JP2005035904A - Method for producing 2-hydroxycarboxylic acid - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing 2-hydroxycarboxylic acid, by which the 2-hydroxycarboxylic acid can profitably be produced from an easily available raw material with a general purpose reactor. <P>SOLUTION: The 2-hydroxycarboxylic acid can be produced by adding an alkali aqueous solution to a 2-chlorocarboxylic acid at a pH 9 or lower. Thereby, the 2-hydroxycarboxylic acid can be produced in a high yield with an ordinary glass-lined reaction facility. The obtained 2-hydroxycarboxylic acid can be esterified and oxidized to produce the 2-oxocarboxylate which can be used as an intermediate for medicines. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

【０００７】
（ここで、Ｒ^１は炭素数１〜４のアルキル基を示す。）で表されるクロルカルボン酸を、アルカリ水溶液でｐＨを９以下に保ちながら反応させることで、一般式（２）
【０００８】
【化６】

【０００９】
（ここで、Ｒ^１は前記と同様）で表される２−ヒドロキシカルボン酸を製造する方法である。さらには、一般式（２）をエステル化して一般式（３）
【００１０】
【化７】

【００１１】
（ここで、Ｒ^１は前記と同様、Ｒ^２は炭素数１〜４のアルキル基を示す。）で表される２−ヒドロキシカルボン酸エステルを製造し、次いで次亜塩素酸で酸化して一般式（４）
【００１２】
【化８】

【００１３】
（ここで、Ｒ^１、Ｒ^２は前記と同様）で表される２−オキソカルボン酸エステルを製造する方法である。一般に、ハロゲン化物をアルカリ、例えば水酸化ナトリウム水溶液と加熱して、クロル基を水酸基に変換する方法は良く知られているが、一般式（１）の２−クロルカルボン酸の場合には、ナトリウム塩を加熱するとオリゴマーやポリマーが生成する（Ｌｉｅｂｉｇｓ Ａｎｎａｌｅｎ／Ｒｅｃｕｅｉｌ（１９９７）、（１）、８１−８５）ことも知られている。また、過剰の水酸化ナトリウムを使用すると脱塩酸反応が進行し、不純物が多く生成し、収率が低下する。脱塩酸を抑制する目的で反応温度８０℃以下に低下させると、反応の進行は極端に低下するために、工業的製造法としては採用できない。
【００１４】
【化９】

【００１５】
設備面では、強アルカリ性の反応液はガラスを腐食することから、グラスライニングの反応設備が使用できず、また、原料の２−クロルカルボン酸中には分解生成物の塩酸が混入していることが多いために、ＳＵＳの汎用装置は使用できず、特殊な生産設備が必要となる。このように生産設備の制約も多いことから、２−クロルカルボン酸を原料とする２−ヒドロキシカルボン酸の工業的製造法は知られていなかった。
【００１６】
本発明のｐＨで実施すると、驚くべきことに非常に高い選択率でクロル基が水酸基に変換できることを見出し、本発明を完成させた。尚、本発明を実施するには、原料の２−クロルカルボン酸に耐性のあるグラスライニングの汎用製造設備が一貫して使用できるので、工業的な製造法といえる。
【００１７】
【発明の実施の形態】
本発明を具体的に述べる。原料の一般式（１）で表される２−クロルカルボン酸としては、２−クロル酪酸、２−クロル吉草酸、２−クロルヘキサン酸、２−クロルヘプタン酸等が挙げられるが、好ましくは２−クロル酪酸である。これらの２−クロルカルボン酸は化学純度が９０％以上のものが好ましいが、カルボン酸をクロル化して得た反応液の濃縮物をそのまま使用することもできる。また、光学活性な２−クロルカルボン酸も同様に使用することができる。
【００１８】
反応は２−クロルカルボン酸をそのまま、あるいは溶媒で希釈して実施する。
希釈溶媒としては水、メタノール、エタノール等のアルコール類、あるいはこれらの混合物が挙げられるが、好ましくは水である。
【００１９】
使用するアルカリとしては、水酸化ナトリウム、水酸化カリウム、水酸化リチウム等のアルカリ金属水酸化物、炭酸水素ナトリウム、炭酸水素カリウム、炭酸水素リチウム等のアルカリ金属炭酸水素塩、炭酸ナトリウム、炭酸カリウム、炭酸リチウム等のアルカリ金属炭酸塩、水酸化カルシウム、水酸化マグネシウム等のアルカリ土類金属水酸化物が挙げられるが、好ましくは水酸化ナトリウム、水酸化カリウム、水酸化リチウム等のアルカリ金属水酸化物、炭酸水素ナトリウム、炭酸水素カリウム、炭酸水素リチウム等のアルカリ金属炭酸水素塩、炭酸ナトリウム、炭酸カリウム、炭酸リチウム等のアルカリ金属炭酸塩であり、特に好ましくは水酸化ナトリウム、水酸化カリウム、炭酸水素ナトリウム、炭酸水素カリウム、炭酸ナトリウム、炭酸カリウムである。これらは水溶液や固体のままで反応に供給することもできるが、水溶液として滴下する方がｐＨ管理も容易であり、好ましい。アルカリ水溶液の濃度は特に規定しないが、５〜４８％水溶液が使用できる。２−クロルカルボン酸を希釈しないで使用する場合には、急激な反応を抑えるためにもアルカリ水溶液の濃度は薄い方が好ましいが、２−クロルカルボン酸を予め溶媒で希釈してある場合には、反応液濃度を実用的な濃度にするために添加するアルカリ水溶液の濃度は濃い方が好ましい。反応温度は８０℃以上であるが、好ましくは８５℃以上、さらに好ましくは９０℃以上である。温度が低いと反応が遅く、工業生産する上で好ましくない。
【００２０】
反応時間は２−クロルカルボン酸やアルカリの種類、反応液濃度、反応温度によって異なるが、通常は１〜２０時間である。
【００２１】
反応方法は、２−クロルカルボン酸をそのまま、あるいは溶媒に希釈して反応装置に仕込み、所定温度で攪拌しながら、アルカリをｐＨが９以下となるように、好ましくはｐＨ６〜９を維持するように滴下する方法が採用できる。
【００２２】
反応終了後、生成物の２−ヒドロキシカルボン酸を単離する。単離法は通常の方法が採用できる。例えば、（ｉ）室温まで冷却してから硫酸、塩酸等の無機酸を添加し、２−ヒドロキシカルボン酸を遊離状態にした後、有機溶媒で抽出する方法、（ｉｉ）カルシウム塩として水溶液から濾過分離し、改めて水中で解塩し、遊離した２−ヒドロキシカルボン酸を回収する方法等があり、いずれの方法も採用する事ができる。
【００２３】
かくして得られた２−ヒドロキシカルボン酸を炭素数１〜４のアルコールと反応させて２−ヒドロキシカルボン酸エステルを製造する。エステル化反応は硫酸等の酸触媒共存下、２−ヒドロキシカルボン酸とアルコールを加熱する通常の方法が採用できる。ここで製造した２−ヒドロキシカルボン酸エステルを蒸留等で精製するか、あるいは濃縮した粗体を次工程の酸化反応に供する。
【００２４】
２−ヒドロキシカルボン酸エステルを酸化して２−オキソカルボン酸エステルを製造する。酸化反応はビス（２，２，６，６−テトラメチル−４−ピペリジル）セバケート等のヒンダード２級アミン存在下で次亜塩素酸による酸化法が採用できる。酸化剤として使用する次亜塩素酸はアルカリ金属塩水溶液を使用するのが好ましい。反応液は、予め、または反応の途中で酸を加えて反応液のｐＨを６以下に保ちながら、次亜塩素酸はアルカリ金属塩水溶液を滴下する方法が好ましい。
【００２５】
かくして得られた２−オキソカルボン酸エステルは通常の方法で単離する。例えば、酸性水溶液から有機溶媒で抽出した後、濃縮・蒸留することにより、高純度の２−オキソカルボン酸エステルが得られる。
【００２６】
【実施例】
以下、実施例を挙げて本発明を詳細に説明するが、本発明はこれらに限定されるものではない。
【００２７】
なお、実施例において、反応液の組成分析や蒸留品の化学純度分析はＨＰＬＣ、ＧＣのａｒｅａ％で算出した。分析条件は対象物によって異なるので一律には記載できないが、代表例として２−クロル酪酸、２−ヒドロキシ酪酸のＨＰＬＣ分析条件を記載する。
ＨＰＬＣ分析条件

【００２８】
参考例１ ２−クロル酪酸の製造法
攪拌機、ジムロートコンデンサー、温度計、塩素ガス導入器を装着した１ｌの４口フラスコに、酪酸４４１ｇ（５．０モル）と無水酪酸８０ｇ（０．５モル）を仕込み、１１５〜１２５℃を保ちながら塩素ガスを１２ｌ／ｈｒ導入し、１２時間反応した。反応終了後、水９ｇを添加して８０〜９０℃で３０分間攪拌して２−クロル酪酸反応液７１６ｇ得た。化学純度は９５．１％であり、多種類の不純物が検出されたが、これを原料とした。
【００２９】
実施例１
攪拌機、ジムロートコンデンサー、温度計、塩素ガス導入器を装着した１ｌの４口フラスコ（ハリオガラス 柴田ハリオ製）に、参考例で製造した２−クロル酪酸２００．３ｇ（１．５５モル）を仕込み、６０℃で攪拌した。ｐＨを７以下に保ちながら２５％水酸化ナトリウム水溶液を滴下し、反応液温度を１００℃まで昇温させた。１００℃にて、ｐＨを７〜９に保ちながら２５％水酸化ナトリウム水溶液を約６時間で滴下した。添加した２５％水酸化ナトリウム水溶液は５０５ｇ（３．１６モル）であった。
【００３０】
反応終了後、攪拌しながら室温まで冷却して分析した結果、２−ヒドロキシ酪酸の収率は９３％であり、脱塩酸による副生物クロトン酸は０．３％であった。また、ガラス製のフラスコは全く失透しなかった。
【００３１】
実施例２
実施例１と同様にして、ｐＨを６〜７に保ちながら２５％水酸化ナトリウム水溶液を約６時間で滴下した。添加した２５％水酸化ナトリウム水溶液は４８２ｇ（３．０１モル）であった。同様にして反応液を分析した結果、２−ヒドロキシ酪酸の収率は８４％、未反応２−クロル酪酸は約７％であり、脱塩酸による副生物クロトン酸は０．３％であった。また、ガラス製のフラスコは全く失透しなかった。
【００３２】
比較例１
攪拌機、温度計、ジムロートコンデンサー、滴下ロートを装着した１ｌの４口フラスコ（ハリオガラス 柴田ハリオ製）に、２−クロロ酪酸２００．３ｇ（１．５５モル 化学純度９５．１％）を仕込み、６０℃で攪拌した。２５％水酸化ナトリウム水溶液５１５ｇ（３．２２モル）を滴下しながら１００℃に昇温し、約１．５時間で全量を滴下した。反応液のｐＨは１０以上であった。約１００℃でさらに７時間攪拌を継続したのち、室温まで冷却した。反応液のｐＨは１２．６であり、分析したところ、２−ヒドロキシ酪酸の収率は８８％であったが、フラスコは失透していた。
【００３３】
比較例２
比較例１と同様にして、反応温度を７０〜８０℃で実施したところ、２−クロル酪酸の転化率を８０％以上にするために２０時間を要した。反応液を分析した結果、２−ヒドロキシ酪酸の収率は７７％であり、脱塩酸生成物であるクロトン酸が約７．５％生成していた。
実施例３
実施例１と同様にして、２−ヒドロキシ酪酸１５０．０ｇ（１．４４モル）を含む反応液を得た。室温から３５℃で攪拌しながら９５％硫酸８８ｇ（０．８５モル）を約１時間で滴下したのち、メチルエチルケトン４００ｇで２回抽出した。抽出した有機層を濃縮し、２−ヒドロキシ酪酸１４４．０ｇ（１．３８モル）を含む濃縮液１８０ｇを得た。
【００３４】
攪拌機、温度計、ジムロートコンデンサーを装着した１ｌの３口フラスコに、濃縮液１８０ｇとメタノール４４１．６ｇ（１３．８モル）、および９８％硫酸１．６ｇを仕込み、攪拌しながら約２時間加熱還流した。室温まで冷却後、炭酸ナトリウム１．７ｇを添加して約１０分攪拌した。
【００３５】
ジムロートコンデンサーを５段の精留塔に置き換え、常圧でメタノールを回収したのち減圧蒸留に切り替え、７０〜７４℃／４．０〜０．７ｋＰａの留分として２−ヒドロキシ酪酸メチル１３９．４ｇ（１．１８モル、化学純度９７％）を得た。
【００３６】
攪拌機、温度計、ｐＨセンサー、滴下ロートを装着した５００ｍｌの４口フラスコに、前記２−ヒドロキシ酪酸メチル２４．４ｇ（０．２モル）、酢酸エチル９０ｇ、サノールＬＳ−７７０（三共製）から調整した酸化触媒調整液０．４ｇ（参考例２に記載）、水２．３ｇ、１２ｗｔ％塩酸水溶液２．４ｇを仕込み、１０〜１５℃に冷却しながら攪拌した。１３％次亜塩素酸ナトリウム水溶液１２０．０ｇ（日本軽金属製）を５時間かけて添加し、さらに２０〜２５℃で２時間攪拌した。この間、反応液のｐＨを３〜４．５保持するために１２ｗｔ％塩酸水溶液を添加した。反応終了後、反応液に炭酸ナトリウムを添加してｐＨを６〜６．５に調整したのち、酢酸エチル層を分液した。さらに水層を９０ｇの酢酸エチルで抽出し、両酢酸エチル層を混合し、減圧濃縮して２−オキソ酪酸メチル２２．０ｇ（０．１９モル）を含む濃縮液２８ｇを得た。
【００３７】
約５段の精留塔を装着した蒸留装置に前記濃縮液２８ｇとビスフェノールＡタイプのエポキシ化合物ＹＤ−１２８ ０．２ｇ（東都化成製）を仕込み、減圧蒸留し、７０〜７５℃／５．３〜２．７ｋＰａの留分として２−オキソ酪酸メチル２０．１ｇ（０．１７モル、化学純度９８％）を得た。
【００３８】
参考例２ サノールＬＳ−７７０（三共製）から酸化触媒調整液の製造法
攪拌機、温度計、ジムロートコンデンサー、滴下ロートを装着した５００ｍｌの４口フラスコに、酢酸エチル２２５ｇとビス（２，２，６，６−テトラメチル−４−ピペリジル）セバケート（サノールＬＳ−７７０ 三共製）３５ｇを仕込み、常温で攪拌して溶解させた。次いで、攪拌しながら３５ｗｔ％過酸化水素水３５ｇを添加し、攪拌しながら６０℃まで昇温して２０時間攪拌した。反応液を静置して２層分離させ、下層の水層を除去した。上層の酢酸エチル層を２５ｇの水で洗浄し、触媒調整液２４７ｇ得た。
【００３９】
【発明の効果】
本発明によれば、通常のグラスライニングの反応設備を使用して２−ヒドロキシカルボン酸を高収率で製造することができる。得られた２−ヒドロキシカルボン酸は医薬中間体として有用な２−オキソカルボン酸エステルの製造原料として使用することができる。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a process for producing 2-hydroxycarboxylic acid and further 2-oxocarboxylic acid ester, which are important compounds as synthetic raw materials for pharmaceuticals and agricultural chemicals.
[0002]
[Prior art]
As a general method for producing 2-hydroxycarboxylic acid, (A) a method of hydrolyzing 2-acetyloxybutyric acid nitrile (see, for example, Patent Document 1), (B) 1,2-butanediol is converted into a microorganism (Rhodococcus) Methods for oxidizing (see, for example, Patent Document 2), (C) methods for reacting butene with nitrogen tetraoxide (for example, see Patent Document 3), and the like are known.
[0003]
[Patent Document 1]
Japanese Patent Laid-Open No. 11-180928 [Patent Document 2]
Japanese Patent Laid-Open No. 2-257874 [Patent Document 3]
Japanese Patent Laid-Open No. 50-14625
[Problems to be solved by the invention]
The method for hydrolyzing 2-acetyloxybutyric acid nitrile of (A) is also an excellent method with a high reaction yield, but since it goes through a complicated process to produce a raw material, I can't say that. The method of oxidizing (B) 1,2-butanediol with a microorganism (Rhodococcus) is excellent in that it can be produced from an inexpensive raw material, but the substrate concentration is low and a long reaction time is required. It is not an industrial manufacturing method. The method of reacting nitrogen tetraoxide with butene of (C) has disadvantages as an industrial production method such that special equipment is required. Therefore, an industrially advantageous method for producing 2-hydroxycarboxylic acid from a readily available raw material using a general-purpose production apparatus has been desired.
[0005]
[Means for Solving the Problems]
As a result of intensive studies on a method for solving the above problems, the present inventors have reached the present invention. That is, the general formula (1)
[0006]
[Chemical formula 5]

[0007]
(Here, R ¹ represents an alkyl group having 1 to 4 carbon atoms.) By reacting the chlorocarboxylic acid represented by the formula (2) while maintaining the pH at 9 or less with an aqueous alkaline solution.
[0008]
[Chemical 6]

[0009]
(Where R ¹ is the same as described above). Furthermore, general formula (2) is esterified to give general formula (3)
[0010]
[Chemical 7]

[0011]
(Wherein R ¹ is the same as described above, R ² is an alkyl group having 1 to 4 carbon atoms), and the 2-hydroxycarboxylic acid ester represented by Formula (4)
[0012]
[Chemical 8]

[0013]
(Wherein R ¹ and R ² are the same as described above). In general, a method of converting a chloro group to a hydroxyl group by heating a halide with an alkali such as an aqueous sodium hydroxide solution is well known. In the case of 2-chlorocarboxylic acid of the general formula (1), sodium is used. It is also known that oligomers and polymers are formed when salts are heated (Liebigs Analen / Recueil (1997), (1), 81-85). In addition, when excess sodium hydroxide is used, the dehydrochlorination reaction proceeds, a large amount of impurities are generated, and the yield decreases. If the reaction temperature is lowered to 80 ° C. or lower for the purpose of suppressing dehydrochlorination, the progress of the reaction is extremely lowered and cannot be adopted as an industrial production method.
[0014]
[Chemical 9]

[0015]
In terms of equipment, glassy-lined reaction equipment cannot be used because strongly alkaline reaction liquids corrode glass, and the decomposition product hydrochloric acid is mixed in 2-chlorocarboxylic acid as a raw material. For this reason, SUS general-purpose devices cannot be used, and special production facilities are required. Thus, since there are many restrictions on production facilities, an industrial production method of 2-hydroxycarboxylic acid using 2-chlorocarboxylic acid as a raw material has not been known.
[0016]
Surprisingly, it has been found that when carried out at the pH of the present invention, a chloro group can be converted to a hydroxyl group with very high selectivity, and the present invention has been completed. In order to carry out the present invention, it can be said that it is an industrial production method because general-purpose production equipment for glass lining resistant to 2-chlorocarboxylic acid as a raw material can be used consistently.
[0017]
DETAILED DESCRIPTION OF THE INVENTION
The present invention will be specifically described. Examples of the 2-chlorocarboxylic acid represented by the general formula (1) of the raw material include 2-chlorobutyric acid, 2-chlorovaleric acid, 2-chlorohexanoic acid, 2-chloroheptanoic acid, etc., preferably 2 -Chlorbutyric acid. These 2-chlorocarboxylic acids preferably have a chemical purity of 90% or more, but a concentrate of the reaction solution obtained by chlorinating the carboxylic acid can be used as it is. Moreover, optically active 2-chlorocarboxylic acid can be used similarly.
[0018]
The reaction is carried out by diluting 2-chlorocarboxylic acid as it is or with a solvent.
Examples of the diluting solvent include water, alcohols such as methanol and ethanol, or a mixture thereof, preferably water.
[0019]
Examples of the alkali used include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide, alkali metal hydrogen carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate and lithium hydrogen carbonate, sodium carbonate, potassium carbonate, Alkali metal carbonates such as lithium carbonate and alkaline earth metal hydroxides such as calcium hydroxide and magnesium hydroxide can be mentioned, but preferably alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide Alkali metal hydrogen carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate and lithium hydrogen carbonate, and alkali metal carbonates such as sodium carbonate, potassium carbonate and lithium carbonate, particularly preferably sodium hydroxide, potassium hydroxide and hydrogen carbonate Sodium, potassium bicarbonate, sodium carbonate It is a potassium carbonate. These can be supplied to the reaction in the form of an aqueous solution or solid, but dropping as an aqueous solution is preferable because pH control is easy. The concentration of the alkaline aqueous solution is not particularly limited, but a 5 to 48% aqueous solution can be used. When 2-chlorocarboxylic acid is used without diluting, it is preferable that the concentration of the alkaline aqueous solution is low in order to suppress a rapid reaction. However, when 2-chlorocarboxylic acid is previously diluted with a solvent, The concentration of the aqueous alkali solution added to make the reaction solution concentration practical is preferably higher. Although reaction temperature is 80 degreeC or more, Preferably it is 85 degreeC or more, More preferably, it is 90 degreeC or more. If the temperature is low, the reaction is slow, which is not preferable for industrial production.
[0020]
The reaction time varies depending on the type of 2-chlorocarboxylic acid and alkali, the concentration of the reaction solution, and the reaction temperature, but is usually 1 to 20 hours.
[0021]
The reaction method is such that 2-chlorocarboxylic acid is used as it is or diluted in a solvent and charged into a reaction apparatus, and while stirring at a predetermined temperature, the alkali is preferably maintained at pH 6 to 9 so that the pH is 9 or less. The method of dripping can be adopted.
[0022]
After the reaction is complete, the product 2-hydroxycarboxylic acid is isolated. A usual method can be adopted as the isolation method. For example, (i) a method in which an inorganic acid such as sulfuric acid or hydrochloric acid is added after cooling to room temperature to make 2-hydroxycarboxylic acid in a free state, followed by extraction with an organic solvent, (ii) filtration from an aqueous solution as a calcium salt There is a method of separating, re-salting in water, and recovering free 2-hydroxycarboxylic acid, and any method can be employed.
[0023]
The 2-hydroxycarboxylic acid thus obtained is reacted with an alcohol having 1 to 4 carbon atoms to produce a 2-hydroxycarboxylic acid ester. For the esterification reaction, a usual method of heating 2-hydroxycarboxylic acid and alcohol in the presence of an acid catalyst such as sulfuric acid can be employed. The 2-hydroxycarboxylic acid ester produced here is purified by distillation or the like, or the concentrated crude product is subjected to an oxidation reaction in the next step.
[0024]
2-Hydroxycarboxylic acid ester is oxidized to produce 2-oxocarboxylic acid ester. As the oxidation reaction, an oxidation method using hypochlorous acid can be employed in the presence of a hindered secondary amine such as bis (2,2,6,6-tetramethyl-4-piperidyl) sebacate. As the hypochlorous acid used as the oxidizing agent, an aqueous alkali metal salt solution is preferably used. The reaction solution is preferably added by adding an aqueous alkali metal salt solution to hypochlorous acid while keeping the pH of the reaction solution at 6 or less by adding an acid in advance or in the middle of the reaction.
[0025]
The 2-oxocarboxylic acid ester thus obtained is isolated by a conventional method. For example, high-purity 2-oxocarboxylic acid ester can be obtained by extraction from an acidic aqueous solution with an organic solvent, followed by concentration and distillation.
[0026]
【Example】
EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated in detail, this invention is not limited to these.
[0027]
In the examples, the composition analysis of the reaction solution and the chemical purity analysis of the distillate were calculated by area% of HPLC and GC. The analysis conditions vary depending on the object and cannot be described uniformly, but as typical examples, the HPLC analysis conditions for 2-chlorobutyric acid and 2-hydroxybutyric acid are described.
HPLC analysis conditions

[0028]
Reference Example 1 2-Chlorbutyric Acid Production Method A 1 l 4-necked flask equipped with a stirrer, Dimroth condenser, thermometer, and chlorine gas introducer was charged with 441 g (5.0 mol) butyric acid and 80 g (0.5 mol) butyric anhydride. Then, chlorine gas was introduced at 12 l / hr while maintaining 115 to 125 ° C., and the reaction was carried out for 12 hours. After completion of the reaction, 9 g of water was added and stirred at 80 to 90 ° C. for 30 minutes to obtain 716 g of a 2-chlorobutyric acid reaction solution. The chemical purity was 95.1%, and many types of impurities were detected.
[0029]
Example 1
Into a 1 liter four-necked flask equipped with a stirrer, a Dimroth condenser, a thermometer, and a chlorine gas introducer (Hario Glass manufactured by Shibata Hario) was charged 200.3 g (1.55 mol) of 2-chlorobutyric acid prepared in Reference Example, Stir at 60 ° C. While maintaining the pH at 7 or less, a 25% aqueous sodium hydroxide solution was added dropwise to raise the temperature of the reaction solution to 100 ° C. At 100 ° C., a 25% aqueous sodium hydroxide solution was added dropwise over about 6 hours while maintaining the pH at 7-9. The added 25% aqueous sodium hydroxide solution was 505 g (3.16 mol).
[0030]
As a result of analyzing by cooling to room temperature with stirring after the reaction was completed, the yield of 2-hydroxybutyric acid was 93%, and the byproduct crotonic acid by dehydrochlorination was 0.3%. Further, the glass flask was not devitrified at all.
[0031]
Example 2
In the same manner as in Example 1, a 25% aqueous sodium hydroxide solution was added dropwise over about 6 hours while maintaining the pH at 6-7. The added 25% aqueous sodium hydroxide solution was 482 g (3.01 mol). As a result of analyzing the reaction solution in the same manner, the yield of 2-hydroxybutyric acid was 84%, unreacted 2-chlorobutyric acid was about 7%, and byproduct crotonic acid by dehydrochlorination was 0.3%. Further, the glass flask was not devitrified at all.
[0032]
Comparative Example 1
A 1 l four-necked flask equipped with a stirrer, thermometer, Dimroth condenser, and dropping funnel (Hario Glass, manufactured by Hario Shibata) was charged with 200.3 g of 2-chlorobutyric acid (1.55 mol, chemical purity 95.1%), 60 Stir at ° C. While dropping 515 g (3.22 mol) of 25% aqueous sodium hydroxide solution, the temperature was raised to 100 ° C., and the whole amount was added dropwise in about 1.5 hours. The pH of the reaction solution was 10 or more. After further stirring for 7 hours at about 100 ° C., the mixture was cooled to room temperature. The pH of the reaction solution was 12.6, and when analyzed, the yield of 2-hydroxybutyric acid was 88%, but the flask was devitrified.
[0033]
Comparative Example 2
When the reaction temperature was 70 to 80 ° C. in the same manner as in Comparative Example 1, it took 20 hours to make the conversion rate of 2-chlorobutyric acid 80% or more. As a result of analyzing the reaction solution, the yield of 2-hydroxybutyric acid was 77%, and about 7.5% of crotonic acid as a dehydrochlorination product was produced.
Example 3
In the same manner as in Example 1, a reaction solution containing 150.0 g (1.44 mol) of 2-hydroxybutyric acid was obtained. While stirring at room temperature to 35 ° C., 88 g (0.85 mol) of 95% sulfuric acid was added dropwise over about 1 hour, and then extracted twice with 400 g of methyl ethyl ketone. The extracted organic layer was concentrated to obtain 180 g of a concentrated solution containing 144.0 g (1.38 mol) of 2-hydroxybutyric acid.
[0034]
A 1 liter three-necked flask equipped with a stirrer, thermometer and Dimroth condenser was charged with 180 g of concentrated liquid, 441.6 g (13.8 mol) of methanol, and 1.6 g of 98% sulfuric acid, and heated under reflux for about 2 hours with stirring. did. After cooling to room temperature, 1.7 g of sodium carbonate was added and stirred for about 10 minutes.
[0035]
The Dimroth condenser was replaced with a 5-stage rectification column, methanol was recovered at normal pressure, and then switched to vacuum distillation. 139.4 g of methyl 2-hydroxybutyrate as a fraction of 70 to 74 ° C./4.0 to 0.7 kPa ( 1.18 mol, chemical purity 97%).
[0036]
A 500 ml four-necked flask equipped with a stirrer, thermometer, pH sensor, and dropping funnel was prepared from 24.4 g (0.2 mol) of methyl 2-hydroxybutyrate, 90 g of ethyl acetate and Sanol LS-770 (manufactured by Sankyo). The prepared oxidation catalyst adjustment liquid 0.4 g (described in Reference Example 2), water 2.3 g, and 12 wt% aqueous hydrochloric acid solution 2.4 g were charged and stirred while cooling to 10 to 15 ° C. 120.0 g of 13% sodium hypochlorite aqueous solution (manufactured by Nippon Light Metal) was added over 5 hours, and the mixture was further stirred at 20 to 25 ° C. for 2 hours. During this time, a 12 wt% aqueous hydrochloric acid solution was added to maintain the pH of the reaction solution at 3 to 4.5. After completion of the reaction, sodium carbonate was added to the reaction solution to adjust the pH to 6 to 6.5, and then the ethyl acetate layer was separated. Further, the aqueous layer was extracted with 90 g of ethyl acetate, and both ethyl acetate layers were mixed and concentrated under reduced pressure to obtain 28 g of a concentrated solution containing 22.0 g (0.19 mol) of methyl 2-oxobutyrate.
[0037]
A distillation apparatus equipped with about 5 rectification towers was charged with 28 g of the concentrated liquid and 0.2 g of bisphenol A type epoxy compound YD-128 (manufactured by Tohto Kasei) and distilled under reduced pressure, 70 to 75 ° C./5.3 As a fraction of ˜2.7 kPa, 20.1 g (0.17 mol, chemical purity 98%) of methyl 2-oxobutyrate was obtained.
[0038]
Reference Example 2 Production method of oxidation catalyst adjustment liquid from Sanol LS-770 (manufactured by Sankyo) In a 500 ml four-necked flask equipped with a stirrer, thermometer, Dimroth condenser, and dropping funnel, 225 g of ethyl acetate and bis (2,2,6 , 6-tetramethyl-4-piperidyl) sebacate (Sanol LS-770 Sankyo) 35 g was charged and dissolved by stirring at room temperature. Next, 35 g of 35 wt% hydrogen peroxide water was added with stirring, the temperature was raised to 60 ° C. while stirring, and the mixture was stirred for 20 hours. The reaction solution was allowed to stand to separate two layers, and the lower aqueous layer was removed. The upper ethyl acetate layer was washed with 25 g of water to obtain 247 g of a catalyst adjustment solution.
[0039]
【The invention's effect】
According to the present invention, 2-hydroxycarboxylic acid can be produced in a high yield using a normal glass lining reaction equipment. The obtained 2-hydroxycarboxylic acid can be used as a raw material for producing a 2-oxocarboxylic acid ester useful as a pharmaceutical intermediate.

Claims (7)

General formula (1)

(Wherein R ¹ represents an alkyl group having 1 to 4 carbon atoms) An aqueous alkali solution is added to the chlorocarboxylic acid represented by the formula (2) while maintaining the pH at 9 or less.

(Here, R ¹ is the same as described above). 2. The method for producing 2-hydroxycarboxylic acid according to claim 1, wherein the alkali is an alkali metal hydroxide, an alkali metal carbonate, an alkali metal hydrogen carbonate, or an alkaline earth metal hydroxide. pH is 6-9, The manufacturing method of 2-hydroxycarboxylic acid of any one of Claims 1, 2 characterized by the above-mentioned. The method for producing 2-hydroxycarboxylic acid according to any one of claims 1 to 3, wherein the reaction is performed at 80 ° C or higher. The method for producing 2-hydroxycarboxylic acid according to any one of claims 1 to 3, wherein the general formula (1) is 2-chlorobutyric acid and the general formula (2) is 2-hydroxybutyric acid. . The 2-hydroxycarboxylic acid obtained by the method according to any one of claims 1 to 5 is esterified to give a general formula (3)

(Wherein R ¹ represents an alkyl group having 1 to 4 carbon atoms, and R ² represents an alkyl group having 1 to 4 carbon atoms). General formula (4)

(Wherein R ¹ and R ² are the same as described above). The process for producing a 2-oxocarboxylic acid ester according to claim 6, wherein the oxidation is carried out with hypochlorous acid.