JPH02223585A - Indole derivative - Google Patents
Indole derivativeInfo
- Publication number
- JPH02223585A JPH02223585A JP1111088A JP11108889A JPH02223585A JP H02223585 A JPH02223585 A JP H02223585A JP 1111088 A JP1111088 A JP 1111088A JP 11108889 A JP11108889 A JP 11108889A JP H02223585 A JPH02223585 A JP H02223585A
- Authority
- JP
- Japan
- Prior art keywords
- compound
- formula
- solvent
- organic solvent
- acid
- 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.)
- Pending
Links
- 150000002475 indoles Chemical class 0.000 title claims description 4
- 239000002253 acid Substances 0.000 claims abstract description 12
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 8
- 239000000126 substance Substances 0.000 claims abstract 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 9
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 6
- 150000001340 alkali metals Chemical group 0.000 claims description 4
- 229910052783 alkali metal Inorganic materials 0.000 claims description 3
- 229940054051 antipsychotic indole derivative Drugs 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 abstract description 47
- 239000003960 organic solvent Substances 0.000 abstract description 12
- -1 nitroacetic acid ester Chemical class 0.000 abstract description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 abstract description 6
- 239000012279 sodium borohydride Substances 0.000 abstract description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 abstract description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 abstract description 4
- 150000004820 halides Chemical class 0.000 abstract description 3
- VZAWCLCJGSBATP-UHFFFAOYSA-N 1-cycloundecyl-1,2-diazacycloundecane Chemical compound C1CCCCCCCCCC1N1NCCCCCCCCC1 VZAWCLCJGSBATP-UHFFFAOYSA-N 0.000 abstract description 2
- 230000004069 differentiation Effects 0.000 abstract description 2
- 125000005843 halogen group Chemical group 0.000 abstract description 2
- 230000001939 inductive effect Effects 0.000 abstract description 2
- 230000020411 cell activation Effects 0.000 abstract 1
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- 239000002904 solvent Substances 0.000 description 19
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- 239000002585 base Substances 0.000 description 11
- 239000000203 mixture Substances 0.000 description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 230000003213 activating effect Effects 0.000 description 4
- 238000009835 boiling Methods 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 4
- ZKQFHRVKCYFVCN-UHFFFAOYSA-N ethoxyethane;hexane Chemical compound CCOCC.CCCCCC ZKQFHRVKCYFVCN-UHFFFAOYSA-N 0.000 description 4
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 3
- 229910003446 platinum oxide Inorganic materials 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- QHKABHOOEWYVLI-UHFFFAOYSA-N 3-methyl-2-oxobutanoic acid Chemical compound CC(C)C(=O)C(O)=O QHKABHOOEWYVLI-UHFFFAOYSA-N 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical group [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 238000010531 catalytic reduction reaction Methods 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 235000011181 potassium carbonates Nutrition 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 229910052703 rhodium Inorganic materials 0.000 description 2
- 239000010948 rhodium Substances 0.000 description 2
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- JWKARZDECJVQDJ-UHFFFAOYSA-N 2-fluoro-1-methylpyridin-1-ium Chemical class C[N+]1=CC=CC=C1F JWKARZDECJVQDJ-UHFFFAOYSA-N 0.000 description 1
- IQUPABOKLQSFBK-UHFFFAOYSA-N 2-nitrophenol Chemical compound OC1=CC=CC=C1[N+]([O-])=O IQUPABOKLQSFBK-UHFFFAOYSA-N 0.000 description 1
- TYEYBOSBBBHJIV-UHFFFAOYSA-N 2-oxobutanoic acid Chemical compound CCC(=O)C(O)=O TYEYBOSBBBHJIV-UHFFFAOYSA-N 0.000 description 1
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 1
- WDYVUKGVKRZQNM-UHFFFAOYSA-N 6-phosphonohexylphosphonic acid Chemical compound OP(O)(=O)CCCCCCP(O)(O)=O WDYVUKGVKRZQNM-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- 102100028138 F-box/WD repeat-containing protein 7 Human genes 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 101001060231 Homo sapiens F-box/WD repeat-containing protein 7 Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical group [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 229940022663 acetate Drugs 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical compound [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- UTBIMNXEDGNJFE-UHFFFAOYSA-N collidine Natural products CC1=CC=C(C)C(C)=N1 UTBIMNXEDGNJFE-UHFFFAOYSA-N 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- WUESWDIHTKHGQA-UHFFFAOYSA-N cyclohexylurea Chemical compound NC(=O)NC1CCCCC1 WUESWDIHTKHGQA-UHFFFAOYSA-N 0.000 description 1
- SPWVRYZQLGQKGK-UHFFFAOYSA-N dichloromethane;hexane Chemical compound ClCCl.CCCCCC SPWVRYZQLGQKGK-UHFFFAOYSA-N 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229940050411 fumarate Drugs 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- UHXOPEVCNMQIAA-UHFFFAOYSA-N methyl 2-nitropropanoate Chemical compound COC(=O)C(C)[N+]([O-])=O UHXOPEVCNMQIAA-UHFFFAOYSA-N 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- NTWUAOHAQNZERF-UHFFFAOYSA-N n,n-dimethyl-1-(4-nitro-1h-indol-3-yl)methanamine Chemical compound C1=CC([N+]([O-])=O)=C2C(CN(C)C)=CNC2=C1 NTWUAOHAQNZERF-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 1
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 125000004436 sodium atom Chemical group 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- NASFKTWZWDYFER-UHFFFAOYSA-N sodium;hydrate Chemical compound O.[Na] NASFKTWZWDYFER-UHFFFAOYSA-N 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229940086735 succinate Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 1
- 229940095064 tartrate Drugs 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
- HFRXJVQOXRXOPP-UHFFFAOYSA-N thionyl bromide Chemical compound BrS(Br)=O HFRXJVQOXRXOPP-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- GRGCWBWNLSTIEN-UHFFFAOYSA-N trifluoromethanesulfonyl chloride Chemical compound FC(F)(F)S(Cl)(=O)=O GRGCWBWNLSTIEN-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】 産業上の利用分野 本発明はインドール誘導体及びその中間体に関する。[Detailed description of the invention] Industrial applications The present invention relates to indole derivatives and intermediates thereof.
従来の技術
本発明の化合物と同様の作用（細胞活性化作用）を有し
、構造類似の化合物としてテトラヘドロン耽≠！ゴ［第
４２巻、第５９０５ページ（１９８６年〉］に］インド
ラクタムーが報告されている。Prior Art Tetrahedron is a compound that has the same effect (cell activating effect) as the compound of the present invention and has a similar structure. Go [Vol. 42, Page 5905 (1986)] Indraktam is reported.
発明が解決しようとする課題
しかしながら、インドラクタム−■の作用は十分とは言
えない。Problems to be Solved by the Invention However, the action of indlactam-■ cannot be said to be sufficient.
本発明の目的は、優れた細胞活性化作用を有する化合物
及びその中間体を提供することにある。An object of the present invention is to provide a compound having an excellent cell activating effect and an intermediate thereof.
課題を解決するための手段
本発明者は、前記目的を達成するために鋭意研究を進め
た結果、式
（式中、Ｒ１及びＲ２は水素原子又は炭素原子数１〜４
のアルキル基であり、Ｒ３は水素原子、アルカリ金属原
子又は炭素原子数１〜４のアルキル基である。）で表さ
れる化合物が前記目的を達成することを見いだし本発明
を完成した。Means for Solving the Problems As a result of intensive research in order to achieve the above object, the present inventor found that the formula (wherein R1 and R2 are hydrogen atoms or carbon atoms 1 to 4)
R3 is a hydrogen atom, an alkali metal atom, or an alkyl group having 1 to 4 carbon atoms. ) The present invention was completed by discovering that a compound represented by the following formula achieves the above object.
すなわち、本発明は、式Ｉで表されるイントル誘導体及
びその酸付加塩であり、また式（式中、Ｒ１及びＲ２は
水素原子又は炭素原子数１〜４のアルキル基であり、Ｒ
３は水素原子、アルカリ金属原子又は炭素原子数１〜４
のアルキル基である。）で表される式Ｉの化合物の中間
体及びその酸付加塩である。That is, the present invention is an intole derivative represented by the formula I and an acid addition salt thereof, and also an intole derivative represented by the formula I (wherein R1 and R2 are a hydrogen atom or an alkyl group having 1 to 4 carbon atoms,
3 is a hydrogen atom, an alkali metal atom, or a carbon atom number of 1 to 4
is an alkyl group. ) and acid addition salts thereof.
本発明において、炭素原子数１〜４のアルキル基は直鎖
のものでも、側鎖を有しているものでもよい。これらを
例示すると、メチル基、エチル基、ｎ−プロピル基、イ
ソプロピル基、ｎ−ブチル基、ｔ−ブチル基などである
。In the present invention, the alkyl group having 1 to 4 carbon atoms may be linear or may have a side chain. Examples of these include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, and t-butyl group.
また、アルカリ金属原子とはリチウム原子、ナトリウム
原子、カリウム原子などである。Furthermore, the alkali metal atoms include lithium atoms, sodium atoms, potassium atoms, and the like.
式Ｉ及び式■の化合物の酸付加塩とは塩酸塩、硫酸塩、
酢酸塩、フマル酸塩、コハク酸塩、酒石酸塩、リンゴ酸
塩などの塩である。Acid addition salts of compounds of formula I and formula ■ include hydrochloride, sulfate,
Salts such as acetate, fumarate, succinate, tartrate, and malate.
式Ｉ及び■の化合物は、次のような工程を経て製造する
ことができる。Compounds of formulas I and (2) can be produced through the following steps.
Ｔ？２
（Ｉｎ）
［工程１］
（ＩＶ）
［工程２］
すなわち、まず、式■で表される化合物（式中、Ｘはハ
ロゲン原子などの任意の反応性基である。）と、式
％式％
（式中、ＲＭは前記と同意義である。）で表されるニト
ロ酢酸エステルを塩基存在下、有機溶媒中又は無溶媒で
反応させることにより式■で表される化合物を製造する
（工程ｌ）。ここで、塩基としてはトリエチルアミン、
ジイソプロピルエチルアミン、ピリジン、コリジン、水
酸化カリウム、水酸化ナトリウム、液酸カリウム、酢酸
ナトリウム、リチウムジイソプロピルアミドなどを使用
することができる。また、有機溶媒としてはテトラヒド
ロフラン、Ｎ、Ｎ−ジメチルホルムアミド、ジメチルス
ルホキシド、ジオキサン、エタノール、メタノール、ア
セトン、酢酸、酢酸エチル、ジクロロメタン、クロロベ
ンゼンなどを使用することができる。反応温度は室温か
ら溶媒の沸点である。T? 2 (In) [Step 1] (IV) [Step 2] That is, first, a compound represented by the formula ■ (wherein, X is any reactive group such as a halogen atom) and a compound represented by the formula % % (wherein RM has the same meaning as above) in the presence of a base, in an organic solvent or without a solvent to produce a compound represented by formula (1). l). Here, the base is triethylamine,
Diisopropylethylamine, pyridine, collidine, potassium hydroxide, sodium hydroxide, potassium hydroxide, sodium acetate, lithium diisopropylamide, and the like can be used. Further, as the organic solvent, tetrahydrofuran, N,N-dimethylformamide, dimethylsulfoxide, dioxane, ethanol, methanol, acetone, acetic acid, ethyl acetate, dichloromethane, chlorobenzene, etc. can be used. The reaction temperature is from room temperature to the boiling point of the solvent.
次いで、式■の化合物を１０％パラジウム−炭素、５％
パラジウム−炭素、酸化白金、ロジウムなどの触媒を用
いて接触還元反応を行うことにより式Ｖで表される化合
物とする（工程２）。溶媒としてはメタノール、エタノ
ール、酢酸エチルなどを使用することができる。反応温
度は０〜４０°Ｃであるが、好ましくは、０〜３０°Ｃ
である。Then, the compound of formula (■) was mixed with 10% palladium-carbon, 5%
A compound represented by formula V is obtained by performing a catalytic reduction reaction using a catalyst such as palladium-carbon, platinum oxide, or rhodium (Step 2). Methanol, ethanol, ethyl acetate, etc. can be used as a solvent. The reaction temperature is 0 to 40°C, preferably 0 to 30°C.
It is.
次に、式Ｖの化合物と、式
Ｒ”−Ｃｏ−ＣＯ２Ｈ
（式中、Ｒ２は前記と同意義である。）で表される２−
オキソアルカン酸を反応させてイミド化合物とし、これ
に直ちに還元剤を加えることにより式■で表される化合
物とする（工程３）。２−オキソアルカン酸としては、
２−オキソイソ酪酸、２−オキソ酪酸、２−オキソイソ
吉草酸、２−オキツカブロン酸、ピルビン酸などであり
、還元剤としては水素化ホウ素ナトリウム、水素化シア
ン化ホウ素ナトリウムなどを用いることができる。Next, a compound of formula V and a 2-
The oxoalkanoic acid is reacted to form an imide compound, and a reducing agent is immediately added to this to form a compound represented by formula (3) (Step 3). As 2-oxoalkanoic acid,
These include 2-oxoisobutyric acid, 2-oxobutyric acid, 2-oxoisovaleric acid, 2-oxocabronic acid, pyruvic acid, etc., and sodium borohydride, sodium cyanoborohydride, etc. can be used as the reducing agent.
また、溶媒としてはＮ、Ｎ−ジメチルホルムアミド、テ
トラヒドロフラン、ジオキサン、酢酸エチル、ジクロロ
メタンなどのアミンと反応しない溶媒を用いることがで
きる。反応温度はＯｏＣから溶媒の沸点までである。Further, as the solvent, a solvent that does not react with the amine, such as N,N-dimethylformamide, tetrahydrofuran, dioxane, ethyl acetate, and dichloromethane, can be used. The reaction temperature is from OoC to the boiling point of the solvent.
この式■の化合物を、Ｎ−ヒドロキシコハク酸イミド、
Ｎ−ヒドロキシスクシンイミド、Ｎ−メチル−２−フル
オロピリジニウム塩又はニトロフェノールなどの活性化
剤を用いてエステル体とする。溶媒はアセトニトリルな
どを用いることができる。これを１０％パラジウム−炭
素、５％パラジウム−炭素、酸化白金、ロジウムなどの
触媒を用いて接触還元反応を行うことにより、式■の化
合物（式■においてＲ１が水素原子である化合物）を得
る（工程４）。溶媒としては、工程２において例示した
溶媒と同しものを使用することができる。This compound of formula (■) is converted into N-hydroxysuccinimide,
An ester is formed using an activator such as N-hydroxysuccinimide, N-methyl-2-fluoropyridinium salt or nitrophenol. Acetonitrile or the like can be used as the solvent. By carrying out a catalytic reduction reaction using a catalyst such as 10% palladium-carbon, 5% palladium-carbon, platinum oxide, or rhodium, a compound of formula (■) (a compound in which R1 is a hydrogen atom in formula (■)) is obtained. (Step 4). As the solvent, the same solvent as exemplified in step 2 can be used.
式■において、Ｒ′が炭素原子数１〜４のアルキル基で
ある化合物は、前記化合物を塩基存在下、ジアルキル硫
酸、アルキルハライド、トルエンスルボン酸アルキルな
どのアルキル化剤と厚比させて得る（工程４゛）。ここ
で、塩基としては重炭酸ナトリウム、重炭酸カリウム、
炭酸カリウム、水素化ナトリウム、ナトリウムエトキシ
ド、ナトリウムメトキシドなどを用いることができる。In formula (2), a compound in which R' is an alkyl group having 1 to 4 carbon atoms can be obtained by mixing the above compound with an alkylating agent such as dialkyl sulfuric acid, alkyl halide, or alkyl toluene sulfonate in the presence of a base. (Step 4). Here, the bases include sodium bicarbonate, potassium bicarbonate,
Potassium carbonate, sodium hydride, sodium ethoxide, sodium methoxide, etc. can be used.
溶媒としては、メタノール、エタノール、ジメチルスル
ホキシド、テトラヒドロフラン、ジオキサンなどを用い
ることができる。反応温度は０°Ｃから溶媒の沸点まで
である。As the solvent, methanol, ethanol, dimethyl sulfoxide, tetrahydrofuran, dioxane, etc. can be used. The reaction temperature is from 0°C to the boiling point of the solvent.
上記の方法で得られた式■の化合物は立体異性体の混合
物であるが、それぞれの化合物は塩基存在下、異性化す
ることができる。ここで、塩基としては、重炭酸ナトリ
ウム、炭酸カリウム、トリエチルアミン、ピリジンなど
を用いることができる。The compound of formula (1) obtained by the above method is a mixture of stereoisomers, and each compound can be isomerized in the presence of a base. Here, as the base, sodium bicarbonate, potassium carbonate, triethylamine, pyridine, etc. can be used.
このようにして得られた式■の化合物は、以下のように
して式■の化合物とする。The compound of formula (1) thus obtained is converted into a compound of formula (2) as follows.
まず、式■の化合物を有機溶媒中、水素化ホウ素ナトリ
、ウム、水素化リチウムアルミニウム、水素化ジイソブ
チルアルミニウムなどと反応させて式■の化合物とする
（工程５）。First, the compound of formula (1) is reacted with sodium borohydride, aluminum hydride, lithium aluminum hydride, diisobutylaluminum hydride, etc. in an organic solvent to form a compound of formula (1) (step 5).
有機溶媒としてはエーテル、テトラヒドロフラン、ジオ
キサンなどを用いることができる。Ether, tetrahydrofuran, dioxane, etc. can be used as the organic solvent.
次いで、式■の化合物を塩基の存在下、有機溶媒中で酸
ハロゲン化物と反応きせることにより、式■（式中、Ｙ
は塩素原子、臭素原子、トリプルオロメタンスルホニル
オキシ基、ｐ−トルエンスルホニルオキシ基又はメタン
スルホキシ基のいずれかを示す。）で表される化合物と
する（工程６）。Next, by reacting the compound of formula (1) with an acid halide in an organic solvent in the presence of a base, the compound of formula (2) (in which Y
represents a chlorine atom, a bromine atom, a triple olomethanesulfonyloxy group, a p-toluenesulfonyloxy group, or a methanesulfoxy group. ) (Step 6).
ここで、酸ハロゲン化物とはチオニルクロリド、チオニ
ルプロミド、トリフルオロメタンスルポン酸りロリド、
ｐ−トルエンスルポン酸クロリド又はメタンスルホン酸
クロリドである。Here, acid halides include thionyl chloride, thionyl bromide, trifluoromethanesulfonic acid chloride,
p-toluenesulfonic acid chloride or methanesulfonic acid chloride.
塩基としてはピリジン、トリエチルアミンであり、また
、有機溶媒としてはトルエン、ヘキサン、クロロホルム
、ジクロロメタンなどを用いることができる。なお、前
記塩基は有機溶媒を兼ねることができる。As the base, pyridine or triethylamine can be used, and as the organic solvent, toluene, hexane, chloroform, dichloromethane, etc. can be used. Note that the base can also serve as an organic solvent.
反応温度は０°Ｃ〜溶媒の沸点である。The reaction temperature is 0°C to the boiling point of the solvent.
最後に、上記で得た化合物を塩基の存在下、有機溶媒中
で閉環反応を行い、式Ｉの化合物を得る（工程７）。Finally, the compound obtained above is subjected to a ring-closing reaction in an organic solvent in the presence of a base to obtain a compound of formula I (Step 7).
ここで、塩基としてはジアザビシクロウンデカン、ピリ
ジン、トリエチルアミン、ジイソプロピルエチルアミン
などであり、有機溶媒としてはメタノール、エタノール
、プロパツール、ブタノール、ベンゼン、トルエン、ク
ロロホルム、Ｎ、Ｎジメチルホルムアミドなどを用いる
ことができる。Here, the base may be diazabicycloundecane, pyridine, triethylamine, diisopropylethylamine, etc., and the organic solvent may be methanol, ethanol, propatool, butanol, benzene, toluene, chloroform, N,N dimethylformamide, etc. can.
発明の効果
本発明の式Ｉの化合物は、細胞活性化作用及び分化誘導
作用を有する。また、本発明の式■の化合物は細胞活性
化作用を有し、また、式Ｉの化合物を容易かつ短工程で
製造できる中間体として有用である。Effects of the Invention The compound of formula I of the present invention has a cell activating effect and a differentiation inducing effect. In addition, the compound of formula (1) of the present invention has a cell activating effect and is useful as an intermediate that allows the compound of formula I to be produced easily and in a short process.
実施例
以下、本発明の実施例を挙げて、本発明を更に具体的に
説明する。EXAMPLES Hereinafter, the present invention will be explained in more detail with reference to Examples.
実施例１
（１）４−ニトロインドール−３−メタノール１．．０
２ ｇをピリジン５ｍＩ！、に溶かし、無水酢酸０．７
５ｍＪ！を加え、室温で２時間放置した後、反応液を濃
縮乾固した。残渣にα−ニトロ酢酸メチル０．９５ ｇ
を加え、Ｎ、Ｎ−ジメチルホルムアミド３Ｍに溶解し、
更にトリエチルアミン１．１ｍｇを加えた後、６００Ｃ
で１時間加熱した。Example 1 (1) 4-nitroindole-3-methanol 1. ．． 0
2 g to 5 mI of pyridine! , dissolved in acetic anhydride 0.7
5mJ! was added, and after standing at room temperature for 2 hours, the reaction solution was concentrated to dryness. 0.95 g of methyl α-nitroacetate in the residue
and dissolved in 3M N,N-dimethylformamide,
After further adding 1.1 mg of triethylamine, 600C
It was heated for 1 hour.
反応液をＩＮ塩酸中に投入し、ジクロロメタンで４回抽
出した。抽出液を無水硫酸ナトリウムで乾燥した後、濃
縮した。残渣をエーテルで再結晶し、２−ニトロ−３−
（４−ニトロ−３−インドリル）プロピオン酸メチル１
．３９ ｇを得た。The reaction solution was poured into IN hydrochloric acid and extracted four times with dichloromethane. The extract was dried over anhydrous sodium sulfate and then concentrated. The residue was recrystallized from ether to give 2-nitro-3-
Methyl (4-nitro-3-indolyl)propionate 1
．． 39 g was obtained.
（１） ’ （（１）の別法）４−ニトロ−３−ジメチ
ルアミノメチルインドール１３．７ ｇをクロロベンゼ
ン２４６ｄ及びＮ、Ｎ−ジメチルホルムアミド２８ｄの
混合溶媒に溶解し、α−ニトロ酢酸メチル１１．１ ｇ
を加え、更にトリエチルアミン４．３ｄを加え、１００
℃で４５分間加熱した。(1) ' (Alternative method for (1)) 13.7 g of 4-nitro-3-dimethylaminomethylindole was dissolved in a mixed solvent of 246 d of chlorobenzene and 28 d of N,N-dimethylformamide, and 11 g of methyl α-nitroacetate was dissolved. .1 g
was added, and 4.3 d of triethylamine was added, and 100
Heat at ℃ for 45 minutes.
反応液をＩＮ塩酸中に投入して有機層を分離し、更に水
層より酢酸エチルで４回抽出した。有機層を集め、無水
硫酸ナトリウムで乾燥した後、濃縮した。残渣をエーテ
ルーヘキザンで再結晶し、２−ニトロ−３−（４−ニト
ロ−３−インドノル）プロピオン酸メチル１４．７ ｇ
を得た。The reaction solution was poured into IN hydrochloric acid to separate the organic layer, and the aqueous layer was extracted four times with ethyl acetate. The organic layers were collected, dried over anhydrous sodium sulfate, and then concentrated. The residue was recrystallized from ether-hexane to give 14.7 g of methyl 2-nitro-3-(4-nitro-3-indonol)propionate.
I got it.
（り上記で得た化合物６．Ｏｇ及び１０％パラジウム−
炭素１．２ｇにメタノール６０ｒｆｄｌ及び酢酸エチル
１２０ｄを加え、水素ガス置換後、室温で７時間撹拌し
た。触媒を炉別後、炉液を濃縮、エーテル−ヘキサンで
再結晶して３−く４−アミノ−２−インドノル）−２−
ニトロプロピオン酸メチル４．９ｇを得た。(Compound 6 obtained above.Og and 10% palladium-
60 rfdl of methanol and 120 d of ethyl acetate were added to 1.2 g of carbon, and after replacing the mixture with hydrogen gas, the mixture was stirred at room temperature for 7 hours. After the catalyst was separated from the furnace, the furnace liquid was concentrated and recrystallized from ether-hexane to give 3-(4-amino-2-indonol)-2-
4.9 g of methyl nitropropionate was obtained.
（３）」二記で得た化合物２．０ｇをＮ、Ｎ−ジメチル
ホルムアミド２０ｍｇに溶解し、窒素気流下、２−オキ
ソイソ吉草酸１．３２ｇを加え、室温で１０分間撹拌し
た。反応液に、水素化シアン化ホウ素ナトリウム０．７
２ｇを５分間で加え、更に室温で１０分間撹拌した。(3) 2.0 g of the compound obtained in section 2 was dissolved in 20 mg of N,N-dimethylformamide, 1.32 g of 2-oxoisovaleric acid was added under a nitrogen stream, and the mixture was stirred at room temperature for 10 minutes. Add 0.7 sodium borohydrocyanide to the reaction solution.
2 g was added over 5 minutes, and the mixture was further stirred at room temperature for 10 minutes.
反応液を飽和食塩水中に投入し、更にＩＮ硫酸水素カリ
ウムでｐＨ２〜３に調整しながらジクロ０メタンで４回
抽出した。抽出液を、無水硫酸ナトリウムで乾燥した後
、濃縮した。残渣をシリカゲルカラムクロマトグラフィ
ー［溶媒：酢酸エチル−ヘキサン（１：１）溶液］で粗
精製した。The reaction solution was poured into saturated brine and extracted four times with dichloromethane while adjusting the pH to 2 to 3 with IN potassium hydrogen sulfate. The extract was dried over anhydrous sodium sulfate and then concentrated. The residue was roughly purified by silica gel column chromatography [solvent: ethyl acetate-hexane (1:1) solution].
（４）得られた粗精製物２．０５ ｇをアセトニトリル
４１−に溶解し、更に、Ｎ−ヒドロキシスクシンイミド
１、３５ ｇを溶解した後、室温で５分間かけてジシク
ロへキシルカルボジイミド１．３１ｇを加えた。室温で
更に１時間撹拌後、精製したＮ、Ｎ’−シクロへキシル
ウレアを炉別し、炉液を濃縮後、シリカゲルカラムクロ
マトグラフィー［溶媒：酢酸エチルヘキサン（１：２）
溶液コで精製し、黄色アモルファス２．３７ ｇを得た
。(4) After dissolving 2.05 g of the obtained crude product in 41-mL acetonitrile and further dissolving 1.35 g of N-hydroxysuccinimide, 1.31 g of dicyclohexylcarbodiimide was dissolved at room temperature for 5 minutes. added. After stirring for another 1 hour at room temperature, the purified N,N'-cyclohexylurea was separated in a furnace, the furnace liquid was concentrated, and then subjected to silica gel column chromatography [solvent: ethyl acetate hexane (1:2)]
Purification was carried out using a solution solution to obtain 2.37 g of yellow amorphous.
この化合物２．３６ ｇと酸化白金１．２０ｇの混合物
にメタノール３Ｍを加え、水素置換後、室温で３時間半
撹拌した。3M methanol was added to a mixture of 2.36 g of this compound and 1.20 g of platinum oxide, and after hydrogen substitution, the mixture was stirred at room temperature for 3.5 hours.
反応後、触媒を炉別し、炉液を濃縮後、シリカゲルカラ
ムクロマトグラフィー（溶媒＝１％メタノール／ジクロ
ロメタン）で精製した。これをジクロロメタン−ヘキサ
ンで再結晶し、式■の化合物［Ｒ１＝水素原子、Ｒ２−
イソプロピル基 Ｒ８−メチル基、（±〉体コの白色粉
末６７．４ｍｇを得た。After the reaction, the catalyst was separated from the furnace, the furnace liquid was concentrated, and then purified by silica gel column chromatography (solvent = 1% methanol/dichloromethane). This was recrystallized from dichloromethane-hexane to form a compound of formula (1) [R1=hydrogen atom, R2-
67.4 mg of white powder of isopropyl group R8-methyl group (±> form) was obtained.
ｍ、ｐ、 ２４９°Ｃ
（４）゛上記で得た化合物２７．９ｍｇ及び炭酸水素す
） ＩＪウム０．５６ ｇをメタノール２．８−に懸濁
し、硫酸ジメチル０．５−を加え、窒素気流下、４０″
Ｃで２時間半撹拌した。m, p, 249°C (4) 27.9 mg of the compound obtained above and 0.56 g of hydrogen carbonate were suspended in 2.8 g of methanol, 0.5 g of dimethyl sulfate was added, and nitrogen was added. Under air flow, 40″
The mixture was stirred at C for 2.5 hours.
反応液を生理食塩水中に投入し、ジクロロメタンで３回
抽出した。抽出液を、無水硫酸ナトリウムで乾燥後、濃
縮し、ただちにシリカゲル薄層クロマトグラフィー（溶
媒ニジクロロメタン）で分画し、式■の化合物（ＲＩ−
メチル基、Ｒ２−イソプロピル基、Ｒ８＝メチル基）の
（＋）体１０．８ｍｇ及び（−）体９．７ｍｇを得た。The reaction solution was poured into physiological saline and extracted three times with dichloromethane. The extract was dried over anhydrous sodium sulfate, concentrated, and immediately fractionated by silica gel thin layer chromatography (solvent dichloromethane) to obtain a compound of formula (RI-
10.8 mg of (+) form and 9.7 mg of (-) form of methyl group, R2-isopropyl group, R8=methyl group) were obtained.
（＋）体
’ ＨＮ Ｍ Ｒ（２００Ｍｚ 、 ＣＤＣ４）＆ ｐ
ｌ）ｍｏ、９４（３Ｈ，ｄ、Ｊ＝７．５Ｈｚ）、１．２
３（３Ｈ，ｄ、Ｊ＝７．５Ｈｚ＞。(+) body' HN MR (200Mz, CDC4)&p
l) mo, 94 (3H, d, J=7.5Hz), 1.2
3 (3H, d, J=7.5Hz>.
２、３６（ＬＨ，ｍ＞ 、 ２．７３（３Ｈ，ｓ） 。2, 36 (LH, m>, 2.73 (3H, s).
３、０４（ＬＨ，ｄ、Ｊ−９Ｈｚ） 。3, 04 (LH, d, J-9Hz).
３、１３（ＩＨ，ｄｄ、 Ｊ＝１５Ｈｚ、 ２Ｈｚ）
。3, 13 (IH, dd, J=15Hz, 2Hz)
.
３、２５（ＬＨ，ｄｄ、 Ｊ−１５Ｈｚ、 ５Ｈｚ）
、 ３．６９（３Ｈ，ｓ＞ 。3, 25 (LH, dd, J-15Hz, 5Hz)
, 3.69 (3H,s>.
５、１２（ＩＨ，ｂｒ、 ｄ、 Ｊ＝１０１（ｚ） 。5, 12 (IH, br, d, J=101(z).
５、２５（ＬＨ，ｂｒ、 ｄ、 Ｊ＝１０Ｈｚ） 。5, 25 (LH, br, d, J=10Hz).
６．９０〜７．３０（４Ｈ，ａｒｏｍ） 、 ８．１９
（ＩＨ，ｂｒ、 ５）（−）体
ＩＨ
Ｎ Ｍ Ｒ（２００Ｍｚ 、 ＣＤＣｌｌ５ ） Ｓ
ｐｐｍ０、６９（３Ｈ，ｄ、 Ｊ＝７．５Ｈｚ）
、 ０．７５（３Ｈ，ｄ、 Ｊ＝７．５Ｈｚ）。6.90-7.30 (4H, arom), 8.19
(IH, br, 5) (-) body IH NMR (200Mz, CDCll5) S
ppm0, 69 (3H, d, J=7.5Hz)
, 0.75 (3H, d, J=7.5Hz).
２、６５（ＩＨ，ｍ） 、 ３．１３（３Ｈ，ｓ） 。2, 65 (IH, m), 3.13 (3H, s).
３、３０（ＩＨ，ｄｄ、 Ｊ＝１５Ｈｚ、 ４Ｈｚ）
。3, 30 (IH, dd, J=15Hz, 4Hz)
.
３．４８（ＬＨ，ｄｄ、Ｊ＝１５Ｈｚ、２Ｈｚ）。3.48 (LH, dd, J=15Hz, 2Hz).
３．７９（ＬＨ，ｄ、Ｊ＝１０Ｈｚ） ３．９３（３Ｈ
，ｓ） 。3.79 (LH, d, J = 10Hz) 3.93 (3H
,s).
４．４９（ＩＨ，ｍ）、 ６．６６（ＬＨ，ｂｒ、ｄ
、Ｊ＝９Ｈｚ） 。4.49 (IH, m), 6.66 (LH, br, d
, J=9Hz).
６．７８（ＬＨ，ｄ、Ｊ＝８Ｈｚ）、６．９７（ＬＨ，
ｄ、Ｊ＝８Ｈｚ＞。6.78 (LH, d, J=8Hz), 6.97 (LH,
d, J=8Hz>.
７、０３（ＩＩ（、ｂｒ、 ｓ） 、 ７．０８（ＩＨ
，ｔ、Ｊ＝８Ｈｚ＞ 。7,03(II(,br,s), 7.08(IH
, t, J=8Hz>.
８、０３（ＩＨ，ｂｒ、 ｓ）
実施例２
（１）実施例１で製造した化合物のラセミ体７８５．６
ｍｇを、エタノール３９．３１ＴＬｅに溶解し、水素化
ホウ素ナトリウム０．８０ ｇを加え、室温で４時間撹
拌した。8,03 (IH, br, s) Example 2 (1) Racemic compound 785.6 of the compound produced in Example 1
mg was dissolved in 39.31 TLe of ethanol, 0.80 g of sodium borohydride was added, and the mixture was stirred at room temperature for 4 hours.
反応液を、Ｒ酸水素すトリウム水溶液中に投入し、ジク
ロロメタンで６回抽出した。抽出液を、無水硫酸ナトリ
ウムで乾燥後、濃縮し、シリカゲルカラムクロマトグラ
フィー（溶媒：５％メタノール／ジクロロメタン）で精
製した。残渣をエーテル−ヘキサンで再結晶し、式■の
化合物（Ｒ１＝メチル基、Ｒ２＝イソプロピル基）の白
色粉末７７０．２ｍｇを得た。The reaction solution was poured into an aqueous solution of sodium hydrogen oxide and extracted six times with dichloromethane. The extract was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (solvent: 5% methanol/dichloromethane). The residue was recrystallized from ether-hexane to obtain 770.2 mg of a white powder of the compound of formula (1) (R1 = methyl group, R2 = isopropyl group).
（２）上記で得た化合物６３．５ｍｇを、ピリジン３．
２ｄに溶かし、メタンスルホニルクロリド２４．５４を
滴下後、１時間撹拌した。反応液を飽和重曹水に投入し
、これをジクロロメタン１０ｍＥで４回抽出した。(2) 63.5 mg of the compound obtained above was mixed with 3.5 mg of pyridine.
After adding 24.54 g of methanesulfonyl chloride dropwise, the mixture was stirred for 1 hour. The reaction solution was poured into saturated aqueous sodium bicarbonate solution, and extracted four times with 10 mE of dichloromethane.
有機層を合わせ、無水硫酸すｌ・リウムで乾燥した後、
減圧下濃縮した。濃縮液をシリカゲル薄層クロマトグラ
フィー（展開溶媒；酢酸エチル：ヘキサン−１：１）に
付し、紫外部吸収のある部分をかきとり、酢酸エチルで
抽出、濃縮し、化合物■（Ｒ＋ ＝メチル基、Ｒ２−イ
ソプロピル基） ７９．０＋Ｂｇを得た。After combining the organic layers and drying with anhydrous sulfur and lithium,
It was concentrated under reduced pressure. The concentrated solution was subjected to silica gel thin layer chromatography (developing solvent: ethyl acetate:hexane-1:1), the part with ultraviolet absorption was scraped off, extracted with ethyl acetate, concentrated, and the compound (R+ = methyl group, R2-isopropyl group) 79.0+Bg was obtained.
’Ｈ−ＮＭＲ（ＣＤＣｌｌ５） ＆ｐｐｍＮＭＲは配座
異性体の混合物（１： １）として観測される。'H-NMR (CDCll5) &ppm NMR is observed as a mixture of conformers (1:1).
０．６４．０．９４．０．９４．１．２６（３Ｈ，ｄ、
Ｊ＝８Ｈｚ）ｘ２ 。0.64.0.94.0.94.1.26 (3H, d,
J=8Hz)x2.
２．４１．２．６６（ＩＨ，ｍ） 、 ２．７５．２．
９３（３Ｈ，ｓ） 。2.41.2.66 (IH, m), 2.75.2.
93 (3H, s).
３．０４．３．０８（３Ｈ，ｓ） 、 ６．０８（ＩＨ
，ｂｒ、ｓ） 。3.04.3.08 (3H, s), 6.08 (IH
,br,s).
６、５６（ＬＨ，ｄ、 Ｊ＝８１（ｚ） 。6, 56 (LH, d, J = 81 (z).
８．０６．８．３４（ＩＨ，ｂｒ、 ５）（３）上記で
得た化合物７９ｍｇをメタノール４ｄに溶かし、トリエ
チルアミン０．１ｄを加え、６０℃で１時間半加熱した
後、反応液を飽和重曹水に投入した。これをジクロロメ
タンＬＭで５回抽出後、有機層を合わせ、無水硫酸ナト
リウムで乾燥した後、減圧下濃縮した。残渣をシリカゲ
ル薄層クロマトグラフィー（展開溶媒；酢酸エチル：ヘ
キサン＝１：１）に付し、紫外部吸収のある部分をかき
とり、酢酸エチルで抽出、濃縮後、エーテル−ヘキサン
より再結晶して化合物Ｉ （Ｒ’＝メチル基、Ｒ２−イ
ソプロピル基） ４４ｍｇを得た。8.06.8.34 (IH, br, 5) (3) Dissolve 79 mg of the compound obtained above in 4 d of methanol, add 0.1 d of triethylamine, heat at 60°C for 1.5 hours, and then saturate the reaction solution. It was added to baking soda solution. After extracting this with dichloromethane LM five times, the organic layers were combined, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel thin layer chromatography (developing solvent: ethyl acetate:hexane = 1:1), the part with ultraviolet absorption was scraped off, extracted with ethyl acetate, concentrated, and recrystallized from ether-hexane to obtain the compound. 44 mg of I (R'=methyl group, R2-isopropyl group) was obtained.
ｍ 、 ｐ 、 ２２１〜２２６°Ｃ
’Ｈ−ＮＭ Ｒ（ＣＤＣＩ Ｓｐｐｍ１．００（３Ｈ
，ｄ、Ｊ＝８Ｈｚ）、 １．２３（３Ｈ，ｄ、Ｊ＝８
Ｈｚ＞。m, p, 221-226 °C'H-NMR (CDCI Sppm 1.00 (3H
, d, J=8Hz), 1.23(3H, d, J=8
Hz＞.
２、４０（ＩＨ，ｍ） 、 ２．８８（３Ｈ，ｓ） 。2, 40 (IH, m), 2.88 (3H, s).
２、９２（２Ｌｄ、Ｊ＝４Ｈｚ） 、 ３．２０（１）
１．ｄ、Ｊ＝１２Ｈｚ＞３、７０（２Ｈ，ｄ、Ｊ＝４／
Ｈｚ） 、 ４．５０（ＩＨ，ｍ） 。2, 92 (2Ld, J=4Hz), 3.20 (1)
1. d, J=12Hz>3,70 (2H, d, J=4/
Hz), 4.50 (IH, m).
Claims (2)
１〜４のアルキル基である。）で表されるインドール誘
導体及びその酸付加塩。(1) Indole derivatives represented by the formula ▲ Numerical formulas, chemical formulas, tables etc. Acid addition salts.
〜４のアルキル基であり、Ｒ＾３は水素原子、アルカリ
金属原子又は炭素原子数１〜４のアルキル基である。）
で表されるインドール誘導体及びその酸付加塩。(2) Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1 and R^2 are hydrogen atoms or 1 carbon atom
~4 alkyl group, and R^3 is a hydrogen atom, an alkali metal atom, or an alkyl group having 1 to 4 carbon atoms. )
Indole derivatives and acid addition salts thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63-288685 | 1988-11-15 | ||
| JP28868588 | 1988-11-15 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH02223585A true JPH02223585A (en) | 1990-09-05 |
Family
ID=17733360
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1111088A Pending JPH02223585A (en) | 1988-11-15 | 1989-04-28 | Indole derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH02223585A (en) |
-
1989
- 1989-04-28 JP JP1111088A patent/JPH02223585A/en active Pending
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