JP4395953B2 - Process for producing α-amino acid amides - Google Patents

Description

（Ｒ² およびＲ³ はＣ₁ 〜Ｃ₄ の直鎖あるいは分岐した低級アルキル基であり、それぞれ同一でも異なっても良く、また、Ｒ² およびＲ³ は結合し五員環あるいは六員環を形成しても良い）
【０００８】
Ｒ¹ ＣＨ（ＮＨ₂ ）ＣＯＮＨ₂ （３）
（Ｒ¹ は水素原子、低級アルキル基、置換低級アルキル基、シクロヘキシル基、置換シクロヘキシル基、フェニル基、置換フェニル基、ベンジル基、置換ベンジル基、複素環基および置換複素環基である）
【０００９】
【発明の実施の形態】
本発明の反応は通常、アルデヒド類とケトンのシアンヒドリン類の混合液へ触媒およびアンモニア水を添加することにより行われる。
【００１０】
一般式（１）で示されるアルデヒド類のＲ¹ の低級アルキル基には特に制限はないが、例えばメチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、sec-ブチルおよびt-ブチルなどのＣ₁ 〜Ｃ₄ の直鎖または分枝した低級アルキル基であり、複素環基としては、フリル基、ピリジル基、チアゾリル基、イミダゾリル基およびインドリル基であり、また、置換低級アルキル基、置換シクロヘキシル基、置換フェニル基、置換ベンジル基および置換複素環基のそれぞれに含まれる置換基は、例えばヒドロキシ、メトキシ、メルカプト、メチルメルカプト、アセタール、カルボキシル、カルボクサミド、ハロゲン、イミダゾリルおよびインドリルなどである。
一般式（２）で示されるケトンのシアンヒドリン類のＲ² ，Ｒ³ の低級アルキル基には特に制限はないが、例えばメチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、sec-ブチルおよびt-ブチルなどである。
本発明の一般式（３）で示されるα−アミノ酸アミド類の代表例としては、グリシンアミド、アラニンアミド、バリンアミド、ロイシンアミド、イソロイシンアミド、t-ロイシンアミド、セリンアミド、スレオニンアミド、システインアミド、シスチンアミド、メチオニンアミド、アリシンエチレンアセタールアミド、アスパラギンアミド、グルタミンアミド、フェニルグリシンアミド、フェニルアラニンアミド、チロシンアミド、トリプトファンアミドおよびヒスチジンアミドなどが挙げられる。
原料のアルデヒド類とケトンのシアンヒドリン類との比率は、アルデヒド類１モルに対してケトンのシアンヒドリン類０．５〜２モルの範囲、好ましくは１モルである。少なければ未反応アルデヒドが多く、多ければ未反応のケトンのシアンヒドリンが多くなり、経済的に好ましくない上、これらの未反応物の副反応により、得られるα−アミノ酸アミドの品質が低下する。
【００１１】
本発明で用いられるアンモニア水のアンモニア濃度は、特に限定されないが、通常は市販の２５〜２８wt％アンモニア水が用いられる。アンモニア水の使用量は、原料アルデヒド１モルに対してアンモニア１〜１０モルの範囲、好適には２〜５モルである。
【００１２】
本発明の反応は触媒を用いなくとも進行するが、反応が遅いことから触媒を用いることが好ましい。触媒としては、有機あるいは無機の強塩基性物質であればよく、実用上、例えば水酸化ナトリウム、水酸化カリウムなどのアルカリ金属水酸化物、ならびに水酸化テトラメチルアンモニウム、水酸化テトラエチルアンモニウムおよび水酸化テトラ−ｎ−プロピルアンモニウムなどの有機第四級アンモニウム化合物、および強塩基性イオン交換樹脂などが使用される。使用量は少ない方が経済的には有利であるが、少な過ぎると反応が遅いことから、原料アルデヒド１モルに対して０．００１〜０．５モルの範囲、好適には０．０１〜０．１モルである。
本発明の方法は溶媒を必要としないが、溶媒を使用することを除くものではない。
【００１３】
反応温度は、高いと生成するα−アミノ酸アミドの過剰加水分解によりα−アミノ酸の生成が増大し、このため反応系へ加えられる強塩基性物質がα−アミノ酸の塩となって消費され好ましくないことから、反応温度は比較的低温とされ、０〜２０℃が好適である。 反応時間は原料のアルデヒド類またはケトンのシアンヒドリン類の種類、触媒の種類および量、反応温度などにより異なるが、通常は１〜３０時間である。
反応で生成したα−アミノ酸アミド含有液は、反応に使用した強塩基性物質を酸で中和後、過剰のアンモニアおよび反応で副生するケトンを減圧蒸発により除去した後、そのまま、あるいは抽出等により不純物を分離精製後、アミノ酸生成反応原料として使用することができる。
【００１４】
【実施例】
以下に本発明を実施例によりさらに具体的に説明するが、本発明はこの実施例により限定されるものではない。
実施例１
撹拌機および温度計を付した５０ml三ツ口フラスコに、アセトアルデヒド４．４１ｇ（０．１００モル）およびアセトンシアンヒドリン８．５１ｇ（０．１００モル）を加え、５℃で撹拌下、水酸化ナトリウム０．０８ｇ（０．００２モル）および２８％アンモニア水１８．２ｇ（ＮＨ₃ ０．３００モル）を添加し、そのまま５℃で２０時間撹拌した。反応終了後、反応液組成を液体クロマトグラフィーで分析したところ、アラニンアミド７．８４ｇが生成していた。
この結果は、仕込アセトアルデヒドに対するアラニンアミドの収率８９％である。
【００１５】
実施例２
実施例１と同様な反応器に、イソブチルアルデヒド７．２１ｇ（０．１００モル）およびメチルエチルケトンシアンヒドリン９．９１ｇ（０．１００モル）を加え、５℃で撹拌下、水酸化カリウム０．１７ｇ（０．００３モル）および２８％アンモニア水３０．４ｇ（ＮＨ₃ ０．５００モル）を添加し、そのまま５℃で１０時間撹拌した。反応終了後、反応液組成を液体クロマトグラフィーで分析したところ、バリンアミド１０．５ｇが生成していた。
この結果は、仕込イソブチルアルデヒドに対するバリンアミドの収率９０％である。
【００１６】
実施例３
実施例１と同様な反応器に、ベンズアルデヒド１０．６１ｇ（０．１００モル）およびシクロヘキサノンシアンヒドリン１２．５２ｇ（０．１００モル）を加え、１５℃で撹拌下、１０％水酸化テトラメチルアンモニウム／ＭｅＯＨ溶液４．５６ｇ（０．００５モル）および２８％アンモニア水１８．２ｇ（ＮＨ₃ ０．３００モル）を添加し、そのまま１５℃で３０時間撹拌した。反応終了後、反応液組成を液体クロマトグラフィーで分析したところ、フェニルグリシンアミド１２．５ｇが生成していた。
この結果は、仕込ベンズアルデヒドに対するフェニルグリシンアミドの収率８３％である。
【００１７】
実施例４〜１０
原料アルデヒドに各種アルデヒドを使用した以外は実施例１と同様にして反応を行った。結果を表１に示す。
【００１８】

【００１９】
比較例１
触媒を使用しないで、反応時間を３０時間とした以外は、実施例１と同様にして反応を行った。反応終了後、反応液組成を液体クロマトグラフィーで分析したところ、アラニンアミド５．２９ｇが生成していた。
この結果は、仕込アセトアルデヒドに対するアラニンアミドの収率６０％である。
【００２０】
【発明の効果】
本発明の方法によれば、アルデヒド類とケトンのシアンヒドリン類とアンモニア水からα−アミノ酸アミド類が、アミノニトリル合成工程を必要とすることなく簡略化された方法にて、容易に高収率で製造できる。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a method for producing α-amino acid amides. α-amino acid amides are extremely important substances as intermediates for various industrial chemicals, and as raw materials for producing α-amino acids important as agricultural chemicals, cosmetics, feed additives, food additives, and pharmaceuticals.
[0002]
[Prior art]
As a method for producing an α-amino acid amide, a method for producing an α-amino acid amide from α-amino nitrile in the presence of a carbonyl compound has been conventionally known. For example, a method in which α-amino nitrile and a ketone are reacted in an aqueous medium at pH 11 to 14 to obtain an α-amino acid amide (Japanese Examined Patent Publication No. 59-36899), 0.05 to 1 mol of α-amino nitrile. A method of reacting a carbonyl derivative with α-amino nitrile in the presence of 0.3 mol of hydroxyl ion to obtain α-amino acid amide (Japanese Patent Laid-Open No. 53-82707), and the amount of strongly basic substance used is α -A method of obtaining an α-amino acid amide by adding a ketone to the reaction system such that the pH of the reaction solution exceeds 14 with respect to 1 mol of amino nitrile (JP-A 57-158743). ), Etc. are known.
[0003]
[Problems to be solved by the invention]
All the conventional α-amino acid amide production methods use α-amino nitrile as the raw material, but α-amino nitrile is reacted with ammonia after synthesizing cyanohydrin from hydrogen cyanide, aldehyde and ammonia, or from hydrogen cyanide and aldehyde. , And the like. However, aminonitriles are extremely unstable and have a problem in handling that they gradually turn reddish brown even when stored at room temperature or lower, and eventually turn black to form a tar-like product.
An object of the present invention is to provide a simplified method for producing α-amino acid amides which does not require an α-amino nitrile synthesis step having these problems.
[0004]
[Means for Solving the Problems]
As a result of earnest studies on the production method of α-amino acid amides having the above-mentioned problems, the present inventor made an α-amino nitrile synthesis step by reacting aldehydes with ketone cyanohydrins and aqueous ammonia. The inventors have found that α-amino acid amides can be easily obtained in a high yield without necessity, and have reached the present invention.
[0005]
That is, the present invention is represented by the general formula (3), characterized by reacting an aldehyde represented by the general formula (1), a cyanohydrin of a ketone represented by the general formula (2), and aqueous ammonia. The method for producing α-amino acid amides is preferably a catalyst, and an organic or inorganic strong basic substance is used as the catalyst.
[0006]
R ¹ CHO (1)
(R ¹ is a hydrogen atom, a lower alkyl group, a substituted lower alkyl group, a cyclohexyl group, a substituted cyclohexyl group, a phenyl group, a substituted phenyl group, a benzyl group, a substituted benzyl group, a heterocyclic group, and a substituted heterocyclic group)
[0007]
[Chemical formula 2]

(R ² and R ³ are C _{1 to} C ₄ linear or branched lower alkyl groups, which may be the same or different, and R ² and R ³ are bonded to form a 5-membered or 6-membered ring. May be formed)
[0008]
R ¹ CH (NH ₂ ) CONH ₂ (3)
(R ¹ is a hydrogen atom, a lower alkyl group, a substituted lower alkyl group, a cyclohexyl group, a substituted cyclohexyl group, a phenyl group, a substituted phenyl group, a benzyl group, a substituted benzyl group, a heterocyclic group, and a substituted heterocyclic group)
[0009]
DETAILED DESCRIPTION OF THE INVENTION
The reaction of the present invention is usually carried out by adding a catalyst and aqueous ammonia to a mixture of aldehydes and ketone cyanohydrins.
[0010]
The lower alkyl group of R ¹ of the aldehyde represented by the general formula (1) is not particularly limited, but for example, C ₁ -such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and t-butyl C ₄ linear or branched lower alkyl group, and heterocyclic groups include furyl group, pyridyl group, thiazolyl group, imidazolyl group and indolyl group, and substituted lower alkyl group, substituted cyclohexyl group, substituted Examples of the substituent contained in each of the phenyl group, substituted benzyl group and substituted heterocyclic group include hydroxy, methoxy, mercapto, methyl mercapto, acetal, carboxyl, carboxamide, halogen, imidazolyl and indolyl.
The lower alkyl group of R ² and R ³ of the cyanohydrin of the ketone represented by the general formula (2) is not particularly limited, but for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and t-butyl Etc.
Representative examples of the α-amino acid amides represented by the general formula (3) of the present invention include glycine amide, alanine amide, valine amide, leucine amide, isoleucine amide, t-leucine amide, serine amide, threonine amide, cysteine amide, cystine. Examples include amide, methionine amide, allicin ethylene acetal amide, asparagine amide, glutamine amide, phenyl glycinamide, phenylalanine amide, tyrosine amide, tryptophan amide and histidine amide.
The ratio of the raw material aldehydes to the ketone cyanohydrins is in the range of 0.5 to 2 moles, preferably 1 mole, of the ketone cyanohydrins to 1 mole of the aldehydes. If the amount is small, the amount of unreacted aldehyde increases, and if the amount is large, the amount of unreacted ketone cyanohydrin increases. This is not economically preferable, and the side reaction of these unreacted products lowers the quality of the α-amino acid amide obtained.
[0011]
The ammonia concentration of the ammonia water used in the present invention is not particularly limited, but usually a commercially available 25 to 28 wt% ammonia water is used. The amount of ammonia water used is in the range of 1 to 10 moles of ammonia, preferably 2 to 5 moles per mole of raw aldehyde.
[0012]
Although the reaction of the present invention proceeds without using a catalyst, it is preferable to use a catalyst because the reaction is slow. The catalyst may be an organic or inorganic strong basic substance. In practice, for example, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, tetramethylammonium hydroxide, tetraethylammonium hydroxide and hydroxide Organic quaternary ammonium compounds such as tetra-n-propylammonium and strong basic ion exchange resins are used. A smaller amount is economically advantageous, but if it is too small, the reaction is slow. Therefore, it is in the range of 0.001 to 0.5 moles, preferably 0.01 to 0 moles per mole of raw material aldehyde. .1 mole.
The method of the present invention does not require a solvent, but does not exclude the use of a solvent.
[0013]
When the reaction temperature is high, the production of α-amino acid increases due to excessive hydrolysis of the α-amino acid amide that is produced, and therefore, a strongly basic substance added to the reaction system is consumed as a salt of α-amino acid, which is not preferred Therefore, the reaction temperature is relatively low, and 0 to 20 ° C. is preferable. The reaction time varies depending on the type of raw material aldehyde or ketone cyanohydrin, the type and amount of catalyst, the reaction temperature, etc., but is usually 1 to 30 hours.
The α-amino acid amide-containing liquid produced by the reaction is neutralized with an acid after the strong basic substance used in the reaction is removed, excess ammonia and ketone produced as a by-product in the reaction are removed by evaporation under reduced pressure, or is directly extracted. After separating and purifying the impurities, it can be used as an amino acid production reaction raw material.
[0014]
【Example】
The present invention will be described more specifically with reference to the following examples. However, the present invention is not limited to the examples.
Example 1
To a 50 ml three-necked flask equipped with a stirrer and a thermometer, 4.41 g (0.100 mol) of acetaldehyde and 8.51 g (0.100 mol) of acetone cyanohydrin were added. 0.08 g (0.002 mol) and 28% aqueous ammonia 18.2 g (NH ₃ 0.300 mol) were added, and the mixture was stirred at 5 ° C. for 20 hours. After completion of the reaction, the reaction solution composition was analyzed by liquid chromatography. As a result, 7.84 g of alaninamide was produced.
This result is an alaninamide yield of 89% with respect to the charged acetaldehyde.
[0015]
Example 2
To a reactor similar to that of Example 1, 7.21 g (0.100 mol) of isobutyraldehyde and 9.91 g (0.100 mol) of methyl ethyl ketone cyanohydrin were added, and 0.17 g of potassium hydroxide was stirred at 5 ° C. (0.003 mol) and 30.4 g of 28% aqueous ammonia (NH ₃ 0.500 mol) were added and the mixture was stirred at 5 ° C. for 10 hours. After completion of the reaction, the composition of the reaction solution was analyzed by liquid chromatography. As a result, 10.5 g of valinamide was produced.
This result is a valinamide yield of 90% based on the charged isobutyraldehyde.
[0016]
Example 3
To the same reactor as in Example 1, 10.61 g (0.100 mol) of benzaldehyde and 12.52 g (0.100 mol) of cyclohexanone cyanohydrin were added with stirring at 15 ° C., 10% tetramethylammonium hydroxide. / MeOH solution 4.56 g (0.005 mol) and 28% aqueous ammonia 18.2 g (NH ₃ 0.300 mol) were added, and the mixture was stirred at 15 ° C. for 30 hours. After completion of the reaction, the reaction solution composition was analyzed by liquid chromatography. As a result, 12.5 g of phenylglycinamide was produced.
This result is a 83% yield of phenylglycinamide based on the charged benzaldehyde.
[0017]
Examples 4-10
The reaction was performed in the same manner as in Example 1 except that various aldehydes were used as the raw material aldehyde. The results are shown in Table 1.
[0018]

[0019]
Comparative Example 1
The reaction was carried out in the same manner as in Example 1 except that the catalyst was not used and the reaction time was 30 hours. After completion of the reaction, the composition of the reaction solution was analyzed by liquid chromatography. As a result, 5.29 g of alaninamide was produced.
This result is a 60% yield of alaninamide relative to the charged acetaldehyde.
[0020]
【The invention's effect】
According to the method of the present invention, α-amino acid amides from aldehydes, cyanohydrins of ketones and aqueous ammonia can be easily obtained in a high yield by a simplified method without requiring an amino nitrile synthesis step. Can be manufactured.

Claims (2)

Was added the general formula (1) aldehyde represented by the general formula (2) with the ketone catalyst and ammonia water to a mixture of cyanohydrins such as represented, characterized by reacting at 0 to 20 ° C., A method for producing an α-amino acid amide represented by the general formula (3).
R ¹ CHO (1)
(R ¹ is a hydrogen atom, a lower alkyl group, a substituted lower alkyl group, a cyclohexyl group, a substituted cyclohexyl group, a phenyl group, a substituted phenyl group, a benzyl group, a substituted benzyl group, a heterocyclic group, and a substituted heterocyclic group)

(R ² and R ³ are C ₁ -C ₄ linear or branched lower alkyl groups which may be the same or different, and R ² and R ³ are bonded to form a 5-membered or 6-membered ring. May be formed)
R ¹ CH (NH ₂ ) CONH ₂ (3)
(R ¹ is a hydrogen atom, a lower alkyl group, a substituted lower alkyl group, a cyclohexyl group, a substituted cyclohexyl group, a phenyl group, a substituted phenyl group, a benzyl group, a substituted benzyl group, a heterocyclic group, and a substituted heterocyclic group) The production method according to claim 1, wherein an organic or inorganic strong basic substance is used as the catalyst.