JP2017160153A - Indolobenzothiazine compound and method of producing the same - Google Patents
Indolobenzothiazine compound and method of producing the same Download PDFInfo
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- JP2017160153A JP2017160153A JP2016045848A JP2016045848A JP2017160153A JP 2017160153 A JP2017160153 A JP 2017160153A JP 2016045848 A JP2016045848 A JP 2016045848A JP 2016045848 A JP2016045848 A JP 2016045848A JP 2017160153 A JP2017160153 A JP 2017160153A
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- indolobenzothiazine
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- -1 Indolobenzothiazine compound Chemical class 0.000 title claims abstract description 46
- 238000000034 method Methods 0.000 title abstract description 8
- 238000004519 manufacturing process Methods 0.000 claims abstract description 30
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 12
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 12
- GFISDBXSWQMOND-UHFFFAOYSA-N 2,5-dimethoxyoxolane Chemical group COC1CCC(OC)O1 GFISDBXSWQMOND-UHFFFAOYSA-N 0.000 claims abstract description 9
- 125000004432 carbon atom Chemical group C* 0.000 claims description 21
- 125000003545 alkoxy group Chemical group 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 125000005843 halogen group Chemical group 0.000 claims description 12
- 125000004429 atom Chemical group 0.000 claims description 11
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 9
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 claims description 8
- PCSMJKASWLYICJ-UHFFFAOYSA-N Succinic aldehyde Chemical compound O=CCCC=O PCSMJKASWLYICJ-UHFFFAOYSA-N 0.000 claims description 7
- 238000006243 chemical reaction Methods 0.000 abstract description 21
- 229910052736 halogen Inorganic materials 0.000 abstract description 2
- 150000002367 halogens Chemical class 0.000 abstract description 2
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 abstract 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 description 31
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 238000005481 NMR spectroscopy Methods 0.000 description 8
- BUVHDOMYPXPQFV-UHFFFAOYSA-N indolo[1,2-b][1,2]benzothiazin-11-one Chemical compound C1=CC=C2C(=C1)C=C3C(=O)C4=CC=CC=C4N3S2 BUVHDOMYPXPQFV-UHFFFAOYSA-N 0.000 description 6
- 125000001424 substituent group Chemical group 0.000 description 6
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- OYQFERJYPQMRBT-UHFFFAOYSA-N pyrrolo[1,2-b][1,2]benzothiazin-10-one Chemical compound C1=CC=C2C(=O)C3=CC=CN3SC2=C1 OYQFERJYPQMRBT-UHFFFAOYSA-N 0.000 description 5
- 125000000168 pyrrolyl group Chemical group 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 4
- 239000000417 fungicide Substances 0.000 description 4
- 239000004009 herbicide Substances 0.000 description 4
- WXWQBXGFVMJQHS-UHFFFAOYSA-N pyrrolo[2,3-h][1,2]benzothiazine Chemical compound C1=NSC2=C3C=CN=C3C=CC2=C1 WXWQBXGFVMJQHS-UHFFFAOYSA-N 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- GUJOJGAPFQRJSV-UHFFFAOYSA-N dialuminum;dioxosilane;oxygen(2-);hydrate Chemical compound O.[O-2].[O-2].[O-2].[Al+3].[Al+3].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O GUJOJGAPFQRJSV-UHFFFAOYSA-N 0.000 description 3
- SPWVRYZQLGQKGK-UHFFFAOYSA-N dichloromethane;hexane Chemical compound ClCCl.CCCCCC SPWVRYZQLGQKGK-UHFFFAOYSA-N 0.000 description 3
- 230000000855 fungicidal effect Effects 0.000 description 3
- 230000002363 herbicidal effect Effects 0.000 description 3
- 125000001041 indolyl group Chemical group 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 229910052901 montmorillonite Inorganic materials 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- CAAVOCSQPRRDTC-UHFFFAOYSA-N thiazino[5,6-c]carbazole Chemical class S1N=CC=C2C1=C1C(C=C2)=NC=2C=CC=CC=21 CAAVOCSQPRRDTC-UHFFFAOYSA-N 0.000 description 3
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 2
- DHKHKXVYLBGOIT-UHFFFAOYSA-N 1,1-Diethoxyethane Chemical compound CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 2
- RYQXPVFRXUDGNJ-UHFFFAOYSA-N 2-thia-3-azapentacyclo[11.8.0.03,11.04,9.015,20]henicosa-1(21),4,6,8,10,13,15,17,19-nonaen-12-one Chemical compound C1=CC=C2C=C3C(=CC2=C1)C(=O)C4=CC5=CC=CC=C5N4S3 RYQXPVFRXUDGNJ-UHFFFAOYSA-N 0.000 description 2
- KYYKOMKXFMKYJS-UHFFFAOYSA-N Cc(cc1)cc(S[n](c2c3)c4c3cccc4)c1C2=O Chemical compound Cc(cc1)cc(S[n](c2c3)c4c3cccc4)c1C2=O KYYKOMKXFMKYJS-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- BESWHXQCLIOARP-UHFFFAOYSA-N O=C(c1c2)c(ccc(Cl)c3)c3S[n]1c1c2cccc1 Chemical compound O=C(c1c2)c(ccc(Cl)c3)c3S[n]1c1c2cccc1 BESWHXQCLIOARP-UHFFFAOYSA-N 0.000 description 2
- AKIHQTVHWFPATK-UHFFFAOYSA-N O=C1c(cccc2)c2S[n]2c3ccccc3cc12 Chemical compound O=C1c(cccc2)c2S[n]2c3ccccc3cc12 AKIHQTVHWFPATK-UHFFFAOYSA-N 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 2
- 229940092714 benzenesulfonic acid Drugs 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 239000012039 electrophile Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 230000002140 halogenating effect Effects 0.000 description 2
- 150000002391 heterocyclic compounds Chemical class 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- QAZLUNIWYYOJPC-UHFFFAOYSA-M sulfenamide Chemical compound [Cl-].COC1=C(C)C=[N+]2C3=NC4=CC=C(OC)C=C4N3SCC2=C1C QAZLUNIWYYOJPC-UHFFFAOYSA-M 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- HPBSFVQFGDHXCQ-UHFFFAOYSA-N (2-benzylphenyl)-(1H-pyrrol-2-yl)methanethione Chemical compound C(C1=CC=CC=C1)C1=C(C(=S)C=2NC=CC=2)C=CC=C1 HPBSFVQFGDHXCQ-UHFFFAOYSA-N 0.000 description 1
- KUVJOLCCKRCZAN-UHFFFAOYSA-N (2-ethylsulfinylphenyl)-(1h-pyrrol-2-yl)methanone Chemical compound CCS(=O)C1=CC=CC=C1C(=O)C1=CC=CN1 KUVJOLCCKRCZAN-UHFFFAOYSA-N 0.000 description 1
- 0 *C(C1C2=O)C(*)=C(*)C(*)=C1N*1C2=CC=C1 Chemical compound *C(C1C2=O)C(*)=C(*)C(*)=C1N*1C2=CC=C1 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- 150000004898 1,2-thiazines Chemical class 0.000 description 1
- MISTZQJSHHTDCF-UHFFFAOYSA-N 1-(1-propoxyethoxy)propane Chemical compound CCCOC(C)OCCC MISTZQJSHHTDCF-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- JEYYAUCRWMPEMM-UHFFFAOYSA-N 2,5-dipropoxyoxolane Chemical compound CCCOC1CCC(OCCC)O1 JEYYAUCRWMPEMM-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- QLLQEHPXINXZQB-UHFFFAOYSA-N 7-chloropyrrolo[1,2-b][1,2]benzothiazin-10-one Chemical compound C1=CN2C(=C1)C(=O)C3=C(S2)C=C(C=C3)Cl QLLQEHPXINXZQB-UHFFFAOYSA-N 0.000 description 1
- VDQMHQWYVKALDE-UHFFFAOYSA-N 7-methylpyrrolo[1,2-b][1,2]benzothiazin-10-one Chemical compound Cc1ccc2c(c1)sn1cccc1c2=O VDQMHQWYVKALDE-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- YZYRKAACCUKNSZ-UHFFFAOYSA-N 8-chloroindolo[1,2-b][1,2]benzothiazin-11-one Chemical compound C1=CC=C2C(=C1)C=C3C(=O)C4=C(N3S2)C=C(C=C4)Cl YZYRKAACCUKNSZ-UHFFFAOYSA-N 0.000 description 1
- ZQCZXPRNYWJIDX-UHFFFAOYSA-N 8-methylindolo[1,2-b][1,2]benzothiazin-11-one Chemical compound CC1=CC2=C(C=C1)C(=O)C3=CC4=CC=CC=C4SN32 ZQCZXPRNYWJIDX-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- ZRVUJXDFFKFLMG-UHFFFAOYSA-N Meloxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=NC=C(C)S1 ZRVUJXDFFKFLMG-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- BXKZLPQAEVCFSP-UHFFFAOYSA-N O=C(C=CC=C1N=C2C=C3)C1=C2C1=C3C=CNS1 Chemical compound O=C(C=CC=C1N=C2C=C3)C1=C2C1=C3C=CNS1 BXKZLPQAEVCFSP-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000000862 absorption spectrum Methods 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- DMSMPAJRVJJAGA-UHFFFAOYSA-N benzo[d]isothiazol-3-one Chemical compound C1=CC=C2C(=O)NSC2=C1 DMSMPAJRVJJAGA-UHFFFAOYSA-N 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 229920001429 chelating resin Polymers 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000002933 cyclohexyloxy group Chemical group C1(CCCCC1)O* 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000000131 cyclopropyloxy group Chemical group C1(CC1)O* 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000007350 electrophilic reaction Methods 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000002510 isobutoxy group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])O* 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- OXROWJKCGCOJDO-JLHYYAGUSA-N lornoxicam Chemical compound O=C1C=2SC(Cl)=CC=2S(=O)(=O)N(C)\C1=C(\O)NC1=CC=CC=N1 OXROWJKCGCOJDO-JLHYYAGUSA-N 0.000 description 1
- 229960002202 lornoxicam Drugs 0.000 description 1
- 229960001929 meloxicam Drugs 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000004115 pentoxy group Chemical group [*]OC([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 229960002702 piroxicam Drugs 0.000 description 1
- QYSPLQLAKJAUJT-UHFFFAOYSA-N piroxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 QYSPLQLAKJAUJT-UHFFFAOYSA-N 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000011973 solid acid Substances 0.000 description 1
- 238000010183 spectrum analysis Methods 0.000 description 1
- 125000004646 sulfenyl group Chemical group S(*)* 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 150000004897 thiazines Chemical class 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Landscapes
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Description
本発明は、新規なインドロベンゾチアジン化合物とその製造方法に関するものである。 The present invention relates to a novel indolobenzothiazine compound and a method for producing the same.
分子内に窒素−硫黄結合を有するスルフェンアミド化合物は、種々の機能性を持つことが報告されている（非特許文献１）。たとえば、ゴムの加硫化剤（特許文献１，２）、発芽前処理用除草剤（特許文献３）、殺菌剤（特許文献４）等が知られている。特に、環内に窒素−硫黄結合を有する複素環化合物の場合は、１，２−ベンゾイソチアゾリジン−３−オンの様に殺菌作用を有する化合物として有効であり（非特許文献２）、また、１，２−チアジン化合物は、メロキシカム、ピロキシカム、ロルノキシカム等のオキシカム系非ステロイド性抗炎症薬に見られるように重要な骨格に導くことができる重要な骨格である。 It has been reported that a sulfenamide compound having a nitrogen-sulfur bond in the molecule has various functions (Non-patent Document 1). For example, rubber vulcanizing agents (Patent Documents 1 and 2), herbicides for pre-emergence treatment (Patent Document 3), fungicides (Patent Document 4) and the like are known. In particular, in the case of a heterocyclic compound having a nitrogen-sulfur bond in the ring, it is effective as a compound having a bactericidal action such as 1,2-benzisothiazolidine-3-one (Non-patent Document 2). 1,2-thiazine compounds are important skeletons that can lead to important skeletons as seen in oxicam non-steroidal anti-inflammatory drugs such as meloxicam, piroxicam, and lornoxicam.
また、インドール骨格は、天然・合成を問わず多くの生理活性化合物の基本的な構成骨格である（特許文献５、非特許文献３）。その窒素原子上がスルフェニル基で置換したＮ−スルフェニルインドールは、上記のスルフェンアミドにあたり、その生理活性が調べられているという重要な化合物である（非特許文献４）。 The indole skeleton is a basic constituent skeleton of many physiologically active compounds regardless of natural or synthetic (Patent Literature 5, Non-Patent Literature 3). N-sulfenylindole substituted on the nitrogen atom with a sulfenyl group is an important compound in which the physiological activity of the sulfenamide has been investigated (Non-patent Document 4).
ピロロベンゾチアジン化合物は、インドロベンゾチアジン化合物の類縁体と考えられるが、ピロロベンゾチアジン化合物の合成において報告されている例として、２−（２−エチルスルフィニルベンゾイル）ピロールを加熱により環化させて窒素−硫黄結合を形成して合成する方法がある（非特許文献５）。しかしながら、この方法では反応に長時間を要しているにも係わらず反応率は低く、種々の異性体が生成してくる。また、報告されている誘導体も１種類だけである。
また、２−（２−ベンジルチオベンゾイル）ピロールとＮＣＳやＮＢＳの強力なハロゲン化剤を反応させて窒素−硫黄結合を形成する方法も報告されている（非特許文献６）。しかしながら、この方法ではハロゲン化剤の反応性が高いためにピロール環にもハロゲンが導入されてしまい、その結果さまざまな生成物の混合物としてのみ得られることが報告されている。
さらに、Ｎ−スルフェニルピロールの分子内環化を行い、ピロロベンゾチアジンを製造する方法があり、上記の方法に比べ、種々の置換基を有する誘導体の合成ができ、副反応も起こらない（非特許文献７、非特許文献８）。しかし、この製造方法をインドロベンゾチアジン化合物に適用するために必要なＮ−スルフェニルインドールの合成が困難である。
このように、類縁体であるピロロベンゾチアジンの製造方法は特殊な置換基を有する誘導体に限られている場合が多く、インドロベンゾチアジン化合物の合成例に関しては全く報告例が無い。したがって、インドロベンゾチアジン化合物を製造する方法の開発が望まれてきた。
A pyrrolobenzothiazine compound is considered to be an analog of an indolobenzothiazine compound. As an example reported in the synthesis of a pyrrolobenzothiazine compound, 2- (2-ethylsulfinylbenzoyl) pyrrole is heated to form a ring. There is a method of synthesizing by forming nitrogen-sulfur bonds (Non-patent Document 5). However, although this method requires a long time for the reaction, the reaction rate is low and various isomers are produced. Also, only one type of derivative has been reported.
In addition, a method for forming a nitrogen-sulfur bond by reacting 2- (2-benzylthiobenzoyl) pyrrole with a strong halogenating agent such as NCS or NBS has been reported (Non-patent Document 6). However, it has been reported that in this method, since the halogenating agent has high reactivity, halogen is also introduced into the pyrrole ring, and as a result, it can be obtained only as a mixture of various products.
Furthermore, there is a method for producing pyrrolobenzothiazine by intramolecular cyclization of N-sulfenylpyrrole. Compared with the above method, derivatives having various substituents can be synthesized, and side reactions do not occur ( Non-patent document 7, Non-patent document 8). However, it is difficult to synthesize N-sulfenylindole necessary for applying this production method to indolobenzothiazine compounds.
Thus, in many cases, the production method of pyrrolobenzothiazine, which is an analog, is limited to derivatives having a special substituent, and there is no report at all regarding synthesis examples of indolobenzothiazine compounds. Therefore, development of a method for producing an indolobenzothiazine compound has been desired.
本発明の課題は、新規なインドロベンゾチアジン化合物を提供することであり、工業的に有利なこれらの製造方法を提供することである。 An object of the present invention is to provide a novel indolobenzothiazine compound, and to provide an industrially advantageous production method thereof.
一般に、ピロリル基は電子豊富な複素環化合物として知られており、求電子試薬である１，４−ジカルボニル化合物あるいは１，４−ジカルボニル化合物等価体と反応してインドール化合物を与えることが知られているが（Adv. Synth. Catal., 2006, 348, 2191.）、この反応をピロロベンゾチアジン化合物にも応用できるかは全く解明されていない。そこで、本発明者は、鋭意検討を重ねた結果、ピロロベンゾチアジン化合物に対して、求電子試薬である１，４−ジカルボニル化合物等価体を酸の存在下反応させることで、インドロベンゾチアジン化合物が合成できることを見いだした。本発明は、当該知見に基づいてなされたものである。 In general, pyrrolyl groups are known as electron-rich heterocyclic compounds, and are known to react with 1,4-dicarbonyl compounds or 1,4-dicarbonyl compound equivalents as electrophiles to give indole compounds. Although it has been described (Adv. Synth. Catal., 2006, 348, 2191.), it has not been elucidated at all whether this reaction can be applied to pyrrolobenzothiazine compounds. Therefore, as a result of extensive studies, the present inventor made an indolobenzoate by reacting a pyrrolobenzothiazine compound with an 1,4-dicarbonyl compound equivalent, which is an electrophile, in the presence of an acid. We found that thiazine compounds can be synthesized. This invention is made | formed based on the said knowledge.
すなわち、本発明者らは、ピロロベンゾチアジンに対して、酸存在下で１，４−ジカルボニル化合物やその等価体を反応させると、窒素−硫黄結合はこのような反応条件においても切断することはなく、ピロール環上で求電子反応が進行してインドロベンゾチアジン化合物が得られることを見いだし、本発明を完成するに至った。 That is, when the present inventors react pyrrolobenzothiazine with a 1,4-dicarbonyl compound or an equivalent thereof in the presence of an acid, the nitrogen-sulfur bond is cleaved even under such reaction conditions. However, the inventors have found that an electrophilic reaction proceeds on the pyrrole ring to obtain an indolobenzothiazine compound, thereby completing the present invention.
すなわち、本発明によれば、以下の発明が提供される。
（１）下記一般式（Ａ）で表されるインドロベンゾチアジン化合物。
（２）下記一般式（Ａ）で表されるインドロベンゾチアジン化合物を製造する方法において、下記一般式（Ｂ）で表されるピロロベンゾチアジン化合物に対し、１，４−ジカルボニル化合物またはその等価体を反応させることにより製造する下記一般式（Ａ）で表されるインドロベンゾチアジン化合物の製造方法。
（３）上記（２）のインドロベンゾチアジン化合物製造において、１，４−ジカルボニル化合物等価体として２，５−ジメトキシテトラヒドロフランを用いることを特徴とするインドロベンゾチアジン化合物の製造方法。
（４）上記（２）のインドロベンゾチアジン化合物製造において、１，４−ジカルボニル化合物等価体としてスクシンアルデヒド＝ビス（ジメチルアセタール）を用いることを特徴とするインドロベンゾチアジン化合物の製造方法。
（５）上記（２）〜（４）のいずれか１項のインドロベンゾチアジン化合物製造において、酸を用いることを特徴とするインドロベンゾチアジン化合物の製造方法。
That is, according to the present invention, the following inventions are provided.
(1) An indolobenzothiazine compound represented by the following general formula (A).
(2) In the method for producing an indolobenzothiazine compound represented by the following general formula (A), a 1,4-dicarbonyl compound is used for the pyrrolobenzothiazine compound represented by the following general formula (B). Or the manufacturing method of the indolobenzothiazine compound represented by the following general formula (A) manufactured by making the equivalent react.
(3) A method for producing an indolobenzothiazine compound, wherein 2,5-dimethoxytetrahydrofuran is used as the 1,4-dicarbonyl compound equivalent in the production of the indolobenzothiazine compound of (2) above.
(4) In the production of an indolobenzothiazine compound according to (2) above, a succinaldehyde = bis (dimethylacetal) is used as the 1,4-dicarbonyl compound equivalent. Production method.
(5) A method for producing an indolobenzothiazine compound, wherein an acid is used in the production of the indolobenzothiazine compound according to any one of (2) to (4) above.
本発明で得られるインドロベンゾチアジン化合物は、抗菌剤、殺菌剤、除草剤として用いることができる。
本発明のインドロベンゾチアジン化合物の製造方法は、対応するピロロベンゾチアジン化合物のピロール環をインドール環に導く製造方法であり、従来に無い全く新しい製造方法である。
The indolobenzothiazine compound obtained in the present invention can be used as an antibacterial agent, fungicide, and herbicide.
The production method of the indolobenzothiazine compound of the present invention is a production method in which the pyrrole ring of the corresponding pyrrolobenzothiazine compound is led to an indole ring, and is a completely new production method that has not been conventionally available.
本発明の目的化合物であるインドロベンゾチアジン化合物は、以下の一般式（Ａ）により示される化合物である。
上記一般式（Ａ）の置換基は、以下の通りである。
Ｒ1〜Ｒ4は、水素原子、炭素数１〜６のアルキル基、炭素数１〜６のアルコキシル基、ハロゲン原子、ニトロ基、シアノ基から選ばれる基又は原子を表す。ただしＲ1とＲ2、Ｒ2とＲ3、あるいはＲ3、Ｒ4は連結して互いに環を成してもよい。
アルキル基の具体例としては、メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、ｔ−ブチル基、イソブチル基、ペンチル基、イソペンチル基、ヘキシル基、イソヘキシル基、シクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基等が挙げられる。
アルコキシル基の具体例としては、メトキシ基、エトキシ基、プロポキシ基、イソプロポキシ基、シクロプロポキシ基、ブトキシ基、イソブトキシ基、ｔ−ブトキシ基、ペンチロキシ基、ヘキシロキシ基、シクロヘキシロキシ基等が挙げられる。
ハロゲン原子の具体例としては、塩素、フッ素、ヨウ素、臭素が挙げられる。
また、Ｒ1とＲ2、Ｒ2とＲ3、あるいはＲ3とＲ4は連結して互いに環を成してもよい、とは、それぞれの置換基が連結して環状構造を成していることを示し、その結果、芳香族基としては具体例としてナフチル基、テトラヒドロナフチル基が挙げられる。
The substituents of the general formula (A) are as follows.
R 1 to R 4 represent a group or atom selected from a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, a halogen atom, a nitro group, and a cyano group. However, R 1 and R 2 , R 2 and R 3 , or R 3 and R 4 may be linked to form a ring.
Specific examples of the alkyl group include methyl group, ethyl group, propyl group, isopropyl group, butyl group, t-butyl group, isobutyl group, pentyl group, isopentyl group, hexyl group, isohexyl group, cyclopropyl group, cyclobutyl group, A cyclopentyl group, a cyclohexyl group, etc. are mentioned.
Specific examples of the alkoxyl group include methoxy group, ethoxy group, propoxy group, isopropoxy group, cyclopropoxy group, butoxy group, isobutoxy group, t-butoxy group, pentyloxy group, hexyloxy group, cyclohexyloxy group and the like.
Specific examples of the halogen atom include chlorine, fluorine, iodine and bromine.
R 1 and R 2 , R 2 and R 3 , or R 3 and R 4 may be linked to each other to form a ring, which means that each substituent is linked to form a cyclic structure. As a result, specific examples of the aromatic group include a naphthyl group and a tetrahydronaphthyl group.
本発明の出発物質の一つであるピロロベンゾチアジン化合物は、以下の一般式（Ｂ）により示される化合物である。
上記一般式（Ｂ）の置換基は、上記一般式（Ａ）の場合と同様である。 The substituent of the said general formula (B) is the same as that of the said general formula (A).
本発明のもう一つの出発原料である１，４−ジカルボニル化合物等価体は、加水分解により１，４−ジカルボニル化合物を与える化合物であり、具体的には２，５−ジメトキシテトラヒドロフラン、２，５−ジエトキシテトラヒドロフラン、２，５−ジプロポキシテトラヒドロフラン、スクシンアルデヒド＝ビス（ジメチルアセタール）、スクシンアルデヒド＝ビス（ジエチルアセタール）、スクシンアルデヒド＝ビス（ジプロピルアセタール）等が挙げられる。 Another starting material of the present invention, 1,4-dicarbonyl compound equivalent, is a compound that gives 1,4-dicarbonyl compound by hydrolysis, specifically 2,5-dimethoxytetrahydrofuran, Examples include 5-diethoxytetrahydrofuran, 2,5-dipropoxytetrahydrofuran, succinaldehyde = bis (dimethylacetal), succinaldehyde = bis (diethylacetal), succinaldehyde = bis (dipropylacetal), and the like.
上記原料物質である化合物（Ｂ）は公知物質である。その製造法の一例を挙げれば、下記一般式（Ｃ）で示される酸塩化物をルイス酸存在下で環化反応をすることにより製造することができる。
もう一方の原料物質である２，５−ジメトキシテトラヒドロフランあるいはスクシンアルデヒド＝ビス（ジメチルアセタール）は、市販の化合物である。
The compound (B) which is the raw material is a known substance. If an example of the manufacturing method is given, it can manufacture by carrying out the cyclization reaction in the presence of a Lewis acid in the acid chloride shown by the following general formula (C).
The other raw material, 2,5-dimethoxytetrahydrofuran or succinaldehyde = bis (dimethylacetal), is a commercially available compound.
本発明の製造方法を、ピロロ［１，２］ベンゾチアジン−１０−オン（ｂ）（一般式（Ｂ）においてＲ1〜Ｒ4＝Ｈ）を酸存在下、１，４−ジカルボニル化合物等価体として２，５−ジメトキシテトラヒドロフランと反応させ環化反応を行い、インドロ［１，２］ベンゾチアジン−１１−オン（ａ）（一般式（Ａ）においてＲ1〜Ｒ4＝Ｈ）を合成する場合を例にとり説明する。
本発明による１，４−ジカルボニル化合物等価体の使用量（仕込み量）は、式（Ｂ）で表されるピロロベンゾチアジン化合物に対してモル比で、通常１.５倍以上、好ましくは２倍以上、より好ましくは２.５倍以上であり、通常８倍以下、好ましくは５倍以下、より好ましくは４倍以下である。上記範囲内であると、より収率よくインドロベンゾチアジン化合物を製造することができる。 The use amount (charge amount) of the 1,4-dicarbonyl compound equivalent according to the present invention is usually 1.5 times or more in terms of molar ratio with respect to the pyrrolobenzothiazine compound represented by the formula (B), preferably It is 2 times or more, more preferably 2.5 times or more, usually 8 times or less, preferably 5 times or less, more preferably 4 times or less. When it is within the above range, an indolobenzothiazine compound can be produced with higher yield.
本発明によるピロロベンゾチアジン化合物の製造は、酸の存在下に行なわれる。酸としては、ｐ−トルエンスルホン酸、ベンゼンスルホン酸、１０−カンファースルホン酸、メタンスルホン酸、トリフルオロメタンスルホン酸、ギ酸、酢酸等が使用される。また、アンバーリスト、モンモリロナイト等の固体酸が使用される。これらのうち、ｐ−トルエンスルホン酸が特に好ましい。 The production of the pyrrolobenzothiazine compound according to the present invention is carried out in the presence of an acid. As the acid, p-toluenesulfonic acid, benzenesulfonic acid, 10-camphorsulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, formic acid, acetic acid and the like are used. Further, solid acids such as amberlist and montmorillonite are used. Of these, p-toluenesulfonic acid is particularly preferred.
本発明による酸の使用量（仕込み量）は、式（Ｂ）で表されるピロロベンゾチアジン化合物に対してモル比で、通常０.２倍以上、好ましくは０.５倍以上、より好ましくは０.７５倍以上であり、通常３倍以下、好ましくは２倍以下、より好ましくは１倍以下である。上記範囲内であると、より収率よくインドロベンゾチアジン化合物を製造することができる。 The amount of acid used (charged amount) according to the present invention is usually 0.2 times or more, preferably 0.5 times or more, more preferably in molar ratio to the pyrrolobenzothiazine compound represented by formula (B). Is 0.75 times or more, usually 3 times or less, preferably 2 times or less, more preferably 1 time or less. When it is within the above range, an indolobenzothiazine compound can be produced with higher yield.
上記製造方法は、好ましくは反応溶媒の存在下で実施される。溶媒としてはトルエン、ベンゼン、キシレン、クロロベンゼン、ブロモベンゼン、ニトロベンゼン、塩化メチレン、１，２−ジクロロエタン、アセトニトリル等の有機溶媒が用いられる。これらの溶媒は単独で、または混合溶媒の形で使用される。 The above production method is preferably carried out in the presence of a reaction solvent. As the solvent, an organic solvent such as toluene, benzene, xylene, chlorobenzene, bromobenzene, nitrobenzene, methylene chloride, 1,2-dichloroethane, acetonitrile or the like is used. These solvents are used alone or in the form of a mixed solvent.
上記製造方法における反応温度は、４０℃〜１５０℃付近の温度とすることができる。この温度範囲未満の反応温度では、反応時間が遅くなる。この温度範囲を超えて高すぎる条件下に反応させると、異常な分解反応や副反応が多くなる。上記温度範囲は、６０℃〜１００℃の範囲であると、さらに好ましい。
反応時間は反応温度により左右され、一概に定めることはできないが、通常は２〜６時間で十分である。
The reaction temperature in the said manufacturing method can be made into the temperature of 40 to 150 degreeC vicinity. At reaction temperatures below this temperature range, the reaction time is slow. When the reaction is carried out under conditions that are too high beyond this temperature range, abnormal decomposition reactions and side reactions increase. The temperature range is more preferably in the range of 60 ° C to 100 ° C.
The reaction time depends on the reaction temperature and cannot be determined in general, but usually 2 to 6 hours is sufficient.
本発明で得られるインドロベンゾチアジン化合物の具体例としては、以下の化学式（１）から（４）で示される化合物を例示することができる。これらの化合物は、以下に記載する実施例により得られる化合物である。
本発明で得られるインドロベンゾチアジン化合物は、新規化合物であり、インドール環を有し、窒素−硫黄結合を有するスルフェンアミド構造を有することにより、殺菌剤として有効なものであり、その他、ゴムの加硫化剤、除草剤として有用な化合物である。 The indolobenzothiazine compound obtained in the present invention is a novel compound, has an indole ring, and has a sulfenamide structure having a nitrogen-sulfur bond, so that it is effective as a fungicide. It is a useful compound as a rubber vulcanizing agent and herbicide.
次に、本発明を実施例により詳細に説明する。本発明で得られる化合物は、この実施例に挙げた化合物に限定されるものではない。
下記実施例において得られたインドロベンゾチアジン化合物は、各種スペクトルと元素分析の結果を主要な判定基準として同定した。
また、製造された化合物（１）から（４）は、前記で示した化合物（１）から（４）に対応するもので、その物性値としては、融点、核磁気共鳴スペクトル（1Ｈ−ＮＭＲ，13Ｃ−ＮＭＲ）、赤外吸収スペクトル（ＩＲ）の順にそれぞれ記した。
Next, the present invention will be described in detail with reference to examples. The compounds obtained in the present invention are not limited to the compounds mentioned in this example.
The indolobenzothiazine compounds obtained in the following examples were identified by using various spectra and elemental analysis results as main criteria.
Further, the produced compounds (1) to (4) correspond to the compounds (1) to (4) shown above, and their physical property values include melting point, nuclear magnetic resonance spectrum ( 1 H-NMR). , 13 C-NMR) and infrared absorption spectrum (IR).
実施例１
内容積１００ｍｌのガラス製容器中にピロロ［１，２−ｂ］［１，２］ベンゾチアジン−１０−オン（６０ｍｇ，０.３ｍｍｏｌ）をトルエン（２０ｍｌ）に溶解させ、２，５−ジメトキシテトラヒドロフラン（０.９ｍｍｏｌ）を加えた後、ｐ−トルエンスルホン酸（０.２ｍｍｏｌ）を加え、８０℃で３.５時間加熱攪拌した。反応終了後、トリエチルアミンを加えて塩基性にし、溶媒を減圧下留去させた。粗生成物を、塩化メチレンを溶出液とするシリカゲルクロマトグラフィーで精製して目的化合物（１）であるインドロ［１，２−ｂ］［１，２］ベンゾチアジン−１１−オンを収率２９％で得た。
融点１５３.８−１５４.８℃（酢酸エチルから再結晶）
1H NMR (CDCl3) δ7.27 (1H, td, J=7.8, 0.9 Hz) , 7.36 (1H, d, J=8.2 Hz) , 7.45-7.41 (2H, m) , 7.53 (1H, dt, J=8.2, 0.9 Hz) , 7.59 (1H, td, J=7.8, 1.4 Hz) , 7.76 (1H, d, J=0.9 Hz) , 7.82 (1H, dt, J=8.2, 0.9 Hz), 8.50 (1H, dd, J=7.8, 1.4 Hz).
13C NMR (CDCl3) δ109.7, 111.1, 121.8, 122.2, 123.5, 125.9, 126.5, 127.4, 127.9, 129.6, 132.8, 134.3, 136.0, 138.1, 175.0.
IR (KBr) νmax 3053, 1640, 1524, 1348, 1313, 1234, 1129, 730 cm-1.
Anal. Calcd for C15H9NOS: C, 71.69; H, 3.61; N, 5.57.
Found: C, 71.64; H, 3.47; N, 5.44.
Example 1
In a glass container having an internal volume of 100 ml, pyrrolo [1,2-b] [1,2] benzothiazin-10-one (60 mg, 0.3 mmol) was dissolved in toluene (20 ml), and 2,5-dimethoxytetrahydrofuran ( 0.9 mmol) was added, p-toluenesulfonic acid (0.2 mmol) was added, and the mixture was heated and stirred at 80 ° C. for 3.5 hours. After completion of the reaction, triethylamine was added to make it basic, and the solvent was distilled off under reduced pressure. The crude product was purified by silica gel chromatography using methylene chloride as an eluent to obtain the target compound (1) indolo [1,2-b] [1,2] benzothiazin-11-one in 29% yield. Obtained.
Melting point 153.8-154.8 ° C. (recrystallization from ethyl acetate)
1 H NMR (CDCl 3 ) δ 7.27 (1H, td, J = 7.8, 0.9 Hz), 7.36 (1H, d, J = 8.2 Hz), 7.45-7.41 (2H, m), 7.53 (1H, dt, J = 8.2, 0.9 Hz), 7.59 (1H, td, J = 7.8, 1.4 Hz), 7.76 (1H, d, J = 0.9 Hz), 7.82 (1H, dt, J = 8.2, 0.9 Hz), 8.50 ( (1H, dd, J = 7.8, 1.4 Hz).
13 C NMR (CDCl 3 ) δ 109.7, 111.1, 121.8, 122.2, 123.5, 125.9, 126.5, 127.4, 127.9, 129.6, 132.8, 134.3, 136.0, 138.1, 175.0.
IR (KBr) ν max 3053, 1640, 1524, 1348, 1313, 1234, 1129, 730 cm -1 .
Anal.Calcd for C 15 H 9 NOS: C, 71.69; H, 3.61; N, 5.57.
Found: C, 71.64; H, 3.47; N, 5.44.
実施例２
実施例１において、トルエンの代わりにアセトニトリルを用いて同様な反応を６時間行い、目的化合物（１）であるインドロ［１，２−ｂ］［１，２］ベンゾチアジン−１１−オンを収率５％で得た。
Example 2
In Example 1, the same reaction was carried out for 6 hours using acetonitrile instead of toluene, and the target compound (1), indolo [1,2-b] [1,2] benzothiazin-11-one, was obtained at a yield of 5 %.
実施例３
実施例１において、ｐ−トルエンスルホン酸の代わりにベンゼンスルホン酸を用いて同様な反応を行い、目的化合物（１）であるインドロ［１，２−ｂ］［１，２］ベンゾチアジン−１１−オンを収率１９％で得た。
Example 3
In Example 1, the same reaction was carried out using benzenesulfonic acid instead of p-toluenesulfonic acid, and the target compound (1) indolo [1,2-b] [1,2] benzothiazin-11-one Was obtained in a yield of 19%.
実施例４
実施例１において、ｐ−トルエンスルホン酸の代わりに１０−カンファースルホン酸、トルエンの替わりにアセトニトリルを用いて同様な反応を６時間行い、目的化合物（１）であるインドロ［１，２−ｂ］［１，２］ベンゾチアジン−１１−オンを収率１％で得た。
Example 4
In Example 1, the same reaction was performed for 6 hours using 10-camphorsulfonic acid instead of p-toluenesulfonic acid and acetonitrile instead of toluene for 6 hours to obtain the target compound (1), indolo [1,2-b]. [1,2] Benzothiazin-11-one was obtained in a yield of 1%.
実施例５
実施例１において、ｐ−トルエンスルホン酸の代わりにアンバーリスト（３７ｍｇ）を用いて同様な反応を４時間行った。反応終了後、アンバーリストをろ過により取り除き、その後同様の操作を行い、目的化合物（１）であるインドロ［１，２−ｂ］［１，２］ベンゾチアジン−１１−オンを収率２％で得た。
Example 5
In Example 1, the same reaction was performed for 4 hours using Amberlyst (37 mg) instead of p-toluenesulfonic acid. After completion of the reaction, the amberlist was removed by filtration, and then the same operation was performed to obtain the target compound (1), indolo [1,2-b] [1,2] benzothiazin-11-one, in a yield of 2%. It was.
実施例６
内容積５ｍｌのガラス製容器中にピロロ［１，２−ｂ］［１，２］ベンゾチアジン−１０−オン（６０ｍｇ，０.３ｍｍｏｌ）を塩化メチレン（３ｍｌ）に溶解させ、２，５−ジメトキシテトラヒドロフラン（０.９ｍｍｏｌ）を加えた後、モンモリロナイト（１２５ｍｇ）を加え、８０℃で１０分マイクロウェーブ照射による加熱を行い攪拌した。反応終了後、ろ過によりモンモリロナイトを取り除き、その後同様の操作を行い、目的化合物（１）であるインドロ［１，２−ｂ］［１，２］ベンゾチアジン−１１−オンを収率１％で得た。
Example 6
In a glass container having an internal volume of 5 ml, pyrrolo [1,2-b] [1,2] benzothiazin-10-one (60 mg, 0.3 mmol) is dissolved in methylene chloride (3 ml) to give 2,5-dimethoxytetrahydrofuran. (0.9 mmol) was added, montmorillonite (125 mg) was added, and the mixture was heated at 80 ° C. for 10 minutes by microwave irradiation and stirred. After completion of the reaction, montmorillonite was removed by filtration, and then the same operation was performed to obtain the target compound (1), indolo [1,2-b] [1,2] benzothiazin-11-one, in a yield of 1%. .
実施例７
実施例１において、２，５−ジメトキシテトラヒドロフランの代わりにスクシンアルデヒド（ビスジメチルアセタール）を用いて同様な反応を６時間行い、目的化合物（１）であるインドロ［１，２−ｂ］［１，２］ベンゾチアジン−１１−オンを収率３０％で得た。
Example 7
In Example 1, a similar reaction was performed for 6 hours using succinaldehyde (bisdimethylacetal) instead of 2,5-dimethoxytetrahydrofuran, and the target compound (1), indolo [1,2-b] [1 , 2] benzothiazin-11-one was obtained in a yield of 30%.
実施例８
実施例１において、ピロロ［１，２−ｂ］［１，２］ベンゾチアジン−１０−オンの代わりに７−クロロピロロ［１，２−ｂ］［１，２］ベンゾチアジン−１０−オンを用いて同様な反応を行い、目的化合物（２）である８−クロロインドロ［１，２−ｂ］［１，２］ベンゾチアジン−１１−オンを収率２９％で得た。
融点２３５.５−２３７.６℃（塩化メチレン−ヘキサンから再結晶）
1H NMR (CDCl3) δ7.30 (1H, td, J=7.8, 0.9 Hz), 7.40-7.38 (2H, m), 7.49 (1H, td, J = 7.8, 0.9 Hz), 7.55 (1H, dt, J = 8.2, 0.9 Hz), 7.78 (1H, d, J = 0.9 Hz), 7.84 (1H, dt, J=8.2, 0.9 Hz), 8.45 (1H, dd, J=8.2, 0.9 Hz).
13C NMR (CDCl3) δ110.3, 111.1, 121.4, 122.5, 123.7, 126.2, 126.4, 127.2, 127.5, 131.1, 137.5, 138.2, 139.6, 174.1.
IR (KBr) νmax 3060, 1631, 1527, 1349, 1105, 734 cm-1.
Anal. Calcd for C15H8ClNOS: C, 63.05; H, 2.82; N, 4.90.
Found: C, 62.74; H, 2.79; N, 4.86.
Example 8
In Example 1, 7-chloropyrrolo [1,2-b] [1,2] benzothiazin-10-one was used instead of pyrrolo [1,2-b] [1,2] benzothiazin-10-one. The target compound (2), 8-chloroindolo [1,2-b] [1,2] benzothiazin-11-one, was obtained in a yield of 29%.
Melting point 235.5-237.6 ° C. (recrystallization from methylene chloride-hexane)
1 H NMR (CDCl 3 ) δ 7.30 (1H, td, J = 7.8, 0.9 Hz), 7.40-7.38 (2H, m), 7.49 (1H, td, J = 7.8, 0.9 Hz), 7.55 (1H, dt, J = 8.2, 0.9 Hz), 7.78 (1H, d, J = 0.9 Hz), 7.84 (1H, dt, J = 8.2, 0.9 Hz), 8.45 (1H, dd, J = 8.2, 0.9 Hz).
13 C NMR (CDCl 3 ) δ110.3, 111.1, 121.4, 122.5, 123.7, 126.2, 126.4, 127.2, 127.5, 131.1, 137.5, 138.2, 139.6, 174.1.
IR (KBr) ν max 3060, 1631, 1527, 1349, 1105, 734 cm -1 .
Anal.Calcd for C 15 H 8 ClNOS: C, 63.05; H, 2.82; N, 4.90.
Found: C, 62.74; H, 2.79; N, 4.86.
実施例９
実施例１において、ピロロ［１，２−ｂ］［１，２］ベンゾチアジン−１０−オンの代わりに７−メチルピロロ［１，２−ｂ］［１，２］ベンゾチアジン−１０−オンを用いて同様な反応を行い、目的化合物（３）である８−メチルインドロ［１，２−ｂ］［１，２］ベンゾチアジン−１１−オンを収率２６％で得た。
融点１８２.８−１８４.５℃（塩化メチレン−ヘキサンから再結晶）
1H NMR (CDCl3) δ2.44 (3H, s), 7.13 (1H, s), 7.20 (1H, d, J = 7.8 Hz), 7.26 (1H, td, J=8.2, 0.9 Hz), 7.43 (1H, td, J=8.2, 0.9 Hz), 7.51 (1H, dd, J=8.2, 0.9 Hz), 7.74 (1H, d, J=0.9 Hz), 7.81 (1H, dt, J=8.2, 0.9 Hz), 8.38 (1H, d, J=7.8 Hz).
13C NMR (CDCl3) δ21.8, 109.3, 111.0, 121.6, 122.1, 123.5, 125.6, 125.7, 127.4, 127.9, 129.6, 134.3, 136.0, 138.0, 144.1, 174.8.
IR (KBr) νmax 3037, 2915, 1638, 1524, 1347, 1137, 745 cm-1.
Anal. Calcd for C16H11NOS: C, 72.43; H, 4.18; N, 5.28.
Found: C, 72.29; H, 4.13; N, 5.13.
Example 9
In Example 1, 7-methylpyrrolo [1,2-b] [1,2] benzothiazin-10-one was used instead of pyrrolo [1,2-b] [1,2] benzothiazin-10-one. Then, 8-methylindolo [1,2-b] [1,2] benzothiazin-11-one as the target compound (3) was obtained in a yield of 26%.
Melting point 182.8-184.5 ° C. (recrystallization from methylene chloride-hexane)
1 H NMR (CDCl 3 ) δ2.44 (3H, s), 7.13 (1H, s), 7.20 (1H, d, J = 7.8 Hz), 7.26 (1H, td, J = 8.2, 0.9 Hz), 7.43 (1H, td, J = 8.2, 0.9 Hz), 7.51 (1H, dd, J = 8.2, 0.9 Hz), 7.74 (1H, d, J = 0.9 Hz), 7.81 (1H, dt, J = 8.2, 0.9 Hz), 8.38 (1H, d, J = 7.8 Hz).
13 C NMR (CDCl 3 ) δ21.8, 109.3, 111.0, 121.6, 122.1, 123.5, 125.6, 125.7, 127.4, 127.9, 129.6, 134.3, 136.0, 138.0, 144.1, 174.8.
IR (KBr) ν max 3037, 2915, 1638, 1524, 1347, 1137, 745 cm -1 .
Anal.Calcd for C 16 H 11 NOS: C, 72.43; H, 4.18; N, 5.28.
Found: C, 72.29; H, 4.13; N, 5.13.
実施例１０
実施例１において、ピロロ［１，２−ｂ］［１，２］ベンゾチアジン−１０−オンの代わりにナフト［２，３−ｅ］ピロロ［１，２−ｂ］［１，２］チアジン−１２−オンを用いて同様な反応を行い、目的化合物（３）であるナフト［２，３−ｅ］インドロ［１，２−ｂ］［１，２］チアジン−１３−オンを収率２９％で得た。
融点２３８.５−２３９.５℃（塩化メチレン−ヘキサンから再結晶）
1H NMR (CDCl3) δ7.26 (1H, td, J=7.5, 1.4 Hz), 7.47 (1H, td, J=7.5, 1.4 Hz), 7.57-7.53 (2H, m), 7.63 (1H, td, J=7.5, 1.4 Hz), 7.83-7.80 (4H, m), 8.03 (1H, d, J=8.2 Hz), 9.02 (1H, s).
13C NMR (CDCl3) δ111.0, 111.4, 120.6, 122.1, 123.6, 126.3, 126.9, 127.3, 127.5, 129.8, 130.1, 130.7, 131.4, 134.9, 135.7, 138.8, 176.0.
IR (KBr) νmax 3053, 1648, 1523, 1324, 1120, 741 cm-1.
Anal. Calcd for C19H11NOS: C, 75.73; H, 3.68; N, 4.65.
Found: C, 75.40; H, 3.62; N, 4.63.
Example 10
In Example 1, naphtho [2,3-e] pyrrolo [1,2-b] [1,2] thiazine-12 instead of pyrrolo [1,2-b] [1,2] benzothiazin-10-one The same reaction was performed using -one, and the target compound (3), naphtho [2,3-e] indolo [1,2-b] [1,2] thiazin-13-one, was obtained in a yield of 29%. Obtained.
Melting point 238.5-239.5 ° C. (recrystallization from methylene chloride-hexane)
1 H NMR (CDCl 3 ) δ7.26 (1H, td, J = 7.5, 1.4 Hz), 7.47 (1H, td, J = 7.5, 1.4 Hz), 7.57-7.53 (2H, m), 7.63 (1H, td, J = 7.5, 1.4 Hz), 7.83-7.80 (4H, m), 8.03 (1H, d, J = 8.2 Hz), 9.02 (1H, s).
13 C NMR (CDCl 3 ) δ111.0, 111.4, 120.6, 122.1, 123.6, 126.3, 126.9, 127.3, 127.5, 129.8, 130.1, 130.7, 131.4, 134.9, 135.7, 138.8, 176.0.
IR (KBr) ν max 3053, 1648, 1523, 1324, 1120, 741 cm -1 .
Anal.Calcd for C 19 H 11 NOS: C, 75.73; H, 3.68; N, 4.65.
Found: C, 75.40; H, 3.62; N, 4.63.
本発明で得られるインドロベンゾチアジン化合物は、抗菌剤、殺菌剤、除草剤として利用することができる。 The indolobenzothiazine compound obtained in the present invention can be used as an antibacterial agent, fungicide, and herbicide.
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