JPS61178954A - Production of ethyl alpha-(1-carboxyethyl)amino-gamma-oxo-gamma-phenylbutyrate and reduced compound thereof - Google Patents
Production of ethyl alpha-(1-carboxyethyl)amino-gamma-oxo-gamma-phenylbutyrate and reduced compound thereofInfo
- Publication number
- JPS61178954A JPS61178954A JP1948385A JP1948385A JPS61178954A JP S61178954 A JPS61178954 A JP S61178954A JP 1948385 A JP1948385 A JP 1948385A JP 1948385 A JP1948385 A JP 1948385A JP S61178954 A JPS61178954 A JP S61178954A
- Authority
- JP
- Japan
- Prior art keywords
- ethyl
- amino
- carboxyethyl
- phenylbutyrate
- alanine
- 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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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
【発明の詳細な説明】
(産業上の利用分野)
本発明は、α−(1−カルボキシエチル)アミノ−γ−
オキソ−γ−フェニル酪酸エチルトリわけ、光学活性な
(αg、1s)体(1)の効率的な製造法に関し、
(式中、星印(@は不斉炭素に対して(−)配置を表わ
す、)
優れたアンジオテンシン変換酵素(ACE)阻害活性の
為、抗高血圧剤としての利用が期待されている種々のア
ミノ酸誘導体側)などに共通の原子に対して(1g)配
置を表わす。)製造中間体として極めて有用な(αS、
Z+)−α−(1−カルボキシエチル)アミノ−γ−7
エ二ル酪酸エチル(II)の前駆体を有利に製造するこ
とを目的とする
(式中、星印(@は不斉炭素原子に対して(8)配置を
表わす。)
(従来の技術)
α−(1−力ルボキシエチル)アミノ−γ−オキソ−r
−フェニル酪酸エチルの製造法としては、既に次式に示
す如く、β−ベンゾイルアクリル酸エチル(IV) ト
(8)−アラニンベンジルエステル(マ)をトリエチル
アミン存在下、いわゆるミカエル(Michae e)
付加反応せしめ死後に水素添加分解によってベンジル基
を開裂する方法が知られている(公開特許公報昭58−
108864α戦およびTetrahedronLet
ters 、 Vo125Q]) 、 1148 、
(1984年))。Detailed Description of the Invention (Industrial Field of Application) The present invention provides α-(1-carboxyethyl)amino-γ-
Concerning an efficient method for producing ethyl oxo-γ-phenylbutyrate, optically active (αg, 1s) form (1), , ) represents the (1g) configuration with respect to the atom common to various amino acid derivatives that are expected to be used as antihypertensive agents due to their excellent angiotensin-converting enzyme (ACE) inhibitory activity. ) Extremely useful as a production intermediate (αS,
Z+)-α-(1-carboxyethyl)amino-γ-7
The purpose is to advantageously produce a precursor of ethyl(II) enylbutyrate (wherein the asterisk (@ represents the (8) configuration with respect to the asymmetric carbon atom) (Prior art) α-(1-hydroxyethyl)amino-γ-oxo-r
As a method for producing ethyl phenylbutyrate, as shown in the following formula, β-benzoyl acrylate ethyl (IV) and (8)-alanine benzyl ester (MA) are mixed in the presence of triethylamine using the so-called Michael e.g.
A method is known in which the benzyl group is cleaved by hydrogenolysis after the addition reaction and after death (Japanese Patent Application Publication No. 1983-1999).
108864α battle and Tetrahedron Let
ters, Vo125Q]), 1148,
(1984)).
(5) ff)
(αS、1g) ・・・・・・(資)(α凰、18)
・・・・・・(2)
またその際、(a)−アラニンエステルを用いた場合、
好ましい(α11,111)配置を有するジアステレオ
マー(至)が優勢に生じ、結晶化させるかまたはシリー
カゲルでクロマトグラフ分離することにより(αg,1
s)ジアステレオマー(至)が取得できることが明らか
Kされている。(5) ff) (αS, 1g) ...... (Shi) (α凰, 18)
......(2) Also, in that case, when (a)-alanine ester is used,
Diastereomers with the preferred (α11,111) configuration occur predominately, and by crystallization or chromatographic separation on silica gel (αg,1
It is clear that diastereomers (s) can be obtained.
(発明が解決しようとする問題点)
しかしながら、この(8)−アラニンエステルを用いる
方法では、(8)−アラニンのエステル化操作に加え、
エステル化時に使用し九酸と塩を形成したCa1−アラ
ニンエステルのアミ7基部分を遊離化すせる操作が必要
であり、更にこのエステル自身、最終的にβ−ベンゾイ
ルアクリル酸エチルに由来するエチルエステル部分を安
定に保ちつつ選択的に除去可能な基でなければならず、
ベンジルエステルもしくはtert−ブチルエステルな
ど比較的調製に手間どるエステルとすることが必要であ
る。(Problems to be Solved by the Invention) However, in this method using (8)-alanine ester, in addition to the esterification operation of (8)-alanine,
It is necessary to perform an operation to liberate the amine 7 group moiety of the Ca1-alanine ester used during esterification to form a salt with nonacid, and furthermore, this ester itself is finally converted into an ethyl ester derived from ethyl β-benzoyl acrylate. It must be a group that can be selectively removed while keeping the moiety stable;
It is necessary to use an ester such as benzyl ester or tert-butyl ester, which is relatively difficult to prepare.
またそれらの除去も水素添加分解ないしはトリプルオロ
酢酸処理といった選択的エステル分解除去に必須な複雑
な操作が必要であるなど(αg、1g)−α−(1−カ
ルボキシエチル)アミノ−γ−オキソ−γ−フェニル酪
酸エチルの工業的製造法としては操作性および経済性に
おいて種々の難点を有している。In addition, their removal also requires complicated operations such as hydrogenolysis or triple-oacetic acid treatment, which are essential for selective ester decomposition removal. As an industrial method for producing ethyl γ-phenylbutyrate, there are various difficulties in terms of operability and economy.
(問題点を解決する為の手段およびその作用)本発明者
らは、経済性に優れ簡便力1つ効率的な(αg、ts)
−α−(1−カルボキシエチル)アミノ−γ−オキソ−
γ−フェニル酪酸エチルの工業的#造波を確立すべく鋭
意検討した結果、アラニンを、アルカリ金属イオン又は
アルカリ土類金属イオンの存在下β−ベンゾイルアクリ
ル酸エチルと反応させることにより極めて高収率でα−
(1−カルボキシエチル)アミノ−r−オキソ−γ−フ
ェニル酪酸エチルが得られること、さらに特定の制御さ
れた反応条件下に(s)−アラニンの金属塩を用いて反
応させることKよシ(αa、Hg)体ジアステレオマー
を(αB、111)体に比較し極めて優先的に生成させ
得ることを見いだすとともに、付加反応後、当量の酸を
添加し中和するのみで、(αS、lS)体が選択的に結
晶として析出し、はぼ純粋な(αS、tS)体が簡便な
操作で高収率に得られること、及びα−(1−カルボキ
シエチル)アミノ−γ−オキソ−γ−フェニル酪酸エチ
ルを接触還元することKより、α−(1−カルボキシエ
チル)アミノ−γ−フェニル酪酸エチルを容易に製造で
きることを明らかにして本発明を完成した。(Means for Solving the Problems and Their Effects) The present inventors have developed a method that is economical, simple, and efficient (αg, ts).
-α-(1-carboxyethyl)amino-γ-oxo-
As a result of intensive studies to establish industrial #wave generation of ethyl γ-phenylbutyrate, we found that a very high yield was achieved by reacting alanine with ethyl β-benzoyl acrylate in the presence of alkali metal ions or alkaline earth metal ions. α−
It is possible to obtain ethyl (1-carboxyethyl)amino-r-oxo-γ-phenylbutyrate and to further react it with a metal salt of (s)-alanine under certain controlled reaction conditions. It was discovered that the αa, Hg) diastereomer can be produced extremely preferentially compared to the (αB, 111) diastereomer, and the (αS, lS ) is selectively precipitated as crystals, and an almost pure (αS, tS) isomer can be obtained in high yield with a simple operation, and α-(1-carboxyethyl)amino-γ-oxo-γ The present invention was completed by revealing that ethyl α-(1-carboxyethyl)amino-γ-phenylbutyrate can be easily produced by catalytic reduction of ethyl-phenylbutyrate.
すなわち、本発明はβ−ベンゾイルアクリル酸エチルと
アルカリ金属イオンまたはアルカリ土類金属イオンの存
在下、アラニンを反応させることを特徴とするα−(1
−力ルボキシエチル)アミノ−γ−オキソ−γ−フェニ
ル酪酸エチルの製造法に関し、とりゎけ(幻−アラニン
を用い、制御され九条件下に(αi、xa)体に比しく
αs、ts)体ジアステレオマーを優先的に合成する製
造法に関するものであり又、接触還元にょるα−(1−
カルボキシエチル)アミノ−γ−フェニル酪酸エチルの
製造法1c関するものである。That is, the present invention provides α-(1
Regarding the production method of ethyl (alpha)amino-γ-oxo-γ-phenylbutyrate, the (αi, xa) form is compared with the αs, ts form under controlled conditions using phantom-alanine. This relates to a production method that preferentially synthesizes diastereomers, and also relates to a production method that preferentially synthesizes diastereomers.
The present invention relates to method 1c for producing ethyl (carboxyethyl)amino-γ-phenylbutyrate.
以下に本発明の詳細な説明する。The present invention will be explained in detail below.
原料のtrans−β−ベンゾイルアクリル酸エチルは
ベンゼンと無水マレイン酸の7リーデル・クラフッアシ
ル化反応、或いはグリオキシル酸とアセトフェノンの脱
水縮合反応といった公知方法により得られるtrans
−β−ベンゾイルアクリル酸をエチルエステル化するな
どして容易に合成することができる。゛また、cis−
β−ベンゾイルアクリル酸エチルはtrans体の光照
射により異性化して調製することができる。The raw material trans-β-benzoylacrylate ethyl acrylate is a trans-β-benzoyl acrylate obtained by known methods such as the 7-Riedel-Crafu acylation reaction of benzene and maleic anhydride, or the dehydration condensation reaction of glyoxylic acid and acetophenone.
It can be easily synthesized by ethyl esterifying -β-benzoyl acrylic acid.゛Also, cis-
Ethyl β-benzoyl acrylate can be prepared by isomerizing the trans form by light irradiation.
アラニンのアルカリ金属塩およびアルカリ土類金属塩の
調製方法としては、アラニンを化学量論的必要量の適当
なアルカリ金属水酸化物、アルカリ土類金属水酸化物ま
たはアルカリ金属炭酸塩の存在下、水あるいはアルコー
ル類を溶媒とし、室温或いは加温下撹拌するといった簡
便な操作が採用工きる。必要とあらば、Wgv&を減圧
下溜去してアラニンの金属塩として単離することも可能
である。また、β−ベンゾイルアクリル酸エチルとアラ
ニンの混合物中にアルカリ金属水酸化物、アルカリ土類
金属水酸化物またはアルカリ金属炭酸塩を添加して、y
応系においてin 5itu に、アラニンのとれら
iff塩t−調製することも可能である。A method for preparing alkali metal salts and alkaline earth metal salts of alanine includes: alanine in the presence of a stoichiometric amount of a suitable alkali metal hydroxide, alkaline earth metal hydroxide, or alkali metal carbonate; A simple operation such as using water or alcohol as a solvent and stirring at room temperature or under heating can be adopted. If necessary, Wgv& can be distilled off under reduced pressure to isolate it as a metal salt of alanine. Furthermore, by adding an alkali metal hydroxide, an alkaline earth metal hydroxide, or an alkali metal carbonate to a mixture of β-benzoyl ethyl acrylate and alanine, y
It is also possible to prepare salts of alanine in situ in a reaction system.
β−ベンゾイルアクリル酸エチルとアラニンのアルカリ
金属塩或いはアルカリ土類金属塩とのミカエル(Mic
haeJ )付加反応は、非常に広範な溶媒、例えば水
、メタノール、エタノール、プロパツール、ブタノール
などのアルコール類、クロロホルム、アセトニトリル、
n−へキサン、ジオキサン、テトラLドロ7ランあるい
はこれらの混合物などを用いて行なうことができるが、
通常はアルコール溶媒を用いるのが適当である。Mic of ethyl β-benzoyl acrylate and alkali metal salt or alkaline earth metal salt of alanine.
haeJ) The addition reaction can be carried out using a very wide range of solvents, such as water, alcohols such as methanol, ethanol, propatool, butanol, chloroform, acetonitrile,
It can be carried out using n-hexane, dioxane, tetra-L-Dolo7ran, or a mixture thereof, but
It is usually appropriate to use an alcohol solvent.
不均一系での反応は別として、アルコール溶媒を用いた
均−系の付加反応は極めて達やかく進行し、通常、室温
下数分ないし1時間内に完結する。Apart from heterogeneous reactions, homogeneous addition reactions using alcoholic solvents proceed extremely rapidly and are usually completed within a few minutes to an hour at room temperature.
反応温度は特に限定されず(−10〜60″C)の広範
囲で行なえるが、生成するα−(1−カルボキシエチル
)アミノ−γ−オキンーr−フェニル酪酸エチルが反応
系のようなアルカリに比較的不安定なことから高温度で
の反応は好ましくない。The reaction temperature is not particularly limited (-10 to 60"C), but it can be carried out in a wide range from -10 to 60"C. Due to its relative instability, reactions at high temperatures are not preferred.
また、この生成物の反応系での不安定性は反応中のみな
らず反応終了後も同様に認められ、経時的な生成物含有
量の減少とともに、ジアステレオマー間の組成比におい
ても変化が認められる。しかし、反応終了後、使用した
アルカリに対して当量以上の酸、特に塩酸、硫酸のよう
な鉱酸を加え、系を酸性北すると生成物の変化は認めら
れなくなり、安定化でき、その後の操作が容易となる。In addition, the instability of this product in the reaction system was observed not only during the reaction but also after the completion of the reaction, and as well as a decrease in the product content over time, changes were also observed in the composition ratio between diastereomers. It will be done. However, after the reaction is complete, if the system is made acidic by adding an equivalent amount of acid or more to the alkali used, especially a mineral acid such as hydrochloric acid or sulfuric acid, no change in the product will be observed and it can be stabilized, allowing subsequent operations. becomes easier.
α−(1−力ルボキシエチル)アミノ−γ−オキソ−γ
−フェニル酪酸エチルの単離は、常法どうり、アルカリ
?酸で中和後、溶媒を減圧涌去して結晶化することによ
って容易になし得るが、必要とあらば溶媒を減圧溜夫後
、捜査に水を加え、p H8,5〜5でジクロルメタン
等で抽出して、通常の操作により単離することも可能で
ある。熱論、単離せずに次の還元操作に移り、α−(1
−力ルボキシエチル)アミノ−T−フェニル酪酸エチル
として単離することもできる。α-(1-hydroxyethyl)amino-γ-oxo-γ
- Is ethyl phenylbutyrate isolated using a conventional method or alkali? This can be easily achieved by neutralizing with an acid, removing the solvent under reduced pressure, and crystallizing, but if necessary, remove the solvent under reduced pressure, add water to the sample, and dichloromethane etc. at pH 8.5 to 5. It is also possible to extract and isolate by normal operations. Heat theory, move on to the next reduction operation without isolation, α-(1
It can also be isolated as ethyl (hydroxyethyl)amino-T-phenylbutyrate.
β−ベンゾイルアクリル酸エチルと(8)−アラニンの
金jII塩とのミカエル(MichaeJ )付加反応
により、(αS、1g)体ジアステレオマーの生成率を
選択的に高める好ましい反応条件は反応試剤の組み合せ
Kより異なるが、大きく影響をおよぼす要因としては、
(g)−アラニンの金属塩の種類、反応手順、K広濃度
などがあげられる。アルカリ金属、アルカリ土類金属と
しては、リチウム、ナトリウム、カリウムが適しており
カルシウムはムシろ(αR,l!+)体ジアステレオマ
ーの生成を促進することから好ましくない。エタノール
を反応溶媒として使用する場合は、(11)−アラニン
をリチウムおよびカリウムの塩とすることが望ましいが
、使用するβ−ベンゾイルアクリル酸エチルのtran
s 。Preferred reaction conditions for selectively increasing the production rate of the (αS, 1g) diastereomer by the Michael addition reaction between β-benzoylacrylate ethyl acrylate and the gold jII salt of (8)-alanine are as follows: Factors that are different from combination K but have a large influence are:
Examples include the type of metal salt of (g)-alanine, the reaction procedure, and the wide K concentration. Lithium, sodium, and potassium are suitable as alkali metals and alkaline earth metals, and calcium is not preferable because it promotes the formation of musil (αR, l!+) diastereomers. When ethanol is used as a reaction solvent, it is preferable to use (11)-alanine as a lithium and potassium salt;
s.
或いはcis配置によって最も好ましい(8)−アラニ
ンの金属塩は異なってくる。すなわち、trans−β
−ベンゾイルアクリル酸エチルの場合は(S)−アラニ
ンのリチウム塩が、またcis−β−ベンゾイルアクリ
ル酸エチルの場合はカリウム塩が最も高い(αS、lS
)体ジアステレオマー生成率を示す。Alternatively, the most preferred metal salt of (8)-alanine differs depending on the cis configuration. That is, trans-β
- In the case of ethyl benzoylacrylate, the lithium salt of (S)-alanine is the highest, and in the case of cis-β-ethyl benzoylacrylate, the potassium salt is the highest (αS, lS
) diastereomer production rate.
このように使用するβ−ベンゾイルアクリル酸エチルの
異性体の種類によって最適条件が大きく異なり、好適な
条件を一律に規定することは出来ないが、tran’!
4体の場合は、(8)−アラニンのリチウム塩に対して
当量ないしは過剰量のβ−ベンゾイルアクリル酸エチル
を用い、(S)−アラニンのリチウム塩を5分ないし1
時間かけてゆっくり添加してゆくのが好ましく、反応系
の濃度についても50mM〜500mMと比較的低い濃
度での反応が適している。一方、cis体の場合は、(
8)−アラニンのカリウム塩とβ−ベンゾイルアクリル
酸エチルを高濃度に一挙に混合反応させる方が好ましい
。As described above, the optimal conditions vary greatly depending on the type of isomer of β-benzoylacrylate ethyl acrylate used, and it is not possible to uniformly define suitable conditions, but tran'!
In the case of 4 bodies, use an equivalent or excess amount of ethyl β-benzoyl acrylate to the lithium salt of (8)-alanine, and heat the lithium salt of (S)-alanine for 5 minutes to 1 hour.
It is preferable to add slowly over time, and it is suitable to react at a relatively low concentration of 50 mM to 500 mM in the reaction system. On the other hand, in the case of cis body, (
8) It is preferable to mix and react the potassium salt of -alanine and ethyl β-benzoyl acrylate at a high concentration all at once.
いずれの場合も、添加終了後6分ないし1時間のうちに
付加反応は完結する。また反応温度を変化させでも、特
にジアステレオマー組成比はあまり影響されない。In either case, the addition reaction is completed within 6 minutes to 1 hour after the addition is complete. Furthermore, even if the reaction temperature is changed, the diastereomer composition ratio is not affected much.
総合的にtrans体とcis体を比較した場合、生成
するα−(1−カルボキシエチル)アミノ−r−オキソ
−γ−フェニル酪酸エチルの(αs、1g)/(αm、
ts)ジアステレオマー比は、trans体の方が高い
傾向にあり、以上の好適な条件を採用するとtran@
体で((1B 、 1 B ) / (el R、I
B )比を4〜5、またcis体で2〜8とすることが
可能である。Comprehensively comparing the trans and cis forms, the ratio of (αs, 1g)/(αm,
ts) The diastereomer ratio tends to be higher for the trans form, and if the above preferable conditions are adopted, the tran@
body ((1B, 1B) / (el R, I
B) It is possible to set the ratio to 4 to 5, or 2 to 8 in the cis form.
生成物は、付加反応後、反応系に速やかに塩酸、硫酸な
どの酸を加え、生成したα−(1−カルボキシエチル)
アミノ−γ−オキソ−γ−フェニル醋酸エチルの金属塩
を、α−(1−カルボキシエチル)アミノ−γ−オキソ
−γ−フェニル醋酸、或いはその塩酸塩や硫酸塩に変換
し、ジアステレオマー混合物として単離することもでき
るが、エタノール溶媒の場合は反応液を冷却しつつ使用
したアルカリに対して当量の塩酸を加え撹拌するだけで
、光学的にほぼ純粋な(αS、XS)ジアステレオマー
が結晶として析出し、極めて高い回収率で目的物のみを
単離することが可能である。この操作を利用すると、通
常の合成反応操作では必須の煩雑な光学分割が不要とな
り極めて効率的K(αs 、Bs)−a−(1−カルボ
キシエチル)アミノ−γ−オキソ−γ−フェニル酪酸エ
チルを製造することができる。After the addition reaction, an acid such as hydrochloric acid or sulfuric acid is immediately added to the reaction system to produce the α-(1-carboxyethyl) product.
The metal salt of ethyl amino-γ-oxo-γ-phenyl acetate is converted into α-(1-carboxyethyl)amino-γ-oxo-γ-phenyl acetic acid, or its hydrochloride or sulfate to form a diastereomer mixture. However, in the case of using ethanol as a solvent, the optically almost pure (αS, precipitates as crystals, making it possible to isolate only the target product with an extremely high recovery rate. Using this procedure, the complicated optical resolution that is essential in normal synthetic reaction operations is unnecessary, and extremely efficient K(αs, Bs)-a-(1-carboxyethyl)amino-γ-oxo-γ-phenylbutyrate ethyl can be manufactured.
また、エタノールを溶媒とする付加反応液に使用したア
ルカリに対して当量以上の硫酸を加え、α−(1−カル
ボキシエチル)アミノ−γ−オキソ−γ−フェニル酪酸
エチルで単離することなく次の還元操作を連続的に実施
することができる。In addition, an equivalent amount or more of sulfuric acid was added to the alkali used in the addition reaction solution using ethanol as a solvent, and the following was performed without isolation with ethyl α-(1-carboxyethyl)amino-γ-oxo-γ-phenylbutyrate. The reduction operation can be carried out continuously.
「α−(1−カルボキシエチル)アミノ−γ−オキソ−
γ−フェニル酪酸エチルのα−(1−カルボキシエチル
)アミノ−7−フェニル酪酸エチルへの接触還元は、少
量の酸(FIIL酸、塩酸、リン酸など)の存在下、た
とえば、アルコール(好ましくはエタノール)またはカ
ルボン酸(たとえば酢酸)のような極性のプロトン性溶
媒中、穏やかに収率よく進行する。適当な触媒の例とし
てはラネーニッケルおよびパラジウムまたは白金などを
挙げることができる。」
1例として、パラジウムカーボンを用いる反応例につい
てのべるとα−(1−カルボキシエチル)アミノ−γ−
オキソ−γ−フェニル酪酸エチルに対し2チ〜70チ程
度のパラジウムカーボンを加えO℃〜50℃好ましく#
′i20℃〜40℃で、エタノール等のアルコールを溶
媒として、数時間〜80時間反応させることによりほば
定量的にα−(1−カルボキシエチル)アミノ−γ−フ
ェニル酪酸エチルに変換することができる。もちろん触
媒量を増加することにより、反応時間の短縮も可能であ
る。“α-(1-carboxyethyl)amino-γ-oxo-
Catalytic reduction of ethyl γ-phenylbutyrate to ethyl α-(1-carboxyethyl)amino-7-phenylbutyrate can be carried out in the presence of a small amount of acid (FIIL acid, hydrochloric acid, phosphoric acid, etc.), e.g., with an alcohol (preferably The process proceeds slowly and with good yield in polar protic solvents such as ethanol) or carboxylic acids (eg acetic acid). Examples of suitable catalysts include Raney nickel and palladium or platinum. ” As an example, regarding a reaction example using palladium carbon, α-(1-carboxyethyl)amino-γ-
About 2 to 70 inches of palladium carbon is added to ethyl oxo-γ-phenylbutyrate at 0°C to 50°C, preferably #
It can be almost quantitatively converted to ethyl α-(1-carboxyethyl)amino-γ-phenylbutyrate by reacting at 20°C to 40°C with an alcohol such as ethanol as a solvent for several hours to 80 hours. can. Of course, the reaction time can also be shortened by increasing the amount of catalyst.
反応終了後は、触媒を分離後、アルカリ(例えば水酸化
ナトリウム)で酸を中和し、溶媒を除去後再結晶などを
行った後光学分割を行い(αR,1g)又ハ(αS、S
S)α−(1−カルボキシエチル)アミノ−T−フェニ
ル酪酸エチルの高純度結晶として得ることができる。ま
た原料として(αg、1g)−α−(1−カルボキシエ
チル)アミノ−T−オキソ−γ−フェニル酪酸エチルを
用いると(αs。After the reaction is complete, the catalyst is separated, the acid is neutralized with an alkali (e.g. sodium hydroxide), the solvent is removed, recrystallization is performed, and optical resolution is performed to obtain (αR, 1g) or c(αS, S).
S) Can be obtained as high purity crystals of ethyl α-(1-carboxyethyl)amino-T-phenylbutyrate. Furthermore, when ethyl (αg, 1g)-α-(1-carboxyethyl)amino-T-oxo-γ-phenylbutyrate is used as a raw material, (αs.
l5)−α−(1−カルボキシエチル)−γ−7エ二ル
f?r[エチルを得ることができる。l5)-α-(1-carboxyethyl)-γ-7enyl f? r [ethyl can be obtained.
(実施例)
以下に実施例を挙げて本発明を説明するが、もとより本
発明はこれに限定されるものではない。(Example) The present invention will be described below with reference to Examples, but the present invention is not limited thereto.
分析にあたっては、高速液体クロマトグラフィー(HP
LC)による部分が多いが、先述した如く、α−(1−
力ルボキシエチル)アミノ−r−オキソ−γ−フェニル
酪酸エチルはアルカリ性で若干不安定で、また(αs、
ss)体は(αa、ts)体に熱力学的に変換しやすい
ことから、被験液は充分配性化して組成変化を停止した
後分析に供した。For analysis, high performance liquid chromatography (HP
LC), but as mentioned earlier, α-(1-
Ethyl (αs,
Since the ss) isomer is easily thermodynamically converted into the (αa, ts) isomer, the test solution was subjected to analysis after sufficient compatibility was achieved to stop the change in composition.
また分析には下記条件を使用した。The following conditions were used for analysis.
カラム: Finepak SIL C1g (日本
分光(株)製)(4,6關IDX2500)
移動相: 60mMリン酸緩衝液(1)82.5 )/
アセ) ニド!J ル= 85/15 (V/V )流
速l 1,5ml/min
検出:210nm
内部標準:5−ベンジルヒダントイン
なお、本1(PLC分析においては、α−(1−カルボ
キシエチル)アミノ−r−オキソ−γ−フェニル酪酸エ
チルおよびα−(1−カルボキシエチル)アミノ−γ−
フェニル酪酸エチルの(αs。Column: Finepak SIL C1g (manufactured by JASCO Corporation) (4,6 columns IDX2500) Mobile phase: 60mM phosphate buffer (1) 82.5 )/
Ace) Nido! J = 85/15 (V/V) Flow rate l 1.5 ml/min Detection: 210 nm Internal standard: 5-benzylhydantoin Note that this 1 (in PLC analysis, α-(1-carboxyethyl)amino-r- Ethyl oxo-γ-phenylbutyrate and α-(1-carboxyethyl)amino-γ-
of ethyl phenylbutyrate (αs.
llり、(αi、ts) 等ジアステレオマーの分離定
食が可能であり、実施例中の異性体含有量等の分析は末
法によった。It is possible to prepare separate meals for diastereomers such as (αi, ts), etc., and the analysis of isomer content, etc. in the examples was performed using the final method.
実施例1
trans−β−ベンゾイルアクリル酸エチル(以下t
−EBAとする)87m9をエタ/ −ル0.5 vl
に溶かした溶液中に表−1に示す(8)−アラニンのア
ルカリ金属(0,18mmol)またはアルカリ土類金
属(0,09mmog )をエタノール0.5 ytl
に溶かした溶液を室温で迅速に加えて、そのま15分間
撹拌後、酸を添加して反応を停止させて、IIPLcに
て生成物の分析を行ない、以下に示す様なα−(1−カ
ルボキシエチル)アミノ−r−オキソ−r−フェニル酪
酸エチルの生成を認めた。Example 1 Ethyl trans-β-benzoyl acrylate (hereinafter referred to as t
- EBA) 87m9 / -le 0.5 vl
The alkali metal (0.18 mmol) or alkaline earth metal (0.09 mmog) of (8)-alanine shown in Table 1 was added to a solution dissolved in 0.5 ytl of ethanol.
A solution of α-(1- Formation of ethyl (carboxyethyl)amino-r-oxo-r-phenylbutyrate was observed.
表−1
実施例2
小型試験管に(II)−アラニンのリチウム塩80〜を
計如込み、表−2に示す各種溶媒2.5 mlで洗い込
ンだ。室温下、マグネチツクスターラーで撹拌しつつ、
ついでこれKt−EBA120plCIB5■)をそれ
ぞれ加え付加反応を実施した。適宜酸を加え反応を停止
後HPLCKて生成物を分析して表−2に示す様なα−
(1−カルボキシエチル)−アミノ−γ−オキソ−γ−
フェニル酪酸エチルの生成?認めた。Table 1 Example 2 80~ of lithium salt of (II)-alanine was added to a small test tube and washed in with 2.5 ml of various solvents shown in Table 2. While stirring with a magnetic stirrer at room temperature,
Next, 120 pl of Kt-EBA and 120 pl of CIB5) were added to each to carry out an addition reaction. After stopping the reaction by adding an appropriate acid, the product was analyzed by HPLC and α-
(1-carboxyethyl)-amino-γ-oxo-γ-
Generation of ethyl phenylbutyrate? Admitted.
表−2
実施例8
100m容の三ツロ丸底7ラスコにt −EBAl、0
2gおよび(8)−アラニン2281M9とエタノール
F30mlを加え、室温下マグネチツクスターラーで撹
拌した。この@濁液に水酸化リチウム601n9を含む
エタノール溶液20m1を80分かかつて連続的に添加
すると反応液は次第に透明となり均一化した。そ−のま
ま5分撹拌後、この溶液Ka酸150μ4加え反応を停
止させて、HPLCにて生成物の分析を行ない、α−(
1−カルボキシエチル)アミノ−γ−オキソ−γ−フェ
ニル酪酸エチル6764の生成を認めた((α8,1s
)/(αB、 1B) :’ (65/85))。Table 2 Example 8 t-EBAl, 0 in a 100 m capacity three-sided round bottom 7 lasco
2 g of (8)-alanine 2281M9 and 30 ml of ethanol F were added, and the mixture was stirred with a magnetic stirrer at room temperature. When 20 ml of an ethanol solution containing lithium hydroxide 601n9 was continuously added to this suspension for 80 minutes, the reaction solution gradually became transparent and homogenized. After stirring for 5 minutes, 150 μ4 of Ka acid was added to this solution to stop the reaction, and the product was analyzed by HPLC.
Formation of ethyl 1-carboxyethyl)amino-γ-oxo-γ-phenylbutyrate 6764 was observed ((α8,1s
)/(αB, 1B) :' (65/85)).
実施例4
t −EBA 78■に(8)−アラニンのカリウム塩
46〜を表−8に示す量のエタノールに溶かした溶液を
室温で迅速に加えて、そのま′115分間撹拌後、実施
例1と同様に分析を行ない、以下の結果を得た。Example 4 A solution of potassium salt 46 of (8)-alanine dissolved in ethanol in the amount shown in Table 8 was quickly added to t-EBA 78 at room temperature, and after stirring for 115 minutes, Example Analysis was conducted in the same manner as in 1, and the following results were obtained.
実施例5
t−EBA78ダIc(s)−アラニンのリチウム塩8
4ダをエタノール111Itに溶力為した溶液を室温下
表−4に示す添加速度で加え入れ、添加後、8分間撹拌
を続け、実施例1と同様に分析を行ない、以下の結果を
得た。Example 5 Lithium salt of t-EBA78 da Ic(s)-alanine 8
A solution prepared by dissolving 111 It of ethanol in 111 It of ethanol was added at room temperature at the addition rate shown in Table 4. After the addition, stirring was continued for 8 minutes, and analysis was conducted in the same manner as in Example 1, and the following results were obtained. .
表−4
実施例6
t−EBA78111fを表−5に示す量のエタノール
に溶かした溶液に、 (s)−アラニンのカリウム墳4
6ダをエタノールlj/に溶かした溶液と室温で8分間
かけて加え入れ、添加後、8分間撹拌した。以下、実施
例1と同様に分析を行ない以下の結果を得た。Table 4 Example 6 Potassium mounds of (s)-alanine 4 were added to a solution of t-EBA78111f dissolved in ethanol in the amount shown in Table 5.
A solution prepared by dissolving 6 daphne in ethanol lj/ was added over 8 minutes at room temperature, and after the addition, the mixture was stirred for 8 minutes. Thereafter, analysis was conducted in the same manner as in Example 1, and the following results were obtained.
表−5
¥雄側7
t−EBAのかわりにcis−β−ベンゾイルアクリル
酸エチル(以下c−EBAとする)を用いて実施例1と
同様の実験を行ない表−6に示す結果を得た。Table 5 ¥ Male side 7 An experiment similar to Example 1 was conducted using ethyl cis-β-benzoyl acrylate (hereinafter referred to as c-EBA) instead of t-EBA, and the results shown in Table 6 were obtained. .
表−6
9!施例8
cmEBA114#’(rエタノール8 g/に溶かし
た溶液中に、(S)−アラニンのリチウム塩18rn9
ヲエタノールl、 5 Mlに溶かした溶液分室温で5
分間かけて加え入れ、添加後、8分間撹拌した。以下、
実施例1と同様に分析を行ない、α−(1−カルボキシ
エチル)アミノ−γ−オキソ−γ−フェニル酪酸エチル
128■の生成を認めた〔(αS、IBy(a m 、
1 g ) : 50 / 50 )。Table-6 9! Example 8 cmEBA114#' (lithium salt of (S)-alanine 18rn9 in solution in 8 g/ethanol)
5 ml of solution dissolved in 1 ml of ethanol at room temperature
The mixture was added over a period of minutes and stirred for 8 minutes after the addition. below,
Analysis was carried out in the same manner as in Example 1, and the formation of ethyl α-(1-carboxyethyl)amino-γ-oxo-γ-phenylbutyrate (128 μm) [(αS, IBy(am,
1 g): 50/50).
実施例9
cmEBA 190ffiりをエタノ−/L’ 0.5
wlに1容かした溶液に、(S)−アラニンのカリウ
ム塩118%”eエタノール0.6震jに溶かした溶液
を室温で迅速に加えて、そのま18分間撹拌後、実施例
1と同様に分析を行ない、α−(1−カルボキシエチル
)アミノ−γ−オキソ−γ−フェニル酪酸エチル698
■の生成を認めた〔(αs、rs)/(αR,1日)
= 69781 〕。Example 9 cmEBA 190ffi ethanol/L' 0.5
A solution of potassium salt of (S)-alanine dissolved in 118% ethanol and 0.6 g of ethanol was quickly added at room temperature to 1 volume of the solution in 1 ml of solution, and after stirring for 18 minutes, Example 1 was added. Analyzes were conducted in the same manner and ethyl α-(1-carboxyethyl)amino-γ-oxo-γ-phenylbutyrate 698
Formation of ■ was observed [(αs, rs)/(αR, 1 day)
= 69781].
実施例10
j−EBA 2.59 gをエタノール77m1K溶か
した溶液に、(8)−アラニンのリチウム!0.608
gをエタノール42.6 wlに溶かした溶液をネ温で
80分間かけて添加した。添加終了後さらに5分間撹拌
した後、#塩酸0.529 ml を加え、氷水で冷却
し種晶として(αs、1g)体67.9 ’9を添加し
て撹拌し、晶析を行なった。4時間後析出した結晶をν
取し、EtOHで洗浄、乾燥後α−(1−カルボキシエ
チル)アミノ−r−オキソ−γ−7エ二ル酪酸エチル1
.2γgを得た( 11B、 ts)/ (aR,1g
)=9515)。Example 10 Lithium of (8)-alanine was added to a solution of 2.59 g of j-EBA dissolved in 77 ml of ethanol! 0.608
A solution prepared by dissolving 1.0 g of ethanol in 42.6 wl of ethanol was added over 80 minutes at room temperature. After the addition was completed, the mixture was further stirred for 5 minutes, then 0.529 ml of #hydrochloric acid was added, cooled with ice water, and 67.9'9 of (αs, 1 g) was added as a seed crystal and stirred to perform crystallization. The crystals precipitated after 4 hours are ν
After washing with EtOH and drying, ethyl α-(1-carboxyethyl)amino-r-oxo-γ-7enylbutyrate 1
.. Obtained 2γg ( 11B, ts) / (aR, 1g
)=9515).
mp 200〜225℃(分解)
/H−NMR(DMSO−d6): 1.0〜1.4
(t 、 6)1)、8.2〜5.0(m、8H)7.
21〜8.1(m、5H)。mp 200-225°C (decomposition) /H-NMR (DMSO-d6): 1.0-1.4
(t, 6) 1), 8.2-5.0 (m, 8H)7.
21-8.1 (m, 5H).
IR(Cm−1) : (KBr disk) 80
70 、1785゜1680.1620.1580
〔α〕乳8=+26.8 (C= 1.0 、 N−H
cl )実施例11
cmEBA 680ダをエタノール1.8 g/に溶か
した溶液に(8)−アラニンのカリウム塩42211#
9をエタノール1.8 mlに溶かした溶液を室温で迅
速に加えて、そのまま8分間撹拌後、Hg504827
W(8,8mmoJ )を加えて反応を停止させ、水
−ヘキサンに分配した。分離した水層にトリエチルアミ
ン8881n9を加えて、ジクロルメタンで8回抽出し
、ジクロルメタン層を無水硫酸マグネシウムで脱水後、
エバポレートして溶媒を除去し、減圧にて充分乾燥後、
α−(1−カルボキシエチル)アミノ−γ−オキソ−7
−フェニル酪酸エチル507■を得たC(αg、1g)
/(αa、ts)= 78/27)。IR (Cm-1): (KBr disk) 80
70, 1785° 1680.1620.1580 [α] Milk 8 = +26.8 (C = 1.0, N-H
cl) Example 11 Potassium salt of (8)-alanine 42211# was added to a solution of cmEBA 680 da dissolved in 1.8 g/ethanol.
A solution of 9 dissolved in 1.8 ml of ethanol was quickly added at room temperature, and after stirring for 8 minutes, Hg504827
The reaction was stopped by adding W (8.8 mmoJ) and partitioned between water and hexane. Triethylamine 8881n9 was added to the separated aqueous layer, extracted 8 times with dichloromethane, and the dichloromethane layer was dehydrated with anhydrous magnesium sulfate.
After removing the solvent by evaporation and thoroughly drying under reduced pressure,
α-(1-carboxyethyl)amino-γ-oxo-7
-C obtained ethyl phenylbutyrate 507■ (αg, 1g)
/(αa, ts) = 78/27).
実施例12
実施例10で得られたα−(1−カルボキシエチル)ア
之ノーT−オキソ−γ−フェニル酪酸0.4gを8.0
dの1.6 e4 (v/v) H2SO4−Ac0
1(に溶解し、これに0.1 gの10チPd/Cを加
えて室温、常圧下で水素添加を実施した。反応後触媒を
吸引濾過し、このH2SO4−AcOH溶液にN−Ni
OH2、5mlを加えた後減圧濃縮し残留物を水に溶解
する。この水溶液をp)18.OK調節しジクロロメタ
ンで抽出し、有機層を飽和食塩水で洗浄後、減圧aaし
残渣を酢酸エチルで結晶化させα−(1−カルポキシエ
チル)アミノ−7−フェニル酪酸エチル0.25gを得
た〔(αg、ts)/(αn 、 1 m )=99/
1 )。Example 12 0.4 g of α-(1-carboxyethyl)ano-T-oxo-γ-phenylbutyric acid obtained in Example 10 was added to 8.0
1.6 e4 (v/v) H2SO4-Ac0
After the reaction, the catalyst was suction filtered, and N-Ni
After adding 5 ml of OH2, the mixture was concentrated under reduced pressure and the residue was dissolved in water. This aqueous solution p)18. The organic layer was adjusted to OK and extracted with dichloromethane, and the organic layer was washed with saturated brine and then subjected to vacuum aa, and the residue was crystallized with ethyl acetate to obtain 0.25 g of ethyl α-(1-carpoxyethyl)amino-7-phenylbutyrate [ (αg, ts)/(αn, 1 m)=99/
1).
mp:149〜149.5℃
/H−NMRCCDC18) : 1.1〜1.4(
t、8H)、1.4〜1.6 (d 、8H)、1.9
〜2.8 (m、 2H)、2.5〜2.9 (m 、
2H)、8.2〜8.7 (m 、 2H)、4.0〜
4.4 (Q 、2H)、6.9〜7.4(m、5H)
IR(cm−’): (KBr disk)8080.
2950.1740.1600
(a) 乙” = + 29.8 (C= 1.0.
MeOH)実施例18
実施例10で得られたα−(1−力ルボキシエチル)ア
ミノ−T−オキソ−γ−フェニル酪酸0.20gを11
.0胃lの1 % (v/v ) H2S04−EtO
HK溶解しこれに0.05gの10 * pd/Cを加
えて室温、常圧下で水素添加を実施した。反応後触媒を
吸引濾過し、このエタノール溶液を水酸化ナトリウムで
中和した後、溶媒を減圧留去した。残留物に水を加えて
溶解しジクロロメタンで抽出し、有機層を減圧濃縮し残
渣を酢酸エチルで結晶化させα−(1−カルボキシエチ
ル)アミノ−γ−フェニル酪酸エチル0.152gを得
た〔(αg、ts)/(α” 111)=99/1 )
。mp: 149-149.5°C /H-NMRCCDC18): 1.1-1.4(
t, 8H), 1.4-1.6 (d, 8H), 1.9
~2.8 (m, 2H), 2.5~2.9 (m,
2H), 8.2~8.7 (m, 2H), 4.0~
4.4 (Q, 2H), 6.9-7.4 (m, 5H)
IR (cm-'): (KBr disk) 8080.
2950.1740.1600 (a) "Otsu" = + 29.8 (C = 1.0.
MeOH) Example 18 0.20 g of α-(1-hydroxyethyl)amino-T-oxo-γ-phenylbutyric acid obtained in Example 10 was dissolved in 11
.. 0 gastric 1% (v/v) H2S04-EtO
HK was dissolved, 0.05 g of 10*pd/C was added thereto, and hydrogenation was carried out at room temperature and normal pressure. After the reaction, the catalyst was suction filtered, and the ethanol solution was neutralized with sodium hydroxide, and then the solvent was distilled off under reduced pressure. The residue was dissolved in water and extracted with dichloromethane. The organic layer was concentrated under reduced pressure and the residue was crystallized from ethyl acetate to obtain 0.152 g of ethyl α-(1-carboxyethyl)amino-γ-phenylbutyrate. (αg, ts)/(α” 111) = 99/1)
.
実施例14
t−EBA 10.2gをエタノール800茸lに溶
かした溶液に、(S)−アラニン°のリチウム42.4
gをエタノール160w1に溶かした溶液を室温で80
分間かけて添加し、さらに5分間撹拌した後、浪硫酸4
.41加えて反応を停止した。このエタノール溶液を減
圧濃縮してE t onを留去し残留物をn−ヘキサン
で洗浄した後これに酢酸150g/を加え溶解した。こ
れに1.65gの104pd/cを加えて室温、常圧下
で水素添加を実施した。反応後触媒を吸引濾過し、との
d酸−酢酸溶液にN−NaOH44,9mlを加え死後
、減圧濃縮し残留物を水に溶解した。この溶液をpH3
,0に調節しジクロロメタン800 mlで抽出し、有
碕層を飽和食塩水で洗浄した後減圧a縮し残渣を酢酸エ
チルで結晶化させα−(1−カルボキシエチル)アミノ
−γ−フェニル酪酸エチル4. Og&得た〔(α11
、18 )/(lXu、ts)=9515)。Example 14 In a solution of 10.2 g of t-EBA dissolved in 800 liters of ethanol, 42.4 g of lithium (S)-alanine was added.
A solution of 160w of ethanol dissolved in 80g of
After stirring for an additional 5 minutes,
.. 41 was added to stop the reaction. This ethanol solution was concentrated under reduced pressure to remove E ton, and the residue was washed with n-hexane, and then 150 g of acetic acid was added and dissolved. To this was added 1.65 g of 104 pd/c, and hydrogenation was carried out at room temperature and under normal pressure. After the reaction, the catalyst was suction filtered, and 44.9 ml of N-NaOH was added to the d-acid-acetic acid solution. After death, the mixture was concentrated under reduced pressure and the residue was dissolved in water. This solution has a pH of 3
, 0, and extracted with 800 ml of dichloromethane. The aurisaki layer was washed with saturated saline, and then condensed under reduced pressure. The residue was crystallized with ethyl acetate to obtain ethyl α-(1-carboxyethyl)amino-γ-phenylbutyrate. 4. Og & got [(α11
, 18 )/(lXu,ts)=9515).
実施例15
t −EBA 616.0In9をエタノール18.2
g+/に溶かし九溶液K (s)−アラニンのリチウム
塩148.6mL9をエタノールL(1++lに溶かし
た芯液を室温で80分間かけて添加し、そのまま5分間
撹拌後5. Omlずつ試験管にとυ塩酸あるい/ri
硫酸を加え、HFLCにて生成物の経時的な安定性を検
討し以下の結果を得た。Example 15 t-EBA 616.0In9 to ethanol 18.2
Add 148.6 mL of the 9 solution K (s)-alanine lithium salt dissolved in ethanol L (1++ L) over 80 minutes at room temperature, stir for 5 minutes, and then add 5.0 mL of the lithium salt to the test tube. and υhydrochloric acid/ri
Sulfuric acid was added, and the stability of the product over time was examined by HFLC, and the following results were obtained.
実施例16
t −EBA 1.42 gをエタノール42露lに溶
かした溶液に(R)−アラニンのリチウム塩0.882
gをエタノール28slに溶かした溶液を室温で20分
間かけて添加した。添加終了後さらに8分間撹拌後、#
塩酸0.29 mlを加え氷水で冷却し種晶として(α
m、ts)体20rlI9を添加して撹拌し晶析を行な
った。4時間後、析出した結晶tF取しEtol(で洗
浄、乾燥後、α−(1−カルボキシエチル)アミノ−T
−オキソ−7−フェニルflHmエチル61111に9
を得* ((as、 xi)/(am、1g)=96/
43゜mp 202〜220℃(分解)
’HNMR(DMSO−da): 1.0〜1.4(t
、6H)、8.2〜5.0 (m、8H)、7.8〜8
.1 (m 、 5H)IR(cm−’): (KBr
disk)8070.1785.1680.162
0.1680
〔α〕邑”=−26,7(C=1.0.N−HCJ)(
発明の効果)
以上、ミカエル(M 1chael)付加反応及びその
処理条件を整えれば、安価なtrans+、β−ベンゾ
イルアクリル酸エチル或いはcim−β−ベンゾイルア
クリル酸エチルと(II)−アラニンの金属塩から、(
αs、ts)−α−(1−カルボキシエチル)アミノ−
γ−オキソ−r−フェニル酪酸エチル(1)を極めて高
収率で得ることが可能であり、本発明は、アンジオテン
シン変検酵素(ALEIII害剤の重要な製造中間体で
ある(αS,1s)−α−(1−カルボキシエチル)ア
ミノ−γ−フェニル酪酸エチルI)の極めて簡便かつ効
率的な製造法を提供するものである。Example 16 0.882 g of lithium salt of (R)-alanine was added to a solution of 1.42 g of t-EBA in 42 L of ethanol.
A solution prepared by dissolving 1.0 g in 28 sl of ethanol was added over 20 minutes at room temperature. After stirring for an additional 8 minutes after the addition, #
Add 0.29 ml of hydrochloric acid, cool with ice water, and use as seed crystals (α
m, ts) body 20rlI9 was added and stirred to perform crystallization. After 4 hours, the precipitated crystals tF were collected, washed with Etol (and dried, α-(1-carboxyethyl)amino-T
-oxo-7-phenyl flHm ethyl 61111 to 9
Obtain* ((as, xi)/(am, 1g)=96/
43゜mp 202~220℃ (decomposition) 'HNMR (DMSO-da): 1.0~1.4 (t
, 6H), 8.2-5.0 (m, 8H), 7.8-8
.. 1 (m, 5H)IR (cm-'): (KBr
disk) 8070.1785.1680.162
0.1680 [α] ”=-26,7 (C=1.0.N-HCJ) (
Effects of the Invention) As described above, if the Michael addition reaction and its treatment conditions are prepared, an inexpensive metal salt of trans+, β-benzoylacrylate ethyl or cim-β-benzoylacrylate ethyl and (II)-alanine can be produced. from,(
αs, ts)-α-(1-carboxyethyl)amino-
It is possible to obtain ethyl γ-oxo-r-phenylbutyrate (1) in an extremely high yield, and the present invention is an important production intermediate for angiotensin modified enzyme (ALE III inhibitor (αS, 1s)). -α-(1-carboxyethyl)amino-γ-phenylbutyrate ethyl I) is provided as an extremely simple and efficient manufacturing method.
Claims (11)
類金属イオンの存在下、β−ベンゾイルアクリル酸エチ
ルと反応させることを特徴とするα−(1−カルボキシ
エチル)アミノ−γ−オキソ−γ−フェニル酪酸エチル
の製造法。(1) α-(1-carboxyethyl)amino-γ-oxo-γ-phenyl characterized by reacting alanine with ethyl β-benzoylacrylate in the presence of an alkali metal ion or an alkaline earth metal ion. Method for producing ethyl butyrate.
属塩を、β−ベンゾイルアクリル酸エチルと反応させる
特許請求の範囲第1項記載の製造法。(2) The production method according to claim 1, wherein an alkali metal salt or alkaline earth metal salt of alanine is reacted with ethyl β-benzoyl acrylate.
合液中にアルカリ金属またはアルカリ土類金属の水酸化
物を添加して反応を行なう特許請求の範囲第1項記載の
製造法。(3) The production method according to claim 1, wherein the reaction is carried out by adding an alkali metal or alkaline earth metal hydroxide to a mixed solution of alanine and β-benzoylacrylate ethyl acrylate.
(αR,1s)−α−(1−カルボキシエチル)アミノ
−γ−オキソ−γ−フェニル酪酸エチルを合成する特許
請求の範囲第1項〜第8項いづれかの項記載の製造法。(4) Using (s)-alanine, (αs, 1s) and (αR, 1s)-α-(1-carboxyethyl)amino-γ-oxo-γ-phenylbutyrate ethyl is synthesized. The manufacturing method described in any one of Items 1 to 8.
を、trans−β−ベンゾイルアクリル酸エチルと反
応せしめ、(αs,1s)−α−(1−カルボキシエチ
ル)アミノ−γ−オキソ−γ−フェニル酪酸エチルを優
先的に合成する特許請求の範囲第1項、第2項、第4項
のいづれかの項記載の製造法。(5) The lithium or potassium salt of (s)-alanine is reacted with ethyl trans-β-benzoylacrylate, and (αs,1s)-α-(1-carboxyethyl)amino-γ-oxo-γ- The manufacturing method according to any one of claims 1, 2, and 4, which preferentially synthesizes ethyl phenylbutyrate.
ンゾイルアクリル酸エチルと反応せしめ、 (αs,1s)−α−(1−カルボキシエチル)アミノ
−γ−オキソ−γ−フェニル酪酸エチルを優先的に合成
する特許請求の範囲第1項、第2項、第4項いづれかの
項記載の製造法。(6) Reacting the potassium salt of (s)-alanine with ethyl cis-β-benzoylacrylate to produce ethyl (αs,1s)-α-(1-carboxyethyl)amino-γ-oxo-γ-phenylbutyrate. A manufacturing method according to any one of claims 1, 2, and 4, which involves preferential synthesis.
囲第1項〜第6項のいづれかの項記載の製造法。(7) The manufacturing method according to any one of claims 1 to 6, in which ethanol is used as a reaction solvent.
定化させる特許請求の範囲第1項〜第7項いづれかの項
記載の製造法。(8) The production method according to any one of claims 1 to 7, wherein after the addition reaction, an equivalent or more amount of mineral acid is added to stabilize the product.
、(αs,1s)−α−(1−カルボキシエチル)アミ
ノ−γ−オキソ−γ−フェニル酪酸エチルを結晶として
析出せしめ採取する特許請求の範囲第1項〜第8項いづ
れかの項記載の製造法。(9) After the addition reaction, acid is added to neutralize the alkali metal, and ethyl (αs, 1s)-α-(1-carboxyethyl)amino-γ-oxo-γ-phenylbutyrate is precipitated as crystals and collected. A manufacturing method according to any one of claims 1 to 8.
キソ−γ−フェニル酪酸エチルを接触還元してα−(1
−カルボキシエチル)アミノ−γ−フェニル酪酸エチル
に変換することを特徴とするα−(1−カルボキシエチ
ル)アミノ−γ−フェニル酪酸エチルの製造法。(10) Catalytic reduction of α-(1-carboxyethyl)amino-γ-oxo-γ-phenylbutyrate ethyl
A method for producing ethyl α-(1-carboxyethyl)amino-γ-phenylbutyrate, which comprises converting it into ethyl -carboxyethyl)amino-γ-phenylbutyrate.
求の範囲第10項記載の製造法。(11) The production method according to claim 10, wherein catalytic reduction is carried out in ethanol containing a mineral acid.
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP1948385A JPS61178954A (en) | 1985-02-04 | 1985-02-04 | Production of ethyl alpha-(1-carboxyethyl)amino-gamma-oxo-gamma-phenylbutyrate and reduced compound thereof |
EP19860101313 EP0190687B1 (en) | 1985-02-04 | 1986-02-01 | Process for preparing ethyl-alpha-(1-carboxyethyl)-amino-gamma-oxo-gamma-phenylbutyrate |
DE8686101313T DE3660868D1 (en) | 1985-02-04 | 1986-02-01 | Process for preparing ethyl-alpha-(1-carboxyethyl)-amino-gamma-oxo-gamma-phenylbutyrate |
CA000500972A CA1286308C (en) | 1985-02-04 | 1986-02-03 | PROCESS FOR PREPARING ETHYL-.alpha.-(1-CARBOXYETHYL)AMINO- -OXO- -PHENYLBUTYRATE |
ES551591A ES8705368A1 (en) | 1985-02-04 | 1986-02-03 | Process for preparing ethyl-alpha-(1-carboxyethyl)-amino-gamma-oxo-gamma-phenylbutyrate. |
ES557568A ES8800134A1 (en) | 1985-02-04 | 1987-05-28 | Process for preparing ethyl-alpha-(1-carboxyethyl)-amino-gamma-oxo-gamma-phenylbutyrate. |
US07/324,497 US4925969A (en) | 1985-02-04 | 1989-03-16 | Process for preparing ethyl-alpha-amino-gamma-oxo-gamma-phenybutyrate derivatives |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP1948385A JPS61178954A (en) | 1985-02-04 | 1985-02-04 | Production of ethyl alpha-(1-carboxyethyl)amino-gamma-oxo-gamma-phenylbutyrate and reduced compound thereof |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2243019A Division JPH03115254A (en) | 1990-09-12 | 1990-09-12 | Production of alpha-(1-carboxyethyl)amino-gamma-phenylbutyric acid ethyl ester |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS61178954A true JPS61178954A (en) | 1986-08-11 |
JPH0322867B2 JPH0322867B2 (en) | 1991-03-27 |
Family
ID=12000590
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP1948385A Granted JPS61178954A (en) | 1985-02-04 | 1985-02-04 | Production of ethyl alpha-(1-carboxyethyl)amino-gamma-oxo-gamma-phenylbutyrate and reduced compound thereof |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS61178954A (en) |
-
1985
- 1985-02-04 JP JP1948385A patent/JPS61178954A/en active Granted
Non-Patent Citations (2)
Title |
---|
CHEMICAL ABSTRACTS=1978 * |
TETRAHEDRON LETTERS=1984 * |
Also Published As
Publication number | Publication date |
---|---|
JPH0322867B2 (en) | 1991-03-27 |
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