JP2008001632A - Reduction reaction by borohydride compound in the presence of metal salt using tetrahydropyran as solvent - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To solve problems in a method for manufacturing an alcohol compound by reducing an ester compound by a borohydride compound that, when lithium borohydride or the like is used as the borohydride compound, it is difficult to extract a resultant alcohol and that, when sodium borohydride or the like is used as the borohydride compound, its reducing power is too weak to reduce the ester compound. <P>SOLUTION: Reduction using a composition comprising a borohydride compound and a metal salt in tetrahydropyran permits the use of a borohydride compound that does not react with water violently while it has weak reduction power and is easily handleable. As the same solvent can be used as a reaction solvent and an extraction solvent, simplification of reaction processes, reduction of energy costs and the like are realized. Further, the use of low toxic tetrahydropyran as the solvent enhances safety to a living organism. Thus, the reduction reaction or the like of the ester compound can be carried out more efficiently. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a composition containing a borohydride compound and a metal salt in tetrahydropyran, and a method for producing an alcohol compound using the composition.

Conventionally, the reduction reaction of an ester compound with a borohydride compound is generally performed in a non-aqueous solvent.
Examples of the borohydride compound used in such a method include lithium borohydride (J. Am. Chem. Soc., 62 p3429 (1940): Non-Patent Document 1), calcium borohydride (Collect. Czech. Chem). Comm. 37 p2962 (1972): Non-patent document 2), zinc borohydride, tin borohydride and the like are known. However, these compounds are difficult to handle because they are easily decomposed by moisture in the atmosphere and react violently with water.

  For example, calcium borohydride can easily reduce an ester compound in a solvent having a high salt solubility, such as tetrahydrofuran and diethylene glycol dimethyl ether (diglyme). In order to separate it, it is necessary to add water after the reduction reaction. At this time, tetrahydrofuran and diglyme used in the solvent are miscible with water and cannot be separated easily, and it is difficult to recover the produced alcohol. There is a problem that there is.

  On the other hand, sodium borohydride and potassium borohydride are not easily decomposed by moisture in the atmosphere and are easy to handle, but their reducing power is weak and they cannot generally reduce ester compounds (Reduction in Organic Chemistry, Ellis Horwood Ltd., Chichester (1984): Non-Patent Document 3).

J. Am. Chem. Soc., 62 p3429 (1940) Collect. Czech. Chem. Comm. 37 p2962 (1972) Reduction in Organic Chemistry, Ellis Horwood Ltd., Chichester (1984)

  The object of the present invention is to solve the above problems in the method of producing an alcohol compound by reducing an ester compound with a borohydride compound, that is, the problem that extraction of the produced alcohol is difficult, and hydrogenation with strong reducing power. The boron compound has a poor handleability, and a borohydride compound having a low reducing power is to solve the problem of poor reactivity.

As a result of diligent efforts in view of the above problems, the present inventors have used the composition containing a borohydride compound and a metal salt in tetrahydropyran in the reduction reaction of the ester compound, thereby reducing the reducing power of the borohydride compound. It is possible to use a borohydride compound that is easy to handle but has a high reducing power and a low reducing power. Also, since the reaction solvent and the extraction solvent can be the same, the reaction process is simplified and the energy cost is reduced. The present inventors have found that the reduction of the safety and the like can be realized, and further that the use of tetrahydropyran having low toxicity as a solvent increases the safety to living bodies, and the present invention has been completed.
That is, this invention relates to the manufacturing method of the following compositions and alcohol compounds.
[1] A composition comprising a borohydride compound and a metal salt in tetrahydropyran.
[2] The composition according to 1 above, wherein the borohydride compound is one or more selected from the group consisting of sodium borohydride, potassium borohydride, and ammonium borohydride.
[3] The composition according to 1 or 2 above, wherein the metal salt is one or more selected from Group 2 metal and Group 14 metal salts.
[4] The composition as described in 1 or 2 above, wherein the metal salt is at least one selected from salts of Group 3 to Group 12 metals.
[5] The composition according to the above [1] or [2], wherein the metal salt is one or more selected from lanthanoid metal salts.
[6] The composition according to the above 1-2, wherein the metal salt is a lithium salt.
[7] A method for producing an alcohol compound, comprising reducing an ester compound with the composition according to any one of 1 to 6 above.
[8] The method for producing an alcohol compound according to the above 7, wherein water is added after the reduction reaction of the ester compound, and the alcohol compound produced by the reaction is extracted into the tetrahydropyran layer.
[9] A method for adjusting the reducing power of the former by coexisting a borohydride compound and a metal salt of a different type from the borohydride compound in tetrahydropyran.

  By using the composition of the present invention, it is possible to use a borohydride compound that is weak in reducing power but does not react vigorously with water and is easy to handle. In addition, since the reaction solvent and the extraction solvent can be the same, the reaction process can be simplified and the energy cost can be reduced. Furthermore, by using tetrahydropyran having low toxicity as a solvent, safety to living bodies is enhanced. For this reason, the reduction reaction of an ester compound etc. can be performed more efficiently.

The present invention is described in detail below.
The present invention relates to a composition containing a borohydride compound and a metal salt in tetrahydropyran, and a method for producing an alcohol compound in which an ester compound is reduced using the composition.

（式中、Ｍは１価の陽イオンとなり得る金属または原子団を表す。）
で表される化合物である。 [Boron hydride compound]
The borohydride compound used in the present invention has the following formula:

(In the formula, M represents a metal or an atomic group that can be a monovalent cation.)
It is a compound represented by these.

  Here, examples of the borohydride compound in which M is a metal include lithium borohydride, sodium borohydride, and potassium borohydride. In addition, as a borohydride compound in which M can be a monovalent cation, a borohydride compound having organic ammonium (referred to as ammonium borohydride in the present application), for example, tetramethylammonium borohydride, hydrogenated Examples thereof include tetraethylammonium borohydride, tetrabutylammonium borohydride, trimethyloctylammonium borohydride, and trimethylbenzylammonium borohydride.

Among these borohydride compounds, sodium borohydride, potassium borohydride, and ammonium borohydride are particularly preferably used.
As described above, sodium borohydride, potassium borohydride and the like cannot reduce the ester compound in any solvent, but the ester can be reduced by using a metal salt in combination with the tetrahydropyran solvent. It becomes like this. The reason for this will be described later.

[Metal salt]
The metal salt used in the composition with a borohydride compound in the present invention is preferably one that can be dissociated into a metal ion and an anion in tetrahydropyran, particularly one that can be dissolved in tetrahydropyran. Metal salts of Group 2, Group 14, Group 3-12, metal salts of lanthanoids and lithium salts can be used, acetates, nitrates, nitrites, sulfates, phosphates of those metals, Hydrochloride, hydrobromide, hydroiodide, perchlorate, trifluoromethanesulfone, metal alkoxide, and the like can be used.

Specifically, magnesium chloride, magnesium bromide, calcium chloride, and the like can be used as the metal salts of Group 2;
As the metal salt of Group 14, tin chloride, tin bromide, tin trifluoromethanesulfonate, etc. can be used,
As the metal salts of Group 3, yttrium chloride, scandium triflate, etc. can be used,
As the metal salts of Group 4, titanium tetrachloride, titanium tetraisopropoxide, zirconium tetraisopropoxide, etc. can be used.
As the metal salt of Group 5, vanadium chloride, niobium chloride, etc. can be used,
As the metal salt of Group 6, chromium trichloride can be used,
As the metal salt of Group 7, manganese acetate, manganese bromide and the like can be used.
As the metal salt of Group 8, ferric chloride, ferric acetate, ruthenium chloride and the like can be used.
As the metal salt of group 9, cobalt nitrate, cobalt acetate, cobalt chloride, rhodium acetate, rhodium chloride, etc. can be used.
As the metal salt of Group 10, nickel acetate, nickel nitrate, nickel chloride, palladium acetate, palladium chloride and the like can be used.
As the metal salt of Group 11, metal salts such as cuprous chloride, cupric chloride, copper acetate, silver perchlorate can be used,
As the metal salt of group 12, zinc nitrate, zinc acetate, zinc chloride, zinc bromide, zinc iodide, etc. can be used,
As metal salts of lanthanoids, lanthanum trifulate, yttrium triflate, samarium iodide, cerium chloride, etc. can be used.
As the lithium salt, lithium chloride, lithium bromide, or the like can be used.
Among these, tin chloride, tin bromide, zinc chloride, zinc bromide and lithium bromide are particularly preferably used.

[Composition of borohydride compound and metal salt]
Next, the composition of a borohydride compound and a metal salt will be described.
The borohydride compound and the metal salt are dissolved or dispersed in tetrahydropyran at an arbitrary quantitative ratio.
This can be done by dissolving or dispersing a premixed borohydride compound and metal salt in tetrahydropyran, or by first dispersing the borohydride compound in tetrahydropyran and then dissolving the metal salt, or tetrahydropyran. First, any method of dissolving the metal salt and then dispersing the borohydride compound may be used.

  Regarding the quantitative ratio of the borohydride compound and the metal salt, for example, when a borohydride compound having a monovalent alkali metal cation such as sodium borohydride is used as the borohydride compound, the monovalent metal salt 1 mol equivalent of sodium borohydride per 1 mol equivalent, 2 mol equivalent of sodium borohydride per 1 mol equivalent of divalent metal salt, 3 mol equivalent of sodium borohydride per 1 mol of trivalent metal salt Is preferred.

Although it is not clear what composition the borohydride compound and the metal salt form in the tetrahydropyran (THP) solvent, as described above, sodium borohydride is any solvent. In particular, the ester compound cannot be reduced. However, in tetrahydropyran, lithium borohydride reduces the ester.
From this fact, it is presumed that sodium borohydride and lithium bromide exchanged in tetrahydropyran (THP) as shown in the following reaction formula (1) to produce lithium borohydride. .

このことより、他の金属塩に関しても同様に塩交換しているものと推定されるが、本発明はこのような反応を経ているか否かによって限定されるものではない。

From this, it is presumed that other metal salts are similarly subjected to salt exchange, but the present invention is not limited by whether or not such a reaction has been performed.

  Thus, the former reducing power can be adjusted by coexisting a boron hydride compound and a metal salt of a different type from the metal contained in the borohydride compound in tetrahydropyran. That is, it is possible to solve the problem that a borohydride compound having a strong reducing power is poor in handleability and a borohydride compound having a low reducing power is poor in reactivity.

[Ester compound]
The present invention can be used for the reduction reaction of various organic compounds, and can be particularly suitably used for the reduction of ester compounds.
There is no particular limitation on the ester compound used in the present invention, for example, methyl formate, methyl acetate, butyl acetate, methyl propionate, methyl butyrate, methyl hexanoate, methyl octylate, methyl cyclohexanecarboxylate, butyl phenyl acetate, Aliphatic ester compounds such as ethyl acetoacetate, polyvalent aliphatic ester compounds such as dimethyl oxalate, diethyl malonate, diethyl succinate, dimethyl maleate, diethyl glutarate, ethyl benzoate, methyl anisate, 2-naphthalenecarboxylic acid Aromatic ester compounds such as methyl, dimethyl terephthalate, diethyl isophthalate, dioctyl phthalate, trimethyl trimellitic acid, tetramethyl pyromellitic acid, etc., ethyl 2-pyridinecarboxylate, 5-carbohydrate Etc. can be used a heterocyclic ester compound such as phenoxyethyl indole.

  The borohydride compound is used in an amount of at least 2 mol equivalent to the ester compound in terms of hydride. That is, when sodium borohydride is used as the borohydride compound, sodium borohydride has four hydrides, so 0.5 mol equivalent to the ester compound is required.

  The reaction temperature can be between the melting point of tetrahydropyran (−45 ° C.) and the reflux temperature, and is preferably in the range of 0 to 88 ° C.

  In the present invention, by adding water after completion of the reaction, the inorganic substance can be extracted and separated into the aqueous layer and the produced alcohol compound can be separated into the tetrahydropyran layer. That is, it is possible to directly extract and separate the reaction solvent containing the produced alcohol compound without concentrating it or adding a separate extraction solvent, thereby simplifying the reaction process and reducing the energy cost.

Hereinafter, the present invention will be specifically described with reference to typical examples, but the present invention is not limited to these.
In addition, in the analysis of each component in the Examples, a gas chromatography apparatus 6890N (manufactured by Agilent Technologies) was used, and a DB-1 column (manufactured by J & W Scientific, length 30 m, diameter 0.32 mm, A film thickness of 1 μm) was used.

[Example 1]
A stirring bar, 1.34 g (10 mmol) of methyl 3-phenylpropion, 0.38 g (10 mmol) of sodium borohydride, 0.87 g (10 mmol) of lithium bromide, and 10 ml of tetrahydropyran were added to an eggplant flask having a capacity of 30 ml and stirred vigorously. The reaction was allowed to proceed for 8 hours under reflux. After the reaction, 10 ml of water was added and a liquid separation operation was performed between the tetrahydropyran layer and the aqueous layer, and the formation of 3-phenylpropanol extracted into the tetrahydropyran layer was confirmed by GC. The yield was 88%.

[Comparative Example 1: No metal salt added, THP solvent]
A stirring bar, 1.34 g (10 mmol) of methyl 3-phenylpropion, 0.38 g (10 mmol) of sodium borohydride, and 10 ml of tetrahydropyran were added to a eggplant flask having a capacity of 30 ml, and reacted for 2 hours under reflux with vigorous stirring. . When a part of the reaction solution was sampled and analyzed by GC, formation of 3-phenylpropanol was not confirmed.

[Comparative Example 2: No metal salt added, methanol solvent]
A stirring bar, 1.34 g (10 mmol) of 3-phenylpropionmethyl, 0.38 g (10 mmol) of sodium borohydride, and 10 ml of methanol were added to an eggplant flask having a volume of 30 ml, and the mixture was reacted under reflux with vigorous stirring for 2 hours. The reaction solution became uniform. When a part of the reaction solution was sampled and analyzed by GC, formation of 3-phenylpropanol was not confirmed.

[Comparative Example 3: LiBH ₄ reduction in THF solvent]
A stirring bar, 1.34 g (10 mmol) of 3-phenylpropionmethyl, 0.22 g (10 mmol) of lithium borohydride, and 10 ml of tetrahydrofuran were added to an eggplant flask having a volume of 30 ml, and the mixture was reacted under reflux with vigorous stirring for 2 hours. 2 ml of water was added to decompose excess lithium borohydride. The reaction solution is a mixture of water, tetrahydrofuran, and the product. In order to separate the produced 3-phenylpropanol, the reaction solution is distilled off with an evaporator, and then 10 ml of water and 10 ml of ethyl acetate are added to the concentrated solution. It was necessary to perform a liquid separation operation.

[Example 2: Metal salt of Group 2]
A stirring bar, 1.34 g (10 mmol) of 3-phenylpropionmethyl, 0.38 g (10 mmol) of sodium borohydride (SBH), magnesium bromide and 10 ml of tetrahydropyran were added to a 30 ml eggplant flask, and the mixture was refluxed with vigorous stirring. For 8 hours. After the reaction, 10 ml of water was added and a liquid separation operation was performed between the tetrahydropyran layer and the aqueous layer, and the formation of 3-phenylpropanol (alcohol) extracted into the tetrahydropyran layer was confirmed by GC.

[Example 3: Group 14 metal salt]
A stirring bar, 1.34 g (10 mmol) of methyl 3-phenylpropion, 0.38 g (10 mmol) of sodium borohydride (SBH), tin (II) chloride, and 10 ml of tetrahydropyran were added to a 30 ml eggplant flask with vigorous stirring. The reaction was carried out for 8 hours under reflux. After the reaction, 10 ml of water was added and a liquid separation operation was performed between the tetrahydropyran layer and the aqueous layer, and the formation of 3-phenylpropanol (alcohol) extracted into the tetrahydropyran layer was confirmed by GC. The yield was 46%.

[Example 4: Group 3-12 metal salt]
A stirring bar, 1.34 g (10 mmol) of 3-phenylpropionmethyl, 0.38 g (10 mmol) of sodium borohydride (SBH), a metal salt (Table 2), and 10 ml of tetrahydropyran were added to a 30 ml eggplant flask with vigorous stirring. The reaction was carried out for 8 hours under reflux. After the reaction, 10 ml of water was added and a liquid separation operation was performed between the tetrahydropyran layer and the aqueous layer, and the formation of 3-phenylpropanol (alcohol) extracted into the tetrahydropyran layer was confirmed by GC. The results are shown in Table 1.

[Example 5: Lanthanoid metal salt]
A stirring bar, 1.34 g (10 mmol) of 3-phenylpropionmethyl, 0.38 g (10 mmol) of sodium borohydride (SBH), a metal salt (Table 3), and 10 ml of tetrahydropyran were added to a 30 ml eggplant flask with vigorous stirring. The reaction was carried out for 8 hours under reflux. After the reaction, 10 ml of water was added and a liquid separation operation was performed between the tetrahydropyran layer and the aqueous layer, and the formation of 3-phenylpropanol (alcohol) extracted into the tetrahydropyran layer was confirmed by GC. The results are shown in Table 2.

By using the composition of the present invention, it becomes possible to use a borohydride compound that is weak in reducing power but does not react vigorously with water and is easy to handle. In addition, since the reaction solvent and the extraction solvent can be the same, the reaction process can be simplified and the energy cost can be reduced. Furthermore, by using tetrahydropyran having low toxicity as a solvent, safety to the living body is enhanced. For this reason, the reduction reaction of an ester compound etc. can be performed more efficiently.

Claims (9)

  A composition comprising a borohydride compound and a metal salt in tetrahydropyran.   The composition according to claim 1, wherein the borohydride compound is one or more selected from the group consisting of sodium borohydride, potassium borohydride, and ammonium borohydride.   The composition according to claim 1 or 2, wherein the metal salt is one or more selected from a group 2 metal and a group 14 metal salt.   The composition according to claim 1 or 2, wherein the metal salt is one or more selected from salts of Group 3 to Group 12 metals.   The composition according to claim 1, wherein the metal salt is one or more selected from salts of a lanthanoid metal.   The composition according to claim 1 or 2, wherein the metal salt is a lithium salt.   A method for producing an alcohol compound, comprising reducing an ester compound with the composition according to claim 1.   The method for producing an alcohol compound according to claim 7, wherein water is added after the reduction reaction of the ester compound, and the alcohol compound produced by the reaction is extracted into the tetrahydropyran layer. A method of adjusting the former reducing power by coexisting a boron hydride compound and a metal salt of a different type from the borohydride compound in tetrahydropyran.