JPS5817753B2 - Method for producing acid amide - Google Patents
Method for producing acid amideInfo
- Publication number
- JPS5817753B2 JPS5817753B2 JP754979A JP754979A JPS5817753B2 JP S5817753 B2 JPS5817753 B2 JP S5817753B2 JP 754979 A JP754979 A JP 754979A JP 754979 A JP754979 A JP 754979A JP S5817753 B2 JPS5817753 B2 JP S5817753B2
- Authority
- JP
- Japan
- Prior art keywords
- chloro
- benzothiazolinone
- hydroxyethyl
- carbonylmethyl
- piperazinyl
- 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
- 238000004519 manufacturing process Methods 0.000 title claims description 4
- 150000001408 amides Chemical class 0.000 title 1
- 239000003960 organic solvent Substances 0.000 claims description 8
- 125000004494 ethyl ester group Chemical group 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 5
- 238000010992 reflux Methods 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 3
- BXQNSPXDWSNUKE-UHFFFAOYSA-N 1,3-benzothiazole 1-oxide Chemical compound C1=CC=C2S(=O)C=NC2=C1 BXQNSPXDWSNUKE-UHFFFAOYSA-N 0.000 claims description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 9
- 238000009835 boiling Methods 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 3
- HTJXMOGUGMSZOG-UHFFFAOYSA-N tiaramide Chemical compound C1CN(CCO)CCN1C(=O)CN1C(=O)SC2=CC=C(Cl)C=C21 HTJXMOGUGMSZOG-UHFFFAOYSA-N 0.000 description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 2
- STDASPDWOPQGAL-UHFFFAOYSA-N 2-piperazin-1-ium-1-ylethanol;chloride Chemical compound Cl.OCCN1CCNCC1 STDASPDWOPQGAL-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- -1 amino ester Chemical class 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- WFCKVQRJUKAVBI-UHFFFAOYSA-N C(=O)=CC1=CC=CC2=C1NC(S2)=O Chemical compound C(=O)=CC1=CC=CC2=C1NC(S2)=O WFCKVQRJUKAVBI-UHFFFAOYSA-N 0.000 description 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 239000003874 central nervous system depressant Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Landscapes
- Thiazole And Isothizaole Compounds (AREA)
Description
【発明の詳細な説明】
本発明は
式
で示される５−クロロ−２−ベンゾチアゾリノン−３−
酢酸２−（１−ピペラジノ）エチルエステルを有機溶剤
中加熱還流させることを特徴とする式
で示される５−クロロ−３−（４−（２−ヒドロキシエ
チル）−１−ピペラジニル）−カルボニルメチル−２−
ベンゾチアゾリノンの製造に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention provides 5-chloro-2-benzothiazolinone-3-
5-chloro-3-(4-(2-hydroxyethyl)-1-piperazinyl)-carbonylmethyl-, which is characterized by heating refluxing acetic acid 2-(1-piperazino)ethyl ester in an organic solvent. 2-
Concerning the production of benzothiazolinone.
本発明の方法で得られる５−クロロ−３−（４−（２−
ヒドロキシエチル）−１−ピペラジニル）−カルボニル
メチル−２−ベンゾチアゾリノンはその酸付加塩類とと
もに鎮痛、消炎作用があり、また中枢神経抑制作用など
により広く医薬品として用いられている。5-chloro-3-(4-(2-
Hydroxyethyl)-1-piperazinyl)-carbonylmethyl-2-benzothiazolinone, together with its acid addition salts, has analgesic and anti-inflammatory effects, and is widely used as a medicine due to its central nervous system depressant effect.
従来式（ＩＩ）で示される５−クロ０−３−９４−（２
−ヒドロキシエチル）−１−ピペラジニル）−カルボニ
ルメチル−２−ベンゾチアゾリノンの製造方法として多
くの方法が提案されているが、工程が多く各段階の収率
が低いことから有利な方法とは言えず、本発明者らは研
究の結果、５−クロロ−２−ベンゾチアソリノン−３−
４Ｅ酸ト１−（２−ヒドロキシエチル）−ピペラジン塩
酸塩でアミンエステルとしてから酸アミドの式（■）で
示される５−クロロ−３−（４−−（２−ヒドロキシエ
チル）−ピペラジニル） −カルボニルメチル−２−ベ
ンゾチアゾリノンに変換するという今まで行なわれてい
ない反応経過を経ることにより工程の簡易化と収率の向
上に成功し、本発明を完成した。5-chloro0-3-94-(2
Many methods have been proposed for the production of -hydroxyethyl)-1-piperazinyl)-carbonylmethyl-2-benzothiazolinone, but none of them is advantageous because it involves many steps and the yield at each step is low. As a result of research, the present inventors found that 5-chloro-2-benzothiazolinone-3-
4E acid 5-chloro-3-(4-(2-hydroxyethyl)-piperazinyl)- The present invention was completed by successfully simplifying the process and improving the yield by undergoing a reaction process that had not been performed before, ie, converting it into carbonylmethyl-2-benzothiazolinone.
本発明の方法を具体的に説明する。The method of the present invention will be specifically explained.
原料物質の５−クロロ−２−ベンゾチアソリノン−３−
酢酸２−（１−ピペラジノ）エチルエステルは５−クロ
ロ−２−ベンゾチアゾリノン−３−酢酸と１−（２−ヒ
ドロキシエチル）−ピペラジン塩酸塩を二塩化メタン、
二塩化エタン、クロロホルムなどの溶媒中で加熱するこ
とにより容易に得られる。Raw material 5-chloro-2-benzothiazolinone-3-
Acetic acid 2-(1-piperazino)ethyl ester is obtained by combining 5-chloro-2-benzothiazolinone-3-acetic acid and 1-(2-hydroxyethyl)-piperazine hydrochloride with methane dichloride,
It can be easily obtained by heating in a solvent such as ethane dichloride or chloroform.
得られた淡黄褐色の粘稠な油状物は次のような物性を示
す。The obtained pale yellowish brown viscous oil exhibits the following physical properties.
屈折率 ｎＤ２５１．５８３
’ＨＮＭＲ（δ値）
１．８０（Ｓ、ＩＨ２級アミン）
２．３０〜２．９０ （ｍ、 １０Ｈ１ピペラジン環及
び直結のメチレン）
４、ｚＯ〜４．４０ （ｔ、 ２Ｈエステル基のメチレ
ン）
４．６５（Ｓ、２Ｈチアゾリノン環のＮに直結のメチレ
ン）
６．９０〜７．４２ （ｍ、３Ｈ芳香環）赤外スペクト
ル（１−１）
３３５０．２９６０．２８２０．１７４０、６７０
ここで得られるアミノエステルは塩酸塩として精製する
ことが出来るが、本発明の方法に使用する場合特にその
ような精製工程を経ることなく使用することが出来る。Refractive index nD251.583 'HNMR (δ value) 1.80 (S, IH secondary amine) 2.30-2.90 (m, 10H1 piperazine ring and directly connected methylene) 4, zO ~ 4.40 (t, 2H Methylene of ester group) 4.65 (S, methylene directly connected to N of 2H thiazolinone ring) 6.90-7.42 (m, 3H aromatic ring) Infrared spectrum (1-1) 3350.2960.2820.1740 , 670 The amino ester obtained here can be purified as a hydrochloride, but when used in the method of the present invention, it can be used without such a purification step.
上記で得られた式（Ｉ）の５−クロロ−２−ベンゾチア
ゾリノン−３−酢酸２−（１−ピペラジノ）エチルエス
テルを沸点の高い有機溶剤で加熱還流することにより目
的物の式（ＩＩ）で示される５−クロロ−３−（４−（
２−ヒドロキシエチル）−ピペラジニル）−カルボニル
メチル−２−ベンゾチアゾリノンが高収率で得られる。By heating and refluxing 5-chloro-2-benzothiazolinone-3-acetic acid 2-(1-piperazino)ethyl ester of formula (I) obtained above in an organic solvent with a high boiling point, the desired product of formula ( 5-chloro-3-(4-(
2-Hydroxyethyl)-piperazinyl)-carbonylmethyl-2-benzothiazolinone is obtained in high yield.
さらに必要があれば５−クロロ−３−（４−（２−ヒド
ロキシエチル）−ピペラジニル）−カルボニルメチル−
２−ベンゾチアゾリノンを常法により塩化水素ガスと反
応させて５−クロロ−３−（４−（２−ヒドロキシエチ
ル）−ピペラジニル）−カルボニルメチル−２−ペンツ
チアソリノンの塩酸塩を得ることが出来る。If necessary, 5-chloro-3-(4-(2-hydroxyethyl)-piperazinyl)-carbonylmethyl-
2-Benzothiazolinone is reacted with hydrogen chloride gas by a conventional method to obtain 5-chloro-3-(4-(2-hydroxyethyl)-piperazinyl)-carbonylmethyl-2-penzthiazolinone hydrochloride. I can do it.
本発明の方法に使用される有機溶剤はトルエン、キシレ
ン、テトラリンなどの高沸点芳香族炭化水素またはその
他の反応に関与しない高沸点有機溶剤が挙げられる。Examples of the organic solvent used in the method of the present invention include high-boiling aromatic hydrocarbons such as toluene, xylene, and tetralin, and other high-boiling organic solvents that do not participate in the reaction.
本発明の反応温度は特に限定されないが、通常使用され
る有機溶剤の沸点付近で行うことが望ましく、また反応
時間は使用される有機溶剤によって異なり、長時間を要
するがテトラリンのような高沸点溶剤を用いることによ
って短縮することが出来る。The reaction temperature of the present invention is not particularly limited, but it is preferable to carry out the reaction near the boiling point of a commonly used organic solvent, and the reaction time varies depending on the organic solvent used, and although it takes a long time, it is preferable to carry out the reaction at a temperature near the boiling point of a commonly used organic solvent. It can be shortened by using .
次にこの発明を実施例によって説明する。Next, the invention will be explained by way of examples.
実施例
５−クロロ−２−ベンゾチアソリノン−３−酢酸９７２
および１−（２−ヒドロキシエチル）−ピペラジン塩酸
塩９．７２を二塩化エタン１５０ｍ１に溶解し、加熱還
流しながら脱水を行う。Example 5-Chloro-2-benzothiazolinone-3-acetic acid 972
and 9.72 ml of 1-(2-hydroxyethyl)-piperazine hydrochloride are dissolved in 150 ml of dichloroethane, and dehydrated while heating under reflux.
反応終了後減圧下に二塩化エタンを留去し、残渣にトル
エンを加えて２％炭酸水素ナトリウム水溶液で中和し、
トルエン層を飽和食塩水で２回洗浄したのち硫酸マグネ
シウムで乾燥し、減圧下でトルエンを留去して粗５−ク
ロロー２−ペンゾチアゾリノ７−３−酢酸２− （１−
４−’ヘラジノ）エチルエステル１４１を得た。After the reaction was completed, ethane dichloride was distilled off under reduced pressure, toluene was added to the residue, and the mixture was neutralized with a 2% aqueous sodium hydrogen carbonate solution.
The toluene layer was washed twice with saturated brine, dried over magnesium sulfate, and the toluene was distilled off under reduced pressure to obtain crude 5-chloro-2-penzothiazolino-7-3-acetic acid 2-(1-
4-'helazino)ethyl ester 141 was obtained.
このアミンエステルをテトラリン５ｏｒｎｌに溶解し加
熱して沸点付近で５時間加熱還流したのち冷却し減圧下
にテトラリンを留去すると粗５−クロロ−３−４４−（
２−ヒドロキシエチル）−１−ピペラジニル）−カルボ
ニルメチル−２−ベンゾチアゾリノンを得た。This amine ester was dissolved in 5 ornl of tetralin, heated and refluxed for 5 hours near the boiling point, then cooled and the tetralin was distilled off under reduced pressure to obtain crude 5-chloro-3-44-(
2-Hydroxyethyl)-1-piperazinyl)-carbonylmethyl-2-benzothiazolinone was obtained.
この粗５−クロロ−３−（４，−（２−ヒドロキシエチ
ル）−１−ピペラジニル）−カルボニルメチル−２−ベ
ンゾチアゾリノンをメタノールから再結晶して融点１５
９〜１６０℃の白色結晶の目的物質１２．５２を得た。This crude 5-chloro-3-(4,-(2-hydroxyethyl)-1-piperazinyl)-carbonylmethyl-2-benzothiazolinone was recrystallized from methanol with a melting point of 15.
The desired substance 12.52 was obtained as white crystals with a temperature of 9 to 160°C.
さらにこの結晶をアセトンに溶解し、０℃で塩化水素ガ
スを注入すると５−クロロ−３−（４−（２−ヒドロキ
シエチル）−１−ヒペラジニル）−カルボニルメチル−
２−ベンゾチアゾリノンの塩酸塩を得た。Furthermore, when this crystal was dissolved in acetone and hydrogen chloride gas was injected at 0°C, 5-chloro-3-(4-(2-hydroxyethyl)-1-hyperazinyl)-carbonylmethyl-
The hydrochloride of 2-benzothiazolinone was obtained.
この塩酸塩を９５％エタ／°−ルで再結晶すれば融点２
６５℃（分解）の白色結晶が得られ、その元素分析値は
次の通りであった。If this hydrochloride is recrystallized from 95% ethanol/°-ol, it will have a melting point of 2.
White crystals at 65° C. (decomposed) were obtained, and the elemental analysis values thereof were as follows.
Claims (1)
４￥酸２− （１−ピペラジノ）エチルエステルを有機
溶剤中で加熱還流させることを特徴とする 式 で示される５−クロロ−３−（４−（２−ヒドロキシエ
チル）−１−ピペラジニル）−カルボニルメチル−２−
ベンゾチアゾリノンの製造方法。[Claims] 5-chloro-2-benzothiazolinone-3- represented by formula 1
5-chloro-3-(4-(2-hydroxyethyl)-1-piperazinyl)-, which is characterized by heating and refluxing 4￥ acid 2-(1-piperazino)ethyl ester in an organic solvent. carbonylmethyl-2-
Method for producing benzothiazolinone.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP754979A JPS5817753B2 (en) | 1979-01-24 | 1979-01-24 | Method for producing acid amide |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP754979A JPS5817753B2 (en) | 1979-01-24 | 1979-01-24 | Method for producing acid amide |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP3578179A Division JPS6032108B2 (en) | 1979-03-27 | 1979-03-27 | Device for detecting the insertion and removal of containers, etc. in automatic refrigerator management equipment |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS55100373A JPS55100373A (en) | 1980-07-31 |
| JPS5817753B2 true JPS5817753B2 (en) | 1983-04-09 |
Family
ID=11668870
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP754979A Expired JPS5817753B2 (en) | 1979-01-24 | 1979-01-24 | Method for producing acid amide |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS5817753B2 (en) |
-
1979
- 1979-01-24 JP JP754979A patent/JPS5817753B2/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| JPS55100373A (en) | 1980-07-31 |
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