JP2007119418A - ベンジルオキシ含窒素環状化合物の製造法 - Google Patents
ベンジルオキシ含窒素環状化合物の製造法 Download PDFInfo
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- JP2007119418A JP2007119418A JP2005315791A JP2005315791A JP2007119418A JP 2007119418 A JP2007119418 A JP 2007119418A JP 2005315791 A JP2005315791 A JP 2005315791A JP 2005315791 A JP2005315791 A JP 2005315791A JP 2007119418 A JP2007119418 A JP 2007119418A
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- Japan
- Prior art keywords
- nitrogen
- group
- benzyloxy
- containing cyclic
- cyclic compound
- 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.)
- Granted
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- XATKTZSGLJUBMR-UHFFFAOYSA-N [N]OCc1ccccc1 Chemical compound [N]OCc1ccccc1 XATKTZSGLJUBMR-UHFFFAOYSA-N 0.000 title claims abstract description 31
- 150000001923 cyclic compounds Chemical class 0.000 title claims abstract description 31
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 18
- -1 nitrogen-containing cyclic alcohol derivative Chemical class 0.000 claims abstract description 48
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims abstract description 36
- 238000000034 method Methods 0.000 claims abstract description 20
- 239000002904 solvent Substances 0.000 claims abstract description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 13
- 239000001257 hydrogen Substances 0.000 claims abstract description 13
- 125000003302 alkenyloxy group Chemical group 0.000 claims abstract description 9
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 9
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 9
- 125000002102 aryl alkyloxo group Chemical group 0.000 claims abstract description 7
- 125000003118 aryl group Chemical group 0.000 claims abstract description 7
- 150000001555 benzenes Chemical group 0.000 claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims description 43
- 125000004432 carbon atom Chemical group C* 0.000 claims description 18
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 9
- 239000000126 substance Substances 0.000 claims description 8
- 230000002378 acidificating effect Effects 0.000 claims description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 3
- 239000012295 chemical reaction liquid Substances 0.000 claims 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract description 3
- 229910052783 alkali metal Inorganic materials 0.000 abstract description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 abstract description 2
- 150000001340 alkali metals Chemical class 0.000 abstract 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- 239000000243 solution Substances 0.000 description 15
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 12
- 229940073608 benzyl chloride Drugs 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 125000004122 cyclic group Chemical group 0.000 description 7
- 150000002431 hydrogen Chemical class 0.000 description 7
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 238000005574 benzylation reaction Methods 0.000 description 6
- CWBMYKUPMLRKQK-UHFFFAOYSA-N 3-phenylmethoxypyrrolidine Chemical compound C=1C=CC=CC=1COC1CCNC1 CWBMYKUPMLRKQK-UHFFFAOYSA-N 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- ROYJGLFMGPICMM-UHFFFAOYSA-N 2-phenylmethoxyazetidine Chemical compound C(C1=CC=CC=C1)OC1NCC1 ROYJGLFMGPICMM-UHFFFAOYSA-N 0.000 description 4
- ILJHWVWEYBJDDM-UHFFFAOYSA-N 4-phenylmethoxypiperidine Chemical compound C=1C=CC=CC=1COC1CCNCC1 ILJHWVWEYBJDDM-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- JHHZLHWJQPUNKB-SCSAIBSYSA-N (3r)-pyrrolidin-3-ol Chemical compound O[C@@H]1CCNC1 JHHZLHWJQPUNKB-SCSAIBSYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 230000009257 reactivity Effects 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- APCBTRDHCDOPNY-UHFFFAOYSA-N tert-butyl 3-hydroxypyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(O)C1 APCBTRDHCDOPNY-UHFFFAOYSA-N 0.000 description 3
- VOVVHNIABAJHJZ-UHFFFAOYSA-N 3-phenylmethoxypiperidine Chemical compound C=1C=CC=CC=1COC1CCCNC1 VOVVHNIABAJHJZ-UHFFFAOYSA-N 0.000 description 2
- QEKAHXVPQJMWQN-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1C(CC1)OCC1=CC=CC=C1 Chemical compound C(C)(C)(C)OC(=O)N1C(CC1)OCC1=CC=CC=C1 QEKAHXVPQJMWQN-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 238000010306 acid treatment Methods 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 230000032683 aging Effects 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 2
- JXTHNDFMNIQAHM-UHFFFAOYSA-N dichloroacetic acid Chemical compound OC(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-N 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
- 239000012535 impurity Substances 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 230000020477 pH reduction Effects 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- YRRKTNRXKPWPET-UHFFFAOYSA-N tert-butyl 2-hydroxyazetidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC1O YRRKTNRXKPWPET-UHFFFAOYSA-N 0.000 description 2
- SNDPVESSAGLHJB-UHFFFAOYSA-N tert-butyl 3-phenylmethoxypyrrolidine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCC1OCC1=CC=CC=C1 SNDPVESSAGLHJB-UHFFFAOYSA-N 0.000 description 2
- CRFSWDBNKHNGGA-UHFFFAOYSA-N tert-butyl 4-hydroxyazepane-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCC(O)CC1 CRFSWDBNKHNGGA-UHFFFAOYSA-N 0.000 description 2
- PWQLFIKTGRINFF-UHFFFAOYSA-N tert-butyl 4-hydroxypiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(O)CC1 PWQLFIKTGRINFF-UHFFFAOYSA-N 0.000 description 2
- BRCKRGMQJJSBCG-UHFFFAOYSA-N tert-butyl 4-phenylmethoxyazepane-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCCC1OCC1=CC=CC=C1 BRCKRGMQJJSBCG-UHFFFAOYSA-N 0.000 description 2
- GKGCPWOZAGTHMX-UHFFFAOYSA-N (4-hydroxypiperidin-1-yl)-(4-nitrophenyl)methanone Chemical compound C1CC(O)CCN1C(=O)C1=CC=C([N+]([O-])=O)C=C1 GKGCPWOZAGTHMX-UHFFFAOYSA-N 0.000 description 1
- FWLWTILKTABGKQ-UHFFFAOYSA-N 1-(bromomethyl)-3-methylbenzene Chemical compound CC1=CC=CC(CBr)=C1 FWLWTILKTABGKQ-UHFFFAOYSA-N 0.000 description 1
- GYFDUIHVBNYYFE-UHFFFAOYSA-N 1-(bromomethyl)-3-propan-2-ylbenzene Chemical compound CC(C)C1=CC=CC(CBr)=C1 GYFDUIHVBNYYFE-UHFFFAOYSA-N 0.000 description 1
- VQRBXYBBGHOGFT-UHFFFAOYSA-N 1-(chloromethyl)-2-methylbenzene Chemical compound CC1=CC=CC=C1CCl VQRBXYBBGHOGFT-UHFFFAOYSA-N 0.000 description 1
- DUBCVXSYZVTCOC-UHFFFAOYSA-N 1-(chloromethyl)-4-ethylbenzene Chemical compound CCC1=CC=C(CCl)C=C1 DUBCVXSYZVTCOC-UHFFFAOYSA-N 0.000 description 1
- DMHZDOTYAVHSEH-UHFFFAOYSA-N 1-(chloromethyl)-4-methylbenzene Chemical compound CC1=CC=C(CCl)C=C1 DMHZDOTYAVHSEH-UHFFFAOYSA-N 0.000 description 1
- GJUMZNFPQSOVCL-UHFFFAOYSA-N 1-phenylmethoxypiperidine Chemical class C=1C=CC=CC=1CON1CCCCC1 GJUMZNFPQSOVCL-UHFFFAOYSA-N 0.000 description 1
- CRMFPAIIUYIHIL-UHFFFAOYSA-N 1-propan-2-yloxypiperidin-3-ol Chemical compound C(C)(C)ON1CC(CCC1)O CRMFPAIIUYIHIL-UHFFFAOYSA-N 0.000 description 1
- WAXIFMGAKWIFDQ-UHFFFAOYSA-N 1-tert-butyl-4-(chloromethyl)benzene Chemical compound CC(C)(C)C1=CC=C(CCl)C=C1 WAXIFMGAKWIFDQ-UHFFFAOYSA-N 0.000 description 1
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 1
- JRZGVPGPRWXFDM-UHFFFAOYSA-N 2-hydroxyazetidine-1-carbaldehyde Chemical compound OC1CCN1C=O JRZGVPGPRWXFDM-UHFFFAOYSA-N 0.000 description 1
- XWYMWPRUBQGGOZ-UHFFFAOYSA-N 2-hydroxypiperidine-1-carbaldehyde Chemical compound OC1CCCCN1C=O XWYMWPRUBQGGOZ-UHFFFAOYSA-N 0.000 description 1
- AZXQGKUOXUFORU-UHFFFAOYSA-N 2-hydroxypyrrolidine-1-carbaldehyde Chemical compound OC1CCCN1C=O AZXQGKUOXUFORU-UHFFFAOYSA-N 0.000 description 1
- LYZCLVPWIVNKHJ-UHFFFAOYSA-N 2-phenylmethoxypiperidine Chemical compound C=1C=CC=CC=1COC1CCCCN1 LYZCLVPWIVNKHJ-UHFFFAOYSA-N 0.000 description 1
- PVJGUKGYBZCDOH-UHFFFAOYSA-N 2-phenylmethoxypyrrolidine Chemical compound C=1C=CC=CC=1COC1CCCN1 PVJGUKGYBZCDOH-UHFFFAOYSA-N 0.000 description 1
- PFIAMJBVZHAKEV-UHFFFAOYSA-N 2-phenylmethoxypyrrolidine-1-carbaldehyde Chemical compound C(=O)N1C(CCC1)OCC1=CC=CC=C1 PFIAMJBVZHAKEV-UHFFFAOYSA-N 0.000 description 1
- BXLCENGNDVFRAZ-UHFFFAOYSA-N 3-hydroxyazetidine-1-carbaldehyde Chemical compound OC1CN(C=O)C1 BXLCENGNDVFRAZ-UHFFFAOYSA-N 0.000 description 1
- XTFVHMIHMKMJMH-UHFFFAOYSA-N 3-hydroxypiperidine-1-carbaldehyde Chemical compound OC1CCCN(C=O)C1 XTFVHMIHMKMJMH-UHFFFAOYSA-N 0.000 description 1
- HDACDDSPBQTVCH-UHFFFAOYSA-N 3-hydroxypyrrolidine-1-carbaldehyde Chemical compound OC1CCN(C=O)C1 HDACDDSPBQTVCH-UHFFFAOYSA-N 0.000 description 1
- FGZCCEDRDCVGEP-UHFFFAOYSA-N 3-phenylmethoxy-1-propan-2-yloxypiperidine Chemical compound C(C)(C)ON1CC(CCC1)OCC1=CC=CC=C1 FGZCCEDRDCVGEP-UHFFFAOYSA-N 0.000 description 1
- FJVSSNCNHKAMHI-UHFFFAOYSA-N 3-phenylmethoxyazetidine Chemical compound C=1C=CC=CC=1COC1CNC1 FJVSSNCNHKAMHI-UHFFFAOYSA-N 0.000 description 1
- OLGSVXNKRSYYTD-UHFFFAOYSA-N 3-phenylmethoxyazetidine-1-carbaldehyde Chemical compound C(=O)N1CC(C1)OCC1=CC=CC=C1 OLGSVXNKRSYYTD-UHFFFAOYSA-N 0.000 description 1
- XREIECZSECBSCQ-UHFFFAOYSA-N 3-phenylmethoxypyrrolidine-1-carbaldehyde Chemical compound C1N(C=O)CCC1OCC1=CC=CC=C1 XREIECZSECBSCQ-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
- OXCVNPHTSWKTBC-UHFFFAOYSA-N 4-hydroxypiperidine-1-carbaldehyde Chemical compound OC1CCN(C=O)CC1 OXCVNPHTSWKTBC-UHFFFAOYSA-N 0.000 description 1
- QZYFNCLJBXXYFP-UHFFFAOYSA-N 4-phenylmethoxyazepane Chemical compound C=1C=CC=CC=1COC1CCCNCC1 QZYFNCLJBXXYFP-UHFFFAOYSA-N 0.000 description 1
- DRJAHUBPUQWWQL-UHFFFAOYSA-N 4-phenylmethoxypiperidine-1-carbaldehyde Chemical compound C1CN(C=O)CCC1OCC1=CC=CC=C1 DRJAHUBPUQWWQL-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- ZFKGKAQDSIORKN-UHFFFAOYSA-N C(=O)N1C(CC1)OCC1=CC=CC=C1 Chemical compound C(=O)N1C(CC1)OCC1=CC=CC=C1 ZFKGKAQDSIORKN-UHFFFAOYSA-N 0.000 description 1
- WHIQENVZTRZKQU-UHFFFAOYSA-N C(=O)N1CC(CCC1)OCC1=CC=CC=C1 Chemical compound C(=O)N1CC(CCC1)OCC1=CC=CC=C1 WHIQENVZTRZKQU-UHFFFAOYSA-N 0.000 description 1
- ABTRRWOZDCUEJT-UHFFFAOYSA-N C1CC(CCN(C1)C=O)OCC2=CC=CC=C2 Chemical compound C1CC(CCN(C1)C=O)OCC2=CC=CC=C2 ABTRRWOZDCUEJT-UHFFFAOYSA-N 0.000 description 1
- XBMWGVIMXDLOJJ-SYPWQXSBSA-N NC1[C@@H](CI)C1 Chemical compound NC1[C@@H](CI)C1 XBMWGVIMXDLOJJ-SYPWQXSBSA-N 0.000 description 1
- XQGCNPDIEFHWOH-UHFFFAOYSA-N OC1CCCN(CC1)C=O Chemical compound OC1CCCN(CC1)C=O XQGCNPDIEFHWOH-UHFFFAOYSA-N 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000005456 alcohol based solvent Substances 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- JKIUUDJOCYHIGY-UHFFFAOYSA-N benzyl 4-hydroxypiperidine-1-carboxylate Chemical compound C1CC(O)CCN1C(=O)OCC1=CC=CC=C1 JKIUUDJOCYHIGY-UHFFFAOYSA-N 0.000 description 1
- MBXXQYJBFRRFCK-UHFFFAOYSA-N benzyl fluoride Chemical compound FCC1=CC=CC=C1 MBXXQYJBFRRFCK-UHFFFAOYSA-N 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 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
- 238000010511 deprotection reaction Methods 0.000 description 1
- 229960005215 dichloroacetic acid Drugs 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- AQCCUQNJHACLSY-UHFFFAOYSA-N ethyl 3-hydroxypyrrolidine-1-carboxylate Chemical compound CCOC(=O)N1CCC(O)C1 AQCCUQNJHACLSY-UHFFFAOYSA-N 0.000 description 1
- WWIOQNHFHGFDSL-UHFFFAOYSA-N ethyl 3-phenylmethoxypyrrolidine-1-carboxylate Chemical compound C1N(C(=O)OCC)CCC1OCC1=CC=CC=C1 WWIOQNHFHGFDSL-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000010813 internal standard method Methods 0.000 description 1
- XJTQJERLRPWUGL-UHFFFAOYSA-N iodomethylbenzene Chemical compound ICC1=CC=CC=C1 XJTQJERLRPWUGL-UHFFFAOYSA-N 0.000 description 1
- NDCSCYJKWHOTCY-UHFFFAOYSA-N methyl 2-hydroxyazetidine-1-carboxylate Chemical compound COC(=O)N1C(CC1)O NDCSCYJKWHOTCY-UHFFFAOYSA-N 0.000 description 1
- OVQYYLMTELZSJH-UHFFFAOYSA-N methyl 2-phenylmethoxyazetidine-1-carboxylate Chemical compound COC(=O)N1C(CC1)OCC1=CC=CC=C1 OVQYYLMTELZSJH-UHFFFAOYSA-N 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- LKPFBGKZCCBZDK-UHFFFAOYSA-N n-hydroxypiperidine Chemical class ON1CCCCC1 LKPFBGKZCCBZDK-UHFFFAOYSA-N 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- ARYQJCFLKYAKHY-UHFFFAOYSA-N prop-2-enyl 3-hydroxypyrrolidine-1-carboxylate Chemical compound OC1CCN(C(=O)OCC=C)C1 ARYQJCFLKYAKHY-UHFFFAOYSA-N 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
- 238000011084 recovery Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- YVOXWSGODURQLO-CQSZACIVSA-N tert-butyl (2r)-2-phenylmethoxypyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC[C@H]1OCC1=CC=CC=C1 YVOXWSGODURQLO-CQSZACIVSA-N 0.000 description 1
- APCBTRDHCDOPNY-SSDOTTSWSA-N tert-butyl (3r)-3-hydroxypyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC[C@@H](O)C1 APCBTRDHCDOPNY-SSDOTTSWSA-N 0.000 description 1
- MWDHRTQFUAQSMK-UHFFFAOYSA-N tert-butyl 4-phenylmethoxypiperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1OCC1=CC=CC=C1 MWDHRTQFUAQSMK-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 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
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Pyrrole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
【解決手段】一般式(1)
【化1】
(式中、R1は、i)水素、ii)炭素数1〜4のアルコキシル基、iii)炭素数2〜4のアルケニルオキシ基、iv)アラルキルオキシ基、v)アルキル基、vi)アリール基から選択された基を示し、式中nは、3〜6の整数を示す)で表される含窒素環状アルコール誘導体を、ジメチルスルホキシド溶媒中、アルカリ金属の水酸化物存在下、ベンジルハライド誘導体と反応させることを特徴とする、一般式(2)
【化2】
(式中R1は、式(1)中のR1と同様の基を示し、式中Arは、置換もしくは無置換のベンゼン環を示し、式中nは、3〜6の整数を示す)で表されるベンジルオキシ含窒素環状化合物の製造法。
【選択図】なし
Description
1−(p−ニトロベンゾイル)−4−ヒドロキシピペリジンを大過剰(11.5モル倍)の塩化ベンジルと反応させる方法が知られている(特許文献3)。この方法では、塩化ベンジルを反応剤、兼溶媒として使用するため、大過剰用いる必要がある。この方法は経済効率の面からも優れた方法とは言えない。また、1−ベンジルオキシカルボニル−4−ピペリジノールをN,N−ジメチルホルムアミド(DMF)溶媒中、水素化ナトリウム−臭化ベンジルによりベンジル化する方法(非特許文献2)が知られているが、収率面及び上記と同様、安全上の問題により工業的製法として適さない。
カラム RP−18 C18、4.6mm×150mm(関東化学)
移動相 5mM ドデシル硫酸ナトリウム水溶液(リン酸でpH2.5に調整)/CH3CN=70/30(0−30min.)→30/70(30−45min.)
流量 1.0ml/min
温度 40℃
検出器 UV(210nm)
また、R−BocBHPの光学純度は、Boc基を脱保護してR−3BHPに変換した後、O,O’−ジ−p−トルオイル−L−酒石酸無水物で処理し光学活性酒石酸誘導体のジアステレオマーにしてHPLC分析することで求めることができる。HPLC分析条件は以下の通りである。
4.6mmφ×250mm(資生堂)
移動相 0.03%アンモニア水(pH4.5;酢酸で調整)/メタノール
=41/59(v/v)
流量 1.0ml/min.
検出器 UV234nm
温度 40℃
参考例1
本発明で用いる光学活性R−BocHPの合成は以下の通りである。
(R−BocBHPの製造)
以上で得られたR−BocHPに塩化ベンジルを反応させてR−BocBHPを合成する方法について以下に説明する。
温度計、滴下ロートを装着した1L四つ口フラスコにジメチルスルホキシド
182.0gを仕込み、上記で得られたR−BocHP121.3g(0.65モル)を添加し撹拌して溶解させた。次に、48%水酸化ナトリウム162.0g(1.94モル)(R−BocHPに対して3.0当量)を添加し、撹拌しながら水浴中で塩化ベンジル106.6g(0.84モル)(R−BocHPに対して1.3当量)を内温が30〜40℃になるように滴下した。7時間熟成後、反応液を上記HPLC分析法を用いて定量分析した結果、R−BocBHPの生成量は171gであった(反応収率95%)。
実施例1において、各成分の使用量を下記のとおりとし、水酸化ナトリウムの形態を種々変えて検討した結果を表1に示す。表中、溶媒使用量とはR−BocHPに対する重量倍数を表す。
実施例1において、48%水酸化ナトリウムの使用量を種々変えて検討した結果を表2に示す。
実施例1において、塩化ベンジルの使用量を変えてベンジル化反応の検討を実施した結果を表3に示す。
実施例1において、溶媒使用量を変えてベンジル化反応の検討を実施した結果を表4に示す。
実施例1において、反応温度を変えてベンジル化反応の検討を実施した結果を表5に示す。
実施例1において、溶媒を種々変えて検討した結果を表6に示す。
Claims (6)
- 一般式(1)
- アルカリ金属の水酸化物の使用量が、含窒素環状アルコール誘導体に対して2.0モル倍以上であることを特徴とする請求項1または2記載のベンジルオキシ含窒素環状化合物の製造法。
- 反応温度が20〜70℃であることを特徴とする請求項1〜3のいずれか1項記載のベンジルオキシ含窒素環状化合物の製造法。
- 請求項1〜4のいずれか1項記載の方法により得られた反応液からベンジルオキシ含窒素環状化合物を単離することなく、反応液に酸性物質を添加することにより酸処理することを特徴とする請求項5記載のベンジルオキシ環状アミン誘導体の製造法。
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JP2005315791A JP5004067B2 (ja) | 2005-10-31 | 2005-10-31 | ベンジルオキシ含窒素環状化合物の製造法 |
CA2627502A CA2627502C (en) | 2005-10-31 | 2006-10-30 | Process for production of benzyloxypyrrolidine derivative, and process for production of hydrochloride salt powder of optically active benzyloxypyrrolidine derivative |
US12/084,316 US7772406B2 (en) | 2005-10-31 | 2006-10-30 | Process for production of benzyloxypyrrolidine derivative, and process for production of hydrochloride salt powder of optically active benzyloxypyrrolidine derivative |
CN200680040655.5A CN101300228B (zh) | 2005-10-31 | 2006-10-30 | 苄氧基吡咯烷衍生物的制造方法及光学活性苄氧基吡咯烷衍生物盐酸盐粉体的制造方法 |
PCT/JP2006/321611 WO2007052578A1 (ja) | 2005-10-31 | 2006-10-30 | ベンジルオキシピロリジン誘導体の製造方法および光学活性ベンジルオキシピロリジン誘導体塩酸塩粉体の製造法 |
EP06822568.9A EP1950198B1 (en) | 2005-10-31 | 2006-10-30 | Process for production of benzyloxypyrrolidine derivative, and process for production of hydrochloride salt powder of optically active benzyloxypyrrolidine derivative |
KR1020087010663A KR101215924B1 (ko) | 2005-10-31 | 2008-05-02 | 벤질옥시피롤리딘 유도체의 제조 방법 및 광학 활성벤질옥시피롤리딘 유도체 염산염 분체의 제조법 |
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JP2007131597A (ja) * | 2005-11-11 | 2007-05-31 | Toray Fine Chemicals Co Ltd | ベンジルオキシピロリジン誘導体の製造方法 |
JP2007332049A (ja) * | 2006-06-13 | 2007-12-27 | Toray Fine Chemicals Co Ltd | 光学活性ベンジルオキシピロリジン誘導体塩酸塩粉体及びその製造法 |
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CN112209865A (zh) * | 2019-07-09 | 2021-01-12 | 中山澳达特罗生物科技有限公司 | 一种(R)-(-)-N-Boc-3-吡咯烷醇的生产方法 |
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WO2004099137A1 (en) * | 2003-05-02 | 2004-11-18 | Cardiome Pharma Corp. | Aminocyclohexyl ether compounds and uses thereof |
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JP2007131597A (ja) * | 2005-11-11 | 2007-05-31 | Toray Fine Chemicals Co Ltd | ベンジルオキシピロリジン誘導体の製造方法 |
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WO2004099137A1 (en) * | 2003-05-02 | 2004-11-18 | Cardiome Pharma Corp. | Aminocyclohexyl ether compounds and uses thereof |
WO2005094897A2 (en) * | 2004-04-01 | 2005-10-13 | Cardiome Pharma Corp. | Pegylated ion channel modulating compounds |
WO2005097087A2 (en) * | 2004-04-01 | 2005-10-20 | Cardiome Pharma Corp. | Merged ion channel modulating compounds and uses thereof |
WO2007052578A1 (ja) * | 2005-10-31 | 2007-05-10 | Toray Fine Chemicals Co., Ltd. | ベンジルオキシピロリジン誘導体の製造方法および光学活性ベンジルオキシピロリジン誘導体塩酸塩粉体の製造法 |
JP2007131597A (ja) * | 2005-11-11 | 2007-05-31 | Toray Fine Chemicals Co Ltd | ベンジルオキシピロリジン誘導体の製造方法 |
JP2007332049A (ja) * | 2006-06-13 | 2007-12-27 | Toray Fine Chemicals Co Ltd | 光学活性ベンジルオキシピロリジン誘導体塩酸塩粉体及びその製造法 |
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JP2007131597A (ja) * | 2005-11-11 | 2007-05-31 | Toray Fine Chemicals Co Ltd | ベンジルオキシピロリジン誘導体の製造方法 |
JP2007332049A (ja) * | 2006-06-13 | 2007-12-27 | Toray Fine Chemicals Co Ltd | 光学活性ベンジルオキシピロリジン誘導体塩酸塩粉体及びその製造法 |
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