JP2008001648A - Method for producing alcohol compound by using tetrahydropyran as reaction solvent - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To solve the problems such as the separation of a reaction solvent and reaction product in the reduction reaction of an organic compound using a hydrogenated aluminum compound such as aluminum lithium hydride. <P>SOLUTION: The invention relates to a method for reducing an organic compound such as aldehyde compound, ketone compound, ester compound, carboxylic acid compound, acid chloride compound and oxirane compound using a composition composed of tetrahydropyran and a hydrogenated aluminum compound such as aluminum lithium hydride to enable the use of the same solvent as the reaction solvent and the extraction solvent and, accordingly, realize the simplification of the reaction process, the reduction of energy cost, etc. The safety to organism is increased by the use of tetrahydropyran having low toxicity as the solvent. The produced alcohol is efficiently separated by treating the water layer of the reaction product with an acid. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

The present invention is a composition comprising an aluminum hydride compound such as lithium aluminum hydride (LiAlH ₄ ) and tetrahydropyran, and the composition reduces an aldehyde compound, a ketone compound, an ester compound, a carboxylic acid compound, an acid chloride compound, and an oxirane compound. The present invention relates to a method for producing an alcohol compound, and a method for efficiently isolating a produced alcohol compound by adding water or an acidic aqueous solution to a solution after reduction.

Conventionally, lithium aluminum hydride (LiAlH ₄ ) has been used as a simple and powerful reducing agent for the reduction reaction of a wide range of organic compounds (Journal of Synthetic Organic Chemistry, Vol. 52, p616 (1994): Non-Patent Document 1). ).
Since lithium aluminum hydride is sensitive to moisture and reacts violently with water, it is usually used in an aprotic solvent in which organic compounds and salts are appropriately dissolved. Of these, ether solvents having base resistance are preferably used. As such an ether solvent, ether, tetrahydrofuran, diglyme (diethylene glycol dimethyl ether) or the like is used.

  However, ether is a low-boiling special flammable substance and has high anesthetic properties, and there is a problem in using it as a solvent in the production process for safety management.

In the reduction reaction of lithium aluminum hydride, after the reaction, it is necessary to decompose excess hydride by adding water, and simultaneously separate the product into an organic layer and the metal salt into an aqueous layer. Therefore, when tetrahydrofuran or diglyme that is miscible with water is used as a solvent, separation is difficult and recovery of the produced alcohol or the like is difficult.
In addition, when an alcohol compound produced by the reaction is obtained by concentrating the reaction solution and adding an extraction solvent, high-boiling diglyme, diethylene glycol, and water having a high latent heat of evaporation are distilled off, and the extraction solvent is different from the reaction solvent. Therefore, there is a problem in that the reaction process is complicated and energy costs are increased.

  Lithium aluminum hydride can also be used in tetrahydropyran, but it removes impurity chlorine contained in the epoxy resin (Japanese Patent Laid-Open No. 1-108218: Patent Document), reductive decomposition of the oxime group of impurities in polymethacrolein. (Soedineniya, Seria A, 11 p2049 (1969): Non-Patent Document 2) is only known for limited examples.

Moreover, since aluminum hydroxide produced by adding water after the reaction is precipitated as a sol-gel substance, it is difficult to separate from the reaction solvent.
Filtration is usually used for separation of aluminum hydroxide, but sol-gel aluminum hydroxide is poor in filterability, often causing clogging of the filter and lowering productivity. In addition, there is a problem that the alcohol generated in the sol-gel hydroxide is taken in, making it difficult to recover the alcohol.

Journal of Synthetic Organic Chemistry, Volume 52, p616 (1994) Soedineniya, Seria A, 11 p2049 (1969) Japanese Patent Laid-Open No. 1-108218

  An object of the present invention is to solve problems such as separation of a reaction solvent and a product as described above in a reduction reaction of an organic compound using an aluminum hydride compound such as lithium aluminum hydride.

  As a result of diligent efforts in view of the above problems, the present inventors reduced the organic compound using a composition comprising an aluminum hydride compound such as lithium aluminum hydride and tetrahydropyran, thereby making the reaction solvent and the extraction solvent the same. Therefore, simplification of the reaction process, reduction of energy costs, etc. can be realized, and by using tetrahydropyran having low toxicity as a solvent, safety to the living body is increased, By treating the aqueous layer after the reaction with an acid, it was found that the produced alcohol could be isolated efficiently, and the present invention was completed.

（式中、ＭはＸ価の陽イオンとなり得る金属または原子団を表し、Ｘは１〜３の整数を表す。）で示される化合物とテトラヒドロピランからなる組成物。
［２］式（１）で表される化合物がＮａＡｌＨ₄である前記１記載の組成物。
［３］式（１）で表される化合物がＭｇ（ＡｌＨ₄）₂である前記１記載の組成物。
［４］前記１に記載の組成物中で、アルデヒド化合物、ケトン化合物、エステル化合物、カルボン酸化合物、酸クロライド化合物を還元したのち水を加えてテトラヒドロピラン中に反応生成物であるアルコール化合物を回収することを特徴とするアルコール化合物の製造方法。
［５］前記１に記載の組成物中で、アルデヒド化合物、ケトン化合物、エステル化合物、カルボン酸化合物、酸クロライド化合物を還元したのち酸性水溶液を加えてテトラヒドロピラン中に反応生成物であるアルコール化合物を回収する前記４に記載のアルコール化合物の製造方法。
［６］酸性水溶液中の酸がプロトン酸である前記５に記載の製造方法。
［７］酸性水溶液中の酸がリンを含む酸である前記５または６に記載の製造方法。
［８］酸性水溶液中の酸がリン酸及び／またはリン酸塩を含む前記５〜７のいずれかに記載の製造方法。
［９］水層のｐＨが５以下であることを特徴とする前記５〜８のいずれかに記載の製造方法。 That is, this invention relates to the manufacturing method of the following alcohol compounds.
[1] The following formula (1)

(Wherein M represents a metal or an atomic group that can be an X-valent cation, and X represents an integer of 1 to 3) and a composition comprising tetrahydropyran.
[2] The composition according to 1 above, wherein the compound represented by the formula (1) is NaAlH ₄ .
[3] The composition according to 1 above, wherein the compound represented by formula (1) is Mg (AlH ₄ ) ₂ .
[4] In the composition described in 1 above, after reducing the aldehyde compound, ketone compound, ester compound, carboxylic acid compound, and acid chloride compound, water is added to recover the alcohol compound that is a reaction product in tetrahydropyran. And a method for producing an alcohol compound.
[5] In the composition described in 1 above, after reducing an aldehyde compound, a ketone compound, an ester compound, a carboxylic acid compound and an acid chloride compound, an acidic aqueous solution is added, and an alcohol compound which is a reaction product is added to tetrahydropyran. 5. The method for producing an alcohol compound as described in 4 above.
[6] The production method according to 5 above, wherein the acid in the acidic aqueous solution is a protonic acid.
[7] The production method according to 5 or 6, wherein the acid in the acidic aqueous solution is an acid containing phosphorus.
[8] The production method according to any one of 5 to 7, wherein the acid in the acidic aqueous solution contains phosphoric acid and / or a phosphate.
[9] The method according to any one of 5 to 8, wherein the pH of the aqueous layer is 5 or less.

In the method for reducing organic compounds such as aldehyde compounds, ketone compounds, ester compounds, carboxylic acid compounds, acid chloride compounds, and oxirane compounds of the present invention, a composition comprising tetrahydropyran and an aluminum hydride compound such as lithium aluminum hydride is used. As a result, the reaction solvent and the extraction solvent can be made the same, so that the reaction process can be simplified and the energy cost can be reduced. Moreover, the safety | security to a biological body also increases by using tetrahydropyran with low toxicity as a solvent.
Furthermore, the produced | generated alcohol can be efficiently isolated by processing the aqueous layer after reaction with an acid.

（式中、ＭはＸ価の陽イオンとなり得る金属または原子団を表し、Ｘは１〜３の整数を表す。）で示される水素化アルミニウムリチウムなどの水素化アルミニウム化合物とテトラヒドロピランからなる組成物、及び該組成物を用いてアルデヒド化合物、ケトン化合物、エステル化合物、カルボン酸化合物、酸クロライド化合物、オキシラン化合物を還元するアルコール化合物の製造方法、及び反応後溶液に水または酸性水溶液を添加することにより、生成したアルコールを効率的に単離する方法に関する。 The specific contents of the present invention will be described in detail below.
The present invention provides the following formula (1)

(Wherein M represents a metal or atomic group that can be an X-valent cation, and X represents an integer of 1 to 3), and a composition comprising an aluminum hydride compound such as lithium aluminum hydride and tetrahydropyran. And a method for producing an alcohol compound that reduces an aldehyde compound, a ketone compound, an ester compound, a carboxylic acid compound, an acid chloride compound, and an oxirane compound using the composition, and adding water or an acidic aqueous solution to the solution after the reaction Relates to a method for efficiently isolating the produced alcohol.

[Aluminum hydride compound]
The aluminum hydride compound used in the present invention will be described.
As the aluminum borohydride compound used in the present invention, lithium aluminum hydride (LiAlH ₄ ), sodium aluminum hydride (NaAlH ₄ ), and magnesium aluminum hydride (Mg (AlH ₄ ) ₂ ) are preferably used. These can be powder products that are usually commercially available.
Since these compounds are easily decomposed by moisture and react violently with water, handling is usually performed under an inert atmosphere.

[solvent]
As the solvent, ether solvents such as tetrahydrofuran, dioxane and diglyme, and mixed solvents of hydrocarbon solvents such as toluene and xylene and tetrahydropyran can be used. From the viewpoint of recovery and reuse, tetrahydropyran can be used. It is desirable to use it alone.
Tetrahydropyran is usually used after being distilled and treated with a dehydrating agent.
The amount of tetrahydropyran used is 2 to 50 times, preferably 5 to 30 times the weight of the aluminum hydride compound.

[Composition comprising aluminum hydride compound and tetrahydropyran]
The composition comprising the aluminum hydride compound and tetrahydropyran of the present invention is produced by dissolving or dispersing the above-described aluminum hydride compound in tetrahydropyran.
The composition comprising the aluminum hydride compound and tetrahydropyran is stably present under an inert atmosphere such as nitrogen or argon, and can be used at a temperature between the melting point and the reflux temperature of tetrahydropyran.

[Reduction reaction with a composition comprising an aluminum hydride compound and tetrahydropyran]
The amount of aluminum hydride compound used varies depending on the compound used for the reduction. For example, when lithium aluminum hydride is used as the aluminum hydride compound, there is 4 mol of hydride per 1 mol of lithium aluminum hydride, so when reducing carbonyl compounds such as aldehydes and ketone compounds, an amount of at least about 0.25 mol is required. is there. There is at least about 0.5 mol equivalent when reducing the ester compound, at least about 0.75 mol equivalent when reducing the carboxylic acid compound, and at least about 0.5 mol equivalent lithium aluminum hydride when reducing the carboxylic acid chloride. Used.

This reduction reaction is usually performed under an inert atmosphere such as nitrogen or argon.
Usually, it is carried out by adding an organic compound to a composition comprising tetrahydropyran and an aluminum hydride compound. The reaction temperature at this time is in the range of −45 ° C. to the reflux temperature of the reaction liquid to be added, and particularly preferably in the range of 0 ° C. to the reflux temperature of the reaction liquid.

[Isolation of product after reduction]
In the present invention, water can be added to the reaction solution after the reduction reaction, the inorganic substance can be extracted and separated into an aqueous layer, and the resulting product can be separated into a tetrahydropyran layer. That is, since tetrahydropyran serves as a reaction solvent and an extraction solvent, it is not necessary to concentrate the reaction solvent or add an additional extraction solvent, and the reaction product can be directly extracted and separated.
Further, when water is added after the reduction reaction, the aqueous layer becomes basic. At this time, the aluminum hydride compound is decomposed, and the generated sol-gel aluminum hydroxide is also dispersed in the aqueous layer and the organic layer. Therefore, when an acidic aqueous solution is added to make the solution acidic, the aluminum hydroxide is dissolved in the aqueous layer, so that the inorganic substance can be separated into the aqueous layer and the product can be separated into the tetrahydropyran layer.

[Acid aqueous solution]
After the reaction, the aluminum hydroxide compound produced by adding water becomes sol-gel from basic to neutral and is difficult to separate from the product. Therefore, it is preferable to separate the aluminum hydroxide by making the aqueous layer acidic and dissolving the aluminum hydroxide in water for separation.
Protic acid is preferable as the acid used in this case. Protonic acid such as sulfuric acid, nitric acid, hydrochloric acid, phosphoric acid, hydrobromic acid, sodium hydrogen sulfate, potassium hydrogen sulfate, sodium dihydrogen phosphate, dihydrogen phosphate A salt having a proton such as potassium can be used. Of these, sulfuric acid and phosphoric acid can be preferably used, and phosphoric acid is most preferred.

  The amount of acid to be added varies depending on the amount of the aluminum hydride compound used at the time of charging the reaction and the type of acid used. As a measure of the amount to be added, it is added until a clear interface is formed between the tetrahydropyran layer and the aqueous layer and the tetrahydropyran layer becomes transparent.

When these acids are used, the pH of the aqueous layer is preferably 5 or less, more preferably 2 or less, and most preferably 1 or less.
Moreover, it is preferable to maintain pH at 4-5 with the buffering action of a phosphate using a phosphate with respect to the compound weak to an acid.

  Although this invention can be used for the reduction reaction of various organic compounds, it can be used suitably especially for the reduction reaction of the compound mentioned below.

[Aldehyde compound]
There is no restriction | limiting in particular about the aldehyde compound used by this invention. Aliphatic aldehyde compounds such as formaldehyde, acetaldehyde, butyraldehyde, crotonaldehyde, 3-phenylpropionaldehyde, propionaldehyde, valeroaldehyde, cyclohexanecarbaldehyde, phenylacetaldehyde, glyoxal, malonaldehyde, succinaldehyde, glutaraldehyde, benzaldehyde, anise Aromatic aldehyde compounds such as aldehyde, p-chlorobenzaldehyde, p-methylbenzaldehyde, vanillin, 2-naphthalene aldehyde, terephthalaldehyde, phthalaldehyde, isophthalaldehyde, and 1,2-naphthalenedicarbaldehyde can be used.

[Ketone compounds]
There is no restriction | limiting in particular about the ketone compound used by this invention. Acetone, methyl ethyl ketone, diethyl ketone, isophorone, cyclopentanone, cyclohexanone, cyclohexyl acetone, acetylacetone, aliphatic ketone compounds such as methyl acetoacetate, acetophenone, propiophenone, benzophenone, deoxybenzoin, acetonaphthophenone, butyronaphthophenone, Aromatic ketone compounds such as inden-1-one and fluoren-9-one can be used.

[Ester compound]
There is no restriction | limiting in particular about the ester compound used by this invention. Methyl formate, methyl acetate, butyl acetate, methyl propionate, methyl butyrate, methyl hexanoate, methyl octylate, methyl cyclohexanecarboxylate, ethyl phenylacetate, ethyl acetoacetate, dimethyl oxalate, diethyl malonate, medethyl succinate, malein Aliphatic ester compounds such as dimethyl acid and diethyl glutarate, ethyl benzoate, methyl anisate, methyl 2-naphthalenecarboxylate, dimethyl terephthalate, diethyl isophthalate, dioctyl phthalate, trimethyl trimellitic acid, tetramethyl pyromellitic acid An aromatic ester compound such as can be used.

[Carboxylic acid compound]
There is no restriction | limiting in particular about the carboxylic acid compound used by this invention. Aliphatic carboxylic acid compounds such as formic acid, acetic acid, propion, butanoic acid, butyric acid, hexanoic acid, octylic acid, cyclohexanecarboxylic acid, phenylacetic acid, acetoacetic acid, oxalic acid, malonic acid, succinic acid, maleic acid, glutaric acid, benzoic acid An aromatic carboxylic acid compound such as acid, anisic acid, 2-naphthalenecarboxylic acid, terephthalic acid, isophthalic acid, phthalic acid, trimellitic acid, and pyromellitic acid can be used.

[Carboxyl chloride]
There is no restriction | limiting in particular about the carboxylic acid chloride used by this invention. Formic acid chloride, acetic acid chloride, propionic acid chloride, butanoic acid chloride, butyric acid chloride, hexanoic acid chloride, octyl acid chloride, cyclohexanecarboxylic acid chloride, phenylacetic acid chloride, acetoacetic acid chloride, oxalic acid dichloride, malonic acid dichloride, succinic acid dichloride, Aliphatic carboxylic acid chlorides such as maleic acid dichloride and glutaric acid dichloride, benzoic acid chloride, anisic acid chloride, 2-naphthalenecarboxylic acid chloride, terephthalic acid dichloride, isophthalic acid dichloride, phthalic acid dichloride, trimellitic acid trichloride, pyro An aromatic carboxylic acid compound such as merit acid tetrachloride can be used.

[Oxirane compounds]
There is no restriction | limiting in particular about the oxirane compound used by this invention. Oxirane compounds such as ethylene oxide, propylene oxide, 1,2-epoxyhexane, cyclohexene oxide, styrene oxide, and epichlorohydrin can be used.

Hereinafter, the present invention will be specifically described with reference to typical examples, but the present invention is not limited to these.
In addition, the gas chromatograph apparatus 6890N (made by Agilent Technology) was used for the analysis of each component in an Example, DB-1 column (J & W Scientific company make, length 30m, diameter 0.32mm, membrane) as an analysis column A thickness of 1 μm) was used.

[Example 1]
A stirring bar, 0.37 g (10 mmol) of lithium aluminum hydride, and 15 ml of tetrahydropyran were added to an eggplant flask having a capacity of 100 ml under ice cooling and stirred.
Thereafter, a solution of 2.4 g (20 mmol) of acetophenone in 5 ml of tetrahydropyran was added over 20 minutes under ice zero, and the mixture was further stirred at room temperature for 2 hours.
20 ml of water was added to the reaction solution, sol-gel aluminum hydroxide was separated with Kiriyama filter paper 5A, and the solution was separated. The tetrahydropyran layer and the aqueous layer of 1-phenylethanol were quantified by GC. The results are shown in Table 1.

[Example 2]
The same procedure as in Example 1 was followed, and after the reduction reaction, 20 g of 85% phosphoric acid was added to the aqueous layer. As a result, aluminum hydroxide was clearly dissolved in the aqueous layer, and both the tetrahydropyran layer and the aqueous layer became colorless and transparent. It was. The pH of the aqueous layer at this time was 1. The solution was separated, and 1-phenylethanol in the tetrahydropyran layer and the aqueous layer was quantified by GC. The results are shown in Table 1.

[Comparative Example 1]
The procedure was the same as in Example 1 except that tetrahydrofuran was used instead of tetrahydropyran as a solvent. The reaction results are shown in Table 1.

[Comparative Example 2]
The same procedure as in Example 2 was performed, except that tetrahydrofuran was used instead of tetrahydropyran as a solvent. The reaction results are shown in Table 1.

[Example 3]
After performing the reduction reaction by performing the same procedure as in Example 1, 20 ml of water was added, and 2 g of sulfuric acid was further added. As a result, the tetrahydropyran layer and the aqueous layer were colorless and transparent and separated. The pH of the aqueous layer at this time was 1.
When 1-phenylethanol in the tetrahydropyran layer was quantified by GC, the yield was 94%.

[Example 4]
The same procedure as in Example 1 was followed to carry out the reduction reaction, 20 ml of water was added, and 6 g of sodium dihydrogen phosphate was further added. As a result, the tetrahydropyran layer became colorless and transparent and the aqueous layer became cloudy. Liquid separation was performed. The pH of the aqueous layer at this time was 4.
When 2-phenylethanol in the tetrahydropyran layer was quantified by GC, the yield was 95%.

[Example 5]
A stirring bar, 0.37 g (10 mmol) of lithium aluminum hydride, and 15 ml of tetrahydropyran were added to an eggplant flask having a capacity of 100 ml under ice cooling and stirred.
Thereafter, a solution of 1.50 g (10 mmol) of ethyl benzoate in 5 ml of tetrahydropyran was added over 20 minutes under ice zero, and the mixture was further stirred at room temperature for 2 hours. When 10 ml of water was added to the reaction solution and 20 g of phosphoric acid was further added, the tetrahydropyran layer and the aqueous layer were colorless and transparent and separated. The pH of the aqueous layer at this time was 1.
When benzyl alcohol with the tetrahydropyran layer was quantified by GC, the yield was 88%.

[Example 6]
The reduction reaction was carried out in the same procedure as in Example 1 except that 0.54 g (10 mmol) of sodium aluminum hydride was used as the aluminum hydride compound. The treatment after the reduction reaction was performed in the same manner as in Example 2. The results are shown in Table 2.

[Example 7]
The reduction reaction was performed in the same procedure as in Example 1, except that 0.43 g (5 mmol) of magnesium aluminum hydride was used as the aluminum hydride compound. The treatment after the reduction reaction was performed in the same manner as in Example 2. The results are shown in Table 2.

[Example 8: Phosphate treatment]
After performing the reduction reaction by performing the same procedure as in Example 1, 30 ml of water was added, and 5 g of sodium dihydrogen phosphate was further added. The tetrahydropyran layer was colorless and transparent, and the aqueous layer was white and separated. did. At this time, the pH of the aqueous layer was 5.
When 1-phenylethanol in the tetrahydropyran layer was quantified by GC, the yield was 91%.

In the method for reducing organic compounds such as aldehyde compounds, ketone compounds, ester compounds, carboxylic acid compounds, acid chloride compounds, and oxirane compounds of the present invention, a composition comprising tetrahydropyran and an aluminum hydride compound such as lithium aluminum hydride is used. As a result, the reaction solvent and the extraction solvent can be made the same, so that the reaction process can be simplified and the energy cost can be reduced. Moreover, the safety | security to a biological body also increases by using tetrahydropyran with low toxicity as a solvent.
Furthermore, the produced | generated alcohol can be efficiently isolated by processing the aqueous layer after reaction with an acid.

Claims (9)

Following formula (1)

(Wherein M represents a metal or atomic group that can be an X-valent cation, and X represents an integer of 1 to 3) and a composition comprising tetrahydropyran. The composition according to claim 1, wherein the compound represented by the formula (1) is NaAlH ₄ . The composition according to claim 1, wherein the compound represented by the formula (1) is Mg (AlH ₄ ) ₂ .   In the composition according to claim 1, after reducing an aldehyde compound, a ketone compound, an ester compound, a carboxylic acid compound and an acid chloride compound, water is added to recover an alcohol compound which is a reaction product in tetrahydropyran. A process for producing an alcohol compound characterized by the above.   In the composition according to claim 1, after reducing an aldehyde compound, a ketone compound, an ester compound, a carboxylic acid compound and an acid chloride compound, an acidic aqueous solution is added to recover an alcohol compound which is a reaction product in tetrahydropyran. The manufacturing method of the alcohol compound of Claim 4.   The production method according to claim 5, wherein the acid in the acidic aqueous solution is a protonic acid.   The production method according to claim 5 or 6, wherein the acid in the acidic aqueous solution is an acid containing phosphorus.   The manufacturing method in any one of Claims 5-7 in which the acid in acidic aqueous solution contains phosphoric acid and / or a phosphate. The pH of an aqueous layer is 5 or less, The manufacturing method in any one of Claims 5-8 characterized by the above-mentioned.