JPS6328917B2 - - Google Patents
Info
- Publication number
- JPS6328917B2 JPS6328917B2 JP10305580A JP10305580A JPS6328917B2 JP S6328917 B2 JPS6328917 B2 JP S6328917B2 JP 10305580 A JP10305580 A JP 10305580A JP 10305580 A JP10305580 A JP 10305580A JP S6328917 B2 JPS6328917 B2 JP S6328917B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- formula
- tetrahydro
- reaction
- carboline
- 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
- -1 Tetrahydro-β-carboline compound Chemical class 0.000 claims description 48
- 238000006243 chemical reaction Methods 0.000 claims description 44
- APJYDQYYACXCRM-UHFFFAOYSA-N Tryptamine Natural products C1=CC=C2C(CCN)=CNC2=C1 APJYDQYYACXCRM-UHFFFAOYSA-N 0.000 claims description 24
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- DZQLQEYLEYWJIB-UHFFFAOYSA-N 4-aminobutanal Chemical compound NCCCC=O DZQLQEYLEYWJIB-UHFFFAOYSA-N 0.000 claims description 11
- ZXLDQJLIBNPEFJ-UHFFFAOYSA-N tetrahydro-beta-carboline Natural products C1CNC(C)C2=C1C1=CC=C(OC)C=C1N2 ZXLDQJLIBNPEFJ-UHFFFAOYSA-N 0.000 claims description 11
- 238000004519 manufacturing process Methods 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- 230000002378 acidificating effect Effects 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- 125000002252 acyl group Chemical group 0.000 claims description 3
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 3
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 2
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 17
- 239000000243 solution Substances 0.000 description 17
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- 238000000034 method Methods 0.000 description 11
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 150000001875 compounds Chemical class 0.000 description 9
- CFTOTSJVQRFXOF-UHFFFAOYSA-N 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole Chemical class N1C2=CC=CC=C2C2=C1CNCC2 CFTOTSJVQRFXOF-UHFFFAOYSA-N 0.000 description 8
- 239000013078 crystal Substances 0.000 description 7
- 238000010438 heat treatment Methods 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- ANOPCGQVRXJHHD-UHFFFAOYSA-N 3-[3-(3-aminopropyl)-2,4,8,10-tetraoxaspiro[5.5]undecan-9-yl]propan-1-amine Chemical compound C1OC(CCCN)OCC21COC(CCCN)OC2 ANOPCGQVRXJHHD-UHFFFAOYSA-N 0.000 description 5
- 150000001241 acetals Chemical class 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 4
- RSJKGSCJYJTIGS-UHFFFAOYSA-N undecane Chemical compound CCCCCCCCCCC RSJKGSCJYJTIGS-UHFFFAOYSA-N 0.000 description 4
- 150000001298 alcohols Chemical class 0.000 description 3
- KDFBGNBTTMPNIG-UHFFFAOYSA-N hydron;2-(1h-indol-3-yl)ethanamine;chloride Chemical compound Cl.C1=CC=C2C(CCN)=CNC2=C1 KDFBGNBTTMPNIG-UHFFFAOYSA-N 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 229940067157 phenylhydrazine Drugs 0.000 description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- TYVAXMOICMBSMT-UHFFFAOYSA-N 4,4-dimethoxybutan-1-amine Chemical compound COC(OC)CCCN TYVAXMOICMBSMT-UHFFFAOYSA-N 0.000 description 2
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- ZERVJPYNQLONEK-UHFFFAOYSA-N canthin-6-one Chemical compound C12=CC=CC=C2N2C(=O)C=CC3=NC=CC1=C32 ZERVJPYNQLONEK-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- DZGCGKFAPXFTNM-UHFFFAOYSA-N ethanol;hydron;chloride Chemical compound Cl.CCO DZGCGKFAPXFTNM-UHFFFAOYSA-N 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- WXZMFSXDPGVJKK-UHFFFAOYSA-N pentaerythritol Chemical compound OCC(CO)(CO)CO WXZMFSXDPGVJKK-UHFFFAOYSA-N 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- RXPRRQLKFXBCSJ-GIVPXCGWSA-N vincamine Chemical compound C1=CC=C2C(CCN3CCC4)=C5[C@@H]3[C@]4(CC)C[C@](O)(C(=O)OC)N5C2=C1 RXPRRQLKFXBCSJ-GIVPXCGWSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- QCUCAQZMPVIYAJ-UHFFFAOYSA-N 2-(4-methyl-1h-indol-3-yl)ethanamine Chemical compound CC1=CC=CC2=C1C(CCN)=CN2 QCUCAQZMPVIYAJ-UHFFFAOYSA-N 0.000 description 1
- CGHUQJRRADEHTQ-UHFFFAOYSA-N 2-(5-bromo-1h-indol-3-yl)ethanamine Chemical compound C1=C(Br)C=C2C(CCN)=CNC2=C1 CGHUQJRRADEHTQ-UHFFFAOYSA-N 0.000 description 1
- FVQKQPVVCKOWLM-UHFFFAOYSA-N 2-(5-chloro-1h-indol-3-yl)ethanamine Chemical compound C1=C(Cl)C=C2C(CCN)=CNC2=C1 FVQKQPVVCKOWLM-UHFFFAOYSA-N 0.000 description 1
- RBHDFGBPJGEYCK-UHFFFAOYSA-N 2-(5-methyl-1h-indol-3-yl)ethylazanium;chloride Chemical compound Cl.CC1=CC=C2NC=C(CCN)C2=C1 RBHDFGBPJGEYCK-UHFFFAOYSA-N 0.000 description 1
- IUWVJCIEWSQGHH-UHFFFAOYSA-N 2-(5-phenylmethoxy-1h-indol-3-yl)ethylazanium;chloride Chemical compound Cl.C1=C2C(CCN)=CNC2=CC=C1OCC1=CC=CC=C1 IUWVJCIEWSQGHH-UHFFFAOYSA-N 0.000 description 1
- GEVXFHYJXGYXJP-UHFFFAOYSA-N 2-(6-methyl-1H-indol-3-yl)ethanamine Chemical compound CC1=CC=C2C(CCN)=CNC2=C1 GEVXFHYJXGYXJP-UHFFFAOYSA-N 0.000 description 1
- QKRNGBURTLCWBQ-UHFFFAOYSA-N 2-(7-chloro-1h-indol-3-yl)ethanamine Chemical compound C1=CC=C2C(CCN)=CNC2=C1Cl QKRNGBURTLCWBQ-UHFFFAOYSA-N 0.000 description 1
- SGGBZKQTWMKXHD-UHFFFAOYSA-N 2-(7-methyl-1h-indol-3-yl)ethanamine Chemical compound CC1=CC=CC2=C1NC=C2CCN SGGBZKQTWMKXHD-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- FGEPRNXUNITOCW-UHFFFAOYSA-N 2-aminobutanal Chemical compound CCC(N)C=O FGEPRNXUNITOCW-UHFFFAOYSA-N 0.000 description 1
- GFLPSABXBDCMCN-UHFFFAOYSA-N 4,4-diethoxybutan-1-amine Chemical compound CCOC(OCC)CCCN GFLPSABXBDCMCN-UHFFFAOYSA-N 0.000 description 1
- NLHHRLWOUZZQLW-UHFFFAOYSA-N Acrylonitrile Chemical compound C=CC#N NLHHRLWOUZZQLW-UHFFFAOYSA-N 0.000 description 1
- 125000003047 N-acetyl group Chemical group 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- KXBQYMQMSNZAKO-UHFFFAOYSA-N canthin-6-one Natural products C12=CC=CC=C2N2C(=O)CCC3=NC=CC1=C32 KXBQYMQMSNZAKO-UHFFFAOYSA-N 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- AIFRHYZBTHREPW-UHFFFAOYSA-N cis-beta-Carboline Acid Natural products N1=CC=C2C3=CC=CC=C3NC2=C1 AIFRHYZBTHREPW-UHFFFAOYSA-N 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- RXPRRQLKFXBCSJ-UHFFFAOYSA-N dl-Vincamin Natural products C1=CC=C2C(CCN3CCC4)=C5C3C4(CC)CC(O)(C(=O)OC)N5C2=C1 RXPRRQLKFXBCSJ-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- 229930005303 indole alkaloid Natural products 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 1
- HKOOXMFOFWEVGF-UHFFFAOYSA-N phenylhydrazine Chemical compound NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 description 1
- JOVOSQBPPZZESK-UHFFFAOYSA-N phenylhydrazine hydrochloride Chemical compound Cl.NNC1=CC=CC=C1 JOVOSQBPPZZESK-UHFFFAOYSA-N 0.000 description 1
- 229940038531 phenylhydrazine hydrochloride Drugs 0.000 description 1
- 150000004031 phenylhydrazines Chemical class 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000009877 rendering Methods 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 229960002726 vincamine Drugs 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
本発明は新規なテトラヒドロ−β−カルボリン
化合物とその製造方法に関するものである。さら
に詳しくは、本発明は一般式（）：
〔但し、式中R1は水素原子、炭素原子数が１な
いし６のアルキル基、ハロゲン基、又はベンジル
オキシ基を表わし、R2は水素原子、炭素原子数
が１ないし６のアルキル基、アラルキル基、アシ
ル基又はベンゾイル基を表す〕
で表わされる新規な１−（3′−アミノプロピル）
テトラヒドロ−β−カルボリン化合物及びその製
造方法に関するものである。
本発明の１−（3′−アミノプロピル）テトラヒ
ドロ−β−カルボリン化合物は、医薬として有用
な、インドールアルカロイド化合物、例えば抗菌
剤として有用な下記化学式のカンチン−６−オ
ン：
或は、脳血管拡張剤として有用な下記化学式のビ
ンカミン：
などの合成中間体として有用な化合物である。
テトラヒドロ−β−カルボリン誘導体について
R.A.Abramouitchら（advan.Heterocyc.
chem.；３、83〜84（1969）及びW.M.Whaleyら
（Org.Reactions；６、153、173〜４ 185〜７
（1951）はトリプタミンとアセトアルデヒドなど
アルデヒド類とを縮合させたテトラヒドロ−β−
カルボリン化合物について述べているが、これら
は無置換体又は炭化水素基、ヒドロキシ基、ある
いはカルボキシ基の置換体で本発明のアミノプロ
ピル基のごとき窒素原子を含む１−アルキル置換
体は見出されていない。
本発明者らは、フエニルヒドラジンと４−アミ
ノブタナールジアルキルアセタールとを縮合環化
してトリプタミン化合物を製造する際、生成した
トリプタミンと４−アミノブタナールジアルキル
アセタールがさらに縮合し、１−（3′−アミノプ
ロピル）テトラヒドロ−β−カルボリンが得られ
ることを見いだし本発明を完成するに至つたもの
である。
すなわち、本発明は、一般式（）
（式中、R1およびR2は前記定義に同じ）で表わ
される新規な１−（3′−アミノプロピル）テトラ
ヒドロ−β−カルボリン化合物と、その製造方法
を提供することを目的とするものである。
本発明の１−（3′−アミノプロピル）テトラヒ
ドロ−β−カルボリン化合物の製造方法は、一般
式（）：
（式中、R1は前記定義に同じ）で表わされるト
リプタミン化合物と、一般式（）
〔但し、式中R2は前記定義に同じであり、R3及
びR4は、それぞれ炭素数１ないし４のアルキル
基であつて、互に同一でも相異つてもよく、
The present invention relates to a novel tetrahydro-β-carboline compound and a method for producing the same. More specifically, the present invention relates to the general formula (): [However, in the formula, R 1 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a halogen group, or a benzyloxy group, and R 2 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aralkyl group. group, acyl group or benzoyl group] Novel 1-(3'-aminopropyl) represented by
The present invention relates to a tetrahydro-β-carboline compound and a method for producing the same. The 1-(3'-aminopropyl)tetrahydro-β-carboline compound of the present invention is an indole alkaloid compound useful as a medicine, such as canthin-6-one of the following chemical formula useful as an antibacterial agent: Alternatively, vincamine with the following chemical formula is useful as a cerebral vasodilator: It is a compound useful as a synthetic intermediate such as. About tetrahydro-β-carboline derivatives
RA Abramouitch et al. (advan. Heterocyc.
chem.; 3 , 83-84 (1969) and WMWhaley et al. (Org. Reactions; 6 , 153, 173-4 185-7
(1951) is a tetrahydro-β-condensed product of tryptamine and aldehydes such as acetaldehyde.
Although carboline compounds are mentioned, these are unsubstituted or substituted with a hydrocarbon group, hydroxy group, or carboxy group, and 1-alkyl substituted with a nitrogen atom such as the aminopropyl group of the present invention has not been found. do not have. The present inventors discovered that when phenylhydrazine and 4-aminobutanal dialkyl acetal are condensed and cyclized to produce a tryptamine compound, the generated tryptamine and 4-aminobutanal dialkyl acetal are further condensed, and 1-(3 It was discovered that tetrahydro-β-carboline ('-aminopropyl) could be obtained, and the present invention was completed. That is, the present invention provides the general formula () The present invention aims to provide a novel 1-(3'-aminopropyl)tetrahydro-β-carboline compound represented by the formula (wherein R 1 and R 2 are the same as defined above) and a method for producing the same. be. The method for producing the 1-(3'-aminopropyl)tetrahydro-β-carboline compound of the present invention has the general formula (): (wherein R 1 is the same as defined above) and a tryptamine compound represented by the general formula () [However, in the formula, R 2 is the same as defined above, and R 3 and R 4 are each an alkyl group having 1 to 4 carbon atoms, and may be the same or different from each other,
【式】はエチレン基、又はプロピレン基、或
は
〔但し、式中R2は前記定義に同じ〕で示される、
４−アミノブタナールジアルキルアセタール化合
物とを、水又は親水性溶媒或はそれらの混合物溶
媒中で反応液を酸性に保ちながら反応させること
を特徴とするものである。
本発明の１−（3′−アミノプロピル）テトラヒ
ドロ−β−カルボリン化合物の製造方法の一実施
態様を示すと、前記二つの出発物質を溶媒に溶解
して酸性とした後加熱縮合するか、二つの出発物
質をそれぞれの溶媒に溶解してその一方又は両者
を酸性となし、一方の溶液を他方の溶液に滴下し
ながら加熱下に反応させることによつて実施され
る。この際の反応は反応液の温度を60ないし140
℃で好ましくは90ないし120℃で、30分ないし６
時間加熱して反応させる。反応生成物は、反応終
了後、反応液を濃縮して酸類の塩として晶析させ
るか、反応液をアルカリ性としてジクロロメタ
ン、クロロホルム等の有機溶剤で抽出して再結晶
などで精製すると遊離形として１−（3′−アミノ
プロピル）テトラヒドロ−β−カルボリン化合物
が得られる。
本発明の製造方法において原料として用いられ
る一般式（）のトリプタミン化合物は遊離の形
でも、その無機あるいは有機酸との塩でも用いる
ことができる。この一般式（）の化合物を得る
方法は多数あるが本発明者らにより特許出願され
た、（特開昭56−90056号）フエニルヒドラジン類
と４−アミノブタナールジアルキルアセタールと
を弱酸性下に反応させる方法によつて容易に得る
ことができる。本反応に用いられるトリプタミン
化合物の例をあげるとトリプタミン、７−メチル
トリプタミン、５−クロルトリプタミン、７−ク
ロルトリプタミン、５−ブロムトリプタミン、４
−メチル−トリプタミン、および６−メチル−ト
リプタミン、などがある。
本発明の製造方法において他方の原料として用
いられらる前記４−アミノブタナールジアルキル
アセタール化合物としては、例えば、４−アミノ
ブタナールジメチルアセタール、４−アミノブタ
ナールジエチルアセタール、３，９−ビス（３−
アミノプロピル）−２，４，８，10−テトラオキ
サスピロ〔５，５〕ウンデカン（以下ATUと略
称する。その分子式は下記の通りである。
など、及びこれらのＮ−メチル、Ｎ−エチル、Ｎ
−シクロヘキシル、Ｎ−トルイル、Ｎ−ベンジ
ル、Ｎ−アセチル、Ｎ−プロピオニル、およびＮ
−ベンゾイル置換体などがある。これらの４−ア
ミノブタナールジアルキルアセタール化合物を得
る方法の１例として下記のような方法がある。す
なわち、アクリロニトリルのオキソ反応で得られ
るβ−シアノピロピオンアルデヒドをアルコール
でアセタール化した後シアノ基を還元して、４−
アミノブタナールジアルキルアセタールを得る。
さらにこの化合物のアミノ基を通常の方法により
アルキル化、アリル化又はアシル化すれば４−ア
ミノブタナールジアルキルアセタールのＮ−置換
体が得られる。前記一般式（）の化合物におい
て、基[Formula] is an ethylene group, a propylene group, or [However, R 2 in the formula is the same as the above definition],
This method is characterized by reacting a 4-aminobutanal dialkyl acetal compound in water, a hydrophilic solvent, or a mixture thereof while keeping the reaction solution acidic. In one embodiment of the method for producing a 1-(3'-aminopropyl)tetrahydro-β-carboline compound of the present invention, the two starting materials are dissolved in a solvent to make it acidic and then heated and condensed. The reaction is carried out by dissolving two starting materials in their respective solvents, rendering one or both of them acidic, and allowing the reaction to occur under heating while dropping one solution into the other. During this reaction, the temperature of the reaction solution should be kept at 60 to 140℃.
℃ preferably 90 to 120℃ for 30 minutes to 6
Heat for some time to react. After the reaction is complete, the reaction product can be obtained as a free form by concentrating the reaction solution and crystallizing it as an acid salt, or by making the reaction solution alkaline, extracting it with an organic solvent such as dichloromethane or chloroform, and purifying it by recrystallization. A -(3'-aminopropyl)tetrahydro-β-carboline compound is obtained. The tryptamine compound of the general formula () used as a raw material in the production method of the present invention can be used in a free form or as a salt with an inorganic or organic acid. There are many methods for obtaining the compound of the general formula (), but the method proposed by the present inventors (Japanese Patent Application Laid-open No. 56-90056) is to combine phenylhydrazines and 4-aminobutanal dialkyl acetal under weak acidity. It can be easily obtained by a method of reacting with. Examples of tryptamine compounds used in this reaction are tryptamine, 7-methyltryptamine, 5-chlortryptamine, 7-chlortryptamine, 5-bromotryptamine, 4
-methyl-tryptamine, and 6-methyl-tryptamine. Examples of the 4-aminobutanal dialkyl acetal compound used as the other raw material in the production method of the present invention include 4-aminobutanal dimethyl acetal, 4-aminobutanal diethylacetal, 3,9-bis( 3-
Aminopropyl)-2,4,8,10-tetraoxaspiro[5,5]undecane (hereinafter abbreviated as ATU). Its molecular formula is as follows. etc., and these N-methyl, N-ethyl, N
-cyclohexyl, N-tolyl, N-benzyl, N-acetyl, N-propionyl, and N
-benzoyl substituted products, etc. An example of a method for obtaining these 4-aminobutanal dialkyl acetal compounds is the following method. Specifically, β-cyanopyrropionaldehyde obtained by the oxo reaction of acrylonitrile is acetalized with alcohol, and then the cyano group is reduced to form 4-cyanopropionaldehyde.
The aminobutanal dialkyl acetal is obtained.
Further, by alkylating, allylating or acylating the amino group of this compound by a conventional method, an N-substituted 4-aminobutanal dialkyl acetal can be obtained. In the compound of the general formula (), the group
【式】はアセタール化したアルコ
ールの残基であつて、このアルコールとしては、
メタノール、エタノール、プロパノールなどのよ
うな１価アルコールや、エチレングリコール、
１，３−ブタンジオール、ペンタエリスリトール
（この場合は２個のヒドロキシ基が４−アミノブ
タナール化合物をアセタール化してある）のよう
な多価アルコールがある。
本発明方法において用いられるトリプタミン化
合物と４−アミノブタナールジアルキルアセター
ル化合物のモル数は両者の理論量であればよく、
これで充分目的を達することができるが、両化合
物のいずれかを理論量よりも過剰に用いることを
妨げるものではない。
本発明の製造方法においてその反応系の溶液を
酸性に保つ目安は溶液のPHを４以下とすることが
必要である。この反応系を酸性に保つために用い
る酸は塩酸、硫酸およびりん酸などの無機酸、ｐ
−トルエンスルホン酸、強酸性イオン交換樹脂等
の有機強酸、酢酸、プロピオン酸などの低級有機
カルボン酸などがあげられる。この酸の用い方と
しては一般的には原料のアミノ基がアシル化され
ているときは低級有機カルボン酸をそれ以外のと
きは無機酸又は強酸性有機酸を用いることが好ま
しい。
本発明方法で用いられる溶媒は、水又は、メタ
ノール、エタノール、プロパノール、エチレング
リコール、グリセリンのようなアルコール類、グ
リコールエーテル類、及びジオキサンなどの親水
性溶媒、或はこれらの２種以上の混合物などであ
る。
本発明方法の反応に際し、その温度としては好
ましくは60ないし140℃、より好ましくは90ない
し120℃が採用される。反応温度が60℃未満では
反応がおそく反応完結に長時間を要する場合があ
り、140℃を超えた温度で反応を行つても、格別
のメリツトがない。
さらに本発明方法を実施するにあたつて、生成
する１−（3′−アミノプロピル）テトラヒドロ−
β−カルボリン化合物の前記一般式（）におい
て２−位のＮ置換基R2と3′−位のＮ置換基R3が
同一でかつR4が水素原子である化合物を得る場
合は、
一般式（）：
〔但し、式中Ｒ及びR1は前記定義に同じ〕で示
されるフエニルヒドラジン化合物と４−アミノブ
タナールジアルキルアセタール化合物とを酸性化
に反応させてトリプタミン化合物とし、生成した
トリプタミンを分離せず引続き４−アミノブタナ
ールジアルキルアセタール化合物とを反応させる
ことによつても目的物を得ることができる。この
際反応系の酸のPHによつては第二段の反応が極め
て速かに進行することが認められる。この反応に
おいて用いる酸、溶媒及び反応条件はトリプタミ
ンと４−アミノブタナールジアルキルアセタール
化合物との反応の場合と同一である。
本発明方法で得られるカルボリン化合物は次の
一般式
〔但し、式中R1およびR2は前記定義に同じ〕で
示される化合物で、これらの化合物は前に記載し
た二つの出発物質に対応して得られる。１−
（3′−アミノプロピル）テトラヒドロ−β−カル
ボリン化合物の例をあげれば、たとえば１−
（3′−アミノプロピル）テトラヒドロ−β−カル
ボリン、１−（3′−Ｎ−ベンジルアミノプロピル）
テトラヒドロ−β−カルボリン、１−（3′−Ｎ−
シクロヘキシルアミノプロピル）テトラヒドロ−
β−カルボリン、１−（3′−アミノプロピル）−６
−ブロムテトラヒドロ−β−カルボリン、１−
（3′−アミノプロピル）−８−クロル−テトラヒド
ロ−β−カルボリン、１−（3′−Ｎ−シクロヘキ
シルアミノプロピル）−６−メチルテトラヒドロ
−β−カルボリン、１−（3′−アミノプロピル）−
６−ベンジルオキシテトラヒドロカルボリン、１
−（3′−Ｎ−ベンゾイルアミノプロピル）テトラ
ヒドロ−β−カルボリン、１−（3′−Ｎ−アセチ
ルアミノプロピル）テトラヒドロ−β−カルボリ
ンなどである。
以下実施例によつて本発明を詳細に説明する。
実施例中収率とは用いられたトリプタミン化合物
又はフエニルヒドラジン化合物に対する１−
（3′−アミノプロピル）テトラヒドロ−β−カル
ボリン化合物の理論収率である。
実施例 １
ジムロート冷却管、温度計および気密撹拌器を
取り付けたフラスコにトリプタミン8.01ｇ（50ｍ
mol）とATU7.13ｇ（26ｍmol）を入れ、水150
mlを加えて溶解し、さらにｐ−トルエンスルホン
酸−水和物22.83ｇ（120ｍmol）を加えると白色
懸濁液となつた。この懸濁液を加熱撹拌すると、
90℃付近で透明な液となり、さらに昇温して、３
時間、加熱還流した。反応終了後、反応液を冷却
して析出した固体をろ取して白色板状結晶として
１−（3′−アミノプロピル）テトラヒドロ−β−
カルボリンの２・ｐ−トルエンスルホン酸塩
26.11ｇが得られ、分析値は、
●融点 239〜241℃
●Ｎ含量 6.98％（計算値7.32％）
であつた。
この１−（3′−アミノプロピル）テトラヒドロ
−β−カルボリンの２・ｐ−トルエンスルホン酸
塩を水50mlに加え加熱溶解し、クロロホルム50ml
を加え、水層に48％水酸化ナトリウム水溶液を加
えて水層のPHを12以上として、クロロホルム層を
分液し、水層はさらにクロロホルム50mlで抽出し
た。クロロホルム層を合一して、飽和食塩水50ml
で２回洗浄した。クロロホルムを減圧下に除去し
て得られる無状物を酢酸エチル50mlから結晶化さ
せ、白色プリズム状結晶の１−（3′−アミノプロ
ピル）テトラヒドロ−β−カルボリン1.5ｇが得
られた。そのものの分析値は次のとおりであつ
た。
●融点；100.6℃
●Ｎ含量；17.97％（C14H9N3としてのＮ含有計
算値18.32％）
●MS；M+229（35.4％）、171（100％、Ｐ−
C3H8N）
●ir（KBr、Vmax（cm-1）；3420、3170、2930、
2860、1565、1445、1315、1305、1000、730
●nmr（δ（ppm）CDCl3）
1.35（ｓ、3H、−ＮＨ 2、ＮＨ）
1.5〜2.1（ｍ、4H、−CH2−）
2.4〜3.5（ｍ、6H、−CH2−）
3.95（br.s、1H、CH）
6.8〜7.6（ｍ、4H、aramatic Ｈ）
9.07（br.s、1H、indole NH）
実施例 ２
ジムロート冷却管、温度計、滴下ロート及び気
密撹拌器をつけたフラスコ中でトリプタミン3.20
ｇ（20ｍmole）を1N硫酸20mlに溶解して加熱
し、85〜90℃で４−アミノブタナールジメチルア
セタール2.80ｇ（21ｍmole）を水20mlに溶解し
て50％硫酸水溶液で中和した水溶液を20分間で滴
下した。加熱・撹拌しながら４時間還流温度を保
つた。反応終了後、反応液を放冷し、減圧下に約
半量まで濃縮し、48％水酸化ナトリウム水溶液で
アルカリ性として、クロロホルムで抽出した。抽
出液はクロロホルムを除去し、得られた残液に酢
酸エチルを加えて結晶化して、１−（3′−アミノ
プロピル）テトラヒドロ−β−カルボリン3.49ｇ
（収率76％）を得た。
実施例 ３
85％リン酸3.46ｇ（30ｍmole）を溶解したｎ
−プロパノール−水（vol １／１）50mlに、トリ
プタミン1.60ｇ（10ｍmole）とATU1.37ｇ（５
ｍmole）を加えて溶解し、加熱、撹拌し、還流
温度（87℃）で24時間反応させた。反応終了後、
溶媒を減圧下に除去し、得られた固状残渣に水20
mlを加えて、実施例２と同様に処理して１−
（3′−アミノプロピル）テトラヒドロ−β−カル
ボリン1.22ｇ（収率53％）を得た。
実施例 ４
フエニルヒドラジン塩酸塩3.61ｇ（25ｍmole）
を0.1N塩酸水溶液50mlに加えて撹拌下に加熱溶
解し、95℃に達したところで、ATU7.13ｇ（26
ｍmole）を水40mlに溶解して15％塩酸で中和し
た水溶液を１時間で滴下した。さらに加熱撹拌し
ながら、還流温度を３時間保つた。反応終了後、
反応液を約半量まで濃縮し、実施例２と同様に処
理して、１−（3′−アミノプロピル）テトラヒド
ロ−β−カルボリン4.78ｇ（収率84％）を得た。
実施例 ５
トリプタミン塩酸塩1.97ｇ（10ｍmole）と３，
９−ビス（Ｎ−ベンジルアミノプロピル）−２，
４，８，10−テトラオキサスピロ〔５，５〕ウン
デカン2.33ｇ（5.1ｍmole）を1N塩酸水溶液70ml
に加えて、撹拌下に加熱溶解し、還流温度で５時
間反応させた。反応終了後、反応液を氷冷下に冷
却して析出する固体をろ取し、得られた固体をエ
タノールで再結晶して、白色粉末結晶の１−
（3′−Ｎ−ベンジルアミノプロピル）テトラヒド
ロ−β−カルボリンの２塩酸塩2.99ｇ（収率76
％）を得た。このものの融点は232〜234℃であつ
た。
実施例 ６〜８
実施例５と同様に、第１表に示す１−（3′−ア
ミノプロピル）テトラヒドロ−β−カルボリン誘
導体を合成した。[Formula] is the residue of an acetalized alcohol, and as this alcohol,
Monohydric alcohols such as methanol, ethanol, propanol, etc., ethylene glycol,
There are polyhydric alcohols such as 1,3-butanediol and pentaerythritol (in this case two hydroxy groups are acetalized from a 4-aminobutanal compound). The number of moles of the tryptamine compound and the 4-aminobutanal dialkyl acetal compound used in the method of the present invention may be any theoretical amount of both,
Although this is sufficient to achieve the purpose, it does not preclude the use of either of the two compounds in excess of the stoichiometric amount. In the production method of the present invention, it is necessary to keep the solution in the reaction system acidic so that the pH of the solution is 4 or less. The acids used to keep this reaction system acidic include inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid;
Examples include strong organic acids such as toluenesulfonic acid and strongly acidic ion exchange resins, and lower organic carboxylic acids such as acetic acid and propionic acid. In general, when the amino group of the raw material is acylated, it is preferable to use a lower organic carboxylic acid, and in other cases, it is preferable to use an inorganic acid or a strongly acidic organic acid. The solvent used in the method of the present invention is water, alcohols such as methanol, ethanol, propanol, ethylene glycol, glycerin, glycol ethers, and hydrophilic solvents such as dioxane, or a mixture of two or more thereof. It is. During the reaction in the method of the present invention, the temperature is preferably 60 to 140°C, more preferably 90 to 120°C. If the reaction temperature is less than 60°C, the reaction will be slow and it may take a long time to complete the reaction, and even if the reaction is carried out at a temperature higher than 140°C, there is no particular merit. Furthermore, when carrying out the method of the present invention, the 1-(3'-aminopropyl)tetrahydro-
When obtaining a compound in which the N substituent R 2 at the 2-position and the N substituent R 3 at the 3'-position are the same and R 4 is a hydrogen atom in the general formula () of the β-carboline compound, the general formula (): [However, in the formula, R and R 1 are the same as defined above] A phenylhydrazine compound represented by the formula and a 4-aminobutanal dialkyl acetal compound are acidified and reacted to form a tryptamine compound, and the generated tryptamine is not separated. The desired product can also be obtained by subsequent reaction with a 4-aminobutanal dialkyl acetal compound. At this time, it is recognized that the second stage reaction proceeds extremely quickly depending on the pH of the acid in the reaction system. The acid, solvent and reaction conditions used in this reaction are the same as for the reaction of tryptamine and 4-aminobutanal dialkyl acetal compound. The carboline compound obtained by the method of the present invention has the following general formula: Compounds represented by the formula [wherein R 1 and R 2 are the same as defined above] are obtained corresponding to the two starting materials described above. 1-
An example of a (3'-aminopropyl)tetrahydro-β-carboline compound is, for example, 1-
(3'-aminopropyl)tetrahydro-β-carboline, 1-(3'-N-benzylaminopropyl)
Tetrahydro-β-carboline, 1-(3′-N-
cyclohexylaminopropyl)tetrahydro-
β-carboline, 1-(3'-aminopropyl)-6
-bromotetrahydro-β-carboline, 1-
(3'-aminopropyl)-8-chloro-tetrahydro-β-carboline, 1-(3'-N-cyclohexylaminopropyl)-6-methyltetrahydro-β-carboline, 1-(3'-aminopropyl)-
6-benzyloxytetrahydrocarboline, 1
-(3'-N-benzoylaminopropyl)tetrahydro-β-carboline, 1-(3'-N-acetylaminopropyl)tetrahydro-β-carboline, and the like. The present invention will be explained in detail below with reference to Examples.
In the examples, the yield refers to 1- to the tryptamine compound or phenylhydrazine compound used.
This is the theoretical yield of the (3'-aminopropyl)tetrahydro-β-carboline compound. Example 1 8.01 g of tryptamine (50 m
mol) and 7.13g (26mmol) of ATU, and 150g of water.
ml was added to dissolve, and 22.83 g (120 mmol) of p-toluenesulfonic acid hydrate was added to form a white suspension. When this suspension is heated and stirred,
It becomes a transparent liquid at around 90℃, and when the temperature is further increased, 3
The mixture was heated to reflux for an hour. After the reaction, the reaction solution was cooled and the precipitated solid was collected by filtration to give 1-(3'-aminopropyl)tetrahydro-β- as white plate-like crystals.
Carboline 2-p-toluenesulfonate
26.11g was obtained, and the analytical values were: -Melting point: 239-241°C -N content: 6.98% (calculated value: 7.32%). This 2-p-toluenesulfonate of 1-(3'-aminopropyl)tetrahydro-β-carboline was added to 50 ml of water, dissolved by heating, and 50 ml of chloroform was added.
was added, 48% aqueous sodium hydroxide solution was added to the aqueous layer to adjust the pH of the aqueous layer to 12 or higher, the chloroform layer was separated, and the aqueous layer was further extracted with 50 ml of chloroform. Combine the chloroform layers and add 50ml of saturated saline.
Washed twice with The amorphous substance obtained by removing chloroform under reduced pressure was crystallized from 50 ml of ethyl acetate to obtain 1.5 g of 1-(3'-aminopropyl)tetrahydro-β-carboline in the form of white prismatic crystals. The analytical values were as follows. ●Melting point: 100.6℃ ●N content: 17.97% (N content calculated as C 14 H 9 N 3 18.32%) ●MS: M + 229 (35.4%), 171 (100%, P-
C 3 H 8 N) ●ir (KBr, Vmax (cm -1 ); 3420, 3170, 2930,
2860, 1565, 1445, 1315, 1305, 1000, 730 ● nmr (δ (ppm) CDCl 3 ) 1.35 (s, 3H, -NH 2 , NH ) 1.5 to 2.1 (m, 4H, -CH 2 -) 2.4-3.5 (m, 6H, -CH 2 -) 3.95 (br.s, 1H, CH) 6.8-7.6 (m, 4H, aramatic H) 9.07 (br.s, 1H, indole NH) Example 2 Dimroth cooling Tryptamine 3.20 in a flask equipped with a tube, thermometer, addition funnel and airtight stirrer.
g (20 mmole) was dissolved in 20 ml of 1N sulfuric acid and heated. 2.80 g (21 mmole) of 4-aminobutanal dimethyl acetal was dissolved in 20 ml of water and neutralized with a 50% aqueous sulfuric acid solution at 85 to 90°C. It was dripped in minutes. The reflux temperature was maintained for 4 hours while heating and stirring. After the reaction was completed, the reaction solution was allowed to cool, concentrated under reduced pressure to about half its volume, made alkaline with a 48% aqueous sodium hydroxide solution, and extracted with chloroform. Chloroform was removed from the extract, and the resulting residue was crystallized by adding ethyl acetate to yield 3.49 g of 1-(3'-aminopropyl)tetrahydro-β-carboline.
(yield 76%). Example 3 3.46 g (30 mmole) of 85% phosphoric acid dissolved in n
- Propanol - In 50 ml of water (vol 1/1), tryptamine 1.60 g (10 mmole) and ATU 1.37 g (5
mmole) was added and dissolved, heated, stirred, and reacted at reflux temperature (87°C) for 24 hours. After the reaction is complete,
The solvent was removed under reduced pressure and the resulting solid residue was diluted with water for 20 min.
ml and treated in the same manner as in Example 2 to obtain 1-
1.22 g (yield 53%) of (3'-aminopropyl)tetrahydro-β-carboline was obtained. Example 4 Phenylhydrazine hydrochloride 3.61g (25mmole)
was added to 50ml of 0.1N hydrochloric acid aqueous solution and dissolved by heating with stirring. When the temperature reached 95℃, ATU7.13g (26
mmole) in 40 ml of water and neutralized with 15% hydrochloric acid was added dropwise over 1 hour. The reflux temperature was maintained for 3 hours while further heating and stirring. After the reaction is complete,
The reaction solution was concentrated to about half its volume and treated in the same manner as in Example 2 to obtain 4.78 g (yield: 84%) of 1-(3'-aminopropyl)tetrahydro-β-carboline. Example 5 Tryptamine hydrochloride 1.97g (10mmole) and 3,
9-bis(N-benzylaminopropyl)-2,
2.33 g (5.1 mmole) of 4,8,10-tetraoxaspiro[5,5]undecane was added to 70 ml of 1N hydrochloric acid aqueous solution.
In addition, the mixture was heated and dissolved under stirring, and reacted at reflux temperature for 5 hours. After the reaction is complete, the reaction solution is cooled on ice, the precipitated solid is collected by filtration, and the obtained solid is recrystallized with ethanol to obtain 1-
(3'-N-benzylaminopropyl)tetrahydro-β-carboline dihydrochloride 2.99g (yield 76
%) was obtained. The melting point of this product was 232-234°C. Examples 6 to 8 In the same manner as in Example 5, 1-(3'-aminopropyl)tetrahydro-β-carboline derivatives shown in Table 1 were synthesized.
【表】
実施例 ９
５−メチルトリプタミン塩酸塩0.53ｇ（2.5ｍ
mole）と３，９−ビス（３−Ｎ−シクロヘキシ
ルアミノプロピル）−２，４，８，10−テトラオ
キサスピロ〔５，５〕ウンデカン0.61ｇ（1.4ｍ
mole）を水25mlとエチレングリコール25mlの混
合溶媒に溶解して、濃塩酸１mlを加えて加熱し、
撹拌しながら110℃で３時間反応させた。反応終
了後、反応液に48％水酸化ナトリウム水溶液を加
えてアルカリ性とし、ジクロロメタン20mlで２回
抽出した。抽出液は水洗後、ジクロロメタンを減
圧下に留去し、得られた油状物をエタノール10ml
に溶解して、17％エタノール−塩酸を加えて析出
する固体をろ取した。淡黄色小針状結晶として、
１−（3′−Ｎ−シクロヘキシルアミノプロピル）−
６−メチルテトラヒドロ−β−カルボリン・２塩
酸塩0.3ｇ（収率30％）が得られた。このものの
融点は280℃（分解）であつた。
実施例 10
５−ベンジルオキシトリプタミン塩酸塩0.61ｇ
（２ｍmole）とATU0.3ｇ（1.1ｍmole）をイソブ
タノール40mlに加え、さらに16％エタノール−塩
酸２mlを加えて、加熱、撹拌し、２時間還流下に
反応させた。反応終了後、反応液を放冷して析出
するペンタエリスリトールをろ過して得られたろ
液を、減圧下に約10mlまで濃縮し、氷冷下に冷却
すると、緑色の小針状結晶として、１−（3′−ア
ミノプロピル）−６−ベンジルオキシテトラヒド
ロ−β−カルボリンの２塩酸塩0.71ｇ（収率87
％）を得た。
実施例 11
トリプタミン塩酸塩0.98ｇ（５ｍmole）と４
−ベンゾイルアミノブタナールジメチルアセター
ル1.25ｇ（5.2ｍmole）を酢酸40mlに加熱溶解し、
撹拌しながら、85〜90℃で４時間反応させた。反
応終了後、酢酸を減圧下に留去し、得られた残渣
に水30mlを加えて熱時溶解し、室温に放値して析
出する結晶をろ取して、白色板状結晶の１−
（3′−Ｎ−ベンゾイルアミノプロピル）テトラヒ
ドロ−β−カルボリン塩酸塩0.76ｇ（収率40％）
が得られた。このものの融点は202〜205℃であつ
た。
実施例 12
トリプタミン塩酸塩0.98ｇ（５ｍmole）と３，
９−ビス（３−Ｎ−アセチルアミノプロピル）−
２，４，８，10−テトラオキサスピロ〔５，５〕
ウンデカン0.93ｇ（2.6ｍmole）をイソブタノー
ル40mlに入れ、さらに酢酸５mlを加えて、加熱、
撹拌し、還流下に26時間反応させた。反応終了
後、不溶物をろ過して除去し、減圧下に溶媒を留
去し、得られた残渣にエタノール５mlを加えて溶
解し、さらに酢酸エチル（10mlを加えて析出する
結晶をろ取して、白色小針状結晶の１−（3′−Ｎ
−アセチルアミノプロピル）テトラヒドロ−β−
カルボリン塩酸塩0.31ｇ（収率31％）が得られ
た。このものの融点は161〜165℃であつた。[Table] Example 9 5-methyltryptamine hydrochloride 0.53g (2.5m
mole) and 0.61 g (1.4 m
mole) in a mixed solvent of 25 ml of water and 25 ml of ethylene glycol, add 1 ml of concentrated hydrochloric acid and heat.
The reaction was carried out at 110° C. for 3 hours while stirring. After the reaction was completed, the reaction solution was made alkaline by adding 48% aqueous sodium hydroxide solution, and extracted twice with 20 ml of dichloromethane. After washing the extract with water, dichloromethane was distilled off under reduced pressure, and the resulting oil was added to 10 ml of ethanol.
17% ethanol-hydrochloric acid was added, and the precipitated solid was collected by filtration. As small pale yellow needle-like crystals,
1-(3'-N-cyclohexylaminopropyl)-
0.3 g (yield 30%) of 6-methyltetrahydro-β-carboline dihydrochloride was obtained. The melting point of this product was 280°C (decomposition). Example 10 5-benzyloxytryptamine hydrochloride 0.61g
(2 mmole) and 0.3 g (1.1 mmole) of ATU were added to 40 ml of isobutanol, and further 2 ml of 16% ethanol-hydrochloric acid was added, heated and stirred, and reacted under reflux for 2 hours. After the reaction is completed, the reaction solution is allowed to cool and the precipitated pentaerythritol is filtered. The obtained filtrate is concentrated under reduced pressure to about 10 ml and cooled on ice. As a result, 1- (3'-aminopropyl)-6-benzyloxytetrahydro-β-carboline dihydrochloride 0.71 g (yield 87
%) was obtained. Example 11 Tryptamine hydrochloride 0.98g (5mmole) and 4
-Dissolve 1.25 g (5.2 mmole) of benzoylaminobutanal dimethyl acetal in 40 ml of acetic acid by heating.
The reaction was carried out at 85 to 90°C for 4 hours while stirring. After the reaction was completed, acetic acid was distilled off under reduced pressure, and 30 ml of water was added to the resulting residue to dissolve it while heating. The crystals that precipitated at room temperature were collected by filtration, and white plate-like crystals of 1-
(3'-N-benzoylaminopropyl)tetrahydro-β-carboline hydrochloride 0.76g (yield 40%)
was gotten. The melting point of this product was 202-205°C. Example 12 Tryptamine hydrochloride 0.98g (5mmole) and 3,
9-bis(3-N-acetylaminopropyl)-
2,4,8,10-tetraoxaspiro [5,5]
Put 0.93 g (2.6 mmole) of undecane in 40 ml of isobutanol, add 5 ml of acetic acid, and heat.
The mixture was stirred and reacted under reflux for 26 hours. After the reaction, insoluble matter was removed by filtration, the solvent was distilled off under reduced pressure, 5 ml of ethanol was added to the resulting residue to dissolve it, and 10 ml of ethyl acetate was added, and the precipitated crystals were collected by filtration. 1-(3′-N) of white needle-like crystals
-acetylaminopropyl)tetrahydro-β-
0.31 g (yield 31%) of carboline hydrochloride was obtained. The melting point of this product was 161-165°C.
Claims (1)
いし６のアルキル基、ハロゲン原子、又はベンジ
ルオキシ基を表わし、R2は水素原子、炭素原子
数が１ないし６のアルキル基、アラルキル基、ア
シル基又はベンゾイル基を表す〕 で表わされる、新規な１−（3′−アミノプロピル）
テトラヒドロ−β−カルボリン化合物。 ２ 下記一般式（）： 〔但し、式中R1は水素原子、炭素原子数が１な
いし６のアルキル基、ハロゲン原子、又はベンジ
ルオキシ基を表わし、R2は水素原子、炭素原子
数が１ないし６のアルキル基、アラルキル基、ア
シル基、又はベンゾイル基を表す〕 で表わされる、１−（3′−アミノプロピル）テト
ラヒドロ−β−カルボリン化合物を得るに際し、
下記一般式（）： 〔但し、式中R1は前記定義に同じ〕 で表わされるトリプタミン化合物と、下記一般式
（）： 〔但し、式中R2は前記定義に同じであり、R3及
びR4は、下記(a)、(b)および(c)のいずれかからな
る基を表す。 (a) 炭素原子数が１ないし４のアルキル基、但し
R3とR4は同一でも相異つてもよい、 (b) 【式】 がエチレン基、又はプロピレン基を形成してい
る、 (c) 【式】が下記構造式： （但し、式中R2は前記定義と同じ）で示され
る基を形成している。〕 で示される４−アミノブタナールジアルキルアセ
タール化合物とを、水及び／又は親水性溶媒中で
反応液を酸性に保ちながら、反応温度60ないし
140℃で反応させることを特徴とする、前記一般
式（）の１−（3′−アミノプロピル）テトラヒ
ドロ−β−カルボリン化合物の製造方法。[Claims] 1. The following general formula (): [However, in the formula, R 1 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a halogen atom, or a benzyloxy group, and R 2 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aralkyl group. group, acyl group or benzoyl group] A novel 1-(3'-aminopropyl) represented by
Tetrahydro-β-carboline compound. 2 The following general formula (): [However, in the formula, R 1 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a halogen atom, or a benzyloxy group, and R 2 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aralkyl group. group, acyl group, or benzoyl group] When obtaining a 1-(3'-aminopropyl)tetrahydro-β-carboline compound,
The following general formula (): [However, in the formula, R 1 is the same as defined above] A tryptamine compound represented by the following general formula (): [However, in the formula, R 2 is the same as defined above, and R 3 and R 4 represent a group consisting of any of the following (a), (b) and (c). (a) an alkyl group having 1 to 4 carbon atoms, provided that
R 3 and R 4 may be the same or different; (b) [Formula] forms an ethylene group or a propylene group; (c) [Formula] is the following structural formula: (However, in the formula, R 2 is the same as defined above). ] 4-aminobutanal dialkyl acetal compound shown in water and/or a hydrophilic solvent while keeping the reaction solution acidic at a reaction temperature of 60 to 60℃.
A method for producing a 1-(3'-aminopropyl)tetrahydro-β-carboline compound of the general formula (), characterized in that the reaction is carried out at 140°C.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP10305580A JPS5728087A (en) | 1980-07-29 | 1980-07-29 | Novel 1-(3'-aminopropyl)tetrahydro-beta-carboline compound and its preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP10305580A JPS5728087A (en) | 1980-07-29 | 1980-07-29 | Novel 1-(3'-aminopropyl)tetrahydro-beta-carboline compound and its preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5728087A JPS5728087A (en) | 1982-02-15 |
| JPS6328917B2 true JPS6328917B2 (en) | 1988-06-10 |
Family
ID=14343980
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP10305580A Granted JPS5728087A (en) | 1980-07-29 | 1980-07-29 | Novel 1-(3'-aminopropyl)tetrahydro-beta-carboline compound and its preparation |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS5728087A (en) |
-
1980
- 1980-07-29 JP JP10305580A patent/JPS5728087A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5728087A (en) | 1982-02-15 |
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