JP2011116677A - Method for producing alcohol - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a simple method for producing a highly pure alcohol of low toxicity as a raw material of a pharmaceutical, an agrochemical, a liquid crystal, a polymer, or the like. <P>SOLUTION: The method for producing an alcohol represented by formula (1) includes the following processes; a process (I) of reducing a carboxylic acid represented by R<SB>1</SB>-CH(XR<SB>2</SB>)COOR<SB>3</SB>in the presence of hydrogenated bis(2-methoxyethoxy)aluminum compound; a process (II) of chelating aluminum of the reducing agent present in the reaction liquid of the reduction reaction; a process (III) of adding a solvent forming an azeotrope with 2-methoxyethanol into the reaction liquid; and a process (IV) of removing 2-methoxyethanol by distillation. In the formulae, R<SB>1</SB>, R<SB>2</SB>, and R<SB>3</SB>may be the same or different and each represents a hydrogen atom, a 1-20C alkyl group that may contain a substituent, a 1-20C aryl group that may contain a substituent, a 1-20C alkenyl group that may contain a substituent, or a 1-20C aralkyl group that may contain a substituent; and X represents a nitrogen atom, an oxygen atom, or a sulfur atom. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

The present invention relates to a method for producing alcohol.

Alcohol is a compound useful as a raw material for pharmaceuticals, agricultural chemicals, liquid crystals, polymers and the like.
As a method for producing an alcohol from a carboxylic acid derivative, (1) a method of reducing with borane generated from metal borohydride and alkyl iodide (see Patent Document 1), (2) in the presence of a ruthenium catalyst, 50 to A method of performing a hydrogenation reaction at 200 ° C. and 50 to 200 kg / cm ² (see Patent Document 2), (3) A cyclic amino alcohol is obtained by reducing a cyclic carboxylic acid with sodium bis (2-methoxyethoxy) aluminum hydride. A manufacturing method (see Patent Document 3 and Non-Patent Document 1) and the like are known.
However, in the method (1), borane having high toxicity and pyrophoricity is used, and in the method (2), the reduction reaction is performed under high temperature and high pressure. Not suitable for mass production on scale.

JP-A-5-221935 JP-T-2002-501817 JP 2004-26762 A

Indian Journal of Chemistry, 12, 290-291 (1974)

On the other hand, in the method (3), proline in which a heteroatom forms a ring is used as a substrate to be reduced. However, when the method is applied to a substrate in which a heteroatom does not form a ring, only alcohol with a very low purity is used. It was not obtained.
Therefore, the main object of the present invention is to obtain a high-purity alcohol (particularly an alcohol in which a hetero atom does not form a ring) by a simple method.

As a result of intensive studies to solve the above-mentioned problems, the present inventor can highly remove 2-methoxyethanol from alcohol obtained by reducing carboxylic acid by distillation using a specific solvent. As a result, the present invention has been completed.
That is, the present invention is as follows.

  General formula (1) including the following steps

（式中、Ｒ_１及びＲ_２は、同一又は異なって、水素原子又は置換基を有していてもよい炭素数１〜２０のアルキル基、アリール基、アルケニル基又はアラルキル基を示す。Ｘは、窒素原子、酸素原子又は硫黄原子を示す。）
で示されるアルコールの製造方法。
（I）下記一般式（２）

(Wherein R ₁ and R ₂ are the same or different and each represents a hydrogen atom or an optionally substituted alkyl group, aryl group, alkenyl group or aralkyl group which may have a substituent. X represents , Represents a nitrogen atom, an oxygen atom or a sulfur atom.)
The manufacturing method of alcohol shown by.
(I) The following general formula (2)

（式中、Ｒ_１、Ｒ_２及びＸは前記と同じ。Ｒ_３は、水素原子又は置換基を有していてもよい炭素数１〜２０のアルキル基、アリール基、アルケニル基又はアラルキル基を示す。）
で示されるカルボン酸類を、水素化ビス（２−メトキシエトキシ）アルミニウム化合物の存在下に還元する工程
（II）前記還元反応における反応液中に存在する還元剤のアルミニウムをキレートする工程
（III）前記反応液に、２−メトキシエタノールと共沸する溶媒を添加する工程
（IV）蒸留により２−メトキシエタノール除去する工程

(In the formula, R ₁ , R ₂ and X are the same as above. R ₃ represents a hydrogen atom or an optionally substituted alkyl group, aryl group, alkenyl group or aralkyl group having 1 to 20 carbon atoms. Show.)
(II) a step of chelating aluminum as a reducing agent present in the reaction solution in the reduction reaction (III) the step of reducing the carboxylic acid represented by formula (II) in the presence of a bis (2-methoxyethoxy) aluminum hydride compound A step of adding a solvent azeotropic with 2-methoxyethanol to the reaction solution (IV) A step of removing 2-methoxyethanol by distillation

According to the present invention, high-purity alcohol can be obtained by a simple method.

(B) Reduction reaction
(1) Alcohol The alcohol produced in the present invention has the following general formula (1)

で示されるアルコールである。
式中、Ｒ_１及びＲ_２は、同一又は異なって、水素原子又は置換基を有していてもよい炭素数１〜２０のアルキル基、アリール基、アルケニル基又はアラルキル基を示す。Ｘは、窒素原子、酸素原子又は硫黄原子を示す。

It is alcohol shown by.
In formula, R < ₁ > and R < ₂ > are the same or different, and show the C1-C20 alkyl group, aryl group, alkenyl group, or aralkyl group which may have a hydrogen atom or a substituent. X represents a nitrogen atom, an oxygen atom or a sulfur atom.

  In the present specification, the alkyl group having 1 to 20 carbon atoms which may have a substituent is not particularly limited, and examples thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, and an isobutyl group. , Sec-butyl group, t-butyl group, pentyl group, isopentyl group, neopentyl group, t-pentyl group, hexyl group, isohexyl group, hydroxymethyl group and the like.

Although it does not specifically limit as a C1-C20 aryl group which may have a substituent, For example, a phenyl group, 2-chlorophenyl group, 3-chlorophenyl group, benzyl group, phenethyl group, 1-naphthyl Methyl group, 2-naphthylmethyl group, 1-phenylethyl group, phenylpropyl group, phenylbutyl group, phenylpentyl group, phenylhexyl group, methylbenzyl group, dimethylbenzyl group, trimethylbenzyl group, ethylbenzyl group, methylphenethyl group , Dimethylphenethyl group, diethylbenzyl group and the like.
Although it does not specifically limit as a C1-C20 aralkyl group which may have a substituent, For example, an ethynyl group, a propynyl group, a butynyl group etc. are mentioned.
Preferred alcohols used for purification in the present invention include, for example, when X is nitrogen, alaninol, valinol, leucinol, isoleucinol, tert-leucinol, serinol, threoninol, cysteinol, methioninol, asparaginol, glutaminol, pro Examples include amino alcohol derivatives such as linol, hydroxyprolinol, phenylalaninol, phenylglycinol, tyrosinol, tryptophanol, aspartidiol, glutamidiol, and 2-aminobutanol.
When X is oxygen, 1,2-propanediol, 1-phenyl-1,2-ethanediol, 1- (2-chlorophenyl) -1,2-ethanediol, 1- (3-chlorophenyl) -1, 2-ethanediol, 1- (4-chlorophenyl) -1,2-ethanediol, 1- (2-methylphenyl) -1,2-ethanediol, 1- (3-methylphenyl) 1,2-ethanediol 1- (4-methylphenyl) -1,2-ethanediol, 1- (2-hydroxyphenyl) -1,2-ethanediol, 1- (3-hydroxyphenyl) -1,2-1ethanediol, 1- (4-hydroxyphenyl) -1,2-ethanediol, 1- (2-methoxyphenyl) -1,2-ethanediol, 1- (3-methoxyphenyl) -1,2-ethanediol 1- (4-methoxyphenyl) -1,2-ethanediol, 1- (2-trifluoromethylphenyl) -1,2-ethanediol, 1- (3-trifluoromethylphenyl) -1,2 -Ethanediol, 1- (4-trifluoromethylphenyl) -1,2-ethanediol, 1- (2-aminophenyl) -1,2-ethanediol, 1- (3-aminophenyl) -1,2 -Ethanediol, 1- (4-aminophenyl) -1,2-ethanediol, 1- (2-nitrophenyl) -1,2-ethanediol, 1- (3-nitrophenyl) -1,2-ethane Diol, 1- (4-nitrophenyl) -1,2-ethanediol, 1- (2,4-dichlorophenyl) -1,2-ethanediol, 1- (2,4-difluorophenyl) -1,2- D Njioru, 1- (3,4-methylenedioxyphenyl) -1,2-ethanediol 1,2-diol derivatives such diols.
Among these compounds, tert-leucinol is preferable in that high chemical purity and high optical purity can be obtained.
Such an alcohol can be obtained by reducing the corresponding carboxylic acid as shown below.
(2) Carboxylic acids In the present invention, the following general formula (2) is used as a raw material (starting material) for obtaining an alcohol.

で示されるカルボン酸類である。
式中、Ｒ_１、Ｒ_２及びＸは、前記の通りである。Ｒ_３は、水素原子又は置換基を有していてもよい炭素数１〜２０のアルキル基、アリール基、アルケニル基又はアラルキル基を示す。Ｒ_３は、Ｒ_１又はＲ_２と同様の基を例示することができる。
ここでは、カルボン酸類とは、カルボン酸だけでなくカルボン酸エステルも含む。
より詳細には、Ｘが窒素原子の場合、グリシン、アラニン、セリン、トレオニン、バリン、ロイシン、イソロイシン、ｔｅｒｔ−ロイシン、アスパラギン酸、グルタミン酸、アスパラギン、グルタミン、フェニルアラニン等のカルボン酸又はカルボン酸誘導体が挙げられる。
Ｘが酸素原子の場合は、乳酸、マンデル酸、２−クロロマンデル酸、３−クロロマンデル酸、４−クロロマンデル酸、２−メチルマンデル酸、３−メチルマンデル酸、４−メチルマンデル酸、２−ヒドロキシマンデル酸、３−ヒドロキシマンデル酸、４−ヒドロキシマンデル酸、２−メトキシマンデル酸、３−メトキシマンデル酸、４−メトキシマンデル酸、２−トリフルオロメチルマンデル酸、３−トリフルオロメチルマンデル酸、４−トリフルオロメチルマンデル酸、２−アミノマンデル酸、３−アミノマンデル酸、４−アミノマンデル酸、２−ニトロマンデル酸、３−ニトロマンデル酸、４−ニトロマンデル酸、２，４−ジクロロマンデル酸、２，４−ジフルオロマンデル酸、３，４−メチレンジオキシマンデル酸等のヒドロキシ酸およびヒドロキシ酸誘導体が挙げられる。
また、Ｘが硫黄原子の場合はチオ乳酸などが挙げられる。
本発明で使用されるカルボン酸は、光学活性を有していても良い。例えば、ラセミ体であってもよいし、Ｄ体又はＬ体のどちらかが多く含まれている混合物であってもよいし、純粋にＤ体又はＬ体であってもよい。
本発明では、光学活性を有するアルコールを製造する場合には、その光学活性を有するカルボン酸を使用することにより、当該光学活性を保持したまま、所望の光学活性を有するアルコールを得ることができる。
（３）還元剤
本発明で使用する還元剤は、当該還元剤が分解された際に、２−メトキシエタノールが生じる化合物を好適に使用することができる。このような化合物としては、反応性などの観点から水素化ビス（２−メトキシエトキシ）アルミニウム化合物が好ましい。その中でも、特に、水素化ビス（２−メトキシエトキシ）アルミニウムナトリウム、水素化ビス（２−メトキシエトキシ）アルミニウムカリウム、水素化ビス（２−メトキシエトキシ）アルミニウムリチウムが好ましい。
還元反応における水素化ビス（２−メトキシエトキシ）アルミニウムナトリウムの使用量は、効率良くカルボン酸のカルボキシル基やエステル基等が水酸基に還元されれば限定さない。例えば、カルボン酸に対して、１〜５当量が好ましく、２〜４当量であることがより好ましい。１当量以上使用するのは、還元反応を効率良く進めることができるからである。また、５当量以下とするのは、反応後に未反応の還元剤が残存し、後処理において時間を要するという問題を防ぐことができるからである。
（４）還元反応
還元反応に使用する溶媒は、触媒として使用する水素化ビス（２−メトキシエトキシ）アルミニウム化合物に対して不活性な化合物である。例えば、ｎ−ヘキサン、ｎ−ヘプタン、トルエン、キシレン等の炭化水素系溶媒；ジメチルエーテル、ジエチルエーテル、ジイソプロピルエーテル、メチル−ｔｅｒｔ−ブチルエーテル、エチレングルコールジメチルエーテル、テトラヒドロフラン、１，４−ジオキサン等のエーテル系溶媒を使用することができる。
本発明における還元反応時の反応温度も特には限定されない。例えば、−２０〜８０℃、好ましくは０〜６０℃である。−２０℃以上で反応を行うことにより、十分な反応速度を得ることができる。また、８０℃以下で反応を行うことにより、不純物の増加を防ぐことができる。
還元反応により生成物（アルコール）が得られたことや原料（カルボン酸）が消失したことは、公知の方法、例えば、液体クロマトグラフィー等によって確認することができる。
（ロ）アルミニウムのキレート
還元反応が終了した後、生成物（アルコール）を精製する。本発明では、まず、還元剤として使用した水素化ビス（２−メトキシエトキシ）アルミニウム化合物に含まれるアルミニウムをキレートした後に、アルコールを抽出・精製する。
触媒として使用した水素化ビス（２−メトキシエトキシ）アルミニウム化合物をキレートするために使用する化合物としては、ジカルボン酸を挙げることができる。ジカルボン酸とは、ジカルボン酸及びその塩を含む。
より詳細には、酒石酸、メソ酒石酸、シュウ酸、マロン酸、コハク酸、グルタル酸、アジピン酸、ピメリン酸、スベリン酸、アゼライン酸、セバシン酸、フタル酸、イソフタル酸、テレフタル酸等を挙げることができる。これらの中でも、好ましくは、酒石酸、メソ酒石酸等であり、酒石酸がより好ましい。酒石酸はＤ体でもＬ体でもラセミ体でもどちらでもよい。
ジカルボン酸の塩としては、アルカリ金属が挙げられ、この中でもリチウム、ナトリウム及びカリウムからなる群から選ばれる少なくとも一種が好ましい。ジカルボン酸が当該塩を２つ含む場合、その２つの塩は同じであってもよいし異なっていてもよい。ジカルボン酸塩のうち、例えば、酒石酸ナトリウムカリウム、酒石酸ナトリウム、酒石酸カリウム等が挙げられ、酒石酸ナトリウムカリウムがより好ましい。
ジカルボン酸を還元反応の反応液に添加する場合、固体のままで添加してもよいし、水溶液として添加することもできる。操作のし易さ、安全面から水溶液として使用するのが好ましい。その場合のジカルボン酸水溶液中のジカルボン酸の濃度は限定されないが、例えば、１０〜５０質量％とすればよい、２０〜４０質量％がより好ましい。
アルミニウムをキレートするために使用するジカルボン酸の使用量は、還元剤由来のアルミニウムを十分にキレートできる量であれば限定されない。例えば、還元剤に対して０．１〜３モル当量が好ましく、０．５〜２モル当量であることがよりに好ましい。
０．１モル当量以上使用することにより、アルミニウムのキレートが不十分であるためにアルミニウムが溶解したジカルボン酸の水溶液の粘性が高くなり、以降の操作で生成物であるアルコールの抽出が困難となるという問題を避けることができる。また、３モル当量以下使用することにより、抽出溶媒の使用量が増加することにより抽出の効率が悪くなるという問題を回避することができる。
キレートを行う際の温度は、０〜８０℃が好ましく、２０〜５０℃であることがより好ましい。０℃以上で行うことにより、還元剤由来のアルミニウムとジカルボン酸との錯体形成を効率良く行うことができ、アルコールの回収率を低減させるという問題を避けることができる。また、８０℃以下で行うことにより、アルコールのジカルボン酸の水溶液への溶解が大きくなり、その結果、生成物であるアルコールの収率を低減させるという問題を避けることができる。反応時間は特に限定されないが、例えば、０．５〜３時間、好ましくは１〜２時間とすればよい。
上記のようにしてジカルボン酸の水溶液で処理した反応液は、有機相を分離することでアルコールを回収することができる。しかしながら、使用するジカルボン酸の種類によっては、水に対する溶解度が高く、有機相への回収率が低下する場合がある。そのような場合には、水相からの再抽出を行えばよい。
再抽出に用いる溶媒としては、該水溶液と混合しない溶媒であれば特に限定するものではないが、例えばｎ−プロパノール、２−プロパノール、ｎ−ブタノール、２−ブタノールなどのアルコール溶媒、ｎ−ヘキサン、ｎ−ヘプタン、トルエン、キシレンなどの炭化水素系溶媒、酢酸エチルなどのエステル系溶媒、ジメチルエーテル、ジエチルエーテル、ジイソプロピルエーテル、メチル−ｔｅｒｔ−ブチルエーテル、エチレングルコールジメチルエーテル、テトラヒドロフラン、１，４−ジオキサンなどのエーテル系溶媒などが挙げられる。
（ハ）２−メトキシエタノールの除去（アルコールの精製）
次に、上記で得られた有機相から、生成物であるアルコールを回収すればよい。本発明の方法で得られた有機相には、還元剤由来の２−メトキシエタノールが含まれている。生成物であるアルコールとこの２−メトキシエタノールとが高い親和性を有するために、通常の濃縮工程では２−メトキシエタノールを優先的には除去することができない。そこで、２−メトキシエタノールを除去するという操作が必要となる。
なお、必要に応じて、２−メトキシエタノールを除去する前に、上記有機相を濃縮してもよい。濃縮操作により溶媒の量を減らして、後の工程の操作効率が良くすることができるからである。有機相を濃縮する際の温度は、０〜５０℃が好ましく、１０〜４０℃であることがより好ましい。圧力に関しては限定されず、常圧でも減圧下でもよい。
２−メトキシエタノールを除去する方法は、上記有機相に２−メトキシエタノールと共沸する溶媒を添加して蒸留を行うことにより、有機相から当該溶媒と共に２−メトキシエタノールを除去することができる。
上記２−メトキシエタノールと共沸する溶媒としては、カルボン酸の還元反応において使用する溶媒とは異なる溶媒であって、２−メトキシエタノールと共沸するものであれば特に限定されるものではない。例えば、水、トルエン、ヘプタン、オクタン、ｏ−キシレン、ｍ−キシレン、２−ペンタノール、酢酸エチル、酢酸ブチル等が挙げられる。これらの中でも、水、トルエン、ヘプタンが好ましい。
当該溶媒の使用量は特には限定されないが、例えば、２−メトキシエタノールに対して１〜１０倍量が好ましく、２〜８倍量であることがより好ましい。１倍量以上の溶媒を使用することにより、２−メトキシエタノールを十分に除去でき高純度のアルコールが得られる。一方、１０倍量以下とすることにより、濃縮に要する時間を短縮するという利点がある。
メトキシエタノールを除去する（蒸留を行う）際の条件については限定されないが、例えば、以下の表に示すような条件を採用することができる。蒸留時間も限定されず、適宜選択することができる。例えば、２−メトキシエタノール含量が反応液中１質量％以下、好ましくは０．５質量％となった時点で反応を停止すればよい。
メトキシエタノールが十分に除去できたことは、公知の方法、例えば、液体クロマトグラフィー等によって確認することができる。

It is carboxylic acid shown by these.
In the formula, R ₁ , R ₂ and X are as described above. R ₃ represents a hydrogen atom or an optionally substituted alkyl group, aryl group, alkenyl group or aralkyl group having 1 to 20 carbon atoms. R ₃ can exemplify the same group as R ₁ or R ₂ .
Here, carboxylic acids include not only carboxylic acids but also carboxylic acid esters.
More specifically, when X is a nitrogen atom, examples thereof include carboxylic acids or carboxylic acid derivatives such as glycine, alanine, serine, threonine, valine, leucine, isoleucine, tert-leucine, aspartic acid, glutamic acid, asparagine, glutamine, and phenylalanine. It is done.
When X is an oxygen atom, lactic acid, mandelic acid, 2-chloromandelic acid, 3-chloromandelic acid, 4-chloromandelic acid, 2-methylmandelic acid, 3-methylmandelic acid, 4-methylmandelic acid, 2 -Hydroxymandelic acid, 3-hydroxymandelic acid, 4-hydroxymandelic acid, 2-methoxymandelic acid, 3-methoxymandelic acid, 4-methoxymandelic acid, 2-trifluoromethylmandelic acid, 3-trifluoromethylmandelic acid 4-trifluoromethylmandelic acid, 2-aminomandelic acid, 3-aminomandelic acid, 4-aminomandelic acid, 2-nitromandelic acid, 3-nitromandelic acid, 4-nitromandelic acid, 2,4-dichloro Hydroxy acids such as mandelic acid, 2,4-difluoromandelic acid, 3,4-methylenedioxymandelic acid Fine hydroxy acid derivatives.
Moreover, thiolactic acid etc. are mentioned when X is a sulfur atom.
The carboxylic acid used in the present invention may have optical activity. For example, it may be a racemate, a mixture containing a large amount of either D-form or L-form, or pure D-form or L-form.
In the present invention, when an alcohol having optical activity is produced, by using a carboxylic acid having optical activity, an alcohol having desired optical activity can be obtained while maintaining the optical activity.
(3) Reducing agent As the reducing agent used in the present invention, a compound capable of producing 2-methoxyethanol when the reducing agent is decomposed can be suitably used. As such a compound, a bis (2-methoxyethoxy) aluminum hydride compound is preferable from the viewpoint of reactivity and the like. Of these, sodium bis (2-methoxyethoxy) aluminum hydride, potassium bis (2-methoxyethoxy) aluminum hydride, and lithium bis (2-methoxyethoxy) aluminum hydride are particularly preferable.
The amount of sodium bis (2-methoxyethoxy) aluminum hydride used in the reduction reaction is not limited as long as the carboxyl group or ester group of the carboxylic acid is efficiently reduced to a hydroxyl group. For example, 1-5 equivalent is preferable with respect to carboxylic acid, and it is more preferable that it is 2-4 equivalent. The reason for using 1 equivalent or more is that the reduction reaction can proceed efficiently. The reason why it is 5 equivalents or less is that it is possible to prevent the problem that unreacted reducing agent remains after the reaction and time is required for the post-treatment.
(4) Reduction reaction The solvent used for the reduction reaction is an inactive compound with respect to the bis (2-methoxyethoxy) aluminum hydride compound used as a catalyst. For example, hydrocarbon solvents such as n-hexane, n-heptane, toluene, xylene; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, methyl-tert-butyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, 1,4-dioxane A solvent can be used.
The reaction temperature during the reduction reaction in the present invention is not particularly limited. For example, it is -20-80 degreeC, Preferably it is 0-60 degreeC. A sufficient reaction rate can be obtained by carrying out the reaction at -20 ° C or higher. Further, by performing the reaction at 80 ° C. or lower, an increase in impurities can be prevented.
It can be confirmed by a known method, for example, liquid chromatography, that the product (alcohol) has been obtained by the reduction reaction and that the raw material (carboxylic acid) has disappeared.
(B) After completion of the chelate reduction reaction of aluminum , the product (alcohol) is purified. In the present invention, first, the aluminum contained in the bis (2-methoxyethoxy) aluminum hydride compound used as the reducing agent is chelated, and then the alcohol is extracted and purified.
Examples of the compound used for chelating the bis (2-methoxyethoxy) aluminum hydride compound used as a catalyst include dicarboxylic acid. The dicarboxylic acid includes dicarboxylic acids and salts thereof.
More specifically, tartaric acid, mesotartaric acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid, phthalic acid, isophthalic acid, terephthalic acid, etc. it can. Among these, tartaric acid and mesotartaric acid are preferable, and tartaric acid is more preferable. Tartaric acid may be in D form, L form or racemic form.
Examples of the salt of the dicarboxylic acid include alkali metals. Among these, at least one selected from the group consisting of lithium, sodium and potassium is preferable. When the dicarboxylic acid contains two such salts, the two salts may be the same or different. Among dicarboxylates, for example, sodium potassium tartrate, sodium tartrate, potassium tartrate and the like are mentioned, and sodium potassium tartrate is more preferable.
When dicarboxylic acid is added to the reaction solution for the reduction reaction, it may be added as a solid or may be added as an aqueous solution. It is preferably used as an aqueous solution from the viewpoint of ease of operation and safety. In this case, the concentration of the dicarboxylic acid in the aqueous dicarboxylic acid solution is not limited, but it may be, for example, 10 to 50% by mass, and more preferably 20 to 40% by mass.
The amount of dicarboxylic acid used for chelating aluminum is not limited as long as it can sufficiently chelate aluminum derived from a reducing agent. For example, 0.1-3 molar equivalent is preferable with respect to a reducing agent, and it is more preferable that it is 0.5-2 molar equivalent.
By using 0.1 molar equivalent or more, since the aluminum chelate is insufficient, the viscosity of the aqueous solution of dicarboxylic acid in which aluminum is dissolved becomes high, and it becomes difficult to extract the product alcohol in the subsequent operations. Can be avoided. Further, by using 3 molar equivalents or less, it is possible to avoid the problem that the extraction efficiency is deteriorated due to an increase in the amount of extraction solvent used.
0-80 degreeC is preferable and, as for the temperature at the time of chelating, it is more preferable that it is 20-50 degreeC. By carrying out at 0 degreeC or more, the complex formation with aluminum and dicarboxylic acid derived from a reducing agent can be performed efficiently, and the problem of reducing the recovery rate of alcohol can be avoided. Moreover, by performing at 80 degrees C or less, melt | dissolution to the aqueous solution of the dicarboxylic acid of alcohol increases, As a result, the problem of reducing the yield of the alcohol which is a product can be avoided. Although reaction time is not specifically limited, For example, what is necessary is just to set it as 0.5 to 3 hours, Preferably it is 1-2 hours.
The reaction liquid treated with the aqueous solution of dicarboxylic acid as described above can recover the alcohol by separating the organic phase. However, depending on the type of dicarboxylic acid used, the solubility in water is high, and the recovery rate to the organic phase may decrease. In such a case, re-extraction from the aqueous phase may be performed.
The solvent used for re-extraction is not particularly limited as long as it is a solvent that is not mixed with the aqueous solution. For example, alcohol solvents such as n-propanol, 2-propanol, n-butanol, and 2-butanol, n-hexane, hydrocarbon solvents such as n-heptane, toluene, xylene, ester solvents such as ethyl acetate, dimethyl ether, diethyl ether, diisopropyl ether, methyl-tert-butyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, 1,4-dioxane, etc. Examples include ether solvents.
(C) Removal of 2-methoxyethanol (purification of alcohol)
Next, what is necessary is just to collect | recover the alcohol which is a product from the organic phase obtained above. The organic phase obtained by the method of the present invention contains 2-methoxyethanol derived from a reducing agent. Since the product alcohol and 2-methoxyethanol have a high affinity, 2-methoxyethanol cannot be preferentially removed in a normal concentration step. Therefore, an operation of removing 2-methoxyethanol is necessary.
If necessary, the organic phase may be concentrated before removing 2-methoxyethanol. This is because the amount of the solvent can be reduced by the concentration operation, and the operation efficiency of the subsequent steps can be improved. 0-50 degreeC is preferable and, as for the temperature at the time of concentrating an organic phase, it is more preferable that it is 10-40 degreeC. The pressure is not limited and may be normal pressure or reduced pressure.
In the method of removing 2-methoxyethanol, 2-methoxyethanol can be removed together with the solvent from the organic phase by adding a solvent azeotropic with 2-methoxyethanol to the organic phase and performing distillation.
The solvent azeotroped with 2-methoxyethanol is not particularly limited as long as it is a solvent different from the solvent used in the reduction reaction of carboxylic acid and azeotropes with 2-methoxyethanol. Examples thereof include water, toluene, heptane, octane, o-xylene, m-xylene, 2-pentanol, ethyl acetate, butyl acetate and the like. Among these, water, toluene, and heptane are preferable.
Although the usage-amount of the said solvent is not specifically limited, For example, 1-10 times amount is preferable with respect to 2-methoxyethanol, and it is more preferable that it is 2-8 times amount. By using one or more times the amount of solvent, 2-methoxyethanol can be sufficiently removed, and a high-purity alcohol can be obtained. On the other hand, when the amount is 10 times or less, there is an advantage that the time required for concentration is shortened.
Although the conditions for removing methoxyethanol (distilling) are not limited, for example, conditions as shown in the following table can be employed. The distillation time is not limited and can be appropriately selected. For example, the reaction may be stopped when the 2-methoxyethanol content becomes 1% by mass or less, preferably 0.5% by mass in the reaction solution.
Whether or not methoxyethanol has been sufficiently removed can be confirmed by a known method such as liquid chromatography.

このようにして２−メトキシエタノールを留去された反応液から、目的とするアルコールを蒸留によって得ることもできる。蒸留の条件も限定されず、適宜選択することができる。

Thus, the target alcohol can also be obtained by distillation from the reaction liquid from which 2-methoxyethanol has been distilled off. The conditions for distillation are not limited and can be appropriately selected.

The conversion rate of L-tere-leucine was measured using high-performance liquid chromatography, gas chromatography for chemical purity analysis of L-tert-leucinol, and a polarimeter for optical purity measurement of L-tert-leucinol. Carried out.
[Concentration analysis of carboxylic acid derivatives]
L-tere-leucine purity analysis sample preparation method: 125 mg of sample dissolved in 25 mL of eluent: column oven 865-CO manufactured by JASCO Corporation
UV 870-UV manufactured by JASCO
Pump 880-PU manufactured by JASCO Corporation
C-R3A manufactured by Shimadzu Corporation
Column: ODS-3V (manufactured by GL Sciences)
Carrier: 0.1% phosphoric acid aqueous solution Column temperature: 40 ° C
Flow rate: 1 mL / min
Wavelength: 210 nm.
[Purity analysis of alcohol by gas chromatography]
Gas chromatography: GC-17A (Shimadzu Corporation)
Column: DB-5 (J & W Scientific, 0.32 mm ID × 30 m)
Carrier: Helium (1.8ml / min / 50 ° C)
Column temperature: 50 ° C. → 250 ° C. (10 ° C./min)
Injector: Split 50: 1 (250 ° C)
Detector: FID (250 ° C.).
[Measurement of optical purity of alcohol]
Sample preparation: Weigh 1.5 g of alcohol in a 100 ml volumetric flask and measure up.
Cell length: 100mm
Polarimeter: HORIBA SEPA-300.
<Example 1>
A 2000 ml three-necked flask equipped with a stirrer and a thermometer was charged with 500.0 g (1.73 mol) of 70% sodium bis (2-methoxyethoxy) aluminum hydride and 625 ml of tetrahydrofuran, and 75.7 g of L-tert-leucine (0.7. 58 mol) was added at 15 to 20 ° C over 1 hour, and then stirred at 45 to 50 ° C for 2 hours. It was confirmed by high performance liquid chromatography that L-tert-leucine had substantially disappeared, and the reaction solution was cooled to 30 ° C.
This reaction solution was dropped into 454.0 g of 28 wt% aqueous sodium potassium tartrate solution at 35 to 40 ° C. over 1 hour, and then stirred at 50 ° C. for 1 hour.
The reaction solution was allowed to stand at 35 to 40 ° C. for 1 hour, and then separated into an aqueous phase and an organic phase. The collected organic phase was concentrated under reduced pressure at 130 hPa and 25 ° C. to obtain 160.5 g of crude L-tert-leucinol (purity 36.8%, yield 86.9%).
150.0 g of pure water was added to the crude L-tert-leucinol, and the solution was concentrated under reduced pressure at 130 hPa and 50 ° C. to reduce the content of 2-methoxyethanol, and the purity of L-tert-leucinol was 92.6%. Improved.
Furthermore, 44.9 g of L-tert-leucinol was obtained by distilling this crude product at 4 kPa and 130 ° C. (chemical purity 99.0%, optical purity 99.5% ee or more, yield 76.0%). ).
<Comparative Example 1>
In the same manner as in Example 1, a reduction reaction, treatment with a potassium sodium tartrate solution, and concentration were used to distill 64.2 g (purity 36.8%) of crude L-tert-leucinol at 4 kPa and 130 ° C. L-tert-leucinol (37.8 g, purity 50.0%) was obtained (experiment was performed in the same manner as in Example 1 except that distillation was performed using a solvent azeotropic with 2-methoxyethanol).
From this result, it was shown that only a very low-purity alcohol can be obtained when distillation is not performed using a solvent azeotropic with 2-methoxyethanol.

Claims (2)

General formula (1) including the following steps

(Wherein R ₁ and R ₂ are the same or different and each represents a hydrogen atom or an optionally substituted alkyl group, aryl group, alkenyl group or aralkyl group which may have a substituent. X represents , Represents a nitrogen atom, an oxygen atom or a sulfur atom.)
The manufacturing method of alcohol shown by.
(I) The following general formula (2)

(In the formula, R ₁ , R ₂ and X are the same as above. R ₃ represents a hydrogen atom or an optionally substituted alkyl group, aryl group, alkenyl group or aralkyl group having 1 to 20 carbon atoms. Show.)
(II) a step of chelating aluminum as a reducing agent present in the reaction solution in the reduction reaction (III) the step of reducing the carboxylic acid represented by formula (II) in the presence of a bis (2-methoxyethoxy) aluminum hydride compound A step of adding a solvent azeotropic with 2-methoxyethanol to the reaction solution (IV) A step of removing 2-methoxyethanol by distillation The solvent azeotropic with 2-methoxyethanol is at least one selected from the group consisting of water, toluene, heptane, octane, o-xylene, m-xylene, 2-pentanol, ethyl acetate and butyl acetate. Item 2. The method according to Item 1.