JPH0430949B2 - - Google Patents
Info
- Publication number
- JPH0430949B2 JPH0430949B2 JP19196084A JP19196084A JPH0430949B2 JP H0430949 B2 JPH0430949 B2 JP H0430949B2 JP 19196084 A JP19196084 A JP 19196084A JP 19196084 A JP19196084 A JP 19196084A JP H0430949 B2 JPH0430949 B2 JP H0430949B2
- Authority
- JP
- Japan
- Prior art keywords
- threo
- methoxyphenyl
- aminophenylthio
- hydroxy
- propionic acid
- 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
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Substances CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 12
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 230000003287 optical effect Effects 0.000 claims description 2
- NUSLQDOXLCYVTQ-UHFFFAOYSA-N 2-(2-methoxyphenyl)propanoic acid Chemical compound COC1=CC=CC=C1C(C)C(O)=O NUSLQDOXLCYVTQ-UHFFFAOYSA-N 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 150000003839 salts Chemical class 0.000 description 10
- 150000001875 compounds Chemical class 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 239000013078 crystal Substances 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- RQEUFEKYXDPUSK-UHFFFAOYSA-N 1-phenylethylamine Chemical compound CC(N)C1=CC=CC=C1 RQEUFEKYXDPUSK-UHFFFAOYSA-N 0.000 description 1
- XAVRCJUDEZXSEC-UHFFFAOYSA-N 2-(1,2-benzothiazepin-5-yl)-N,N-dimethylethanamine Chemical class CN(C)CCC1=CC=NSC2=C1C=CC=C2 XAVRCJUDEZXSEC-UHFFFAOYSA-N 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- -1 compound () 1,2-diphenylethylamine salt Chemical class 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000000304 vasodilatating effect Effects 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明はスレオ−ｄ−２−ヒドロキシ−３−
（2′−アミノフエニルチオ）−３−（4″−メトキシ
フエニル）−プロピオン酸の新規な製造法に関す
る。DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to threo-d-2-hydroxy-3-
This invention relates to a novel method for producing (2'-aminophenylthio)-3-(4''-methoxyphenyl)-propionic acid.
次式（）
で表わされる２−ヒドロキシ−３−（2′−アミノ
フエニルチオ）−３−（4″−メトキシフエニル）−
プロピオン酸は、優れた冠血管拡張作用及び脳波
覚醒化作用を有する次式（）
で表わされる５−（Ｎ，Ｎ−ジメチルアミノエチ
ル）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（特開昭57−136581号）。
The following formula () 2-hydroxy-3-(2′-aminophenylthio)-3-(4″-methoxyphenyl)-
Propionic acid has the following formula () which has excellent coronary vasodilatory effect and brain wave awakening effect. It is a compound useful as a synthetic intermediate for the 5-(N,N-dimethylaminoethyl)benzothiazepine derivative represented by (Japanese Patent Application Laid-Open No. 136581/1981).
而して、（）式の化合物のうちで、シス−
（＋）−２−（4′−メトキシフエニル）−３−アセト
キシ−５−（Ｎ，Ｎ−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）−オンは特に優れた効果を有する（特
公昭53−18038号）ことから、原料として使用さ
れる（）式の化合物はスレオ−ｄ−体であるこ
とが望ましい。 Therefore, among the compounds of formula (), cis-
(+)-2-(4'-methoxyphenyl)-3-acetoxy-5-(N,N-dimethylaminoethyl)-
2,3-dihydro-1,5-benzothiazepine-
Since 4-(5H)-one has particularly excellent effects (Japanese Patent Publication No. 53-18038), it is desirable that the compound of formula () used as a raw material is in the threo-d-form.
従来、スレオ−ｄ−２−ヒドロキシ−３−
（2′−アミノフエニルチオ）−３−（4″−メトキシ
フエニル）−プロピオン酸を得る方法としては、
（）式の化合物のスレオ−dl−体をα−フエニ
ルエチルアミンを分割剤として使用して光学分割
する方法が知られている（特開昭57−136581号）。 Conventionally, threo-d-2-hydroxy-3-
The method for obtaining (2′-aminophenylthio)-3-(4″-methoxyphenyl)-propionic acid is as follows:
A method for optically resolving the threo-dl-isomer of the compound of formula () using α-phenylethylamine as a resolving agent is known (Japanese Patent Application Laid-Open No. 136581/1981).
本発明者は（）式のスレオ−dl−体を工業的
有利に光学分割することのできる分割剤を見出す
べく鋭意研究を行つた結果、ｌ−１，２−ジフエ
ニルエチルアミンが優れた分割剤であることを見
出し、本発明を完成した。
The present inventor conducted intensive research to find a resolving agent that can optically resolve the threo-dl-isomer of formula () with industrial advantage, and found that l-1,2-diphenylethylamine was an excellent resolving agent. They found that this is the case, and completed the present invention.
すなわち、本発明は、（）式で表わされるス
レオ−dl−２−ヒドロキシ−３−（2′−アミノフ
エニルチオ）−３−（4″−メトキシフエニル）−プ
ロピオン酸を分割剤としてｌ−１，２−ジフエニ
ルエチルアミンを使用して光学分割することを特
徴とするスレオ−ｄ−２−ヒドロキシ−３−
（2′−アミノフエニルチオ）−３−（4″−メトキシ
フエニル）−プロピオン酸の製造法を提供するも
のである。 That is, the present invention uses threo-dl-2-hydroxy-3-(2'-aminophenylthio)-3-(4''-methoxyphenyl)-propionic acid represented by the formula () as a resolving agent. -threo-d-2-hydroxy-3- characterized by optical resolution using -1,2-diphenylethylamine
A method for producing (2'-aminophenylthio)-3-(4''-methoxyphenyl)-propionic acid is provided.
本発明を実施するには、スレオ−dl−２−ヒド
ロキシ−３−（2′−アミノフエニルチオ）−３−
（4″−メトキシフエニル）−プロピオン酸（）に
ｌ−１，２−ジフエニルエチルアミンを作用させ
て２種のジアステレオマー塩を生成させる。 To practice the invention, threo-dl-2-hydroxy-3-(2'-aminophenylthio)-3-
(4″-Methoxyphenyl)-propionic acid () is reacted with l-1,2-diphenylethylamine to produce two diastereomeric salts.
分割剤のｌ−１，２−ジフエニルエチルアミン
は化合物（）に対して１〜1.2当量を使用する
のが好ましい。溶媒としては、２種のジアステレ
オマー塩の溶解度差が大きいものを使用するのが
好ましく、例えばメタノール又は含水メタノール
が挙げられる。 It is preferable to use l-1,2-diphenylethylamine as a resolving agent in an amount of 1 to 1.2 equivalents based on compound (). As the solvent, it is preferable to use a solvent in which the difference in solubility between the two diastereomeric salts is large, such as methanol or water-containing methanol.
斯くするとき、化合物（）のｄ−体のｌ−
１，２−ジフエニルエチルアミン塩が難溶性塩と
して析出してくる。この難溶性塩の析出は反応液
を冷却する方法、濃縮する方法等によつてなし得
る。このようにして得られる難溶性ジアステレオ
マー塩は過等によつて採取し、必要によりメタ
ノール等から再結晶すれば光学的に純粋な化合物
（）のｄ−体のｌ−１，２−ジフエニルエチル
アミン塩を得ることができる。 In this case, the l- of the d-form of the compound ()
1,2-diphenylethylamine salt precipitates as a sparingly soluble salt. Precipitation of this poorly soluble salt can be achieved by cooling the reaction solution, concentrating it, or the like. The sparingly soluble diastereomeric salt obtained in this way is collected by filtration, etc., and if necessary recrystallized from methanol etc. to obtain an optically pure l-1,2-diphthalate of the d-isomer of the compound (). Enylethylamine salt can be obtained.
斯くして得た化合物（）のｄ−体のｌ−１，
２−ジフエニルエチルアミン塩は、常法により、
例えば鉱酸を加えて分解すれば光学活性体のスレ
オ−ｄ−ヒドロキシ−３−（2′−アミノフエニル
チオ）−３−（4″−メトキシフエニル）−プロピオ
ン酸を得ることができる。 l-1 of the d-isomer of the compound () thus obtained,
2-diphenylethylamine salt is prepared by a conventional method.
For example, by adding a mineral acid and decomposing it, optically active threo-d-hydroxy-3-(2'-aminophenylthio)-3-(4''-methoxyphenyl)-propionic acid can be obtained.
一方、難溶性ジアステレオマー塩を分離した母
液中に含まれる易溶性ジアステレオマー塩から
は、この母液に鉱酸を加えて分解すれば、化合物
（）のｌ−体が回収される。 On the other hand, from the readily soluble diastereomeric salt contained in the mother liquor from which the poorly soluble diastereomeric salt is separated, the l-isomer of the compound () can be recovered by adding a mineral acid to the mother liquor for decomposition.
次に実施例を挙げて説明する。 Next, an example will be given and explained.
実施例 １
スレオ−dl−２−ヒドロキシ−３−（2′−アミ
ノフエニルチオ）−３−（4″−メトキシフエニル）
−プロピオン酸3.2ｇ及びｌ−１，２−ジフエニ
ルエチルアミン2.05ｇをメタノール17.5mlに加熱
溶解し、室温にした後、冷蔵庫に１日放置した。
析出した結晶を取乾燥して粗結晶2.3ｇを得た。
これをメタノールから再結晶してスレオ−ｄ−２
−ヒドロキシ−３−（2′−アミノフエニルチオ）−
３−（4″−メトキシフエニル）−プロピオン酸のｌ
−１，２−ジフエニルエチルアミン塩2.0ｇを得
た。融点169℃。〔α〕25 D＋259°〔Ｃ＝0.52、エタノ
ール〕。Example 1 Threo-dl-2-hydroxy-3-(2′-aminophenylthio)-3-(4″-methoxyphenyl)
3.2 g of -propionic acid and 2.05 g of l-1,2-diphenylethylamine were dissolved in 17.5 ml of methanol under heating, and the mixture was brought to room temperature and left in the refrigerator for one day.
The precipitated crystals were dried to obtain 2.3 g of crude crystals.
This was recrystallized from methanol and threo-d-2
-Hydroxy-3-(2'-aminophenylthio)-
l of 3-(4″-methoxyphenyl)-propionic acid
2.0 g of -1,2-diphenylethylamine salt was obtained. Melting point: 169℃. [α] 25 D +259° [C=0.52, ethanol].
実施例 ２
実施例１で得た塩1.3ｇをメタノール15ml及び
水15mlの混液に加熱溶解し、攪拌下1N塩酸３ml
を加えた。氷冷下３時間攪拌し、析出した結晶を
取、乾燥して、スレオ−ｄ−２−ヒドロキシ−
３−（2′−アミノフエニルチオ）−３−（4″−メト
キシフエニル）−プロピオン酸0.7ｇを得た。融点
138℃。〔α〕25 D＋332°〔Ｃ＝0.37、エタノール〕。Example 2 1.3 g of the salt obtained in Example 1 was heated and dissolved in a mixture of 15 ml of methanol and 15 ml of water, and 3 ml of 1N hydrochloric acid was added with stirring.
added. After stirring for 3 hours under ice cooling, the precipitated crystals were collected and dried to give threo-d-2-hydroxy-
0.7 g of 3-(2′-aminophenylthio)-3-(4″-methoxyphenyl)-propionic acid was obtained. Melting point
138℃. [α] 25 D +332° [C=0.37, ethanol].
Claims (1)
（2′−アミノフエニルチオ）−３−（4″−メトキシ
フエニル）−プロピオン酸を分割剤としてｌ−１，
２−ジフエニルエチルアミンを使用して光学分割
することを特徴とするスレオ−ｄ−２−ヒドロキ
シ−３−（2′−アミノフエニルチオ）−３−（4″−
メトキシフエニル）−プロピオン酸の製造法。[Claims] Linear formula threo-dl-2-hydroxy-3-
l-1, using (2′-aminophenylthio)-3-(4″-methoxyphenyl)-propionic acid as a resolving agent,
Threo-d-2-hydroxy-3-(2′-aminophenylthio)-3-(4″-), which is characterized by optical resolution using 2-diphenylethylamine.
Method for producing (methoxyphenyl)-propionic acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP19196084A JPS6169756A (en) | 1984-09-13 | 1984-09-13 | Production of threo-d-2-hydroxy-3-(2'-aminophenylthio)-3-(4"-methoxyphenyl)-propionic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP19196084A JPS6169756A (en) | 1984-09-13 | 1984-09-13 | Production of threo-d-2-hydroxy-3-(2'-aminophenylthio)-3-(4"-methoxyphenyl)-propionic acid |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS6169756A JPS6169756A (en) | 1986-04-10 |
| JPH0430949B2 true JPH0430949B2 (en) | 1992-05-25 |
Family
ID=16283306
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP19196084A Granted JPS6169756A (en) | 1984-09-13 | 1984-09-13 | Production of threo-d-2-hydroxy-3-(2'-aminophenylthio)-3-(4"-methoxyphenyl)-propionic acid |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS6169756A (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 |
-
1984
- 1984-09-13 JP JP19196084A patent/JPS6169756A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS6169756A (en) | 1986-04-10 |
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