ハロゲン化アルキルカルボン酸エステルとを接触させればよい。すなわち、反応容器内に４−ヒドロキシピリジン、前記ハロゲン化アルキルカルボン酸エステル、及び触媒を添加した後、さらに水素をガス配管等より継続的に供給しても良いし、あるいは、反応容器内に４−ヒドロキシピリジン、前記ハロゲン化アルキルカルボン酸エステル、及び、触媒の存在下において分解して水素を発生させる化合物を添加した後、触媒を添加し反応を開始させても良い。また、反応を効率的に進めるために、反応系内を攪拌混合することが好ましい。
(Reaction conditions)
In the production method of the present invention, 4-hydroxypyridine is reacted with the halogenated alkylcarboxylic acid ester in the presence of a catalyst and hydrogen. Regarding the reaction method, 4-hydroxypyridine may be brought into contact with the halogenated alkylcarboxylic acid ester in the presence of a catalyst and hydrogen. That is, after adding 4-hydroxypyridine, the halogenated alkylcarboxylic acid ester, and the catalyst into the reaction container, hydrogen may be continuously supplied from a gas pipe or the like, or 4 hydrogen may be supplied into the reaction container. After adding the hydroxypyridine, the halogenated alkylcarboxylic acid ester, and the compound that decomposes in the presence of a catalyst to generate hydrogen, a catalyst may be added to start the reaction. Further, in order to efficiently proceed the reaction, it is preferable to stir and mix the inside of the reaction system.
本発明の製造方法における反応温度は、特に制限されるものではなく用いる触媒によって適宜選択すればよいが、室温以上、２５０℃以下であることが好ましい。反応時間は、水素の供給量、反応温度によって異なるが、通常１時間〜２４時間で十分である。反応の終結は、薄層クロマトグラフィー（ＴＬＣ）等により、４−ヒドロキシピリジンの消費量を確認して決定すればよい。 The reaction temperature in the production method of the present invention is not particularly limited and may be appropriately selected depending on the catalyst used, but is preferably room temperature or higher and 250 ° C. or lower. The reaction time varies depending on the amount of hydrogen supplied and the reaction temperature, but 1 hour to 24 hours is usually sufficient. The termination of the reaction may be determined by confirming the consumption amount of 4-hydroxypyridine by thin layer chromatography (TLC) or the like.
このような本発明の製造方法によって、下記式（２） According to the manufacturing method of the present invention, the following formula (2)
（式中、Ｒおよびａは前記式（１）におけるものと同義である）
で示される（４−ヒドロキシ）−１−ピペリジノアルキルカルボン酸エステルが得られる。前述のとおり、ベポタスチンの製造原料として有益であるとの観点から、上記式（２）におけるａが３である、（４−ヒドロキシ）−１−ピペリジノブタン酸エチルエステルが好ましい。
(In the formula, R and a have the same meanings as in the formula (1))
A (4-hydroxy) -1-piperidinoalkylcarboxylic acid ester represented by As described above, from the viewpoint of being useful as a raw material for producing bepotastine, (4-hydroxy) -1-piperidinobutanoic acid ethyl ester in which a in the above formula (2) is 3 is preferable.
（ピペリジノアルキルカルボン酸エステルの精製方法）
上記本発明の製造方法で得られた、（４−ヒドロキシ）−１−ピペリジノアルキルカルボン酸エステルは、ろ過等の操作によって触媒等を除去した後、そのまま、所望の目的に使用することもできるが、（４−ヒドロキシ）−１−ピペリジノアルキルカルボン酸エステルを精製した後、所望の目的に使用することもできる。（４−ヒドロキシ）−１−ピペリジノアルキルカルボン酸エステルの精製方法としては、公知の方法が採用できる。具体的には、上記反応終了後、触媒を除去した後の反応溶液をアルカリ溶液、水等で洗浄し、反応溶媒を除去した後、公知の精製手段（再結晶、洗浄、カラム分離）により精製する方法が挙げられる。
(Method for purifying piperidinoalkylcarboxylic acid ester)
The (4-hydroxy) -1-piperidinoalkylcarboxylic acid ester obtained by the production method of the present invention may be used as it is for a desired purpose after removing the catalyst and the like by an operation such as filtration. However, the (4-hydroxy) -1-piperidinoalkylcarboxylic acid ester can be purified and then used for a desired purpose. A known method can be adopted as a method for purifying the (4-hydroxy) -1-piperidinoalkylcarboxylic acid ester. Specifically, after the completion of the above reaction, the reaction solution after removing the catalyst is washed with an alkaline solution, water or the like, and after removing the reaction solvent, it is purified by a known purification means (recrystallization, washing, column separation). There is a method of doing.
このようにして得られた、（４−ヒドロキシ）−１−ピペリジノアルキルカルボン酸エステルは、例えばベポタスチンの合成原料等に用いることができる。以下、本発明の製造方法によって得られた、（４−ヒドロキシ）−１−ピペリジノブタン酸エチルエステルを用いた、ベポタスチンの製造方法について説明する。 The (4-hydroxy) -1-piperidinoalkylcarboxylic acid ester thus obtained can be used, for example, as a raw material for synthesizing bepotastine. Hereinafter, a method for producing bepotastine using (4-hydroxy) -1-piperidinobutanoic acid ethyl ester obtained by the production method of the present invention will be described.
（４−［４−［（４−クロロフェニル）（２−ピリジル）メトキシ］ピペリジノ］ブタン酸（ベポタスチン）の製造方法）
前記製造方法で得られる（４−ヒドロキシ）−１−ピペリジノブタン酸エチルエステルと、下記式（３）
(Method for producing 4- [4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoic acid (bepotastine))
(4-hydroxy) -1-piperidinobutanoic acid ethyl ester obtained by the above-mentioned production method and the following formula (3)
（式中、Ｘはハロゲン原子または活性エステル基である）
で示される２−［（４−クロロフェニル）メチル］ピリジン化合物とを塩基の存在下、エーテル化反応をさせることにより、４−［４−［（４−クロロフェニル）（２−ピリジル）メトキシ］ピペリジノ］ブタン酸を製造することができる。
(In the formula, X is a halogen atom or an active ester group)
4- [4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidino] by an etherification reaction with a 2-[(4-chlorophenyl) methyl] pyridine compound represented by Butanoic acid can be produced.
（２−［（４−クロロフェニル）メチル］ピリジン化合物）
本発明の製造方法に用いる前記式（３）で示される化合物において置換基Ｘは、塩基存在下、前記２−［（４−クロロフェニル）メチル］ピリジン化合物と（４−ヒドロキシ）−１−ピペリジノブチル酸エチルエステルとが反応する際に脱離し、４−［４−［（４−クロロフェニル）（２−ピリジル）メトキシ］ピペリジノ］ブタン酸が得られる置換基であればよい。置換基Ｘとしては、塩素原子、臭素原子、ヨウ素原子といったハロゲン原子、メシル基、トシル基、硫酸エステル基、アセチル基といった活性エステル基を挙げることが出来る。これらの置換基の中で、合成が容易であることから塩素原子が好ましい。
(2-[(4-chlorophenyl) methyl] pyridine compound)
In the compound represented by the formula (3) used in the production method of the present invention, the substituent X is the 2-[(4-chlorophenyl) methyl] pyridine compound and (4-hydroxy) -1-piperidinobutyric acid in the presence of a base. Any substituent may be used as long as it is eliminated during the reaction with ethyl ester to give 4- [4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoic acid. Examples of the substituent X include halogen atoms such as chlorine atom, bromine atom and iodine atom, and active ester groups such as mesyl group, tosyl group, sulfate ester group and acetyl group. Among these substituents, a chlorine atom is preferable because it is easy to synthesize.
前記式（３）で示される２−［（４−クロロフェニル）メチル］ピリジン化合物は、公知の方法で製造することができる。例えば、特許文献（国際公開９２／０６９７１号パンフレット）に記載の方法に従い製造することができる。 The 2-[(4-chlorophenyl) methyl] pyridine compound represented by the above formula (3) can be produced by a known method. For example, it can be manufactured according to the method described in the patent document (International Publication 92/06971 pamphlet).
（塩基）
本発明の製造方法に用いる塩基とは水と接触させたときに水酸化物イオン（ＯＨ−）を出す物質のことを示す。塩基としては、特に制限されるものではなく、公知の塩基を使用することができる。具体的には、炭酸ナトリウム、炭酸カリウム、炭酸セシウム、炭酸マグネシウム、炭酸カルシウム、炭酸リチウム、炭酸水素ナトリウム、炭酸水素カリウム、炭酸水素リチウム等の無機炭酸塩；水酸化ナトリウム、水酸化カリウム、水酸化リチウム、水酸化マグネシウム、水酸化カルシウム等の水酸化物；ナトリウムメトキシド、カリウムメトキシド、カリウムｔ−ブトキシド等のアルカリ金属アルコキシド類；金属ナトリウム、金属カリウム等のアルカリ金属；水素化ナトリウム、水素化カリウム、水素化ホウ素ナトリウム等の水素化物；トリエチルアミン、トリブチルアミン等の脂肪族三級アミン化合物；ピリジン、４−Ｎ，Ｎ−ジメチルアミノピリジン等の芳香族三級アミン化合物等を挙げることができる。これらの中でも、反応が進みやすいことから、水酸化ナトリウム、水酸化カリウム等の水酸化物、炭酸カリウム、炭酸セシウム等の無機炭酸塩を使用するのが好適である。
(base)
The base used in the production method of the present invention refers to a substance that produces a hydroxide ion (OH − ) when brought into contact with water. The base is not particularly limited, and a known base can be used. Specifically, inorganic carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, magnesium carbonate, calcium carbonate, lithium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, lithium hydrogen carbonate; sodium hydroxide, potassium hydroxide, and hydroxide. Hydroxides such as lithium, magnesium hydroxide and calcium hydroxide; alkali metal alkoxides such as sodium methoxide, potassium methoxide and potassium t-butoxide; alkali metals such as sodium metal and potassium potassium; sodium hydride and hydrogenation Examples thereof include hydrides such as potassium and sodium borohydride; aliphatic tertiary amine compounds such as triethylamine and tributylamine; aromatic tertiary amine compounds such as pyridine and 4-N, N-dimethylaminopyridine. Among these, it is preferable to use hydroxides such as sodium hydroxide and potassium hydroxide, and inorganic carbonates such as potassium carbonate and cesium carbonate because the reaction easily proceeds.
上記塩基の使用量は、反応が進行するに十分な量を用いれば良く、特に制限されるものではないが、前記式（３）で示される２−［（４−クロロフェニル）メチル］ピリジン化合物１モルに対して、０．５〜１０モルとすることが好ましく、１〜３モルとすることがさらに好ましい。 The amount of the base used is not particularly limited as long as it is an amount sufficient for the reaction to proceed, but is not limited, but the 2-[(4-chlorophenyl) methyl] pyridine compound 1 represented by the formula (3) is used. The amount is preferably 0.5 to 10 mol, and more preferably 1 to 3 mol with respect to the mol.
（反応溶媒）
本発明の製造方法においては、反応を円滑に進めるために反応溶媒を用いることが好ましい。反応溶媒として具体的には、水；メタノール、エタノール、１−プロピルアルコール、１−ブチルアルコール等の炭素数１〜６のアルコール類；ジエチルエーテル、テトラヒドロフラン、２−メチルテトラヒドロフラン、ｔｅｒｔ−ブチルメチルエーテル等のエーテル類；ジメチルホルムアミド、ジメチルアセトアミド、Ｎ−メチルピロリドン等のアミド類；ジメチルスルホキシドを例示することができる。これらの中でも、原料化合物の溶解性が高いことからアミド類、ジメチルスルホキシドを使用することが好ましい。また、反応溶媒として、複数の溶媒を組み合わせて使用する事も出来る。
(Reaction solvent)
In the production method of the present invention, it is preferable to use a reaction solvent in order to smoothly proceed the reaction. Specific examples of the reaction solvent include water; alcohols having 1 to 6 carbon atoms such as methanol, ethanol, 1-propyl alcohol, 1-butyl alcohol; diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, tert-butylmethyl ether, etc. And amides such as dimethylformamide, dimethylacetamide, N-methylpyrrolidone and the like; and dimethylsulfoxide. Among these, it is preferable to use amides and dimethylsulfoxide because the raw material compounds have high solubility. Further, a plurality of solvents can be used in combination as the reaction solvent.
反応溶媒の使用量は、反応が進行するに十分な量を用いれば良く、特に制限されるものではない。反応収率の点から前記式（３）で示される２−［（４−クロロフェニル）メチル］ピリジン化合物１質量部に対して、反応溶媒を１〜１００質量部となる範囲で使用することが好ましく、さらに５〜３０質量部となる範囲で使用することが好ましい。 The amount of the reaction solvent used is not particularly limited as long as it is an amount sufficient for the reaction to proceed. From the viewpoint of reaction yield, it is preferable to use the reaction solvent in an amount of 1 to 100 parts by mass relative to 1 part by mass of the 2-[(4-chlorophenyl) methyl] pyridine compound represented by the formula (3). Further, it is preferable to use it in a range of 5 to 30 parts by mass.
（反応条件）
本発明において、原料化合物の使用量は、反応が進行するに十分な量を用いれば良く、特に制限されるものではない。反応収率の点から、前記式（３）で示される２−［（４−クロロフェニル）メチル］ピリジン化合物１モルに対して、（４−ヒドロキシ）−１−ピペリジノブタン酸エチルエステルを０．８〜５モルの範囲で使用することが好ましく、さらに１〜２モルの範囲で使用することが好ましい。
(Reaction conditions)
In the present invention, the amount of the raw material compound used may be an amount sufficient for the reaction to proceed, and is not particularly limited. From the viewpoint of reaction yield, 0.8 mol of ethyl ester of (4-hydroxy) -1-piperidinobutanoic acid is added to 1 mol of the 2-[(4-chlorophenyl) methyl] pyridine compound represented by the formula (3). It is preferably used in the range of 5 mol, and more preferably in the range of 1 to 2 mol.
また、本発明の製造方法における、前記２−［（４−クロロフェニル）メチル］ピリジン化合物、（４−ヒドロキシ）−１−ピペリジノブタン酸エチルエステル、及び塩基の添加方法は特に制限されない。また、反応を円滑に進行させるために、反応中は攪拌混合させることが好ましい。反応方法として具体的には、反応溶媒で希釈した前記２−［（４−クロロフェニル）メチル］ピリジン化合物、反応溶媒で希釈した（４−ヒドロキシ）−１−ピペリジノブタン酸エチルエステル、及び反応溶媒で希釈した塩基を同時に反応装置に投入して、攪拌混合を行う方法；反応溶媒で希釈した（４−ヒドロキシ）−１−ピペリジノブチル酸エチルエステル及び塩基を反応装置内に投入し、攪拌混合しながら、前記２−［（４−クロロフェニル）メチル］ピリジン化合物を反応装置に添加する方法；反応装置に投入した前記２−［（４−クロロフェニル）メチル］ピリジン化合物、（４−ヒドロキシ）−１−ピペリジノブタン酸エチルエステル、及び塩基の混合物に反応溶媒を加えて混合撹拌する方法等が挙げられる。また、前記２−［（４−クロロフェニル）メチル］ピリジン化合物、（４−ヒドロキシ）−１−ピペリジノブタン酸エチルエステル、塩基のいずれかを撹拌混合する段階では一部を添加し、反応中に残量を追加で反応系に追加してもよい。 Further, in the production method of the present invention, the method for adding the 2-[(4-chlorophenyl) methyl] pyridine compound, (4-hydroxy) -1-piperidinobutanoic acid ethyl ester, and the base is not particularly limited. In order to allow the reaction to proceed smoothly, it is preferable to stir and mix during the reaction. As a reaction method, specifically, the 2-[(4-chlorophenyl) methyl] pyridine compound diluted with a reaction solvent, (4-hydroxy) -1-piperidinobutanoic acid ethyl ester diluted with a reaction solvent, and the reaction solvent are diluted. The same base is charged into the reactor at the same time to perform stirring and mixing; (4-hydroxy) -1-piperidinobutyric acid ethyl ester diluted with a reaction solvent and the base are charged into the reactor, and the mixture is stirred and mixed. A method of adding a 2-[(4-chlorophenyl) methyl] pyridine compound to a reaction device; the above-mentioned 2-[(4-chlorophenyl) methyl] pyridine compound charged into the reaction device, ethyl (4-hydroxy) -1-piperidinobutanoate A method in which a reaction solvent is added to a mixture of an ester and a base and the mixture is mixed and stirred can be mentioned. In addition, at the stage of stirring and mixing any of the 2-[(4-chlorophenyl) methyl] pyridine compound, (4-hydroxy) -1-piperidinobutanoic acid ethyl ester, and a base, a part thereof is added, and the remaining amount is left during the reaction. May be additionally added to the reaction system.
本発明の製造方法において反応温度は、特に制限されるものではないが、０℃以上反応混合物の還流温度以下の範囲が好ましく、２５℃以上８０℃以下の範囲がさらに好ましい。また、反応時の雰囲気も、特に制限されるものではなく、空気雰囲気下、窒素雰囲気下の何れであってもよい。反応時の圧力も、加圧下、大気圧下、減圧下の何れであってもよい。このような条件下で、反応時間は、原料化合物の消費状態を確認して適宜最適時間を決めればよいが、通常であれば、１〜２４時間程度である。 In the production method of the present invention, the reaction temperature is not particularly limited, but is preferably in the range of 0 ° C or higher and the reflux temperature of the reaction mixture or lower, and more preferably 25 ° C or higher and 80 ° C or lower. The atmosphere at the time of reaction is not particularly limited and may be either an air atmosphere or a nitrogen atmosphere. The pressure during the reaction may be any of increased pressure, atmospheric pressure and reduced pressure. Under such conditions, the reaction time may be appropriately determined by confirming the consumption state of the raw material compound, but is usually about 1 to 24 hours.
以上のような条件で前記２−［（４−クロロフェニル）メチル］ピリジン化合物と（４−ヒドロキシ）−１−ピペリジノブタン酸エチルエステルとを反応させることにより、４−［４−［（４−クロロフェニル）（２−ピリジル）メトキシ］ピペリジノ］ブタン酸（ベポタスチン）を製造することができる。 By reacting the 2-[(4-chlorophenyl) methyl] pyridine compound with (4-hydroxy) -1-piperidinobutanoic acid ethyl ester under the conditions as described above, 4- [4-[(4-chlorophenyl) (2-Pyridyl) methoxy] piperidino] butanoic acid (bepotastine) can be produced.
上記本発明の製造方法で得られた、４−［４−［（４−クロロフェニル）（２−ピリジル）メトキシ］ピペリジノ］ブタン酸は、そのまま、所望の目的に使用することもできるが、４−［４−［（４−クロロフェニル）（２−ピリジル）メトキシ］ピペリジノ］ブタン酸を精製した後、所望の目的に使用することもできる。４−［４−［（４−クロロフェニル）（２−ピリジル）メトキシ］ピペリジノ］ブタン酸の精製方法としては、公知の方法が採用できる。具体的には、上記反応終了後の反応溶液をアルカリ溶液、水等で洗浄し、反応溶媒を除去した後、公知の精製手段（再結晶、洗浄、カラム分離）により精製する方法が挙げられる。 The 4- [4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoic acid obtained by the above-mentioned production method of the present invention can be used as it is for a desired purpose. [4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoic acid can be purified and then used for the desired purpose. As a method for purifying 4- [4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoic acid, a known method can be adopted. Specifically, there may be mentioned a method in which the reaction solution after the above reaction is washed with an alkaline solution, water or the like to remove the reaction solvent, and then purified by a known purification means (recrystallization, washing, column separation).
以下実施例を挙げて、本発明を詳細に説明するが、本発明はこれらにより限定されるものではない。 Hereinafter, the present invention will be described in detail with reference to Examples, but the present invention is not limited thereto.
実施例１ （４−ヒドロキシ）−４−ピペリジノブタン酸エチルエステルの製造方法（Ｎｉ系触媒）
４−ヒドロキシピリジン９．５ｇ（０．１０ｍｍｏｌ）、４−ブロモ酪酸エチルエステル１９．５ｇ（０．１０ｍｏｌ）、ラネーニッケル触媒１ｇ、エタノール８０ｍｌを３００ｍｌ容オートクレーブに入れ、容器内を水素で置換した。容器内に水素ガスを導入しながら、反応器を撹拌しながら２２０℃に加熱し、水素圧４．９×１０６Ｐａにて１２時間反応を行った。反応器を放冷後、ＴＬＣにて４−ヒドロキシピリジンの消失を確認した。触媒をろ別して得られた反応液を濃縮した。残渣に水１００ｍｌを加え、酢酸エチル６０ｍｌで抽出し、有機層を乾燥、濃縮した。得られた固形物を減圧乾燥後、（４−ヒドロキシ）−４−ピペリジノブタン酸エチルエステル１７．７ｇ得た（０．０８２ｍｍｏｌ、収率８２％）。１Ｈ−ＮＭＲ（ＣＤＣｌ３）：１．２（３Ｈ）、１．８−２．２（４Ｈ）、２．３−２．８（１０Ｈ）、３．４（１Ｈ）、４．０（２Ｈ）．
Example 1 Method for producing ethyl (4-hydroxy) -4-piperidinobutanoic acid (Ni-based catalyst)
4-Hydroxypyridine 9.5 g (0.10 mmol), 4-bromobutyric acid ethyl ester 19.5 g (0.10 mol), Raney nickel catalyst 1 g, and ethanol 80 ml were put into a 300 ml autoclave, and the inside of the container was replaced with hydrogen. While introducing hydrogen gas into the vessel, the reactor was heated to 220 ° C. with stirring, and the reaction was carried out at a hydrogen pressure of 4.9 × 10 6 Pa for 12 hours. After allowing the reactor to cool, the disappearance of 4-hydroxypyridine was confirmed by TLC. The reaction solution obtained by filtering off the catalyst was concentrated. 100 ml of water was added to the residue and extracted with 60 ml of ethyl acetate, the organic layer was dried and concentrated. After drying the obtained solid material under reduced pressure, 17.7 g of (4-hydroxy) -4-piperidinobutanoic acid ethyl ester was obtained (0.082 mmol, yield 82%). 1 H-NMR (CDCl 3 ): 1.2 (3H), 1.8-2.2 (4H), 2.3-2.8 (10H), 3.4 (1H), 4.0 (2H). ).
実施例２ （４−ヒドロキシ）−４−ピペリジノブタン酸エチルエステルの製造方法（Ｐｄ／Ｃ触媒）
４−ヒドロキシピリジン９．５ｇ（０．１０ｍｏｌ）、４−ブロモ酪酸エチルエステル２１．５ｇ（０．１１ｍｏｌ）、５％Ｐｄ／Ｃ触媒０．５ｇ、エタノール８０ｍｌを３００ｍｌ容オートクレーブに入れ、容器内を水素で置換した。容器内に水素ガスを導入しながら、反応器を撹拌しながら１００℃に加熱し、水素圧４．９×１０５Ｐａにて９時間反応を行った。反応器を放冷後、ＴＬＣにて４−ヒドロキシピリジンの消失を確認した。触媒をろ別して得られた反応液を濃縮した。残渣に水１００ｍｌを加え、酢酸エチル６０ｍｌで抽出し、有機層を乾燥、濃縮した。得られた固形物を減圧乾燥後、（４−ヒドロキシ）−４−ピペリジノブタン酸エチルエステルを１８．３ｇ得た（８５ｍｍｏｌ、収率８５％）。
Example 2 Method for producing (4-hydroxy) -4-piperidinobutanoic acid ethyl ester (Pd / C catalyst)
4-Hydroxypyridine 9.5 g (0.10 mol), 4-bromobutyric acid ethyl ester 21.5 g (0.11 mol), 5% Pd / C catalyst 0.5 g, and ethanol 80 ml were put into a 300 ml autoclave, and the inside of the container was closed. Replaced with hydrogen. While introducing hydrogen gas into the vessel, the reactor was heated to 100 ° C. with stirring, and the reaction was performed at a hydrogen pressure of 4.9 × 10 5 Pa for 9 hours. After allowing the reactor to cool, the disappearance of 4-hydroxypyridine was confirmed by TLC. The reaction solution obtained by filtering off the catalyst was concentrated. 100 ml of water was added to the residue and extracted with 60 ml of ethyl acetate, the organic layer was dried and concentrated. The obtained solid was dried under reduced pressure, and 18.3 g of (4-hydroxy) -4-piperidinobutanoic acid ethyl ester was obtained (85 mmol, yield 85%).
実施例３ ベポタスチンの製造方法
３００ｍｌナスフラスコに、２−［クロロ（４−クロロフェニル）メチル］ピリジン１０ｇ（４２ｍｍｏｌ）、（４−ヒドロキシ）−４−ピペリジノブタン酸エチルエステル９．９ｇ（４２ｍｍｏｌ）、ジメチルスルホキシド１００ｍｌを入れ窒素雰囲気下、室温で撹拌しながら、水酸化カリウム４．７ｇ（８２ｍｍｏｌ）を加えた。その後、６０℃に昇温し５時間を行ったのち、ＴＬＣにて２−［クロロ（４−クロロフェニル）メチル］ピリジンの消失を確認した。放冷後、ジメチルスルホキシドを留去し、塩化メチレン、水を加えた後１Ｎ塩酸を加えて中和した。水層を分離後、有機層を濃縮し４−［４−［（４−クロロフェニル）（２−ピリジル）メトキシ］ピペリジノ］ブタン酸を１４．３ｇ（３７ｍｍｏｌ、収率８７％）得た。
Example 3 Method for producing bepotastine In a 300 ml eggplant-shaped flask, 10 g (42 mmol) of 2- [chloro (4-chlorophenyl) methyl] pyridine, 9.9 g (42 mmol) of (4-hydroxy) -4-piperidinobutanoic acid ethyl ester, and dimethyl sulfoxide were added. Into a nitrogen atmosphere was added 100 ml, and 4.7 g (82 mmol) of potassium hydroxide was added with stirring at room temperature. After that, the temperature was raised to 60 ° C., and after 5 hours, the disappearance of 2- [chloro (4-chlorophenyl) methyl] pyridine was confirmed by TLC. After cooling, dimethyl sulfoxide was distilled off, methylene chloride and water were added, and 1N hydrochloric acid was added to neutralize. After separating the aqueous layer, the organic layer was concentrated to obtain 14.3 g (37 mmol, yield 87%) of 4- [4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoic acid.
参考例１ （４−ヒドロキシ）−４−ピペリジノブタン酸エチルエステルの製造方法（４−ヒドロキシピペリジン原料）
５００ｍｌフラスコに４−ヒドロキシピペリジン１０．１ｇ（０．１０ｍｍｏｌ）、４−ブロモ酪酸エチルエステル１９．５ｇ（０．１０ｍｏｌ）、炭酸カリウム２７．６ｇ、ヨウ化カリウム０．５ｇ、メチルイソブチルケトン２００ｍｌを入れ２４時間加熱還流した後、ＴＬＣにて４−ヒドロキシピペリジンの消失を確認した。放冷後、水１００ｍｌを加え、酢酸エチル６０ｍｌで抽出し、有機層を乾燥、濃縮した。得られた固形物を減圧乾燥後、（４−ヒドロキシ）−４−ピペリジノブタン酸エチルエステルを１５．５ｇ得た（０．０７２ｍｍｏｌ、収率７２％）。
Reference Example 1 Method for producing (4-hydroxy) -4-piperidinobutanoic acid ethyl ester (raw material for 4-hydroxypiperidine)
4-hydroxypiperidine 10.1 g (0.10 mmol), 4-bromobutyric acid ethyl ester 19.5 g (0.10 mol), potassium carbonate 27.6 g, potassium iodide 0.5 g, and methyl isobutyl ketone 200 ml were put into a 500 ml flask. After heating under reflux for 24 hours, disappearance of 4-hydroxypiperidine was confirmed by TLC. After allowing to cool, 100 ml of water was added, and the mixture was extracted with 60 ml of ethyl acetate, and the organic layer was dried and concentrated. After drying the obtained solid substance under reduced pressure, 15.5 g of (4-hydroxy) -4-piperidinobutanoic acid ethyl ester was obtained (0.072 mmol, yield 72%).
Claims (4)
で示されるハロゲン化アルキルカルボン酸エステルとを触媒及び水素の存在下反応させて、下記式（２）
で示される（４−ヒドロキシ）−１−ピペリジノアルキルカルボン酸エステルを得ることを特徴とする、（４−ヒドロキシ）−１−ピペリジノアルキルカルボン酸エステルの製造方法。 4-hydroxypyridine and the following formula (1)
A halogenated alkylcarboxylic acid ester represented by the formula (2) below is reacted in the presence of a catalyst and hydrogen.
The method for producing (4-hydroxy) -1-piperidinoalkylcarboxylic acid ester is characterized by obtaining (4-hydroxy) -1-piperidinoalkylcarboxylic acid ester represented by
とを塩基の存在下反応させることを特徴とする、４−［４−［（４−クロロフェニル）（２−ピリジル）メトキシ］ピペリジノ］ブタン酸の製造方法。 The ( 4-hydroxy) -1-piperidinobutanoic acid ethyl ester is obtained by the production method according to claim 2 , and then the obtained (4-hydroxy) -1-piperidinobutanoic acid ethyl ester and the following formula (3):
And [4] are reacted in the presence of a base to prepare 4- [4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidino] butanoic acid.
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