JP5281152B2 - Method for producing 2-alkyl-3-aminothiophene derivative - Google Patents
Method for producing 2-alkyl-3-aminothiophene derivative Download PDFInfo
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- JP5281152B2 JP5281152B2 JP2011509320A JP2011509320A JP5281152B2 JP 5281152 B2 JP5281152 B2 JP 5281152B2 JP 2011509320 A JP2011509320 A JP 2011509320A JP 2011509320 A JP2011509320 A JP 2011509320A JP 5281152 B2 JP5281152 B2 JP 5281152B2
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- 238000004519 manufacturing process Methods 0.000 title claims abstract description 77
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 99
- 150000001875 compounds Chemical class 0.000 claims abstract description 72
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 48
- 238000000034 method Methods 0.000 claims abstract description 26
- 125000001424 substituent group Chemical group 0.000 claims abstract description 16
- 125000005843 halogen group Chemical group 0.000 claims abstract description 14
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 12
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 11
- 125000004434 sulfur atom Chemical group 0.000 claims abstract description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 6
- -1 1,3-dimethylbutyl group Chemical group 0.000 claims description 44
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 28
- 239000003795 chemical substances by application Substances 0.000 claims description 24
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 claims description 16
- UYQPORADLIPLIO-UHFFFAOYSA-N 3-nitro-2,5-dihydrothiophene Chemical class [O-][N+](=O)C1=CCSC1 UYQPORADLIPLIO-UHFFFAOYSA-N 0.000 claims description 15
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 14
- YUIOPHXTILULQC-UHFFFAOYSA-N 1,4-Dithiane-2,5-diol Chemical compound OC1CSC(O)CS1 YUIOPHXTILULQC-UHFFFAOYSA-N 0.000 claims description 12
- BWGLULGGFIAHBG-UHFFFAOYSA-N 3-nitrothiolane Chemical class [O-][N+](=O)C1CCSC1 BWGLULGGFIAHBG-UHFFFAOYSA-N 0.000 claims description 12
- LHYIFXPNAVCSGE-UHFFFAOYSA-N 4-nitrothiolan-3-ol Chemical class OC1CSCC1[N+]([O-])=O LHYIFXPNAVCSGE-UHFFFAOYSA-N 0.000 claims description 12
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 claims description 10
- FLJWVVUJGVNXMZ-UHFFFAOYSA-N 2-sulfanylacetaldehyde Chemical compound SCC=O FLJWVVUJGVNXMZ-UHFFFAOYSA-N 0.000 claims description 9
- 230000002140 halogenating effect Effects 0.000 claims description 9
- 125000003118 aryl group Chemical group 0.000 claims description 6
- 150000001602 bicycloalkyls Chemical group 0.000 claims description 6
- 125000001188 haloalkyl group Chemical group 0.000 claims description 6
- 239000003905 agrochemical Substances 0.000 claims description 4
- 239000000417 fungicide Substances 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 230000001590 oxidative effect Effects 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 93
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 75
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 69
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 51
- 239000002904 solvent Substances 0.000 description 48
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 42
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 36
- 238000006243 chemical reaction Methods 0.000 description 35
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 29
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 28
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 27
- 239000000243 solution Substances 0.000 description 25
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 24
- 239000002585 base Substances 0.000 description 24
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 21
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 21
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 21
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
- 239000000203 mixture Substances 0.000 description 18
- 238000010898 silica gel chromatography Methods 0.000 description 17
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 16
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 16
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- 229910052757 nitrogen Inorganic materials 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- 238000005160 1H NMR spectroscopy Methods 0.000 description 14
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 14
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 14
- 150000007529 inorganic bases Chemical class 0.000 description 14
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 14
- 235000019341 magnesium sulphate Nutrition 0.000 description 14
- 150000007530 organic bases Chemical class 0.000 description 14
- 239000012044 organic layer Substances 0.000 description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 11
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 11
- 125000004971 nitroalkyl group Chemical group 0.000 description 10
- 239000002253 acid Substances 0.000 description 9
- 239000000543 intermediate Substances 0.000 description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 8
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 8
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 8
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 8
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 8
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 8
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 8
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 8
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 8
- 150000001350 alkyl halides Chemical class 0.000 description 8
- 150000001408 amides Chemical class 0.000 description 8
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 8
- 238000009835 boiling Methods 0.000 description 8
- 150000002148 esters Chemical class 0.000 description 8
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 8
- 229930195733 hydrocarbon Natural products 0.000 description 8
- 150000002430 hydrocarbons Chemical class 0.000 description 8
- YAMHXTCMCPHKLN-UHFFFAOYSA-N imidazolidin-2-one Chemical compound O=C1NCCN1 YAMHXTCMCPHKLN-UHFFFAOYSA-N 0.000 description 8
- 238000002844 melting Methods 0.000 description 8
- 230000008018 melting Effects 0.000 description 8
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- 239000008096 xylene Substances 0.000 description 8
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 7
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 7
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 7
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 7
- 150000001299 aldehydes Chemical class 0.000 description 7
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 7
- 150000008041 alkali metal carbonates Chemical class 0.000 description 7
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 7
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 7
- 229910021529 ammonia Inorganic materials 0.000 description 7
- 235000011114 ammonium hydroxide Nutrition 0.000 description 7
- HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 description 7
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 description 7
- 229910001863 barium hydroxide Inorganic materials 0.000 description 7
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 7
- 239000000920 calcium hydroxide Substances 0.000 description 7
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 7
- UTBIMNXEDGNJFE-UHFFFAOYSA-N collidine Natural products CC1=CC=C(C)C(C)=N1 UTBIMNXEDGNJFE-UHFFFAOYSA-N 0.000 description 7
- 239000011736 potassium bicarbonate Substances 0.000 description 7
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 7
- 235000015497 potassium bicarbonate Nutrition 0.000 description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 description 7
- 235000011181 potassium carbonates Nutrition 0.000 description 7
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 7
- 150000003222 pyridines Chemical class 0.000 description 7
- 238000006722 reduction reaction Methods 0.000 description 7
- 229920006395 saturated elastomer Polymers 0.000 description 7
- 229910000029 sodium carbonate Inorganic materials 0.000 description 7
- 235000017550 sodium carbonate Nutrition 0.000 description 7
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 7
- 125000005270 trialkylamine group Chemical group 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 6
- 150000001721 carbon Chemical group 0.000 description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 6
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 5
- HCUYBXPSSCRKRF-UHFFFAOYSA-N diphosgene Chemical compound ClC(=O)OC(Cl)(Cl)Cl HCUYBXPSSCRKRF-UHFFFAOYSA-N 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 5
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 5
- HDECRAPHCDXMIJ-UHFFFAOYSA-N 2-methylbenzenesulfonyl chloride Chemical compound CC1=CC=CC=C1S(Cl)(=O)=O HDECRAPHCDXMIJ-UHFFFAOYSA-N 0.000 description 4
- DQPLRCYBRBOYFV-UHFFFAOYSA-N 5-(4-methylpentan-2-yl)-4-nitrothiolan-3-ol Chemical compound CC(C)CC(C)C1SCC(O)C1[N+]([O-])=O DQPLRCYBRBOYFV-UHFFFAOYSA-N 0.000 description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 4
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 description 4
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 4
- 239000012346 acetyl chloride Substances 0.000 description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 4
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 150000001244 carboxylic acid anhydrides Chemical class 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 4
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- GRGCWBWNLSTIEN-UHFFFAOYSA-N trifluoromethanesulfonyl chloride Chemical compound FC(F)(F)S(Cl)(=O)=O GRGCWBWNLSTIEN-UHFFFAOYSA-N 0.000 description 4
- HRCISEMYPHMUNE-UHFFFAOYSA-N 2-(4-methylpentan-2-yl)-3-nitrothiophene Chemical compound CC(C)CC(C)C=1SC=CC=1[N+]([O-])=O HRCISEMYPHMUNE-UHFFFAOYSA-N 0.000 description 3
- IFWWHXZKIXSPNM-UHFFFAOYSA-N 3,5-dimethyl-1-nitrohexan-2-ol Chemical compound CC(C)CC(C)C(O)C[N+]([O-])=O IFWWHXZKIXSPNM-UHFFFAOYSA-N 0.000 description 3
- SIPCFXFCVTUAID-UHFFFAOYSA-N 3-nitrothiophene Chemical compound [O-][N+](=O)C=1C=CSC=1 SIPCFXFCVTUAID-UHFFFAOYSA-N 0.000 description 3
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 235000011150 stannous chloride Nutrition 0.000 description 3
- 229930192474 thiophene Natural products 0.000 description 3
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 3
- TXRMJBZQEPEPNV-UHFFFAOYSA-N (3,5-dimethyl-1-nitrohexan-2-yl) acetate Chemical compound CC(C)CC(C)C(C[N+]([O-])=O)OC(C)=O TXRMJBZQEPEPNV-UHFFFAOYSA-N 0.000 description 2
- 125000005918 1,2-dimethylbutyl group Chemical group 0.000 description 2
- FTZILAQGHINQQR-UHFFFAOYSA-N 2-Methylpentanal Chemical compound CCCC(C)C=O FTZILAQGHINQQR-UHFFFAOYSA-N 0.000 description 2
- PFLKTUYXFDIOTN-UHFFFAOYSA-N 2-chloro-3,5-dimethyl-1-nitrohexane Chemical compound CC(C)CC(C)C(Cl)C[N+]([O-])=O PFLKTUYXFDIOTN-UHFFFAOYSA-N 0.000 description 2
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 2
- 125000005916 2-methylpentyl group Chemical group 0.000 description 2
- QHXHSPJEWDGKBI-UHFFFAOYSA-N 3,5-dimethyl-1-nitrohex-1-ene Chemical compound CC(C)CC(C)C=C[N+]([O-])=O QHXHSPJEWDGKBI-UHFFFAOYSA-N 0.000 description 2
- MXJVWKMCKLHMOH-UHFFFAOYSA-N 3-methyl-1-nitrohex-1-ene Chemical compound CCCC(C)C=C[N+]([O-])=O MXJVWKMCKLHMOH-UHFFFAOYSA-N 0.000 description 2
- 125000003542 3-methylbutan-2-yl group Chemical group [H]C([H])([H])C([H])(*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000005917 3-methylpentyl group Chemical group 0.000 description 2
- QHEITFYVLMRVEC-UHFFFAOYSA-N 3-nitro-2-pentan-2-yl-2,5-dihydrothiophene Chemical compound CCCC(C)C1SCC=C1[N+]([O-])=O QHEITFYVLMRVEC-UHFFFAOYSA-N 0.000 description 2
- UNVRHFCUWHHJKZ-UHFFFAOYSA-N 4-nitro-5-pentan-2-ylthiolan-3-ol Chemical compound CCCC(C)C1SCC(O)C1[N+]([O-])=O UNVRHFCUWHHJKZ-UHFFFAOYSA-N 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 2
- 239000007848 Bronsted acid Substances 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
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- XTEGARKTQYYJKE-UHFFFAOYSA-N chloric acid Chemical compound OCl(=O)=O XTEGARKTQYYJKE-UHFFFAOYSA-N 0.000 description 1
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- 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 description 1
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- WTZQMDJBWPQYAU-UHFFFAOYSA-N oxalyl dichloride;thionyl dichloride Chemical compound ClS(Cl)=O.ClC(=O)C(Cl)=O WTZQMDJBWPQYAU-UHFFFAOYSA-N 0.000 description 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 1
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- IREVRWRNACELSM-UHFFFAOYSA-J ruthenium(4+);tetrachloride Chemical compound Cl[Ru](Cl)(Cl)Cl IREVRWRNACELSM-UHFFFAOYSA-J 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
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- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 1
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Classifications
-
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Abstract
Description
本発明は2−アルキル−3−アミノチオフェンの製造方法およびその製造中間体に関する。 The present invention relates to a method for producing 2-alkyl-3-aminothiophene and a production intermediate thereof.
2−アルキル−3−アミノチオフェンの製造方法としては、3−アミノチオフェン誘導体と各種カルボニル化合物を反応させ2−アルケニル−3−アミノチオフェン誘導体を製造し、還元工程を経ることによる製造方法が開示されている(例えば、特開2008−120710号公報参照)。
また2−アルキル−3−ニトロチオフェンの製造方法として、3−ニトロチオフェンとグリニャール試薬を反応させた後、酸化することによる製造方法が開示されている(例えば、TETRAHEDORN 第44巻 第20号 (1988年)6435頁参照)。
さらに3−ニトロチオフェンの製造方法として、チオフェンをニトロ化する製造方法が開示されている(例えば、JUSTUS LIEBIGS ANNALEN DER CHEMIE 第501巻 (1933年) 174頁参照)。As a method for producing 2-alkyl-3-aminothiophene, a production method by reacting a 3-aminothiophene derivative with various carbonyl compounds to produce a 2-alkenyl-3-aminothiophene derivative and undergoing a reduction step is disclosed. (For example, refer to JP 2008-120710 A).
Further, as a method for producing 2-alkyl-3-nitrothiophene, a production method in which 3-nitrothiophene and a Grignard reagent are reacted and then oxidized is disclosed (for example, TETRAHEDORN Vol. 44 No. 20 (1988). (Year) page 6435).
Further, as a method for producing 3-nitrothiophene, a production method for nitrating thiophene is disclosed (for example, see JUSTUS LIEBIGS ANNALEN DER CHEMIE Vol. 501 (1933) p. 174).
しかし、特開2008−120710号公報に記載の製造方法では、3−アミノチオフェン誘導体は不安定であり取り扱いが難しいためアミノ基の保護基としてアシル基、カーバメート基等を使用することが必要であり、保護基の着脱工程を要することなど操作性、経済性の観点から改善の余地がある。
一方、ニトロ基は接触水素添加反応に代表される還元反応により、アミノ基に変換できることが公知であることから、2−アルキル−3−ニトロチオフェン誘導体を還元することにより、3−アミノ−2−アルキルチオフェン誘導体が製造できることが予想される。しかしながら、2−アルキル−3−ニトロチオフェン誘導体が製造困難であることから、これまで2−アルキル−3−ニトロチオフェン誘導体を還元することによる、2−アルキル−3−アミノチオフェン誘導体の製造方法は報告されていない。However, in the production method described in Japanese Patent Application Laid-Open No. 2008-120710, it is necessary to use an acyl group, a carbamate group or the like as a protective group for an amino group because 3-aminothiophene derivatives are unstable and difficult to handle. There is room for improvement from the viewpoint of operability and economy, such as requiring a step for attaching and detaching the protecting group.
On the other hand, since it is known that a nitro group can be converted to an amino group by a reduction reaction typified by a catalytic hydrogenation reaction, by reducing a 2-alkyl-3-nitrothiophene derivative, 3-amino-2- It is expected that alkylthiophene derivatives can be produced. However, since the production of 2-alkyl-3-nitrothiophene derivatives is difficult, a method for producing 2-alkyl-3-aminothiophene derivatives by reducing 2-alkyl-3-nitrothiophene derivatives has been reported so far. It has not been.
ここで、TETRAHEDORN 第44巻 第20号 (1988年)6435頁に記載の2−アルキル−3−ニトロチオフェンの製造方法では、該製造方法における出発原料である3−ニトロチオフェン自体が製造困難であることから改善の余地がある。また、JUSTUS LIEBIGS ANNALEN DER CHEMIE 第501巻 (1933年) 174頁に記載の製造方法では、生成物が位置異性体混合物として得られるため低収率である。また異性体の分離工程を必要とするなど、経済性および操作性の観点から改善の余地がある。 Here, in the production method of 2-alkyl-3-nitrothiophene described in TETRAHEDORN Vol. 44 No. 20 (1988), p. 6435, 3-nitrothiophene itself, which is a starting material in the production method, is difficult to produce. There is room for improvement. Further, in the production method described in JUSTUS LIEBIGS ANNALEN DER CHEMIE Vol. 501 (1933), page 174, the product is obtained as a mixture of regioisomers, so the yield is low. In addition, there is room for improvement from the viewpoint of economy and operability, such as requiring a separation step of isomers.
本発明は2−アルキル−3−アミノチオフェンを効率的に製造する方法を提供することを目的とする。 An object of the present invention is to provide a method for efficiently producing 2-alkyl-3-aminothiophene.
本発明者は上記課題を解決するために、鋭意検討を行い、新規な2−アルキル−3−ニトロチオフェン誘導体の製造方法を見出し、該2−アルキル−3−ニトロチオフェン誘導体を還元することによる効率的な2−アルキル−3−アミノチオフェン誘導体の製造方法として、本発明を完成させるに至った。すなわち本発明は以下の通りである。 In order to solve the above-mentioned problems, the present inventor has intensively studied, discovered a method for producing a novel 2-alkyl-3-nitrothiophene derivative, and reduced the efficiency of the 2-alkyl-3-nitrothiophene derivative. As a typical method for producing a 2-alkyl-3-aminothiophene derivative, the present invention has been completed. That is, the present invention is as follows.
<1> 下記一般式(1) <1> The following general formula (1)
[一般式(1)中、Rは炭素数1から10のアルキル基もしくは炭素数3から10のシクロアルキル基で置換されてもよい炭素数1から18のアルキル基、炭素数1から10のアルキル基もしくは炭素数3から10のシクロアルキル基で置換されてもよい炭素数3から10のシクロアルキル基、または、炭素数1から10のアルキル基もしくは炭素数3から10のシクロアルキル基で置換されてもよい炭素数6から12のビシクロアルキル基を表す。Xはヒドロキシ基、ハロゲン原子、または下記一般式(2) [In General Formula (1), R is an alkyl group having 1 to 18 carbon atoms and an alkyl group having 1 to 10 carbon atoms which may be substituted with an alkyl group having 1 to 10 carbon atoms or a cycloalkyl group having 3 to 10 carbon atoms. A cycloalkyl group having 3 to 10 carbon atoms which may be substituted with a group or a cycloalkyl group having 3 to 10 carbon atoms, or an alkyl group having 1 to 10 carbon atoms or a cycloalkyl group having 3 to 10 carbon atoms. Represents a bicycloalkyl group having 6 to 12 carbon atoms. X is a hydroxy group, a halogen atom, or the following general formula (2)
(式中、Aは炭素原子または硫黄原子を表し、Aが炭素原子の場合nは1を表し、Aが硫黄原子の場合nは1または2を表す。Qは炭素数1から10のアルキル基、炭素数3から10のシクロアルキル基、炭素数1から10のハロアルキル基、炭素数1から10のヒドロカルビルオキシ基、または、炭素数1から6のアルキル基で置換されてもよいアリール基を表す。#は結合位置を表す。)で表される置換基を表す。)]で表される化合物を酸化して、下記一般式(3) (In the formula, A represents a carbon atom or a sulfur atom. When A is a carbon atom, n represents 1. When A represents a sulfur atom, n represents 1 or 2. Q represents an alkyl group having 1 to 10 carbon atoms. Represents an aryl group which may be substituted with a cycloalkyl group having 3 to 10 carbon atoms, a haloalkyl group having 1 to 10 carbon atoms, a hydrocarbyloxy group having 1 to 10 carbon atoms, or an alkyl group having 1 to 6 carbon atoms. # Represents a bonding position). The compound represented by the following general formula (3)
[一般式(3)中、Rは前記一般式(1)におけるRと同一である]で表される化合物を得る工程(A)と、
前記一般式(3)で表される化合物を還元する工程(B)と、を含む下記一般式(4)[In the general formula (3), R is the same as R in the general formula (1)] (A) to obtain a compound represented by:
A step (B) of reducing the compound represented by the general formula (3), and the following general formula (4):
[一般式(4)中、Rは前記一般式(1)におけるRと同一である]で表される2−アルキル−3−アミノチオフェン誘導体の製造方法。
<2> 前記Rが、下記一般式(6)[In general formula (4), R is the same as R in the said General formula (1)] The manufacturing method of the 2-alkyl-3-aminothiophene derivative represented.
<2> R is the following general formula (6)
[一般式(6)中、R1は水素原子、または、炭素数1から6の直鎖もしくは分岐のアルキル基を表す。#は結合位置を表す。]で表される置換基である前記<1>に記載の製造方法。
<3> 前記Rが、1,3−ジメチルブチル基である前記<1>または<2>に記載の製造方法。
<4> 前記工程(A)が、下記一般式(8)[In General Formula (6), R 1 represents a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms. # Represents a bonding position. ] The manufacturing method as described in said <1> which is a substituent represented by.
<3> The production method according to <1> or <2>, wherein R is a 1,3-dimethylbutyl group.
<4> The step (A) is represented by the following general formula (8)
[一般式(8)中、Rは前記一般式(1)におけるRと同一である。]で表される化合物を、エステル化剤またはハロゲン化剤と反応させて、下記一般式(1a) [In General Formula (8), R is the same as R in General Formula (1). The compound represented by the general formula (1a) is reacted with an esterifying agent or a halogenating agent.
[一般式(1a)中、Rは前記一般式(1)におけるRと同一である。Xaはハロゲン原子または前記一般式(2)で表される置換基を表す。]で表される化合物を得る工程と、前記一般式(Ia)で表される化合物から、前記一般式(3)で表される化合物を得る工程と、をさらに含む前記<1>〜<3>のいずれか1項に記載の製造方法。
<5> 前記工程(A)が、前記一般式(1)で表される化合物から、Xを脱離させて、下記一般式(5)
[In General Formula (1a), R is the same as R in General Formula (1). Xa represents a halogen atom or a substituent represented by the general formula (2). And the step of obtaining the compound represented by the general formula (3) from the compound represented by the general formula (Ia). <1> to <3 The manufacturing method of any one of>.
<5> In the step (A), X is eliminated from the compound represented by the general formula (1), and the following general formula (5)
[一般式(5)中、Rは前記一般式(1)におけるRと同一である。]で表される化合物を得る工程(A−1)と、前記一般式(5)で表される化合物を脱水反応させて、前記一般式(3)で表される化合物を得る工程(A−2)と、をさらに含む前記<1>〜<3>のいずれか1項に記載の製造方法。
<6> 下記一般式(7)
[In General Formula (5), R is the same as R in General Formula (1). Step (A-1) for obtaining a compound represented by the general formula (5) and a step (A-) for obtaining a compound represented by the general formula (3) by subjecting the compound represented by the general formula (5) to a dehydration reaction . 2) and the manufacturing method according to any one of <1> to <3>.
<6> The following general formula (7)
[一般式(7)中、Rは前記一般式(1)におけるRと同一であり、X7はハロゲン原子または前記一般式(2)で表される置換基を表す。]で表される化合物と、α−メルカプトアセトアルデヒドまたは1,4−ジチアン−2,5−ジオールとを反応させて、下記一般式(8)[In General Formula (7), R is the same as R in General Formula (1), and X 7 represents a halogen atom or a substituent represented by General Formula (2). And a compound represented by general formula (8) below, and α-mercaptoacetaldehyde or 1,4-dithian-2,5-diol.
[一般式(8)中、Rは前記一般式(1)におけるRと同一である。]で表される化合物を得る工程をさらに含む、前記<1>〜<5>のいずれか1項に記載の製造方法。
<7> 下記一般式(9)[In General Formula (8), R is the same as R in General Formula (1). The manufacturing method of any one of said <1>-<5> which further includes the process of obtaining the compound represented by this.
<7> The following general formula (9)
[一般式(9)中、Rは前記一般式(1)におけるRと同一である。]で表される化合物を、エステル化剤またはハロゲン化剤と反応させて、前記一般式(7)で表される化合物を得る工程を、更に含む前記<6>に記載の製造方法。 [In General Formula (9), R is the same as R in General Formula (1). ] The manufacturing method as described in said <6> which further includes the process of obtaining the compound represented by the said General formula (7) by making the compound represented by an esterifying agent or a halogenating agent react .
[一般式(10)中、Rは前記一般式(1)におけるRと同一である。]で表される化合物と、ニトロメタンとを反応させて、前記一般式(9)で表される化合物を得る工程を、さらに含む請求項7に記載の製造方法。
<9> 下記一般式(11)[In General Formula (10), R is the same as R in General Formula (1). The method according to claim 7, further comprising a step of reacting the compound represented by formula (II) with nitromethane to obtain the compound represented by the general formula (9).
<9> The following general formula (11)
[一般式(11)中、Rは前記一般式(1)におけるRと同一である。]で表される化合物と、α−メルカプトアセトアルデヒドまたは1,4−ジチアン−2,5−ジオールとを反応させて、下記一般式(8) [In General Formula (11), R is the same as R in General Formula (1). And a compound represented by general formula (8) below, and α-mercaptoacetaldehyde or 1,4-dithian-2,5-diol.
[一般式(8)中、Rは前記一般式(1)におけるRと同一である。]で表される化合物を得る工程を、さらに含む前記<1>〜<5>のいずれか1項に記載の製造方法。
<10> 下記一般式(9)[In General Formula (8), R is the same as R in General Formula (1). ] The manufacturing method of any one of said <1>-<5> which further includes the process of obtaining the compound represented by this.
<10> The following general formula (9)
[一般式(9)中、Rは前記一般式(1)におけるRと同一である。]で表される化合物を脱水反応させて、前記一般式(11)で表される化合物を得る工程を、さらに含む前記<9>に記載の製造方法。
<11> 下記一般式(10)[In General Formula (9), R is the same as R in General Formula (1). ] The manufacturing method as described in said <9> which further includes the process of dehydrating the compound represented by and obtaining the compound represented by the said General formula (11).
<11> The following general formula (10)
[一般式(10)中、Rは前記一般式(1)におけるRと同一である。]で表される化合物と、ニトロメタンとを反応させて、前記一般式(9)で表される化合物を得る工程を、さらに含む前記<10>に記載の製造方法。 [In General Formula (10), R is the same as R in General Formula (1). ] And a compound represented by is reacted with a nitromethane, producing how according to obtain a compound represented by the general formula (9), to <10>, further comprising.
<12> 下記一般式(8) <12 > The following general formula (8)
[一般式(8)中、Rは下記一般式(6)
(一般式(6)中、R 1 は水素原子、または、炭素数1から6の直鎖もしくは分岐のアルキル基を表す。#は結合位置を表す。)で表される置換基を表す。]で表される3−ヒドロキシ−4−ニトロテトラヒドロチオフェン誘導体。
[In general formula (8), R represents the following general formula (6)
(In General Formula (6), R 1 represents a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms. # Represents a bonding position) . ] The 3-hydroxy-4-nitrotetrahydrothiophene derivative represented by this .
<13> 前記一般式(8)におけるRが、1,3−ジメチルブチル基である前記<12>に記載の3−ヒドロキシ−4−ニトロテトラヒドロチオフェン誘導体。
<14> 下記一般式(1)
<13 > The 3-hydroxy-4-nitrotetrahydrothiophene derivative according to < 12 >, wherein R in the general formula (8) is a 1,3-dimethylbutyl group.
< 14 > The following general formula (1)
[一般式(1)中、Rは前記一般式(6)で表される置換基を表す。Xは、ヒドロキシ基、ハロゲン原子、または、下記一般式(2) [In General Formula (1), R represents a substituent represented by General Formula (6) . X is a hydroxy group, a halogen atom, or the following general formula (2)
(一般式(2)中、Aは炭素原子または硫黄原子を表し、Aが炭素原子の場合nは1を表し、Aが硫黄原子の場合nは1または2を表す。Qは炭素数1から10のアルキル基、炭素数3から10のシクロアルキル基、炭素数1から10のハロアルキル基、炭素数1から10のヒドロカルビルオキシ基、または、炭素数1から6のアルキル基で置換されてもよいアリール基を表す。#は結合位置を表す。)で表される置換基を表す。]で表される3−ニトロテトラヒドロチオフェン誘導体。
<15> 一般式(1)におけるRが、1,3−ジメチルブチル基である前記<14>に記載の3−ニトロテトラヒドロチオフェン誘導体。
<16> 下記一般式(5)
(In the general formula (2), A represents a carbon atom or a sulfur atom, n represents 1 when A is a carbon atom, and n represents 1 or 2 when A is a sulfur atom. Q represents 1 to 2 carbon atoms. It may be substituted with an alkyl group having 10 carbon atoms, a cycloalkyl group having 3 to 10 carbon atoms, a haloalkyl group having 1 to 10 carbon atoms, a hydrocarbyloxy group having 1 to 10 carbon atoms, or an alkyl group having 1 to 6 carbon atoms. Represents an aryl group, and # represents a bonding position. 3-Nitro tetrahydrothiophene induction member represented by.
< 15 > The 3-nitrotetrahydrothiophene derivative according to < 14 >, wherein R in the general formula (1) is a 1,3-dimethylbutyl group.
< 16 > The following general formula (5)
[一般式(5)中、Rは炭素数1から10のアルキル基もしくは炭素数3から10のシクロアルキル基で置換されてもよい炭素数1から18のアルキル基、炭素数1から10のアルキル基もしくは炭素数3から10のシクロアルキル基で置換されてもよい炭素数3から10のシクロアルキル基、または、炭素数1から10のアルキル基もしくは炭素数3から10のシクロアルキル基で置換されてもよい炭素数6から12のビシクロアルキル基を表す。]で表される3−ニトロ−2,5−ジヒドロチオフェン誘導体。
<17> 一般式(5)におけるRが、下記一般式(6)
[In General Formula (5), R is an alkyl group having 1 to 18 carbon atoms which may be substituted with an alkyl group having 1 to 10 carbon atoms or a cycloalkyl group having 3 to 10 carbon atoms, or an alkyl group having 1 to 10 carbon atoms. A cycloalkyl group having 3 to 10 carbon atoms which may be substituted with a group or a cycloalkyl group having 3 to 10 carbon atoms, or an alkyl group having 1 to 10 carbon atoms or a cycloalkyl group having 3 to 10 carbon atoms. Represents a bicycloalkyl group having 6 to 12 carbon atoms. ] The 3-nitro-2,5-dihydrothiophene derivative represented by this.
< 17 > R in the general formula (5) is represented by the following general formula (6).
[一般式(6)中、R1は水素原子、または、炭素数1から6の直鎖もしくは分岐のアルキル基を表す。#は結合位置を表す。]で表される置換基である前記<16>に記載の3−ニトロ−2,5−ジヒドロチオフェン誘導体。
<18> 一般式(5)におけるRが、1,3−ジメチルブチル基である前記<16>に記載の3−ニトロ−2,5−ジヒドロチオフェン誘導体。
<19> 下記一般式(3)
[In General Formula (6), R 1 represents a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms. # Represents a bonding position. ] The 3-nitro-2,5-dihydrothiophene derivative according to < 16 >, which is a substituent represented by
< 18 > The 3-nitro-2,5-dihydrothiophene derivative according to < 16 >, wherein R in the general formula (5) is a 1,3-dimethylbutyl group.
< 19 > The following general formula (3)
[一般式(3)中、Rは前記一般式(6)で表される置換基を表す。]で表される2−アルキル−3−ニトロチオフェン誘導体。 [In General Formula (3), R represents a substituent represented by General Formula (6) . 2-alkyl-3-nitro-thiophene-induced body represented by.
<20> 一般式(3)におけるRが、1,3−ジメチルブチル基である前記<19>に記載の2−アルキル−3−ニトロチオフェン誘導体。
<21> 前記<12>から<20>のいずれか1項に記載の下記一般式(12)
< 20 > The 2-alkyl-3-nitrothiophene derivative according to < 19 >, wherein R in the general formula (3) is a 1,3-dimethylbutyl group.
<21> the <12> to <20> below following general formula according to any one of (12)
[一般式(12)中、YおよびZは、それぞれ独立にハロゲン原子または水素原子を表す。Rは前記一般式(6)で表される置換基を表す。]で表される農園芸用殺菌剤の医農薬製造中間体。 [In General Formula (12), Y and Z each independently represent a halogen atom or a hydrogen atom. R represents a substituent represented by the general formula (6) . Pharmaceutical and agrochemical manufacturing intermediates agricultural and horticultural fungicide which is represented by.
<22> 一般式(12)におけるRが1,3−ジメチルブチル基、Yがフッ素原子、Zが水素原子である前記<21>に記載の医農薬製造中間体。 < 22 > The intermediate for producing pharmaceutical and agricultural chemicals according to < 21 >, wherein R in the general formula (12) is a 1,3-dimethylbutyl group, Y is a fluorine atom, and Z is a hydrogen atom .
本発明の下記一般式(4)で表される2−アルキル−3−アミノチオフェン誘導体の製造方法は、下記一般式(1)で表される化合物を酸化して、下記一般式(3)で表される化合物を得る工程(A)と、前記一般式(3)で表される化合物を還元する工程(B)と、を含む。 The method for producing a 2-alkyl-3-aminothiophene derivative represented by the following general formula (4) of the present invention comprises oxidizing the compound represented by the following general formula (1) to obtain the following general formula (3): The process (A) which obtains the compound represented, and the process (B) which reduces the compound represented by the said General formula (3) are included.
一般式(1)、一般式(3)および一般式(4)中、Rは炭素数1から10のアルキル基もしくは炭素数3から10のシクロアルキル基で置換されてもよい炭素数1から18のアルキル基、炭素数1から10のアルキル基もしくは炭素数3から10のシクロアルキル基で置換されてもよい炭素数3から10のシクロアルキル基、または、炭素数1から10のアルキル基もしくは炭素数3から10のシクロアルキル基で置換されてもよい炭素数6から12のビシクロアルキル基を表す。Xはヒドロキシ基、ハロゲン原子、または上記一般式(2)で表される置換基を表す。
Aは炭素原子または硫黄原子を表し、Aが炭素原子の場合nは1を表し、Aが硫黄原子の場合nは1または2を表す。Qは炭素数1から10のアルキル基、炭素数3から10のシクロアルキル基、炭素数1から10のハロアルキル基、炭素数1から10のヒドロカルビルオキシ基、または、炭素数1から6のアルキル基で置換されてもよいアリール基を表す。#は結合位置を表す。In general formula (1), general formula (3), and general formula (4), R is an alkyl group having 1 to 10 carbon atoms or a cycloalkyl group having 3 to 10 carbon atoms that may be substituted with 1 to 18 carbon atoms. An alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 3 to 10 carbon atoms that may be substituted with an alkyl group having 1 to 10 carbon atoms, or a cycloalkyl group having 3 to 10 carbon atoms, or an alkyl group or carbon having 1 to 10 carbon atoms It represents a C 6-12 bicycloalkyl group that may be substituted with a C 3-10 cycloalkyl group. X represents a hydroxy group, a halogen atom, or a substituent represented by the general formula (2).
A represents a carbon atom or a sulfur atom, n represents 1 when A is a carbon atom, and n represents 1 or 2 when A is a sulfur atom. Q is an alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 3 to 10 carbon atoms, a haloalkyl group having 1 to 10 carbon atoms, a hydrocarbyloxy group having 1 to 10 carbon atoms, or an alkyl group having 1 to 6 carbon atoms. Represents an aryl group which may be substituted with # Represents a bonding position.
本発明においては前記Rが、下記一般式(6)で表される置換基であることが好ましく、前記Rが、1,3−ジメチルブチル基であることがより好ましい。 In the present invention, the R is preferably a substituent represented by the following general formula (6), and the R is more preferably a 1,3-dimethylbutyl group.
一般式(6)中、R1は水素原子、または、炭素数1から6の直鎖もしくは分岐のアルキル基を表す。#は結合位置を表す。In General Formula (6), R 1 represents a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms. # Represents a bonding position.
また前記前記工程(A)が、下記一般式(8)で表される化合物から、下記一般式(1a)で表される化合物を得る工程と、前記一般式(Ia)で表される化合物から、前記一般式(3)で表される化合物を得る工程と、をさらに含むことが好ましい。 In addition, the step (A) includes a step of obtaining a compound represented by the following general formula (1a) from a compound represented by the following general formula (8), and a compound represented by the above general formula (Ia). And a step of obtaining a compound represented by the general formula (3).
一般式(8)および一般式(1a)中、Rは前記一般式(1)におけるRと同一である。Xaはハロゲン原子または前記一般式(2)で表される置換基を表す。In general formula (8) and general formula (1a), R is the same as R in the general formula (1). Xa represents a halogen atom or a substituent represented by the general formula (2).
また前記工程(A)が、前記一般式(1)で表される化合物から、下記一般式(5)で表される化合物を得る工程(A−1)と、前記一般式(5)で表される化合物から、前記一般式(3)で表される化合物を得る工程(A−2)と、をさらに含むこともまた好ましい。 The step (A) is a step (A-1) for obtaining a compound represented by the following general formula (5) from the compound represented by the general formula (1), and the general formula (5). It is also preferable to further include the step (A-2) of obtaining the compound represented by the general formula (3) from the compound to be formed.
一般式(5)中、Rは前記一般式(1)におけるRと同一である。 In the general formula (5), R is the same as R in the general formula (1).
また本発明の製造方法は、下記一般式(7)で表される化合物と、α−メルカプトアセトアルデヒドまたは1,4−ジチアン−2,5−ジオールとを反応させて、下記一般式(8)で表される化合物を得る工程をさらに含むことが好ましい。さらに前記一般式(7)で表される化合物を、下記一般式(9)で表される化合物から得る工程を含むことがより好ましく、前記一般式(9)で表される化合物を下記一般式(10)で表される化合物と、ニトロメタンとを反応させて得る工程をさらに含むがより好ましい。 Further, the production method of the present invention comprises reacting a compound represented by the following general formula (7) with α-mercaptoacetaldehyde or 1,4-dithian-2,5-diol, and the following general formula (8): Preferably, the method further includes a step of obtaining the represented compound. Further, it is more preferable to include a step of obtaining the compound represented by the general formula (7) from the compound represented by the following general formula (9). The compound represented by the general formula (9) is represented by the following general formula: More preferably, the method further includes a step obtained by reacting the compound represented by (10) with nitromethane.
一般式(7)から一般式(10)中、Rは前記一般式(1)におけるRと同一であり、X7はハロゲン原子または前記一般式(2)で表される置換基を表す。In General Formula (7) to General Formula (10), R is the same as R in General Formula (1), and X 7 represents a halogen atom or a substituent represented by General Formula (2).
また本発明の製造方法は、下記一般式(11)で表される化合物と、α−メルカプトアセトアルデヒドまたは1,4−ジチアン−2,5−ジオールとを反応させて、下記一般式(8)で表される化合物を得る工程を、さらに含むことが好ましい。さらに前記一般式(11)で表される化合物を、下記一般式(9)で表される化合物を脱水反応させて得る工程をさらに含むことがより好ましく、前記一般式(9)で表される化合物を、下記一般式(10)で表される化合物と、ニトロメタンとを反応させて得る工程を、さらに含むことがより好ましい。 Further, the production method of the present invention comprises reacting a compound represented by the following general formula (11) with α-mercaptoacetaldehyde or 1,4-dithian-2,5-diol, and the following general formula (8): It is preferable to further include a step of obtaining the represented compound. More preferably, the method further comprises a step of obtaining the compound represented by the general formula (11) by dehydrating the compound represented by the following general formula (9), represented by the general formula (9). It is more preferable to further include a step of obtaining the compound by reacting the compound represented by the following general formula (10) with nitromethane.
一般式(8)から一般式(11)中、Rは前記一般式(1)におけるRと同一である。 In the general formulas (8) to (11), R is the same as R in the general formula (1).
以下、本発明をさらに詳細に説明する。
本発明において、一般式(10)で表されるアルデヒド類、一般式(9)で表されるヒドロキシニトロアルカン類、一般式(11)で表されるニトロオレフィン類、一般式(7)で表されるニトロアルカン類、一般式(8)で表される3−ヒドロキシ−4−ニトロテトラヒドロチオフェン類、一般式(5)で表される3−ニトロ−2,5−ジヒドロチオフェン類、一般式(1)で表される3−ニトロテトラヒドロチオフェン類、一般式(3)で表される2−アルキル−3−ニトロチオフェン誘導体、および一般式(4)で表される3−アミノアルキルチオフェン誘導体において、Rで表される炭素数1から10のアルキル基もしくは炭素数3から10のシクロアルキル基で置換されてもよい炭素数1から18のアルキル基、炭素数1から10のアルキル基もしくは炭素数3から10のシクロアルキル基で置換されてもよい炭素数3から10のシクロアルキル基、または、炭素数1から10のアルキル基もしくは炭素数3から10のシクロアルキル基で置換されてもよい炭素数4から12のビシクロアルキル基としては、例えば、メチル基、エチル基、プロピル基、ブチル基、ペンチル基、ヘキシル基、イソプロピル基、イソブチル基、第二ブチル基、第三ブチル基、1−メチルブチル基、2−メチルブチル基、3−メチルブチル基、1,1−ジメチルプロピル基、2,2−ジメチルプロピル基、1,2−ジメチルプロピル基、1−メチルペンチル基、2−メチルペンチル基、3−メチルペンチル基、4−メチルペンチル基、1,1−ジメチルブチル基、1,2−ジメチルブチル基、1,3−ジメチルブチル基、2,2−ジメチルブチル基、2,3−ジメチルブチル基、3,3−ジメチルブチル基、シクロプロピルメチル基、シクロペンチルメチル基、シクロヘキシルエチル基、シクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基、メチルシクロヘキシル基、シクロヘキシルシクロヘキシル基、ヘキサヒドロインダン−1−イル基、ヘキサヒドロインダン−2−イル基、ヘキサヒドロインダン−4−イル基、ヘキサヒドロインダン−5−イル基、デカヒドロナフタレン−1−イル基、デカヒドロナフタレン−2−イル基などを挙げることができる。Hereinafter, the present invention will be described in more detail.
In the present invention, aldehydes represented by general formula (10), hydroxynitroalkanes represented by general formula (9), nitroolefins represented by general formula (11), and general formula (7) Nitroalkanes, 3-hydroxy-4-nitrotetrahydrothiophenes represented by general formula (8), 3-nitro-2,5-dihydrothiophenes represented by general formula (5), In 3-nitrotetrahydrothiophenes represented by 1), 2-alkyl-3-nitrothiophene derivatives represented by general formula (3), and 3-aminoalkylthiophene derivatives represented by general formula (4): An alkyl group having 1 to 10 carbon atoms which may be substituted with an alkyl group having 1 to 10 carbon atoms or a cycloalkyl group having 3 to 10 carbon atoms represented by R; Substituted with an alkyl group or an optionally substituted cycloalkyl group having 3 to 10 carbon atoms, an cycloalkyl group having 3 to 10 carbon atoms, or an alkyl group having 1 to 10 carbon atoms or a cycloalkyl group having 3 to 10 carbon atoms Examples of the bicycloalkyl group having 4 to 12 carbon atoms that may be used include a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, an isopropyl group, an isobutyl group, a secondary butyl group, and a tertiary butyl group. Group, 1-methylbutyl group, 2-methylbutyl group, 3-methylbutyl group, 1,1-dimethylpropyl group, 2,2-dimethylpropyl group, 1,2-dimethylpropyl group, 1-methylpentyl group, 2-methyl Pentyl group, 3-methylpentyl group, 4-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, , 3-dimethylbutyl group, 2,2-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, cyclopropylmethyl group, cyclopentylmethyl group, cyclohexylethyl group, cyclopropyl group, cyclobutyl group , Cyclopentyl group, cyclohexyl group, methylcyclohexyl group, cyclohexylcyclohexyl group, hexahydroindan-1-yl group, hexahydroindan-2-yl group, hexahydroindan-4-yl group, hexahydroindan-5-yl group , Decahydronaphthalen-1-yl group, decahydronaphthalen-2-yl group and the like.
また、一般式(2)中、Qで表される炭素数1から10のアルキル基、炭素数3から10のシクロアルキル基、炭素数1から10のハロアルキル基、炭素数1から10のヒドロカルビルオキシ基、炭素数1から6のアルキル基で置換されてもよいアリール基としては、例えば、メチル基、エチル基、プロピル基、ブチル基、ペンチル基、ヘキシル基、イソプロピル基、イソブチル基、第二ブチル基、第三ブチル基、1−メチルブチル基、2−メチルブチル基、3−メチルブチル基、1,1−ジメチルプロピル基、2,2−ジメチルプロピル基、1,2−ジメチルプロピル基、1−メチルペンチル基、2−メチルペンチル基、3−メチルペンチル基、4−メチルペンチル基、1,1−ジメチルブチル基、1,2−ジメチルブチル基、1,3−ジメチルブチル基、2,2−ジメチルブチル基、2,3−ジメチルブチル基、3,3−ジメチルブチル基、シクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基、トリフルオロメチル基、2,2,2−トリフルオロエチル基、メトキシ基、エトキシ基、第三ブチルオキシ基、ベンジルオキシ基、フェニル基、ナフチル基、2−メチルフェニル基、3−メチルフェニル基、4−メチルフェニル基などを挙げることができる。 In addition, in the general formula (2), an alkyl group having 1 to 10 carbon atoms represented by Q, a cycloalkyl group having 3 to 10 carbon atoms, a haloalkyl group having 1 to 10 carbon atoms, and a hydrocarbyloxy having 1 to 10 carbon atoms Examples of the aryl group which may be substituted with an alkyl group having 1 to 6 carbon atoms include, for example, methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, isopropyl group, isobutyl group, sec-butyl Group, tert-butyl group, 1-methylbutyl group, 2-methylbutyl group, 3-methylbutyl group, 1,1-dimethylpropyl group, 2,2-dimethylpropyl group, 1,2-dimethylpropyl group, 1-methylpentyl Group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 1,3-di- Tylbutyl group, 2,2-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, trifluoromethyl group, 2,2,2 -Trifluoroethyl group, methoxy group, ethoxy group, tert-butyloxy group, benzyloxy group, phenyl group, naphthyl group, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, etc. .
また、一般式(10)で表されるアルデヒド類、一般式(9)で表されるヒドロキシニトロアルカン類、一般式(11)で表されるニトロオレフィン類、一般式(7)で表されるニトロアルカン類、一般式(8)で表される3−ヒドロキシ−4−ニトロテトラヒドロチオフェン類、一般式(5)で表される3−ニトロ−2,5−ジヒドロチオフェン類、一般式(1)で表される3−ニトロテトラヒドロチオフェン類、一般式(3)で表される2−アルキル−3−ニトロチオフェン誘導体、および一般式(4)で表される2−アルキル−3−アミノチオフェン類は、ジアステレオ異性体が存在する場合は、そのいずれか一つの化合物、またはその内2種類以上の任意の割合の混合物でよく、その構造は限定されない。 In addition, aldehydes represented by general formula (10), hydroxynitroalkanes represented by general formula (9), nitroolefins represented by general formula (11), and general formula (7) Nitroalkanes, 3-hydroxy-4-nitrotetrahydrothiophenes represented by general formula (8), 3-nitro-2,5-dihydrothiophenes represented by general formula (5), general formula (1) The 3-nitrotetrahydrothiophenes represented by general formula (2), the 2-alkyl-3-nitrothiophene derivatives represented by general formula (3), and the 2-alkyl-3-aminothiophenes represented by general formula (4) are: In the case where diastereoisomers are present, any one of them, or a mixture of any two or more of them may be used, and the structure is not limited.
また、一般式(10)で表されるアルデヒド類、一般式(9)で表されるヒドロキシニトロアルカン類、一般式(11)で表されるニトロオレフィン類、一般式(7)で表されるニトロアルカン類、一般式(8)で表される3−ヒドロキシ−4−ニトロテトラヒドロチオフェン類、一般式(5)で表される3−ニトロ−2,5−ジヒドロチオフェン類、一般式(1)で表される3−ニトロテトラヒドロチオフェン類、一般式(3)で表される2−アルキル−3−ニトロチオフェン誘導体、および一般式(4)で表される3−アミノアルキルチオフェン類は、鏡像異性体が存在する場合は、そのいずれか一方の化合物、または両者の任意の割合の混合物でよく、その構造は限定されない。
また、一般式(11)で表されるニトロオレフィン類は、シス体、トランス体のいずれか一方の化合物、または両者の任意の割合の混合物でよく、その構造は限定されない。In addition, aldehydes represented by general formula (10), hydroxynitroalkanes represented by general formula (9), nitroolefins represented by general formula (11), and general formula (7) Nitroalkanes, 3-hydroxy-4-nitrotetrahydrothiophenes represented by general formula (8), 3-nitro-2,5-dihydrothiophenes represented by general formula (5), general formula (1) 3-nitrotetrahydrothiophenes represented by general formula (3), 2-alkyl-3-nitrothiophene derivatives represented by general formula (3), and 3-aminoalkylthiophenes represented by general formula (4) are enantiomers. When a body is present, any one of the compounds or a mixture of both in any ratio may be used, and the structure is not limited.
Further, the nitroolefin represented by the general formula (11) may be either a cis isomer or a trans isomer, or a mixture of both in any ratio, and the structure is not limited.
本発明で出発化合物として用いられる一般式(10)で表されるアルデヒドは多くの場合市販されており、容易に入手できる。また、入手困難なものについても種々の製造方法が公知であり、例えば、JORNAL OF AMERICAN CHEMICAL SOCIETY 第75巻 第20号 (1953年) 4995頁に開示されている方法により製造することができる。 In many cases, the aldehyde represented by the general formula (10) used as a starting compound in the present invention is commercially available and can be easily obtained. In addition, various production methods are known for those which are difficult to obtain, and can be produced, for example, by the method disclosed in JORNAL OF AMERICAN CHEMICAL SOCIETY Vol. 75 No. 20 (1953), p.
本発明により開示される新規な製造方法によれば、一般式(9)で表されるヒドロキシニトロアルカン類は、一般式(10)で示されるアルデヒド類とニトロメタンとを塩基の存在下反応させることにより得られる。
一般式(10)で示されるアルデヒド類に対して用いるニトロメタンおよび塩基の当量には特に制限を設けないが、経済的観点から3当量以下とすることが望ましい。
用いる塩基は無機の塩基、有機の塩基のいずれでもよい。無機の塩基としては、アルカリ金属の水酸化物、アルカリ土類金属の水酸化物、アルカリ金属の炭酸塩、アンモニア類等を用いることができる。有機の塩基としては、トリアルキルアミン、ピリジン類等を用いることができる。塩基として具体的には、水酸化リチウム、水酸化ナトリウム、水酸化カリウム、水酸化カルシウム、水酸化バリウム、炭酸ナトリウム、炭酸カリウム、炭酸水素ナトリウム、炭酸水素カリウム、液体アンモニア、アンモニア水溶液、トリエチルアミン、トリブチルアミン、ピリジン、コリジン、2,6−ルチジン、4−ジメチルアミノピリジンなどを挙げることができる。これらの塩基はそれぞれ単独で用いてもよいが、2種類以上を任意の割合で組み合わせて使用することもできる。According to the novel production method disclosed by the present invention, the hydroxynitroalkane represented by the general formula (9) reacts the aldehyde represented by the general formula (10) with nitromethane in the presence of a base. Is obtained.
No particular limitation is imposed on the equivalents of nitromethane and base used for the aldehydes represented by the general formula (10), but it is preferably 3 equivalents or less from an economical viewpoint.
The base used may be either an inorganic base or an organic base. As the inorganic base, alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates, ammonia and the like can be used. As the organic base, trialkylamine, pyridines and the like can be used. Specific examples of the base include lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, liquid ammonia, aqueous ammonia solution, triethylamine, triethylamine, Examples include butylamine, pyridine, collidine, 2,6-lutidine, 4-dimethylaminopyridine, and the like. These bases may be used alone or in combination of two or more at any ratio.
本発明の一般式(9)で表されるヒドロキシニトロアルカン類の製造方法においては、適宜溶媒を使用することができるが、用いる溶媒には特に制限はない。溶媒としては、例えば、ジクロロメタン、クロロホルム等のハロゲン化アルキル類、ベンゼン、トルエン、キシレン等の芳香族炭化水素類、ヘキサン、ヘプタン、シクロヘキサン等の炭化水素類、ジエチルエーテル、ジイソプロピルエーテル、1,2−ジメトキシエタン、テトラヒドロフラン、ジオキサン等のエーテル類、酢酸エチル、酢酸ブチル等のエステル類、N,N−ジメチルホルムアミド、N,N−ジメチルアセトアミド、N−メチルピロリドン等のアミド類、N,N’−ジメチルイミダゾリジノン、アセトニトリル、水などを挙げることができる。これらの溶媒はそれぞれ単独で用いてもよいが、2種類以上を任意の割合で組み合わせて使用することもできる。 In the method for producing hydroxynitroalkanes represented by the general formula (9) of the present invention, a solvent can be appropriately used, but the solvent to be used is not particularly limited. Examples of the solvent include alkyl halides such as dichloromethane and chloroform, aromatic hydrocarbons such as benzene, toluene and xylene, hydrocarbons such as hexane, heptane and cyclohexane, diethyl ether, diisopropyl ether, 1,2- Ethers such as dimethoxyethane, tetrahydrofuran and dioxane, esters such as ethyl acetate and butyl acetate, amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone, N, N′-dimethyl Examples include imidazolidinone, acetonitrile, water and the like. Each of these solvents may be used alone, but two or more kinds may be used in combination at any ratio.
反応に用いる溶媒の量については特に制限を設けないが、経済的観点から一般式(10)で示されるアルデヒド類の重量に対して50倍量以下とすることが好ましい。
また反応温度については特に制限を設けないが、操作効率の観点から溶媒の融点以上沸点以下とすることが好ましい。The amount of the solvent used in the reaction is not particularly limited, but it is preferably 50 times or less with respect to the weight of the aldehyde represented by the general formula (10) from the economical viewpoint.
Moreover, although there is no restriction | limiting in particular about reaction temperature, it is preferable to set it as more than melting | fusing point and below boiling point of a solvent from a viewpoint of operation efficiency.
また、本発明により開示される新規な製造方法によれば一般式(11)で表されるニトロオレフィン類は、一般式(9)で表されるヒドロキシニトロアルカン類を脱水反応させることで得られる。
本発明のニトロオレフィン類の製造方法においては、反応補助のため酸を用いてもよい。用いる酸は無機の酸、有機の酸のいずれでもよく、またブレンステッド酸、ルイス酸のいずれでもよい。
具体的には例えば、硫酸、発煙硫酸、クロロ硫酸、硝酸、発煙硝酸、塩酸、リン酸、臭化水素、酢酸、トリフルオロ酢酸、シュウ酸、酒石酸、フマル酸、マレイン酸、安息香酸、メタンスルホン酸、ベンゼンスルホン酸、トシル酸、トリフルオロメタンスルホン酸、塩化アルミ、四塩化チタン、三フッ化ホウ素ジエチルエーテル錯体などを挙げることができる。これらの酸は、それぞれ単独で用いてもよいが、2種類以上を任意の割合で組み合わせて使用することもできる。Further, according to the novel production method disclosed by the present invention, the nitroolefin represented by the general formula (11) can be obtained by dehydrating the hydroxynitroalkane represented by the general formula (9). .
In the method for producing nitroolefins of the present invention, an acid may be used to assist the reaction. The acid used may be either an inorganic acid or an organic acid, and may be either a Bronsted acid or a Lewis acid.
Specifically, for example, sulfuric acid, fuming sulfuric acid, chlorosulfuric acid, nitric acid, fuming nitric acid, hydrochloric acid, phosphoric acid, hydrogen bromide, acetic acid, trifluoroacetic acid, oxalic acid, tartaric acid, fumaric acid, maleic acid, benzoic acid, methanesulfone Examples thereof include acid, benzenesulfonic acid, tosylic acid, trifluoromethanesulfonic acid, aluminum chloride, titanium tetrachloride, and boron trifluoride diethyl ether complex. These acids may be used alone or in combination of two or more at any ratio.
本発明のニトロオレフィン類の製造方法においては、反応補助のため塩基を用いてもよい。用いる塩基は無機の塩基、有機の塩基のいずれでもよい。無機の塩基としてはアルカリ金属の水酸化物、アルカリ土類金属の水酸化物、アルカリ金属の炭酸塩、アンモニア類等を用いることができる。有機の塩基としては、トリアルキルアミン、ピリジン類等を用いることができる。具体的には、水酸化リチウム、水酸化ナトリウム、水酸化カリウム、水酸化カルシウム、水酸化バリウム、炭酸ナトリウム、炭酸カリウム、炭酸水素ナトリウム、炭酸水素カリウム、液体アンモニア、アンモニア水溶液、トリエチルアミン、トリブチルアミン、ピリジン、コリジン、2,6−ルチジン、4−ジメチルアミノピリジンなどを挙げることができる。これらの塩基は、それぞれ単独で用いてもよいが、2種類以上を任意の割合で組み合わせて使用することもできる。 In the method for producing nitroolefins of the present invention, a base may be used to assist the reaction. The base used may be either an inorganic base or an organic base. As the inorganic base, alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates, ammonia and the like can be used. As the organic base, trialkylamine, pyridines and the like can be used. Specifically, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, liquid ammonia, aqueous ammonia solution, triethylamine, tributylamine, Examples thereof include pyridine, collidine, 2,6-lutidine, 4-dimethylaminopyridine and the like. These bases may be used alone or in combination of two or more at an arbitrary ratio.
さらに本発明のニトロオレフィン類の製造方法においては、反応補助のため公知の脱水剤を用いてもよい。用いる脱水剤として塩化アセチル、塩化ベンゾイルなどのカルボン酸ハロゲン化物、無水酢酸、無水トリフルオロ酢酸などのカルボン酸無水物、塩化トルエンスルホニル、塩化メタンスルホニル、塩化トリフルオロメタンスルホニルなどのスルホン酸ハロゲン化物、塩化チオニル、塩化スルフリル、シュウ酸クロリド、ホスゲン、ジホスゲン、トリホスゲン、五塩化リン、三塩化リン、オキシ塩化リン、三臭化リン、五酸化リン、アルカリ金属硫酸塩、アルカリ土類金属硫酸塩、アルカリ土類金属塩酸塩などを挙げることができる。これらの脱水剤は、それぞれ単独で用いてもよいが、2種類以上を任意の割合で組み合わせて使用することもできる。 Furthermore, in the method for producing nitroolefins of the present invention, a known dehydrating agent may be used to assist the reaction. Dehydrating agents used include carboxylic acid halides such as acetyl chloride and benzoyl chloride, carboxylic acid anhydrides such as acetic anhydride and trifluoroacetic anhydride, sulfonic acid halides such as toluenesulfonyl chloride, methanesulfonyl chloride, trifluoromethanesulfonyl chloride, and chloride. Thionyl, sulfuryl chloride, oxalic chloride, phosgene, diphosgene, triphosgene, phosphorus pentachloride, phosphorus trichloride, phosphorus oxychloride, phosphorus tribromide, phosphorus pentoxide, alkali metal sulfate, alkaline earth metal sulfate, alkaline earth And the like. These dehydrating agents may be used alone or in combination of two or more at any ratio.
本発明のニトロオレフィン類の製造方法においては、適宜溶媒を使用することができるが、用いる溶媒には特に制限はない。溶媒としては、例えば、ジクロロメタン、クロロホルム等のハロゲン化アルキル類、ベンゼン、トルエン、キシレン等の芳香族炭化水素類、ヘキサン、ヘプタン、シクロヘキサン等の炭化水素類、ジエチルエーテル、ジイソプロピルエーテル、1,2−ジメトキシエタン、テトラヒドロフラン、ジオキサン等のエーテル類、酢酸エチル、酢酸ブチル等のエステル類、N,N−ジメチルホルムアミド、N,N−ジメチルアセトアミド、N−メチルピロリドン等のアミド類、N,N’−ジメチルイミダゾリジノン、アセトニトリル、水などを挙げることができる。これらの溶媒はそれぞれ単独で用いてもよいが、2種類以上を任意の割合で組み合わせて使用することもできる。
反応に用いる溶媒の量については特に制限を設けないが、経済的観点から一般式(9)で表されるヒドロキシニトロアルカン類の重量に対して50倍量以下とすることが好ましい。
反応温度については特に制限を設けないが、操作効率の観点から溶媒の融点以上沸点以下とすることが好ましい。In the method for producing nitroolefins of the present invention, a solvent can be appropriately used, but the solvent to be used is not particularly limited. Examples of the solvent include alkyl halides such as dichloromethane and chloroform, aromatic hydrocarbons such as benzene, toluene and xylene, hydrocarbons such as hexane, heptane and cyclohexane, diethyl ether, diisopropyl ether, 1,2- Ethers such as dimethoxyethane, tetrahydrofuran and dioxane, esters such as ethyl acetate and butyl acetate, amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone, N, N′-dimethyl Examples include imidazolidinone, acetonitrile, water and the like. Each of these solvents may be used alone, but two or more kinds may be used in combination at any ratio.
The amount of the solvent used in the reaction is not particularly limited, but is preferably 50 times or less with respect to the weight of the hydroxynitroalkane represented by the general formula (9) from the economical viewpoint.
The reaction temperature is not particularly limited, but it is preferably from the melting point to the boiling point of the solvent from the viewpoint of operation efficiency.
また、本発明により開示される新規な製造方法によれば、一般式(7)で表されるニトロアルカン類は一般式(9)で表されるヒドロキシニトロアルカン類を公知のエステル化剤またはハロゲン化剤と反応させることにより得られる。 In addition, according to the novel production method disclosed by the present invention, the nitroalkane represented by the general formula (7) is converted from the hydroxynitroalkane represented by the general formula (9) by a known esterifying agent or halogen. It is obtained by reacting with an agent.
本発明の一般式(7)で表されるニトロアルカン類の製造方法においては反応補助のため塩基を用いてもよい。用いる塩基は無機の塩基、有機の塩基のいずれでもよい。無機の塩基としてはアルカリ金属の水酸化物、アルカリ土類金属の水酸化物、アルカリ金属の炭酸塩、アンモニア類等を用いることができる。有機の塩基としては、トリアルキルアミン、ピリジン類等を用いることができる。具体的には水酸化リチウム、水酸化ナトリウム、水酸化カリウム、水酸化カルシウム、水酸化バリウム、炭酸ナトリウム、炭酸カリウム、炭酸水素ナトリウム、炭酸水素カリウム、液体アンモニア、アンモニア水溶液、トリエチルアミン、トリブチルアミン、ピリジン、コリジン、2,6−ルチジン、4−ジメチルアミノピリジンなどを挙げることができる。これらの塩基は、それぞれ単独で用いてもよいが、2種類以上を任意の割合で組み合わせて使用することもできる。 In the method for producing a nitroalkane represented by the general formula (7) of the present invention, a base may be used for assisting the reaction. The base used may be either an inorganic base or an organic base. As the inorganic base, alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates, ammonia and the like can be used. As the organic base, trialkylamine, pyridines and the like can be used. Specifically, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, liquid ammonia, aqueous ammonia solution, triethylamine, tributylamine, pyridine , Collidine, 2,6-lutidine, 4-dimethylaminopyridine and the like. These bases may be used alone or in combination of two or more at an arbitrary ratio.
本発明の一般式(7)で表されるニトロアルカン類の製造方法に用いるエステル化剤またはハロゲン化剤としては、塩化アセチル、塩化ベンゾイルなどのカルボン酸ハロゲン化物、無水酢酸、無水トリフルオロ酢酸などのカルボン酸無水物、塩化トルエンスルホニル、塩化メタンスルホニル、塩化トリフルオロメタンスルホニルなどのスルホン酸ハロゲン化物、塩化チオニル、塩化スルフリル、シュウ酸クロリド、ホスゲン、ジホスゲン、トリホスゲン、五塩化リン、三塩化リン、オキシ塩化リン、三臭化リンなどを挙げることができる。これらのエステル化剤またはハロゲン化剤はそれぞれ単独で用いてもよいが、2種類以上を任意の割合で組み合わせて使用することもできる。 Examples of the esterifying agent or halogenating agent used in the method for producing a nitroalkane represented by the general formula (7) of the present invention include carboxylic acid halides such as acetyl chloride and benzoyl chloride, acetic anhydride, trifluoroacetic anhydride, and the like. Carboxylic anhydride, sulfonyl halides such as toluenesulfonyl chloride, methanesulfonyl chloride, trifluoromethanesulfonyl chloride, thionyl chloride, sulfuryl chloride, oxalic chloride, phosgene, diphosgene, triphosgene, phosphorus pentachloride, phosphorus trichloride, oxy Examples include phosphorus chloride and phosphorus tribromide. These esterifying agents or halogenating agents may be used alone or in combination of two or more at any ratio.
本発明の一般式(7)で表されるニトロアルカン類の製造方法においては、適宜溶媒を使用することができるが、用いる溶媒には特に制限はない。溶媒としては、例えば、ジクロロメタン、クロロホルム等のハロゲン化アルキル類、ベンゼン、トルエン、キシレン等の芳香族炭化水素類、ヘキサン、ヘプタン、シクロヘキサン等の炭化水素類、ジエチルエーテル、ジイソプロピルエーテル、1,2−ジメトキシエタン、テトラヒドロフラン、ジオキサン等のエーテル類、酢酸エチル、酢酸ブチル等のエステル類、N,N−ジメチルホルムアミド、N,N−ジメチルアセトアミド、N−メチルピロリドン等のアミド類、N,N’−ジメチルイミダゾリジノン、アセトニトリル、水などを挙げることができる。これらの溶媒はそれぞれ単独で用いてもよいが、2種類以上を任意の割合で組み合わせて使用することもできる。 In the method for producing nitroalkanes represented by the general formula (7) of the present invention, a solvent can be appropriately used, but the solvent to be used is not particularly limited. Examples of the solvent include alkyl halides such as dichloromethane and chloroform, aromatic hydrocarbons such as benzene, toluene and xylene, hydrocarbons such as hexane, heptane and cyclohexane, diethyl ether, diisopropyl ether, 1,2- Ethers such as dimethoxyethane, tetrahydrofuran and dioxane, esters such as ethyl acetate and butyl acetate, amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone, N, N′-dimethyl Examples include imidazolidinone, acetonitrile, water and the like. Each of these solvents may be used alone, but two or more kinds may be used in combination at any ratio.
反応に用いる溶媒の量については特に制限を設けないが、経済的観点から一般式(9)で表されるヒドロキシニトロアルカン類の重量に対して50倍量以下とすることが好ましい。
反応温度については特に制限を設けないが、操作効率の観点から溶媒の融点以上沸点以下とすることが好ましい。The amount of the solvent used in the reaction is not particularly limited, but is preferably 50 times or less with respect to the weight of the hydroxynitroalkane represented by the general formula (9) from the economical viewpoint.
The reaction temperature is not particularly limited, but it is preferably from the melting point to the boiling point of the solvent from the viewpoint of operation efficiency.
また、本発明により開示される新規な製造方法によれば一般式(8)で表される3−ヒドロキシ−4−ニトロテトラヒドロチオフェン類は、一般式(11)で表されるニトロオレフィン類または一般式(7)で表されるニトロアルカン類と、α−メルカプトアセトアルデヒドまたは1,4−ジチアン−2,5−ジオールとを反応させることで得られる。 Further, according to the novel production method disclosed by the present invention, the 3-hydroxy-4-nitrotetrahydrothiophene represented by the general formula (8) is a nitroolefin represented by the general formula (11) or It can be obtained by reacting the nitroalkane represented by the formula (7) with α-mercaptoacetaldehyde or 1,4-dithian-2,5-diol.
反応に際して、一般式(11)で表されるニトロオレフィン類または一般式(7)で表されるニトロアルカン類に対して用いるα−メルカプトアセトアルデヒドおよび1,4−ジチアン−2,5−ジオールの当量には特に制限を設けないが、経済的観点から(α−メルカプトアルデヒド換算で)3当量以下とすることが望ましい。α−メルカプトアセトアルデヒドはそのもの自身を単量体として用いることもできるが、一般に市販されている二量体である1,4−ジチアン−2,5−ジオールがより好適に使用される。 In the reaction, the equivalent of α-mercaptoacetaldehyde and 1,4-dithian-2,5-diol used for the nitroolefin represented by the general formula (11) or the nitroalkane represented by the general formula (7) Is not particularly limited, but it is preferably 3 equivalents or less (in terms of α-mercaptoaldehyde) from an economical viewpoint. Although α-mercaptoacetaldehyde itself can be used as a monomer, 1,4-dithian-2,5-diol, which is a commercially available dimer, is more preferably used.
本発明の一般式(8)で表される3−ヒドロキシ−4−ニトロテトラヒドロチオフェン類の製造方法においては、反応補助のため塩基を用いてもよい。用いる塩基は、無機の塩基、有機の塩基のいずれでもよい。無機の塩基としては、アルカリ金属の水酸化物、アルカリ土類金属の水酸化物、アルカリ金属の炭酸塩、アンモニア類等を用いることができる。有機の塩基としては、トリアルキルアミン、ピリジン類等を用いることができる。塩基として具体的には、水酸化リチウム、水酸化ナトリウム、水酸化カリウム、水酸化カルシウム、水酸化バリウム、炭酸ナトリウム、炭酸カリウム、炭酸水素ナトリウム、炭酸水素カリウム、液体アンモニア、アンモニア水溶液、トリエチルアミン、トリブチルアミン、ピリジン、コリジン、2,6−ルチジン、4−ジメチルアミノピリジンなどを挙げることができる。これらの塩基はそれぞれ単独で用いてもよいが、2種類以上を任意の割合で組み合わせて使用することもできる。 In the method for producing 3-hydroxy-4-nitrotetrahydrothiophenes represented by the general formula (8) of the present invention, a base may be used for assisting the reaction. The base used may be either an inorganic base or an organic base. As the inorganic base, alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates, ammonia and the like can be used. As the organic base, trialkylamine, pyridines and the like can be used. Specific examples of the base include lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, liquid ammonia, aqueous ammonia solution, triethylamine, triethylamine, Examples include butylamine, pyridine, collidine, 2,6-lutidine, 4-dimethylaminopyridine, and the like. These bases may be used alone or in combination of two or more at any ratio.
本発明の一般式(8)で表される3−ヒドロキシ−4−ニトロテトラヒドロチオフェン類の製造方法においては、適宜溶媒を使用することができるが、用いる溶媒には特に制限はない。溶媒としては、例えば、ジクロロメタン、クロロホルム等のハロゲン化アルキル類、ベンゼン、トルエン、キシレン等の芳香族炭化水素類、ヘキサン、ヘプタン、シクロヘキサン等の炭化水素類、ジエチルエーテル、ジイソプロピルエーテル、1,2−ジメトキシエタン、テトラヒドロフラン、ジオキサン等のエーテル類、酢酸エチル、酢酸ブチル等のエステル類、N,N−ジメチルホルムアミド、N,N−ジメチルアセトアミド、N−メチルピロリドン等のアミド類、N,N’−ジメチルイミダゾリジノン、アセトニトリル、水などを挙げることができる。これらの溶媒はそれぞれ単独で用いてもよいが、2種類以上を任意の割合で組み合わせて使用することもできる。 In the method for producing 3-hydroxy-4-nitrotetrahydrothiophenes represented by the general formula (8) of the present invention, a solvent can be appropriately used, but the solvent to be used is not particularly limited. Examples of the solvent include alkyl halides such as dichloromethane and chloroform, aromatic hydrocarbons such as benzene, toluene and xylene, hydrocarbons such as hexane, heptane and cyclohexane, diethyl ether, diisopropyl ether, 1,2- Ethers such as dimethoxyethane, tetrahydrofuran and dioxane, esters such as ethyl acetate and butyl acetate, amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone, N, N′-dimethyl Examples include imidazolidinone, acetonitrile, water and the like. Each of these solvents may be used alone, but two or more kinds may be used in combination at any ratio.
反応に用いる溶媒の量については特に制限を設けないが、経済的観点から一般式(11)で表されるニトロオレフィン類または一般式(7)で表されるニトロアルカン類の重量に対して50倍量以下とすることが好ましい。
反応温度については特に制限を設けないが、操作効率の観点から溶媒の融点以上沸点以下とすることが好ましい。The amount of the solvent used for the reaction is not particularly limited, but is 50% based on the weight of the nitroolefin represented by the general formula (11) or the nitroalkane represented by the general formula (7) from the economical viewpoint. It is preferable to set it to a double amount or less.
The reaction temperature is not particularly limited, but it is preferably from the melting point to the boiling point of the solvent from the viewpoint of operation efficiency.
また、本発明により開示される新規な製造方法によれば、一般式(5)で表される3−ニトロ−2,5−ジヒドロチオフェン類は、一般式(8)で表される3−ヒドロキシ−4−ニトロテトラヒドロチオフェン類を脱水反応させることで得られる。 In addition, according to the novel production method disclosed by the present invention, 3-nitro-2,5-dihydrothiophene represented by the general formula (5) is a 3-hydroxy represented by the general formula (8). It can be obtained by dehydrating -4-nitrotetrahydrothiophenes.
本発明の3−ニトロ−2,5−ジヒドロチオフェン類の製造方法においては、反応補助のため酸を用いてもよい。用いる酸は無機の酸、有機の酸のいずれでもよく、またブレンステッド酸、ルイス酸のいずれでもよい。酸としては、例えば、硫酸、発煙硫酸、クロロ硫酸、硝酸、発煙硝酸、塩酸、リン酸、臭化水素、酢酸、トリフルオロ酢酸、シュウ酸、酒石酸、フマル酸、マレイン酸、安息香酸、メタンスルホン酸、ベンゼンスルホン酸、トシル酸、トリフルオロメタンスルホン酸、塩化アルミ、四塩化チタン、三フッ化ホウ素ジエチルエーテル錯体などを挙げることができる。これらの酸はそれぞれ単独で用いてもよいが、2種類以上を任意の割合で組み合わせて使用することもできる。 In the method for producing 3-nitro-2,5-dihydrothiophenes of the present invention, an acid may be used to assist the reaction. The acid used may be either an inorganic acid or an organic acid, and may be either a Bronsted acid or a Lewis acid. Examples of acids include sulfuric acid, fuming sulfuric acid, chlorosulfuric acid, nitric acid, fuming nitric acid, hydrochloric acid, phosphoric acid, hydrogen bromide, acetic acid, trifluoroacetic acid, oxalic acid, tartaric acid, fumaric acid, maleic acid, benzoic acid, methanesulfone. Examples thereof include acid, benzenesulfonic acid, tosylic acid, trifluoromethanesulfonic acid, aluminum chloride, titanium tetrachloride, and boron trifluoride diethyl ether complex. These acids may be used alone or in combination of two or more at any ratio.
本発明の3−ニトロ−2,5−ジヒドロチオフェン類の製造方法においては、反応補助のため塩基を用いてもよい。用いる塩基は無機の塩基、有機の塩基のいずれでもよい。無機の塩基としてはアルカリ金属の水酸化物、アルカリ土類金属の水酸化物、アルカリ金属の炭酸塩、アンモニア類等を用いることができる。有機の塩基としては、トリアルキルアミン、ピリジン類等を用いることができる。具体的には、水酸化リチウム、水酸化ナトリウム、水酸化カリウム、水酸化カルシウム、水酸化バリウム、炭酸ナトリウム、炭酸カリウム、炭酸水素ナトリウム、炭酸水素カリウム、液体アンモニア、アンモニア水溶液、トリエチルアミン、トリブチルアミン、ピリジン、コリジン、2,6−ルチジン、4−ジメチルアミノピリジンなどを挙げることができる。これらの塩基はそれぞれ単独で用いてもよいが、2種類以上を任意の割合で組み合わせて使用することもできる。 In the method for producing 3-nitro-2,5-dihydrothiophenes of the present invention, a base may be used to assist the reaction. The base used may be either an inorganic base or an organic base. As the inorganic base, alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates, ammonia and the like can be used. As the organic base, trialkylamine, pyridines and the like can be used. Specifically, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, liquid ammonia, aqueous ammonia solution, triethylamine, tributylamine, Examples thereof include pyridine, collidine, 2,6-lutidine, 4-dimethylaminopyridine and the like. These bases may be used alone or in combination of two or more at any ratio.
本発明の一般式(5)で表される3−ニトロ−2,5−ジヒドロチオフェン類の製造方法においては、反応補助のため公知の脱水剤を用いてもよい。用いる脱水剤として塩化アセチル、塩化ベンゾイルなどのカルボン酸ハロゲン化物、無水酢酸、無水トリフルオロ酢酸などのカルボン酸無水物、塩化トルエンスルホニル、塩化メタンスルホニル、塩化トリフルオロメタンスルホニルなどのスルホン酸ハロゲン化物、塩化チオニル、塩化スルフリル、シュウ酸クロリド、ホスゲン、ジホスゲン、トリホスゲン、五塩化リン、三塩化リン、オキシ塩化リン、三臭化リン、五酸化リン、アルカリ金属硫酸塩、アルカリ土類金属硫酸塩、アルカリ土類金属塩酸塩などを挙げることができる。これらの脱水剤は、それぞれ単独で用いてもよいが、2種類以上を任意の割合で組み合わせて使用することもできる。 In the method for producing 3-nitro-2,5-dihydrothiophenes represented by the general formula (5) of the present invention, a known dehydrating agent may be used for assisting the reaction. Dehydrating agents used include carboxylic acid halides such as acetyl chloride and benzoyl chloride, carboxylic acid anhydrides such as acetic anhydride and trifluoroacetic anhydride, sulfonic acid halides such as toluenesulfonyl chloride, methanesulfonyl chloride, trifluoromethanesulfonyl chloride, and chloride. Thionyl, sulfuryl chloride, oxalic chloride, phosgene, diphosgene, triphosgene, phosphorus pentachloride, phosphorus trichloride, phosphorus oxychloride, phosphorus tribromide, phosphorus pentoxide, alkali metal sulfate, alkaline earth metal sulfate, alkaline earth And the like. These dehydrating agents may be used alone or in combination of two or more at any ratio.
本発明の一般式(5)で表される3−ニトロ−2,5−ジヒドロチオフェン類の製造方法においては、適宜溶媒を使用することができるが、用いる溶媒には特に制限はない。溶媒としては、例えば、ジクロロメタン、クロロホルム等のハロゲン化アルキル類、ベンゼン、トルエン、キシレン等の芳香族炭化水素類、ヘキサン、ヘプタン、シクロヘキサン等の炭化水素類、ジエチルエーテル、ジイソプロピルエーテル、1,2−ジメトキシエタン、テトラヒドロフラン、ジオキサン等のエーテル類、酢酸エチル、酢酸ブチル等のエステル類、N,N−ジメチルホルムアミド、N,N−ジメチルアセトアミド、N−メチルピロリドン等のアミド類、N,N’−ジメチルイミダゾリジノン、アセトニトリル、水などを挙げることができる。これらの溶媒はそれぞれ単独で用いてもよいが、2種類以上を任意の割合で組み合わせて使用することもできる。 In the method for producing 3-nitro-2,5-dihydrothiophenes represented by the general formula (5) of the present invention, a solvent can be appropriately used, but the solvent to be used is not particularly limited. Examples of the solvent include alkyl halides such as dichloromethane and chloroform, aromatic hydrocarbons such as benzene, toluene and xylene, hydrocarbons such as hexane, heptane and cyclohexane, diethyl ether, diisopropyl ether, 1,2- Ethers such as dimethoxyethane, tetrahydrofuran and dioxane, esters such as ethyl acetate and butyl acetate, amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone, N, N′-dimethyl Examples include imidazolidinone, acetonitrile, water and the like. Each of these solvents may be used alone, but two or more kinds may be used in combination at any ratio.
反応に用いる溶媒の量については特に制限を設けないが、経済的観点から一般式(8)で表される3−ヒドロキシ−4−ニトロテトラヒドロチオフェン類の重量に対して50倍量以下とすることが好ましい。
反応温度については特に制限を設けないが、操作効率の観点から溶媒の融点以上沸点以下とすることが好ましい。The amount of the solvent used in the reaction is not particularly limited, but it should be 50 times or less with respect to the weight of the 3-hydroxy-4-nitrotetrahydrothiophene represented by the general formula (8) from the economical viewpoint. Is preferred.
The reaction temperature is not particularly limited, but it is preferably from the melting point to the boiling point of the solvent from the viewpoint of operation efficiency.
また、本発明により開示される新規な製造方法によれば、一般式(1a)で表される3−ニトロテトラヒドロチオフェン類は、一般式(8)で表される3−ヒドロキシ−4−ニトロテトラヒドロチオフェン類を公知のエステル化剤またはハロゲン化剤と反応させることにより得られる。 In addition, according to the novel production method disclosed by the present invention, 3-nitrotetrahydrothiophenes represented by the general formula (1a) are represented by 3-hydroxy-4-nitrotetrahydro represented by the general formula (8). It can be obtained by reacting thiophenes with a known esterifying agent or halogenating agent.
本発明の一般式(1a)で表される3−ニトロテトラヒドロチオフェン類の製造方法においては反応補助のため塩基を用いてもよい。用いる塩基は無機の塩基、有機の塩基のいずれでもよい。無機の塩基としてはアルカリ金属の水酸化物、アルカリ土類金属の水酸化物、アルカリ金属の炭酸塩、アンモニア類等を用いることができる。有機の塩基としては、トリアルキルアミン、ピリジン類等を用いることができる。具体的には水酸化リチウム、水酸化ナトリウム、水酸化カリウム、水酸化カルシウム、水酸化バリウム、炭酸ナトリウム、炭酸カリウム、炭酸水素ナトリウム、炭酸水素カリウム、液体アンモニア、アンモニア水溶液、トリエチルアミン、トリブチルアミン、ピリジン、コリジン、2,6−ルチジン、4−ジメチルアミノピリジンなどを挙げることができる。これらの塩基は、それぞれ単独で用いてもよいが、2種類以上を任意の割合で組み合わせて使用することもできる。 In the method for producing 3-nitrotetrahydrothiophenes represented by the general formula (1a) of the present invention, a base may be used for assisting the reaction. The base used may be either an inorganic base or an organic base. As the inorganic base, alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates, ammonia and the like can be used. As the organic base, trialkylamine, pyridines and the like can be used. Specifically, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, liquid ammonia, aqueous ammonia solution, triethylamine, tributylamine, pyridine , Collidine, 2,6-lutidine, 4-dimethylaminopyridine and the like. These bases may be used alone or in combination of two or more at an arbitrary ratio.
本発明の一般式(1a)で表される3−ニトロテトラヒドロチオフェン類の製造方法に用いるエステル化剤またはハロゲン化剤としては、塩化アセチル、塩化ベンゾイルなどのカルボン酸ハロゲン化物、無水酢酸、無水トリフルオロ酢酸などのカルボン酸無水物、塩化トルエンスルホニル、塩化メタンスルホニル、塩化トリフルオロメタンスルホニルなどのスルホン酸ハロゲン化物、塩化チオニル、塩化スルフリル、シュウ酸クロリド、ホスゲン、ジホスゲン、トリホスゲン、五塩化リン、三塩化リン、オキシ塩化リン、三臭化リンなどを挙げることができる。これらのエステル化剤またはハロゲン化剤はそれぞれ単独で用いてもよいが、2種類以上を任意の割合で組み合わせて使用することもできる。 Examples of the esterifying agent or halogenating agent used in the method for producing 3-nitrotetrahydrothiophene represented by the general formula (1a) of the present invention include carboxylic acid halides such as acetyl chloride and benzoyl chloride, acetic anhydride, Carboxylic anhydrides such as fluoroacetic acid, sulfonic acid halides such as toluenesulfonyl chloride, methanesulfonyl chloride, trifluoromethanesulfonyl chloride, thionyl chloride, sulfuryl chloride, oxalic chloride, phosgene, diphosgene, triphosgene, phosphorus pentachloride, trichloride Examples thereof include phosphorus, phosphorus oxychloride, and phosphorus tribromide. These esterifying agents or halogenating agents may be used alone or in combination of two or more at any ratio.
本発明の一般式(1a)で表される3−ニトロテトラヒドロチオフェン類の製造方法においては、適宜溶媒を使用することができるが、用いる溶媒には特に制限はない。溶媒としては、例えば、ジクロロメタン、クロロホルム等のハロゲン化アルキル類、ベンゼン、トルエン、キシレン等の芳香族炭化水素類、ヘキサン、ヘプタン、シクロヘキサン等の炭化水素類、ジエチルエーテル、ジイソプロピルエーテル、1,2−ジメトキシエタン、テトラヒドロフラン、ジオキサン等のエーテル類、酢酸エチル、酢酸ブチル等のエステル類、N,N−ジメチルホルムアミド、N,N−ジメチルアセトアミド、N−メチルピロリドン等のアミド類、N,N’−ジメチルイミダゾリジノン、アセトニトリル、水などを挙げることができる。これらの溶媒はそれぞれ単独で用いてもよいが、2種類以上を任意の割合で組み合わせて使用することもできる。 In the method for producing 3-nitrotetrahydrothiophenes represented by the general formula (1a) of the present invention, a solvent can be appropriately used, but the solvent to be used is not particularly limited. Examples of the solvent include alkyl halides such as dichloromethane and chloroform, aromatic hydrocarbons such as benzene, toluene and xylene, hydrocarbons such as hexane, heptane and cyclohexane, diethyl ether, diisopropyl ether, 1,2- Ethers such as dimethoxyethane, tetrahydrofuran and dioxane, esters such as ethyl acetate and butyl acetate, amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone, N, N′-dimethyl Examples include imidazolidinone, acetonitrile, water and the like. Each of these solvents may be used alone, but two or more kinds may be used in combination at any ratio.
反応に用いる溶媒の量については特に制限を設けないが、経済的観点から一般式(8)で表される3−ヒドロキシ−4−ニトロテトラヒドロチオフェン類の重量に対して50倍量以下とすることが好ましい。
反応温度については特に制限を設けないが、操作効率の観点から溶媒の融点以上沸点以下とすることが好ましい。The amount of the solvent used in the reaction is not particularly limited, but it should be 50 times or less with respect to the weight of the 3-hydroxy-4-nitrotetrahydrothiophene represented by the general formula (8) from the economical viewpoint. Is preferred.
The reaction temperature is not particularly limited, but it is preferably from the melting point to the boiling point of the solvent from the viewpoint of operation efficiency.
また、本発明により開示される新規な製造方法によれば一般式(3)で表される2−アルキル−3−ニトロチオフェン誘導体は一般式(5)で表される3−ニトロ−2,5−ジヒドロチオフェン類もしくは一般式(1a)で表される3−ニトロテトラヒドロチオフェン類を酸化剤を用いて酸化することにより得られる。 Further, according to the novel production method disclosed by the present invention, the 2-alkyl-3-nitrothiophene derivative represented by the general formula (3) is a 3-nitro-2,5 represented by the general formula (5). -Obtained by oxidizing dihydrothiophenes or 3-nitrotetrahydrothiophenes represented by the general formula (1a) using an oxidizing agent.
本発明の一般式(3)で表される2−アルキル−3−ニトロチオフェン誘導体の製造方法において、使用される酸化剤としては、マンガン化合物、クロム酸類、四塩化鉛、四塩化オスミウム、四塩化ルテニウム、塩素、臭素、ヨウ素、次亜塩素酸またはその塩、塩素酸またはその塩、臭素酸またはその塩、酸素、オゾン、過酸化水素、有機過酸化物、有機過酸、塩化スルフリル、塩化チオニル、シュウ酸クロリド、ホスゲン、ジホスゲン、トリホスゲンなどを挙げることができるが、塩素、塩化スルフリルが好適に使用される。 In the method for producing a 2-alkyl-3-nitrothiophene derivative represented by the general formula (3) of the present invention, as the oxidizing agent used, manganese compounds, chromic acids, lead tetrachloride, osmium tetrachloride, tetrachloride Ruthenium, chlorine, bromine, iodine, hypochlorous acid or its salt, chloric acid or its salt, bromic acid or its salt, oxygen, ozone, hydrogen peroxide, organic peroxide, organic peracid, sulfuryl chloride, thionyl chloride Oxalic chloride, phosgene, diphosgene, triphosgene and the like, and chlorine and sulfuryl chloride are preferably used.
本発明の一般式(3)で表される2−アルキル−3−ニトロチオフェン誘導体の製造方法においては、反応補助のため塩基を用いてもよい。用いる塩基は無機の塩基、有機の塩基のいずれでもよい。無機の塩基としては、アルカリ金属の水酸化物、アルカリ土類金属の水酸化物、アルカリ金属の炭酸塩、アンモニア類等を用いることができる。有機の塩基としては、トリアルキルアミン、ピリジン類等を用いることができる。具体的には、水酸化リチウム、水酸化ナトリウム、水酸化カリウム、水酸化カルシウム、水酸化バリウム、炭酸ナトリウム、炭酸カリウム、炭酸水素ナトリウム、炭酸水素カリウム、液体アンモニア、アンモニア水溶液、トリエチルアミン、トリブチルアミン、ピリジン、コリジン、2,6−ルチジン、4−ジメチルアミノピリジンなどを挙げることができる。これらの塩基はそれぞれ単独で用いてもよいが、2種類以上を任意の割合で組み合わせて使用することもできる。 In the method for producing a 2-alkyl-3-nitrothiophene derivative represented by the general formula (3) of the present invention, a base may be used for assisting the reaction. The base used may be either an inorganic base or an organic base. As the inorganic base, alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates, ammonia and the like can be used. As the organic base, trialkylamine, pyridines and the like can be used. Specifically, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, liquid ammonia, aqueous ammonia solution, triethylamine, tributylamine, Examples thereof include pyridine, collidine, 2,6-lutidine, 4-dimethylaminopyridine and the like. These bases may be used alone or in combination of two or more at any ratio.
本発明の2−アルキル−3−ニトロチオフェン誘導体の製造方法においては、適宜溶媒を使用することができるが、用いる溶媒に特に制限を設けない。溶媒としては、例えば、ジクロロメタン、クロロホルム等のハロゲン化アルキル類、ベンゼン、トルエン、キシレン等の芳香族炭化水素類、ヘキサン、ヘプタン、シクロヘキサン等の炭化水素類、ジエチルエーテル、ジイソプロピルエーテル、1,2−ジメトキシエタン、テトラヒドロフラン、ジオキサン等のエーテル類、酢酸エチル、酢酸ブチル等のエステル類、N,N−ジメチルホルムアミド、N,N−ジメチルアセトアミド、N−メチルピロリドン等のアミド類、N,N’−ジメチルイミダゾリジノン、アセトニトリル、水などを挙げることができる。これらの溶媒はそれぞれ単独で用いてもよいが、2種類以上を任意の割合で組み合わせて使用することもできる。 In the method for producing a 2-alkyl-3-nitrothiophene derivative of the present invention, a solvent can be appropriately used, but the solvent to be used is not particularly limited. Examples of the solvent include alkyl halides such as dichloromethane and chloroform, aromatic hydrocarbons such as benzene, toluene and xylene, hydrocarbons such as hexane, heptane and cyclohexane, diethyl ether, diisopropyl ether, 1,2- Ethers such as dimethoxyethane, tetrahydrofuran and dioxane, esters such as ethyl acetate and butyl acetate, amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone, N, N′-dimethyl Examples include imidazolidinone, acetonitrile, water and the like. Each of these solvents may be used alone, but two or more kinds may be used in combination at any ratio.
反応に用いる溶媒の量については特に制限を設けないが、経済的観点から一般式(5)で表される3−ニトロ−2,5−ジヒドロチオフェン類もしくは一般式(1a)で表される3−ニトロテトラヒドロチオフェン類の重量に対して50倍量以下とすることが好ましい。
反応温度については特に制限を設けないが、操作効率の観点から溶媒の融点以上沸点以下とすることが好ましい。The amount of the solvent used in the reaction is not particularly limited, but 3-nitro-2,5-dihydrothiophenes represented by the general formula (5) or 3 represented by the general formula (1a) from the economical viewpoint. -It is preferable to make it 50 times or less with respect to the weight of nitrotetrahydrothiophenes.
The reaction temperature is not particularly limited, but it is preferably from the melting point to the boiling point of the solvent from the viewpoint of operation efficiency.
また、本発明により開示される新規な製造方法によれば一般式(4)で表される2−アルキル−3−アミノチオフェン誘導体は一般式(3)で表される2−アルキル−3−ニトロチオフェン誘導体を還元することにより得られる。 Further, according to the novel production method disclosed by the present invention, the 2-alkyl-3-aminothiophene derivative represented by the general formula (4) is a 2-alkyl-3-nitro represented by the general formula (3). It can be obtained by reducing a thiophene derivative.
本発明の2−アルキル−3−アミノチオフェン誘導体の製造方法において使用される還元方法としては接触水素添加法、液体アンモニア中アルカリ金属を用いて還元する方法、鉄、亜鉛、アルミニウム、スズなどの金属による還元法、塩化スズ(II)などの金属塩による還元法、水素化ホウ素ナトリウム、水素化アルミニウムリチウムなどの水素化金属錯体による還元法などを挙げることができるが、接触水素添加法、鉄による還元法および塩化スズ(II)による還元法が好適に使用される。 Examples of the reduction method used in the method for producing a 2-alkyl-3-aminothiophene derivative of the present invention include a catalytic hydrogenation method, a method using an alkali metal in liquid ammonia, and a metal such as iron, zinc, aluminum, and tin. Reduction method using metal salt such as tin (II) chloride, reduction method using metal hydride complex such as sodium borohydride, lithium aluminum hydride, etc. A reduction method and a reduction method with tin (II) chloride are preferably used.
本発明の2−アルキル−3−アミノチオフェン誘導体の製造方法においては、適宜溶媒を使用することができるが、用いる溶媒に特に制限を設けない。溶媒としては、例えば、ジクロロメタン、クロロホルム等のハロゲン化アルキル類、ベンゼン、トルエン、キシレン等の芳香族炭化水素類、ヘキサン、ヘプタン、シクロヘキサン等の炭化水素類、ジエチルエーテル、ジイソプロピルエーテル、1,2−ジメトキシエタン、テトラヒドロフラン、ジオキサン等のエーテル類、酢酸エチル、酢酸ブチル等のエステル類、N,N−ジメチルホルムアミド、N,N−ジメチルアセトアミド、N−メチルピロリドン等のアミド類、N,N’−ジメチルイミダゾリジノン、アセトニトリル、水などを挙げることができる。これらの溶媒はそれぞれ単独で用いてもよいが、2種類以上を任意の割合で組み合わせて使用することもできる。 In the method for producing a 2-alkyl-3-aminothiophene derivative of the present invention, a solvent can be appropriately used, but the solvent to be used is not particularly limited. Examples of the solvent include alkyl halides such as dichloromethane and chloroform, aromatic hydrocarbons such as benzene, toluene and xylene, hydrocarbons such as hexane, heptane and cyclohexane, diethyl ether, diisopropyl ether, 1,2- Ethers such as dimethoxyethane, tetrahydrofuran and dioxane, esters such as ethyl acetate and butyl acetate, amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone, N, N′-dimethyl Examples include imidazolidinone, acetonitrile, water and the like. Each of these solvents may be used alone, but two or more kinds may be used in combination at any ratio.
反応に用いる溶媒の量については特に制限を設けないが、経済的観点から一般式(3)で表される2−アルキル−3−ニトロチオフェン誘導体の重量に対して50倍量以下とすることが好ましい。
反応温度については特に制限を設けないが、操作効率の観点から溶媒の融点以上沸点以下とすることが好ましい。The amount of the solvent used for the reaction is not particularly limited, but may be 50 times or less with respect to the weight of the 2-alkyl-3-nitrothiophene derivative represented by the general formula (3) from the economical viewpoint. preferable.
The reaction temperature is not particularly limited, but it is preferably from the melting point to the boiling point of the solvent from the viewpoint of operation efficiency.
本発明の2−アルキル−3−アミノチオフェンの製造方法で得られる2−アルキル−3−アミノチオフェンは、農園芸用殺菌剤製造中間体、農園芸用殺虫剤製造中間体、農園芸用除草剤製造中間体、あるいは医薬品製造中間体として利用することができる。例えば、特開平09−235282号公報に記載の農園芸用殺菌剤の中間体として有用である。 The 2-alkyl-3-aminothiophene obtained by the method for producing 2-alkyl-3-aminothiophene of the present invention comprises an agricultural and horticultural fungicide production intermediate, an agricultural and horticultural insecticide production intermediate, and an agricultural and horticultural herbicide It can be used as a production intermediate or a pharmaceutical production intermediate. For example, it is useful as an intermediate for agricultural and horticultural fungicides described in JP-A 09-235282.
日本出願2009−100217号の開示はその全体を本明細書に援用する。
本明細書に記載された全ての文献、特許出願、および技術規格は、個々の文献、特許出願、および技術規格が参照により取り込まれることが具体的かつ個々に記された場合と同程度に、本明細書に参照により取り込まれる。The disclosure of Japanese application 2009-100197 is incorporated herein in its entirety.
All documents, patent applications, and technical standards mentioned in this specification are to the same extent as if each individual document, patent application, and technical standard were specifically and individually described to be incorporated by reference, Incorporated herein by reference.
以下、具体的に説明するために実施例を挙げるが、本発明はこれらの実施例に限定されるものではない。 Hereinafter, examples will be described for specific description, but the present invention is not limited to these examples.
[実施例 1−1]
水50ml、エタノール50ml中に4℃で水酸化ナトリウム7.0gを溶解させたのち、ニトロメタン10.7g、2−メチルペンタナール10.0gを加え、室温に戻した後2時間攪拌した。エタノールを減圧下濃縮後、1mol/l塩酸で溶液のpHが7付近になるように中和した。酢酸エチルを溶液に加え、飽和食塩水溶液で洗浄して有機層を硫酸マグネシウムで乾燥後濃縮させ、シリカゲルクロマトグラフィー(ヘキサン/酢酸エチル=8/1)で精製し、3−メチル−1−ニトロ−2−ヘキサノール13.3g(収率:94.2%)を得た。 After dissolving 7.0 g of sodium hydroxide in 50 ml of water and 50 ml of ethanol at 4 ° C., 10.7 g of nitromethane and 10.0 g of 2-methylpentanal were added, and the mixture was returned to room temperature and stirred for 2 hours. Ethanol was concentrated under reduced pressure, and neutralized with 1 mol / l hydrochloric acid so that the pH of the solution was around 7. Ethyl acetate was added to the solution, washed with a saturated saline solution, the organic layer was dried over magnesium sulfate, concentrated, purified by silica gel chromatography (hexane / ethyl acetate = 8/1), and 3-methyl-1-nitro- 13.3 g (yield: 94.2%) of 2-hexanol was obtained.
1H−NMR(CDCl3):δ=0.90−0.96(6H,m),1.18−1.47(4H,m),1.62(1H,m),4.15(1H,m),4.39(2H,m) 1 H-NMR (CDCl 3 ): δ = 0.90-0.96 (6H, m), 1.18-1.47 (4H, m), 1.62 (1H, m), 4.15 ( 1H, m), 4.39 (2H, m)
[実施例 1−2]
水25ml、エタノール25ml中に4℃で水酸化ナトリウム5.0gを溶解させたのち、ニトロメタン7.7g、2,4−ジメチルペンタナール7.2gを加え、室温に戻した後1時間攪拌した。エタノールを減圧下濃縮後、1mol/l塩酸で溶液のpHが7付近になるように中和した。酢酸エチルを溶液に加え、飽和食塩水溶液で洗浄して有機層を硫酸マグネシウムで乾燥後濃縮させ、シリカゲルクロマトグラフィー(ヘキサン/酢酸エチル=8/1)で精製し、3,5−ジメチル−1−ニトロ−2−ヘキサノール9.0g(収率:81.4%)を得た。 After dissolving 5.0 g of sodium hydroxide in 25 ml of water and 25 ml of ethanol at 4 ° C., 7.7 g of nitromethane and 7.2 g of 2,4-dimethylpentanal were added, and the mixture was returned to room temperature and stirred for 1 hour. Ethanol was concentrated under reduced pressure, and neutralized with 1 mol / l hydrochloric acid so that the pH of the solution was around 7. Ethyl acetate was added to the solution, washed with a saturated aqueous sodium chloride solution, the organic layer was dried over magnesium sulfate, concentrated, purified by silica gel chromatography (hexane / ethyl acetate = 8/1), and 3,5-dimethyl-1- 9.0 g (yield: 81.4%) of nitro-2-hexanol was obtained.
1H−NMR(CDCl3):δ=0.85−0.95(9H,m),1.12−1.28(2H,m),1.64−1.69(2H,m),4.22−4.24(1H,m),4.44−4.46(2H,m) 1 H-NMR (CDCl 3 ): δ = 0.85-0.95 (9H, m), 1.12-1.28 (2H, m), 1.64-1.69 (2H, m), 4.22-4.24 (1H, m), 4.44-4.46 (2H, m)
[実施例 2−1]
ジクロロメタン100mlに3−メチル−1−ニトロ−2−ヘキサノール15.0gを溶解させ、続いて4℃でメシルクロライド11.7g、トリエチルアミン18.8gをそれぞれゆっくりと滴下した後、溶液を室温に戻して1時間攪拌した。水で反応を停止させ、ジクロロメタンで抽出した。有機層を硫酸マグネシウムで乾燥後濃縮させ、シリカゲルクロマトグラフィー(ヘキサン/酢酸エチル=10/1)で精製し、3−メチル−1−ニトロヘキサ−1−エン9.0g(収率:81.4%)を得た。 After dissolving 15.0 g of 3-methyl-1-nitro-2-hexanol in 100 ml of dichloromethane and subsequently slowly dropping 11.7 g of mesyl chloride and 18.8 g of triethylamine at 4 ° C., the solution is returned to room temperature. Stir for 1 hour. The reaction was quenched with water and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, concentrated, and purified by silica gel chromatography (hexane / ethyl acetate = 10/1) to give 9.0 g of 3-methyl-1-nitrohex-1-ene (yield: 81.4%). )
1H−NMR(CDCl3):δ=0.90−0.93(3H,t, 7.2),1.11−1.13(3H,d, 6.8),1.26−1.46(4H,m),2.41−4.45(1H,m),6.93−6.96(1H,d, J=13.2), 7.16−7.22(1H, dd, J=13.8, 5.6) 1 H-NMR (CDCl 3 ): δ = 0.90-0.93 (3H, t, 7.2), 1.11-1.13 (3H, d, 6.8), 1.26-1 .46 (4H, m), 2.41-4.45 (1H, m), 6.93-6.96 (1H, d, J = 13.2), 7.16-7.22 (1H, dd, J = 13.8, 5.6)
[実施例 2−2]
ジクロロメタン100mlに3,5−ジメチル−1−ニトロ−2−ヘキサノール9.0gを溶解させ、続いて4℃でメシルクロライド6.5g、トリエチルアミン10.4gをそれぞれゆっくりと滴下した後、溶液を室温に戻して1.5時間攪拌した。水で反応を停止させ、ジクロロメタンで抽出した。有機層を硫酸マグネシウムで乾燥後濃縮させ、シリカゲルクロマトグラフィー(ヘキサン/酢酸エチル=10/1)で精製し、3, 5−ジメチル−1−ニトロヘキサ−1−エン6.8g(収率:83.9%)を得た。 After dissolving 9.0 g of 3,5-dimethyl-1-nitro-2-hexanol in 100 ml of dichloromethane and subsequently slowly dropping 6.5 g of mesyl chloride and 10.4 g of triethylamine at 4 ° C., the solution was brought to room temperature. The mixture was returned and stirred for 1.5 hours. The reaction was quenched with water and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, concentrated and purified by silica gel chromatography (hexane / ethyl acetate = 10/1) to give 6.8 g of 3,5-dimethyl-1-nitrohex-1-ene (yield: 83. 9%).
1H−NMR(CDCl3):δ=0.89−0.95(6H,m),1.10−1.12(3H,d, J=6.8),1.25−1.43(2H,m),1.56−1.62(1H,m),2.49−2.53(1H,m), 6.95−6.99(1H, d, J=13.8), 7.14−7.20(1H, dd, J=13.8, 8.3) 1 H-NMR (CDCl 3 ): δ = 0.89-0.95 (6H, m), 1.10-1.12 (3H, d, J = 6.8), 1.25-1.43 (2H, m), 1.56-1.62 (1H, m), 2.49-2.53 (1H, m), 6.95-6.99 (1H, d, J = 13.8) , 7.14-7.20 (1H, dd, J = 13.8, 8.3)
[実施例 2−3]
[Example 2-3]
ピリジン30mlに3, 5-ジメチル−1−ニトロヘキサン−2−オール7.8gを溶解させ、無水酢酸10ml加えて室温で2.5時間攪拌した。酢酸エチルを溶液に加え、1mol/lの塩酸水溶液および飽和食塩水溶液で洗浄して、有機層を硫酸マグネシウムで乾燥後濃縮した。シリカゲルクロマトグラフィー(ヘキサン/酢酸エチル=10/1)で精製し、3, 5−ジメチル-1−ニトロヘキサン−2−イルアセテート8.4g(87.3%)を得た。
1H−NMR(CDCl3):δ=0.85−0.95(9H,m),1.12−1.28(2H,m),1.64−1.67(2H,m),2.23(3H,s),4.22−4.24(2H,m), 4.45(1H, m)7.8 g of 3,5-dimethyl-1-nitrohexane-2-ol was dissolved in 30 ml of pyridine, 10 ml of acetic anhydride was added, and the mixture was stirred at room temperature for 2.5 hours. Ethyl acetate was added to the solution, washed with 1 mol / l hydrochloric acid aqueous solution and saturated brine solution, and the organic layer was dried over magnesium sulfate and concentrated. Purification by silica gel chromatography (hexane / ethyl acetate = 10/1) gave 8.4 g (87.3%) of 3,5-dimethyl-1-nitrohexane-2-yl acetate.
1 H-NMR (CDCl 3 ): δ = 0.85-0.95 (9H, m), 1.12-1.28 (2H, m), 1.64-1.67 (2H, m), 2.23 (3H, s), 4.22-4.24 (2H, m), 4.45 (1H, m)
[実施例 2−4]
トルエン15mlに3,5−ジメチル−1−ニトロ−2−ヘキサノール2.0gを溶解させ、塩化チオニル4.1gおよびN,N−ジメチルホルムアミドを2滴加えて80℃で2.5時間攪拌した。室温に冷却したのち濃縮して、シリカゲルクロマトグラフィー(ヘキサン/酢酸エチル=8/1)で精製し、2−クロロ−3,5−ジメチル−1−ニトロヘキサン1.5g(収率:72.4%)を得た。 2.0 g of 3,5-dimethyl-1-nitro-2-hexanol was dissolved in 15 ml of toluene, 4.1 g of thionyl chloride and 2 drops of N, N-dimethylformamide were added, and the mixture was stirred at 80 ° C. for 2.5 hours. After cooling to room temperature, the mixture was concentrated and purified by silica gel chromatography (hexane / ethyl acetate = 8/1) to give 1.5 g of 2-chloro-3,5-dimethyl-1-nitrohexane (yield: 72.4). %).
1H−NMR(CDCl3):δ=0.86−1.36(9H,m),1.14−1.17(2H,m),1.64−1.68(2H,m),4.40−4.42(1H,m), 4.59−4.61(2H, m) 1 H-NMR (CDCl 3 ): δ = 0.86-1.36 (9H, m), 1.14-1.17 (2H, m), 1.64-1.68 (2H, m), 4.40-4.42 (1H, m), 4.59-4.61 (2H, m)
[実施例 3−1]
エタノール6mlに3−メチル−1−ニトロヘキサ−1−エン0.30gを溶解させ、続いてトリエチルアミン0.32g、1,4−ジチアン−2, 5−ジオール0.16gを加えた後、溶液を50℃に加熱して1時間攪拌した。室温に戻した後、酢酸エチルで希釈して、1mol/lの塩酸水溶液、飽和食塩水溶液でそれぞれ洗浄して有機層を硫酸マグネシウムで乾燥後濃縮させ、シリカゲルクロマトグラフィー(ヘキサン/酢酸エチル=8/1)で精製し、4−ニトロ−5−(ペンタン−2−イル)テトラヒドロチオフェン−3−オール0.18g(収率:42.6%)を得た。 After dissolving 0.30 g of 3-methyl-1-nitrohex-1-ene in 6 ml of ethanol and subsequently adding 0.32 g of triethylamine and 0.16 g of 1,4-dithian-2,5-diol, The mixture was heated to ° C and stirred for 1 hour. After returning to room temperature, the mixture was diluted with ethyl acetate, washed with 1 mol / l aqueous hydrochloric acid and saturated aqueous sodium chloride, and the organic layer was dried over magnesium sulfate and concentrated. Silica gel chromatography (hexane / ethyl acetate = 8 / Purification by 1) gave 0.18 g (yield: 42.6%) of 4-nitro-5- (pentan-2-yl) tetrahydrothiophen-3-ol.
1H−NMR(CDCl3):δ=0.87−1.03(6H,m),1.22−1.32(4H,m),1.64−1.69(1H,m),2.85−2.91(1H,m),3.08−3.11(1H,m), 3.30(1H, Brs), 3.79−3.85(1H, m), 4.70−4.76(2H, m) 1 H-NMR (CDCl 3 ): δ = 0.87-1.03 (6H, m), 1.22-1.32 (4H, m), 1.64-1.69 (1H, m), 2.85-2.91 (1H, m), 3.08-3.11 (1H, m), 3.30 (1H, Brs), 3.79-3.85 (1H, m), 4. 70-4.76 (2H, m)
[実施例 3−2]
ジクロロメタン40mlに3,5−ジメチル−1−ニトロヘキサ−1−エン6.8gを溶解させ、続いてトリエチルアミン6.7g、1,4−ジチアン−2,5−ジオール3.6gを加えた後、1.5時間攪拌した。酢酸エチルで希釈して、1mol/lの塩酸水溶液、飽和食塩水溶液でそれぞれ洗浄して有機層を硫酸マグネシウムで乾燥後濃縮させ、シリカゲルクロマトグラフィー(ヘキサン/酢酸エチル=8/1)で精製し、5−(4−メチルペンタン−2−イル)−4−ニトロテトラヒドロチオフェン−3−オール10.9g(収率:93.5%)を得た。 6.8 g of 3,5-dimethyl-1-nitrohex-1-ene was dissolved in 40 ml of dichloromethane, and then 6.7 g of triethylamine and 3.6 g of 1,4-dithian-2,5-diol were added. Stir for 5 hours. Diluted with ethyl acetate, washed with 1 mol / l aqueous hydrochloric acid solution and saturated aqueous sodium chloride solution, the organic layer was dried over magnesium sulfate, concentrated and purified by silica gel chromatography (hexane / ethyl acetate = 8/1), 10.9 g (yield: 93.5%) of 5- (4-methylpentan-2-yl) -4-nitrotetrahydrothiophen-3-ol was obtained.
1H−NMR(CDCl3):δ=0.87−1.01(6H,m),1.14−1.28(5H,m),1.64−1.72(2H,m),2.85−3.12(3H,m), 4.11−4.31(1H, m), 4.70−4.83(2H, m) 1 H-NMR (CDCl 3 ): δ = 0.87-1.01 (6H, m), 1.14-1.28 (5H, m), 1.64-1.72 (2H, m), 2.85-3.12 (3H, m), 4.11-4.31 (1H, m), 4.70-4.83 (2H, m)
[実施例 3−3]
[Example 3-3]
3, 5-ジメチル−1−ニトロヘキサン−2−イルアセテート1.20gをトルエン7.0mlに溶解させた後、トリエチルアミン0.80gおよび1,4−ジチアン−2,5−ジオール0.60gを加えた。室温で30分攪拌したのち、不溶成分をろ過した。ろ液を濃縮したのち、シリカゲルクロマトグラフィー(ヘキサン/酢酸エチル=8/1)で精製し、5−(4−メチルペンタン−2−イル)−4−ニトロテトラヒドロチオフェン−3−オール1.26g(99.0%)を得た。 After dissolving 1.20 g of 3,5-dimethyl-1-nitrohexane-2-yl acetate in 7.0 ml of toluene, 0.80 g of triethylamine and 0.60 g of 1,4-dithian-2,5-diol were added. It was. After stirring at room temperature for 30 minutes, insoluble components were filtered off. The filtrate was concentrated and purified by silica gel chromatography (hexane / ethyl acetate = 8/1) to give 1.26 g of 5- (4-methylpentan-2-yl) -4-nitrotetrahydrothiophen-3-ol. 99.0%).
[実施例 3−4]
2−クロロ−3,5−ジメチル−1−ニトロヘキサン1.5gをトルエン10mlに溶解させた後、4℃でトリエチルアミン0.9gおよび1,4−ジヒドロキシジチアン0.9gを加えた。室温で4.5時間攪拌したのち、固形物をろ過して、溶液を濃縮した。シリカゲルクロマトグラフィー(ヘキサン/酢酸エチル=8/1)で精製し、5−(4−メチルペンタン−2−イル)−4−ニトロテトラチオフェン−3−オール0.7g(収率:39.3%)を得た。 After 1.5 g of 2-chloro-3,5-dimethyl-1-nitrohexane was dissolved in 10 ml of toluene, 0.9 g of triethylamine and 0.9 g of 1,4-dihydroxydithiane were added at 4 ° C. After stirring at room temperature for 4.5 hours, the solid was filtered and the solution was concentrated. Purification by silica gel chromatography (hexane / ethyl acetate = 8/1) gave 0.7 g of 5- (4-methylpentan-2-yl) -4-nitrotetrathiophen-3-ol (yield: 39.3%). )
[実施例 4−1]
ジクロロメタン4mlに4−ニトロ−5−(ペンタン−2−イル)テトラヒドロチオフェン−3−オール150mgを溶解させ、続いて4℃でメシルクロライド86mg、トリエチルアミン138mgをそれぞれゆっくりと滴下した後、溶液を室温に戻して3.5時間攪拌した。水で反応を停止させ、ジクロロメタンで抽出した。有機層を硫酸マグネシウムで乾燥後濃縮させ、シリカゲルクロマトグラフィー(ヘキサン/酢酸エチル=10/1)で精製し、3−ニトロ−2−(ペンタン−2−イル)−2,5−ジヒドロチオフェン78mg(収率:57.3%)を得た。 In 4 ml of dichloromethane, 150 mg of 4-nitro-5- (pentan-2-yl) tetrahydrothiophen-3-ol was dissolved. Subsequently, 86 mg of mesyl chloride and 138 mg of triethylamine were each slowly added dropwise at 4 ° C. The mixture was returned and stirred for 3.5 hours. The reaction was quenched with water and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, concentrated and purified by silica gel chromatography (hexane / ethyl acetate = 10/1) to give 78 mg of 3-nitro-2- (pentan-2-yl) -2,5-dihydrothiophene ( Yield: 57.3%).
1H−NMR(CDCl3):δ=0.84−0.98(6H,m),1.17−1.40(4H,m),2.10−2.25(1H,m),3.76−3.80(2H,m),4.60−4.75(1H,m), 7.22−7.24(1H, m) 1 H-NMR (CDCl 3 ): δ = 0.84-0.98 (6H, m), 1.17-1.40 (4H, m), 2.10-2.25 (1H, m), 3.76-3.80 (2H, m), 4.60-4.75 (1H, m), 7.22-7.24 (1H, m)
[実施例 4−2]
ジクロロメタン4mlに5−(4−メチルペンタン−2−イル)−4−ニトロテトラヒドロチオフェン−3−オール0.50gを溶解させ、続いて4℃でメシルクロライド0.27g、トリエチルアミン0.33gをそれぞれゆっくりと滴下した後、溶液を室温に戻して7.5時間攪拌した。水で反応を停止させ、ジクロロメタンで抽出した。有機層を硫酸マグネシウムで乾燥後濃縮させ、シリカゲルクロマトグラフィー(ヘキサン/酢酸エチル=10/1)で精製し、2−(4−メチルペンタン−2−イル)−3−ニトロ−2,5−ジヒドロチオフェン0.22g(収率:47.7%)を得た。 Dissolve 0.50 g of 5- (4-methylpentan-2-yl) -4-nitrotetrahydrothiophen-3-ol in 4 ml of dichloromethane, and then slowly add 0.27 g of mesyl chloride and 0.33 g of triethylamine at 4 ° C. Then, the solution was returned to room temperature and stirred for 7.5 hours. The reaction was quenched with water and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, concentrated and purified by silica gel chromatography (hexane / ethyl acetate = 10/1) to give 2- (4-methylpentan-2-yl) -3-nitro-2,5-dihydro 0.22 g (yield: 47.7%) of thiophene was obtained.
1H−NMR(CDCl3):δ=0.87−1.00(6H,m),1.15−1.30(5H,m),1.64−1.72(2H,m),3.75−3.79(2H,m),4.60−4.74(1H,m), 7.21−7.24(1H, m) 1 H-NMR (CDCl 3 ): δ = 0.87-1.00 (6H, m), 1.15-1.30 (5H, m), 1.64-1.72 (2H, m), 3.75-3.79 (2H, m), 4.60-4.74 (1H, m), 7.21-7.24 (1H, m)
[実施例 4−3]
[Example 4-3]
トルエン10mlに5−(4−メチルペンタン−2−イル)−4−ニトロテトラヒドロチオフェン−3−オール1.00gを溶解させ、ピリジン0.7gおよび無水酢酸1.4gをくわえて室温で2時間攪拌した。水で反応を停止させ、1mol/lの塩酸水溶液および飽和食塩水溶液で洗浄して、有機層を硫酸マグネシウムで乾燥後濃縮した。シリカゲルクロマトグラフィー(ヘキサン/酢酸エチル=9/1)で精製し、5−(4−メチルペンタン−2−イル)−4−ニトロテトラヒドロチオフェン−3−イル−アセテート1.10g(94.8%)を得た。 Dissolve 1.00 g of 5- (4-methylpentan-2-yl) -4-nitrotetrahydrothiophen-3-ol in 10 ml of toluene and stir at room temperature for 2 hours with 0.7 g of pyridine and 1.4 g of acetic anhydride. did. The reaction was stopped with water, washed with 1 mol / l aqueous hydrochloric acid and saturated aqueous sodium chloride, and the organic layer was dried over magnesium sulfate and concentrated. Purification by silica gel chromatography (hexane / ethyl acetate = 9/1) gave 1.10 g (94.8%) of 5- (4-methylpentan-2-yl) -4-nitrotetrahydrothiophen-3-yl-acetate. Got.
1H−NMR(CDCl3):δ=0.87−1.01(6H,m),1.14−1.28(5H,m),1.64−1.72(2H,m),2.41(3H,s),2.85−3.12(3H,m), 4.11−4.31(1H, m), 4.70−4.83(2H, m) 1 H-NMR (CDCl 3 ): δ = 0.87-1.01 (6H, m), 1.14-1.28 (5H, m), 1.64-1.72 (2H, m), 2.41 (3H, s), 2.85-3.12 (3H, m), 4.11-4.31 (1H, m), 4.70-4.83 (2H, m)
[実施例 5−1]
ジクロロメタン2mlに3−ニトロ−2−(ペンタン−2−イル)−2,5−ジヒドロチオフェン78mgを溶解させ、スルフリルクロライド78mgのジクロロメタン2mlの溶液を加えて室温で2.5時間攪拌した。飽和炭酸水素ナトリウム水溶液を加えた後、ジクロロメタンで抽出し、さらに飽和食塩水で洗浄した。有機層を硫酸マグネシウムで乾燥後濃縮させ、NH−シリカゲルクロマトグラフィー(ヘキサン/酢酸エチル=10/1)で精製し、3−ニトロ−2−(ペンタン−2−イル)チオフェン69mg(収率:88.7%)を得た。 78 mg of 3-nitro-2- (pentan-2-yl) -2,5-dihydrothiophene was dissolved in 2 ml of dichloromethane, and a solution of 78 mg of sulfuryl chloride in 2 ml of dichloromethane was added and stirred at room temperature for 2.5 hours. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with dichloromethane and further washed with saturated brine. The organic layer was dried over magnesium sulfate, concentrated and purified by NH-silica gel chromatography (hexane / ethyl acetate = 10/1) to give 69 mg of 3-nitro-2- (pentan-2-yl) thiophene (yield: 88 .7%).
1H−NMR(CDCl3):δ=0.90−0.93(3H,m),1.30−1.42(5H,m),1.60−1.70(2H,m),4.01−4.07(1H,m),7.01−7.10(1H,d, J=5.9Hz), 7.53−7.55(1H, d, J=5.4Hz) 1 H-NMR (CDCl 3 ): δ = 0.90-0.93 (3H, m), 1.30-1.42 (5H, m), 1.60-1.70 (2H, m), 4.01-4.07 (1H, m), 7.01-7.10 (1H, d, J = 5.9 Hz), 7.53-7.55 (1H, d, J = 5.4 Hz)
[実施例 5−2]
ジクロロメタン40mlに2−(4−メチルペンタン−2−イル)−3−ニトロ−2,5−ジヒドロチオフェン2.8gを溶解させ、スルフリルクロライド2.6gのジクロロメタン5mlの溶液を加えて室温で1.5時間攪拌した。飽和炭酸水素ナトリウム水溶液を加えた後、ジクロロメタンで抽出し、さらに飽和食塩水で洗浄した。有機層を硫酸マグネシウムで乾燥後濃縮させ、NH−シリカゲルクロマトグラフィー(ヘキサン/酢酸エチル=10/1)で精製し、2−(4−メチルペンタン−2−イル)−3−ニトロチオフェン2.0g(収率:70.1%)を得た。 2.8 g of 2- (4-methylpentan-2-yl) -3-nitro-2,5-dihydrothiophene was dissolved in 40 ml of dichloromethane, and a solution of 2.6 g of sulfuryl chloride in 5 ml of dichloromethane was added to the solution at room temperature for 1. Stir for 5 hours. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with dichloromethane and further washed with saturated brine. The organic layer was dried over magnesium sulfate, concentrated, purified by NH-silica gel chromatography (hexane / ethyl acetate = 10/1), and 2.0 g of 2- (4-methylpentan-2-yl) -3-nitrothiophene. (Yield: 70.1%) was obtained.
1H−NMR(CDCl3):δ=0.80−0.96(6H,m),1.30−1.34(3H,m),1.44−1.64(2H,m),3.06−3.08(1H,m),4.12−4.14(1H,m), 7.09−7.10(1H, d, J=5.4Hz), 7.53−7.54(1H, d, J=5.9Hz) 1 H-NMR (CDCl 3 ): δ = 0.80-0.96 (6H, m), 1.30-1.34 (3H, m), 1.44-1.64 (2H, m), 3.06-3.08 (1H, m), 4.12-4.14 (1H, m), 7.09-7.10 (1H, d, J = 5.4 Hz), 7.53-7 .54 (1H, d, J = 5.9 Hz)
[実施例 5−3]
[Example 5-3]
5−(4−メチルペンタン−2−イル)−4−ニトロテトラヒドロチオフェン−3−イル−アセテート1.10gを7mlのトルエンに溶解させた後、反応溶液を4℃に冷却した。その後塩化スルフリル0.80gをトルエン2mlに溶かしたものをくわえ、室温に戻した後2時間攪拌した。水で反応を停止させ、1mol/lの水酸化ナトリウム水溶液、飽和食塩水溶液で洗浄した。有機層を硫酸マグネシウムで乾燥後濃縮させ、シリカゲルクロマトグラフィー(ヘキサン/酢酸エチル=10/1)で精製し、2−(4−メチルペンタン−2−イル)−3−ニトロチオフェン0.80g(85.0%)を得た。 After dissolving 1.10 g of 5- (4-methylpentan-2-yl) -4-nitrotetrahydrothiophen-3-yl-acetate in 7 ml of toluene, the reaction solution was cooled to 4 ° C. Thereafter, 0.80 g of sulfuryl chloride dissolved in 2 ml of toluene was added, and the mixture was returned to room temperature and stirred for 2 hours. The reaction was stopped with water and washed with 1 mol / l aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, concentrated and purified by silica gel chromatography (hexane / ethyl acetate = 10/1) to give 0.80 g (85 of 2- (4-methylpentan-2-yl) -3-nitrothiophene. 0.0%).
[実施例6]
エタノール6mlに2−(4−メチルペンタン−2−イル)−3−ニトロチオフェン0.33gを溶解させ、塩化スズ(II)を0.88gおよび濃塩酸を0.97g加えたのち、反応溶液を70℃に加熱して1時間攪拌した。室温に溶液を冷却した後、1mol/lの水酸化ナトリウム水溶液を加えて5分間攪拌した。セライト上でろ過し、溶液を酢酸エチルで抽出して、さらに1mol/lの水酸化ナトリウム水溶液、飽和食塩水で洗浄した。有機層を硫酸マグネシウムで乾燥後濃縮させ、シリカゲルクロマトグラフィー(ヘキサン/酢酸エチル=8/1)で精製し、2−(4−メチルペンタン−2−イル)−3−アミノチオフェンを0.11g(収率:39.0%)を得た。 After dissolving 0.33 g of 2- (4-methylpentan-2-yl) -3-nitrothiophene in 6 ml of ethanol and adding 0.88 g of tin (II) chloride and 0.97 g of concentrated hydrochloric acid, the reaction solution was dissolved. The mixture was heated to 70 ° C. and stirred for 1 hour. After cooling the solution to room temperature, 1 mol / l sodium hydroxide aqueous solution was added and stirred for 5 minutes. The mixture was filtered over celite, and the solution was extracted with ethyl acetate, and further washed with 1 mol / l aqueous sodium hydroxide solution and saturated brine. The organic layer was dried over magnesium sulfate, concentrated and purified by silica gel chromatography (hexane / ethyl acetate = 8/1) to give 0.11 g of 2- (4-methylpentan-2-yl) -3-aminothiophene ( Yield: 39.0%).
1H−NMR(CDCl3):δ=0.83−0.98(6H,m),1.19−1.60(5H,m),2.93−2.95(1H,m),3.38(1H,Brs),6.41−6.55(1H,dd, J=4.9Hz, 5.4Hz), 6.93−7.04(1H, dd, J=4.9Hz, 5.4Hz) 1 H-NMR (CDCl 3 ): δ = 0.83-0.98 (6H, m), 1.19-1.60 (5H, m), 2.93-2.95 (1H, m), 3.38 (1H, Brs), 6.41-6.55 (1H, dd, J = 4.9 Hz, 5.4 Hz), 6.93-7.04 (1H, dd, J = 4.9 Hz, 5.4Hz)
本発明によると、医農薬分野における有効な製造中間体である2−アルキル−3−アミノチオフェン誘導体を効率的に提供することが可能になった。さらに、本発明は工業的にも有利に生産可能であるために産業上の利用価値は高い。 According to the present invention, it has become possible to efficiently provide a 2-alkyl-3-aminothiophene derivative that is an effective production intermediate in the field of medicine and agrochemicals. Furthermore, since the present invention can be advantageously produced industrially, the industrial utility value is high.
Claims (22)
[一般式(1)中、Rは炭素数1から10のアルキル基もしくは炭素数3から10のシクロアルキル基で置換されてもよい炭素数1から18のアルキル基、炭素数1から10のアルキル基もしくは炭素数3から10のシクロアルキル基で置換されてもよい炭素数3から10のシクロアルキル基、または、炭素数1から10のアルキル基もしくは炭素数3から10のシクロアルキル基で置換されてもよい炭素数6から12のビシクロアルキル基を表す。Xはヒドロキシ基、ハロゲン原子、または下記一般式(2)
(式中、Aは炭素原子または硫黄原子を表し、Aが炭素原子の場合nは1を表し、Aが硫黄原子の場合nは1または2を表す。Qは炭素数1から10のアルキル基、炭素数3から10のシクロアルキル基、炭素数1から10のハロアルキル基、炭素数1から10のヒドロカルビルオキシ基、または、炭素数1から6のアルキル基で置換されてもよいアリール基を表す。#は結合位置を表す。)で表される置換基を表す。)]で表される化合物を酸化して、下記一般式(3)
[一般式(3)中、Rは前記一般式(1)におけるRと同一である]で表される化合物を得る工程(A)と、
前記一般式(3)で表される化合物を還元する工程(B)と、を含む下記一般式(4)
[一般式(4)中、Rは前記一般式(1)におけるRと同一である]で表される2−アルキル−3−アミノチオフェン誘導体の製造方法。 The following general formula (1)
[In General Formula (1), R is an alkyl group having 1 to 18 carbon atoms and an alkyl group having 1 to 10 carbon atoms which may be substituted with an alkyl group having 1 to 10 carbon atoms or a cycloalkyl group having 3 to 10 carbon atoms. A cycloalkyl group having 3 to 10 carbon atoms which may be substituted with a group or a cycloalkyl group having 3 to 10 carbon atoms, or an alkyl group having 1 to 10 carbon atoms or a cycloalkyl group having 3 to 10 carbon atoms. Represents a bicycloalkyl group having 6 to 12 carbon atoms. X is a hydroxy group, a halogen atom, or the following general formula (2)
(In the formula, A represents a carbon atom or a sulfur atom. When A is a carbon atom, n represents 1. When A represents a sulfur atom, n represents 1 or 2. Q represents an alkyl group having 1 to 10 carbon atoms. Represents an aryl group which may be substituted with a cycloalkyl group having 3 to 10 carbon atoms, a haloalkyl group having 1 to 10 carbon atoms, a hydrocarbyloxy group having 1 to 10 carbon atoms, or an alkyl group having 1 to 6 carbon atoms. # Represents a bonding position). The compound represented by the following general formula (3)
[In the general formula (3), R is the same as R in the general formula (1)] (A) to obtain a compound represented by:
A step (B) of reducing the compound represented by the general formula (3), and the following general formula (4):
[In general formula (4), R is the same as R in the said General formula (1)] The manufacturing method of the 2-alkyl-3-aminothiophene derivative represented.
[一般式(6)中、R1は水素原子、または、炭素数1から6の直鎖もしくは分岐のアルキル基を表す。#は結合位置を表す。]で表される置換基である請求項1に記載の製造方法。 R is the following general formula (6)
[In General Formula (6), R 1 represents a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms. # Represents a bonding position. The manufacturing method of Claim 1 which is a substituent represented by this.
[一般式(8)中、Rは前記一般式(1)におけるRと同一である。]で表される化合物を、エステル化剤またはハロゲン化剤と反応させて、下記一般式(1a)
[一般式(1a)中、Rは前記一般式(8)におけるRと同一である。Xaはハロゲン原子または前記一般式(2)で表される置換基を表す。]で表される化合物を得る工程と、
前記一般式(Ia)で表される化合物から、前記一般式(3)で表される化合物を得る工程と、
をさらに含む請求項1〜請求項3のいずれか1項に記載の製造方法。 In the step (A), the following general formula (8)
[In General Formula (8), R is the same as R in General Formula (1). The compound represented by the general formula (1a) is reacted with an esterifying agent or a halogenating agent.
[In General Formula (1a), R is the same as R in General Formula (8). Xa represents a halogen atom or a substituent represented by the general formula (2). A step of obtaining a compound represented by:
Obtaining a compound represented by the general formula (3) from the compound represented by the general formula (Ia);
The manufacturing method according to any one of claims 1 to 3, further comprising:
前記一般式(1)で表される化合物から、Xを脱離させて、下記一般式(5)
[一般式(5)中、Rは前記一般式(1)におけるRと同一である。]で表される化合物を得る工程(A−1)と、
前記一般式(5)で表される化合物を脱水反応させて、前記一般式(3)で表される化合物を得る工程(A−2)と、
をさらに含む請求項1〜請求項3のいずれか1項に記載の製造方法。 The step (A)
X is eliminated from the compound represented by the general formula (1), and the following general formula (5)
[In General Formula (5), R is the same as R in General Formula (1). A step of obtaining a compound represented by formula (A-1);
A step of dehydrating the compound represented by the general formula (5) to obtain a compound represented by the general formula (3) (A-2);
The manufacturing method according to any one of claims 1 to 3, further comprising:
[一般式(7)中、Rは前記一般式(1)におけるRと同一であり、X7はハロゲン原子または前記一般式(2)で表される置換基を表す。]で表される化合物と、α−メルカプトアセトアルデヒドまたは1,4−ジチアン−2,5−ジオールとを反応させて、下記一般式(8)
[一般式(8)中、Rは前記一般式(1)におけるRと同一である。]で表される化合物を得る工程をさらに含む請求項1〜請求項5のいずれか1項に記載の製造方法。 The following general formula (7)
[In General Formula (7), R is the same as R in General Formula (1), and X 7 represents a halogen atom or a substituent represented by General Formula (2). And a compound represented by general formula (8) below, and α-mercaptoacetaldehyde or 1,4-dithian-2,5-diol.
[In General Formula (8), R is the same as R in General Formula (1). The manufacturing method of any one of Claims 1-5 which further includes the process of obtaining the compound represented by this.
[一般式(9)中、Rは前記一般式(1)におけるRと同一である。]で表される化合物を、エステル化剤またはハロゲン化剤と反応させて、前記一般式(7)で表される化合物を得る工程を、更に含む請求項6に記載の製造方法。 The following general formula (9)
[In General Formula (9), R is the same as R in General Formula (1). ] The manufacturing method of Claim 6 which further includes the process of obtaining the compound represented by the said General formula (7) by making the compound represented by an esterifying agent or a halogenating agent react .
[一般式(10)中、Rは前記一般式(1)におけるRと同一である。]で表される化合物と、ニトロメタンとを反応させて、前記一般式(9)で表される化合物を得る工程を、さらに含む請求項7に記載の製造方法。 The following general formula (10)
[In General Formula (10), R is the same as R in General Formula (1). The method according to claim 7, further comprising a step of reacting the compound represented by formula (II) with nitromethane to obtain the compound represented by the general formula (9).
[一般式(11)中、Rは前記一般式(1)におけるRと同一である。]で表される化合物と、α−メルカプトアセトアルデヒドまたは1,4−ジチアン−2,5−ジオールとを反応させて、下記一般式(8)
[一般式(8)中、Rは前記一般式(1)におけるRと同一である。]で表される化合物を得る工程を、さらに含む請求項1〜請求項5のいずれか1項に記載の製造方法。 The following general formula (11)
[In General Formula (11), R is the same as R in General Formula (1). And a compound represented by general formula (8) below, and α-mercaptoacetaldehyde or 1,4-dithian-2,5-diol.
[In General Formula (8), R is the same as R in General Formula (1). The manufacturing method of any one of Claims 1-5 which further includes the process of obtaining the compound represented by this.
[一般式(9)中、Rは前記一般式(1)におけるRと同一である。]で表される化合物を脱水反応させて、前記一般式(11)で表される化合物を得る工程を、さらに含む請求項9に記載の製造方法。 The following general formula (9)
[In General Formula (9), R is the same as R in General Formula (1). The production method according to claim 9, further comprising a step of dehydrating the compound represented by formula (II) to obtain the compound represented by the general formula (11).
[一般式(10)中、Rは前記一般式(1)におけるRと同一である。]で表される化合物と、ニトロメタンとを反応させて、前記一般式(9)で表される化合物を得る工程を、さらに含む請求項10に記載の製造方法。 The following general formula (10)
[In General Formula (10), R is the same as R in General Formula (1). The process of Claim 10 which further includes the process of obtaining the compound represented by the said General formula (9) by making the compound represented by this, and nitromethane react.
[一般式(8)中、Rは下記一般式(6)
(一般式(6)中、R 1 は水素原子、または、炭素数1から6の直鎖もしくは分岐のアルキル基を表す。#は結合位置を表す。)で表される置換基を表す。]で表される3−ヒドロキシ−4−ニトロテトラヒドロチオフェン誘導体。 The following general formula (8)
[In general formula (8), R represents the following general formula (6)
(In General Formula (6), R 1 represents a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms. # Represents a bonding position) . ] The 3-hydroxy-4-nitrotetrahydrothiophene derivative represented by this.
[一般式(1)中、Rは下記一般式(6)
(一般式(6)中、R 1 は水素原子、または、炭素数1から6の直鎖もしくは分岐のアルキル基を表す。#は結合位置を表す。)で表される置換基を表す。Xは、ヒドロキシ基、ハロゲン原子、または、下記一般式(2)
(一般式(2)中、Aは炭素原子または硫黄原子を表し、Aが炭素原子の場合nは1を表し、Aが硫黄原子の場合nは1または2を表す。Qは炭素数1から10のアルキル基、炭素数3から10のシクロアルキル基、炭素数1から10のハロアルキル基、炭素数1から10のヒドロカルビルオキシ基、または、炭素数1から6のアルキル基で置換されてもよいアリール基を表す。#は結合位置を表す。)で表される置換基を表す。]で表される3−ニトロテトラヒドロチオフェン誘導体。 The following general formula (1)
[In general formula (1), R represents the following general formula (6)
(In General Formula (6), R 1 represents a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms. # Represents a bonding position) . X is a hydroxy group, a halogen atom, or the following general formula (2)
(In the general formula (2), A represents a carbon atom or a sulfur atom, n represents 1 when A is a carbon atom, and n represents 1 or 2 when A is a sulfur atom. Q represents 1 to 2 carbon atoms. It may be substituted with an alkyl group having 10 carbon atoms, a cycloalkyl group having 3 to 10 carbon atoms, a haloalkyl group having 1 to 10 carbon atoms, a hydrocarbyloxy group having 1 to 10 carbon atoms, or an alkyl group having 1 to 6 carbon atoms. Represents an aryl group, and # represents a bonding position. ] The 3-nitrotetrahydrothiophene derivative represented by this.
[一般式(5)中、Rは炭素数1から10のアルキル基もしくは炭素数3から10のシクロアルキル基で置換されてもよい炭素数1から18のアルキル基、炭素数1から10のアルキル基もしくは炭素数3から10のシクロアルキル基で置換されてもよい炭素数3から10のシクロアルキル基、または、炭素数1から10のアルキル基もしくは炭素数3から10のシクロアルキル基で置換されてもよい炭素数6から12のビシクロアルキル基を表す。]で表される3−ニトロ−2,5−ジヒドロチオフェン誘導体。 The following general formula (5)
[In General Formula (5), R is an alkyl group having 1 to 18 carbon atoms which may be substituted with an alkyl group having 1 to 10 carbon atoms or a cycloalkyl group having 3 to 10 carbon atoms, or an alkyl group having 1 to 10 carbon atoms. A cycloalkyl group having 3 to 10 carbon atoms which may be substituted with a group or a cycloalkyl group having 3 to 10 carbon atoms, or an alkyl group having 1 to 10 carbon atoms or a cycloalkyl group having 3 to 10 carbon atoms. Represents a bicycloalkyl group having 6 to 12 carbon atoms. ] The 3-nitro-2,5-dihydrothiophene derivative represented by this.
[一般式(6)中、R1は水素原子、または、炭素数1から6の直鎖もしくは分岐のアルキル基を表す。#は結合位置を表す。]で表される置換基である請求項16に記載の3−ニトロ−2,5−ジヒドロチオフェン誘導体。 R in the general formula (5) is the following general formula (6)
[In General Formula (6), R 1 represents a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms. # Represents a bonding position. The 3-nitro-2,5-dihydrothiophene derivative according to claim 16 , which is a substituent represented by the formula:
[一般式(3)中、Rは下記一般式(6)
(一般式(6)中、R 1 は水素原子、または、炭素数1から6の直鎖もしくは分岐のアルキル基を表す。#は結合位置を表す。)で表される置換基表す。]で表される2−アルキル−3−ニトロチオフェン誘導体。 The following general formula (3)
[In general formula (3), R represents the following general formula (6)
(In General Formula (6), R 1 represents a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms. # Represents a bonding position) . ] The 2-alkyl-3-nitrothiophene derivative represented by this.
[一般式(12)中、YおよびZは、それぞれ独立にハロゲン原子または水素原子を表す。Rは下記一般式(6)
(一般式(6)中、R 1 は水素原子、または、炭素数1から6の直鎖もしくは分岐のアルキル基を表す。#は結合位置を表す。)で表される置換基を表す。]で表される農園芸用殺菌剤の医農薬製造中間体。 The following general formula (12) according to any one of claims 12 to 20
[In General Formula (12), Y and Z each independently represent a halogen atom or a hydrogen atom. R is the following general formula (6)
(In General Formula (6), R 1 represents a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms. # Represents a bonding position). ] An intermediate for producing agricultural and horticultural fungicides represented by
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