JPH0339056B2 - - Google Patents
Info
- Publication number
- JPH0339056B2 JPH0339056B2 JP1701483A JP1701483A JPH0339056B2 JP H0339056 B2 JPH0339056 B2 JP H0339056B2 JP 1701483 A JP1701483 A JP 1701483A JP 1701483 A JP1701483 A JP 1701483A JP H0339056 B2 JPH0339056 B2 JP H0339056B2
- Authority
- JP
- Japan
- Prior art keywords
- methoxyphenyl
- substituted
- type
- propionic acid
- phenylthio
- 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
- 229920000570 polyether Polymers 0.000 claims description 14
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 13
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 5
- 235000019260 propionic acid Nutrition 0.000 claims description 5
- 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 claims description 5
- 239000003463 adsorbent Substances 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 238000000034 method Methods 0.000 description 16
- 239000004721 Polyphenylene oxide Substances 0.000 description 13
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- -1 2-substituted-3-(p-methoxyphenyl)-3-[(2-substituted)phenylthio]propionic acid Chemical class 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 239000000203 mixture Substances 0.000 description 6
- 230000003287 optical effect Effects 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 125000003006 2-dimethylaminoethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 150000007657 benzothiazepines Chemical class 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- KHQWPNQLSKDWAR-UHFFFAOYSA-N 3-(2-aminophenyl)sulfanyl-2-hydroxy-3-(4-methoxyphenyl)propanoic acid Chemical compound C1=CC(OC)=CC=C1C(C(O)C(O)=O)SC1=CC=CC=C1N KHQWPNQLSKDWAR-UHFFFAOYSA-N 0.000 description 1
- 229920000742 Cotton Polymers 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- GGISZLOBBISXOZ-UHFFFAOYSA-N acetic acid;chloroform Chemical compound CC(O)=O.ClC(Cl)Cl GGISZLOBBISXOZ-UHFFFAOYSA-N 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 229940085242 benzothiazepine derivative selective calcium channel blockers with direct cardiac effects Drugs 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000002633 crown compound Substances 0.000 description 1
- 230000001351 cycling effect Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 230000000506 psychotropic effect Effects 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 239000004576 sand Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 238000000825 ultraviolet detection Methods 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
【発明の詳細な説明】
本発明は、ラセミ型：２−置換−３−（ｐ−メ
トキシフエニル）−３−〔（２−置換）フエニルチ
オ〕プロピオン酸の光学分割法に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for the optical resolution of racemic: 2-substituted-3-(p-methoxyphenyl)-3-[(2-substituted)phenylthio]propionic acid.
本発明で述べる２−置換−３−（ｐ−メトキシ
フエニル）−３−〔（２−置換）フエニルチオ〕プ
ロピオン酸（）は、いずれも医薬品として重要
な抗抑うつ剤・精神々経安定剤・冠状血管抗張剤
ｄ−α−２−（ｐ−メトキシフエニル）−３−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）−オンの合成中間体である。最終的に必要
なこのｄ体の製造のために種々な方法が検討され
て来たが、従来の方法では、ベンゾチアゼピン誘
導体の段階で光学分割するのは困難であり、また
合成中間体の各段階でも、光学分割できるのは、
α−２−ヒドロキシ−３−（ｐ−メトキシフエニ
ル）−３−（２−ニトロフエニルチオ）−プロピオ
ン酸（光学活性有機塩基を用いている）のみであ
り、この段階でｄ体を得、ついで数工程を経て、
目的物を製造している（特公昭53−18038号公
報）。 2-Substituted-3-(p-methoxyphenyl)-3-[(2-substituted)phenylthio]propionic acid () described in the present invention is an antidepressant, psychotropic stabilizer, and important pharmaceutical agent. Coronary vascular tensile agent d-α-2-(p-methoxyphenyl)-3-acetoxy-5-(2-dimethylaminoethyl)-2,
3-dihydro-1,5-benzothiazepine-4
It is a synthetic intermediate of (5H)-one. Various methods have been investigated to produce the d-isomer that is ultimately required, but with conventional methods, it is difficult to optically resolve the benzothiazepine derivative at the stage, and the synthetic intermediate is difficult to resolve. At each stage, what can be optically split is:
Only α-2-hydroxy-3-(p-methoxyphenyl)-3-(2-nitrophenylthio)-propionic acid (using an optically active organic base), and the d-form was obtained at this stage. , then after several steps,
The target product is manufactured (Special Publication No. 18038/1983).
本発明者は、ベンゾチアゼピン誘導体の光学分
割を検討する一方、閉環してベンゾチアゼピンに
する以前の段階でも、各種の光学分割法を検討し
た結果、独創性に富んだ新しい方法でしかも工業
的な有利な方法を見出し、本発明方法を完成する
に至つた。 While investigating the optical resolution of benzothiazepine derivatives, the present inventor also investigated various optical resolution methods before ring-closing to produce benzothiazepines. We have found an advantageous method and completed the method of the present invention.
すなわち、その方法は、一般式（式中、R1
はOHまたはOCOCH3を示し、R2は−NH2基ま
たは−NHCH2CH2N（CH3）2基を示す）で表わさ
れるラセミ型：２−置換−３−（ｐ−メトキシフ
エニル）−３−〔（２−置換）フエニルチオ〕プロ
ピオン酸を、あらかじめキラルな（Ｓ型あるいは
Ｒ型）大環状ポリエーテル（クラウン化合物）を
均等に混合した吸着剤を充填したカラムに通導
し、光学分割することを特徴とする、一般式
（式中、R1とR2は上部に同じ）で表わされる光学
活性２−置換−３−（ｐ−メトキシフエニル）−３
−〔（２−置換）フエニルチオ〕プロピオン酸の製
造法に関するものであり、次に示すフロシートに
よりその特徴がみられる。 That is, the method is based on the general formula (where R 1
represents OH or OCOCH3 , R2 represents -NH2 group or -NHCH2CH2N ( CH3 ) 2 group) Racemic type: 2- substituted -3-(p-methoxyphenyl) -3-[(2-substituted) phenylthio]propionic acid was passed through a column filled with an adsorbent in which a chiral (S-type or R-type) macrocyclic polyether (crown compound) was evenly mixed in advance, and the optical Optically active 2-substituted-3-(p-methoxyphenyl)-3 represented by the general formula (in the formula, R 1 and R 2 are the same at the top), which is characterized by splitting
- This relates to a method for producing [(2-substituted) phenylthio]propionic acid, and its characteristics can be seen in the flow sheet shown below.
R1＝OHまたはOCOCH3；R2＝NH2または
NHCH2CH2N（CH3）2
このようにして得られる一般式で表わされる
ｄ体の２−ヒドロキシ−３−（ｐ−メトキシフエ
ニル）−３−〔（２−アミノ）フエニルチオ〕プロ
ピオン酸（R1＝OH、R2＝NH2：化合物１）は、
公知の方法（特公昭53−18038号公報）により、
また２−ヒドロキシ−３−（ｐ−メトキシフエニ
ル）−３−〔（２−ジメチルアミノエチル）フエニ
ルチオ〕プロピオン酸（R1＝OH、R2＝
NHCH2CH2（CH3）2：化合物２）と２−アセトキ
シ−３−（ｐ−メトキシフエニル）−３−〔（２−ジ
メチルアミノエチル）フエニルチオ〕プロピオン
酸（R1＝OCOCH3、R2＝NHCH2CH2N
（CH3）2：化合物３）とは、本発明者によつて先
に提出された先行特許の方法により、所望のｄ−
α−２−（ｐ−メトキシフエニル）−３−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）
−オンを製造することができる。 R 1 = OH or OCOCH 3 ; R 2 = NH 2 or
NHCH 2 CH 2 N(CH 3 ) 2 The d-form 2-hydroxy-3-(p-methoxyphenyl)-3-[(2-amino)phenylthio]propionic acid represented by the general formula thus obtained (R 1 = OH, R 2 = NH 2 : Compound 1) is
By a known method (Japanese Patent Publication No. 53-18038),
Also, 2-hydroxy-3-(p-methoxyphenyl)-3-[(2-dimethylaminoethyl)phenylthio]propionic acid (R 1 =OH, R 2 =
NHCH 2 CH 2 (CH 3 ) 2 : Compound 2) and 2-acetoxy-3-(p-methoxyphenyl)-3-[(2-dimethylaminoethyl)phenylthio]propionic acid (R 1 = OCOCH 3 , R 2 = NHCH 2 CH 2 N
(CH 3 ) 2 : Compound 3) is a compound prepared by the method of the prior patent previously submitted by the present inventor.
α-2-(p-methoxyphenyl)-3-acetoxy-5-(2-dimethylaminoethyl)-2,3-
Dihydro-1,5-benzothiazepine-4 (5H)
-On can be produced.
本発明の方法を述べれば；光学分割の目的のラ
セミ型：２−置換−３−（ｐ−メトキシフエニル）
−３−〔（２−置換）フエニルチオ〕プロピオン酸
を希有機酸水の含有あるいは飽和する有機溶媒例
えばテトラヒドロフラン、シクロヘキサン、四塩
化炭素、ヘキサン、塩化メチレン、クロロホル
ム、ベンゼン、トルエンあるいはこれらにアルコ
ール類の混合したものに溶解し、あらかじめ準備
したキラルな（Ｓ型またはＲ型）大環状ポリエー
テルが均等に含有する吸着剤の充填したカラムに
通導し、クロマトグラフイーをおこなう。もし、
キラルな大環状ポリエーテルとして、Ｓ型を用い
ると、目的の一般式で示されるｄ体は、このＳ
型とリガンドし、いわゆる錯体を生成するため、
一方のｌ体よりはるかにおくれて溶出する。ま
た、キラルな大環状ポリエーテルとしてＲ型を用
いると、状況はまつたく逆転し、目的のｄ体はｌ
体よりはるかに早く溶出する。このようにして、
得られる光学分割されたｄ体またはｌ体は一度再
結晶するだけでよい。 To describe the method of the present invention: Racemic form for the purpose of optical resolution: 2-substituted-3-(p-methoxyphenyl)
-3-[(2-Substituted) phenylthio]propionic acid is dissolved in a dilute organic acid water-containing or saturated organic solvent such as tetrahydrofuran, cyclohexane, carbon tetrachloride, hexane, methylene chloride, chloroform, benzene, toluene, or alcohols. The mixture is dissolved in the mixture and passed through a column filled with an adsorbent prepared in advance that evenly contains a chiral (S-type or R-type) macrocyclic polyether to perform chromatography. if,
When the S type is used as the chiral macrocyclic polyether, the d-form represented by the desired general formula is this S type.
to form a so-called complex,
It elutes much later than the other l-isomer. Furthermore, when the R type is used as the chiral macrocyclic polyether, the situation is completely reversed, and the desired d-form is the l-form.
It elutes much faster than the body. In this way,
The resulting optically resolved d-form or l-form only needs to be recrystallized once.
光学分割に用いる、あらかじめ準備したカラム
は、例えばキラルな大環状ポリエーテルを酢酸・
水（４：１）の混合液（溶出に用いる溶媒たとえ
ばトルエンなどで飽和しておくとよい）に溶解
し、これに吸着剤例えばセライト、シリカゲルま
たはその混合物に加え、よく混合させてのち、一
夜風乾し、あるいは加熱乾燥し、ドライ法でカラ
ムに充填させたものを用いる。カラムの上層を平
均に保つため、さらに充填剤を置き、さらに微細
な海砂または綿でおさえておく。この用意された
カラムに、分割目的のラセミ体を例えば、酢酸水
で飽和したトルエンを用いてカラムに通導・溶出
する。また、このカラムを自動化し、サンプルの
サイクリングシステムを組み立てることも可能で
あり、このような操作により分割をより良くで
き、量産することもできる。つまり、この本発明
方法を用い工場内で自動化システムを設置すれ
ば、純度の高い光学活性体を大量にコスト安で製
造することができる。 For example, a pre-prepared column used for optical resolution can be used to coat a chiral macrocyclic polyether with acetic acid.
Dissolve in a mixture of water (4:1) (preferably saturated with the solvent used for elution, such as toluene), add to this an adsorbent such as celite, silica gel, or a mixture thereof, mix well, and leave overnight. It is air-dried or heat-dried and packed into a column using the dry method. To keep the top layer of the column even, add more packing material and cover it with fine sea sand or cotton. The racemate to be resolved is passed through the prepared column and eluted using, for example, toluene saturated with aqueous acetic acid. It is also possible to automate this column and assemble a sample cycling system, which allows for better resolution and mass production. In other words, if an automated system is installed in a factory using the method of the present invention, optically active substances with high purity can be produced in large quantities at low cost.
溶出する化合物の同定にも熱検出やUV検出法
が採用できるからカラムの途中でのサンプリング
も可能である。また、オーソドツクスな方法とし
てサンプリングした化合物の薄層クロマトグラフ
イーにより化合物の種類と純度がチエツクでき
る。 Thermal detection and UV detection methods can also be used to identify eluting compounds, making sampling mid-column possible. Furthermore, the type and purity of the compound can be checked by thin layer chromatography of the sampled compound as an orthodox method.
本発明方法で用いるキラルは大環状ポリエーテ
ルとしては、次に示すような例えば（―）−（SS）
−ジビナフト−22−クラウン−６（クラウンＡ）、
その誘導体、クラウンＢ、あるいはクラウンＣま
たクラウンＤ、さらにアミド結合ポリエーテル
（クラウンＥ）などが任意に利用できるのも本発
明方法の特徴の一つと云える。 The chiral macrocyclic polyether used in the method of the present invention includes, for example, (-)-(SS) as shown below.
-Gibinaft-22-Crown-6 (Crown A),
One of the features of the method of the present invention is that its derivatives such as crown B, crown C, crown D, and even amide-bonded polyether (crown E) can be used as desired.
次に、本発明方法を実施例をもつて説明する。 Next, the method of the present invention will be explained using examples.
実施例 １
(a) あらかじめセツトしたクラウンＤのキラル
（Ｓ型）な大環状ポリエーテル（ｎ＝５、Ｒ＝
R′＝CH2OCH2COOH）が均等に混合したセラ
イト・シリカゲル（１：１）のカラム（内径３
cmφ×80cm）（大環状ポリエーテル６ｇをトル
エンで飽和した酢酸・水（４：１）50mlにとか
し、これをセライト・シリカゲル（１：１）60
ｇに加え、混合した。一夜風乾し、内径３cmφ
のカラムに充填した。）の上部に、１ｇのラセ
ミ型：α−２−ヒドロキシ−３−（ｐ−メトキ
シフエニル）−３−〔（２−ジメチルアミノエチ
ル）フエニルチオ〕プロピオン酸（油状物）を
10mlのトルエンで飽和した酢酸・水（４：１）
に溶解して加え、ついで酢酸・水（４：１）で
飽和したトルエンで展開させた。このカラムク
ロマトグラフイーによつて、はじめの方のフラ
クシヨンに、ｌ−α−２−ヒドロキシ−３−
（ｐ−メトキシフエニル）−３−〔（２−ジメチル
アミノエチル）フエニルチオ〕プロピオン酸
（491mg）〔mp.242−243゜（メタノール）；〔α〕23 D
＝−122゜（Ｃ＝0.380、メタノール）〕が、あと
のフラクシヨンから一方のｄ体（495mg）
〔mp.243−244゜、メタノールから；〔α〕23 D＝＋
123゜（Ｃ＝0.350、メタノール）〕が単離できた。Example 1 (a) Preset crown D chiral (S-type) macrocyclic polyether (n=5, R=
A column of celite / silica gel (1:1) (inner diameter 3
cmφ×80cm) (Dissolve 6g of macrocyclic polyether in 50ml of acetic acid/water (4:1) saturated with toluene, and add 60ml of Celite/silica gel (1:1).
g and mixed. Air dry overnight, inner diameter 3cmφ
was packed into a column. ) on top of 1 g of racemic α-2-hydroxy-3-(p-methoxyphenyl)-3-[(2-dimethylaminoethyl)phenylthio]propionic acid (oil).
Acetic acid/water (4:1) saturated with 10ml toluene
The mixture was dissolved in and added to the solution, and then developed with toluene saturated with acetic acid/water (4:1). By this column chromatography, l-α-2-hydroxy-3-
(p-Methoxyphenyl)-3-[(2-dimethylaminoethyl)phenylthio]propionic acid (491 mg) [mp.242-243° (methanol); [α] 23 D
= -122゜ (C = 0.380, methanol)] is one d-isomer (495 mg) from the remaining fraction.
[mp.243−244°, from methanol; [α] 23 D = +
123° (C=0.350, methanol)] was successfully isolated.
(b) 上述(a)の方法で、キラルな大環状ポリエーテ
ルとにＲ型のクラウンＤ（ｎ＝４、Ｒ＝Ｈ、
R′＝CH2OCH2COOH）を用いて同様の実験を
おこないｄ体（496mg）（mp.243−244℃）とｌ
体（492mg）（mp.242−243℃）とを単離した。(b) Using the method described in (a) above, a chiral macrocyclic polyether is coated with an R-type crown D (n=4, R=H,
A similar experiment was carried out using
(492 mg) (mp. 242-243°C) was isolated.
実施例 ２
あらかじめセツトしたクラウン−Ｂのキラル
（Ｒ型）な大環状ポリエーテル（Ｒ＝
CH2OCH2COOH）が均等に混合したセライト・
アルミナ（４：１）のカラム（内径３cmφ×80
cm）〔大環状ポリエーテル６ｇをクロロホルム・
酢酸・メタノール・水（20：0.1：６：0.4）50ml
に溶解し、60ｇのセライト・アルミナ（４：１）
に加え、よく混合した。これを一夜放置、風乾さ
せ、カラムにドライ式で充填。〕に、ラセミ型：
α−２−アセトキシ−３−（ｐ−メトキシフエニ
ル）−３−〔（２−ジメチルアミノエチル）フエニ
ルチオ〕プロピオン酸（油状物）１ｇを少量のク
ロロホルム・酢酸・メタノール・水（20：0.1：
６：0.4）に溶解し、カラムの上層に添加し、つ
いで同様に混合溶剤で展開・溶出した。Example 2 Preset crown-B chiral (R-type) macrocyclic polyether (R=
Celite/Celite with evenly mixed CH 2 OCH 2 COOH)
Alumina (4:1) column (inner diameter 3cmφ x 80
cm) [6 g of macrocyclic polyether in chloroform
Acetic acid/methanol/water (20:0.1:6:0.4) 50ml
60g Celite-Alumina (4:1) dissolved in
and mixed well. Leave this overnight, air dry, and fill the column dry. ], racemic type:
1 g of α-2-acetoxy-3-(p-methoxyphenyl)-3-[(2-dimethylaminoethyl)phenylthio]propionic acid (oil) was added to a small amount of chloroform/acetic acid/methanol/water (20:0.1:
6:0.4), added to the upper layer of the column, and then developed and eluted with a mixed solvent in the same manner.
このカラムクロマトグラフイーにより、はじめ
の方のフラクシヨンに、ｄ−α−２−アセトキシ
−３−（ｐ−メトキシフエニル）−３−〔（２−ジメ
チルアミノエチル）フエニルチオ〕プロピオン酸
（0.495ｇ）〔mp.195−196℃（メタノール）；〔α〕
23 D＝＋119゜（Ｃ＝0.450、メタノール）〕が、おくれ
たフラクシヨンから一方のｌ体（0.490mg）
〔mp.194−195゜（メタノール）；〔α〕23 D＝−119.5
゜
（Ｃ＝0.500、メタノール）〕が単離した。 By this column chromatography, d-α-2-acetoxy-3-(p-methoxyphenyl)-3-[(2-dimethylaminoethyl)phenylthio]propionic acid (0.495 g) was added to the first fraction. [mp.195−196℃ (methanol); [α]
23 D = +119° (C = 0.450, methanol)] is extracted from one l-isomer (0.490 mg) from the delayed fraction.
[mp.194−195゜(methanol); [α] 23 D = −119.5
(C=0.500, methanol)] was isolated.
実施例 ３
dl−α−２−ヒドロキシ−３−（ｐ−メトキシ
フエニル）−３−（ｏ−アミノフエニルチオ）−プ
ロピオン酸（mp.130−133℃）1.0ｇをあらかじめ
準備したクラウン−Ｄのキラル（Ｓ型）な大環状
ポリエーテル（ｎ＝４、Ｒ＝R′＝
CH2OCH2COOH）のカラム（実施例１(a)のカラ
ムと同じように準備した）を用いて、実施例１(a)
と同様にカラムクロマトグラフイーをおこない、
ｄ−α−２−ヒドロキシ−３−（ｐ−メトキシフ
エニル）−３−（ｏ−アミノフエニルチオ）−プロ
ピオン酸の0.496ｇ〔mp.132−133℃（メタノー
ル）；〔α〕23 D＝＋346゜（Ｃ＝0.350、エタノール）
〕
と0.491ｇの一方のｌ体〔mp.130−132℃（メタノ
ール）；〔α〕24 D＝−345゜（Ｃ＝0.450、エタノール
）〕
とを単離した。Example 3 1.0 g of dl-α-2-hydroxy-3-(p-methoxyphenyl)-3-(o-aminophenylthio)-propionic acid (mp. 130-133°C) was prepared in advance in a crown- Chiral (S-type) macrocyclic polyether of D (n=4, R=R′=
EXAMPLE 1 (a)
Perform column chromatography in the same manner as
0.496 g of d-α-2-hydroxy-3-(p-methoxyphenyl)-3-(o-aminophenylthio)-propionic acid [mp.132-133°C (methanol); [α] 23 D = +346° (C = 0.350, ethanol)
]
and 0.491 g of one of the l-isomers [mp.130-132℃ (methanol); [α] 24 D = -345゜ (C = 0.450, ethanol)]
were isolated.
Claims (1)
はNH2基またはNHCH2CH2N（CH3）2を示す）で
表わされるラセミ型：２−置換−３−（ｐ−メト
キシフエニル）−３−〔（２−置換）フエニルチオ〕
プロピオン酸を、あらかじめキラルな大環状ポリ
エーテル（Ｓ型またはＲ型）を均等に混合した吸
着剤を充填したカラムに通導し、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２−置換−３−（ｐ−メトキシフエニル）
−３−〔（２−置換）フエニルチオ〕プロピオン酸
の製造法。[Claims] 1. General formula (In the formula, R 1 represents OH or OCOCH 3 , R 2
represents NH2 group or NHCH2CH2N ( CH3 ) 2 ) Racemic type: 2-substituted-3-(p-methoxyphenyl)-3-[(2-substituted)phenylthio]
A general formula characterized in that propionic acid is passed through a column packed with an adsorbent in which chiral macrocyclic polyether (S type or R type) is evenly mixed in advance and optically resolved. Optically active 2-substituted-3-(p-methoxyphenyl) represented by (wherein R 1 and R 2 are the same as above)
-3-[(2-substituted)phenylthio]propionic acid production method.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1701483A JPS59144751A (en) | 1983-02-04 | 1983-02-04 | Optical resolution of 2-substituted-3-(p-methoxyphenyl)- 3-((2-substituted)phenylthio)propionic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1701483A JPS59144751A (en) | 1983-02-04 | 1983-02-04 | Optical resolution of 2-substituted-3-(p-methoxyphenyl)- 3-((2-substituted)phenylthio)propionic acid |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS59144751A JPS59144751A (en) | 1984-08-18 |
| JPH0339056B2 true JPH0339056B2 (en) | 1991-06-12 |
Family
ID=11932140
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1701483A Granted JPS59144751A (en) | 1983-02-04 | 1983-02-04 | Optical resolution of 2-substituted-3-(p-methoxyphenyl)- 3-((2-substituted)phenylthio)propionic acid |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS59144751A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5225557A (en) * | 1988-05-10 | 1993-07-06 | Hoffmann-La Roche Inc. | Process for making optically active naphtho[1,2-b]thiazepin-4(5H)-ones |
-
1983
- 1983-02-04 JP JP1701483A patent/JPS59144751A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS59144751A (en) | 1984-08-18 |
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