JP6289177B2 - Method for producing nitrogen-containing heterocyclic compound - Google Patents
Method for producing nitrogen-containing heterocyclic compound Download PDFInfo
- Publication number
- JP6289177B2 JP6289177B2 JP2014047821A JP2014047821A JP6289177B2 JP 6289177 B2 JP6289177 B2 JP 6289177B2 JP 2014047821 A JP2014047821 A JP 2014047821A JP 2014047821 A JP2014047821 A JP 2014047821A JP 6289177 B2 JP6289177 B2 JP 6289177B2
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- JP
- Japan
- Prior art keywords
- group
- nitrogen
- reaction
- containing heterocyclic
- heterocyclic compound
- Prior art date
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- -1 nitrogen-containing heterocyclic compound Chemical class 0.000 title claims description 42
- 238000004519 manufacturing process Methods 0.000 title claims description 30
- 238000006243 chemical reaction Methods 0.000 claims description 78
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims description 54
- 125000001424 substituent group Chemical group 0.000 claims description 39
- 239000001569 carbon dioxide Substances 0.000 claims description 27
- 229910002092 carbon dioxide Inorganic materials 0.000 claims description 27
- KUCISDUQDQAGRU-UHFFFAOYSA-N benzene;azide Chemical class [N-]=[N+]=[N-].C1=CC=CC=C1 KUCISDUQDQAGRU-UHFFFAOYSA-N 0.000 claims description 25
- 125000005647 linker group Chemical group 0.000 claims description 22
- 239000003638 chemical reducing agent Substances 0.000 claims description 21
- 239000003960 organic solvent Substances 0.000 claims description 19
- 125000004432 carbon atom Chemical group C* 0.000 claims description 18
- 239000003125 aqueous solvent Substances 0.000 claims description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 239000007810 chemical reaction solvent Substances 0.000 claims description 8
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 150000001875 compounds Chemical class 0.000 claims description 7
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 6
- 239000012948 isocyanate Substances 0.000 claims description 6
- 150000002513 isocyanates Chemical class 0.000 claims description 6
- XYFCBTPGUUZFHI-UHFFFAOYSA-N phosphine group Chemical group P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 6
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 claims description 6
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 4
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 239000003093 cationic surfactant Substances 0.000 claims description 4
- 239000004094 surface-active agent Substances 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 3
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 3
- 150000005621 tetraalkylammonium salts Chemical group 0.000 claims description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 14
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- VYFOAVADNIHPTR-UHFFFAOYSA-N isatoic anhydride Chemical compound NC1=CC=CC=C1CO VYFOAVADNIHPTR-UHFFFAOYSA-N 0.000 description 10
- 238000000034 method Methods 0.000 description 10
- 239000002994 raw material Substances 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 239000005711 Benzoic acid Substances 0.000 description 7
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- 235000010233 benzoic acid Nutrition 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 239000012298 atmosphere Substances 0.000 description 5
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- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 4
- 239000000654 additive Substances 0.000 description 4
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- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical class NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- 239000004210 ether based solvent Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 239000000057 synthetic resin Substances 0.000 description 4
- 229920003002 synthetic resin Polymers 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 3
- 239000007983 Tris buffer Substances 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- SDQJTWBNWQABLE-UHFFFAOYSA-N 1h-quinazoline-2,4-dione Chemical compound C1=CC=C2C(=O)NC(=O)NC2=C1 SDQJTWBNWQABLE-UHFFFAOYSA-N 0.000 description 2
- 0 CC1=CC=C*(*)C=C1CBCC(N)=O Chemical compound CC1=CC=C*(*)C=C1CBCC(N)=O 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-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
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 150000004292 cyclic ethers Chemical class 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 2
- 239000011261 inert gas Substances 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 description 2
- 239000000693 micelle Substances 0.000 description 2
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 2
- 235000019796 monopotassium phosphate Nutrition 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 2
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- KYVBNYUBXIEUFW-UHFFFAOYSA-N 1,1,3,3-tetramethylguanidine Chemical compound CN(C)C(=N)N(C)C KYVBNYUBXIEUFW-UHFFFAOYSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- SSUJUUNLZQVZMO-UHFFFAOYSA-N 1,2,3,4,8,9,10,10a-octahydropyrimido[1,2-a]azepine Chemical compound C1CCC=CN2CCCNC21 SSUJUUNLZQVZMO-UHFFFAOYSA-N 0.000 description 1
- XGINAUQXFXVBND-UHFFFAOYSA-N 1,2,6,7,8,8a-hexahydropyrrolo[1,2-a]pyrimidine Chemical compound N1CC=CN2CCCC21 XGINAUQXFXVBND-UHFFFAOYSA-N 0.000 description 1
- FZKCAHQKNJXICB-UHFFFAOYSA-N 2,1-benzoxazole Chemical compound C1=CC=CC2=CON=C21 FZKCAHQKNJXICB-UHFFFAOYSA-N 0.000 description 1
- NIFRUOQEJBOLBI-UHFFFAOYSA-N 3-benzyl-1h-quinazoline-2,4-dione Chemical compound O=C1NC2=CC=CC=C2C(=O)N1CC1=CC=CC=C1 NIFRUOQEJBOLBI-UHFFFAOYSA-N 0.000 description 1
- KIZGBTDENGRWRS-UHFFFAOYSA-N 5-methoxy-1h-3,1-benzoxazine-2,4-dione Chemical compound N1C(=O)OC(=O)C2=C1C=CC=C2OC KIZGBTDENGRWRS-UHFFFAOYSA-N 0.000 description 1
- QRUPDIJQZCABTC-UHFFFAOYSA-N 7-chloro-1h-3,1-benzoxazine-2,4-dione Chemical compound N1C(=O)OC(=O)C=2C1=CC(Cl)=CC=2 QRUPDIJQZCABTC-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- IWVQFAKCRDSHPV-UHFFFAOYSA-N C(C)(=O)N1C(NC2=CC=CC=C2C1=O)=O Chemical compound C(C)(=O)N1C(NC2=CC=CC=C2C1=O)=O IWVQFAKCRDSHPV-UHFFFAOYSA-N 0.000 description 1
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 1
- JGFDZZLUDWMUQH-UHFFFAOYSA-N Didecyldimethylammonium Chemical class CCCCCCCCCC[N+](C)(C)CCCCCCCCCC JGFDZZLUDWMUQH-UHFFFAOYSA-N 0.000 description 1
- 101000851058 Homo sapiens Neutrophil elastase Proteins 0.000 description 1
- TXJUTRJFNRYTHH-UHFFFAOYSA-N O=C(c1ccccc1N1)OC1=O Chemical compound O=C(c1ccccc1N1)OC1=O TXJUTRJFNRYTHH-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- LINDOXZENKYESA-UHFFFAOYSA-N TMG Natural products CNC(N)=NC LINDOXZENKYESA-UHFFFAOYSA-N 0.000 description 1
- 239000006096 absorbing agent Substances 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000005456 alcohol based solvent Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000003172 aldehyde group Chemical group 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 125000005194 alkoxycarbonyloxy group Chemical group 0.000 description 1
- 125000005211 alkyl trimethyl ammonium group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- IVRMZWNICZWHMI-UHFFFAOYSA-N azide group Chemical group [N-]=[N+]=[N-] IVRMZWNICZWHMI-UHFFFAOYSA-N 0.000 description 1
- 150000001555 benzenes Chemical class 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 229960001701 chloroform Drugs 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 230000005595 deprotonation Effects 0.000 description 1
- 238000010537 deprotonation reaction Methods 0.000 description 1
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003759 ester based solvent Substances 0.000 description 1
- LGLPFJDOUVCBNP-UHFFFAOYSA-N ethyl 4-hydroxy-2-oxo-1h-quinoline-3-carboxylate Chemical compound C1=CC=C2NC(=O)C(C(=O)OCC)=C(O)C2=C1 LGLPFJDOUVCBNP-UHFFFAOYSA-N 0.000 description 1
- 229940093476 ethylene glycol Drugs 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 239000004009 herbicide Substances 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 102000052502 human ELANE Human genes 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000005453 ketone based solvent Substances 0.000 description 1
- 239000003591 leukocyte elastase inhibitor Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- YSWYYGKGAYSAOJ-UHFFFAOYSA-N phosphane Chemical compound P.P YSWYYGKGAYSAOJ-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- BTGNGJJLZOIYID-UHFFFAOYSA-N sivelestat Chemical compound C1=CC(OC(=O)C(C)(C)C)=CC=C1S(=O)(=O)NC1=CC=CC=C1C(=O)NCC(O)=O BTGNGJJLZOIYID-UHFFFAOYSA-N 0.000 description 1
- 229950009343 sivelestat Drugs 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 125000001174 sulfone group Chemical group 0.000 description 1
- 125000000542 sulfonic acid group Chemical group 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- JAYKPAAGOYELFD-UHFFFAOYSA-N tris(2,4-ditert-butylphenyl)phosphane Chemical compound CC(C)(C)C1=CC(C(C)(C)C)=CC=C1P(C=1C(=CC(=CC=1)C(C)(C)C)C(C)(C)C)C1=CC=C(C(C)(C)C)C=C1C(C)(C)C JAYKPAAGOYELFD-UHFFFAOYSA-N 0.000 description 1
- BKHZQJRTFNFCTG-UHFFFAOYSA-N tris(2-methylphenyl) phosphite Chemical compound CC1=CC=CC=C1OP(OC=1C(=CC=CC=1)C)OC1=CC=CC=C1C BKHZQJRTFNFCTG-UHFFFAOYSA-N 0.000 description 1
- COIOYMYWGDAQPM-UHFFFAOYSA-N tris(2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C COIOYMYWGDAQPM-UHFFFAOYSA-N 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Landscapes
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Description
この発明は、オルト置換アジ化ベンゼン誘導体と二酸化炭素とを反応させて含窒素複素環化合物を合成する新規な含窒素複素環化合物の製造方法に関する。 The present invention relates to a novel method for producing a nitrogen-containing heterocyclic compound in which an ortho-substituted azide benzene derivative and carbon dioxide are reacted to synthesize a nitrogen-containing heterocyclic compound.
窒素元素を含んで2種以上の元素で構成される含窒素複素環化合物については様々な構造を有するものが知られており、また、多種多様な分野で様々な用途に用いられている。例えば、炭素、窒素及び酸素からなる環構造を有する無水イサト酸は、急性肺炎の治療薬であるシベレスタット(ヒト好中球エラスターゼ阻害薬)の製造原料として知られており(特許文献1)、また、除草剤や紫外線吸収剤の製造原料としても利用されており、医薬、農薬、合成樹脂用添加剤等の製造原料として重要な化合物である。 Nitrogen-containing heterocyclic compounds composed of two or more elements including nitrogen element are known to have various structures, and are used for various applications in various fields. For example, isatoic anhydride having a ring structure composed of carbon, nitrogen and oxygen is known as a raw material for producing sivelestat (human neutrophil elastase inhibitor), which is a therapeutic agent for acute pneumonia (Patent Document 1). It is also used as a raw material for producing herbicides and ultraviolet absorbers, and is an important compound as a raw material for producing pharmaceuticals, agricultural chemicals, additives for synthetic resins and the like.
そして、このような含窒素複素環化合物の製造方法についても様々な方法が提案されており、例えば、無水イサト酸の製造方法についてみると、対応するアンスラニル酸類又はその塩とホスゲンとを水と有機溶剤との混合溶媒中で反応させる方法(特許文献2)や、アンスラニル酸類とトリホスゲン〔(Cl3CO)2C=O〕とをテトラヒドロフラン等の適当な有機溶媒中で反応させるか、あるいは、アンスラニル酸類を触媒量のトリエチルアミン存在下にクロルギ酸エチル中で還流させる方法(特許文献3)等が知られている。 Various methods for producing such nitrogen-containing heterocyclic compounds have been proposed. For example, regarding the method for producing isatoic anhydride, the corresponding anthranilic acids or salts thereof and phosgene are mixed with water and organic. A method of reacting in a mixed solvent with a solvent (Patent Document 2), anthranilic acid and triphosgene [(Cl 3 CO) 2 C═O] are reacted in an appropriate organic solvent such as tetrahydrofuran, or anthranil A method in which acids are refluxed in ethyl chloroformate in the presence of a catalytic amount of triethylamine is known (Patent Document 3).
しかしながら、アンスラニル酸類と反応させる反応剤(reactant)として、ホスゲンを用いる方法は、ホスゲンが刺激性、窒息性があって吸入により
1394521428601_0
を引き起こす猛毒の気体であり、また、トリホスゲンを用いる方法は、トリホスゲンが、ホスゲンに比べてその取扱いが容易ではあるものの、反応系では3当量のホスゲンに分解して反応に関与するものであり、更に、クロルギ酸エチルを用いる方法は、クロルギ酸エチルがホスゲンとエタノールから作られる腐食性や目、粘膜、皮膚等に対する刺激性の強い液体であり、これらいずれの方法で用いられる反応剤も反応装置に対する腐食の問題やその取扱上の問題のある物質であり、製造コストを押し上げる要因にもなっている。
However, the method using phosgene as a reactant that reacts with anthranilic acids is irritating and suffocating because phosgene is inhaled.
1394521428601_0
In the method using triphosgene, triphosgene is easier to handle than phosgene, but in the reaction system, it is decomposed into 3 equivalents of phosgene and involved in the reaction. Furthermore, the method using ethyl chloroformate is a liquid that is strongly corrosive and irritating to eyes, mucous membranes, skin, etc., where ethyl chloroformate is made from phosgene and ethanol. It is a substance that has a problem of corrosion with respect to and its handling problem, and also increases the manufacturing cost.
ところで、近年、地球温暖化等の問題から環境への意識が高まり、持続可能な社会にとっては再生可能な資源の利用が不可欠であるとし、これまでにも二酸化炭素を炭素源として利用する幾つかの試みが提案されている(例えば、非特許文献1及び非特許文献2等)。しかしながら、二酸化炭素を炭素源として利用することについては、魅力的ではあるものの、二酸化炭素が炭素の最も酸化された安定な状態にあることから、この二酸化炭素を別の物質に変換させるためには大きなエネルギーが必要になり、簡単ではないことも指摘されている(非特許文献2参照)。 By the way, in recent years, awareness of the environment has increased due to issues such as global warming, and the use of renewable resources is indispensable for a sustainable society. Have been proposed (for example, Non-Patent Document 1 and Non-Patent Document 2). However, using carbon dioxide as a carbon source is attractive, but because it is in the most oxidized and stable state of carbon, to convert this carbon dioxide to another substance It has also been pointed out that a large amount of energy is required and is not easy (see Non-Patent Document 2).
そこで、本発明者らは、含窒素複素環化合物の製造において、反応剤として二酸化炭素を有効に活用し、医薬、農薬、合成樹脂の添加剤等の多くの分野で様々な用途に使用される含窒素複素環化合物を工業的に有利に製造することができる方法について鋭意検討を行った結果、π結合を持つ置換基をオルト位に有するアジ化ベンゼン誘導体と二酸化炭素とを反応溶媒中で還元剤の存在下に反応させることにより、無水イサト酸を始めとする含窒素複素環化合物を容易にかつ収率良く合成できることを見出し、本発明を完成した。 Therefore, the present inventors effectively use carbon dioxide as a reactant in the production of nitrogen-containing heterocyclic compounds, and are used for various applications in many fields such as pharmaceuticals, agricultural chemicals, and synthetic resin additives. As a result of intensive studies on a method that can produce a nitrogen-containing heterocyclic compound industrially advantageously, reduction of azide benzene derivative having a substituent having a π bond in the ortho position and carbon dioxide in a reaction solvent It has been found that by reacting in the presence of an agent, nitrogen-containing heterocyclic compounds such as isatoic anhydride can be easily synthesized with good yield, and the present invention has been completed.
従って、本発明の目的は、オルト置換アジ化ベンゼン誘導体と二酸化炭素とから、無水イサト酸を始めとする医薬、農薬、合成樹脂の添加剤等の多くの分野で合成中間体等として有用な含窒素複素環化合物を、容易にかつ収率良く製造することができる新たな含窒素複素環化合物の製造方法を提供することにある。 Accordingly, an object of the present invention is to include useful compounds as synthetic intermediates in many fields such as isatoic anhydride and other pharmaceuticals, agricultural chemicals, synthetic resin additives, etc. from ortho-substituted azide benzene derivatives and carbon dioxide. It is an object of the present invention to provide a novel method for producing a nitrogen-containing heterocyclic compound, which can easily produce a nitrogen heterocyclic compound with good yield.
すなわち、本発明は、以下の通りである。
(1) 下記一般式(1)で表されるオルト置換アジ化ベンゼン誘導体を、反応溶媒中で還元剤の存在下に二酸化炭素と反応させ、下記一般式(2)で表される含窒素複素環化合物を合成することを特徴とする含窒素複素環化合物の製造方法。
〔但し、一般式(1)及び一般式(2)において、Rは、ベンゼン核の3〜6位のいずれかの位置に結合した1〜4個の水素及び/又は水素以外の置換基であって、互いに同じでも異なっていてもよく、
また、一般式(1)において、Aは、反応系内で生成したイソシアネートとの間で分子内環化反応が可能であると共に、この分子内環化反応により一般式(2)の−B−C−結合を形成するオルト置換基であり、
更に、一般式(2)において、Bは下記式(B)から選ばれたいずれかの結合基であって、Cは下記式(C)から選ばれたいずれかの結合基である。
(但し、前記結合基Bの式(B)及び結合基Cの式(C)において、R1、R2、R3は水素、−OH、炭素数1〜4の低級アルキル基、炭素数7〜10のアリールアルキル基、炭素数2〜5のアルキルカルボニル基、炭素数2〜5のアルコキシカルボニル基、アルコキシ基、及びシリル基から選ばれたいずれかの置換基である。)〕
That is, the present invention is as follows.
(1) An ortho-substituted azide benzene derivative represented by the following general formula (1) is reacted with carbon dioxide in the presence of a reducing agent in a reaction solvent to form a nitrogen-containing complex represented by the following general formula (2). A method for producing a nitrogen-containing heterocyclic compound, comprising synthesizing a ring compound.
[However, in the general formula (1) and the general formula (2), R is a 1 to 4 hydrogens and / or other than hydrogen substituent attached to any position of the 3-6-position of the benzene nucleus Can be the same or different,
In the general formula (1), A together with a possible intramolecular cyclization reaction between the produced isocyanate in the reaction system, by the intramolecular cyclization reaction formula (2) -B- An ortho substituent that forms a C-bond ;
Further, in the general formula (2) , B is any bonding group selected from the following formula (B), and C is any bonding group selected from the following formula (C).
(However, in the formula (B) of the linking group B and the formula (C) of the linking group C, R 1 , R 2 , and R 3 are hydrogen, —OH, a lower alkyl group having 1 to 4 carbon atoms, and 7 carbon atoms. -10 arylalkyl group, an alkylcarbonyl group having 2 to 5 carbon atoms, an alkoxycarbonyl group having 2 to 5 carbon atoms, an alkoxy group, and a silyl group.
(2) 前記オルト置換基Aが、下記式(A)
から選ばれた置換基であることを特徴とする前記(1)に記載の含窒素複素環化合物の製造方法。
(2) The ortho substituent A is represented by the following formula (A)
The method for producing a nitrogen-containing heterocyclic compound according to (1), wherein the substituent is selected from the group consisting of:
(3) 前記結合基Bが、−CO−、−CH=、及び−C(OH)=から選ばれた結合基であり、また、前記結合基Cが、−O−、=CH−、=C(COOC2H5)−、−N(Bn)−、及び−N(Ac)−から選ばれた結合基であることを特徴とする前記(1)又は(2)に記載の含窒素複素環化合物の製造方法。 (3) The linking group B is a linking group selected from —CO—, —CH═, and —C (OH) ═, and the linking group C is —O—, ═CH—, ═ The nitrogen-containing complex according to (1) or (2) above, which is a linking group selected from C (COOC 2 H 5 ) —, —N (Bn) —, and —N (Ac) —. A method for producing a ring compound.
(4) 前記還元剤が、ホスフィン(PR3)又はホスファイト〔P(OR)3〕であることを特徴とする前記(1)〜(3)のいずれかに記載の含窒素複素環化合物の製造方法。
(5) 前記反応系が有機溶媒中に還元剤及び塩基が存在する反応系であって、反応温度が40〜100℃であることを特徴とする前記(1)〜(4)のいずれかに記載の含窒素複素環化合物の製造方法。
(4) The nitrogen-containing heterocyclic compound according to any one of (1) to (3), wherein the reducing agent is phosphine (PR 3 ) or phosphite [P (OR) 3 ]. Production method.
(5) The reaction system according to any one of (1) to (4), wherein the reaction system is a reaction system in which a reducing agent and a base are present in an organic solvent, and the reaction temperature is 40 to 100 ° C. The manufacturing method of the nitrogen-containing heterocyclic compound of description.
(6) 前記反応系が水系溶媒中に還元剤及び界面活性剤が存在する反応系であることを特徴とする前記(1)〜(4)のいずれかに記載の含窒素複素環化合物の製造方法。
(7) 前記界面活性剤が陽イオン界面活性剤である前記(6)に記載の含窒素複素環化合物の製造方法。
(6) The production of the nitrogen-containing heterocyclic compound according to any one of (1) to (4), wherein the reaction system is a reaction system in which a reducing agent and a surfactant are present in an aqueous solvent. Method.
(7) The method for producing a nitrogen-containing heterocyclic compound according to (6), wherein the surfactant is a cationic surfactant.
本発明の含窒素複素環化合物の製造方法によれば、オルト置換アジ化ベンゼン誘導体と二酸化炭素とから、無水イサト酸を始めとする医薬、農薬、合成樹脂の添加剤等の多くの分野で合成中間体等として有用な含窒素複素環化合物を、容易にかつ収率良く製造することができる。 According to the method for producing a nitrogen-containing heterocyclic compound of the present invention, it is synthesized from an ortho-substituted azide benzene derivative and carbon dioxide in many fields such as pharmaceuticals, agricultural chemicals, synthetic resin additives including isatoic anhydride. Nitrogen-containing heterocyclic compounds useful as intermediates and the like can be easily produced with good yield.
以下、本発明の含窒素複素環化合物の製造方法について詳細に説明する。
本発明において、製造原料として使用するオルト置換アジ化ベンゼン誘導体は、下記一般式(1)
In the present invention, an ortho-substituted azide benzene derivative used as a production raw material has the following general formula (1)
ここで、製造原料のオルト置換アジ化ベンゼン誘導体において、ベンゼン核の3〜6位に置換する水素以外の置換基Rとしては、例えば水酸基、メチル基(-CH3)等のアルキル基、メトキシ基(-OCH3)等のアルコキシ基、アルコキシカルボニルオキシ基(-OCOR)、アリール基、アミノ基、アルキル置換アミノ基、アルキルカルボニル置換アミノ基(-NHCOR)等の電子供与性の置換基や、例えばカルボキシル基(-COOH)、ニトロ基(-NO2)、シアノ基、アルデヒド基、アルキルカルボニル基(-COR)、アルコキシカルボニル基(-COOR)、スルホン酸基(-SO3H)、スルホン基(-SO2R)、塩素等のハロゲン、モノクロロメチル基、トリクロロメチル基、トリフロロメチル基等の電子求引性の置換基等を挙げることができる。また、これらの置換基において、他の置換基が更に置換した置換基、カルボン酸とその誘導体、スルホン酸とその誘導体、リン酸とその誘導体等の置換基等の各種の置換基の中から選ばれた置換基が1〜5個の範囲内で存在していてもよく、また、4〜7位の各置換位置間においてヘテロ原子を介在して、あるいは、介在することなく縮合環を形成する多環式化合物であってもよい。本発明においては、ベンゼン核の3〜6位に置換する置換基Rとして、広範囲の置換基が置換されたオルト置換アジ化ベンゼン誘導体を製造原料として用いることができる。 Here, in the ortho-substituted azide benzene derivative as the raw material for production, examples of the substituent R other than hydrogen substituted at the 3-6 position of the benzene nucleus include alkyl groups such as a hydroxyl group and a methyl group (—CH 3 ), a methoxy group, and the like. Electron-donating substituents such as alkoxy groups such as (-OCH 3 ), alkoxycarbonyloxy groups (-OCOR), aryl groups, amino groups, alkyl-substituted amino groups, alkylcarbonyl-substituted amino groups (-NHCOR), Carboxyl group (-COOH), nitro group (-NO 2 ), cyano group, aldehyde group, alkylcarbonyl group (-COR), alkoxycarbonyl group (-COOR), sulfonic acid group (-SO 3 H), sulfone group ( -SO 2 R), halogen such as chlorine, electron-withdrawing substituents such as monochloromethyl group, trichloromethyl group, trifluoromethyl group and the like. Also, among these substituents, selected from various substituents such as substituents further substituted with other substituents, carboxylic acid and derivatives thereof, sulfonic acid and derivatives thereof, phosphoric acid and derivatives thereof, and the like. The substituted groups may be present in the range of 1 to 5 and form a condensed ring with or without a heteroatom between the substituted positions of the 4 to 7 positions. It may be a polycyclic compound. In the present invention, an ortho-substituted azide benzene derivative in which a wide range of substituents are substituted can be used as a raw material for production as the substituent R substituted at the 3-6 position of the benzene nucleus.
また、製造原料のオルト置換アジ化ベンゼン誘導体において、オルト置換基Aについては、基本構造であるアジ化ベンゼンのオルト位に置換した置換基であって、アジ化ベンゼンのベンゼン核に隣接するα位とβ位との間にπ結合を有し、このオルト置換アジ化ベンゼン誘導体と二酸化炭素とを反応溶媒中還元剤の存在下に反応させた際に、その反応系内で生成したイソシアネートとの間で分子内環化反応が可能な置換基であればよいが、好ましくは下記式(A)
で表される置換基であるのがよい。
Further, in the ortho-substituted azide benzene derivative as a raw material for production, the ortho substituent A is a substituent substituted at the ortho position of benzene azide, which is the basic structure, and is in the α position adjacent to the benzene nucleus of azide benzene. When the ortho-substituted azide benzene derivative and carbon dioxide are reacted in the reaction solvent in the presence of a reducing agent, the isocyanate produced in the reaction system The substituent may be any substituent capable of undergoing an intramolecular cyclization reaction, but preferably the following formula (A)
It is good that it is a substituent represented by.
このオルト置換基Aについて、オルト置換基A1の好ましい具体例としては、例えば−CH=CH2、−C(CH3)=CH2、-C(OCH3)=CH2、-C(OSi(CH3)3)=CH2等を例示することができ、更に、オルト置換基A2の好ましい具体例としては、例えば−CONHBn(Bn:ベンジル基)、−CONHAc(Ac:アセチル基)等を例示することができ、更にまた、オルト置換基A3の好ましい具体例としては、例えば−C(=O)-CH2-CO2Et、-C(=O)-CH2-C(=O)-CH3等を例示することができる。 Regarding this ortho substituent A, preferred specific examples of the ortho substituent A 1 include, for example, —CH═CH 2 , —C (CH 3 ) ═CH 2 , —C (OCH 3 ) ═CH 2 , —C (OSi (CH 3 ) 3 ) ═CH 2 and the like can be exemplified. Further, preferred specific examples of the ortho substituent A 2 include, for example, —CONHBn (Bn: benzyl group), —CONHAc (Ac: acetyl group) and the like. Furthermore, preferred specific examples of the ortho substituent A 3 include, for example, —C (═O) —CH 2 —CO 2 Et, —C (═O) —CH 2 —C (= O) —CH 3 and the like can be exemplified.
また、本発明においては、上記のオルト置換アジ化ベンゼン誘導体を反応溶媒中で還元剤の存在下に二酸化炭素と反応させるが、ここで用いられる還元剤としては、例えば、ホスフィン(PR3)、ホスファイト〔P(OR)3〕、カルベン等が挙げられ、取扱い上の観点等から、好ましくはトリフェニルホスフィン(PPh3)、トリス(2-トリル)ホスフィン、トリス(2-MeO-フェニル)ホスフィン、トリス(2,4-ジ-タート-ブチルフェニル)ホスフィン等のホスフィンリガンド(PR3)や、トリス(2-トリル)ホスファイト、トリス(2-MeO-フェニル)ホスファイト、トリス(2,4-ジ-タート-ブチルフェニル)ホスファイト等のホスファイトリガンド〔P(OR)3〕である。 In the present invention, the ortho-substituted azide benzene derivative is reacted with carbon dioxide in the presence of a reducing agent in a reaction solvent. Examples of the reducing agent used here include phosphine (PR 3 ), Phosphite [P (OR) 3 ], carbene and the like are mentioned, and from the viewpoint of handling, preferably triphenylphosphine (PPh 3 ), tris (2-tolyl) phosphine, tris (2-MeO-phenyl) phosphine Phosphine ligands (PR 3 ) such as tris (2,4-di-tert-butylphenyl) phosphine, tris (2-tolyl) phosphite, tris (2-MeO-phenyl) phosphite, tris (2,4 A phosphite ligand [P (OR) 3 ] such as -di-tert-butylphenyl) phosphite.
この還元剤の使用量については、オルト置換アジ化ベンゼン誘導体の1モルに対して、通常1モル以上2モル以下、好ましくは1モル以上1.1モル以下であり、この使用量が1モル未満であると未反応原料の残留という問題あり、また、2モルを超えると未反応還元剤の残留という問題ある。 The amount of the reducing agent used is usually 1 mol or more and 2 mol or less, preferably 1 mol or more and 1.1 mol or less with respect to 1 mol of the ortho-substituted azide benzene derivative, and the amount used is less than 1 mol. If it is, there is a problem that unreacted raw material remains, and if it exceeds 2 mol, there is a problem that unreacted reducing agent remains.
本発明において、上記還元剤の存在下に反応溶媒中でオルト置換アジ化ベンゼン誘導体と二酸化炭素とを反応させる反応系については、反応溶媒として有機溶媒を用い、この有機溶媒中に還元剤及び塩基を存在させて反応温度40〜100℃で反応させる反応系と、反応溶媒として水系溶媒を用い、この水系溶媒中に還元剤及び界面活性剤を存在させて反応させる反応系とがある。 In the present invention, for a reaction system in which an ortho-substituted azide benzene derivative and carbon dioxide are reacted in a reaction solvent in the presence of the reducing agent, an organic solvent is used as the reaction solvent, and the reducing agent and the base are contained in the organic solvent. There are a reaction system in which the reaction is carried out at a reaction temperature of 40 to 100 ° C. and a reaction system in which an aqueous solvent is used as the reaction solvent and the reaction is carried out in the presence of a reducing agent and a surfactant in the aqueous solvent.
ここで、上記の有機溶媒の反応系で使用する有機溶剤としては、製造原料のオルト置換アジ化ベンゼン誘導体と反応することなくこのオルト置換アジ化ベンゼン誘導体を溶解することができ、また、使用する還元剤及び塩基と反応することのないものであって、40〜100℃の反応温度を達成できればよく、例えば、ベンゼン、トルエン、キシレン等の芳香族炭化水素系溶剤や、トリクロロメタン、ジクロロメタン、ジクロロエタン(DCE)等のハロゲン化アルキル溶剤や、アセトニトリル、シアン化エチル等のシアン化アルキル系溶剤や、1,4-ジオキサン等の環状エーテル系溶剤や、N,N-ジメチルホルムアミド(DMF)等の非プロトン性極性溶剤や、ヘキサン、シクロヘキサン、ペンタン等の脂肪族炭化水素系溶剤や、メタノール、エタノール、イソブロパノール等のアルコール系溶剤や、アセトン、メチルエチルケトン等のケトン系溶剤や、ジイソプロピルエーテル、エチルフェニルエーテル等のエーテル系溶剤等を例示することができる。 Here, as the organic solvent used in the reaction system of the above organic solvent, the ortho-substituted azide benzene derivative can be dissolved and used without reacting with the ortho-substituted azide benzene derivative as a raw material for production. It does not react with a reducing agent and a base and only needs to achieve a reaction temperature of 40 to 100 ° C., for example, aromatic hydrocarbon solvents such as benzene, toluene, xylene, trichloromethane, dichloromethane, dichloroethane. (DCE), halogenated alkyl solvents, acetonitrile, ethyl cyanide alkyl halide solvents, 1,4-dioxane and other cyclic ether solvents, N, N-dimethylformamide (DMF), etc. Protic polar solvents, aliphatic hydrocarbon solvents such as hexane, cyclohexane, pentane, methanol, ethanol, isopropanol And alcohol solvents such as propanol, acetone, and ketone solvents such as methyl ethyl ketone, diisopropyl ether, can be exemplified an ether-based solvent such as phenyl ether.
また、この有機溶媒の反応系で使用する塩基は、反応系において液相内での二酸化炭素活量を増加させる反応助剤として働くと同時に反応原料の脱プロトン化を行うことで反応性を増大させる塩基として作用するものであり、この塩基としては、炭酸ナトリウム(Na2CO3)、炭酸カリウム(K2CO3)等の無機アルカリ類や、カリウムt-ブトキシド(KOtBu)、ナトリウムエトキシド(NaOC2H5)等のアルコキシド類や、1,8-ジアザビシクロ[5,4,0]ウンデセン(DBU)、トリエチルアミン(TEA)、1,5-ジアザビシクロ[4,3,0]ノネン(DBN)、1,1,3,3-テトラメチルグアニジン等の有機アルカリ類や、カリウムヘキサメチルジシラジド(KHMDS)等のアミド類等を例示することができる。 In addition, the base used in the reaction system of the organic solvent acts as a reaction aid for increasing the carbon dioxide activity in the liquid phase in the reaction system, and at the same time increases the reactivity by deprotonation of the reaction raw material. As the base, inorganic bases such as sodium carbonate (Na 2 CO 3 ) and potassium carbonate (K 2 CO 3 ), potassium t-butoxide (KOtBu), sodium ethoxide ( Alkoxides such as NaOC 2 H 5 ), 1,8-diazabicyclo [5,4,0] undecene (DBU), triethylamine (TEA), 1,5-diazabicyclo [4,3,0] nonene (DBN), Examples include organic alkalis such as 1,1,3,3-tetramethylguanidine, amides such as potassium hexamethyldisilazide (KHMDS), and the like.
上記の有機溶媒の反応系で行う際の反応条件については、反応温度が通常40℃以上100℃以下、好ましくは50℃以上90℃以下であり、また、反応時間が通常6時間以上72時間以下、好ましくは12時間以上30時間以下であるのがよい。また、反応系内への二酸化炭素の供給については、反応系内を二酸化炭素の雰囲気にしたり、あるいは、不活性ガス等の他の気体との混合ガスの雰囲気にすることにより行うことができ、この際の反応時の二酸化炭素の圧力(不活性ガス等の他の気体との混合ガスとして用いた場合には混合ガスの圧力)についても、特に制限されるものではないが、工業的な反応設備や製造プロセス等を考慮すると、好ましくは下限が0.05MPa以上で上限が1MPa程度以下であるのがよく、より好ましくは実質的に大気圧(1atm; 0.1MPa)程度であるのがよい。本発明の製造方法は、反応時の二酸化炭素の圧力を大幅に低減できることにも利点がある。 Regarding the reaction conditions for carrying out the reaction in the above organic solvent, the reaction temperature is usually from 40 ° C. to 100 ° C., preferably from 50 ° C. to 90 ° C., and the reaction time is usually from 6 hours to 72 hours. Preferably, it is 12 hours or more and 30 hours or less. Further, the supply of carbon dioxide into the reaction system can be performed by making the inside of the reaction system an atmosphere of carbon dioxide, or an atmosphere of a mixed gas with another gas such as an inert gas, The pressure of carbon dioxide at the time of the reaction (the pressure of the mixed gas when used as a mixed gas with another gas such as an inert gas) is not particularly limited, but is an industrial reaction. Considering equipment, manufacturing process, etc., the lower limit is preferably 0.05 MPa or more and the upper limit is about 1 MPa or less, more preferably about atmospheric pressure (1 atm; 0.1 MPa). The production method of the present invention is also advantageous in that the pressure of carbon dioxide during the reaction can be greatly reduced.
そして、上記の水系溶媒の反応系で使用する水系溶剤としては、水、水と有機溶剤との混合溶剤、更には緩衝液と有機溶剤との混合溶剤等を用いることができる。ここで、緩衝液としては、そのpH値が通常5.0〜10.0、好ましくは6.0〜8.0のものが用いられ、具体的には例えば、リン酸塩、炭酸水素塩等の酸や金属アルコシド、炭酸塩等の塩基を用いた緩衝液を例示することができる。前記混合溶剤を構成する有機溶剤については、基質、還元剤の溶解度を目的として添加され、水混合系においてミセルを形成し反応場を提供するものであることから、比較的疎水的であるのがよく、例えば、ヘキサン、シクロヘキサン、ペンタン等の脂肪族炭化水素系溶剤や、ベンゼン、トルエン、キシレン等の芳香族炭化水素系溶剤や、エチルエーテル、シクロペンチルメチルエーテル(CPME)、t-ブチルメチルエーテル(MTBE)、ジイソプロピルエーテル(DIPE)等のエーテル系溶剤や、1,4-ジオキサン、テトラヒドロフラン(THF)等の環状エーテル系溶剤や、N,N-ジメチルホルムアミド(DMF)等の非プロトン性極性溶剤や、メチルアルコール、エチルアルコール、イソプロピルアルコール等のアルコール類や、酢酸エチル(EtOAc)等のエステル系溶剤や、エチレングリコール(Ethyleneglycol)のグリコール系溶剤等を例示することができる。 As the aqueous solvent used in the above aqueous solvent reaction system, water, a mixed solvent of water and an organic solvent, a mixed solvent of a buffer solution and an organic solvent, or the like can be used. Here, as the buffer, one having a pH value of usually 5.0 to 10.0, preferably 6.0 to 8.0 is used, and specifically, for example, phosphate, bicarbonate, etc. Examples include buffers using bases such as acids, metal alcosides, and carbonates. The organic solvent constituting the mixed solvent is added for the purpose of solubility of the substrate and the reducing agent, and forms a micelle in the water mixed system to provide a reaction field, so that it is relatively hydrophobic. Well, for example, aliphatic hydrocarbon solvents such as hexane, cyclohexane and pentane, aromatic hydrocarbon solvents such as benzene, toluene and xylene, ethyl ether, cyclopentyl methyl ether (CPME), t-butyl methyl ether ( MTBE), ether solvents such as diisopropyl ether (DIPE), cyclic ether solvents such as 1,4-dioxane and tetrahydrofuran (THF), aprotic polar solvents such as N, N-dimethylformamide (DMF) , Alcohols such as methyl alcohol, ethyl alcohol and isopropyl alcohol; ester solvents such as ethyl acetate (EtOAc); It can be exemplified glycol solvents such glycol (Ethyleneglycol).
また、この水系溶媒の反応系で使用する陽イオン界面活性剤は、反応系においてミセルを形成し疎水的反応場を提供するものとして作用するものであり、例えば、セチルトリメチルアンモニウムブロマイド(Cetyltrimethylammonoum bromide: CTMABr)等のアルキルトリメチルアンモニウム塩、ジデシルジメチルアンモニウム塩等のジアルキルジメチルアンモニウム塩、アルキルベンジルジメチルアンモニウム塩等のテトラアルキルアンモニウム塩を挙げることができる。 Further, the cationic surfactant used in the reaction system of this aqueous solvent acts as a substance that forms a micelle in the reaction system and provides a hydrophobic reaction field.For example, cetyltrimethylammonium bromide: And alkyltrimethylammonium salts such as CTMABr), dialkyldimethylammonium salts such as didecyldimethylammonium salt, and tetraalkylammonium salts such as alkylbenzyldimethylammonium salt.
また、この水系溶媒の反応系で行う際の反応条件については、室温(20℃)で十分に反応が進むので反応温度には特に制限がなく、特に冷却したり、あるいは、加熱したりする必要もないが、使用するオルト置換アジ化ベンゼン誘導体の種類等に応じて、必要により100℃までの温度に加温してもよく、また、反応時間については通常6時間以上72時間以下、好ましくは12時間以上30時間以下であるのがよい。また、反応系内への二酸化炭素の供給については、上記の反応を有機溶媒の反応系で行う場合と同様に実施することができる。 In addition, the reaction conditions for the reaction in this aqueous solvent reaction system are sufficiently limited at room temperature (20 ° C), so the reaction temperature is not particularly limited, and it is particularly necessary to cool or heat. However, depending on the type of ortho-substituted azide benzene derivative used, it may be heated to a temperature of up to 100 ° C. if necessary, and the reaction time is usually from 6 hours to 72 hours, preferably It is good that it is 12 hours or more and 30 hours or less. Moreover, about the supply of the carbon dioxide in a reaction system, it can implement similarly to the case where said reaction is performed in the reaction system of an organic solvent.
本発明の方法において、オルト置換アジ化ベンゼン誘導体と二酸化炭素とを反応させて得られる含窒素複素環化合物としては、分子内環化反応で形成される環構造がオルト置換基Aの種類により異なり、下記一般式(2)
で表される各種の含窒素複素環化合物を挙げることができる。
In the method of the present invention, the nitrogen-containing heterocyclic compound obtained by reacting an ortho-substituted azide benzene derivative with carbon dioxide has a different ring structure formed by intramolecular cyclization depending on the type of ortho substituent A. The following general formula (2)
And various nitrogen-containing heterocyclic compounds represented by the formula:
本発明の方法により得られる含窒素複素環化合物について、具体例としては、例えば、下記の基本構造(a)を有する無水イサト酸及びその誘導体、下記の基本構造(b)を有する2(1H)-キノリノン及びその誘導体、下記の基本構造(c)を有する2,4-キナゾリンジオン及びその誘導体等を例示することができる。
そして、本発明において、オルト置換アジ化ベンゼン誘導体と二酸化炭素とが反応して含窒素複素環化合物が生成する反応機構については、本発明者らは以下の通りであると考察している。
例えば、オルト置換アジ化ベンゼン誘導体として置換基Rが水素(-H)でオルト置換基Aがカルボキシル基(-COOH)であるオルトアジド安息香酸を用い、また、還元剤としてトリフェニルホスフィン(PPh3)を用い、そして、生成する含窒素複素環化合物として結合基Bが-C(=O)-で結合基Cが-O-である無水イサト酸の場合を例にすると、その反応機構は下記の反応式(1)の通りに示すことができる。
In the present invention, the inventors consider that the reaction mechanism in which an ortho-substituted azide benzene derivative and carbon dioxide react to form a nitrogen-containing heterocyclic compound is as follows.
For example, ortho-azide benzoic acid in which the substituent R is hydrogen (—H) and the ortho substituent A is carboxyl group (—COOH) is used as the ortho-substituted azide benzene derivative, and triphenylphosphine (PPh 3 ) is used as the reducing agent. In the case of isatoic anhydride in which the linking group B is —C (═O) — and the linking group C is —O— as an example of the nitrogen-containing heterocyclic compound produced, the reaction mechanism is as follows: It can be shown as reaction formula (1).
すなわち、先ず、反応開始段階ではオルトアジド安息香酸のアジド基がトリフェニルホスフィンと反応してアザホスファトランを形成し、次いでこのアザホスファトランが二酸化炭素(CO2)と反応し、4員環遷移状態を経てイソシアネートに変換され、生成したイソシアネートがオルト位のカルボキシル基(-COOH)と分子内環化反応を起こし、目的の無水イサト酸が生成する。 That is, at the beginning of the reaction, the azide group of orthoazide benzoic acid reacts with triphenylphosphine to form azaphosphatran, which then reacts with carbon dioxide (CO 2 ) to form a 4-membered ring. It is converted to isocyanate through a transition state, and the produced isocyanate undergoes an intramolecular cyclization reaction with an ortho-position carboxyl group (—COOH) to produce the desired isatoic anhydride.
以下、実施例に基づいて、本発明の含窒素複素環化合物の製造方法をより具体的に説明する。 Hereinafter, based on an Example, the manufacturing method of the nitrogen-containing heterocyclic compound of this invention is demonstrated more concretely.
〔実施例1:有機溶媒の反応系による検討〕
有機溶媒の反応系の検討においては、オルト置換アジ化ベンゼン誘導体としてオルトアジド安息香酸を用い、また、還元剤としてトリフェニルホスフィン(PPh3)を用い、そして、表1に示す有機溶剤と表1に示す割合の塩基(base)とを用いた。
先ず、反応容器内に表1に示す有機溶剤2.5mLと、反応に使用するオルトアジド安息香酸(81.6mg:0.0005mol)と、このオルトアジド安息香酸と等量(0.0005mol)の表1に示す塩基とを仕込み、次いで反応容器内を脱気し、二酸化炭素で膨らませた風船を用いて反応容器内の雰囲気を二酸化炭素雰囲気にすると共に、撹拌下に二酸化炭素を30分間バブリングして溶液を二酸化炭素で飽和させた。
[Example 1: Examination by reaction system of organic solvent]
In the examination of the reaction system of the organic solvent, orthoazide benzoic acid is used as the ortho-substituted azide benzene derivative, triphenylphosphine (PPh 3 ) is used as the reducing agent, and the organic solvents shown in Table 1 and Table 1 are used. The indicated proportion of base was used.
First, 2.5 mL of the organic solvent shown in Table 1 in the reaction vessel, orthoazide benzoic acid (81.6 mg: 0.0005 mol) used in the reaction, and the base shown in Table 1 in an equivalent amount (0.0005 mol) to this orthoazide benzoic acid. Then, the inside of the reaction vessel is degassed, and the atmosphere in the reaction vessel is changed to a carbon dioxide atmosphere using a balloon inflated with carbon dioxide, and carbon dioxide is bubbled for 30 minutes with stirring to make the solution carbon dioxide. Saturated with
次に、反応容器内にオルトアジド安息香酸(81.6mg:0.0005mol)とトリフェニルホスフィン(131.2mg:0.0005mol)とを添加し、表1に示す反応温度及び反応時間の条件で撹拌下に反応させ、反応終了時には反応溶液中に5mLの飽和塩化アンモニウム水溶液を添加して反応を終了させた。反応終了後、5mLの塩化メチレンを用いて目的物の抽出を3回行い、得られた合計の抽出液を無水硫酸ナトリウムで乾燥した後、塩化メチレンを減圧下に留去して粗生成物を得た。
この粗生成物を中性シリカゲルのカラムクロマトグラフィにより精製し、表1に示す収率で目的の無水イサト酸を得た。
Next, orthoazidobenzoic acid (81.6 mg: 0.0005 mol) and triphenylphosphine (131.2 mg: 0.0005 mol) are added to the reaction vessel, and the reaction is carried out under the conditions of reaction temperature and reaction time shown in Table 1. At the end of the reaction, 5 mL of saturated ammonium chloride aqueous solution was added to the reaction solution to terminate the reaction. After completion of the reaction, the target product was extracted three times with 5 mL of methylene chloride, and the total extract obtained was dried over anhydrous sodium sulfate, and then methylene chloride was distilled off under reduced pressure to obtain a crude product. Obtained.
The crude product was purified by neutral silica gel column chromatography to obtain the desired isatoic anhydride in the yield shown in Table 1.
この実施例1における反応式(2)を下記に示すと共に、この実施例1で行った試験No.(Ex.No.)1〜17の結果を表1に示す。
〔実施例2:水系溶媒の反応系による検討〕
水系溶媒の反応系の検討においても、オルト置換アジ化ベンゼン誘導体としてオルトアジド安息香酸を用い、また、還元剤としてトリフェニルホスフィン(PPh3)を用い、更に、陽イオン界面活性剤として臭化セチルトリメチルアンモニウム(CTMABr)を用い、そして、水系溶剤として表2に示す水又は水と有機溶剤との9:1混合溶剤を用いた。なお、表2に示す「pH7.6Buffer」は、pH7.6のリン酸二水素カリウム(KH2P04)/水酸化ナトリウム(NaOH)緩衝液である。
[Example 2: Examination by reaction system of aqueous solvent]
In the investigation of the reaction system of the aqueous solvent, orthoazide benzoic acid was used as the ortho-substituted azide benzene derivative, triphenylphosphine (PPh 3 ) was used as the reducing agent, and cetyltrimethyl bromide was used as the cationic surfactant. Ammonium (CTMABr) was used, and water or a 9: 1 mixed solvent of water and an organic solvent shown in Table 2 was used as an aqueous solvent. In addition, “pH7.6Buffer” shown in Table 2 is a pH 7.6 potassium dihydrogen phosphate (KH 2 P0 4 ) / sodium hydroxide (NaOH) buffer solution.
先ず、反応容器内に0.5mLの水(Ex. No. 1の場合)又は有機溶剤(Ex. Nos. 2〜17の場合)を仕込み、この溶剤中に反応に使用するオルトアジド安息香酸(81.6mg:0.0005mol)、このオルトアジド安息香酸と等量(0.0005mol)のトリフェニルホスフィン(131.2mg:0.0005mol)、及びオルトアジド安息香酸の1.5倍当量(0.00075mol)のCTMABrを添加し、20℃で5分間撹拌した。その後、水又はpH7.6のリン酸二水素カリウム(KH2P04)/水酸化ナトリウム(NaOH)緩衝液4.5mLを加えて反応系内を水系溶媒にし、反応容器内を脱気し、二酸化炭素で膨らませた風船を用いて反応容器内を二酸化炭素雰囲気にした後、20℃、18時間の条件で撹拌下に反応させた。 First, 0.5 mL of water (in the case of Ex. No. 1) or an organic solvent (in the case of Ex. Nos. 2 to 17) is charged into a reaction vessel, and orthoazide benzoic acid (81.6) used for the reaction in this solvent. mg: 0.0005 mol), an equivalent amount (0.0005 mol) of triphenylphosphine (131.2 mg: 0.0005 mol) to this orthoazidobenzoic acid, and 1.5 times equivalent (0.00075 mol) of CTMABr of orthoazidebenzoic acid, and 20 Stir at 5 ° C. for 5 minutes. Thereafter, 4.5 mL of water or potassium dihydrogen phosphate (KH 2 P0 4 ) / sodium hydroxide (NaOH) buffer at pH 7.6 is added to make the reaction system an aqueous solvent, and the reaction container is degassed. The inside of the reaction vessel was filled with a carbon dioxide atmosphere using a balloon inflated with carbon dioxide, and then reacted under stirring at 20 ° C. for 18 hours.
反応終了時には、反応溶液中に5mLの飽和塩化アンモニウム水溶液を添加して反応を終了させ、その後、5mLの塩化メチレンを用いて目的物の抽出を3回行い、得られた合計の抽出液を無水硫酸ナトリウムで乾燥した後、塩化メチレンを減圧下に留去して粗生成物を得た。
この粗生成物を中性シリカゲルのカラムクロマトグラフィにより精製し、表1に示す収率で目的の無水イサト酸を得た。
At the end of the reaction, 5 mL of saturated aqueous ammonium chloride solution is added to the reaction solution to terminate the reaction, and then the target product is extracted three times with 5 mL of methylene chloride, and the total extract obtained is anhydrous. After drying with sodium sulfate, methylene chloride was distilled off under reduced pressure to obtain a crude product.
The crude product was purified by neutral silica gel column chromatography to obtain the desired isatoic anhydride in the yield shown in Table 1.
この実施例2における反応式(3)を下記に示すと共に、この実施例2で行った試験No.(Ex.No.)1〜17の結果を表2に示す。
〔実施例3〜13〕
一般式(1)のオルト置換アジ化ベンゼン誘導体として表3に示す置換基R及びオルト置換基Aのものを用いた以外は、実施例2のEx. No.17に従って対応する一般式(2)の含窒素複素環化合物を合成した。
得られた一般式(2)の含窒素複素環化合物の収率を、上記実施例2のEx. No.17の結果と共に表3に示す。
[Examples 3 to 13]
The corresponding general formula (2) according to Ex. No. 17 of Example 2, except that the ortho-substituted azide benzene derivative of the general formula (1) is the one of the substituent R and the ortho substituent A shown in Table 3 A nitrogen-containing heterocyclic compound was synthesized.
The yield of the obtained nitrogen-containing heterocyclic compound of the general formula (2) is shown in Table 3 together with the result of Ex. No. 17 in Example 2 above.
なお、一般式(2)で表される実施例3〜13の含窒素複素環化合物は以下の通りである。
実施例3:8-メチルイサト酸無水物、実施例4:7-メチルイサト酸無水物、実施例5:6-メトキシイサト酸無水物、実施例6:6-ヒドロキシイサト酸無水物、実施例7:7-ニトロイサト酸無水物、実施例8:7-クロロイサト酸無水物、実施例9:2(1H)-キノリノン、実施例10:6-カルボキシルイサト酸無水物、実施例11:下記の化合物(1)で示される3-ベンジル-2,4-キナゾリンジオン、実施例12:下記の化合物(2)で示される3-アセチル-2,4-キナゾリンジオン、及び実施例13:下記の化合物(3)で示される3-エトキシカルボニル-4-ヒドロキシ-2(1H)-キノリノン。
In addition, the nitrogen-containing heterocyclic compound of Examples 3-13 represented by General formula (2) is as follows.
Example 3: 8-methyl isatoic anhydride, Example 4: 7-methyl isatoic anhydride, Example 5: 6-methoxy isatoic anhydride, Example 6: 6-hydroxy isatoic anhydride, Example 7: 7-nitroisatoic anhydride, Example 8: 7-chloroisatoic anhydride, Example 9: 2 (1H) -quinolinone, Example 10: 6-carboxy isatoic anhydride, Example 11: ), 3-benzyl-2,4-quinazolinedione, Example 12: 3-acetyl-2,4-quinazolinedione represented by the following compound (2), and Example 13: the following compound (3) 3-Ethoxycarbonyl-4-hydroxy-2 (1H) -quinolinone represented by
Claims (7)
〔但し、一般式(1)及び一般式(2)において、Rは、ベンゼン核の3〜6位のいずれかの位置に結合した1〜4個の水素及び/又は水素以外の置換基であって、互いに同じでも異なっていてもよく、
また、一般式(1)において、Aは、反応系内で生成したイソシアネートとの間で分子内環化反応が可能であると共に、この分子内環化反応により一般式(2)の−B−C−結合を形成するオルト置換基であり、
更に、一般式(2)において、Bは下記式(B)から選ばれたいずれかの結合基であって、Cは下記式(C)から選ばれたいずれかの結合基である。
(但し、前記結合基Bの式(B)及び結合基Cの式(C)において、R1、R2、及びR3は水素、−OH、炭素数1〜4の低級アルキル基、炭素数7〜10のアリールアルキル基、炭素数2〜5のアルキルカルボニル基、炭素数2〜5のアルコキシカルボニル基、アルコキシ基、及びシリル基から選ばれたいずれかの置換基である。)〕 An ortho-substituted azide benzene derivative represented by the following general formula (1) is reacted with carbon dioxide in the presence of a reducing agent in a reaction solvent to synthesize a nitrogen-containing heterocyclic compound represented by the following general formula (2). And a method for producing a nitrogen-containing heterocyclic compound.
[However, in the general formula (1) and the general formula (2), R is a 1 to 4 hydrogens and / or other than hydrogen substituent attached to any position of the 3-6-position of the benzene nucleus Can be the same or different,
In the general formula (1), A together with a possible intramolecular cyclization reaction between the produced isocyanate in the reaction system, by the intramolecular cyclization reaction formula (2) -B- An ortho substituent that forms a C-bond ;
Further, in the general formula (2) , B is any bonding group selected from the following formula (B), and C is any bonding group selected from the following formula (C).
(However, in the formula (B) of the linking group B and the formula (C) of the linking group C, R 1 , R 2 , and R 3 are hydrogen, —OH, a lower alkyl group having 1 to 4 carbon atoms, and a carbon number. It is a substituent selected from an arylalkyl group having 7 to 10 carbon atoms, an alkylcarbonyl group having 2 to 5 carbon atoms, an alkoxycarbonyl group having 2 to 5 carbon atoms, an alkoxy group, and a silyl group.
から選ばれた置換基であることを特徴とする請求項1に記載の含窒素複素環化合物の製造方法。 The ortho substituent A is represented by the following formula (A)
The method for producing a nitrogen-containing heterocyclic compound according to claim 1, wherein the substituent is selected from the group consisting of:
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