JPS6230987B2 - - Google Patents
Info
- Publication number
- JPS6230987B2 JPS6230987B2 JP16031179A JP16031179A JPS6230987B2 JP S6230987 B2 JPS6230987 B2 JP S6230987B2 JP 16031179 A JP16031179 A JP 16031179A JP 16031179 A JP16031179 A JP 16031179A JP S6230987 B2 JPS6230987 B2 JP S6230987B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- propyl
- formula
- substituted indole
- acyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 150000002475 indoles Chemical class 0.000 claims description 21
- -1 1-substituted indole Chemical class 0.000 claims description 17
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 15
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 11
- 238000004519 manufacturing process Methods 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 125000002252 acyl group Chemical group 0.000 claims description 5
- 150000001244 carboxylic acid anhydrides Chemical class 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical group 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 22
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 22
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 238000000862 absorption spectrum Methods 0.000 description 13
- 229940054051 antipsychotic indole derivative Drugs 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- 238000002955 isolation Methods 0.000 description 9
- 229910052757 nitrogen Inorganic materials 0.000 description 9
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- 239000000047 product Substances 0.000 description 8
- NOGFHTGYPKWWRX-UHFFFAOYSA-N 2,2,6,6-tetramethyloxan-4-one Chemical compound CC1(C)CC(=O)CC(C)(C)O1 NOGFHTGYPKWWRX-UHFFFAOYSA-N 0.000 description 7
- SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- BHNHHSOHWZKFOX-UHFFFAOYSA-N 2-methyl-1H-indole Chemical compound C1=CC=C2NC(C)=CC2=C1 BHNHHSOHWZKFOX-UHFFFAOYSA-N 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 4
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 230000000704 physical effect Effects 0.000 description 4
- 230000002265 prevention Effects 0.000 description 4
- CJWQWJAUMQHKCR-UHFFFAOYSA-N 2-(3-benzoyl-2-methylindol-1-yl)propyl acetate Chemical compound C12=CC=CC=C2N(C(COC(C)=O)C)C(C)=C1C(=O)C1=CC=CC=C1 CJWQWJAUMQHKCR-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 235000011121 sodium hydroxide Nutrition 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- QPFMBZIOSGYJDE-UHFFFAOYSA-N 1,1,2,2-tetrachloroethane Chemical compound ClC(Cl)C(Cl)Cl QPFMBZIOSGYJDE-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- WGWXERSTOIITIQ-UHFFFAOYSA-N [1-(1-hydroxypropan-2-yl)-2-methylindol-3-yl]-phenylmethanone Chemical compound C12=CC=CC=C2N(C(CO)C)C(C)=C1C(=O)C1=CC=CC=C1 WGWXERSTOIITIQ-UHFFFAOYSA-N 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 229940071870 hydroiodic acid Drugs 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- CNUDXZIIVQXZPC-UHFFFAOYSA-N (2-methyl-1h-indol-3-yl)-phenylmethanone Chemical compound CC=1NC2=CC=CC=C2C=1C(=O)C1=CC=CC=C1 CNUDXZIIVQXZPC-UHFFFAOYSA-N 0.000 description 1
- MWUSAETYTBNPDG-UHFFFAOYSA-N (4-chlorobenzoyl) 4-chlorobenzoate Chemical compound C1=CC(Cl)=CC=C1C(=O)OC(=O)C1=CC=C(Cl)C=C1 MWUSAETYTBNPDG-UHFFFAOYSA-N 0.000 description 1
- DLERSMSVIUGNJO-UHFFFAOYSA-N (4-chlorophenyl)-[1-(1-methoxypropan-2-yl)-2-methylindol-3-yl]methanone Chemical compound C12=CC=CC=C2N(C(C)COC)C(C)=C1C(=O)C1=CC=C(Cl)C=C1 DLERSMSVIUGNJO-UHFFFAOYSA-N 0.000 description 1
- ODIGIKRIUKFKHP-UHFFFAOYSA-N (n-propan-2-yloxycarbonylanilino) acetate Chemical compound CC(C)OC(=O)N(OC(C)=O)C1=CC=CC=C1 ODIGIKRIUKFKHP-UHFFFAOYSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- UFELSDKFBQVETC-UHFFFAOYSA-N 1-(2-methoxyethyl)-2-methylindole Chemical compound C1=CC=C2N(CCOC)C(C)=CC2=C1 UFELSDKFBQVETC-UHFFFAOYSA-N 0.000 description 1
- JKFIHNCDODMBKE-UHFFFAOYSA-N 2-(3-benzoylindol-1-yl)propyl acetate Chemical compound C12=CC=CC=C2N(C(COC(C)=O)C)C=C1C(=O)C1=CC=CC=C1 JKFIHNCDODMBKE-UHFFFAOYSA-N 0.000 description 1
- FRSPYKPPUVOBIT-UHFFFAOYSA-N 2-indol-1-ylpropyl acetate Chemical compound C1=CC=C2N(C(COC(C)=O)C)C=CC2=C1 FRSPYKPPUVOBIT-UHFFFAOYSA-N 0.000 description 1
- HJENUMMIFDMCEN-UHFFFAOYSA-N 2-propyl-1h-indole Chemical compound C1=CC=C2NC(CCC)=CC2=C1 HJENUMMIFDMCEN-UHFFFAOYSA-N 0.000 description 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 201000001320 Atherosclerosis Diseases 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
- 206010050902 Postoperative thrombosis Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- ZZHFGUKEUYKLDX-UHFFFAOYSA-N [1-(1-ethoxypropan-2-yl)-2-methylindol-3-yl]-phenylmethanone Chemical compound C12=CC=CC=C2N(C(C)COCC)C(C)=C1C(=O)C1=CC=CC=C1 ZZHFGUKEUYKLDX-UHFFFAOYSA-N 0.000 description 1
- NXUPMJYDJLTZCZ-UHFFFAOYSA-N [1-(1-methoxypropan-2-yl)-2-methylindol-3-yl]-phenylmethanone Chemical compound C12=CC=CC=C2N(C(C)COC)C(C)=C1C(=O)C1=CC=CC=C1 NXUPMJYDJLTZCZ-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000003377 acid catalyst Substances 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 1
- 150000008046 alkali metal hydrides Chemical class 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 230000002744 anti-aggregatory effect Effects 0.000 description 1
- 230000001567 anti-fibrinolytic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 239000012267 brine Substances 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
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 150000002366 halogen compounds Chemical class 0.000 description 1
- 229910000043 hydrogen iodide Inorganic materials 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 229910052500 inorganic mineral 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
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000010446 mirabilite Substances 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 235000011118 potassium hydroxide Nutrition 0.000 description 1
- 125000001325 propanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- RSIJVJUOQBWMIM-UHFFFAOYSA-L sodium sulfate decahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].[O-]S([O-])(=O)=O RSIJVJUOQBWMIM-UHFFFAOYSA-L 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 230000001732 thrombotic effect Effects 0.000 description 1
Landscapes
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
Description
【発明の詳細な説明】
本発明は３―アシル―１―置換インドール誘導
体の製造法に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing 3-acyl-1-substituted indole derivatives.
更に詳しくは、優れた血小板凝集阻止作用を有
する３―アシル―１―置換インドール誘導体の新
規な製造法に関する。 More specifically, the present invention relates to a novel method for producing 3-acyl-1-substituted indole derivatives having excellent platelet aggregation inhibiting activity.
しかして、本発明によれば次の如き製造法が提
供される。 According to the present invention, the following manufacturing method is provided.
すなわち、下記式〔〕、
〔式中、R1は水素原子又は低級アルキル基を
表わし、R6は水素原子又はメチル基を表わし、
R2，R3，R4，R5はそれぞれ独立に水素原子又は
低級アルコキシ基を表わし、R7は低級アルキル
基又は低級アルカノイル基を表わす。〕
で表わされる１―置換インドール誘導体に下記
式〔〕、
〔式中、はハロゲン原子で置換されているか
もしくは非置換のフエニル基もしくはチエニル基
を表わす。〕
で表わされるカルボン酸無水物を沃化水素酸の
存在下縮合せしめることを特徴とする下記式
〔〕、
〔式中、R1，R2，R3，R4，R5，R6，R7及び
は前記定義に同じ。〕
で表わされる３―アシル―１―置換インドール
誘導体の製造法である。 That is, the following formula [], [In the formula, R 1 represents a hydrogen atom or a lower alkyl group, R 6 represents a hydrogen atom or a methyl group,
R 2 , R 3 , R 4 and R 5 each independently represent a hydrogen atom or a lower alkoxy group, and R 7 represents a lower alkyl group or a lower alkanoyl group. ] The 1-substituted indole derivative represented by the following formula [], [In the formula, represents a halogen atom-substituted or unsubstituted phenyl group or thienyl group. ] The following formula [], which is characterized by condensing a carboxylic acid anhydride represented by in the presence of hydriodic acid, [In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and are the same as defined above. ] This is a method for producing a 3-acyl-1-substituted indole derivative represented by the following.
従来、３―アシル―１―置換インドール誘導体
の製造法としては、３―アシルインドール誘導体
に活性化ハロゲン化合物をインドールの１位に反
応せることによつて製造する方法が知られている
（特公昭48−43740号公報、米国特許第3557142号
公報、米国特許第3843683号公報、特公昭48−
19633号公報等参照）。 Conventionally, as a method for producing 3-acyl-1-substituted indole derivatives, a method is known in which a 3-acylindole derivative is reacted with an activated halogen compound at the 1-position of the indole (Japanese Patent Publication No. No. 48-43740, U.S. Patent No. 3557142, U.S. Patent No. 3843683, Japanese Patent Publication No. 1973-
(See Publication No. 19633, etc.)
しかしながら、３―アシル―１―置換インドー
ル誘導体の製造法として、本発明の如く１位に置
換基のあるインドール誘導体を用いて、その３位
をアシル化する製造法は知られていない。 However, as a method for producing 3-acyl-1-substituted indole derivatives, there is no known method for producing 3-acyl-1-substituted indole derivatives using an indole derivative having a substituent at the 1-position and acylating the 3-position.
本発明者らは、１位に置換基のあるインドール
誘導体を用い、特に触媒として沃化水素酸を使用
して、その３位をアシル化することによつて効率
よく３―アシル―１―置換インドール誘導体が得
られることを見出したものである。そして本発明
で得られる上記式〔〕で表わされる３―アシル
―１―置換インドール誘導体は、優れた血小板凝
集阻止作用を有し、それ故、心臓血管系の硬塞の
予防、術後血栓の予防及び治療、外科手術後の血
管の血栓硬塞の予防及び治療及びアテローム性動
脈硬化症、動脈硬化症の予防もしくは治療に、心
筋層の硬塞と卒中発作後の再発の予防又は治療等
に極めて有用な化合物であり、又、本発明で提供
させる３―アシル―１―置換インドール誘導体
は、優れた抗炎症作用線溶活性を有する化合物と
しても期待され、かかる意味からも極めて有用な
化合物である。 The present inventors have efficiently achieved 3-acyl-1-substitution by using an indole derivative having a substituent at the 1-position, and in particular using hydriodic acid as a catalyst to acylate the 3-position. It was discovered that indole derivatives can be obtained. The 3-acyl-1-substituted indole derivative represented by the above formula [] obtained by the present invention has an excellent platelet aggregation inhibiting effect, and therefore can prevent cardiovascular occlusion and post-operative thrombosis. Prevention and treatment, prevention and treatment of thrombotic occlusion of blood vessels after surgical operations, prevention and treatment of atherosclerosis and arteriosclerosis, prevention and treatment of myocardial infarction and recurrence after stroke, etc. The 3-acyl-1-substituted indole derivative provided by the present invention is an extremely useful compound, and is also expected to have excellent anti-inflammatory and fibrinolytic activity, and in this sense, it is an extremely useful compound. be.
本発明で出発原料として用いられる上記式
〔〕で表わされる１―置換インドール誘導体に
おいて、R1は水素原子又は低級アルキル基を表
わし、R6は水素原子又はメチル基を表わす。か
かる低級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、イソプロピル基、ブチル
基、イソブチル基等が挙げられる。なかでも、
R1は水素原子、メチル基又はイソプロピル基、
R6はメチル基が有用な薬理作用を有する化合物
が得られるので好ましい。R2，R3，R4，R5はそ
れぞれ独立に水素原子又は低級アルコキシ基を表
わす。 In the 1-substituted indole derivative represented by the above formula [] used as a starting material in the present invention, R 1 represents a hydrogen atom or a lower alkyl group, and R 6 represents a hydrogen atom or a methyl group. Such lower alkyl groups include, for example, methyl group,
Examples include ethyl group, propyl group, isopropyl group, butyl group, and isobutyl group. Among them,
R 1 is a hydrogen atom, a methyl group or an isopropyl group,
R 6 is preferable because a compound in which the methyl group has a useful pharmacological effect can be obtained. R 2 , R 3 , R 4 and R 5 each independently represent a hydrogen atom or a lower alkoxy group.
低級アルコキシ基としては、例えばメトキシ
基、エトキシ基、プロポキシ基、イソプロポキシ
基、ブトキシ基，イソブトキシ基等が挙げられ
る。 Examples of the lower alkoxy group include methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, and isobutoxy group.
R7は低級アルキル基又は低級アルカノイル基
を表わす。かかる低級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、イソプロピ
ル基、ブチル基、イソブチル基等が挙げられ、低
級アルカノイル基としては例えば、ホルミル基、
アセチル基、プロパノイル基、ブタノイル基等が
挙げられる。 R 7 represents a lower alkyl group or a lower alkanoyl group. Examples of such lower alkyl groups include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, etc., and examples of lower alkanoyl groups include formyl group,
Examples include an acetyl group, a propanoyl group, a butanoyl group, and the like.
このような本発明で出発原料として用いられる
前記式〔〕で表わされる１―置換インドール誘
導体は下記式〔〕
〔式中、R1，R2，R3，R4，R5は前記定義に同
じ〕で表わされるインドール誘導体と酸受容体の
存在下、下記式〔〕
〔式中、Ａはハロゲン原子、R6，R7は前記定
義に同じ。〕
で表わされる化合物と反応することによつて製
造することができる。ここで上記式〔〕におけ
るＡとしては例えば塩素原子、臭素原子、沃素原
子等が挙げられる。酸受容体としては、水素化ナ
トリウム、水素化カリウム等の水素化アルカリ金
属が好ましいものである。かかる反応はベンゼ
ン、トルエン、キシレン、エチレングリコールジ
メチルエーテル、エーテル、ジオキサン、テトラ
ヒドロフラン、ジメチルホルムアミド、ジメチル
スルフオキシド、ヘキサメチルホスホアミド等の
不活性な有機溶媒中で、−20゜〜150℃の温度範囲
で実施することができる。 The 1-substituted indole derivative represented by the above formula [] used as a starting material in the present invention is represented by the following formula [] In the presence of an indole derivative represented by [wherein R 1 , R 2 , R 3 , R 4 , and R 5 are the same as defined above] and an acid acceptor, the following formula [] [In the formula, A is a halogen atom, and R 6 and R 7 are the same as defined above. ] It can be produced by reacting with a compound represented by: Here, A in the above formula [] includes, for example, a chlorine atom, a bromine atom, an iodine atom, and the like. As the acid acceptor, alkali metal hydrides such as sodium hydride and potassium hydride are preferred. This reaction is carried out in an inert organic solvent such as benzene, toluene, xylene, ethylene glycol dimethyl ether, ether, dioxane, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, hexamethylphosphoamide, etc. at a temperature range of -20° to 150°C. It can be carried out in
本発明の製造法における他方の原料である上記
式〔〕で表わされるカルボン酸無水物として
は、はハロゲン原子で置換されているか又は非
置換のフエニル基、２―チエニル基、３―チエニ
ル基等が挙げられる。ハロゲン原子としては塩
素、フツ素、臭素、沃素等が挙げられる。 The carboxylic acid anhydride represented by the above formula [], which is the other raw material in the production method of the present invention, includes a halogen atom-substituted or unsubstituted phenyl group, 2-thienyl group, 3-thienyl group, etc. can be mentioned. Examples of the halogen atom include chlorine, fluorine, bromine, and iodine.
しこうして本発明の３―アシル―１―置換イン
ドール誘導体の製造は、前記式〔〕で表わされ
る１―置換インドール誘導体と前記式〔〕で表
わされるカルボン酸無水物を沃化水素酸を触媒と
して用いて反応させることによつて行なわれる。
反応は無溶媒下においても進行するが、場合によ
つては反応をより円滑に進行させるために有機溶
媒体を用いてもよい。かかる有機溶媒体として
は、反応化合物と不活性であればいかなるものも
使用できるが、具体的に例示すれば、四塩化炭
素、ジクロルメタン、ジクロロエタン、テトラク
ロロエタンの如きハロゲン化アルカン、ニトロベ
ンゼン、クロロベンゼン、トルエン、キシレンの
如き芳香族炭化水素等を好ましいものとして挙げ
ることができる。 Thus, the 3-acyl-1-substituted indole derivative of the present invention can be produced by combining the 1-substituted indole derivative represented by the above formula [] and the carboxylic acid anhydride represented by the above formula [] using hydriodic acid as a catalyst. This is done by reacting using
Although the reaction proceeds even in the absence of a solvent, an organic solvent may be used in some cases to make the reaction proceed more smoothly. Any organic solvent can be used as long as it is inert to the reaction compound, but specific examples include carbon tetrachloride, halogenated alkanes such as dichloromethane, dichloroethane, and tetrachloroethane, nitrobenzene, chlorobenzene, and toluene. Preferred examples include aromatic hydrocarbons such as , xylene, and the like.
本発明において用いられる前記式〔〕のカル
ボン酸無水物は、前記式〔〕の１―置換インド
ール誘導体に対して0.5〜10倍モル、好ましくは
１〜５倍モルであり、触媒の沃化水素酸は前記式
〔〕の１―置換インドール誘導体に対して0.001
〜２倍モル、好ましくは0.01〜0.5倍モルであ
る。又、不活性な有機溶媒体の使用量は反応を円
滑に進行させるに十分な量があれば良く、通常は
原料の１〜100倍容量、好ましくは２〜20倍容量
が用いられる。又、反応温度は50〜180℃で、好
ましくは80〜150℃である。反応時間は0.5〜24時
間、好ましくは１〜６時間である。 The carboxylic acid anhydride of the formula [] used in the present invention is 0.5 to 10 times the mole, preferably 1 to 5 times the mole of the 1-substituted indole derivative of the formula [], and the amount of hydrogen iodide used as a catalyst is The acid is 0.001 for the 1-substituted indole derivative of the above formula []
~2 times the mole, preferably 0.01 to 0.5 times the mole. The amount of inert organic solvent to be used is sufficient as long as the reaction proceeds smoothly, and the amount used is usually 1 to 100 times, preferably 2 to 20 times, the volume of the raw materials. Further, the reaction temperature is 50 to 180°C, preferably 80 to 150°C. The reaction time is 0.5 to 24 hours, preferably 1 to 6 hours.
反応後、前記式〔〕で表わされる３―アシル
―１―置換インドール誘導体を単離するには、次
のようにして行う。所望により媒体を留去した
後、苛性ソーダ、重曹等のアルカリを用いて反応
混合物を処理する。得られた処理液をエーテル、
ベンゼン、酢酸エチル、ジクロルメタン、クロロ
ホルムなどの抽出溶媒を用いて抽出し、得られた
有機層を水、重曹水、食塩水などで洗浄した後、
乾燥、濃縮して粗生成物を得る。このものをカラ
ムクロマトグラフイー、薄層クロマトグラフイ
ー、蒸留、再結晶などの精製手段を用いて分離
し、３―アシル―１―置換インドール誘導体を単
離することができる。 After the reaction, the 3-acyl-1-substituted indole derivative represented by the above formula [] can be isolated as follows. After distilling off the medium if desired, the reaction mixture is treated with an alkali such as caustic soda or sodium bicarbonate. The obtained treatment liquid was mixed with ether,
After extraction using an extraction solvent such as benzene, ethyl acetate, dichloromethane, or chloroform, and washing the obtained organic layer with water, aqueous sodium bicarbonate, or brine,
Dry and concentrate to obtain the crude product. This product can be separated using purification means such as column chromatography, thin layer chromatography, distillation, recrystallization, etc., and the 3-acyl-1-substituted indole derivative can be isolated.
また、本発明で製造される前記式〔〕で表わ
される３―アシル―１―置換インドール誘導体の
うち、R7が水素原子である３―アシル―１―置
換インドール誘導体は、前記式〔〕で表わされ
る１―置換インドール誘導体で、R7が低級アル
カノイル基であるものを用いた上記したアシル化
反応の後に、加水分解反応によつて得られる。こ
の加水分解反応は、それ自体公知の反応であり、
一般には苛性ソーダ、苛性カリの如きアルカリ又
は塩酸の如き鉱酸、好ましくはアルカリの存在下
にメタノール、エタノールの如きアルコール中で
場合によつてはテトラヒデロフラン、ジオキサン
の如きエーテル系溶媒の共存下通常０〜100℃の
温度で処理することにより行われる。反応後の目
的物の単離精製は前述したと同様の方法によつて
行われる。 Further, among the 3-acyl-1-substituted indole derivatives represented by the above formula [] produced in the present invention, the 3-acyl-1-substituted indole derivatives in which R 7 is a hydrogen atom are the 3-acyl-1-substituted indole derivatives represented by the above formula []. It can be obtained by a hydrolysis reaction after the above-described acylation reaction using the 1-substituted indole derivative represented by the formula in which R 7 is a lower alkanoyl group. This hydrolysis reaction is a known reaction per se,
Generally, in the presence of an alkali such as caustic soda or caustic potash or a mineral acid such as hydrochloric acid, preferably an alkali, in an alcohol such as methanol or ethanol, and in some cases in the presence of an ether solvent such as tetrahydrofuran or dioxane. It is carried out by processing at a temperature of 0 to 100°C. Isolation and purification of the target product after the reaction is performed in the same manner as described above.
以上に詳述したように、本発明の如く、１位に
置換基を有するインドール誘導体の３位を沃化水
素酸の触媒の存在下アシル化することによつて効
率よく、高収率で血小板凝集阻止作用を有する有
用な３―アシル―１―置換インドール誘導体が製
造される。 As detailed above, according to the present invention, platelets can be efficiently and in high yield by acylating the 3-position of an indole derivative having a substituent at the 1-position in the presence of a hydriodic acid catalyst. Useful 3-acyl-1-substituted indole derivatives with anti-aggregation properties are produced.
以下、本発明を実施例により詳細に説明する。 Hereinafter, the present invention will be explained in detail with reference to Examples.
実施例 １
１―（１―アセトキシ―２―プロピル）―３―
ベンゾイル―２―メチルインドール及び３―ベ
ンゾイル―１―（１―ヒドロキシ―２―プロピ
ル）―２―メチルインドールの合成
安息香酸無水物4.97ｇ（22ミリモル）と１―
（１―アセトキシ―２―プロピル）―２―メチル
インドール2.54ｇ（11ミリモル）と52％沃化水素
酸0.6mlと窒素気流下135℃で２時間加熱撹拌し
た。反応混合物を室温に放冷後、飽和重曹水30ml
を加え一夜撹拌した。次いで酢酸エチル100mlを
加え抽出し、酢酸エチル層を水50ml、飽和食塩水
50mlで洗浄後、芒硝で乾燥した。溶媒を減圧留去
すると、暗紅色の油状生成物が得られた。この油
状生成物をシリカゲル100ｇのカラムクロマトグ
ラフイーにて精製し、ベンゼン：酢酸エチル＝
25：１の溶出部に１―（１―アセトキシ―２―プ
ロピル）―３―ベンゾイル―２―メチルインドー
ル2.06ｇを得た（収率56％）。Example 1 1-(1-acetoxy-2-propyl)-3-
Synthesis of benzoyl-2-methylindole and 3-benzoyl-1-(1-hydroxy-2-propyl)-2-methylindole 4.97 g (22 mmol) of benzoic anhydride and 1-
2.54 g (11 mmol) of (1-acetoxy-2-propyl)-2-methylindole and 0.6 ml of 52% hydriodic acid were heated and stirred at 135° C. for 2 hours under a nitrogen stream. After cooling the reaction mixture to room temperature, add 30 ml of saturated sodium bicarbonate solution.
was added and stirred overnight. Next, 100ml of ethyl acetate was added for extraction, and the ethyl acetate layer was mixed with 50ml of water and saturated brine.
After washing with 50 ml, it was dried with Glauber's salt. The solvent was removed under reduced pressure to obtain a dark red oily product. This oily product was purified by column chromatography using 100 g of silica gel, and benzene:ethyl acetate=
2.06 g of 1-(1-acetoxy-2-propyl)-3-benzoyl-2-methylindole was obtained in the 25:1 elution fraction (yield 56%).
このものの物性値は次のとおりであつた。 The physical properties of this product were as follows.
赤外線吸収スペクトル
νＣＨＣｌ３ ｎａｘ；
1736，1625，1521，1461，1613，1382，
1230，1174，1050cm-1
核磁気共鳴吸収スペクトル
δＣＤＣｌ３ ＴＭＳ；
1.63（3H，ｄ，Ｊ＝８Hz），1.87（3H，
ｓ），2.52（3H，ｓ），4.3〜4.6（2H，
ｍ），4.6〜5.2（1H，ｍ），6.8〜7.8
（9H，ｍ）
ここで得られた１―（１―アセトキシ―２―プ
ロピル）―３―ベンゾイル―２―メチルインドー
ル597mg（1.78ミリモル）メタノール10mlと1N、
苛性ソーダ溶液５mlに溶かし、室温で３時間撹拌
した。メタノールを減圧留去後、残査を酢酸エチ
ル50mlに溶かし、水50ml飽和食塩水50mlで洗浄し
た。芒硝乾燥後、溶媒を減圧留去し、目的の３―
ベンゾイル―１―（１―ヒドロキシ―２―プロピ
ル）―２―メチルインドールを油状物として520
mg得た（収率100％）。Infrared absorption spectrum ν CHCl3 nax ; 1736, 1625, 1521, 1461, 1613, 1382,
1230, 1174, 1050 cm -1 Nuclear magnetic resonance absorption spectrum δ CDCl3 TMS ; 1.63 (3H, d, J=8Hz), 1.87 (3H,
s), 2.52 (3H, s), 4.3~4.6 (2H,
m), 4.6-5.2 (1H, m), 6.8-7.8
(9H, m) 597 mg (1.78 mmol) of the 1-(1-acetoxy-2-propyl)-3-benzoyl-2-methylindole obtained here, 10 ml of methanol and 1N,
It was dissolved in 5 ml of caustic soda solution and stirred at room temperature for 3 hours. After methanol was distilled off under reduced pressure, the residue was dissolved in 50 ml of ethyl acetate and washed with 50 ml of water and 50 ml of saturated saline. After drying the sodium sulfate, the solvent was distilled off under reduced pressure to obtain the desired 3-
Benzoyl-1-(1-hydroxy-2-propyl)-2-methylindole as an oil 520
mg (yield 100%).
このものの物性値は次のとおりであつた。 The physical properties of this product were as follows.
赤外線吸収スペクトル
νＣＨＣｌ３ ｎａｘ；
3400，1620，1576，1513，1462，1412，
1390，1273，1230，1163，1056，1131，
899cm-1
核磁気共鳴吸収スペクトル
δＣＤＣｌ３ ＴＭＳ；
1.60（3H，ｄ，Ｊ＝８Hz），2.47（3H，
ｓ），2.60（1H，br），3.6〜4.2（2H，
ｍ），4.2〜4.8（1H，ｍ），6.9〜7.8
（9H，ｍ）
実施例 ２
３―ベンゾイル―１―（１―メトキシ―２―プ
ロピル）―２―メチルインドールの合成
１―（１―メトキシ―２―プロピル）―２―メ
チルインドール1.41ｇ（6.9ミリモル）と無水安
息香酸4.52ｇ（13.8ミリモル）と52％沃化水素酸
0.3mlと窒素気流下140℃で1.5時間加熱撹拌し
た。実施例１と同様な後処理、単離操作を行い、
３―ベンゾイル―１―（１―アセトキシ―２―プ
ロピル）―２―メチル―インドールを905mg得た
（収率42％）。Infrared absorption spectrum ν CHCl3 nax ; 3400, 1620, 1576, 1513, 1462, 1412,
1390, 1273, 1230, 1163, 1056, 1131,
899cm -1 nuclear magnetic resonance absorption spectrum δ CDCl3 TMS ; 1.60 (3H, d, J=8Hz), 2.47 (3H,
s), 2.60 (1H, br), 3.6~4.2 (2H,
m), 4.2-4.8 (1H, m), 6.9-7.8
(9H, m) Example 2 Synthesis of 3-benzoyl-1-(1-methoxy-2-propyl)-2-methylindole 1.41 g (6.9 4.52 g (13.8 mmol) of benzoic anhydride and 52% hydriodic acid
0.3 ml was heated and stirred at 140°C for 1.5 hours under a nitrogen stream. Perform the same post-treatment and isolation operations as in Example 1,
905 mg of 3-benzoyl-1-(1-acetoxy-2-propyl)-2-methyl-indole was obtained (yield 42%).
このものの物性値は次のとおりであつた。 The physical properties of this product were as follows.
赤外線吸収スペクトル
νｎｅａｔ ｎａｘ；
2950，2900，1620，1572，1515，1450，
1403，1374，1267，1225，1200，1165，
1108，1036，895，744cm-1
核磁気共鳴スペクトル
δＴＭＳ ＣＤＣｌ３；
1.60（3H，ｄ，Ｊ＝７Hz），2.55（3H，
ｓ），3.23（3H，ｓ），3.6〜4.1（2H，
ｍ），4.5〜5.1（1H，ｍ），6.9〜7.9
（9H.m）
実施例 ３
３―ベンゾイル―１―（１―エトキシ―２―プ
ロピル）―２―メチルインドールの合成
１―（１―エトキシ―２―プロピル）―２―メ
チルインドール1.08ｇ（５ミリモル）と無水安香
酸2.26ｇ（10ミリモル）と52％沃化水素酸0.5ml
を窒素気流下140℃に２時間撹拌した。実施例１
と同様な後処理、単離操作を行い、３―ベンゾイ
ル―１―（１―エトキシ―２―プロピル）―２―
メチルインドールを720mg得た（収率52％）。 Infrared absorption spectrum ν neat nax ; 2950, 2900, 1620, 1572, 1515, 1450,
1403, 1374, 1267, 1225, 1200, 1165,
1108, 1036, 895, 744 cm -1 Nuclear magnetic resonance spectrum δ TMS CDCl3 ; 1.60 (3H, d, J=7Hz), 2.55 (3H,
s), 3.23 (3H, s), 3.6~4.1 (2H,
m), 4.5-5.1 (1H, m), 6.9-7.9
(9H.m) Example 3 Synthesis of 3-benzoyl-1-(1-ethoxy-2-propyl)-2-methylindole 1.08g (5 2.26 g (10 mmol) of benzoic anhydride and 0.5 ml of 52% hydriodic acid
The mixture was stirred at 140°C for 2 hours under a nitrogen stream. Example 1
After performing the same post-treatment and isolation procedure as above, 3-benzoyl-1-(1-ethoxy-2-propyl)-2-
720 mg of methyl indole was obtained (yield 52%).
このものの物性値は次のとおりであつた。 The physical properties of this product were as follows.
赤外線吸収スペクトル
νＣＨＣｌ３ ｎａｘ；
2960，2850，1620，1572，1516，1459，
1445，1407，1381，1254，1268，1210−
1230，1168，1100，1070，1025，896，
696cm-1
核磁気共鳴スペクトル
δＣＤＣｌ３ ＴＭＳ；
1.03（3H，ｔ，Ｊ＝6.5Hz），1.60（3H，
ｄ，Ｊ＝７Hz），2.53（3H，ｓ），3.1〜
3.6（2H，ｍ），3.7〜4.2（2H，ｍ），
4.67（1H，sextet Ｊ＝７Hz），6.9〜7.9
（9H，ｍ）
実施例 ４
３―ベイゾイル―１―（２―メトキシエチル）
―２―メチルインドールの合成
安息香酸無水物2.03ｇ（９ミリモル）と１―
（２―メトキシエチル）―２―メチルインドール
850mg（4.5ミリモル）と52％沃化水素酸0.2mlを
窒素気流下140℃に1.5時間加熱撹拌した。実施例
１と同様な後処理、単離操作を行い、３―ベンゾ
イル―１―（２―メトキシエチル）―２メチルイ
ンドールを560mg得た（収率43％）。Infrared absorption spectrum ν CHCl3 nax ; 2960, 2850, 1620, 1572, 1516, 1459,
1445, 1407, 1381, 1254, 1268, 1210−
1230, 1168, 1100, 1070, 1025, 896,
696cm -1 Nuclear magnetic resonance spectrum δ CDCl3 TMS ; 1.03 (3H, t, J = 6.5Hz), 1.60 (3H,
d, J=7Hz), 2.53 (3H, s), 3.1~
3.6 (2H, m), 3.7~4.2 (2H, m),
4.67 (1H, sextet J=7Hz), 6.9-7.9
(9H, m) Example 4 3-Bayzoyl-1-(2-methoxyethyl)
-Synthesis of 2-methylindole 2.03g (9 mmol) of benzoic anhydride and 1-
(2-methoxyethyl)-2-methylindole
850 mg (4.5 mmol) and 0.2 ml of 52% hydriodic acid were heated and stirred at 140° C. for 1.5 hours under a nitrogen stream. The same post-treatment and isolation operations as in Example 1 were performed to obtain 560 mg of 3-benzoyl-1-(2-methoxyethyl)-2-methylindole (yield: 43%).
赤外線吸収スペクトル
νＣＨＣｌ３ ｎａｘ；
1615，1571，1510，1454，1408，1230，
1167，1120，1060cm-1
核磁気共鳴スペクトル
δＣＤＣｌ３ ＴＭＳ；
2.53（3H，ｓ），3.23（3H，ｓ），3.63
（2H，ｔ，Ｊ＝６Hz），4.27（2H，ｔ，
Ｊ＝６Hz），6.9―7.8（9H，ｍ）
実施例 ５
１―（１―アセトキシ―２―プロピル）―３―
ベンゾイルインドール及び３―ベンゾイル―１
―（１―ヒドロキシ―２―プロピル）インドー
ルの合成
１―（１―アセトキシ―２―プロピル）インド
ール1.51ｇ（７ミリモル）と安息香酸無水物3.14
ｇ（14ミリモル）と52％沃化水素酸0.2mlとを窒
素気流下、140℃に1.5時間加熱撹拌した。実施例
１と同様に後処理、単離操作を行い、目的の１―
（１―アセトキシ―２―プロピル）―３―ベンゾ
イルインドールを0.8ｇ得た（収率37％）。Infrared absorption spectrum ν CHCl3 nax ; 1615, 1571, 1510, 1454, 1408, 1230,
1167, 1120, 1060 cm -1 Nuclear magnetic resonance spectrum δ CDCl3 TMS ; 2.53 (3H, s), 3.23 (3H, s), 3.63
(2H, t, J=6Hz), 4.27 (2H, t,
J=6Hz), 6.9-7.8 (9H, m) Example 5 1-(1-acetoxy-2-propyl)-3-
Benzoylindole and 3-benzoyl-1
-Synthesis of (1-hydroxy-2-propyl)indole 1.51 g (7 mmol) of 1-(1-acetoxy-2-propyl) indole and 3.14 g of benzoic anhydride
(14 mmol) and 0.2 ml of 52% hydriodic acid were heated and stirred at 140° C. for 1.5 hours under a nitrogen stream. Post-treatment and isolation operations were performed in the same manner as in Example 1, and the desired 1-
0.8 g of (1-acetoxy-2-propyl)-3-benzoylindole was obtained (yield 37%).
赤外線吸収スペクトル
νＣＨＣｌ３ ｎａｘ；
1735，1610，1568，1507，1456，1410，
1375，1312，1230―1210，1050，871cm
-1
核磁気共鳴スペクトル
δＣＤＣｌ３ ＴＭＳ；
1.50（3H，ｄ，Ｊ＝７Hz），1.83（3H，
ｓ），4.0―4.4（2H，ｍ），4.4―5.1
（1H，ｍ），7.2―7.8（9H，ｍ），8.35―
8.6（1H，ｍ）
ここで得られた１―（１―アセトキシ―２―プ
ロピル）―３―ベンゾイルインドール0.8ｇ（2.5
ミリモル）をメタノール10mlに溶かし、1N、苛
性ソーダ溶液５ml（５ミリモル）で加水分解反応
を行い、実施例３と同様な後処理、単離操作を
し、目的の３―ベンゾイル―１―（１―ヒドロキ
シ―２―プロピル）インドールを595mg得た（収
率85％）。Infrared absorption spectrum ν CHCl3 nax ; 1735, 1610, 1568, 1507, 1456, 1410,
1375, 1312, 1230―1210, 1050, 871cm
-1 nuclear magnetic resonance spectrum δ CDCl3 TMS ; 1.50 (3H, d, J=7Hz), 1.83 (3H,
s), 4.0-4.4 (2H, m), 4.4-5.1
(1H, m), 7.2―7.8 (9H, m), 8.35―
8.6 (1H, m) 0.8 g (2.5
3-benzoyl-1-(1- 595 mg of hydroxy-2-propyl) indole was obtained (yield 85%).
赤外線吸収スペクトル
νＣＨＣｌ３ ｎａｘ；
3360，2970，1605，1570，1509，1481，
1460，1407，1382，1306，1230―1210，
1177，1049，875cm-1
核磁気共鳴スペクトル
δＣＤＣｌ３ ＴＭＳ；
1.43（3H，ｄ，Ｊ＝７Hz），3.2（1H，
br，ｓ），3.73（2H，br，ｓ），4.3―4.7
（1H，ｍ），7.1―7.8（9H，ｍ），8.1―
8.4（1H，ｍ）
実施例 ６
３―ベンゾイル―２―イソプロピル―１―（１
―メトキシ―２―プロピル）インドールの合成
２―イソプロピル―１―（１―メトキシ―２―
プロピル）インドール1.15ｇ（５ミリモル）と安
息香酸無水物2.26ｇ（10ミリモル）と52％沃化水
素酸0.3mlを窒素気流下140℃に２時間加熱撹拌し
た。実施例１と同様に後処理、単離操作を行い、
３―ベンゾイル―２―イソプロピル―１―（１―
メトキシ―２―プロピル）インドールを1.03ｇ得
た（収率62％）。Infrared absorption spectrum ν CHCl3 nax ; 3360, 2970, 1605, 1570, 1509, 1481,
1460, 1407, 1382, 1306, 1230―1210,
1177, 1049, 875 cm -1 Nuclear magnetic resonance spectrum δ CDCl3 TMS ; 1.43 (3H, d, J=7Hz), 3.2 (1H,
br, s), 3.73 (2H, br, s), 4.3-4.7
(1H, m), 7.1―7.8 (9H, m), 8.1―
8.4 (1H, m) Example 6 3-benzoyl-2-isopropyl-1-(1
Synthesis of -methoxy-2-propyl)indole 2-isopropyl-1-(1-methoxy-2-
1.15 g (5 mmol) of propyl indole, 2.26 g (10 mmol) of benzoic anhydride, and 0.3 ml of 52% hydriodic acid were heated and stirred at 140° C. for 2 hours under a nitrogen stream. Post-treatment and isolation operations were performed in the same manner as in Example 1,
3-benzoyl-2-isopropyl-1-(1-
1.03 g of methoxy-2-propyl) indole was obtained (yield 62%).
赤外線吸収スペクトル
νＣＨＣｌ３ ｎａｘ；
3000，2940，1623，1508，1460，1410，
1240―1205，1103cm-1
核磁気共鳴スペクトル
δＣＤＣｌ３ ＴＭＳ；
1.40（3H，ｄ，Ｊ＝７Hz），1.43（3H，
ｄ，Ｊ＝７Hz），1.60（3H，ｄ，Ｊ＝７
Hz），3.23（3H，ｓ），3.67（1H，ｍ），
3.80（2H，ｄ，Ｊ＝７Hz），4.83（1H，
sextet，Ｊ＝７Hz），6.8―7.9（9H，
ｍ）
実施例 ７
１―（１―メトキシ―２―プロピル）―２―メ
チル―３―チオフインカルボニルインドールの
合成
１―（１―メトキシ―２―プロピル）―２―メ
チルインドール1.55ｇ（7.6ミリモル）とチオフ
インカルボン酸無水物3.14ｇ（15.2ミリモル）と
52％沃化水素酸0.4mlとを窒素気流下140℃に２時
間加熱撹拌した。実施例１と同様に後処理、単離
操作を行い、１―（１―メトキシ―２―プロピ
ル）―２―メチル―３―チオフインカルボニルイ
ンドールを得た。Infrared absorption spectrum ν CHCl3 nax ; 3000, 2940, 1623, 1508, 1460, 1410,
1240-1205, 1103cm -1 Nuclear magnetic resonance spectrum δ CDCl3 TMS ; 1.40 (3H, d, J = 7Hz), 1.43 (3H,
d, J = 7Hz), 1.60 (3H, d, J = 7
Hz), 3.23 (3H, s), 3.67 (1H, m),
3.80 (2H, d, J = 7Hz), 4.83 (1H,
sextet, J=7Hz), 6.8-7.9 (9H,
m) Example 7 Synthesis of 1-(1-methoxy-2-propyl)-2-methyl-3-thiophinecarbonylindole 1.55 g (7.6 mmol) and 3.14 g (15.2 mmol) of thiophinecarboxylic anhydride.
0.4 ml of 52% hydroiodic acid was heated and stirred at 140°C for 2 hours under a nitrogen stream. Post-treatment and isolation operations were performed in the same manner as in Example 1 to obtain 1-(1-methoxy-2-propyl)-2-methyl-3-thiophinecarbonylindole.
赤外線吸収スペクトル
νＣＨＣｌ３ ｎａｘ；
1605，1514，1460，1413，1390，1351，
1267，1220，1165，1106，1082，834cm
-1
核磁気共鳴スペクトル
δＣＤＣｌ３ ＴＭＳ；
1.60（3H，ｄ，Ｊ＝６Hz），2.55（3H，
ｓ），3.18（3H，ｓ），3.5―4.1（2H，
ｍ），4.70（1H，sextet，Ｊ＝６Hz），
6.9―7.75（7H，ｍ）
実施例 ８
３―（ｐ―クロルベンゾイル）―１―（１―メ
トキシ―２―プロピル）―２―メチルインドー
ルの合成
１―（１―メトキシ―２―プロピル）―２―メ
チルインドール0.8ｇ（４ミリモル）とｐ―クロ
ル安息香酸無水物3.48ｇ（11.8ミリモル）と52％
沃化水素酸0.25mlとを窒素気流下140℃に2.5時間
加熱撹拌した。実施例１と同様な後処理、単離操
作を行い、３―（ｐ―クロルベンゾイル）―１―
メトキシ―２―プロピル）―２―メチルインドー
ルを810mg得た（収率66％）。Infrared absorption spectrum ν CHCl3 nax ; 1605, 1514, 1460, 1413, 1390, 1351,
1267, 1220, 1165, 1106, 1082, 834cm
-1 nuclear magnetic resonance spectrum δ CDCl3 TMS ; 1.60 (3H, d, J=6Hz), 2.55 (3H,
s), 3.18 (3H, s), 3.5-4.1 (2H,
m), 4.70 (1H, sextet, J=6Hz),
6.9-7.75 (7H, m) Example 8 Synthesis of 3-(p-chlorobenzoyl)-1-(1-methoxy-2-propyl)-2-methylindole 1-(1-methoxy-2-propyl)- 0.8 g (4 mmol) of 2-methylindole and 3.48 g (11.8 mmol) of p-chlorobenzoic anhydride and 52%
0.25 ml of hydroiodic acid was heated and stirred at 140° C. for 2.5 hours under a nitrogen stream. The same post-treatment and isolation operations as in Example 1 were performed to obtain 3-(p-chlorobenzoyl)-1-
810 mg of methoxy-2-propyl)-2-methylindole was obtained (yield 66%).
赤外線吸収スペクトル
νＣＨＣｌ３ ｎａｘ；
2850，1618，1593，1460，1408，1105，
1089，898，837cm-1
核磁気共鳴スペクトル
δＣＤＣｌ３ ＴＭＳ；
1.62（3H，ｄ，Ｊ＝７Hz），2.58（3H，
ｓ），3.26（3H，ｓ），3.8（2H，ｍ），
4.76（1H，sextet，Ｊ＝７Hz），6.9―
7.8（8H，ｍ）
実施例 ９
３―ベンゾイル―５―メトキシ―１―（１―メ
トキシ―２―プロピル）―２―メチルインドー
ルの合成
５―メトキシ―１―（１―メトキシ―２―プロ
ピル）―２―メチルインドール0.85ｇ（3.2ミリ
モル）と安息香酸無水物1.47ｇ（6.4ミリモル）
と52％沃化水素酸0.2mlとを窒素気流下140℃に２
時間加熱撹拌した。実施例１と同様な後処理、単
離操作を行い、３―ベンゾイル―５―メトキシ―
（１―メトキシ―２―プロピル）―２―メチルイ
ンドールを0.46ｇ得た（収率43％）。Infrared absorption spectrum ν CHCl3 nax ; 2850, 1618, 1593, 1460, 1408, 1105,
1089, 898, 837 cm -1 Nuclear magnetic resonance spectrum δ CDCl3 TMS ; 1.62 (3H, d, J = 7Hz), 2.58 (3H,
s), 3.26 (3H, s), 3.8 (2H, m),
4.76 (1H, sextet, J=7Hz), 6.9―
7.8 (8H, m) Example 9 Synthesis of 3-benzoyl-5-methoxy-1-(1-methoxy-2-propyl)-2-methylindole 5-methoxy-1-(1-methoxy-2-propyl) -2-Methylindole 0.85g (3.2mmol) and benzoic anhydride 1.47g (6.4mmol)
and 0.2 ml of 52% hydriodic acid at 140℃ under a nitrogen stream.
The mixture was heated and stirred for hours. The same post-treatment and isolation operations as in Example 1 were carried out to obtain 3-benzoyl-5-methoxy-
0.46 g of (1-methoxy-2-propyl)-2-methylindole was obtained (yield 43%).
赤外線吸収スペクトル
νＣＨＣｌ３ ｎａｘ；
2960，2900，1610，1572，1506，1474，
1440，1410，1388，1275，1160，1144，
1106，1032，905cm-1
核磁気共鳴スペクトル
δＣＤＣｌ３ ＴＭＳ；
1.57（3H，ｄ，Ｊ＝７Hz），2.47（3H，
ｓ），3.20（3H，ｓ），3.59（3H，ｓ），
3.60（2H，ｍ），4.63（1H，sextet，Ｊ
＝７Hz），6.6―6.9（2H，ｍ），7.2―7.8
（6H，ｍ）。Infrared absorption spectrum ν CHCl3 nax ; 2960, 2900, 1610, 1572, 1506, 1474,
1440, 1410, 1388, 1275, 1160, 1144,
1106, 1032, 905 cm -1 Nuclear magnetic resonance spectrum δ CDCl3 TMS ; 1.57 (3H, d, J=7Hz), 2.47 (3H,
s), 3.20 (3H, s), 3.59 (3H, s),
3.60 (2H, m), 4.63 (1H, sextet, J
=7Hz), 6.6-6.9 (2H, m), 7.2-7.8
(6H, m).
Claims (1)
表わし、R6は水素原子又はメチル基を表わし、
R2，R3，R4，R5はそれぞれ独立に水素原子又は
低級アルコキシ基を表わし、R7は低級アルキル
基又は低級アルカノイル基を表わす。〕 で表わされる１―置換インドール誘導体に下記式
〔〕、 〔式中、はハロゲン原子で置換されているか
もしくは非置換のフエニル基もしくはチエニル基
を表わす。〕 で表わされるカルボン酸無水物を沃化水素酸の存
在下縮合せしめることを特徴とする下記式
〔〕、 〔式中、R1，R2，R3，R4，R5，R6，R7及び
は前記定義に同じ。〕 で表わされる３―アシル―１―置換インドール誘
導体の製造法。[Claims] 1. The following formula [] [In the formula, R 1 represents a hydrogen atom or a lower alkyl group, R 6 represents a hydrogen atom or a methyl group,
R 2 , R 3 , R 4 and R 5 each independently represent a hydrogen atom or a lower alkoxy group, and R 7 represents a lower alkyl group or a lower alkanoyl group. ] The 1-substituted indole derivative represented by the following formula [], [In the formula, represents a halogen atom-substituted or unsubstituted phenyl group or thienyl group. ] The following formula [], which is characterized by condensing a carboxylic acid anhydride represented by in the presence of hydriodic acid, [In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and are the same as defined above. ] A method for producing a 3-acyl-1-substituted indole derivative represented by:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP16031179A JPS5683472A (en) | 1979-12-12 | 1979-12-12 | Preparation of 3-acyl-1-substituted indole derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP16031179A JPS5683472A (en) | 1979-12-12 | 1979-12-12 | Preparation of 3-acyl-1-substituted indole derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5683472A JPS5683472A (en) | 1981-07-08 |
| JPS6230987B2 true JPS6230987B2 (en) | 1987-07-06 |
Family
ID=15712206
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP16031179A Granted JPS5683472A (en) | 1979-12-12 | 1979-12-12 | Preparation of 3-acyl-1-substituted indole derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS5683472A (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0647574B2 (en) * | 1984-08-11 | 1994-06-22 | 日本臓器製薬株式会社 | Novel acylindole derivative and platelet aggregation inhibitor containing the compound as an active ingredient |
| JPH0751560B2 (en) * | 1983-09-28 | 1995-06-05 | 日本臓器製薬株式会社 | Novel acylindole derivative and pharmaceutical composition containing the compound |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3259622A (en) * | 1962-09-07 | 1966-07-05 | Merck & Co Inc | 1-benzyl-3-indolyl-alpha-haloalkyl and alkylidenyl acetic acids |
| JPS524578B2 (en) * | 1971-10-07 | 1977-02-04 |
-
1979
- 1979-12-12 JP JP16031179A patent/JPS5683472A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5683472A (en) | 1981-07-08 |
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