JPH07110844B2 - Method for producing 2-hydroxy-4-phenylbutyric acid amide - Google Patents
Method for producing 2-hydroxy-4-phenylbutyric acid amideInfo
- Publication number
- JPH07110844B2 JPH07110844B2 JP24352388A JP24352388A JPH07110844B2 JP H07110844 B2 JPH07110844 B2 JP H07110844B2 JP 24352388 A JP24352388 A JP 24352388A JP 24352388 A JP24352388 A JP 24352388A JP H07110844 B2 JPH07110844 B2 JP H07110844B2
- Authority
- JP
- Japan
- Prior art keywords
- ppch
- hydroxy
- acid amide
- producing
- reaction
- 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 - Fee Related
Links
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
【発明の詳細な説明】 本発明は、血圧降下剤であるアンジオテンシン変換酵素
阻害剤等の合成中間体として有用であるところの２−ヒ
ドロキシ−４−フェニル酪酸アミド（以下、HPBAMS略記
する）の製造方法に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention is a production of 2-hydroxy-4-phenylbutyric acid amide (hereinafter abbreviated as HPBAMS), which is useful as a synthetic intermediate for angiotensin converting enzyme inhibitors, which are hypotensive agents. Regarding the method.
（従来の技術） 一般にニトリル基は酸またはアルカリ水溶液で加水分解
を受け、カルボン酸アミドを経由してカルボン酸または
その塩に加水分解される。しかし加水分解反応を途中の
カルボン酸アミドの段階で留めるためには、原料化合物
の種類や使用する加水分解薬剤によって反応条件が大巾
に変り一般的な方法は確立されていない。特にシアンヒ
ドリンの加水分解をカルボン酸アミドの段階で留めて、
収率良く２−ヒドロキシカルボン酸アミドを製造するこ
とは困難であり、例えばシアンヒドリンは塩基性水溶液
中では相当するカルボニル化合物と青酸とに分解し、ま
た硫酸水溶液中では２−ヒドロキシカルボン酸にまで加
水分解が進行するとされていた。(Prior Art) Generally, a nitrile group is hydrolyzed by an acid or alkaline aqueous solution, and is hydrolyzed to a carboxylic acid or a salt thereof via a carboxylic acid amide. However, in order to stop the hydrolysis reaction at the stage of the carboxylic acid amide in the middle, the reaction conditions largely vary depending on the kind of the raw material compound and the hydrolysis agent used, and a general method has not been established. Especially by stopping the hydrolysis of cyanohydrin at the stage of carboxamide,
It is difficult to produce 2-hydroxycarboxylic acid amide in good yield. For example, cyanohydrin is decomposed into a corresponding carbonyl compound and hydrocyanic acid in a basic aqueous solution, and is hydrolyzed to 2-hydroxycarboxylic acid in a sulfuric acid aqueous solution. It was said that decomposition would proceed.
３−フェニルプロピオンアルデヒドシアンヒドリン（以
下、PPCHと略記する）からHPBAMを製造する方法とし
て、過酸化水素およびアンモニアの存在下に加水分解を
行う方法が知られている（特開昭62−178555号）。この
方法は、過酸化水素やアンモニアといった比較的高価な
薬剤を多量に使用すること、また反応後の混合物から過
剰量の過酸化水素やアンモニアを除去するために繁雑な
操作を要すること、さらに反応収率が65％と低いことな
どの欠点があり、工業的製法としては満足すべき方法と
はいえない。As a method for producing HPBAM from 3-phenylpropionaldehyde cyanohydrin (hereinafter abbreviated as PPCH), a method of performing hydrolysis in the presence of hydrogen peroxide and ammonia is known (Japanese Patent Laid-Open No. 62-178555). issue). This method uses a large amount of relatively expensive chemicals such as hydrogen peroxide and ammonia, requires complicated operations to remove excess hydrogen peroxide and ammonia from the reaction mixture, and further There are drawbacks such as a low yield of 65%, which is not a satisfactory industrial production method.
（発明が解決しようとする課題） 本発明の目的は従来工業的規模において経済性良く製造
することが困難であったHPBAMを、PPCHから簡便かつ高
収率に製造することにある。(Problems to be Solved by the Invention) An object of the present invention is to produce HPBAM from PPCH, which was conventionally difficult to produce economically on an industrial scale, in a simple and high yield.
（問題点を解決するための手段） 上記目的は、本発明の方法すなわち、PPCHを塩酸存在下
に、15〜50℃で加水分解することによりHPBAMを製造す
る方法により達成することができる。(Means for Solving Problems) The above object can be achieved by the method of the present invention, that is, a method of producing HPBAM by hydrolyzing PPCH in the presence of hydrochloric acid at 15 to 50 ° C.
本発明は、従来法のように特別な薬剤を用い、繁雑な操
作を経ることなしに、PPCHからHPBAMを製造する方法を
提供するものであり、それはPPCHを温和な条件下に塩酸
で処理することにより達成される。The present invention provides a method for producing HPBAM from PPCH by using a special agent as in the conventional method and without performing complicated operations, which treats PPCH with hydrochloric acid under mild conditions. It is achieved by
本発明の方法によってシアンヒドリンの加水分解をヒド
ロキシカルボン酸アミドの段階で留めることができ、分
解などの副反応もなく高収率でHPBAMを製造することが
できる。According to the method of the present invention, hydrolysis of cyanohydrin can be stopped at the stage of hydroxycarboxylic acid amide, and HPBAM can be produced in high yield without side reaction such as decomposition.
（作用） 本発明においてPPCHの加水分解に用いられる塩酸の濃度
は20〜36重量％であり、濃塩酸が好ましく用いられる。
塩酸濃度が20％以下では加水分解反応が十分に進行しな
い。またPPCHに対する塩酸の使用量は0.5〜２倍モルで
あり、好ましくは１〜1.5倍モルの範囲で使用される。
塩酸の使用量が等モル以下では加水分解反応が十分に進
行せず、また1.5倍モル以上使用しても特にメリットは
ない。本発明を実施するにあたり最も重要な条件は反応
温度であり、15〜50℃の範囲で行なわれる。反応温度が
15℃以下の場合には反応完結に長時間を要し実用的でな
く、また50℃以上では２−ヒドロキシ−４−フェニル酪
酸にまで加水分解が進む割合が多くなり、HPBAMの選択
率が低下する。従って本発明においては20〜40℃の範囲
で実施することが特に好ましい。(Function) The concentration of hydrochloric acid used for hydrolysis of PPCH in the present invention is 20 to 36% by weight, and concentrated hydrochloric acid is preferably used.
When the concentration of hydrochloric acid is 20% or less, the hydrolysis reaction does not proceed sufficiently. The amount of hydrochloric acid used with respect to PPCH is 0.5 to 2 times mol, preferably 1 to 1.5 times mol.
If the amount of hydrochloric acid used is equimolar or less, the hydrolysis reaction does not proceed sufficiently, and if it is used 1.5 times or more, there is no particular advantage. The most important condition for carrying out the present invention is the reaction temperature, which is carried out in the range of 15 to 50 ° C. The reaction temperature is
When the temperature is 15 ° C or lower, it takes a long time to complete the reaction, which is not practical, and when it is 50 ° C or higher, the rate of hydrolysis to 2-hydroxy-4-phenylbutyric acid increases and the selectivity of HPBAM decreases. To do. Therefore, in the present invention, it is particularly preferable to carry out the treatment within the range of 20 to 40 ° C.
本発明を実施するにあたりPPCHと塩酸との混合方法は特
に制限はないが、発熱を伴う反応であるため、冷却下に
所定量の塩酸中にPPCHを徐々に添加しながらバッチ方式
で行うか、PPCHと塩酸とを所定の割合で連続的に供給す
る方式が好ましい。反応の進行にともない生成したHPBA
Mの一部は結晶として析出してくるためこれを分離した
のち、母液を濃縮または希釈することにより残部を回収
することができる。In carrying out the present invention, the method of mixing PPCH and hydrochloric acid is not particularly limited, but since it is a reaction accompanied by heat generation, while performing batchwise while gradually adding PPCH in a predetermined amount of hydrochloric acid under cooling, A method of continuously supplying PPCH and hydrochloric acid at a predetermined ratio is preferable. HPBA formed as the reaction progressed
Since a part of M precipitates as crystals, it can be separated and then the mother liquor can be concentrated or diluted to recover the rest.
（実施例） 以下実施例を挙げて本発明をさらに具体的に説明する。(Examples) The present invention will be described more specifically with reference to the following examples.
実施例１ かきまぜ棒、温度計、滴下ロートおよび逆流冷却器を備
えたフラスコに濃塩酸19gを入れ室温に保った。ついで
純度98％のPPCH30gを20分間で滴下した。この間反応液
を氷水で冷却して25℃に保持した。PPCH滴下後同温度で
３時間かきまぜたのち反応液を水40ml中に排出し、析出
した固体を取した。この固体を５％炭酸ナトリウム水
溶液中に再分散させ、十分にかきまぜたのち再度過
し、水30ml、次いでトルエン20mlで洗浄後乾燥して28g
のHPBAMを得た。収率は85.5％であった。Example 1 19 g of concentrated hydrochloric acid was placed in a flask equipped with a stirring rod, a thermometer, a dropping funnel, and a countercurrent condenser, and kept at room temperature. Then, 30 g of PPCH having a purity of 98% was added dropwise over 20 minutes. During this period, the reaction solution was cooled with ice water and kept at 25 ° C. After dropping PPCH, the mixture was stirred at the same temperature for 3 hours, then the reaction solution was discharged into 40 ml of water, and the precipitated solid was collected. This solid was redispersed in a 5% sodium carbonate aqueous solution, thoroughly stirred and then filtered again, washed with 30 ml of water and then 20 ml of toluene and dried to give 28 g.
Got HP BAM. The yield was 85.5%.
比較例１ 反応温度を60℃にする以外は実施例１と同じ方法でPPCH
の加水分解を行い反応液を水中に排出し、析出した固体
を取した。この固定はオイル状物を含み、液体クロマ
トグラフによる分析の結果大部分が２−ヒドロキシ−４
−フェニル酪酸であり、HPBAMの生成量は僅かであっ
た。Comparative Example 1 PPCH was prepared in the same manner as in Example 1 except that the reaction temperature was 60 ° C.
Was hydrolyzed, the reaction solution was discharged into water, and the precipitated solid was collected. This immobilization contained an oily substance, and as a result of analysis by liquid chromatography, most of it was 2-hydroxy-4.
-Phenylbutyric acid, the amount of HPBAM produced was small.
（発明の効果） 本発明によれば、PPCHから簡便な操作で収率良くHPBAM
を製造することができるので、工業的規模における生産
の経済性が向上する。(Effects of the Invention) According to the present invention, HPBAM can be obtained from PPCH in a simple operation with good yield.
Since it can be produced, the economical efficiency of production on an industrial scale is improved.
Claims (1)
ヒドリンを塩酸の存在下に、15〜50℃で加水分解するこ
とを特徴とする２−ヒドロキシ−４−フェニル酪酸アミ
ドの製造方法。1. A process for producing 2-hydroxy-4-phenylbutyric acid amide, which comprises hydrolyzing 3-phenylpropionaldehyde cyanohydrin at 15 to 50 ° C. in the presence of hydrochloric acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP24352388A JPH07110844B2 (en) | 1988-09-28 | 1988-09-28 | Method for producing 2-hydroxy-4-phenylbutyric acid amide |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP24352388A JPH07110844B2 (en) | 1988-09-28 | 1988-09-28 | Method for producing 2-hydroxy-4-phenylbutyric acid amide |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH0291055A JPH0291055A (en) | 1990-03-30 |
| JPH07110844B2 true JPH07110844B2 (en) | 1995-11-29 |
Family
ID=17105173
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP24352388A Expired - Fee Related JPH07110844B2 (en) | 1988-09-28 | 1988-09-28 | Method for producing 2-hydroxy-4-phenylbutyric acid amide |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH07110844B2 (en) |
-
1988
- 1988-09-28 JP JP24352388A patent/JPH07110844B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0291055A (en) | 1990-03-30 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| LAPS | Cancellation because of no payment of annual fees |