JPH04139183A - Production of quinuclidine-4-carboxamide - Google Patents
Production of quinuclidine-4-carboxamideInfo
- Publication number
- JPH04139183A JPH04139183A JP26429190A JP26429190A JPH04139183A JP H04139183 A JPH04139183 A JP H04139183A JP 26429190 A JP26429190 A JP 26429190A JP 26429190 A JP26429190 A JP 26429190A JP H04139183 A JPH04139183 A JP H04139183A
- Authority
- JP
- Japan
- Prior art keywords
- cyanoquinuclidine
- sulfuric acid
- quinuclidine
- carboxamide
- salt
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- IJHIBDLDUXFQNB-UHFFFAOYSA-N 1-azabicyclo[2.2.2]octane-4-carboxamide Chemical compound C1CN2CCC1(C(=O)N)CC2 IJHIBDLDUXFQNB-UHFFFAOYSA-N 0.000 title claims description 19
- 238000004519 manufacturing process Methods 0.000 title claims description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 77
- CEMKLAOKVLRABO-UHFFFAOYSA-N 1-azabicyclo[2.2.2]octane-4-carbonitrile Chemical compound C1CN2CCC1(C#N)CC2 CEMKLAOKVLRABO-UHFFFAOYSA-N 0.000 claims abstract description 35
- 239000003960 organic solvent Substances 0.000 claims abstract description 23
- 150000003839 salts Chemical class 0.000 claims abstract description 23
- 239000003513 alkali Substances 0.000 claims abstract description 16
- 239000000203 mixture Substances 0.000 claims description 23
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 4
- 150000001342 alkaline earth metals Chemical class 0.000 claims description 3
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- 150000001340 alkali metals Chemical class 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 claims description 2
- 150000004649 carbonic acid derivatives Chemical class 0.000 claims description 2
- 150000004679 hydroxides Chemical class 0.000 claims description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 abstract description 51
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 abstract description 15
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 abstract description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 abstract description 9
- 150000001875 compounds Chemical class 0.000 abstract description 7
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 abstract description 3
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 3
- NZOYWQFJJHBAAF-UHFFFAOYSA-N 1-azabicyclo[2.2.2]octane-2-carbonitrile Chemical compound C1CN2C(C#N)CC1CC2 NZOYWQFJJHBAAF-UHFFFAOYSA-N 0.000 abstract description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 abstract description 2
- 239000011259 mixed solution Substances 0.000 abstract 4
- 239000000654 additive Substances 0.000 abstract 1
- 230000000996 additive effect Effects 0.000 abstract 1
- 229940079593 drug Drugs 0.000 abstract 1
- 239000003814 drug Substances 0.000 abstract 1
- 229910000000 metal hydroxide Inorganic materials 0.000 abstract 1
- 150000004692 metal hydroxides Chemical class 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 27
- 238000006386 neutralization reaction Methods 0.000 description 13
- 150000001298 alcohols Chemical class 0.000 description 12
- DLPWZHXPVXGLBC-UHFFFAOYSA-N 1-azabicyclo[2.2.2]octane-4-carbonitrile;sulfuric acid Chemical compound OS(O)(=O)=O.C1CN2CCC1(C#N)CC2 DLPWZHXPVXGLBC-UHFFFAOYSA-N 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 10
- 238000000034 method Methods 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 6
- 230000007423 decrease Effects 0.000 description 6
- -1 for example Chemical compound 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 238000006460 hydrolysis reaction Methods 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 4
- 239000006227 byproduct Substances 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 3
- 239000000920 calcium hydroxide Substances 0.000 description 3
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 3
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000002002 slurry Substances 0.000 description 3
- 150000005846 sugar alcohols Polymers 0.000 description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- XXPLDHNFTITERR-UHFFFAOYSA-N 1-azoniabicyclo[2.2.2]octane-4-carboxylate Chemical compound C1CN2CCC1(C(=O)O)CC2 XXPLDHNFTITERR-UHFFFAOYSA-N 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-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
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 2
- BXDZOYLPNAIDOC-UHFFFAOYSA-N N-[5-[(5-tert-butyl-1,3-oxazol-2-yl)methylsulfanyl]-1,3-thiazol-2-yl]-1-[2-[2-[2-[2-[2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy]ethoxy]ethoxy]ethylamino]-2-oxoethyl]piperidine-4-carboxamide Chemical compound CC(C)(C)c1cnc(CSc2cnc(NC(=O)C3CCN(CC(=O)NCCOCCOCCOCCNc4cccc5C(=O)N(C6CCC(=O)NC6=O)C(=O)c45)CC3)s2)o1 BXDZOYLPNAIDOC-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 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
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 238000007259 addition reaction Methods 0.000 description 2
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 2
- AYJRCSIUFZENHW-UHFFFAOYSA-L barium carbonate Chemical compound [Ba+2].[O-]C([O-])=O AYJRCSIUFZENHW-UHFFFAOYSA-L 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 150000008282 halocarbons Chemical class 0.000 description 2
- ZSIAUFGUXNUGDI-UHFFFAOYSA-N hexan-1-ol Chemical compound CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 0.000 description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- SBYHFKPVCBCYGV-UHFFFAOYSA-N quinuclidine Chemical compound C1CC2CCN1CC2 SBYHFKPVCBCYGV-UHFFFAOYSA-N 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- LCZVSXRMYJUNFX-UHFFFAOYSA-N 2-[2-(2-hydroxypropoxy)propoxy]propan-1-ol Chemical compound CC(O)COC(C)COC(C)CO LCZVSXRMYJUNFX-UHFFFAOYSA-N 0.000 description 1
- ZMPRRFPMMJQXPP-UHFFFAOYSA-N 2-sulfobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1S(O)(=O)=O ZMPRRFPMMJQXPP-UHFFFAOYSA-N 0.000 description 1
- 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 1
- DPBWFNDFMCCGGJ-UHFFFAOYSA-N 4-Piperidine carboxamide Chemical compound NC(=O)C1CCNCC1 DPBWFNDFMCCGGJ-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 description 1
- 229910001863 barium hydroxide Inorganic materials 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 150000003857 carboxamides Chemical class 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- SZXQTJUDPRGNJN-UHFFFAOYSA-N dipropylene glycol Chemical compound OCCCOCCCO SZXQTJUDPRGNJN-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- UQSQSQZYBQSBJZ-UHFFFAOYSA-N fluorosulfonic acid Chemical compound OS(F)(=O)=O UQSQSQZYBQSBJZ-UHFFFAOYSA-N 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- QWDJLDTYWNBUKE-UHFFFAOYSA-L magnesium bicarbonate Chemical compound [Mg+2].OC([O-])=O.OC([O-])=O QWDJLDTYWNBUKE-UHFFFAOYSA-L 0.000 description 1
- 229910000022 magnesium bicarbonate Inorganic materials 0.000 description 1
- 239000002370 magnesium bicarbonate Substances 0.000 description 1
- 235000014824 magnesium bicarbonate Nutrition 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
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- UUCCCPNEFXQJEL-UHFFFAOYSA-L strontium dihydroxide Chemical compound [OH-].[OH-].[Sr+2] UUCCCPNEFXQJEL-UHFFFAOYSA-L 0.000 description 1
- 229910001866 strontium hydroxide Inorganic materials 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 150000008054 sulfonate salts Chemical class 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- ZIBGPFATKBEMQZ-UHFFFAOYSA-N triethylene glycol Chemical compound OCCOCCOCCO ZIBGPFATKBEMQZ-UHFFFAOYSA-N 0.000 description 1
- 229940005605 valeric acid Drugs 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Description
【発明の詳細な説明】
［産業上の利用分野］
本発明は、医薬品の中間体、化学試薬などとして使用で
きるキヌクリジン−４−カルボキサミドの製造方法に関
する。DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a method for producing quinuclidine-4-carboxamide, which can be used as a pharmaceutical intermediate, a chemical reagent, and the like.
［従来の技術］
セファロスポリン系抗生物質の修飾剤、化学試薬として
の用途が期待されているキヌクリジン−４゛−カルボキ
サミドは、４−カルバモイルピペリジンを出発原料とし
て４−シアノキヌクリジンを合成し、この４シアノキヌ
クリジンを加水分解反応に供することにより合成されて
いる。キヌクリジン−４−カルボキサミドの製造方法と
して、例えば、４−シアノキヌクリジンの硫酸溶液に氷
を添加してニトリルを加水分解し、水酸化カリウム水溶
液を添加して中和し、次いで水を留去した残渣から、ア
セトンにより、キヌクリジン−４−カルボキサミドを単
離する方法が知ら゛れている［Ｆｉｓｃｈｅｒ、 Ｈ
，Ｐ、、 Ｇｒｏｂ、 Ｃ，Ａ、、 Ｈｅ１ｖ、
Ｃｈｉｎ、 Ａｃｔａ。[Prior art] Quinuclidine-4'-carboxamide, which is expected to be used as a modifier for cephalosporin antibiotics and a chemical reagent, is produced by synthesizing 4-cyanoquinuclidine using 4-carbamoylpiperidine as a starting material. , is synthesized by subjecting this 4-cyanoquinuclidine to a hydrolysis reaction. As a method for producing quinuclidine-4-carboxamide, for example, ice is added to a sulfuric acid solution of 4-cyanoquinuclidine to hydrolyze the nitrile, neutralized by adding an aqueous potassium hydroxide solution, and then water is distilled off. A method is known for isolating quinuclidine-4-carboxamide from the residue using acetone [Fischer, H.
,P,, Grob, C,A,, He1v,
Chin, Acta.
５１（１）、 １５３−１６３ （１９６８） ］。51(1), 153-163 (1968)].
しかしながら、この方法では、４−シアノキヌクリジン
の硫酸溶液に添加した氷により、４−シアノキヌクリジ
ン硫酸付加体が経時的に分解して、４−カルボキシキヌ
クリジンが生成する。例えば、４−シアノキヌクリジン
硫酸付加体は室温において６０時間程度で約８０％分解
し、４−カルポキシキヌクリジンが生成する。従って、
目的化合物であるキヌクリジン−４−カルボキサミドの
収率が低下する。また、キヌクリジン−４−カルボキサ
ミドは水に対する溶解度が高い。従って、水、硫酸塩や
水酸化カリウムが混在する中和液から、キヌクリジン−
４−カルボキサミドを効率よく分離精製するのが困難で
ある。さらに、中和反応の後、脱水蒸留により得られた
残渣からアセトンにより目的化合物を抽出・単離する場
合には、目的化合物の溶解度との関係から、大過剰量の
アセトンを必要とし、工業的に不利である。However, in this method, the 4-cyanoquinuclidine sulfate adduct is decomposed over time by ice added to the sulfuric acid solution of 4-cyanoquinuclidine, and 4-carboxyquinuclidine is produced. For example, 4-cyanoquinuclidine sulfate adduct is decomposed by about 80% in about 60 hours at room temperature, producing 4-carpoxyquinuclidine. Therefore,
The yield of the target compound, quinuclidine-4-carboxamide, decreases. Moreover, quinuclidine-4-carboxamide has high solubility in water. Therefore, from a neutralizing solution containing water, sulfate, and potassium hydroxide, quinuclidine
It is difficult to efficiently separate and purify 4-carboxamide. Furthermore, when the target compound is extracted and isolated using acetone from the residue obtained by dehydration distillation after the neutralization reaction, a large excess amount of acetone is required due to the relationship with the solubility of the target compound, making it difficult to use industrially. disadvantageous to
従って、本発明の目的は、簡単な操作で収率よく、しか
も工業的にキヌクリジン−４−カルボキサミドを得るこ
とができるキヌクリジン−４−カルボキサミドの製造方
法を提供することにある。Accordingly, an object of the present invention is to provide a method for producing quinuclidine-4-carboxamide, which allows quinuclidine-4-carboxamide to be obtained industrially with simple operations and in good yield.
［発明の構成〕
本発明者らは、前記目的を達成すべく鋭意検討の結果、
４−シアノキヌクリジンと濃硫酸との混合液を、アルカ
リと有機溶媒との混合液に添加する場合には、硫酸とア
ルカリとの中和反応により副生する水により、加水分解
反応が円滑に進行し、かつ４−シアノキヌクリジンの分
解を防止できるごと、中和反応により生成した塩を除去
するたけて、キヌクリジン−４−カルボキサミドが収率
よく得られることを見いだし、本発明を完成した。[Structure of the Invention] As a result of intensive studies to achieve the above object, the present inventors have
When adding a mixture of 4-cyanoquinuclidine and concentrated sulfuric acid to a mixture of an alkali and an organic solvent, the water produced by the neutralization reaction between the sulfuric acid and the alkali facilitates the hydrolysis reaction. The inventors have discovered that quinuclidine-4-carboxamide can be obtained in good yield by removing the salt generated by the neutralization reaction and preventing the decomposition of 4-cyanoquinuclidine, thereby completing the present invention. did.
すなわち、本発明は、４−シアノキヌクリジンまたはそ
の塩と硫酸との混合液、又は４−シアノキヌクリジンま
たはその塩の硫酸付加体を、アルカリと有機溶媒との混
合液に添加するキヌクリジン４−カルボキサミドの製造
方法を提供する。That is, the present invention provides quinuclidine in which a mixture of 4-cyanoquinuclidine or a salt thereof and sulfuric acid, or a sulfuric acid adduct of 4-cyanoquinuclidine or a salt thereof is added to a mixture of an alkali and an organic solvent. A method for producing 4-carboxamide is provided.
本発明の製造方法において、４−シアノキヌクリジンは
塩であってもよい。４−シアノキヌクリジンの塩として
は、例えば、鉱酸塩、有機酸塩、スルホン酸塩などが挙
げられる。鉱酸には、例えば、塩酸、硫酸、硝酸、リン
酸、炭酸などが含まれ、有機酸には、例えば、ギ酸、酢
酸、プロピオン酸、酪酸、吉草酸、カプロン酸、シュウ
酸、マロン酸、コハク酸などが含まれる。スルホン酸と
しては、例えば、メタンスルホン酸、エタンスルホン酸
、ベンゼンスルホン酸、ｐ−）ルエンスルホン酸、ナフ
タレンスルホン酸、スルホ安息香酸、フルオロスルホン
酸、クロロスルホン酸、スルファミン酸などが挙げられ
る。In the production method of the present invention, 4-cyanoquinuclidine may be a salt. Examples of the salts of 4-cyanoquinuclidine include mineral acid salts, organic acid salts, and sulfonate salts. Mineral acids include, for example, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, carbonic acid, etc.; organic acids include, for example, formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, oxalic acid, malonic acid, Contains succinic acid. Examples of the sulfonic acid include methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-)luenesulfonic acid, naphthalenesulfonic acid, sulfobenzoic acid, fluorosulfonic acid, chlorosulfonic acid, and sulfamic acid.
硫酸の添加量は、４−シアノキヌクリジン又はその塩１
モルに対して、１．０モル以上であればよいが、加水分
解反応を完結させるためには、好ましくは１〜１０モル
程度である。なお、４−シアノキヌクリジンまたはその
塩１モルに対して、硫酸を１．０モル以上添加すると、
通常、硫酸との付加反応により、４−シアノキヌクリジ
ン硫酸付加体が生成する。また、４−シアノキヌクリジ
ン硫酸付加体は結晶として単離して使用してもよい。The amount of sulfuric acid added is 4-cyanoquinuclidine or its salt 1
The amount may be 1.0 mol or more, but in order to complete the hydrolysis reaction, it is preferably about 1 to 10 mol. In addition, if 1.0 mol or more of sulfuric acid is added to 1 mol of 4-cyanoquinuclidine or its salt,
Usually, an addition reaction with sulfuric acid produces a 4-cyanoquinuclidine sulfate adduct. Further, the 4-cyanoquinuclidine sulfate adduct may be isolated and used as a crystal.
以下、４−シアノキヌクリジン硫酸付加体の取得方法に
つい説明する。The method for obtaining the 4-cyanoquinuclidine sulfate adduct will be described below.
４−シアノキヌクリジン硫酸付加体は、４−シアノキヌ
クリジンまたはその塩と濃硫酸とを混合し、混合液にア
ルコールを添加することにより晶析する。４−シアノキ
ヌクリジンまたはその塩は、そのまま濃硫酸と混合して
もよく、濃硫酸に対して混和性のない有機溶媒溶液に溶
解し、濃硫酸と混合してもよい。このような有機溶媒と
しては、反応に悪影響を及はさない溶媒、例えば、ヘキ
サン、オクタンなどの脂肪族炭化水素；シクロヘキサン
などの脂環族炭化水素；ベンゼン、トルエン、キシレン
などの芳香族炭化水素；ジクロロメタン、四塩化炭素、
エチレンジクロライド、クロロベンゼンなどのハロゲン
化炭化水素などが挙げられる。The 4-cyanoquinuclidine sulfate adduct is crystallized by mixing 4-cyanoquinuclidine or a salt thereof with concentrated sulfuric acid and adding alcohol to the mixture. 4-cyanoquinuclidine or a salt thereof may be mixed with concentrated sulfuric acid as it is, or may be dissolved in an organic solvent solution that is immiscible with concentrated sulfuric acid and mixed with concentrated sulfuric acid. Examples of such organic solvents include solvents that do not adversely affect the reaction, such as aliphatic hydrocarbons such as hexane and octane; alicyclic hydrocarbons such as cyclohexane; aromatic hydrocarbons such as benzene, toluene, and xylene. ; dichloromethane, carbon tetrachloride,
Examples include halogenated hydrocarbons such as ethylene dichloride and chlorobenzene.
これらの有機溶媒は、一種又は二種以上の混合液として
使用できる。これらの有機溶媒の中で、トルエンなどの
芳香族炭化水素が好ましい。有機溶媒中の４−シアノキ
ヌクリジンの濃度は特に制限されないが、通常、５〜５
０重量％、好ましくは１０〜４０重量％程度である。These organic solvents can be used alone or as a mixture of two or more. Among these organic solvents, aromatic hydrocarbons such as toluene are preferred. The concentration of 4-cyanoquinuclidine in the organic solvent is not particularly limited, but is usually 5 to 5.
It is about 0% by weight, preferably about 10 to 40% by weight.
４−シアノキヌクリジンまたはその塩の有機溶媒溶液と
濃硫酸とを混合する場合には、取扱いが容易であり、か
つ有機溶媒層と濃硫酸層との界面で付加反応が円滑に進
行する。When an organic solvent solution of 4-cyanoquinuclidine or a salt thereof and concentrated sulfuric acid are mixed, handling is easy and addition reaction proceeds smoothly at the interface between the organic solvent layer and the concentrated sulfuric acid layer.
４−シアノキヌクリジンまたはその塩の硫酸付加体を得
る場合、硫酸の量は、付加反応性を阻害せず、しかも硫
酸付加体の収量が低下しない範囲で選択でき、例えば、
４−シアノキヌクリジン又はその塩１モルに対して、濃
硫酸１．５モル以上、好ましくは２〜１０モル、更に好
ましくは４〜７モル程度である。濃硫酸の量が１．５モ
ル未満である場合には、硫酸の付加反応性が低下し易く
、１０モルを越える場合には、硫酸付加体の収量か低下
し易い。When obtaining a sulfuric acid adduct of 4-cyanoquinuclidine or a salt thereof, the amount of sulfuric acid can be selected within a range that does not inhibit the addition reactivity and does not reduce the yield of the sulfuric acid adduct, for example,
The amount of concentrated sulfuric acid is 1.5 mol or more, preferably 2 to 10 mol, more preferably about 4 to 7 mol, per 1 mol of 4-cyanoquinuclidine or its salt. If the amount of concentrated sulfuric acid is less than 1.5 moles, the addition reactivity of sulfuric acid tends to decrease, and if it exceeds 10 moles, the yield of the sulfuric acid adduct tends to decrease.
４−シアノキヌクリジンまたはその塩と濃硫酸との反応
温度は、広い範囲、例えば−１０〜７５℃程度の範囲で
選択できるが、作業性を高めるため、室温で行なっても
よい。反応は、撹拌下、例えば３０分〜２４時間程度で
完了する。The reaction temperature between 4-cyanoquinuclidine or its salt and concentrated sulfuric acid can be selected within a wide range, for example, from about -10 to 75°C, but in order to improve workability, the reaction may be carried out at room temperature. The reaction is completed under stirring, for example, in about 30 minutes to 24 hours.
そして、４−シアノキヌクリジンまたはその塩と濃硫酸
との反応液にアルコールを添加し、４シアノキヌクリジ
ン硫酸付加体を晶析させる。この方法により、４−シア
ノキヌクリジン硫酸付加体が高純度かつ高収率で晶析す
る。Then, alcohol is added to the reaction solution of 4-cyanoquinuclidine or its salt and concentrated sulfuric acid to crystallize the 4-cyanoquinuclidine sulfate adduct. By this method, the 4-cyanoquinuclidine sulfate adduct is crystallized with high purity and high yield.
アルコールとしては、例えば、エタノール、プロパツー
ル、イソプロパツール、ブタノール、イソブタノール、
ｔ−ブタノール、ペンタノール、ヘキサノール、オクタ
ツールなどの一価のアルコ−°ル：エチレングリコール
、ジエチレングリコール、トリエチレングリコール、ポ
リエチレングリコール、プロピレングリコール、ジプロ
ピレングリコール、トリプロピレンクリコール、ポリエ
チレングリコールなどの二価アルコール、グリセリンな
どの多価アルコールなどが挙げられる。これらのアルコ
ールは一種又は二種以上混合して使用できる。また、こ
れらのアルコールはメタツルと併用してもよい。４−シ
アノキヌクリジン硫酸付加体の純度及び収率を高めるた
めには、アルコールの添加に際して、メタノールを除く
他のアルコール；これらのアルコールとメタノールとの
混合液を添加するのが好ましい。これらのアルコールの
中で、メタノールを除（−価のアルコール、特に炭素数
２〜８のアルコール；炭素数２〜８のアルコールとメタ
ノールとの混合液が好ましい。Examples of alcohol include ethanol, propatool, isoproptool, butanol, isobutanol,
Monohydric alcohols such as t-butanol, pentanol, hexanol, and octatool; divalent alcohols such as ethylene glycol, diethylene glycol, triethylene glycol, polyethylene glycol, propylene glycol, dipropylene glycol, tripropylene glycol, and polyethylene glycol; Examples include polyhydric alcohols and polyhydric alcohols such as glycerin. These alcohols can be used singly or in combination. Further, these alcohols may be used in combination with Metazuru. In order to increase the purity and yield of the 4-cyanoquinuclidine sulfate adduct, it is preferable to add an alcohol other than methanol or a mixture of these alcohols and methanol when adding the alcohol. Among these alcohols, excluding methanol (-hydric alcohols, particularly alcohols having 2 to 8 carbon atoms; a mixture of an alcohol having 2 to 8 carbon atoms and methanol is preferred.
特に好ましいアルコールは、エタノール、イソプロパツ
ール、ブタノールなどの炭素数２〜４の一価のアルコー
ル：炭素数２〜４の一価のアルコールとメタノールとの
混合液である。Particularly preferred alcohols are monohydric alcohols with 2 to 4 carbon atoms such as ethanol, isopropanol, and butanol: a mixture of monohydric alcohols with 2 to 4 carbon atoms and methanol.
アルコールの添加量は、晶析系の温度により変化するの
で一概に決定てきないが、反応液の４シアノキヌクリジ
ン１モルに対して、１００〜３０００ｇ程度である。The amount of alcohol to be added cannot be absolutely determined because it varies depending on the temperature of the crystallization system, but it is approximately 100 to 3000 g per mole of 4-cyanoquinuclidine in the reaction solution.
メタノールと他のアルコールとを添加する場合、反応液
の４−シアノキヌクリジン１モルに対するメタノールの
添加量は、５０ｇ以上、好ましくは１００ｇ以上であれ
ばよい。４−シアノキヌクリジン１モルに対するメタノ
ールの好ましい添加量は、１００〜１０００ｇ、さらに
好ましくは１２０〜７５０ｇ程度である。メタノールの
使用量を低減する場合には、１２０〜２００ｇ程度が好
ましい。メタノール以外のアルコールの添加量は、硫酸
付加体を晶析できる限り特に制限されないが、通常、４
−シアノキヌクリジン１モルに対して、５０〜２０００
ｇ、好ましくは１００〜１５００ｇ程度である。メタノ
ール以外のアルコールの添加量が少な過ぎる場合には、
収率が低下し易い。When methanol and other alcohol are added, the amount of methanol added per mole of 4-cyanoquinuclidine in the reaction solution may be 50 g or more, preferably 100 g or more. The preferred amount of methanol added per mole of 4-cyanoquinuclidine is about 100 to 1000 g, more preferably about 120 to 750 g. When reducing the amount of methanol used, it is preferably about 120 to 200 g. The amount of alcohol other than methanol is not particularly limited as long as the sulfuric acid adduct can be crystallized, but usually 4
-50 to 2000 per mole of cyanoquinuclidine
g, preferably about 100 to 1500 g. If the amount of alcohol other than methanol added is too small,
Yield tends to decrease.
晶析温度は、硫酸付加体の晶析および純度を損わない範
囲であればよい。晶析温度は、例えば、３．５℃以下で
ある。晶析温度が３５℃を越える場合には、硫酸付加体
かアルコールと反応し易く、純度が低下し易い。The crystallization temperature may be within a range that does not impair the crystallization and purity of the sulfuric acid adduct. The crystallization temperature is, for example, 3.5°C or lower. When the crystallization temperature exceeds 35°C, the sulfuric acid adduct tends to react with alcohol, and the purity tends to decrease.
晶析物を、慣用の分離手段、例えば、遠心分離、濾過な
どに供し、蒸発乾固することにより、純度の高い４−シ
アノキヌクリジン硫酸付加体が得られる。硫酸付加体の
好ましい回収方法は、簡便な濾過である。A highly pure 4-cyanoquinuclidine sulfate adduct can be obtained by subjecting the crystallized product to conventional separation means, such as centrifugation and filtration, and evaporating to dryness. A preferred method for recovering the sulfuric acid adduct is simple filtration.
なお、前記アルコールとして、多価アルコールなどの高
沸点のアルコールを使用する場合、沸点の低いアルコー
ルで、晶析物を洗浄して高沸点のアルコールを除去した
後、晶析物を乾固させてもよい。In addition, when using a high boiling point alcohol such as a polyhydric alcohol as the alcohol, the crystallized product is washed with a low boiling point alcohol to remove the high boiling point alcohol, and then the crystallized product is dried. Good too.
本発明の特徴は、４−シアノキヌクリジンまたはその塩
と硫酸との混合液、又は前記硫酸付加体を、アルカリと
有機溶媒との混合液に添加する点にある。この方法によ
り、中和反応により副生する水を加水分解反応に利用で
きる。A feature of the present invention is that a mixture of 4-cyanoquinuclidine or its salt and sulfuric acid, or the sulfuric acid adduct, is added to a mixture of an alkali and an organic solvent. With this method, water produced as a by-product of the neutralization reaction can be used for the hydrolysis reaction.
アルカリとしては、硫酸との中和反応により水が副生ず
る化合物であればよく、有機アルカリであってもよいが
、無機アルカリか好ましい。このようなアルカリとして
は、例えば、水酸化ナトリウム、水酸化カリウム、水酸
化リチウムなどのアルカリ金属の水酸化物：炭酸ナトリ
ウム、炭酸力１ウムなどのアルカリ金属の炭酸塩、炭酸
水素ナトリウム、炭酸水素カリウムなどのアルカリ金属
の炭酸水素塩；水酸化マグネシウム、水酸化カルシウム
、水酸化ストロンチウム、水酸化バリウムなどのアルカ
リ土類金属の水酸化物、炭酸マグネシウム、炭酸カルシ
ウム、炭酸バリウムなとのアルカリ土類金属の炭酸塩：
炭酸水素マグネシウムなどのアルカリ土類金属の炭酸水
素塩：これらの化合物の複塩などが挙げられる。The alkali may be any compound that produces water as a by-product through a neutralization reaction with sulfuric acid, and may be an organic alkali, but preferably an inorganic alkali. Such alkalis include, for example, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, and lithium hydroxide; alkali metal carbonates such as sodium carbonate and 1 um carbonate; sodium hydrogen carbonate; and hydrogen carbonate. Bicarbonates of alkali metals such as potassium; hydroxides of alkaline earth metals such as magnesium hydroxide, calcium hydroxide, strontium hydroxide, barium hydroxide; alkaline earth metals such as magnesium carbonate, calcium carbonate, and barium carbonate. Metal carbonates:
Examples include alkaline earth metal hydrogen carbonates such as magnesium hydrogen carbonate: double salts of these compounds.
これらのアルカリは少なくとも一種使用される。At least one of these alkalis is used.
アルカリの使用量は、４−シアノキヌクリジン又はその
塩と硫酸との混合液または硫酸付加体を少なくとも中和
するのに必要な量であればよく、通常、前記混合液又は
硫酸付加体に含まれる硫酸量に対して等モル以上である
。The amount of alkali to be used is just the amount necessary to at least neutralize the mixture of 4-cyanoquinuclidine or its salt and sulfuric acid or the sulfuric acid adduct, and usually, it is sufficient to neutralize the mixture or the sulfuric acid adduct. The amount is equal to or more than the amount of sulfuric acid contained.
有機溶媒としては、例えば、ヘキサン、オクタノなどの
脂肪族炭化水素類；シクロヘキサンなどの脂環族炭化水
素類：ベンゼン、トルエン、キシレンなどの芳香族炭化
水素類：メタノール、エタノール、イソプロパツール、
プロパツール、ブタノール、シクロヘキサノールなとの
アルコール類ニジクロロメタン、四塩化炭素、エチレン
ジクロライド、クロロベンセンなどのハロゲン化炭化水
素類；酢酸メチル、酢酸エチルなどのエステル類アセト
ン、メチルエチルケトンなどのケトン類；ジオキサン、
ジエチルエーテル、テトラヒドロフランなどのエーテル
類；アセトニトリル、Ｎ、 Ｎジメチルホルムアミド、
ジメチルスルホキシドなどの非プロトン性極性溶媒：お
よびこれらの混合溶媒が挙げられる。Examples of organic solvents include aliphatic hydrocarbons such as hexane and octano; alicyclic hydrocarbons such as cyclohexane; aromatic hydrocarbons such as benzene, toluene, and xylene; methanol, ethanol, isopropanol,
Alcohols such as propatool, butanol, and cyclohexanol; Halogenated hydrocarbons such as dichloromethane, carbon tetrachloride, ethylene dichloride, and chlorobenzene; Esters such as methyl acetate and ethyl acetate; Ketones such as acetone and methyl ethyl ketone; Dioxane ,
Ethers such as diethyl ether and tetrahydrofuran; acetonitrile, N, N dimethylformamide,
Examples include aprotic polar solvents such as dimethyl sulfoxide and mixed solvents thereof.
前記アルカリと有機溶媒は、中和反応により生成する硫
酸塩が有機溶媒に対して溶解度が小さいので、適宜組合
せて使用でき、生成した硫酸塩を濾別により、容易に除
去できる。アルカリと有機溶媒との組合せは、例えば、
アルカリ土類金属の水酸化物などのように、中和反応に
より生成する硫酸塩が有機溶媒に対して不溶乃至難溶と
なる組合せか好ましい。なお、アルカリと有機溶媒との
混合液は、均一な溶液状であってもよく、懸濁状やスラ
リー状てあってもよい。また、前記混合液は、キヌクリ
ジン−４−カルボキサミドの収率を低下させず、単離操
作が煩雑化しない範囲であれば、水分を含んでいてもよ
い。The alkali and organic solvent can be used in appropriate combinations since the sulfate produced by the neutralization reaction has low solubility in the organic solvent, and the sulfate produced can be easily removed by filtration. The combination of alkali and organic solvent is, for example,
Combinations such as alkaline earth metal hydroxides in which the sulfate produced by the neutralization reaction is insoluble or sparingly soluble in organic solvents are preferred. The mixed liquid of the alkali and the organic solvent may be in the form of a uniform solution, suspension, or slurry. Further, the liquid mixture may contain water as long as it does not reduce the yield of quinuclidine-4-carboxamide and does not complicate the isolation operation.
アルカリと有機溶媒との混合液に対する４−シアノキヌ
クリジンの硫酸混合液や硫酸付加体の添加温度は、前記
有機溶媒の還流温度以下であればよく、有機溶媒の種類
に応して選択できる。例えば、有機溶媒かメタノール及
びエタノールの場合には、３０℃以下の温度で添加する
のが好ましい。The temperature at which the sulfuric acid mixture or sulfuric acid adduct of 4-cyanoquinuclidine is added to the mixture of alkali and organic solvent may be below the reflux temperature of the organic solvent and can be selected depending on the type of organic solvent. . For example, in the case of organic solvents such as methanol and ethanol, it is preferable to add them at a temperature of 30° C. or lower.
添加温度が高くなるにつれて、通常、キヌクリジン−４
−カルボキサミドの収率が低下し易い。As the addition temperature increases, typically quinuclidine-4
- The yield of carboxamide tends to decrease.
この中和反応は、通常、短時間内に終了すると共に、副
生じた水により、４−シアノキヌクリジンか加水分解さ
れ、キヌクリジン−４−カルボキサミドが生成する。こ
の場合、中和反応により副生じた水を４−シアノキヌク
リジンの加水分解反〆に利用できるので、４−カルボキ
シキヌクリジンなどの副生を著しく抑制できる。生成し
たキヌクリジン−４−カルボキサミドは、慣用の分離方
法、例えば、濾過、蒸留、乾固、再結晶法、溶媒抽出法
やこれらを組合わせた簡便な方法で容易に単離できる。This neutralization reaction usually ends within a short time, and 4-cyanoquinuclidine is hydrolyzed by the by-produced water to produce quinuclidine-4-carboxamide. In this case, since the water produced as a by-product by the neutralization reaction can be used for the hydrolysis reaction of 4-cyanoquinuclidine, the production of by-products such as 4-carboxyquinuclidine can be significantly suppressed. The produced quinuclidine-4-carboxamide can be easily isolated by a conventional separation method, such as filtration, distillation, drying, recrystallization, solvent extraction, or a simple method combining these methods.
なお、カラムクロマトグラフィーなどの方法により、キ
ヌクリジン−４−カルボキサミドを単離してもよい。Incidentally, quinuclidine-4-carboxamide may be isolated by a method such as column chromatography.
［発明の効果］
本発明は、キヌクリジン−４−カルボキサミドを簡単な
操作で収率よく、しかも工業的に得ることができる。[Effects of the Invention] According to the present invention, quinuclidine-4-carboxamide can be obtained industrially with a simple operation and in good yield.
［実施例］
以下に、実施例に基づいて本発明をより詳細に説明する
。[Examples] The present invention will be described in more detail below based on Examples.
実施例１
４−シアノキヌクリジン６．８ｇ （０，０５モル）を
濃硫酸２２ｇに、室温で添加し、４０℃にて２時間撹拌
した。この反応液を、展開剤（クロロホルム／メタノー
ル＝９／１）を用いた薄層クロマトグラフィー および
高速液体クロマトグラフィーに供したところ、４−シア
ノキヌクリジンのスポットは消失していた。反応液中に
は、生成した４−シアノキヌクリジン硫酸付加体が溶解
している。得られた反応液を、メタノール１００ｇ及び
水酸化カルシウム１８ｇからなるスラリー状混合液に、
２０℃で滴下したところ、中和反応が瞬時に完結すると
共に、中和反応液中に沈澱物か生成した。沈澱物を濾別
し、濾液を蒸留・乾固したところ、キヌクリジン−４−
カルボキサミドロ。Example 1 6.8 g (0.05 mol) of 4-cyanoquinuclidine was added to 22 g of concentrated sulfuric acid at room temperature and stirred at 40°C for 2 hours. When this reaction solution was subjected to thin layer chromatography and high performance liquid chromatography using a developing agent (chloroform/methanol = 9/1), the 4-cyanoquinuclidine spot had disappeared. The produced 4-cyanoquinuclidine sulfate adduct is dissolved in the reaction solution. The obtained reaction solution was added to a slurry mixture consisting of 100 g of methanol and 18 g of calcium hydroxide.
When added dropwise at 20°C, the neutralization reaction was completed instantly and a precipitate was formed in the neutralization reaction solution. When the precipitate was filtered and the filtrate was distilled and dried, quinuclidine-4-
Carboxamidro.
７ｇ（収率８７．１％）が得られた。7 g (yield 87.1%) was obtained.
実施例２
４−シアノキヌクリジンのトシル酸塩１８．５ｇ （０
，０６モル）を濃硫酸２９ｇに、室温で添加し、４０℃
にて２時間撹拌した。得られた反応混合液を、アセトニ
トリル１２０ｇ及び水酸化カルシウム２３ｇからなるス
ラリー状混合液に、２０℃で滴下しながら添加し、さら
に昇温しで７０℃て４時間撹拌した後、室温まで冷却し
た。中和反応液中の沈澱物を濾別したところ、得られた
残渣は硫酸カルシウムとキヌクリジン−４−カルボキサ
ミドと混合物であった。残渣をメタノール５０ｇで抽出
・洗浄し、洗浄液を蒸留・乾固したところ、キヌクリジ
ン−４−カルボキサミドア、３ｇ（収率７８，９％）か
得られた。Example 2 Tosylate of 4-cyanoquinuclidine 18.5g (0
, 06 mol) to 29 g of concentrated sulfuric acid at room temperature, and heated at 40°C.
The mixture was stirred for 2 hours. The obtained reaction mixture was added dropwise to a slurry mixture containing 120 g of acetonitrile and 23 g of calcium hydroxide at 20°C, the temperature was further raised to 70°C, and the mixture was stirred for 4 hours, and then cooled to room temperature. . When the precipitate in the neutralization reaction solution was filtered, the resulting residue was a mixture of calcium sulfate and quinuclidine-4-carboxamide. The residue was extracted and washed with 50 g of methanol, and the washing liquid was distilled and dried to obtain 3 g (yield: 78.9%) of quinuclidine-4-carboxamidore.
なお、中和反応後の濾液中には、キヌクリジン−４−カ
ルボキサミド】、１ｇか溶解していた。Incidentally, 1 g of quinuclidine-4-carboxamide was dissolved in the filtrate after the neutralization reaction.
濾液中のキヌクリジン−４−カルボキサミドは、蒸留・
乾固により回収できる。また、濾液は前記と同様な工程
にそのままリサイクルできる。Quinuclidine-4-carboxamide in the filtrate is distilled and
It can be recovered by drying. Further, the filtrate can be directly recycled into the same process as described above.
Claims (1)
合液、又は４−シアノキヌクリジンまたはその塩の硫酸
付加体を、アルカリと有機溶媒との混合液に添加するキ
ヌクリジン−４−カルボキサミドの製造方法。 ２、アルカリが、アルカリ金属又はアルカリ土類金属の
水酸化物、炭酸塩及び炭酸水素塩からなる群から選択さ
れた少なくとも一種の成分である請求項１記載のキヌク
リジン−４−カルボキサミドの製造方法。[Claims] Addition of a mixture of 1,4-cyanoquinuclidine or its salt and sulfuric acid, or a sulfuric acid adduct of 4-cyanoquinuclidine or its salt to a mixture of an alkali and an organic solvent. A method for producing quinuclidine-4-carboxamide. 2. The method for producing quinuclidine-4-carboxamide according to claim 1, wherein the alkali is at least one component selected from the group consisting of hydroxides, carbonates, and hydrogen carbonates of alkali metals or alkaline earth metals.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP26429190A JPH04139183A (en) | 1990-10-01 | 1990-10-01 | Production of quinuclidine-4-carboxamide |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP26429190A JPH04139183A (en) | 1990-10-01 | 1990-10-01 | Production of quinuclidine-4-carboxamide |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH04139183A true JPH04139183A (en) | 1992-05-13 |
Family
ID=17401127
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP26429190A Pending JPH04139183A (en) | 1990-10-01 | 1990-10-01 | Production of quinuclidine-4-carboxamide |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH04139183A (en) |
-
1990
- 1990-10-01 JP JP26429190A patent/JPH04139183A/en active Pending
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