JPS59144777A - Method for optical resolution of benzothiazepine derivative - Google Patents
Method for optical resolution of benzothiazepine derivativeInfo
- Publication number
- JPS59144777A JPS59144777A JP1701583A JP1701583A JPS59144777A JP S59144777 A JPS59144777 A JP S59144777A JP 1701583 A JP1701583 A JP 1701583A JP 1701583 A JP1701583 A JP 1701583A JP S59144777 A JPS59144777 A JP S59144777A
- Authority
- JP
- Japan
- Prior art keywords
- benzothiazepine derivative
- compound
- chiral
- column
- benzothiazepine
- 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)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
【発明の詳細な説明】
本発明は、ペンゾチアゼぎン誘導体であるラセミ型：α
−２−（ｐ−メトキシフェニル）−３−アセトキシ−５
−（２−ジメチルアミノエチル）−２，３−ジヒｒロー
１，５−ペンゾチアゼぎンー４（５Ｈ）−オンおよびそ
の類似化合物を光学分割して４体と１体とを製造する方
法に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention provides a racemic form of a penzothiazegine derivative: α
-2-(p-methoxyphenyl)-3-acetoxy-5
The present invention relates to a method for optically resolving -(2-dimethylaminoethyl)-2,3-dihyro-1,5-penzothiazegin-4(5H)-one and its analogous compounds to produce 4-form and 1-form.
すなわち、本発明は、一般式■（式中、Ｒ１はＨまたは
０ＯＯＨ３を示し、Ｒ２は、ＨまたはＣＨ２０Ｈ２Ｎ（
ＯＨ３）２を示す）で表わされるベンゾチアゼピン誘導
体のラセミ体をキラル（Ｓ型またはＲ型）な大環状ポリ
エーテル（クラウン化合物）が均等に混合した吸着剤を
充填したカラムを用い、有機溶剤を展開剤とするカラム
クロマトグラフィーをおこない、光学分割することを特
徴とする、一般式■（式中、Ｒ１とＲ２は上記に同じ）
で表わされる光学活性ベンゾチアゼピン誘導体の製造法
に関するものであり、次に与えるフロシートによりその
特徴を示すものである。That is, the present invention is based on the general formula
Using a column filled with an adsorbent in which a racemic benzothiazepine derivative represented by OH3)2 is evenly mixed with a chiral (S type or R type) macrocyclic polyether (crown compound), organic solvent The general formula ■ (wherein R1 and R2 are the same as above) is characterized by performing optical resolution by performing column chromatography using as a developing agent.
The present invention relates to a method for producing an optically active benzothiazepine derivative represented by the following formula, and its characteristics are shown in the flow sheet given below.
（ラセミ体）Ｉ （光学活性０体と１体）■Ｒ，
＝ＨまたはｏｃｏｃＨ３；
１’（２＝）（または０Ｈ２０Ｈ２Ｎ（ＯＨ３）２本発
明方法によって得られるｄ−α−２−（ｐ−メトキシフ
ェニル）−６−アセトキシ−５−（２−ジメチルアミン
エチル）−２，３−ジヒドロ−１゜５−ベンゾチアゼピ
ン−４（５ａ）−、ｄ−ｙ（一般式■で、Ｒ１＝＝ ｃ
ｏｃＪ（３、Ｒ＝ ＣＨ２０Ｈ２−Ｎ（Ｃ！Ｈ３）２
）張剤・抗抑うつ剤・精神々経安定剤として臨床に用い
られている重要な薬物である。また、他の類似化合物の
６体〔一般式ＩＩにおいてＲ１＝ ＨとＲ２＝ Ｈ（化
合物１）、Ｒ１＝Ｈと、Ｒ２＝ ０Ｈ２０Ｈ２Ｎ（ＯＨ
３逼（化合物６）およびＲ１＝ Ｃ００Ｈ３とＲ２＝
Ｈ（化合物２）〕は、上述の化合物４の合成中間体であ
り、例えば化合物２をＮ−アシル化（ジメチルアミンエ
チル）しても、化合物６をアセチル化するだけでも容易
に化合物４が製造できる。このように、本発明に示され
るベンゾチアゼピン誘導体の光学分割法は、単に化学の
進歩を与えるのみでなく、医薬品をより新しい技術でよ
シ工業的に有利に製造できる方法を提供するものである
。(racemic form) I (optically active 0 form and 1 form) ■R,
=H or ococH3; 1'(2=) (or 0H20H2N(OH3)2 d-α-2-(p-methoxyphenyl)-6-acetoxy-5-(2-dimethylamineethyl) obtained by the method of the present invention -2,3-dihydro-1゜5-benzothiazepine-4(5a)-, dy (general formula ■, R1 == c
ocJ(3, R= CH20H2-N(C!H3)2
) It is an important drug used clinically as a tonic, antidepressant, and psychotropic stabilizer. In addition, six other similar compounds [in general formula II, R1=H and R2=H (compound 1), R1=H and R2=0H20H2N(OH
3 (Compound 6) and R1= C00H3 and R2=
H (Compound 2)] is a synthetic intermediate for the above-mentioned Compound 4. For example, Compound 4 can be easily produced by simply N-acylating Compound 2 (dimethylamine ethyl) or by acetylating Compound 6. can. As described above, the optical resolution method for benzothiazepine derivatives described in the present invention not only provides an advance in chemistry, but also provides an industrially advantageous method for producing pharmaceuticals using newer technology. be.
従来、ベンゾチアゼピン誘導体の直接光学分割は、たと
え光学活性有機酸や塩基を使用し、溶媒からの溶解度を
利用する方法でも、非常に困難である。そのため、必要
な６体−化合物４を製造するにあたり、その製造の数工
程前の合成中間体であるラセミ型：α−２−ヒＶロキシ
ー３−（ｐ−メトキシフェニル）−３−（０−ニトロフ
ェニル）−ゾロピオン酸を光学活性有機塩基を用いて光
学分割し、得られる６体のみを、つづくアミノ化・閉環
・Ｎ−アシル化・アセチル化などの工程に付し、目的物
を製造（特公昭５３−１８０３８号公報）している状態
である。本発明は、この工業的に不利な方法を改良し、
再検討、新しい方法を検討した結果、独創的なまた新し
いペンゾチアゼぎン誘導体の直接光学分割法を見出し、
本発明を完成するに至った。Conventionally, direct optical resolution of benzothiazepine derivatives has been extremely difficult, even if the method uses optically active organic acids or bases and takes advantage of their solubility in solvents. Therefore, in producing the necessary 6-compound 4, the racemic form, which is a synthetic intermediate several steps before its production: α-2-hyVroxy-3-(p-methoxyphenyl)-3-(0- Nitrophenyl)-zolopionic acid is optically resolved using an optically active organic base, and only the six products obtained are subjected to subsequent steps such as amination, ring closure, N-acylation, and acetylation to produce the desired product ( (Japanese Patent Publication No. 53-18038). The present invention improves this industrially disadvantageous method and
As a result of reexamining and considering new methods, we discovered an original and new direct optical resolution method for penzothiazegine derivatives.
The present invention has now been completed.
すなわち、本発明方法によれば、各種の方法で製造され
るベンゾチアゼピン誘導体を直接光学分割できるため、
製造途中の合成中間体の同定・収率向上など工場内の種
々な検討の必要もなく、よシ経済的な方法とも云える。That is, according to the method of the present invention, benzothiazepine derivatives produced by various methods can be directly optically resolved.
It can also be said to be a more economical method since there is no need for various in-factor studies such as identification of synthetic intermediates during production and improvement of yield.
本発明の方法を述べれば、光学分割の目的のラセミ型：
ベンゾチアゼピン誘導体を適当な有機溶媒を用い、あら
かじめセットしたキラル（Ｓ型あるいはＲ型）な大環状
ポリエーテル（クラウン化合物）が均等に混合した吸着
剤の充填したカラムに展開・溶出させ、カラムクロマト
グラフ分画をおこなうことで光学分割を完成する。もし
、キラルな大環状ポリエーテルとしてＳ型を用い、例え
ばクロロホルムまたはそれを含有する溶媒で展開させる
と、一般式■で表わされるラセミ体のうち、６体はカラ
ム中でＳ型大環状ポリエーテルとりガントし、錯体を形
成するので１体よシ溶出がおくれ、かくして両者を光学
分割するととができる。Describing the method of the present invention, the racemic type for the purpose of optical resolution:
A benzothiazepine derivative is developed and eluted using an appropriate organic solvent on a column packed with an adsorbent in which chiral (S-type or R-type) macrocyclic polyether (crown compound) is evenly mixed. Optical resolution is completed by performing chromatographic fractionation. If an S type is used as the chiral macrocyclic polyether and developed with chloroform or a solvent containing it, six of the racemates represented by the general formula Since the two components are separated and form a complex, the elution of one component is delayed, and thus both can be optically resolved.
一方、キラルな大環状ポリエーテルとしてＲ型を用いる
と、溶出の順位はまったく逆転し、同じように両者を分
離することができる。溶出に用いる有機溶媒としては、
クロロホルムなどハロゲン化炭化水素１テトラヒドロフ
ラン、ベンゼン、トルエン、ＤＭＳＯ，シクロヘキサン
、酢酸エチルなどおよびこれらにアルコール類あるいは
アセトン類を含有させた溶媒も利用できる。カラムに充
填する吸着剤としては、普通のシリカゾル、アルミナ、
フロリジルまた６−アミンプロピルシリカなども適当で
あり、さらに、これらをセライトなどに混合させること
もできる。On the other hand, when type R is used as the chiral macrocyclic polyether, the order of elution is completely reversed, and the two can be separated in the same way. The organic solvent used for elution is
Solvents containing halogenated hydrocarbons such as chloroform, tetrahydrofuran, benzene, toluene, DMSO, cyclohexane, ethyl acetate, etc., and alcohols or acetones in these may also be used. The adsorbents used to fill the column include ordinary silica sol, alumina,
Florisil and 6-amine propyl silica are also suitable, and these can also be mixed with celite or the like.
このようにして、本発明方法によれば、簡単な操作で６
体と１体とが容易に分割でき、溶出液を採集し、濃縮す
る。従って本発明方法は、光学分割と精製とを同時にお
こなっていることになり、とのことは特徴の一つと云え
る。このカラム系をもし組織化して自動化すると、さら
に大量生産ができ、よυ経済的である。また、例えば、
カラムクロマトグラフィーの途中で各溶出液をサンプリ
ングし、チェックすることも可能である。このチェック
の方法として熱検出法、ＵＶ法またオリジ織にカラムシ
ステムを組織し上記の各種チェックを併用させると分離
不充分な試料を再び溶出させることが出来るからむだが
省け、より高純度のしかも指定された光学分割体だけを
とシ出すこともできる。In this way, according to the method of the present invention, 6
One body and one body can be easily separated, and the eluate is collected and concentrated. Therefore, one of the characteristics of the method of the present invention is that optical resolution and purification are performed simultaneously. If this column system were organized and automated, mass production would be possible and it would be more economical. Also, for example,
It is also possible to sample and check each eluate during column chromatography. As a method for this check, if you use the thermal detection method, the UV method, or the original column system and use the above various checks in combination, it is possible to elute samples that are insufficiently separated, thereby eliminating waste and achieving higher purity and specification. It is also possible to extract only the optically segmented body.
本発明方法で用いるキラル々大環状ポリエーテル（クラ
ウン化合物）としては、次のようなものがあり、使用に
際し任意に選択できる。The chiral macrocyclic polyether (crown compound) used in the method of the present invention includes the following, and can be arbitrarily selected for use.
＼＼−一一一
かようにして、本発明方法によシ得られるｄ−α−２−
（ｐ−メトキシフェニル）−６−アセトキシ−５−（２
−ジメチルアミノエチル）−２，３−ジヒドロ−１，５
−ベンゾチアゼピン−４（５Ｈ）−オン（化合物４）は
、その塩酸塩として錠剤・散剤などの剤型に成型し、臨
床に提供できる。また、他の６体すなわち、化合物１、
化合物２および化合物３は、いづれも公知の方法を用い
て化合物４に誘導できる。\\-111 d-α-2- thus obtained by the method of the present invention
(p-methoxyphenyl)-6-acetoxy-5-(2
-dimethylaminoethyl)-2,3-dihydro-1,5
-Benzothiazepine-4(5H)-one (compound 4) can be molded into a dosage form such as a tablet or powder as its hydrochloride and provided for clinical use. In addition, the other six compounds, namely compound 1,
Compound 2 and Compound 3 can both be induced into Compound 4 using known methods.
次に、不発明方法を実施例をもって説明する。Next, the non-inventive method will be explained using examples.
〈実施例１〉
（ａ］ ｄぎ一α−２−（ｐ−メトキシフェニル）−
６−アセドキンー５−（２−ジメチルアミンエチル）−
２，６−シヒドロー１，５−ベンゾチアゼピン−４（５
Ｈ）−オン（ｍｐ、 １８８−１８９°Ｃ）の１ｙを少
量のクロロホルム・メタノール（９：１）に浴解し、少
量のシリカケゞルとミックスし、乾燥してのち、あらか
じめセットしたタイプＤのキラル（Ｓ型）な大環状ポリ
エーテル（ｎ＝５、Ｒ＝ Ｒ’−Ｃ！Ｈ２−ＯＣＨ２Ｃ
ＯＯＨ）が均等に混合した吸着剤（ポリエーテル５ｇを
クロロホルム溶解し、シリカゲル６０ｇと混合したのち
風乾し、ついで１１０°で３０分乾燥した）を充填した
ドライカラム（径３．０ ｃｍφＸ ９０ ａｍ ）の
上部に平に置き、さらに上部に新しいシリカゲルを置い
てから綿でおさ支た。ついで、このドライカラムをはじ
めにクロロホルムで、ついでクロロホルム・メタノール
系で溶出すると、はじめの方のフラクションから１体の
α−２−（ｐ−メトキシフェニル）−ろ−アセトキシ−
５−（２−ジメチルアミンエチル）−２，６−シヒドロ
ー１，５−ベンゾチアゼピン−４（５Ｈ）−オｙ（０，
４９６，！ｉ’）Ｃｍｐ、２０５−２０６° （エタノ
ール）；〔α１２３−−９５．９゜（ａ ＝ ０．５
’Ｏ、メタノール）〕が得られ、あとのフラクションか
ら一方の６体（０，４９８ｇ）［ｍｐ、２０６−２０７
° （エタノール）；〔α：ｐ３−→−９６．５° （
ｃ＝０．６０、メタノール）〕が溶出した。<Example 1> (a) dgi1 α-2-(p-methoxyphenyl)-
6-acedoquine-5-(2-dimethylamineethyl)-
2,6-sihydro1,5-benzothiazepine-4 (5
1y of H)-one (mp, 188-189°C) was dissolved in a small amount of chloroform/methanol (9:1), mixed with a small amount of silica kale, dried, and preset type D. chiral (S-type) macrocyclic polyether (n=5, R= R'-C!H2-OCH2C
A dry column (diameter 3.0 cmφX 90 am) packed with an adsorbent (5 g of polyether dissolved in chloroform, mixed with 60 g of silica gel, air-dried, and then dried at 110° for 30 minutes) in which OOH) was evenly mixed. , and then placed new silica gel on top and supported it with cotton. Then, when this dry column was eluted first with chloroform and then with chloroform/methanol system, one α-2-(p-methoxyphenyl)-ro-acetoxy-
5-(2-dimethylamineethyl)-2,6-sihydro-1,5-benzothiazepine-4(5H)-y(0,
496,! i') Cmp, 205-206° (ethanol); [α123--95.9° (a = 0.5
'O, methanol)] was obtained, and one of the six bodies (0,498 g) [mp, 206-207
° (ethanol); [α: p3-→-96.5° (
c=0.60, methanol)] was eluted.
（ｂｌ 上述（ａｔにおいて、キラルな大環状ポリエ
ーテルとして、タイプＤＯＲ型（ｎ−４、Ｒ＝＝ Ｒ’
＝＝ＣＨ２０ＣＨ２Ｃ００工（）を用いてセットしたシ
リカゲルにドライカラムを用いて同様にクロマトグラフ
分画し、はじめのフラクションから６体（０，４９７，
９’）（ｍｐ、 ２０６−２０７°Ｃ）を、おくれたフ
ラクションから１体（０，４９，ｌ ） （ｍｐ、 ２
’０５−２０６℃）を分離した。(bl mentioned above (at), as a chiral macrocyclic polyether, type DOR type (n-4, R== R'
Chromatographic fractionation was performed in the same manner using a dry column on silica gel set using ==CH20CH2C00 engineering (), and 6 bodies (0,497,
9') (mp, 206-207°C) from the delayed fraction (0,49,l) (mp, 2
'05-206°C) was separated.
〈実施例２〉
ｄｌ−α−２−（ｐ−メトキシフェニル）−３−ヒドロ
オキシ−２，３−ジヒＶロー１，５−ベンゾチアゼピン
−４（５Ｈ）−オン（ｍｐ、１９５−１９８°Ｃ）１．
＠をあらかじめセットしたキラルな大環状ポリエーテル
としてタイプＤＯＲ型（ｎ＝４、Ｒ＝ Ｈ、Ｒ’ ＝
０Ｈ２００Ｈ２０００Ｈ）の混合するシリカゾルカラム
（実施例１（ａ）と同様に充填した）を用いてクロロホ
ルムおよびクロロホルム・メタノール混合溶液で溶出す
るとき、α−２−（ｐ−メトキシフェニル）−３−ヒド
ロオキシ−２，６−シヒドロー１，５−ベンゾチアゼピ
ン−４（５Ｈ）−オンの６体（０，４９８ｇ） Ｃｍｐ
−１９６°−１９８°（エタノール）；〔α〕２３＝＋
１２８．８° （０＝ ０．４８５、エタノール）〕
と４１体 ０．４９７ ｇ） Ｃｍｐ、 １９５°−１
９７°（エタノール）；〔α）２３ ＝−１２８，５°
（ｃ＝０．４８５ 、エタノール）〕が分離して得ら
れた。<Example 2> dl-α-2-(p-methoxyphenyl)-3-hydroxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one (mp, 195-198° C)1.
Type DOR type (n = 4, R = H, R' =
α-2-(p-methoxyphenyl)-3-hydroxy- 6 bodies of 2,6-sihydro-1,5-benzothiazepin-4(5H)-one (0,498g) Cmp
-196°-198° (ethanol); [α]23=+
128.8° (0 = 0.485, ethanol)]
and 41 bodies 0.497 g) Cmp, 195°-1
97° (ethanol); [α)23 = -128,5°
(c=0.485, ethanol)] was separated and obtained.
〈実施例６〉
ｄｌ−α−２−（ｐ−メトキシフェニル）−６−ヒドロ
キシ−５−（β−ジメチルアミノエチル）−２，６−ゾ
ヒげロー１．５−ベンゾチアゼピン−４（５Ｈ）−オン
（油状物）１ｇをあらかじめ用意したキラルな大環状ポ
リエーテルとしてタイプＥ（Ｓ型）を用いて充填したシ
リカゲルカラム（実施例１（ａｌと同じ）中に通導、ク
ロロホルムおよびクロロホルム・メタノール系溶媒を用
いてクロマトグラフィーをおこないｄ−α−２−（ｐ−
メトキシフェニル）−３−ヒドロキシ−５〜（β−ジメ
チルアミノエチル）−２，３−ジヒドロ−１，５−ベン
ゾチアゼピン−４（５Ｈ）−オン（０，４９６、！ｉ！
） ［ｍｐ。１２３１２５°Ｃ（メタノール）；〔α
）２３−＋ ９５．０°ＣＯ＝ ０．５０、メタノール
）〕と一方の１体（０，４９４，９） Ｃｍｐ。<Example 6> dl-α-2-(p-methoxyphenyl)-6-hydroxy-5-(β-dimethylaminoethyl)-2,6-zohigelo 1,5-benzothiazepine-4( 1 g of 5H)-one (oil) was passed through a silica gel column (same as Example 1 (al)) packed using type E (S type) as a pre-prepared chiral macrocyclic polyether, chloroform and chloroform.・Perform chromatography using methanol solvent to obtain d-α-2-(p-
methoxyphenyl)-3-hydroxy-5-(β-dimethylaminoethyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one (0,496,!i!
) [mp. 123125°C (methanol); [α
)23−+95.0°CO=0.50, methanol)] and one (0,494,9) Cmp.
１２２−１２４℃（メタノール）：〔α〕２３＝Ｄ
−９５，５° （Ｃ＝ ０．４８８、メタノール）〕を
得た。122-124°C (methanol): [α]23=D -95,5° (C=0.488, methanol)] was obtained.
代理人 浅 村 皓 外４名 ７０３−Agent Asa Mura Hao 4 other people 703-
Claims (1)
または０Ｈ２０Ｈ２Ｎ（ＯＨ３）２を示す）で表わされ
るベンゾチアゼピン誘導体のラセミ体を、あらかじめセ
ットしたキラル（Ｓ型またはＲ型）な大環状ポリエーテ
ル（クラウン化合物）が均等に混合した吸着剤を充填し
九カラムを用い、有機溶剤を展開剤とするカラムクロマ
トグラフ分画をおこない、光学分割することを特徴とす
る、一般式■（式中、Ｒ１とＲ２は上記に同じ）で表わ
される光学活性ペンゾチアゼぎン誘導体の製造法。[Claims] General formula I
A racemic benzothiazepine derivative represented by 0H20H2N(OH3)2 or Optical activity represented by the general formula (wherein R1 and R2 are the same as above), which is characterized by optical resolution by performing column chromatography fractionation using an organic solvent as a developing agent using a Shiku column. A method for producing a penzothiazegine derivative.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1701583A JPS59144777A (en) | 1983-02-04 | 1983-02-04 | Method for optical resolution of benzothiazepine derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1701583A JPS59144777A (en) | 1983-02-04 | 1983-02-04 | Method for optical resolution of benzothiazepine derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPS59144777A true JPS59144777A (en) | 1984-08-18 |
Family
ID=11932167
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1701583A Pending JPS59144777A (en) | 1983-02-04 | 1983-02-04 | Method for optical resolution of benzothiazepine derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS59144777A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6369220B1 (en) | 1997-12-19 | 2002-04-09 | Jinglin (James T.) Li | Method of preparing enantiomerically-enriched tetrahydrobenzothiepine oxides |
| CN103232373A (en) * | 2013-05-15 | 2013-08-07 | 武汉大学 | Chiral sulfur-containing compound with hexafluoroisopropyl ester based structure as well as synthetic method and application of compound |
-
1983
- 1983-02-04 JP JP1701583A patent/JPS59144777A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6369220B1 (en) | 1997-12-19 | 2002-04-09 | Jinglin (James T.) Li | Method of preparing enantiomerically-enriched tetrahydrobenzothiepine oxides |
| US6875877B2 (en) | 1997-12-19 | 2005-04-05 | Jinglin (James T.) Li | Method of preparing enantiomerically-enriched tetrahydrobenzothiepine oxides |
| CN103232373A (en) * | 2013-05-15 | 2013-08-07 | 武汉大学 | Chiral sulfur-containing compound with hexafluoroisopropyl ester based structure as well as synthetic method and application of compound |
| CN103232373B (en) * | 2013-05-15 | 2014-09-03 | 武汉大学 | Chiral sulfur-containing compound with hexafluoroisopropyl ester based structure as well as synthetic method and application of compound |
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