JPS59144751A - Optical resolution of 2-substituted-3-(p-methoxyphenyl)- 3-((2-substituted)phenylthio)propionic acid - Google Patents
Optical resolution of 2-substituted-3-(p-methoxyphenyl)- 3-((2-substituted)phenylthio)propionic acidInfo
- Publication number
- JPS59144751A JPS59144751A JP1701483A JP1701483A JPS59144751A JP S59144751 A JPS59144751 A JP S59144751A JP 1701483 A JP1701483 A JP 1701483A JP 1701483 A JP1701483 A JP 1701483A JP S59144751 A JPS59144751 A JP S59144751A
- Authority
- JP
- Japan
- Prior art keywords
- substituted
- type
- isomer
- methoxyphenyl
- polyether
- 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.)
- Granted
Links
- 230000003287 optical effect Effects 0.000 title abstract description 10
- -1 2-substituted-3-(p-methoxyphenyl)- 3-((2-substituted)phenylthio)propionic acid Chemical class 0.000 title description 2
- 239000002253 acid Substances 0.000 claims description 9
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 229920000570 polyether Polymers 0.000 abstract description 17
- 239000004721 Polyphenylene oxide Substances 0.000 abstract description 16
- 150000001875 compounds Chemical class 0.000 abstract description 9
- 239000003463 adsorbent Substances 0.000 abstract description 5
- 230000001430 anti-depressive effect Effects 0.000 abstract description 2
- 239000000935 antidepressant agent Substances 0.000 abstract description 2
- 229940005513 antidepressants Drugs 0.000 abstract description 2
- 238000010828 elution Methods 0.000 abstract description 2
- 239000003218 coronary vasodilator agent Substances 0.000 abstract 1
- 239000003446 ligand Substances 0.000 abstract 1
- 229940125725 tranquilizer Drugs 0.000 abstract 1
- 239000003204 tranquilizing agent Substances 0.000 abstract 1
- 230000002936 tranquilizing effect Effects 0.000 abstract 1
- 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 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 238000000034 method Methods 0.000 description 17
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 125000003006 2-dimethylaminoethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 4
- 235000019260 propionic acid Nutrition 0.000 description 4
- 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 description 4
- 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
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 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
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- SYTBZMRGLBWNTM-SNVBAGLBSA-N (R)-flurbiprofen Chemical compound FC1=CC([C@H](C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-SNVBAGLBSA-N 0.000 description 1
- CNPURSDMOWDNOQ-UHFFFAOYSA-N 4-methoxy-7h-pyrrolo[2,3-d]pyrimidin-2-amine Chemical compound COC1=NC(N)=NC2=C1C=CN2 CNPURSDMOWDNOQ-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
- 239000013543 active substance Substances 0.000 description 1
- 229940085242 benzothiazepine derivative selective calcium channel blockers with direct cardiac effects Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 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
- 238000001514 detection method Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012046 mixed solvent Substances 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
- 230000000506 psychotropic effect Effects 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 239000004576 sand Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 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
- 230000001256 tonic effect Effects 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)
Abstract
Description
【発明の詳細な説明】
本発明は、ラセミ型：２−置換−６−（ｐ−メトキシフ
ェニル）−３−［：（２−置換）フェニルチオ〕ゾロピ
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-6-(p-methoxyphenyl)-3-[:(2-substituted)phenylthio]zolopionic acid.
本発明で述べる２−置換−３−（ｐ−メトキシフェニル
）−３−（（２−を換）フェニルチオ〕ゾロピオン酸（
Ｉ）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
シフェニル）−３−ア（５Ｈ）−オンの合成中間体であ
る。最終的に必要なとの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Ｖロキシ−３−（ｐ−メトキシフエニ＃）−３−（２
−ニトロフェニルチオ）−フロピオン酸（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（％公昭５
３−１８０３８号公報）。2-substituted-3-(p-methoxyphenyl)-3-((2-substituted)phenylthio)zolopionic acid (
I) is a synthetic intermediate of d-α-2-(p-methoxyphenyl)-3-a(5H)-one, which is an antidepressant, psychotropic stabilizer, and coronary vascular tonic agent, all of which are important as pharmaceuticals. It is. Various methods have been investigated to produce the final d-isomer, but with conventional methods, it is difficult to optically resolve the benzothiazepine derivative at the stage, and the synthesis intermediate At each stage, only α-2-
HyVroxy-3-(p-methoxypheni#)-3-(2
-nitrophenylthio)-furopionic acid (using an optically active organic base), and the d-form is obtained at this stage,
Then, through several steps, the desired product is manufactured (% Kosho 5
3-18038).
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った。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 discovered 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０ＯＯＯＨ３を示し、Ｒ２は−ＮＨ２基または−Ｎ
ＨＯＨ２０Ｈ２Ｎ（ＯＨ３）２基を示す）で表わされる
ラセミ型＝２−置換−６−（ｐ−メトキシフェニル）−
３−［（２−置換）フェニルチオ〕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＆ ＩＪ
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−６−（ｐ−メトキシフェニル
） −３−（（２−置換）フェニルチオ〕ブローオン酸
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
Racemic type represented by HOH20H2N (indicates 2 OH3 groups) = 2-substituted-6-(p-methoxyphenyl)-
3-[(2-substituted)phenylthio]propionic acid is pre-prepared into a chiral (S-type or R-type) macrocyclic &IJ
Optical activity expressed by the general formula (where R1 and R2 are the same at the top), which is characterized by passing through a column filled with an adsorbent containing an even mixture of ether (crown compound) and performing optical resolution. This invention relates to a method for producing 2-substituted-6-(p-methoxyphenyl)-3-((2-substituted)phenylthio)broonic acid, and its characteristics can be seen in the flow sheet shown below.
（光学活性ｄ体と１体）■
Ｒ１−ＯＨまたは０ＣＯＣ！Ｈ３： 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Ｖロキシ−３−（ｐ−メトキシフェニル）−３−［
：（２−アミン）フェニルチオ〕プロピオン酸（Ｒ１＝
０Ｈ１Ｒ２＝ 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Ｐ
ロキシー３− （ｐ−メトキシフェニル）−３−［（２
−ジメチルアミノエチル）フェニルチオ〕ゾロピオン酸
（Ｒ１＝ＯＨ。(One optically active d-form and one body) ■ R1-OH or 0COC! H3: R2= NH2 or NHCH2CH2N(CH3)2 2 of the d-isomer represented by the general formula (■) thus obtained
-Vroxy-3-(p-methoxyphenyl)-3-[
:(2-amine)phenylthio]propionic acid (R1=
0H1R2=NH2: Compound 1) can be prepared by a known method (
(Special Publication No. 53-18038)
Roxy3-(p-methoxyphenyl)-3-[(2
-dimethylaminoethyl)phenylthio]zolopionic acid (R1=OH.
Ｒ２＝＝ ＮＨＯＨ２０Ｈ２（ＯＨ３）２：化合物２）
と２−アセトキシ−３−（ｐ−メトキシフェニル）−３
−［（２−ジメチルアミノエチル）フェニルチオ〕ゾロ
ピオン酸（Ｒ１＝’ ０ＯＯＯＨ３、Ｒ２＝ ＮＨＣＨ
２ＣＨ２Ｎ（ＯＨ３）２：化合物３）とは、本発明者に
よって先に提出された先行特許の方法によ）、所望の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−ゾヒ）
’Ｃ７−１，５−ベニｙｆｆｌｅｅン−４（５Ｈ）−オ
ンを製造することができる。R2==NHOH20H2(OH3)2: Compound 2)
and 2-acetoxy-3-(p-methoxyphenyl)-3
-[(2-dimethylaminoethyl)phenylthio]zolopionic acid (R1='0OOOH3, R2=NHCH
2CH2N(OH3)2: Compound 3) is obtained by the method of the prior patent previously filed by the present inventor), with the desired d
-α-2-(p-methoxyphenyl)-6-acetoxy-5-(2-dimethylamineethyl)-2,3-zohy)
'C7-1,5-benyffleen-4(5H)-one 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−メトキシフェニル）−３−（（２
−置換）フェニルチオ〕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ｒ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
ロマトグラフィーをおこなう。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型とりガントし、いわゆる錯体
を生成するため、一方の７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、状況はまったく逆転し、目的のｄ体は１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７体は一度再結晶するだけでよ
い。To describe the method of the present invention: Racemic type for the purpose of optical resolution:
2-substituted-3-(p-methoxyphenyl)-3-((2
-Substituted) phenylthio] propionic acid in a dilute organic acid water-containing or saturated organic solvent such as tetrahydrofuran, cyclohexane, carbon tetrachloride, hexane, methylene chloride, chloroform, benzene, toluene, or a mixture of these with an alcohol. The solution is dissolved and passed through a column packed with an adsorbent evenly containing a chiral (S-type or R-type) macrocyclic polyether prepared in advance for chromatography. If the S-form is used as the chiral macrocyclic polyether, the target d-form represented by the general formula and elute. Furthermore, when the R-form is used as the chiral macrocyclic polyether, the situation is completely reversed, and the desired d-form is eluted much earlier than the single-form. In this way, the optically resolved d-form or 7-form obtained 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ＮうＩし
は、例えばム拝奥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、−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。と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。For example, a pre-prepared column used for optical resolution may be prepared by dissolving a macrocyclic polyether in acetic acid and water (4
: Dissolve in the mixture of 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 - air dry at night. Alternatively, it may be dried by heating and packed into a column using a 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 column and eluted using, for example, toluene saturated with aqueous acetic acid.
また、と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
作によシ分割をよυ良くでき、量産することもできる。It is also possible to automate the column and assemble a sample cycling system, and this operation allows for better separation and mass production.
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。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。Since heat detection and UV detection methods can be used to identify eluted compounds, sampling in the middle of the column is also possible.
また、オーツＶ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ィーにより化合物の種類と純
度がチェックできる。Furthermore, the type and purity of the compound can be checked by thin layer chromatography of the sampled compound as an automated 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（＝）−（８Ｂ）−ジビナフ
トー２２−クラウン−６（クラウンＡ）、その誘導体、
クラウンＢ１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。Examples of chiral macrocyclic polyethers used in the method of the present invention include (=)-(8B)-divinaphthol-22-crown-6 (crown A), derivatives thereof,
One of the features of the method of the present invention is that crown B1, 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って説明する。Next, the method of the present invention will be explained using examples.
（Ｓ型）な大環状ポリエーテル（ｎ−５、Ｒ＝ Ｒ’
＝ ｃＨ２ｏａＨ２ａｏｏＨ）が均等に混合したセライ
ト・シリカゾル（１：１）のカラム（内径３−φＸ８０
ｃｍ）（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）５０ｍ／にとかじ、とれをセライト
・シリカゲル（１：１）６０５’に加え、混合した。−
夜風乾し、内径６ｃｍφのカラムに充填した。）の上部
に、１ｇのラセミ型：α−２−ヒｖＯキシ−６−（ｐ−
メトキシフェニル）−３−［（２−ジメチルアミノエチ
ル）フェニルチオ〕プロピオン酸（油状物）を１０ｍ／
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ィーによって、は
じめの方のフラクションに、ｌ−α−２−ヒドロキシ−
３−（ｐ−メトキシフェニル）−３−［（２−ジメチル
アミノエチル）フェニルチオ〕プロピオン酸（４９１ｒ
ｎ９）［ｍｐ。(S type) macrocyclic polyether (n-5, R= R'
Column (inner diameter 3-φX80
cm) (6 g of macrocyclic polyether was dissolved in 50 m of acetic acid/water (4:1) saturated with toluene, and the mixture was added to 605' of Celite/silica gel (1:1) and mixed.-
It was air-dried overnight and packed into a column with an inner diameter of 6 cmφ. ) on top of 1 g of racemic form: α-2-oxy-6-(p-
methoxyphenyl)-3-[(2-dimethylaminoethyl)phenylthio]propionic acid (oil) at 10 m/
of the solution was dissolved in acetic acid/water (4:1) saturated with toluene, and then developed with toluene saturated with acetic acid/water (4:1). This column chromatography gives the first fraction l-α-2-hydroxy-
3-(p-methoxyphenyl)-3-[(2-dimethylaminoethyl)phenylthio]propionic acid (491r
n9) [mp.
２４２−２４３° （メタノール）；〔α〕２３＝＝１
２２°（ｃ ＝ ０．３８０、メタノール）〕が、あと
のフラクションから一方の６体（４９５ｍｇ）Ｃｍｐ、
２４６−２４４°、メタノールから；〔α）２３＝＋１
２３° （ａ ＝ ０．３５０、メタノ−ル）〕が単離
できた。242-243° (methanol); [α]23==1
22° (c = 0.380, methanol)], one of the 6 bodies (495 mg) Cmp from the latter fraction,
246-244°, from methanol; [α)23=+1
23° (a = 0.350, methanol)] could be isolated.
ｆｂ） 上述（ａｔの方法で、キラルな大環状ポリエ
ーテルとにＲ型のクララｙＤ（ｎ＝４、Ｒ＝Ｈ，Ｒ’＝
、、。fb) By the method described above (at), a chiral macrocyclic polyether and R-type Clara yD (n=4, R=H, R'=
,,.
ＣＨ２０ＣＨ２ＣＯＯＨ）を用いて同様の実験をおこな
い６体（４９６ｍ９）（ｍｐ、２４３−２４４°Ｃ）と
ｌ休（４９２ダ）（ｍｐ、２４２−２４３℃）とを単離
した。A similar experiment was carried out using CH20CH2COOH) and 6 bodies (496m9) (mp, 243-244°C) and 1-body (492da) (mp, 242-243°C) were isolated.
〈実施例２〉
あらかじめセットしたクラウン−Ｂのキラル（Ｒ型）な
大環状ポリエーテ＃ （Ｒ−０Ｈ２００Ｈ２０００Ｈ）
が均等に混合したセライト・アルミナ（４：１）のカラ
ム（内径３６ｍφｘ ８０ ａｍ ） Ｃ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（２
０：０．１ ：６：［１，４）５０ｍ／に溶解し、６０
ｇのセライト・アルミナ（４： １）に加え、よく混合
した。これを−夜装置、風乾させ、カラムにｒライ式で
充填。〕に、〕ラセミ型：α−２−アセトキシー３ （
ｐ−メトキシフェニル）−３−〔（２−ジメチルアミノ
エチル）フェニルチオ〕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-0H200H2000H)
A column of celite/alumina (4:1) (inner diameter 36 mφ x 80 am) in which 6 g of C macrocyclic polyether was evenly mixed with chloroform, acetic acid, methanol, and water (2
0:0.1:6:[1,4) Dissolved in 50m/, 60
g of celite/alumina (4:1) and mixed well. This was air-dried overnight and filled into a column using the dry method. ],] racemic form: α-2-acetoxy 3 (
1 g of p-methoxyphenyl)-3-[(2-dimethylaminoethyl)phenylthio]propionic acid (oil) was mixed with a small amount of chloroform, acetic acid, methanol, and 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.
とのカラムクロマトグラフィーにより、はじめの方のフ
ラクションに、ｄ−α−２−アセトキシ−５−（ｐ−メ
トキシフェニル）−３−１：（２−ジメチルアミノエチ
ル）フェニルチオ〕ゾロピオン酸（０，４９５７！ ）
［Ｉ ｍｐ、 １９５−１９６°Ｃ（メタノール）；
〔α）２３＝＋１１９° （ｃ ＝ ０．４５０、メタ
ノール）〕が、おくれたフラクションから一方の１体（
０，４９０■） ［ｍＩ）。１９４−１９５゜（メタノ
ール）；〔α〕２３ ＝ １１９．５° （０＝Ｏ，
５００、メタノール）〕が単離した。By column chromatography with )
[Imp, 195-196°C (methanol);
[α)23=+119° (c = 0.450, methanol)], one body (
0,490■) [mI). 194-195° (methanol); [α]23 = 119.5° (0=O,
500, methanol)] was isolated.
〈実施例６〉
ｄｌ−α−２−ヒドロキシ−６−（ｐ−メトキシフェニ
ル）−３−（ｏ−アミノフェニルチオ）−ゾロピオン酸
（ｍｐ、 １３０−１３３°Ｃ） １．０ ＆をあらヵ
１．ゎ準備しえ、２つ７−っ。ｄフ駈（ｓ型）な大環状
ポリエーテル（ｎ＝４、Ｒ＝Ｒ’＝ＯＨ２００Ｈ２ＣＯ
ＯＨ）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
ロマトグラフィーをおこない、ｃｌ−α−２−ヒドロキ
シ−３−（ｐ−メトキシフェニル）−３−（ｏ−アミノ
フェニルチオ）−ゾロピオン酸の０．４９６ ｇＣｍｐ
。１３２−１３３°Ｃ（メタノール）；Ｃα〕２３＝＋
３４６° （ａ ＝ ０．３５［］、エタノール）〕と
０．４９１ 、！ｉ’の一方の１体［ｍｐ−１３０−１
３２°Ｃ（メタノール）：〔α〕２４＝一６４５° （
ｃ ＝ ０．４５０、エタノール）〕とを単離した。<Example 6> dl-α-2-hydroxy-6-(p-methoxyphenyl)-3-(o-aminophenylthio)-zolopionic acid (mp, 130-133°C) 1.0 1. Get ready, two 7-. d-shaped (s-type) macrocyclic polyether (n=4, R=R'=OH200H2CO
Column chromatography was performed in the same manner as in Example 1(a) using a column of Cl-α-2-hydroxy-3-( 0.496 gCmp of p-methoxyphenyl)-3-(o-aminophenylthio)-zolopionic acid
. 132-133°C (methanol); Cα]23=+
346° (a = 0.35[], ethanol)] and 0.491,! One of i' [mp-130-1
32°C (methanol): [α]24=-645° (
c = 0.450, ethanol)] was isolated.
代理人 浅 村 皓 外４名Agent Asa Mura Hao 4 people outside
Claims (1)
ＮＨ２基またはＮＨＯＨ２０Ｈ２Ｎ（ＯＨ３）２を示す
）で表わされるラセミ型：２−置換−３−（ｐ−メトキ
シフェニル）−３−［（２−ｆｆｉｌ）フェニルチオ〕
フローオン酸を、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−メトキシフェニル）−３−［（
２−置換）フェニルチオコブローオン酸の製造法。[Claims] Racemic type represented by the general formula (wherein, R1 represents OH or OCOCH3, and R2 represents an NH2 group or NHOH20H2N(OH3)2): 2-substituted-3-(p-methoxy phenyl)-3-[(2-ffil)phenylthio]
The general formula ■ (in the formula , R1 and R2 are the same as above).
Method for producing 2-substituted) phenylthiocobroonic acid.
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 true JPS59144751A (en) | 1984-08-18 |
| JPH0339056B2 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) |
Cited By (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
Cited By (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 |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0339056B2 (en) | 1991-06-12 |
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