JPH06298750A - Production of 1,5-benzothiazepin derivative - Google Patents
Production of 1,5-benzothiazepin derivativeInfo
- Publication number
- JPH06298750A JPH06298750A JP6054228A JP5422894A JPH06298750A JP H06298750 A JPH06298750 A JP H06298750A JP 6054228 A JP6054228 A JP 6054228A JP 5422894 A JP5422894 A JP 5422894A JP H06298750 A JPH06298750 A JP H06298750A
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- JP
- Japan
- Prior art keywords
- lower alkyl
- compound
- general formula
- alkyl group
- hydrogen atom
- 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.)
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- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は一般式〔Ｉ〕The present invention relates to the general formula [I]
【０００２】[0002]
【化９】 [Chemical 9]
【０００３】（但し、Ｒ1 及びＲ2 はいずれか一方が低
級アルキル基又はハロゲン原子、他方が水素原子、Ｒ3
は低級アルキル基又は低級アルコキシ基を表す。）で示
される１，５−ベンゾチアゼピン誘導体の新規製法に関
する。(However, one of R 1 and R 2 is a lower alkyl group or a halogen atom, the other is a hydrogen atom, R 3
Represents a lower alkyl group or a lower alkoxy group. ) Relating to a novel process for producing a 1,5-benzothiazepine derivative.
【０００４】[0004]
【従来の技術】上記１，５−ベンゾチアゼピン誘導体
〔Ｉ〕は、例えば優れた降圧作用を有する対応する３−
アセトキシ−５−〔２−（ジメチルアミノ）エチル〕−
１，５−ベンゾチアゼピン誘導体の合成中間体として有
用な化合物である。2. Description of the Related Art The 1,5-benzothiazepine derivative [I] described above is a corresponding 3- (3-) compound having an excellent antihypertensive effect.
Acetoxy-5- [2- (dimethylamino) ethyl]-
It is a compound useful as a synthetic intermediate for 1,5-benzothiazepine derivatives.
【０００５】従来、１，５−ベンゾチアゼピン誘導体
〔Ｉ〕の製法としては、一般式Conventionally, as a method for producing a 1,5-benzothiazepine derivative [I], a general formula has been used.
【０００６】[0006]
【化１０】 [Chemical 10]
【０００７】（但し、Ｒa 及びＲb はいずれか一方が低
級アルキル基又はハロゲン原子、他方が水素原子、Ｒc
は低級アルキル基又は低級アルコキシ基、Ｒd は水素原
子又はエステル残基を表す。）で示されるプロピオン酸
誘導体を、溶媒（例えば、キシレン）中で加熱して分子
内閉環させる方法が知られている（特開昭５９−２２５
１７４及び同６０−２０２８７１）。しかしながら、こ
の方法は、分子内閉環反応に長時間を要するという難点
があり、工業的製法としては必ずしも満足しうるもので
はなかった。(However, one of R a and R b is a lower alkyl group or a halogen atom, the other is a hydrogen atom, R c
Is a lower alkyl group or a lower alkoxy group, and R d represents a hydrogen atom or an ester residue. A method is known in which a propionic acid derivative represented by the formula (4) is heated in a solvent (for example, xylene) to ring-close the molecule (JP-A-59-225).
174 and 60-202871). However, this method has a drawback that it takes a long time for the intramolecular ring closure reaction, and is not necessarily satisfactory as an industrial production method.
【０００８】本発明者らは種々研究を重ねた結果、一般
式〔ＩＩ〕As a result of various studies conducted by the present inventors, the general formula [II]
【０００９】[0009]
【化１１】 [Chemical 11]
【００１０】（但し、Ｒ1 、Ｒ2 及びＲ3 は前記と同一
意味を表し、Ｒ4 はｉ）Ｒ1 及びＲ2のいずれか一方が
低級アルキル基、他方が水素原子のときは、水素原子又
はエステル残基を表し、ｉｉ）Ｒ1 及びＲ2 のいずれか
一方がハロゲン原子、他方が水素原子のときは、水素原
子を表す。）で示される化合物を特定のスルホン酸化合
物の存在下に分子内閉環すれば、短時間の反応で収率よ
く化合物〔Ｉ〕を製造しうることを見い出し、本発明を
完成するに至った。(Wherein R 1 , R 2 and R 3 have the same meanings as described above, and R 4 is i) When one of R 1 and R 2 is a lower alkyl group and the other is a hydrogen atom, hydrogen is used. Represents an atom or an ester residue, and ii) represents a hydrogen atom when one of R 1 and R 2 is a halogen atom and the other is a hydrogen atom. It was found that the compound [I] can be produced in a good yield by a short reaction when the compound represented by the formula (1) is intramolecularly ring-closed in the presence of a specific sulfonic acid compound, and the present invention has been completed.
【００１１】[0011]
【発明が解決しようとする課題】本発明は、例えば優れ
た降圧作用を有する３−アセトキシ−５−〔２−（ジメ
チルアミノ）エチル〕−１，５−ベンゾチアゼピン誘導
体の合成中間体として有用な１，５−ベンゾチアゼピン
誘導体を、短時間の反応で、高収率で純度よく製造する
方法を提供するものである。INDUSTRIAL APPLICABILITY The present invention is useful, for example, as a synthetic intermediate for 3-acetoxy-5- [2- (dimethylamino) ethyl] -1,5-benzothiazepine derivative having an excellent antihypertensive effect. The present invention provides a method for producing a good 1,5-benzothiazepine derivative in a short period of time with high yield and high purity.
【００１２】[0012]
【課題を解決するための手段】本発明によれば、１，５
−ベンゾチアゼピン誘導体〔Ｉ〕は、一般式〔ＩＩ〕According to the present invention, 1,5
The benzothiazepine derivative [I] has the general formula [II]
【００１３】[0013]
【化１２】 [Chemical 12]
【００１４】（但し、記号は前記と同一意味を有す
る。）で示されるプロピオン酸誘導体を、一般式〔ＩＩ
Ｉ〕(Where the symbols have the same meanings as described above), a propionic acid derivative represented by the general formula [II
I]
【００１５】[0015]
【化１３】 [Chemical 13]
【００１６】（但し、Ｒ5 は低級アルキル基又は置換も
しくは非置換フェニル基を表す。）で示されるスルホン
酸化合物の存在下に分子内閉環反応に付すことにより、
製造することができる。(Wherein R 5 represents a lower alkyl group or a substituted or unsubstituted phenyl group) is subjected to an intramolecular ring closure reaction in the presence of a sulfonic acid compound,
It can be manufactured.
【００１７】本発明の分子内閉環反応で使用するスルホ
ン酸化合物〔ＩＩＩ〕としては、例えば一般式〔ＩＩ
Ｉ〕においてＲ5 がメチル基、エチル基、プロピル基又
はブチル基の如き炭素数１〜４のアルキル基又はこれら
アルキル基で置換されていてもよいフェニル基である化
合物があげられ、とりわけメタンスルホン酸又はトルエ
ンスルホン酸を用いるのが好ましい。本スルホン酸化合
物の使用量は特に制限されないが、通常化合物〔ＩＩ〕
に対し０．５〜１０ｗ／ｗ％、好ましくは１〜６ｗ／ｗ
％程度の割合で用いるのがよい。Examples of the sulfonic acid compound [III] used in the intramolecular ring closure reaction of the present invention include compounds represented by the general formula [II]
In the above [I], compounds in which R 5 is an alkyl group having 1 to 4 carbon atoms such as a methyl group, an ethyl group, a propyl group or a butyl group, or a phenyl group which may be substituted with these alkyl groups, and particularly methanesulfone Preference is given to using acids or toluenesulphonic acid. The amount of the sulfonic acid compound used is not particularly limited, but it is usually compound [II]
To 0.5 to 10 w / w%, preferably 1 to 6 w / w
It is preferable to use it at a ratio of about%.
【００１８】本分子内閉環反応は、適当な溶媒中、加熱
還流下に実施するのが好ましい。溶媒としては、キシレ
ン、トルエン、ジクロロベンゼンなどの高沸点溶媒を使
用するのが好ましく、とりわけキシレンを用いるのが好
ましい。反応時間はスルホン酸化合物を存在させない場
合に比べて、極めて短時間でよく、例えば溶媒としてキ
シレンを用いる場合には３０分〜４時間程度で終結させ
ることができる。The intramolecular ring-closing reaction is preferably carried out in a suitable solvent with heating under reflux. As the solvent, it is preferable to use a high boiling point solvent such as xylene, toluene or dichlorobenzene, and it is particularly preferable to use xylene. The reaction time may be extremely short as compared with the case where no sulfonic acid compound is present. For example, when xylene is used as a solvent, the reaction can be completed in about 30 minutes to 4 hours.
【００１９】生成した目的化合物〔Ｉ〕は、例えば反応
液を冷却して析出する結晶をろ取し、適当な溶媒（例え
ば、エタノール、含水エタノール）で洗浄する如き簡易
な操作で、スルホン酸化合物〔ＩＩＩ〕を含まない純品
として単離することができる。The produced target compound [I] can be obtained by a simple operation, for example, by cooling the reaction solution, collecting precipitated crystals by filtration, and washing with a suitable solvent (eg, ethanol, hydrous ethanol). It can be isolated as a pure product containing no [III].
【００２０】上記の如き本発明方法によれば、分子内閉
環反応を短時間で終結せしめることができると共に、高
収率で純度よく目的化合物を得ることができるので、ス
ルホン酸化合物の非存在下で実施する従来法に較べて、
工業的に極めて優れたものである。According to the method of the present invention as described above, the intramolecular ring-closing reaction can be terminated in a short time, and the target compound can be obtained in high yield and in high purity. Therefore, in the absence of the sulfonic acid compound. Compared with the conventional method implemented in
It is extremely excellent industrially.
【００２１】なお、原料化合物〔ＩＩ〕は、例えば特開
昭５９−２２５１７４又は同６０−２０２８７１に記載
の方法により製造することができるが、このうち、一般
式〔ＩＩ−ａ〕The starting compound [II] can be produced, for example, by the method described in JP-A-59-225174 or 60-202871, among which the general formula [II-a] is used.
【００２２】[0022]
【化１４】 [Chemical 14]
【００２３】（但し、Ｒ11及びＲ21はいずれか一方が低
級アルキル基、他方が水素原子、Ｒ41はエステル残基、
＊は当該炭素原子が不斉炭素原子であることを表し、Ｒ
3 は前記と同一意味を有する。）で示される光学活性ス
レオプロピオン酸エステル誘導体は、一般式〔ＩＶ〕(However, one of R 11 and R 21 is a lower alkyl group, the other is a hydrogen atom, R 41 is an ester residue,
* Indicates that the carbon atom is an asymmetric carbon atom, and R
3 has the same meaning as above. ) Is an optically active threopropionate derivative represented by the general formula [IV]
【００２４】[0024]
【化１５】 [Chemical 15]
【００２５】（但し、記号は前記と同一意味を有す
る。）で示されるチオフェノール化合物と、一般式
〔Ｖ〕(Where the symbols have the same meanings as described above) and a thiophenol compound represented by the general formula [V]
【００２６】[0026]
【化１６】 [Chemical 16]
【００２７】（但し、記号は前記と同一意味を有す
る。）で示される光学活性トランスグリシッド酸エステ
ルとを反応させることによっても製造することができ
る。この反応は適当な溶媒（例えば、キシレン、トルエ
ン等）中、加熱下に実施するのが好ましく、反応は円滑
に進行する。化合物〔ＩＩ−ａ〕は単離してもよいが、
単離せず反応液のまま次の分子内閉環反応に付すことも
でき、その場合、同一反応器中で化合物〔ＩＶ〕から短
時間でかつ収率よく光学活性な目的化合物〔Ｉ−ａ〕を
得られるので工業的に極めて有利となる。It can also be produced by reacting with an optically active transglycidic acid ester represented by the symbol (where the symbols have the same meaning as described above). This reaction is preferably carried out in a suitable solvent (eg, xylene, toluene, etc.) under heating, and the reaction proceeds smoothly. Compound [II-a] may be isolated,
The reaction solution can be directly subjected to the next intramolecular ring-closing reaction without isolation, and in this case, the optically active target compound [Ia] can be obtained from the compound [IV] in the same reaction vessel in a short time and in good yield. Since it is obtained, it is extremely advantageous industrially.
【００２８】[0028]
実施例１ （＋）−スレオ−２−ヒドロキシ−３−（２−アミノ−
５−クロロフェニルチオ）−３−（４−メトキシフェニ
ル）プロピオン酸１７．０ｇ、ｐ−トルエンスルホン酸
水和物０．９１ｇ及びキシレン２２０ｍｌの混合物を脱
水装置で水を除去しながら２時間加熱還流する。冷後析
出晶をろ取し、エタノールで洗浄することにより、
（＋）−シス−２−（４−メトキシフェニル）−３−ヒ
ドロキシ−８−クロロ−２，３−ジヒドロ−１，５−ベ
ンゾチアゼピン−４（５Ｈ）−オン１５ｇを得る。Example 1 (+)-threo-2-hydroxy-3- (2-amino-
A mixture of 17.0 g of 5-chlorophenylthio) -3- (4-methoxyphenyl) propionic acid, 0.91 g of p-toluenesulfonic acid hydrate and 220 ml of xylene is heated under reflux for 2 hours while removing water with a dehydrator. . After cooling, the precipitated crystals are collected by filtration and washed with ethanol,
15 g of (+)-cis-2- (4-methoxyphenyl) -3-hydroxy-8-chloro-2,3-dihydro-1,5-benzothiazepin-4 (5H) -one are obtained.
【００２９】収率：９３％ ｍ．ｐ． ２４４〜２４５℃ なお、本反応をｐ−トルエンスルホン酸の非存在下に実
施する特開昭５９−２２５１７４記載の方法では、２０
時間加熱還流しても目的物の収率は７３％である。Yield: 93% m.p. p. In the method described in JP-A-59-225174, the reaction is carried out in the absence of p-toluenesulfonic acid.
The yield of the desired product is 73% even when heated under reflux for 73 hours.
【００３０】実施例２ （＋）−スレオ−２−ヒドロキシ−３−（２−アミノ−
５−クロロフェニルチオ）−３−（４−メトキシフェニ
ル）プロピオン酸１７．０ｇ、ｐ−トルエンスルホン酸
水和物０．９１ｇ及びトルエン２２０ｍｌの混合物を脱
水装置で水を除去しながら８時間加熱還流する。冷後析
出晶をろ取し、エタノールで洗浄することにより、
（＋）−シス−２−（４−メトキシフェニル）−３−ヒ
ドロキシ−８−クロロ−２，３−ジヒドロ−１，５−ベ
ンゾチアゼピン−４（５Ｈ）−オン１４．８ｇを得る。Example 2 (+)-Threo-2-hydroxy-3- (2-amino-)
A mixture of 17.0 g of 5-chlorophenylthio) -3- (4-methoxyphenyl) propionic acid, 0.91 g of p-toluenesulfonic acid hydrate and 220 ml of toluene is heated under reflux for 8 hours while removing water with a dehydrator. . After cooling, the precipitated crystals are collected by filtration and washed with ethanol,
There are obtained 14.8 g of (+)-cis-2- (4-methoxyphenyl) -3-hydroxy-8-chloro-2,3-dihydro-1,5-benzothiazepin-4 (5H) -one.
【００３１】収率：９２％ ｍ．ｐ． ２４４〜２４５℃ 実施例３ （１）２−アミノ−５−メチルチオフェノール１３２ｇ
及び（±）−トランス−３−（４−メチルフェニル）グ
リシッド酸メチルエステル２００ｇをキシレン６００ｍ
ｌに溶解し、窒素気流下１２０〜１３０℃で４時間加熱
攪拌する。４０℃に冷却後ｎ−ヘキサンを加え、さらに
１０℃まで冷却攪拌する。析出晶をろ取し乾燥すること
により、（±）−スレオ−２−ヒドロキシ−３−（２−
アミノ−５−メチルフェニルチオ）−３−（４−メチル
フェニル）プロピオン酸メチルエステル２１８ｇを無色
結晶として得る。Yield: 92% m.p. p. 244-245 ° C Example 3 (1) 132 g of 2-amino-5-methylthiophenol
And (±) -trans-3- (4-methylphenyl) glycidic acid methyl ester 200 g was added to xylene 600 m.
It is dissolved in 1, and heated and stirred at 120 to 130 ° C. for 4 hours under a nitrogen stream. After cooling to 40 ° C, n-hexane is added, and the mixture is further cooled to 10 ° C with stirring. The precipitated crystals were collected by filtration and dried to give (±) -threo-2-hydroxy-3- (2-
218 g of amino-5-methylphenylthio) -3- (4-methylphenyl) propionic acid methyl ester are obtained as colorless crystals.
【００３２】収率：６９％ ｍ．ｐ． １１４〜１１６℃ （２）本品５０ｇをキシレン５００ｇに溶解し、ｐ−ト
ルエンスルホン酸水和物０．５７ｇを加え、４時間加熱
還流する。冷却後、析出晶をろ取し、キシレンで洗浄、
乾燥することにより、（±）−シス−２−（４−メチル
フェニル）−３−ヒドロキシ−８−メチル−２，３−ジ
ヒドロ−１，５−ベンゾチアゼピン−４（５Ｈ）−オン
３９．０ｇを無色結晶として得る。Yield: 69% m.p. p. 114-116 ° C (2) 50 g of this product is dissolved in 500 g of xylene, 0.57 g of p-toluenesulfonic acid hydrate is added, and the mixture is heated under reflux for 4 hours. After cooling, the precipitated crystals are collected by filtration and washed with xylene,
By drying, (±) -cis-2- (4-methylphenyl) -3-hydroxy-8-methyl-2,3-dihydro-1,5-benzothiazepin-4 (5H) -one 39. 0 g are obtained as colorless crystals.
【００３３】収率：８６％ ｍ．ｐ． １８５〜１８６℃ 実施例４ （±）−スレオ−２−ヒドロキシ−３−（２−アミノ−
５−メチルフェニルチオ）−３−（４−メチルフェニ
ル）プロピオン酸メチルエステル４０ｇを純水２００ｍ
ｌ及びメタノール１００ｇの溶液に懸濁し、水酸化カリ
ウム７．４ｇを加え、５０〜５５℃にて３０分間攪拌後
３５％塩酸１３．８ｇを滴下し、純水２００ｍｌを加え
１０℃まで冷却する。析出晶をろ取、水洗することによ
り、（±）−スレオ−２−ヒドロキシ−３−（２−アミ
ノ−５−メチルフェニルチオ）−３−（４−メチルフェ
ニル）プロピオン酸８０ｇ（湿体）を得る。Yield: 86% m.p. p. 185-186 ° C Example 4 (±) -threo-2-hydroxy-3- (2-amino-)
40 g of 5-methylphenylthio) -3- (4-methylphenyl) propionic acid methyl ester was added to 200 m of pure water.
It is suspended in a solution of 1 and 100 g of methanol, 7.4 g of potassium hydroxide is added, 13.8 g of 35% hydrochloric acid is added dropwise after stirring for 30 minutes at 50 to 55 ° C., 200 ml of pure water is added, and the mixture is cooled to 10 ° C. The precipitated crystals were collected by filtration and washed with water to give (±) -threo-2-hydroxy-3- (2-amino-5-methylphenylthio) -3- (4-methylphenyl) propionic acid 80 g (wet form). To get
【００３４】本品（８０ｇ）をトルエン４００ｍｌに懸
濁し、ｐ−トルエンスルホン酸水和物０．４ｇを加え、
留出する水を除去しながら５時間還流する。冷却後、析
出晶をろ取し、トルエンで洗浄後乾燥することにより
（±）−シス−２−（４−メチルフェニル）−３−ヒド
ロキシ−８−メチル−２，３−ジヒドロ−１，５−ベン
ゾチアゼピン−４（５Ｈ）−オン３２．５ｇを得る。This product (80 g) was suspended in 400 ml of toluene, and 0.4 g of p-toluenesulfonic acid hydrate was added,
Reflux for 5 hours while removing distilled water. After cooling, the precipitated crystals were collected by filtration, washed with toluene and dried to obtain (±) -cis-2- (4-methylphenyl) -3-hydroxy-8-methyl-2,3-dihydro-1,5. 32.5 g of benzothiazepin-4 (5H) -one are obtained.
【００３５】収率：９０％ ｍ．ｐ． １８５〜１８６℃ 実施例５ （１）２−アミノ−５−メチルチオフェノール４２ｇ及
び（＋）−トランス−３−（４−メチルフェニル）グリ
シッド酸メチルエステル５８ｇをキシレン４２０ｍｌに
溶解し、窒素気流下２時間加熱還流する。冷後、反応混
合物にｎ−ヘキサンを加え、析出晶をろ取することによ
り、（−）−スレオ−２−ヒドロキシ−３−（２−アミ
ノ−５−メチルフェニルチオ）−３−（４−メチルフェ
ニル）−プロピオン酸メチルエステル６５ｇを無色針状
晶として得る。 収率：６５％ ｍ．ｐ．１０７〜１０９℃ 〔α〕D 20−２３５．４°（ｃ＝１，メタノール） （２）本品２０ｇ、ｐ−トルエンスルホン酸水和物０．
４ｇ及びキシレン１６０ｍｌの混合物を５時間加熱還流
する。冷後、析出晶をろ取することにより、（−）−シ
ス−２−（４−メチルフェニル）−３−ヒドロキシ−８
−メチル−２，３−ジヒドロ−１，５−ベンゾチアゼピ
ン−４（５Ｈ）−オン１５．７ｇを得る。Yield: 90% m.p. p. 185 to 186 ° C. Example 5 (1) 42 g of 2-amino-5-methylthiophenol and 58 g of methyl ester of (+)-trans-3- (4-methylphenyl) glycidic acid were dissolved in 420 ml of xylene, and 2 were dissolved under a nitrogen stream. Heat to reflux for hours. After cooling, n-hexane was added to the reaction mixture, and the precipitated crystals were collected by filtration to give (-)-threo-2-hydroxy-3- (2-amino-5-methylphenylthio) -3- (4-. 65 g of methylphenyl) -propionic acid methyl ester are obtained as colorless needles. Yield: 65% m. p. 107 - 109 ° C. [α] D 20 -235.4 ° (c = 1 , methanol) (2) The product 20 g, p-toluenesulfonic acid hydrate 0.
A mixture of 4 g and xylene 160 ml is heated to reflux for 5 hours. After cooling, the precipitated crystals were collected by filtration to give (-)-cis-2- (4-methylphenyl) -3-hydroxy-8.
15.7 g of -methyl-2,3-dihydro-1,5-benzothiazepin-4 (5H) -one are obtained.
【００３６】収率：８７％ ｍ．ｐ．２０７〜２１２℃ 〔α〕D 20−１２０°（ｃ＝０．３，メタノール）Yield: 87% m.p. p. 207 to 212 ° C. [α] D 20 -120 ° (c = 0.3 , methanol)
【００３７】[0037]
【発明の効果】本発明によれば、医薬品の合成中間体と
して有用な１，５−ベンゾチアゼピン誘導体を、短時間
の反応で、高収率で純度よく製造することができるの
で、工業的に有利な製造法となるものである。INDUSTRIAL APPLICABILITY According to the present invention, a 1,5-benzothiazepine derivative useful as a synthetic intermediate for pharmaceuticals can be produced in a high yield in a high yield in a short reaction time, and thus is industrially useful. This is an advantageous manufacturing method.
Claims (3)
又はハロゲン原子、他方が水素原子、Ｒ3 は低級アルキ
ル基又は低級アルコキシ基、Ｒ4 はｉ）Ｒ1 及びＲ2 の
いずれか一方が低級アルキル基、他方が水素原子のとき
は、水素原子又はエステル残基を表し、ｉｉ）Ｒ1 及び
Ｒ2 のいずれか一方がハロゲン原子、他方が水素原子の
ときは、水素原子を表す。）で示されるプロピオン酸誘
導体を、一般式〔ＩＩＩ〕 【化２】 （但し、Ｒ5 は低級アルキル基又は置換もしくは非置換
フェニル基を表す。）で示されるスルホン酸化合物の存
在下、分子内閉環反応に付し、所望により生成物をその
塩とすることを特徴とする一般式〔Ｉ〕 【化３】 （但し、Ｒ1 、Ｒ2 及びＲ3 は前記と同一意味を有す
る。）で示される１，５−ベンゾチアゼピン誘導体又は
その塩の製法。1. A compound represented by the general formula [II]: (However, one of R 1 and R 2 is a lower alkyl group or a halogen atom, the other is a hydrogen atom, R 3 is a lower alkyl group or a lower alkoxy group, and R 4 is i) One of R 1 and R 2 Is a lower alkyl group, the other is a hydrogen atom, and represents a hydrogen atom or an ester residue, and ii) one of R 1 and R 2 is a halogen atom, and the other is a hydrogen atom, and represents a hydrogen atom. ), A propionic acid derivative represented by the general formula [III] (Wherein R 5 represents a lower alkyl group or a substituted or unsubstituted phenyl group) is subjected to an intramolecular ring-closing reaction in the presence of a sulfonic acid compound, and the product is converted to a salt thereof if desired. General formula [I] (However, R 1 , R 2 and R 3 have the same meanings as described above), and a process for producing a 1,5-benzothiazepine derivative or a salt thereof.
基、他方が水素原子を表す。）で示されるチオフェノー
ル化合物と、一般式〔Ｖ〕 【化５】 （但し、Ｒ3 は低級アルキル基又は低級アルコキシ基、
Ｒ41はエステル残基を表す。）で示される光学活性トラ
ンスグリシッド酸エステルとを反応させて一般式〔ＩＩ
−ａ〕 【化６】 （但し、＊は当該炭素原子が不斉炭素原子であることを
表し、Ｒ11、Ｒ21、Ｒ3及びＲ41は前記と同一意味を有
する。）で示される光学活性スレオプロピオン酸エステ
ル誘導体とし、該化合物〔ＩＩ−ａ〕を一般式〔ＩＩ
Ｉ〕 【化７】 （但し、Ｒ5 は低級アルキル基又は置換もしくは非置換
フェニル基を表す。）で示されるスルホン酸化合物の存
在下、分子内閉環反応に付し、所望により生成物をその
塩とすることを特徴とする一般式〔Ｉ−ａ〕 【化８】 （但し、Ｒ11、Ｒ21、Ｒ3 及び＊は前記と同一意味を有
する。）で示される光学活性シス−１，５−ベンゾチア
ゼピン誘導体又はその塩の製法。2. A compound represented by the general formula [IV]: (However, one of R 11 and R 21 represents a lower alkyl group and the other represents a hydrogen atom.), And a thiophenol compound represented by the general formula [V] (However, R 3 is a lower alkyl group or a lower alkoxy group,
R 41 represents an ester residue. ) Is reacted with an optically active transglycidic acid ester represented by the formula [II]
-A] (However, * represents that the carbon atom is an asymmetric carbon atom, and R 11 , R 21 , R 3 and R 41 have the same meanings as described above.), Which is an optically active threopropionic ester derivative. The compound [II-a] is represented by the general formula [II
I] (Wherein R 5 represents a lower alkyl group or a substituted or unsubstituted phenyl group) is subjected to an intramolecular ring-closing reaction in the presence of a sulfonic acid compound, and the product is converted to a salt thereof if desired. General formula [Ia] (However, R 11 , R 21 , R 3 and * have the same meanings as described above.) A process for producing an optically active cis-1,5-benzothiazepine derivative or a salt thereof.
ホン酸又はｐ−トルエンスルホン酸である請求項１又は
２記載の製法。3. The method according to claim 1, wherein the sulfonic acid compound [III] is methanesulfonic acid or p-toluenesulfonic acid.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1109794A JPH0699409B2 (en) | 1989-04-28 | 1989-04-28 | Process for producing 1,5-benzothiazepine derivative |
| JP6054228A JP2551375B2 (en) | 1989-04-28 | 1994-03-25 | Process for producing 1,5-benzothiazepine derivative |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1109794A JPH0699409B2 (en) | 1989-04-28 | 1989-04-28 | Process for producing 1,5-benzothiazepine derivative |
| JP6054228A JP2551375B2 (en) | 1989-04-28 | 1994-03-25 | Process for producing 1,5-benzothiazepine derivative |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1109794A Division JPH0699409B2 (en) | 1989-04-28 | 1989-04-28 | Process for producing 1,5-benzothiazepine derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH06298750A true JPH06298750A (en) | 1994-10-25 |
| JP2551375B2 JP2551375B2 (en) | 1996-11-06 |
Family
ID=26394975
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1109794A Expired - Fee Related JPH0699409B2 (en) | 1989-04-28 | 1989-04-28 | Process for producing 1,5-benzothiazepine derivative |
| JP6054228A Expired - Fee Related JP2551375B2 (en) | 1989-04-28 | 1994-03-25 | Process for producing 1,5-benzothiazepine derivative |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1109794A Expired - Fee Related JPH0699409B2 (en) | 1989-04-28 | 1989-04-28 | Process for producing 1,5-benzothiazepine derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (2) | JPH0699409B2 (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS60202871A (en) * | 1984-03-10 | 1985-10-14 | Tanabe Seiyaku Co Ltd | 1,5-benzothiazepine derivative and its preparation |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2641535B1 (en) * | 1989-01-11 | 1991-03-15 | Synthelabo | PROCESS FOR THE PREPARATION OF (+) - (2S, 3S) -HYDROXY-3 (METHOXY-4 PHENYL) -2 DIHYDRO-2,3 5H-BENZOTHIAZEPINE-1,5 ONE-4 |
-
1989
- 1989-04-28 JP JP1109794A patent/JPH0699409B2/en not_active Expired - Fee Related
-
1994
- 1994-03-25 JP JP6054228A patent/JP2551375B2/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS60202871A (en) * | 1984-03-10 | 1985-10-14 | Tanabe Seiyaku Co Ltd | 1,5-benzothiazepine derivative and its preparation |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0699409B2 (en) | 1994-12-07 |
| JPH02286671A (en) | 1990-11-26 |
| JP2551375B2 (en) | 1996-11-06 |
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