JPH09255673A - Production of optically active 3-(paramethoxyphenyl) grycidic acid alkali metal salt - Google Patents
Production of optically active 3-(paramethoxyphenyl) grycidic acid alkali metal saltInfo
- Publication number
- JPH09255673A JPH09255673A JP8099187A JP9918796A JPH09255673A JP H09255673 A JPH09255673 A JP H09255673A JP 8099187 A JP8099187 A JP 8099187A JP 9918796 A JP9918796 A JP 9918796A JP H09255673 A JPH09255673 A JP H09255673A
- Authority
- JP
- Japan
- Prior art keywords
- optically active
- alkali metal
- methoxyphenyl
- organic amine
- salt
- 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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Classifications
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/141—Feedstock
Landscapes
- Epoxy Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は、ジルチアゼム（Diltia
zem）に代表される血管拡張作用を有する（＋）−シス
型１，５−ベンゾチアゼピン誘導体の有用な合成中間体
である光学活性３−（ｐ−メトキシフェニル）グリシッ
ド酸アルカリ金属塩の製造法に関する。The present invention relates to diltiazem (Diltiazem).
production of optically active 3- (p-methoxyphenyl) glycidic acid alkali metal salt, which is a useful synthetic intermediate of a (+)-cis type 1,5-benzothiazepine derivative having a vasodilatory action represented by zem) Concerning the law.
【０００２】[0002]
【従来技術】（＋）−シス型の１，５−ベンゾチアゼピ
ン誘導体であるジルチアゼム（４）の一般的な製造法と
しては、例えば下記の反応式：As a general method for producing diltiazem (4) which is a (+)-cis type 1,5-benzothiazepine derivative, for example, the following reaction formula:
【化６】 が知られている（薬学雑誌、１９８８年、７１６頁）。
ここでは、 ｏ−ニトロチオフェノール（５）と、
（−）−３−（ｐ−メトキシフェニル）グリシッド酸メ
チルエステル（６）との付加反応を行い、得られたスレ
オ型中間体のニトロ基を還元後加水分解し、環化、Ｎ−
アルキル化、アセチル化に付している。化合物（４）の
ような、分子内に２つの不斉炭素を有する化合物は、理
論上４種類の光学異性体が存在するが、化合物（４）の
場合、（＋）−シス体のみが強力な薬効を有することが
明らかにされている。従って、所望の（＋）−シス型
１，５−ベンゾチアゼピン誘導体（４）を効率よく製造
するために、光学活性体（６）を出発原料としている
（前掲）。[Chemical 6] Is known (Pharmaceutical Journal, 1988, p.716).
Here, with o-nitrothiophenol (5),
An addition reaction with (−)-3- (p-methoxyphenyl) glycidic acid methyl ester (6) is performed, and the nitro group of the obtained threo-type intermediate is reduced and then hydrolyzed to undergo cyclization, N-
Subjected to alkylation and acetylation. A compound having two asymmetric carbon atoms in the molecule, such as the compound (4), theoretically has four types of optical isomers, but in the case of the compound (4), only the (+)-cis isomer is strong. It has been revealed that it has various medicinal effects. Therefore, in order to efficiently produce the desired (+)-cis 1,5-benzothiazepine derivative (4), the optically active substance (6) is used as a starting material (supra).
【０００３】このように、光学活性化合物（６）の効率
よい製造法の開発は、（＋）−シス型１，５−ベンゾチ
アゼピン誘導体のより効率的な製造法につながることが
期待される。既に化合物（６）の製造法としては、生化
学反応を利用する酵素法と化学合成法が知られており、
化学法合成ではさらに光学分割を経る方法と不斉合成法
の２つの方法が報告されている。光学分割を経て光学活
性化合物（６）を得る方法としては、ラセミ体の３−
（ｐ−メトキシフェニル）グリシッド酸に光学活性アミ
ンを作用させて光学分割した後（収率４４％）、エステ
ル化する方法が既知である（特開昭６０−１３７７５、
特開昭６０−１３７７６）。また、ラセミ体の３−（ｐ
−メトキシフェニル）グリシッド酸アルカリ金属塩に光
学活性な有機アミン類の鉱酸塩を反応させることにより
光学分割し（収率７１％）、その後エステル化するか、
ラセミ体の３−（ｐ−メトキシフェニル）グリシッド酸
アルカリ金属塩に光学活性な有機アミンを加えた後、塩
酸を滴下することにより光学分割し（収率８０％）、そ
の後エステル化する方法も既知である（特公平４−６１
８６７および特開平２−１７１６８）。Thus, the development of an efficient production method of the optically active compound (6) is expected to lead to a more efficient production method of the (+)-cis type 1,5-benzothiazepine derivative. . As a method for producing the compound (6), an enzymatic method and a chemical synthesis method utilizing a biochemical reaction have already been known,
In chemical synthesis, two methods have been reported: a method involving optical resolution and an asymmetric synthesis method. As a method for obtaining an optically active compound (6) through optical resolution, racemic 3-
A method is known in which an optically active amine is allowed to act on (p-methoxyphenyl) glycidic acid for optical resolution (yield 44%), and then esterification is performed (JP-A-60-13775).
JP-A-60-13776). In addition, racemic 3- (p
-Methoxyphenyl) glycidic acid alkali metal salt is optically resolved by reacting a mineral acid salt of an optically active organic amine (yield 71%) and then esterified,
A method is also known in which an optically active organic amine is added to racemic 3- (p-methoxyphenyl) glycidic acid alkali metal salt, followed by optical resolution by dropwise addition of hydrochloric acid (yield 80%), followed by esterification. Is (Japanese Patent Publication No. 4-61)
867 and JP-A-2-17168).
【０００４】しかしながら、この光学分割を経る方法に
は以下のような問題点が存在する。すなわち、特開昭６
０−１３７７５記載の方法では一般に不安定であること
が知られている３−（ｐ−メトキシフェニル）グリシッ
ド酸を単離していることから収率が著しく低下している
ので、工業化には不適当である。また特公平４−６１８
６７記載の方法では、アミンの鉱酸塩を調製しなければ
ならず、さらに分割の際に生じる無機塩を濾去した後に
結晶化しなくてはならないなど操作が煩雑である。一
方、特開平２−１７１６８記載の最後に塩酸を滴下する
方法では、特に工業的手法として大量の反応を行う場
合、強酸性条件での分解産物の生成を抑制するため、大
量の希釈した酸を長時間かけて加える必要がありこれも
工業化には不適である。[0004] However, the method using the optical division has the following problems. That is,
In the method described in 0-13775, the yield is remarkably reduced because 3- (p-methoxyphenyl) glycidic acid, which is generally known to be unstable, is isolated. Is. In addition, Japanese Patent Publication 4-618
In the method described in 67, the procedure is complicated, for example, the mineral acid salt of the amine must be prepared, and the inorganic salt generated during the separation must be filtered off and then crystallized. On the other hand, in the method of dropping hydrochloric acid at the end described in JP-A-2-17168, particularly when a large amount of reaction is performed as an industrial method, a large amount of diluted acid is added in order to suppress the generation of decomposition products under strongly acidic conditions. It needs to be added over a long period of time, which is also unsuitable for industrialization.
【０００５】他方、不斉合成を経る方法では、光学活性
リチウムアミド化合物とアルキルリチウム存在下でのハ
ロゲノ酢酸エステルとベンズアルデヒドとのカップリン
グ反応を経る方法（特開平１−２２６８８１）、および
２−ハロゲノ−３−オキソ−３−フェニルプロピオン酸
誘導体の不斉還元を経る方法（特開平３−１９０８６
５）が既知である。しかしこれらの不斉合成を経る方法
では、収率および光学収率や、不斉源が無駄になるとい
うコスト的な問題があり、工業化には不適当である。On the other hand, a method involving asymmetric synthesis involves a method involving a coupling reaction between a halogenoacetic acid ester and benzaldehyde in the presence of an optically active lithium amide compound and alkyllithium (Japanese Patent Laid-Open No. 1-268881), and 2-halogeno. Asymmetric reduction of 3-oxo-3-phenylpropionic acid derivative (JP-A-3-19086)
5) is known. However, these methods involving asymmetric synthesis are not suitable for industrialization because they have the problems of yield and optical yield and cost of asymmetric sources being wasted.
【０００６】また酵素法では、エステラーゼを用いた方
法（特開平４−２２８０７０）が既知である。しかし、
この方法も特別な装置を使用しなくてはならないこと
や、後処理が困難である等の問題点が存在する。このよ
うに従来法はいずれも、光学活性化合物（６）の工業生
産には多くの問題を有している。最も工業化に適した光
学活性化合物（６）の製造法としては、一般式（３）：As the enzymatic method, a method using esterase (Japanese Patent Laid-Open No. 4-228070) is known. But,
This method also has problems that it requires the use of a special device and that post-treatment is difficult. As described above, all of the conventional methods have many problems in industrial production of the optically active compound (6). The most suitable method for producing the optically active compound (6) for industrialization is represented by the general formula (3):
【化７】 （式中、Ｍ2はアルカリ金属を示し、*は上記と同意義）
で表される光学活性３−（ｐ−メトキシフェニル）グリ
シッド酸アルカリ金属をエステル化することによる、化
学合成法であると考えられる。Embedded image (In the formula, M 2 represents an alkali metal, and * has the same meaning as above)
It is considered to be a chemical synthesis method by esterifying an optically active alkali metal 3- (p-methoxyphenyl) glycidate represented by
【０００７】[0007]
【課題を解決するための手段】本発明者は、式（３）で
示される（−）−３−（ｐ−メトキシフェニル）グリシ
ッド酸アルカリ金属塩の効率的で安全な製造法を目的と
して鋭意研究を重ねた結果、式（１）で示されるアルカ
リ金属塩に光学活性な有機アミンを加えた後、二酸化炭
素を通気することにより式（２）で示される化合物と
し、さらに塩基で処理することにより式（３）で示され
るアルカリ金属塩へと導くことで該目的が達成されるこ
とを見いだし、本発明を完成するに至った。DISCLOSURE OF THE INVENTION The present inventors have eagerly aimed at an efficient and safe method for producing an alkali metal salt of (-)-3- (p-methoxyphenyl) glycidic acid represented by the formula (3). As a result of repeated research, after adding an optically active organic amine to the alkali metal salt represented by the formula (1), the compound represented by the formula (2) is obtained by bubbling carbon dioxide and further treating with a base. It was found that the object can be achieved by leading to the alkali metal salt represented by the formula (3) by the above, and the present invention was completed.
【０００８】即ち、本発明は式（１）：That is, the present invention has the formula (1):
【化８】 (式中Ｍ1はアルカリ金属を示す。）で示される化合物と
光学活性なアミンの存在下、二酸化炭素を通気させ、一
般式（２）：Embedded image (Wherein M 1 represents an alkali metal) and carbon dioxide is bubbled in the presence of an optically active amine to give a compound represented by the general formula (2):
【化９】 （式中、Ａ+は光学活性な有機アミンの共役酸を示し、*
は上記と同意義）で示される光学活性３−（ｐ−メトキ
シフェニル）グリシッド酸塩とした後、これを塩基で処
理することにより、一般式（３）：Embedded image (In the formula, A + represents a conjugate acid of an optically active organic amine,
Is an optically active 3- (p-methoxyphenyl) glycidate represented by the same meaning as above) and then treated with a base to give a compound of the general formula (3):
【化１０】 （式中、Ｍ2はアルカリ金属を示し、*は上記と同意義）
で示される光学活性アルカリ金属塩を得ることを特徴と
する製造法を提供するものである。Embedded image (In the formula, M 2 represents an alkali metal, and * has the same meaning as above)
The present invention provides a process for producing an optically active alkali metal salt represented by
【０００９】本明細書中「ハロゲン」とは、フッ素、塩
素、臭素またはヨウ素を意味する。「アルカリ金属」と
は、リチウム、ナトリウム、カリウムを意味する。「ア
ルコキシ」とは、アルキル部分が直鎖状または分枝状の
Ｃ1〜Ｃ6アルキルオキシを意味し、例えば、メトキシ、
エトキシ、n■プロポキシ、イソプロポキシ、n■ブトキ
シ、イソブトキシ、sec■ブトキシ、およびtert■ブト
キシ等を挙げることができ る。The term "halogen" as used herein means fluorine, chlorine, bromine or iodine. "Alkali metal" means lithium, sodium, potassium. “Alkoxy” means C 1 -C 6 alkyloxy where the alkyl moiety is straight or branched and includes, for example, methoxy,
Examples include ethoxy, n propoxy, isopropoxy, n butoxy, isobutoxy, sec butoxy, and tert butoxy.
【００１０】本発明法の出発物質であるラセミ体のアル
カリ金属塩（１）は既知であり、例えば特公平４−７９
３４６に記載の方法で製造することができる。該ラセミ
体アルカリ金属塩の光学分割は、該アルカリ金属塩１重
量部を、約０〜５０℃、好ましくは室温にて、２〜１４
容量部、好ましくは７容量部の水に懸濁し、３分〜６０
分、好ましくは１５分撹拌した後冷却し、約０〜２５
℃、好ましくは０〜５℃にて、１〜７容量部、好ましく
は３.５容量部のテトラヒドロフラン、ジオキサン、ジ
メトキシエタン等のエーテル系溶媒、ジクロロメタン等
のハロゲン系溶媒、あるいは酢酸エチル、トルエン、ア
セトニトリル等の有機溶媒、好ましくは酢酸エチル溶媒
を加え、さらに、光学活性有機アミン（約１.１当量）
を加えた後、約０〜２５℃、好ましくは０〜５℃にて、
二酸化炭素を通気し１〜３時間好ましくは、２時間反応
させることにより行う。次いで、生じた結晶を濾取する
ことにより、高純度の光学活性な塩（２）を得ることが
できる。次いで、得られた塩（２）１当量を約−２０〜
３０℃、好ましくは−５℃にて、メタノール、エタノー
ル等のアルコール系溶媒に溶解し、ナトリウムメトキシ
ド、カリウムエトキシド等のアルカリ金属のアルコキシ
体、または水酸化ナトリウム、水酸化カリウムなどのア
ルカリ金属のヒドロキシ体を１〜５当量、好ましくは３
当量加え、約−２０〜５０℃、好ましくは−５〜３０℃
にて、１〜３時間、好ましくは１．５時間反応させ、生
じた結晶を濾取することにより高純度の光学活性なアル
カリ金属塩（３）を得ることができる。The racemic alkali metal salt (1), which is the starting material of the method of the present invention, is known, for example, JP-B-4-79.
It can be produced by the method described in 346. Optical resolution of the racemic alkali metal salt is carried out by adding 1 part by weight of the alkali metal salt to about 2 to 14 at about 0 to 50 ° C., preferably room temperature.
Suspend in 3 parts by volume of water, preferably 7 parts by volume, for 3 minutes to 60
Minutes, preferably 15 minutes, then cooled to about 0-25
1 to 7 parts by volume, preferably 3.5 parts by volume of an ether solvent such as tetrahydrofuran, dioxane or dimethoxyethane, a halogen solvent such as dichloromethane, or ethyl acetate or toluene at 0 ° C., preferably 0 to 5 ° C. An organic solvent such as acetonitrile, preferably an ethyl acetate solvent is added, and an optically active organic amine (about 1.1 equivalent) is added.
At about 0 to 25 ° C., preferably 0 to 5 ° C.,
It is carried out by bubbling carbon dioxide and reacting for 1 to 3 hours, preferably 2 hours. Then, the resulting crystals are collected by filtration to obtain a highly pure optically active salt (2). Then, 1 equivalent of the resulting salt (2) is added to about -20 to
Dissolved in an alcoholic solvent such as methanol or ethanol at 30 ° C., preferably −5 ° C., and an alkali metal alkoxy compound such as sodium methoxide or potassium ethoxide, or an alkali metal such as sodium hydroxide or potassium hydroxide. 1 to 5 equivalents, preferably 3
Add equivalent amount, about -20 to 50 ° C, preferably -5 to 30 ° C
At 1 to 3 hours, preferably 1.5 hours, and the resulting crystals are collected by filtration to obtain a highly pure optically active alkali metal salt (3).
【００１１】このように本発明方法によれば、ラセミ体
のアルカリ金属塩（１）を出発原料に用いて、効率よく
光学活性なアルカリ金属塩（３）を得ることができる。
上記から明らかなように本発明法によれば、１工程で光
学分割を行うことができ、さらに二酸化炭素を通気する
ことから、反応系中の一時的なｐＨの上昇を防ぐことが
でき、常にｐＨ７付近で反応が行われるという、工業的
に顕著な利点を有する。次いで、本発明方法で得られた
光学活性なアルカリ金属塩（３）を例えば、特願平０６
−２６２２４２の記載に従い、ピバロイルクロライドを
用いて酸無水物とした後、アルコールで処理することに
よりエステル化し、上記反応式において式（５）で表さ
れるニトロチオフェノールと反応させ、最終的に閉環す
る事により、医薬品であるジルチアゼム（４）を得るこ
とができる。As described above, according to the method of the present invention, an optically active alkali metal salt (3) can be efficiently obtained by using the racemic alkali metal salt (1) as a starting material.
As is clear from the above, according to the method of the present invention, optical resolution can be carried out in one step, and since carbon dioxide is further aerated, it is possible to prevent a temporary increase in pH in the reaction system, and always It has a remarkable industrial advantage that the reaction is carried out at around pH 7. Then, the optically active alkali metal salt (3) obtained by the method of the present invention is used, for example, in Japanese Patent Application No.
-262242, an acid anhydride is formed using pivaloyl chloride, esterified by treating with alcohol, and reacted with the nitrothiophenol represented by the formula (5) in the above reaction formula to obtain the final product. By ring-closing, diltiazem (4), which is a drug, can be obtained.
【００１２】以下の実施例により本発明法を具体的に説
明する。The method of the present invention will be specifically described with reference to the following examples.
【実施例】実施例１ （−）−（２Ｒ，３Ｓ）−３−（ｐ−メトキシフェニ
ル）グリシッド酸アミン塩の合成。 （±）−３−（ｐ−メトキシフェニル）グリシッド酸カ
リウム塩３．４８ｇ（０．０１５ｍｏｌｅ）を水１５ｍ
ｌに懸濁し１５分間室温にて撹拌した後、容器を氷水に
て冷却し、０〜５℃で酢酸エチル４５ｍｌを加えた。さ
らに（−）−（Ｓ）−α−メチルベンジルアミン１．９
２ｇ（０．０１５８ｍｏｌｅ，１．０５当量）を加えた
後、０〜５℃で二酸化炭素を通気した。２時間後（この
間のｐＨを測定したとところ、滴下開始時間より２分後
までのｐＨは９．６４〜８．０、１５分後のｐＨは７．
２３、３０分後のｐＨは７．１９、２時間後のｐＨは
７．１８となっており、ほぼ中性条件で反応が進行して
いることがわかった。）析出した結晶を濾取し光学活性
なアミン塩１．９３ｇ（０．０１２ｍｏｌｅ）を得た
（収率８１％）。 ｍｐ．１２８〜１２９℃； ［α］D 24−１０９．８゜（ｃ＝１．０，メタノール）1 Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６）δ（ｐｐｍ）：１．４
６（３Ｈ，ｄ，Ｊ＝４．５Ｈｚ），３．１６（１Ｈ，
ｄ，Ｊ＝１．０Ｈｚ），３．７０（１Ｈ，ｄ，Ｊ＝１．
０Ｈｚ），３．７４（３Ｈ，ｓ），４．２９（１Ｈ，
ｑ，Ｊ＝４．５Ｈｚ），６．９０（２Ｈ，ｄ，Ｊ＝６．
０Ｈｚ），７．２０（２Ｈ，ｄ，Ｊ＝６．０Ｈｚ），
７．３２〜７．４１（３Ｈ，ｍ），７．４８（２Ｈ，
ｄ，Ｊ＝５．０Ｈｚ）実施例２ （−）−（２Ｒ，３Ｓ）−３−（ｐ−メトキシフェニ
ル）グリシッド酸カリウム塩の合成。 水酸化カリウム９５．９ｇ（１．７１ｍｏｌｅ）をメタ
ノール１．１５Ｌに溶解して窒素雰囲気下撹拌し、容器
を浴温−２０℃にて冷却して、（−）−３−（ｐ−メト
キシフェニル）グリシッド酸塩１５９ｇ（０．５０３ｍ
ｏｌｅ）を加えた後、０〜−５℃で１時間撹拌した。析
出した結晶を濾取し光学活性なカリウム塩１１３ｇ
（０．４８５ｍｏｌｅ）を得た（収率９７％）。 ｍｐ．３１０℃以上； ［α］D 24−１５９゜（ｃ＝１．０，メタノール）1 Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６）δ（ｐｐｍ）：２．９
７（１Ｈ，ｓ），３．６０（１Ｈ，ｓ），３．７４（３
Ｈ，ｓ），６．８８（２Ｈ，ｄ，Ｊ＝８．５Ｈｚ），
７．１６（２Ｈ，ｄ，Ｊ＝８．５Ｈｚ） Example 1 Synthesis of amine salt of (-)-(2R, 3S) -3- (p-methoxyphenyl) glycidic acid. (±) -3- (p-Methoxyphenyl) glycidic acid potassium salt 3.48 g (0.015 mole) in water 15 m
After suspending in 1 and stirred at room temperature for 15 minutes, the container was cooled with ice water, and 45 ml of ethyl acetate was added at 0 to 5 ° C. Furthermore, (-)-(S) -α-methylbenzylamine 1.9.
After adding 2 g (0.0158 mole, 1.05 equivalent), carbon dioxide was bubbled in at 0 to 5 ° C. 2 hours later (when the pH was measured during this period, the pH up to 2 minutes after the dropping start time was 9.64 to 8.0, and the pH after 15 minutes was 7.
The pH after 23 and 30 minutes was 7.19, and the pH after 2 hours was 7.18, indicating that the reaction proceeded under almost neutral conditions. ) The precipitated crystals were collected by filtration to obtain 1.93 g (0.012 mole) of an optically active amine salt (yield 81%). mp. 128-129 ° C .; [α] D 24 -109.8 ° (c = 1.0, methanol) 1 H-NMR (DMSO-d6) δ (ppm): 1.4
6 (3H, d, J = 4.5Hz), 3.16 (1H,
d, J = 1.0 Hz), 3.70 (1H, d, J = 1.
0Hz), 3.74 (3H, s), 4.29 (1H,
q, J = 4.5 Hz), 6.90 (2H, d, J = 6.
0 Hz), 7.20 (2H, d, J = 6.0 Hz),
7.32 to 7.41 (3H, m), 7.48 (2H,
d, J = 5.0 Hz) Example 2 Synthesis of (−)-(2R, 3S) -3- (p-methoxyphenyl) glycidic acid potassium salt. 95.9 g (1.71 mole) of potassium hydroxide was dissolved in 1.15 L of methanol and stirred under a nitrogen atmosphere, and the container was cooled at a bath temperature of -20 ° C to obtain (-)-3- (p-methoxyphenyl). ) Glycidate 159g (0.503m
ole) was added, and the mixture was stirred at 0 to -5 ° C for 1 hr. The precipitated crystals are collected by filtration to give 113 g of optically active potassium salt.
(0.485 mole) was obtained (yield 97%). mp. 310 ° C. or higher; [α] D 24 -159 ° (c = 1.0, methanol) 1 H-NMR (DMSO-d6) δ (ppm): 2.9
7 (1H, s), 3.60 (1H, s), 3.74 (3
H, s), 6.88 (2H, d, J = 8.5 Hz),
7.16 (2H, d, J = 8.5Hz)
【００１３】[0013]
【発明の効果】本発明法は、収率よく高純度の光学活性
な化合物（３）を製造することができ、ジルチアゼム等
の医薬品の製造、開発に貢献しうる。INDUSTRIAL APPLICABILITY The method of the present invention can produce a highly pure optically active compound (3) in high yield, and can contribute to the production and development of pharmaceuticals such as diltiazem.
Claims (7)
−３−（ｐ−メトキシフェニル）グリシッド酸アルカリ
金属塩に光学活性な有機アミンの存在下、二酸化炭素を
通気させ、一般式（２）： 【化２】 （式中、Ａ+は光学活性な有機アミンの共役酸を示し、*
は不斉炭素を示す）で表される光学活性３−（ｐ−メト
キシフェニル）グリシッド酸塩となし、これを塩基によ
り処理することを特徴とする、一般式（３）： 【化３】 （式中、Ｍ2はアルカリ金属を示し、*は上記と同意義）
で表される光学活性３−（ｐ−メトキシフェニル）グリ
シッド酸アルカリ金属塩の製造法。1. General formula (1): (Wherein M 1 represents an alkali metal) (±)
Carbon dioxide was bubbled through an alkali metal salt of -3- (p-methoxyphenyl) glycidic acid in the presence of an optically active organic amine to give a compound represented by the general formula (2): (In the formula, A + represents a conjugate acid of an optically active organic amine,
Represents an asymmetric carbon) and is an optically active 3- (p-methoxyphenyl) glycidate salt, which is treated with a base, represented by the general formula (3): (In the formula, M 2 represents an alkali metal, and * has the same meaning as above)
A method for producing an alkali metal salt of optically active 3- (p-methoxyphenyl) glycid acid represented by:
−メチルベンジルアミン、１−（１−ナフチル）エチル
アミン、ノルエフェドリン、またはエフェドリンである
請求項１記載の製造法。2. The optically active organic amine is an optically active α
The method according to claim 1, which is -methylbenzylamine, 1- (1-naphthyl) ethylamine, norephedrine, or ephedrine.
（Ｓ）−α−メチルベンジルアミンまたは（＋）−
（Ｒ）−α−メチルベンジルアミンである請求項１記載
の製造法。3. The optically active organic amine is (-)-
(S) -α-methylbenzylamine or (+)-
The production method according to claim 1, which is (R) -α-methylbenzylamine.
はヒドロキシ体である請求項１記載の製造法。4. The method according to claim 1, wherein the base is an alkoxy or hydroxy form of an alkali metal.
−３−（ｐ−メトキシフェニル）グリシッド酸アルカリ
金属塩に光学活性な有機アミンの存在下、二酸化炭素を
通気させることを特徴とする、一般式（２）： 【化５】 （式中、Ａ+は光学活性な有機アミンの共役酸を示し、*
は上記と同意義）で表される光学活性３−（ｐ−メトキ
シフェニル）グリシッド酸塩の製造法。5. A compound of the general formula (1): (Wherein M 1 represents an alkali metal) (±)
General formula (2): wherein 3- (p-methoxyphenyl) glycidic acid alkali metal salt is bubbled with carbon dioxide in the presence of an optically active organic amine. (In the formula, A + represents a conjugate acid of an optically active organic amine,
Is a method of producing an optically active 3- (p-methoxyphenyl) glycidate represented by the same meaning as above.
−メチルベンジルアミン、１−（１−ナフチル）エチル
アミン、ノルエフェドリン、またはエフェドリンである
請求項５記載の製造法。6. The optically active organic amine is an optically active α.
The production method according to claim 5, which is -methylbenzylamine, 1- (1-naphthyl) ethylamine, norephedrine, or ephedrine.
（Ｓ）−α−メチルベンジルアミンまたは（＋）−
（Ｒ）−α−メチルベンジルアミンである請求項５記載
の製造法。7. The optically active organic amine is (-)-
(S) -α-methylbenzylamine or (+)-
The method according to claim 5, which is (R) -α-methylbenzylamine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP09918796A JP3828197B2 (en) | 1996-03-27 | 1996-03-27 | Process for producing optically active alkali metal salt of 3- (p-methoxyphenyl) glycidic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP09918796A JP3828197B2 (en) | 1996-03-27 | 1996-03-27 | Process for producing optically active alkali metal salt of 3- (p-methoxyphenyl) glycidic acid |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH09255673A true JPH09255673A (en) | 1997-09-30 |
| JP3828197B2 JP3828197B2 (en) | 2006-10-04 |
Family
ID=14240653
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP09918796A Expired - Fee Related JP3828197B2 (en) | 1996-03-27 | 1996-03-27 | Process for producing optically active alkali metal salt of 3- (p-methoxyphenyl) glycidic acid |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP3828197B2 (en) |
-
1996
- 1996-03-27 JP JP09918796A patent/JP3828197B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JP3828197B2 (en) | 2006-10-04 |
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