JPS6345380B2 - - Google Patents
Info
- Publication number
- JPS6345380B2 JPS6345380B2 JP55010399A JP1039980A JPS6345380B2 JP S6345380 B2 JPS6345380 B2 JP S6345380B2 JP 55010399 A JP55010399 A JP 55010399A JP 1039980 A JP1039980 A JP 1039980A JP S6345380 B2 JPS6345380 B2 JP S6345380B2
- Authority
- JP
- Japan
- Prior art keywords
- formula
- general formula
- chloride
- producing
- reaction
- 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
- 150000001875 compounds Chemical class 0.000 claims description 10
- 239000002841 Lewis acid Substances 0.000 claims description 9
- 150000007517 lewis acids Chemical class 0.000 claims description 9
- 239000002876 beta blocker Substances 0.000 claims description 7
- 229940097320 beta blocking agent Drugs 0.000 claims description 7
- 150000003512 tertiary amines Chemical class 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 3
- 125000001589 carboacyl group Chemical group 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 230000007062 hydrolysis Effects 0.000 claims description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims description 3
- 125000006239 protecting group Chemical group 0.000 claims description 3
- 125000003435 aroyl group Chemical group 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 238000000034 method Methods 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims 1
- 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
- 238000006243 chemical reaction Methods 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000013078 crystal Substances 0.000 description 5
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 4
- LWBPNIJBHRISSS-UHFFFAOYSA-L beryllium dichloride Chemical compound Cl[Be]Cl LWBPNIJBHRISSS-UHFFFAOYSA-L 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 3
- KCHKODKUEPEHCC-UHFFFAOYSA-N 1-[1-(4-methylphenyl)sulfonylindol-4-yl]oxy-3-(propan-2-ylamino)propan-2-ol Chemical compound C1=CC=2C(OCC(O)CNC(C)C)=CC=CC=2N1S(=O)(=O)C1=CC=C(C)C=C1 KCHKODKUEPEHCC-UHFFFAOYSA-N 0.000 description 2
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 2
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 229910001627 beryllium chloride Inorganic materials 0.000 description 2
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- -1 etc.) Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 229960002508 pindolol Drugs 0.000 description 2
- PHUTUTUABXHXLW-UHFFFAOYSA-N pindolol Chemical compound CC(C)NCC(O)COC1=CC=CC2=NC=C[C]12 PHUTUTUABXHXLW-UHFFFAOYSA-N 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000001179 sorption measurement Methods 0.000 description 2
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 2
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- OFDISMSWWNOGFW-UHFFFAOYSA-N 1-(4-ethoxy-3-fluorophenyl)ethanamine Chemical compound CCOC1=CC=C(C(C)N)C=C1F OFDISMSWWNOGFW-UHFFFAOYSA-N 0.000 description 1
- FMEHIMDNLRASDU-UHFFFAOYSA-N 1-azabicyclo[3.3.1]nonane Chemical compound C1CCN2CCCC1C2 FMEHIMDNLRASDU-UHFFFAOYSA-N 0.000 description 1
- VXEGSRKPIUDPQT-UHFFFAOYSA-N 4-[4-(4-methoxyphenyl)piperazin-1-yl]aniline Chemical compound C1=CC(OC)=CC=C1N1CCN(C=2C=CC(N)=CC=2)CC1 VXEGSRKPIUDPQT-UHFFFAOYSA-N 0.000 description 1
- HVCNXQOWACZAFN-UHFFFAOYSA-N 4-ethylmorpholine Chemical compound CCN1CCOCC1 HVCNXQOWACZAFN-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- MKYBYDHXWVHEJW-UHFFFAOYSA-N N-[1-oxo-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propan-2-yl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(C(C)NC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 MKYBYDHXWVHEJW-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-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
- 238000000862 absorption spectrum Methods 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- DAMJCWMGELCIMI-UHFFFAOYSA-N benzyl n-(2-oxopyrrolidin-3-yl)carbamate Chemical compound C=1C=CC=CC=1COC(=O)NC1CCNC1=O DAMJCWMGELCIMI-UHFFFAOYSA-N 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000004210 ether based solvent Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- DIAIBWNEUYXDNL-UHFFFAOYSA-N n,n-dihexylhexan-1-amine Chemical compound CCCCCCN(CCCCCC)CCCCCC DIAIBWNEUYXDNL-UHFFFAOYSA-N 0.000 description 1
- XTAZYLNFDRKIHJ-UHFFFAOYSA-N n,n-dioctyloctan-1-amine Chemical compound CCCCCCCCN(CCCCCCCC)CCCCCCCC XTAZYLNFDRKIHJ-UHFFFAOYSA-N 0.000 description 1
- OOHAUGDGCWURIT-UHFFFAOYSA-N n,n-dipentylpentan-1-amine Chemical compound CCCCCN(CCCCC)CCCCC OOHAUGDGCWURIT-UHFFFAOYSA-N 0.000 description 1
- SNMVRZFUUCLYTO-UHFFFAOYSA-N n-propyl chloride Chemical compound CCCCl SNMVRZFUUCLYTO-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- YHBDIEWMOMLKOO-UHFFFAOYSA-I pentachloroniobium Chemical compound Cl[Nb](Cl)(Cl)(Cl)Cl YHBDIEWMOMLKOO-UHFFFAOYSA-I 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000005049 silicon tetrachloride Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- DUNKXUFBGCUVQW-UHFFFAOYSA-J zirconium tetrachloride Chemical compound Cl[Zr](Cl)(Cl)Cl DUNKXUFBGCUVQW-UHFFFAOYSA-J 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
本発明はβ遮断剤の新規製造法に関する。更に
詳しくは、下記一般式（）で示される化合物
に、不活性溶媒中、第３級アミンの存在または不
存在下にルイス酸を作用させて一般式（）で示
される化合物を製造したのち、保護基であるR1
で表わされるアリールスルホニル、低級アルカノ
イルまたはアロアル基を塩基による加水分解で脱
離させて一般式（）で表わされる化合物を製造
することを特徴とするβ遮断剤の新製法に関す
る。
（式中、
Ｘはハロゲン、
Ｙは直鎖または分枝状の低級アルキル、
Ｒは水素または低級アルキル、
R1はアリールスルホニル、低級アルカノイル
またはアロイルを各々表わす）
近年、循環器疾患の治療薬としてβ遮断剤の有
用性が注目され、それに伴い次々と新しいβ遮断
剤が開発されている。本発明者は産業上利用価値
の高いβ遮断剤の製法を研究し、特願昭54−
27010号（特開昭55−118432号公報）の発明を完
成したが、より簡便に、効率よく、かつ安価な製
造法を見出すべく鋭意研究した結果、本発明を完
成するに至つた。
一般式（）で示される本発明の生成物は、ピ
ンドロール（特公昭42−9954）、メピンドール
（特公昭43−26620）など公知のβ遮断剤を包含す
る。
上記一般式中、Ｘで示されるハロゲンとは、ク
ロロ、ブロモ、またはヨードを意味する。Ｙで示
される直鎖状または分岐状の低級アルキルは炭素
数１〜５のアルキルを意味し、たとえばメチル、
エチル、プロピル、イソプロピル、ブチル、イソ
ブチルなどである。
原料化合物（）は、前述の特願昭54−27010
（特開昭55−118432号公報）に記載の方法で容易
に製造しうる。
前記本発明の反応条件を以下に詳述する。
(1) 不活性溶媒
代表的な溶媒としては炭化水素系溶媒（ベンゼ
ン、トルエン、キシレンなど）、ハロゲン化炭化
水素系溶媒（塩化メチレン、塩化プロピル、１，
２―ジクロロエタン、クロロホルムなど）、エー
テル系溶媒（ジエチルエーテル、ジオキサンな
ど）、ニトロメタンなどを例示できる。これらは
単独または混合物として用いる。
(2) ルイス酸
代表的なルイス酸としては塩化ベリリウム、塩
化ホウ素、臭化ホウ素、塩化マグネシウム、塩化
アルミニウム、四塩化ケイ素、四塩化ジルコニウ
ム、四塩化チタン、塩化第二スズ、三塩化アンチ
モン、五塩化ニオブ、四塩化テルルなどを例示で
きる。殊に塩化ベリリウム、塩化ホウ素、臭化ホ
ウ素、塩化アルミニウム、四塩化チタン、塩化第
二スズなどが好ましい。このルイス酸は上記例示
物に限定されるものではなく、反応条件に応じて
公知ルイス酸から適宜選択できる。ルイス酸使用
量は原料（）または（）に対して当量または
過剰量、殊に１〜６当量が好適である。
(3) 第３級アミン
代表的な第３級アミンとしてはトリエチルアミ
ン、トリプロピルアミン、トリ―ｎ―ブチルアミ
ン、トリ―ｎ―ヘキシルアミン、トリ―ｎ―オク
チルアミン、トリアミルアミン、トリ―ｎ―ラウ
リルアミン、ジヘキシルエチルアミン、ジメチル
フエニルアミン、１―メチルピペリジン、４―メ
チルモルホリン、４―エチルモルホリン、１，４
―ジアザビシクロ［2.2.2］オクタン、１―アザ
ビシクロ［3.3.1］ノナン、１，５―ジアザビシ
クロ［5.4.0］ウンデセン―５、１，５―ジアザ
ビシクロ［3.4.0］ノネン―５などを例示できる。
第３級アミンの使用量は原料（）に対して当量
または過剰量、殊に１〜８当量が好適である。こ
れらの第３級アミンは反応促進剤であつて、添加
しなくても反応は進行する。
(4) 反応温度・反応時間
好適な反応温度は冷却下〜室温下、殊に−80℃
〜20℃である。好適な反応時間は通常0.1〜50時
間である。これらは溶媒、ルイス酸、第３級アミ
ンまたはその量比などにより変動する。
(5) 脱保護
R1で表わされる保護基は常法によりアルカリ
金属塩基で加水分解すれば脱保護できる。
(6) 後処理
粗生成物は濃縮、洗浄、吸着、抽出、沈澱、結
晶化などの常法により未反応原料、溶媒、過剰の
試薬、副生物などから分離し、分別抽出、再結
晶、洗浄、吸着、溶出、クロマトグラフイーなど
の常法により精製できる。
(7) 略号 Ts＝ｐ―トルエンスルホニル。
Me＝メチル。ｉ―pr＝イソプロピル。
以下に実施例を示して本発明の態様を示す。
実施例 ―１
4′―イソプロピルアミノメチル―５―ブロモ―
１―ｐ―トルエンスルホニル―４，５，６，７―
テトラヒドロインドール―４―スピロ―2′―
［１，３］ジオキソラン1.09ｇおよびトリエチル
アミン1.576μlをジクロロメタン16.5mlに溶かし、
−60℃で撹拌下に塩化第二スズ0.65mlのジクロロ
メタン5.5ml溶液を滴下する。反応混液を室温ま
で加温し、５時間撹拌を続け、濃縮後、5N―水
酸化ナトリウム水溶液および酢酸エチルを加えて
振り分ける。酢酸エチル層を分取し、水洗し、硫
酸ナトリウムで乾燥した後、減圧濃縮すると、粗
生成物800mg（収率87.9％）を得る。これを酢酸
エチルで処理すると純粋な目的生成物、４―（２
―ヒドロキシ―３―イソプロピルアミノプロポキ
シ）―１―ｐ―トルエンスルホニルインドール
610mg（収率67％）を泡状物として得る。
NMR：δCD3SOCD30.97d（6.5Hz）6H，2.29S3H，
2.56〜2.90m3H，3.76〜4.20m3H，6.71〜7.92m
（生成物の塩酸塩）
NMR：δCD3SOCD31.28d（6.5Hz）6H，2.29S3H，
2.76〜3.58m，3.93〜4.53m3H，5.92brs1H，
6.73〜7.00m2H，7.15〜7.96m7H，9.09brs2H
実施例 ―２〜20
実施例―１で得られる化合物は以下の表に示
す反応条件によつても得られる。
The present invention relates to a novel method for producing β-blockers. More specifically, after producing a compound represented by the general formula () by reacting a Lewis acid with the compound represented by the following general formula () in an inert solvent in the presence or absence of a tertiary amine, R 1 is a protecting group
The present invention relates to a new method for producing a β-blocker, which comprises producing a compound represented by the general formula () by removing the arylsulfonyl, lower alkanoyl, or aroal group represented by the formula (2) by hydrolysis with a base. (In the formula, X represents halogen, Y represents linear or branched lower alkyl, R represents hydrogen or lower alkyl, and R 1 represents arylsulfonyl, lower alkanoyl or aroyl, respectively.) In recent years, it has been used as a therapeutic agent for cardiovascular diseases. The usefulness of β-blockers has attracted attention, and new β-blockers are being developed one after another. The present inventor researched a method for producing β-blockers that have high industrial value, and filed a patent application for
Although the invention of No. 27010 (Japanese Patent Application Laid-open No. 118432/1983) was completed, the present invention was completed as a result of intensive research to find a simpler, more efficient, and cheaper manufacturing method. The products of the present invention represented by the general formula () include known β-blockers such as pindolol (Japanese Patent Publication No. 42-9954) and mepindol (Japanese Patent Publication No. 43-26620). In the above general formula, the halogen represented by X means chloro, bromo, or iodo. The linear or branched lower alkyl represented by Y means an alkyl having 1 to 5 carbon atoms, such as methyl,
Ethyl, propyl, isopropyl, butyl, isobutyl, etc. The raw material compound () is based on the above-mentioned patent application No. 54-27010.
It can be easily produced by the method described in JP-A-55-118432. The reaction conditions of the present invention will be described in detail below. (1) Inert solvent Typical solvents include hydrocarbon solvents (benzene, toluene, xylene, etc.), halogenated hydrocarbon solvents (methylene chloride, propyl chloride,
Examples include 2-dichloroethane, chloroform, etc.), ether solvents (diethyl ether, dioxane, etc.), and nitromethane. These may be used alone or as a mixture. (2) Lewis acids Typical Lewis acids include beryllium chloride, boron chloride, boron bromide, magnesium chloride, aluminum chloride, silicon tetrachloride, zirconium tetrachloride, titanium tetrachloride, tin chloride, antimony trichloride, and Examples include niobium chloride and tellurium tetrachloride. Particularly preferred are beryllium chloride, boron chloride, boron bromide, aluminum chloride, titanium tetrachloride, and stannic chloride. This Lewis acid is not limited to the above-mentioned examples, and can be appropriately selected from known Lewis acids depending on the reaction conditions. The amount of Lewis acid used is preferably an equivalent or excess amount, particularly 1 to 6 equivalents, relative to the raw material () or (). (3) Tertiary amine Typical tertiary amines include triethylamine, tripropylamine, tri-n-butylamine, tri-n-hexylamine, tri-n-octylamine, triamylamine, tri-n- Laurylamine, dihexylethylamine, dimethylphenylamine, 1-methylpiperidine, 4-methylmorpholine, 4-ethylmorpholine, 1,4
-Diazabicyclo[2.2.2]octane, 1-azabicyclo[3.3.1]nonane, 1,5-diazabicyclo[5.4.0]undecene-5, 1,5-diazabicyclo[3.4.0]nonene-5, etc. .
The amount of tertiary amine to be used is preferably an equivalent or excess amount, particularly 1 to 8 equivalents, relative to the raw material (). These tertiary amines are reaction accelerators, and the reaction proceeds even if they are not added. (4) Reaction temperature/reaction time The preferred reaction temperature is between cooling and room temperature, especially -80℃.
~20℃. Suitable reaction times are usually 0.1 to 50 hours. These vary depending on the solvent, Lewis acid, tertiary amine or their quantitative ratio. (5) Deprotection The protecting group represented by R 1 can be deprotected by hydrolysis with an alkali metal base in a conventional manner. (6) Post-treatment The crude product is separated from unreacted raw materials, solvents, excess reagents, by-products, etc. by conventional methods such as concentration, washing, adsorption, extraction, precipitation, and crystallization, followed by fractional extraction, recrystallization, and washing. It can be purified by conventional methods such as , adsorption, elution, and chromatography. (7) Abbreviation T s = p-toluenesulfonyl. Me=methyl. i-pr=isopropyl. Examples are shown below to illustrate aspects of the present invention. Example-1 4'-isopropylaminomethyl-5-bromo-
1-p-toluenesulfonyl-4,5,6,7-
Tetrahydroindole-4-spiro-2'-
[1,3] Dissolve 1.09 g of dioxolane and 1.576 μl of triethylamine in 16.5 ml of dichloromethane,
A solution of 0.65 ml of stannic chloride in 5.5 ml of dichloromethane is added dropwise under stirring at -60°C. The reaction mixture is warmed to room temperature, stirred for 5 hours, concentrated, and then 5N aqueous sodium hydroxide and ethyl acetate are added and separated. The ethyl acetate layer is separated, washed with water, dried over sodium sulfate, and concentrated under reduced pressure to obtain 800 mg of crude product (yield: 87.9%). Treatment of this with ethyl acetate yields the pure desired product, 4-(2
-Hydroxy-3-isopropylaminopropoxy)-1-p-toluenesulfonylindole
610 mg (67% yield) are obtained as a foam. NMR: δ CD3SOCD3 0.97d (6.5Hz) 6H, 2.29S3H,
2.56-2.90m3H, 3.76-4.20m3H, 6.71-7.92m (hydrochloride of product) NMR: δ CD3SOCD3 1.28d (6.5Hz) 6H, 2.29S3H,
2.76~3.58m, 3.93~4.53m3H, 5.92brs1H,
6.73-7.00m2H, 7.15-7.96m7H, 9.09brs2H Examples-2-20 The compounds obtained in Example-1 can also be obtained under the reaction conditions shown in the table below.
【表】【table】
【表】
実施例 ―１
４―（３―イソプロピルアミノ―２―ヒドロキ
シプロポキシ）―１―ｐ―トルエンスルホニルイ
ンドール100部をエタノール500部にとかし、1N
―水酸化ナトリウム36部を加えて冷却器を付した
フラスコ内で４時間加熱還流する。反応液に1N
―硫酸11部を加えたのち、窒素気流中、結晶析出
が始まるまで濃縮したのち、氷室中に一夜放置す
る。析出した結晶を濾取し、希エタノール100部
で洗う。この粗結晶をエタノールから再結晶すれ
ば４―（３―イソプロピルアミノ―２―ヒドロキ
シブロポキシ）インドールの針状晶45部（収率：
75.5％）を得る。mp172〜173℃）。この結晶はピ
ンドロール標品（mp172.5〜173℃）と混融試験
よび薄層クロマトグラム、赤外吸収スペクトル、
核磁気共鳴スペクトルの比較により同定できる。
実施例 ―２〜４
実施例―１と同様の条件下に対応化合物
（）にルイス酸を作用させて製造した化合物
（）を実施例―１と同様の条件下に水酸化ナ
トリウムで加水分解すれば下記化合物（）を製
造できる。[Table] Example-1 Dissolve 100 parts of 4-(3-isopropylamino-2-hydroxypropoxy)-1-p-toluenesulfonylindole in 500 parts of ethanol, and add 1N
- Add 36 parts of sodium hydroxide and heat under reflux for 4 hours in a flask equipped with a condenser. 1N to reaction solution
- After adding 11 parts of sulfuric acid, concentrate in a nitrogen stream until crystal precipitation begins, then leave in an ice chamber overnight. Filter the precipitated crystals and wash with 100 parts of diluted ethanol. If this crude crystal is recrystallized from ethanol, 45 parts of needle crystals of 4-(3-isopropylamino-2-hydroxybropoxy)indole (yield:
75.5%). mp172-173℃). This crystal was tested with a pindolol sample (mp 172.5-173°C), mixed melting test, thin layer chromatogram, infrared absorption spectrum,
Identification can be made by comparing nuclear magnetic resonance spectra. Examples 2 to 4 Compounds () produced by reacting Lewis acids to the corresponding compounds () under the same conditions as in Example-1 were hydrolyzed with sodium hydroxide under the same conditions as in Example-1. The following compound () can be produced.
Claims (1)
またはアロイルを各々表わす） で示される化合物に、不活性溶媒中、第３級アミ
ンの存在または不存在下にルイス酸を作用させて
一般式 （式中、Ｙ、R1、R2は前記と同意義） で示される化合物を製造したのち、保護基R1を
塩基による加水分解で脱離させて 一般式 （式中、Ｙ、R1、R2は前記と同意義） で表わされる化合物を製造することを特徴とする
β遮断剤の合成法。[Claims] 1. General formula (In the formula, X is halogen, Y is linear or branched lower alkyl, R is hydrogen or lower alkyl, and R 1 is arylsulfonyl, lower alkanoyl, or aroyl, respectively.) In a solvent, in the presence or absence of a tertiary amine, a Lewis acid is reacted to form the general formula (In the formula, Y, R 1 , and R 2 have the same meanings as above.) After producing the compound represented by the formula, the protecting group R 1 is removed by hydrolysis with a base, and the general formula (In the formula, Y, R 1 and R 2 have the same meanings as above.) A method for synthesizing a β-blocker, characterized by producing a compound represented by the following.
Priority Applications (12)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1039980A JPS56108764A (en) | 1980-01-30 | 1980-01-30 | Novel synthesis of beta-blocker |
| CA000346987A CA1139760A (en) | 1979-03-07 | 1980-03-04 | 1,4-dioxaspiro¬4,5| decene compounds |
| US06/127,521 US4506079A (en) | 1979-03-07 | 1980-03-05 | Process for preparing indoles |
| FR8005051A FR2450829A1 (en) | 1979-03-07 | 1980-03-06 | PROCESS FOR THE PREPARATION OF 1,4-DIOXASPIRO- (4,5) DECENE COMPOUNDS AND NOVEL PRODUCTS THUS OBTAINED |
| CH178780A CH646968A5 (en) | 1979-03-07 | 1980-03-06 | 1,4-DIOXASPIRO (4,5) DECENE COMPOUNDS AND METHOD FOR PRODUCING 2-HYDROXY-3-SUBSTITUTED PROPYLARYLAETHERS. |
| DE19803008902 DE3008902A1 (en) | 1979-03-07 | 1980-03-07 | 1,4-DIOXASPIRO SQUARE CLAMP ON 4.5 SQUARE CLAMP FOR DECEN DERIVATIVES |
| IT67367/80A IT1129805B (en) | 1979-03-07 | 1980-03-07 | COMPOUNDS OF 1 4 DIOSSASPIRO 4 5 DE CENE PARTICULARLY USEFUL AS IN TERMEDI FOR THE PREPARATION OF BETA CLINICAL LOCK |
| GB8007793A GB2058745B (en) | 1979-03-07 | 1980-03-07 | 1,4-dioxospiro(4,5)decene compounds |
| HU20281A HU183321B (en) | 1980-01-30 | 1981-01-29 | Process for preparing indole derivatives with beta-blocking activity |
| PL22946181A PL229461A1 (en) | 1980-01-30 | 1981-01-30 | |
| CA000407793A CA1180326A (en) | 1979-03-07 | 1982-07-21 | 1,4-dioxaspiro[4,5]decene compounds |
| US06/684,090 US4582905A (en) | 1979-03-07 | 1984-12-20 | 1,4-Dioxaspiro(4,5)decene compounds |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1039980A JPS56108764A (en) | 1980-01-30 | 1980-01-30 | Novel synthesis of beta-blocker |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS56108764A JPS56108764A (en) | 1981-08-28 |
| JPS6345380B2 true JPS6345380B2 (en) | 1988-09-09 |
Family
ID=11749049
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1039980A Granted JPS56108764A (en) | 1979-03-07 | 1980-01-30 | Novel synthesis of beta-blocker |
Country Status (3)
| Country | Link |
|---|---|
| JP (1) | JPS56108764A (en) |
| HU (1) | HU183321B (en) |
| PL (1) | PL229461A1 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20200059721A (en) * | 2018-11-21 | 2020-05-29 | 엘지디스플레이 주식회사 | Display device and tiling display device |
| WO2020178911A1 (en) * | 2019-03-01 | 2020-09-10 | 三菱電機株式会社 | Multi-display system and video display device |
| KR20210015058A (en) * | 2019-07-31 | 2021-02-10 | 엘지디스플레이 주식회사 | Display Apparatus |
-
1980
- 1980-01-30 JP JP1039980A patent/JPS56108764A/en active Granted
-
1981
- 1981-01-29 HU HU20281A patent/HU183321B/en not_active IP Right Cessation
- 1981-01-30 PL PL22946181A patent/PL229461A1/xx unknown
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20200059721A (en) * | 2018-11-21 | 2020-05-29 | 엘지디스플레이 주식회사 | Display device and tiling display device |
| WO2020178911A1 (en) * | 2019-03-01 | 2020-09-10 | 三菱電機株式会社 | Multi-display system and video display device |
| KR20210015058A (en) * | 2019-07-31 | 2021-02-10 | 엘지디스플레이 주식회사 | Display Apparatus |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS56108764A (en) | 1981-08-28 |
| PL229461A1 (en) | 1981-10-16 |
| HU183321B (en) | 1984-04-28 |
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