JPS58164555A - Production of hydroxyaminobutyric acid - Google Patents

Abstract

PURPOSE:The reaction of glycine with acetaldehyde is carried out in the presence of a specific amount of a copper compound and an alkali metal hydroxide to produce the titled compound used as a feed additive with easy copper separations after the reaction. CONSTITUTION:In the reaction between glycine and acetaldehyde, less than equivalent amount of a copper compound based on glycine (less than 0.5mole of the copper compound per mole of glycine) and 0.5-2 equivalents of an alkali metal hydroxide based on the glycine are used to effect the reaction at room temperature to 100 deg.C, preferably room temperature to 70 deg.C for 20min to 20hr to give beta-hydroxy-alpha-aminobutyric acid. Since hydroxyaminobutyric acid has 2 optically active carbon atoms in its molecule, it has four different kinds of isomers, d and l-threonine and d and l-allothreonine.

Description

【発明の詳細な説明】 本発明は、β−ヒドロキシ−α−アミノ酪酸（以下、ヒ
ドロキシアミノ酪酸と略記する）の製造方法、より詳細
には、グリシンとアセトアルデヒドとを反応させて、ヒ
ドロキシ−了ミノ酪酸を製造する方法に関するものであ
る。DETAILED DESCRIPTION OF THE INVENTION The present invention provides a method for producing β-hydroxy-α-aminobutyric acid (hereinafter abbreviated as hydroxyaminobutyric acid), and more specifically, a method for producing β-hydroxy-α-aminobutyric acid (hereinafter abbreviated as hydroxyaminobutyric acid). The present invention relates to a method for producing minobutyric acid.

ヒドロキシ−アミノ酪酸は、光学活性な炭素原子を分子
内に２ヶ持つために、ｄおよびｌ−）レオニン、ｄおよ
びｌ−アロトレオニンと称スル４種の異性体が存在する
。Since hydroxy-aminobutyric acid has two optically active carbon atoms in its molecule, there are four isomers called d and l-) leonine and d and l-allothreonine.

これらのうちで、生理活性を持ち、栄養素として有用な
ものは、ｄ　＝Ｆ、；よびｌ−）レオニン、特１／ｌ〜
トレオニンで＆’）、ｌ−）レオニンはｃｌ１体の光学
分割で得ることが出来る。Among these, those that have physiological activity and are useful as nutrients are d = F; and l-) leonine, especially 1/l ~
Threonine &'), l-) Leonine can be obtained by optical resolution of cl1 body.

ヒドロキシアミノ酪酸の合成法には種々な方法が、提案
されている。例えば、アセト酢酸エステルを原料とする
方法、ジケテンを原料とする方法、酢酸ビニルを原料と
する方法、およびグリシン銅錯体を原料とする方法等が
古くから知られている。Various methods have been proposed for the synthesis of hydroxyaminobutyric acid. For example, a method using acetoacetate as a raw material, a method using diketene as a raw material, a method using vinyl acetate as a raw material, a method using a glycine copper complex as a raw material, etc. have been known for a long time.

これらの方法は、いずれも反応工程が多段で繁雑であっ
たり、目的とするトレオ体の取得比率が低い、あるいは
多量の副原料が必要でもる等の欠点があった。ト記した
公知の製造方法のうちで、グリシン銅錯体を原料とする
方法は、反応操作が１段で１つ、トレオ体の取得比率が
高い等の長所を持つが、グリシンと当量の銅化合物を反
応させ、牛蜆ｌ吻から、同じ（、当量の銅化合物を除去
する繁雑な操作が必要である。したがって、グリシン銅
錯体を用いる方法に於いて、当量の銅化合物を反応に用
いず、当量以下、すなわち、触媒量の銅化合物で反応が
実施出来れば、優れたヒドロキシアミノ酪酸の製造法と
なり得る。All of these methods have drawbacks such as multi-stage and complicated reaction steps, a low yield of the desired threo isomer, and the need for a large amount of auxiliary raw materials. Among the known production methods mentioned above, the method using glycine-copper complex as a raw material has advantages such as one reaction operation per stage and a high obtainment ratio of threo isomers, It is necessary to perform a complicated operation to react and remove the same amount of copper compound from the oxtail proboscis. Therefore, in the method using glycine copper complex, an equivalent amount of copper compound is not used in the reaction, If the reaction can be carried out using an equivalent amount or less, that is, a catalytic amount of the copper compound, it can be an excellent method for producing hydroxyaminobutyric acid.

本発明の目的とするところは、ト述のような欠点のない
、銅化合物の除去を容易に実施出来る、グリシンとアセ
トアルデヒドを原料とするヒドロキシアミノ酪酸の製造
方法を提倶することにある。An object of the present invention is to provide a method for producing hydroxyaminobutyric acid using glycine and acetaldehyde as raw materials, which does not have the above-mentioned drawbacks and can easily remove copper compounds.

本発明者らは、グリシンとアセトアルデヒドの反応に関
して、種々研究した結果、グリシンに対し、従来、当量
または当量以上の銅化合物を用いて反応させていたのに
対し、グリシンに対して当量以下、すなわち、触媒量の
銅化合物を用い、更ると、ヒドロキシアミノ酪酸が高収
率で得られ、着合物質の生成も少なく、また意外なこと
に、スレオ体の取得比率も、当量の銅化合物を用いた場
合と実質的に差がないことを見出し、本発明を完成する
に至った。The present inventors have conducted various studies regarding the reaction between glycine and acetaldehyde, and found that while glycine was conventionally reacted with an equivalent amount or more of a copper compound, a copper compound of less than an equivalent amount with respect to glycine, i.e. , using a catalytic amount of copper compound, hydroxyaminobutyric acid was obtained in high yield, with less formation of attached substances, and surprisingly, the obtained ratio of threo isomer was also lowered when using an equivalent amount of copper compound. The present inventors have found that there is virtually no difference from the case in which the present invention is used, and have completed the present invention.

すなわち、本発明は゛、グリシンとアセトアルデヒドと
を反応させてβ−ヒドロキシ−α−アミン酪酸を製造す
るに際し、グリシンに対して当量以下、触媒量の銅化合
物を用い、更にアルカリ物質としてアルカリ金噂の水酸
化物をグリシンに対し０．５〜２当量用いることを特徴
とするヒドロキシアミノ酪酸の製造方法である。That is, the present invention uses a catalytic amount of a copper compound in an amount equivalent to or less than that of glycine when reacting glycine and acetaldehyde to produce β-hydroxy-α-amine butyric acid, and further uses alkali metal as an alkali substance. This is a method for producing hydroxyaminobutyric acid, characterized in that 0.5 to 2 equivalents of hydroxide are used relative to glycine.

本発明の方法によれば、用いる銅化合物がグリシンに対
して触媒量で反応が実施されるために、反応生成物から
の銅化合物の除去は、従来法に比較してはるかに容易で
あって、工業的に極めて有利にヒドロキシ−アミノ酪酸
を製造することが出来る。また、本発明の方法に於ける
出発原料はグリシンおよびアセトアルデヒドであって、
いずれも、工業的に安価大量に得られるので、ヒドロキ
シ−アミノ酪酸を安価に大量供給することが可能である
。According to the method of the present invention, since the copper compound used reacts with glycine in a catalytic amount, it is much easier to remove the copper compound from the reaction product compared to conventional methods. , hydroxy-aminobutyric acid can be produced industrially with great advantage. Further, the starting materials in the method of the present invention are glycine and acetaldehyde,
Since both can be obtained industrially at low cost and in large quantities, it is possible to supply hydroxy-aminobutyric acid in large quantities at low cost.

本発明の方法で得られるヒドロキシ−アミノ酪酸、特に
そのトレオ体は、必須アミノ酸として広範な用途をもち
、飼料添加剤として、大量に用途のある極めて有用な化
合物でちる。Hydroxy-aminobutyric acid, particularly its threo form, obtained by the method of the present invention has a wide range of uses as an essential amino acid, and is an extremely useful compound that has a large amount of use as a feed additive.

本発明の方法は、グリシンとアセトアルデヒドを銅化合
物の存在下に反応させるものであって、銅化合物として
は、特に制限はないが、塩基性の銅塩が好ましい。塩基
性銅塩としては、水酸化銅、（１価および■価）、塩基
性炭酸銅（１価および■価）および炭酸鋼等が多用され
る。また、グリシン銅錯体、スレオニン銅錯体等の銅と
アミノ酸との錯化合物も用いられる。The method of the present invention involves reacting glycine and acetaldehyde in the presence of a copper compound, and the copper compound is not particularly limited, but a basic copper salt is preferred. As the basic copper salt, copper hydroxide, (monovalent and ■valent), basic copper carbonate (monovalent and ■valent), carbonated steel, etc. are often used. Further, complex compounds of copper and amino acids such as glycine copper complex and threonine copper complex are also used.

グリシンに対する銅化合物の使用量は、グリシン１モル
に著し銅化合物０゜５七功１当量に相当するので、銅化
合物はＯ６５七し以下を用いる。銅化合物の最適使用量
は、同じくグｌＪ７／１％に対し、０．２５〜飢００１
モ／ｋ。The amount of copper compound to be used relative to glycine is equivalent to 1 equivalent of copper compound 0.5 7.0% per mole of glycine, so the copper compound used is less than 0.65 7. The optimum amount of copper compound to be used is 0.25 to 0.001% for 7/1%
Mo/k.

特に、０．２−０．０２伏の範囲が好ましい。銅化合物
の量が上記範囲より多ければ、反応後の除銅操作が繁雑
になり、一方、上記範囲より少なければ、除銅操作は容
易となるものの、反応時間の延長等による副反応の増加
等の結果を伴うので好ましくない。In particular, a range of 0.2-0.02 is preferred. If the amount of the copper compound is greater than the above range, the copper removal operation after the reaction will be complicated, while if it is less than the above range, the copper removal operation will be easy, but side reactions will increase due to extension of the reaction time, etc. This is not desirable because it has the following consequences.

グリシンとアセトアルデヒドを反応させる際のグリシン
とアセトアルデヒドとのモル比は、グリシン１モルに対
し、アセトアルデヒド１モル以上、通常は１．２〜５モ
ルの範囲が多用される。The molar ratio of glycine and acetaldehyde when reacting glycine and acetaldehyde is often 1 mol or more, usually 1.2 to 5 mol, of acetaldehyde per 1 mol of glycine.

本発明の方法では、グリシンとアセトアルデヒドとを反
応させる際に、さらに、アルカリ物質の共存下に反応を
実施させることを特徴とするもので、用いるアルカリ物
質は苛性ソーダ等のアルカリ金属水酸化物である。炭酸
ソーダ等のアルカリ金属炭酸塩が、従来、当量の銅化合
物を用いて、反応させる際に多用されてきたが、銅化合
物を触媒量で反応させる本発明の方法においては、アル
カリ金属炭酸塩を用い、ると、収率が、アルカリ金属水
酸化物を用いた場合に比較して劣る。更に、本発明の方
法でアルカリ金属水酸化物のかわりにアルカリ金属炭酸
塩を用いると、着色物質の生成が多く、生成物の後処理
工程で、活性炭の使用量が増加する等の欠点も出てくる
。本発明の方法に於けるアルカリ物質、すなわちアルカ
リ金属水酸化物、の使用量は、グリシンに対して、０．
５〜２当量であり、特に０．８〜１．２当量の範囲が好
ましい。アルカリ金属水酸化物の使用量が上記範囲外で
は、収率が低下したり、あるいは、着色物質の生成が増
加する等の好ましくない結果となる。The method of the present invention is characterized in that when reacting glycine and acetaldehyde, the reaction is further carried out in the presence of an alkaline substance, and the alkaline substance used is an alkali metal hydroxide such as caustic soda. . Conventionally, alkali metal carbonates such as soda carbonate have been frequently used in reactions using equivalent amounts of copper compounds, but in the method of the present invention in which copper compounds are reacted in catalytic amounts, alkali metal carbonates such as When used, the yield is inferior to when using an alkali metal hydroxide. Furthermore, when an alkali metal carbonate is used instead of an alkali metal hydroxide in the method of the present invention, there are also drawbacks such as a large amount of colored substances being produced and an increased amount of activated carbon being used in the post-treatment process of the product. It's coming. In the method of the present invention, the amount of the alkaline substance, ie, the alkali metal hydroxide, used is 0.000% relative to glycine.
The amount is 5 to 2 equivalents, particularly preferably 0.8 to 1.2 equivalents. If the amount of alkali metal hydroxide used is outside the above range, unfavorable results such as a decrease in yield or an increase in the production of colored substances will occur.

本発明の方法を実施するには、反応物質を適当な溶媒に
溶解または懸濁させて行なう。溶媒としては、水が多用
されるが、水と低級アルコールとの混合溶媒で反応を実
施してもよい。The method of the invention is carried out by dissolving or suspending the reactants in a suitable solvent. Water is often used as a solvent, but the reaction may also be carried out using a mixed solvent of water and a lower alcohol.

溶媒中に仕込む反応物質の濃度は、グリシン濃度で示せ
ば、１〜４Ｑｗｔ％、特に１０〜３０ｗｔ％の範囲が適
当である。グリシンとアセトアルデヒド、アルカリ物質
および銅化合物を初めから仕込んで反応に供してもよい
が、通常は反応の進行にあわせて、アセトアルデヒドを
逐時添加する方法が多用される。The concentration of the reactant charged in the solvent is suitably in the range of 1 to 4 Qwt%, especially 10 to 30 wt%, expressed as glycine concentration. Although glycine, acetaldehyde, an alkali substance, and a copper compound may be charged from the beginning and subjected to the reaction, a method in which acetaldehyde is added sequentially as the reaction progresses is often used.

本発明を実施する際の反応温度は、室温乃至１００°Ｃ
で、特に室温乃至７０℃の範囲が適当である。反応を完
結させるに要する時間は、反応温度、用いる銅化合物の
量等により変化するが、パッチ式の場合で例示すれば、
２０分乃至２０時間である。The reaction temperature when carrying out the present invention is room temperature to 100°C.
In particular, a temperature range of room temperature to 70°C is suitable. The time required to complete the reaction varies depending on the reaction temperature, the amount of copper compound used, etc., but in the case of a patch method, for example,
The duration ranges from 20 minutes to 20 hours.

反応終了後、反応液に硫化水素ガスを通じ、触媒として
用いた銅化合物を硫化銅として沈殿除去するか、あるい
は、イオン交換樹脂を充填したカラムを通堝させて除銅
操作を行なう９本発明の方法に於いては、用いる銅化合
物が、触媒量であるため、従来法に比較して銅の除去は
、非常に容易である。除銅後の水溶液を濃縮後、アルコ
ールまたはアセトン等の有機溶媒を加えて、冷却放置す
れば、ヒドロキシアミノ酪酸の結晶が析出する。After completion of the reaction, hydrogen sulfide gas is passed through the reaction solution to precipitate and remove the copper compound used as a catalyst as copper sulfide, or copper removal is performed by passing it through a column filled with an ion exchange resin. In this method, since the copper compound used is in a catalytic amount, copper can be removed much more easily than in conventional methods. After concentrating the aqueous solution after copper removal, an organic solvent such as alcohol or acetone is added and the solution is left to cool to precipitate crystals of hydroxyaminobutyric acid.

以下、実施例により本発明を説明する。The present invention will be explained below with reference to Examples.

実施例−１ グリシン１５ｇ、塩基性炭酸銅３゜８ｇ、苛性ソーダ８
りを水１００　ｃｃに溶解懸濁せしめ、５０℃で攪拌し
た。これに８０％アセトアルデヒド水溶液２０りを２０
分間で滴下した。滴下終了後、更に６０分間反応を続行
した。Example-1 15 g of glycine, 3.8 g of basic copper carbonate, 8 g of caustic soda
The solution was dissolved and suspended in 100 cc of water and stirred at 50°C. Add 20 g of 80% acetaldehyde aqueous solution to this.
It was dripped in minutes. After the dropwise addition was completed, the reaction was continued for an additional 60 minutes.

反応終了後、反応液を塩酸で微酸性にし過剰のアルデヒ
ドを減圧下に除去し、イミノジ酢酸型のキレート樹脂（
バイエル社製Ｌｅｗａｔｉｔ　ＴＰ−２０７型イオン交
換樹脂）を通過させて除銅した。除銅後の反応液は殆ん
ど無色澄明であり、着色物質の生成は、無視し得る程度
であり、活性炭による脱色操作は必要でなかった。除銅
後の反応液を高速液体クロマトグラフィーで定量したと
ころ、グリシンの転化率９７％、ヒドロキシアミノ酪酸
への選択率９０１１％でもった。また、ＮＭＲの測定結
果から、生成物はβ−ヒドロキシ−α−アミノ酪酸と同
定された。ＮＭＲの積分値からトレオ体とアロ体の取得
比率は、７５対２５でもった。After the reaction was completed, the reaction solution was made slightly acidic with hydrochloric acid, excess aldehyde was removed under reduced pressure, and iminodiacetic acid type chelate resin (
Copper was removed by passing through Lewatit TP-207 type ion exchange resin (manufactured by Bayer). The reaction solution after copper removal was almost clear and colorless, and the generation of colored substances was negligible, and no decoloring operation using activated carbon was necessary. When the reaction solution after copper removal was quantified by high performance liquid chromatography, the conversion rate of glycine was 97% and the selectivity to hydroxyaminobutyric acid was 9011%. Further, from the NMR measurement results, the product was identified as β-hydroxy-α-aminobutyric acid. The ratio of threo isomer to allo isomer obtained from the NMR integral value was 75:25.

比較例−１ 実施例−１と同じ反応条件で用いる塩基性炭酸銅の量を
１２ｇ（グリシンに対し当量）に増加し、反応を実施し
た。Comparative Example-1 The reaction was carried out under the same reaction conditions as in Example-1, with the amount of basic copper carbonate used increased to 12 g (equivalent to glycine).

反応終了後実施例１と同様の処理を行ない生成物の分析
を行なったところ、グリシンの転化率９９％、ヒドロキ
シアミノ酪酸への選択率９１ｍａ４％であった。また、
トレオ体とアロ体の比率は７７対２３であった。After the reaction was completed, the same treatment as in Example 1 was carried out and the product was analyzed, and the conversion of glycine was 99% and the selectivity to hydroxyaminobutyric acid was 91ma4%. Also,
The ratio of threo and allo isomers was 77:23.

比較例−２ 実施例−１と同じ反応条件で用いるアルカリ物質を炭酸
ソーダ１０．６９にして、反応を実施した。Comparative Example 2 A reaction was carried out under the same reaction conditions as in Example 1, using 10.69% of sodium carbonate as the alkaline substance.

反応終了後実施例−１と同様の処理を行ない、生成物の
分析を行なった結果、グリシンの転化率８７％、ヒドロ
キシアミノ酪酸への選択率７７ｍｄ％であった。また、
スレオ体とアロ体の取得比率は７２対２８でもった。除
銅後の反応液は褐色に着色し、純品を単離するには、活
性炭による脱色操作が必要であった。After the reaction was completed, the same treatment as in Example 1 was carried out, and the product was analyzed. As a result, the conversion of glycine was 87% and the selectivity to hydroxyaminobutyric acid was 77md%. Also,
The acquisition ratio of threo and allo was 72:28. The reaction solution after copper removal was colored brown, and decolorization using activated carbon was required to isolate the pure product.

実施例−２〜５および比較例３〜４ 実施例１と同様の方法で用いる苛性ソーダの量をかえて
反応させた結果を下表に示した。Examples 2 to 5 and Comparative Examples 3 to 4 The table below shows the results of reactions conducted in the same manner as in Example 1 but with different amounts of caustic soda.

Claims (1)

【特許請求の範囲】[Claims] １）グリシンとアセトアルデヒドとを反応させて、β−
ヒドロキシ−α−アミノ酪酸を製造するに際し、グリシ
ンに対し当量以下の銅化合物およびグリシンに対し０．
５〜２当量のアルカリ金属水酸化物の存在下に反応させ
ることを特徴とするβ−ヒドロキシ−α−アミノ酪酸の
製造方法。1) By reacting glycine and acetaldehyde, β-
When producing hydroxy-α-aminobutyric acid, a copper compound of less than the equivalent amount to glycine and 0.0.
A method for producing β-hydroxy-α-aminobutyric acid, which comprises reacting in the presence of 5 to 2 equivalents of alkali metal hydroxide.