JPH09169679A - Method for reducing carboxylic acid or carboxylic acid ester - Google Patents

Abstract

(57) Abstract: In a method for obtaining an alcohol by reducing a carboxylic acid or a carboxylic acid ester with diisobutylaluminum hydride, the reducing ability of diisobutylaluminum hydride is further enhanced, and a corresponding alcohol containing no impurities has a high selectivity. The problem is to obtain a high yield. SOLUTION: In a reaction of reducing a carboxylic acid or a carboxylic acid ester with diisobutylaluminum hydride to obtain an alcohol, a compound represented by the general formula [1] R _3-n AlCl _n (wherein R represents an alkyl group having 1 to 6 carbon atoms) And n is 1, 1.5, 2, or 3), the reduction reaction is carried out in the presence of an alkylaluminum chloride.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a carboxylic acid or a carboxylic acid ester in organic synthesis of pharmaceuticals,
The present invention relates to a method for producing a corresponding alcohol having a small amount of impurities with high selectivity, high yield and at low cost.

[0002]

2. Description of the Related Art A method for obtaining an alcohol by reducing a carboxylic acid or a carboxylic acid ester with diisobutylaluminum hydride is known. In that case, the use of pure diisobutylaluminum hydride is described in New Experimental Chemistry Lecture 12 , page 316, but it is always possible to obtain the corresponding alcohol having a small amount of impurities in a sufficiently satisfactory selectivity and yield. could not. Moreover, diisobutylaluminum hydride is usually
Since it is produced by pyrolyzing triisobutylaluminum, it is difficult to obtain pure diisobutylaluminum hydride, and therefore, diisobutylaluminum hydride containing triisobutylaluminum has always been used. This mixture of triisobutylaluminum reduces the reducing ability of diisobutylaluminum hydride, by-produces an aldehyde as a partial reduction product that causes coloration, or causes an addition reaction to generate a compound that is difficult to decompose, This has been a cause of further lowering both the selectivity and the yield.

Particularly in the field requiring high-purity products such as pharmaceuticals, it is not preferable that even a trace amount of impurities remains.
In order to remove this impurity, an expensive refining process is required, and the process rapidly becomes more expensive if the amount of the impurity increases as much as possible. In addition, for high molecular weight compounds such as pharmaceuticals, it is difficult to use simple purification methods such as distillation and recrystallization that are usually used in the chemical industry. Therefore, a reduction method with high selectivity and high yield has been demanded.

[0004]

Therefore, the present invention further enhances the reducing ability of diisobutylaluminum hydride in a method for obtaining an alcohol by reducing a carboxylic acid or a carboxylic acid ester with diisobutylaluminum hydride, and is free from impurities. It is an object to obtain an alcohol to be used with high selectivity and high yield. Furthermore, the present invention does not reduce the reducing ability of diisobutylaluminum hydride even when using diisobutylaluminum hydride containing triisobutylaluminum, which is more easily and cheaply available than pure diisobutylaluminum hydride, and does not reduce pure diisobutylaluminum. It is an object to obtain a corresponding alcohol that does not contain impurities such as aldehyde, which is a partial reduction product that causes coloration, with the same selectivity and yield as in the case of using hydride.

[0005]

Means for Solving the Problems As a result of intensive studies to solve the above problems, the present inventors have found that a carboxylic acid or a carboxylic acid ester is treated with diisobutylaluminum hydride in the presence of a certain alkylaluminum chloride. It was found that the corresponding alcohol can be obtained with a high selectivity and a high yield by reduction with, and the present invention was completed.

That is, the present invention provides a compound of the general formula [1] in the reaction of reducing a carboxylic acid or a carboxylic acid ester with diisobutylaluminum hydride to obtain an alcohol.
(Formula 3)

Embedded image (Wherein R represents an alkyl group having 1 to 6 carbon atoms and n represents 1, 1.5, 2 or 3), and the reduction reaction is carried out in the presence of an alkylaluminum chloride. , A carboxylic acid or a carboxylic acid ester.

According to another aspect of the present invention, in the reaction of reducing a carboxylic acid or a carboxylic acid ester with diisobutylaluminum hydride to obtain an alcohol, when the diisobutylaluminum hydride contains triisobutylaluminum, the triisobutylaluminum is converted into an alkylaluminum chloride. General formula [2] (Chemical formula 4) in an amount sufficient to change

Embedded image (Wherein R represents an alkyl group having 1 to 6 carbon atoms, m represents 1.5, 2 or 3), and a reduction reaction is carried out by adding an alkylaluminum chloride. It is a method of reducing an acid or a carboxylic acid ester.

[0008]

The present invention will be described in more detail below. The carboxylic acid or carboxylic acid ester used in the present invention may be either an aromatic carboxylic acid or its ester, an aliphatic carboxylic acid or its ester, and the substituent is also a substituent which is not affected by the present reduction reaction. anything is fine. Further, the number of carboxyl groups or ester groups is not limited to one and may be 2 to 4. The alcohol residue of the ester may be any, but an alkyl group having 1 to 5 carbon atoms is preferable. Examples of such compounds include n-butyl caproate, benzoic acid,
Examples thereof include methyl benzoate, methyl naphthoate, methyl methacrylate, diethyl fumarate, malonic acid, diisopropyl malonate and diethyl tartrate.

The reducing agent diisobutylaluminum hydride used in the present invention may be one synthesized by any method, but generally, one synthesized by thermally decomposing triisobutylaluminum is used. Although diisobutylaluminum hydride synthesized by this method can be used as a pure product by distillation under strict conditions, it usually contains a small amount of triisobutylaluminum, and this small amount of triisobutylaluminum is contained. Diisobutylaluminum hydride containing can also be used.

The alkylaluminum chloride necessary for the reaction system is a compound represented by the general formula [1]. R is an alkyl group having 1 to 6 carbon atoms, for example, an ethyl group,
An n-propyl group and an isobutyl group. n is 1, 1.
5, 2 or 3, and preferred examples of these compounds are diethyl aluminum chloride, ethyl aluminum sesquichloride, ethyl aluminum dichloride, isobutyl aluminum dichloride,
Aluminum chloride. The present invention can be carried out even if these compounds are mixed.

When pure diisobutylaluminum hydride is used as the reducing agent, the reaction can be carried out by adding the alkylaluminum chloride of the general formula [1] to the reaction solution, and a sufficient effect can be obtained. When diisobutylaluminum hydride containing a small amount of triisobutylaluminum is used as the reducing agent, by adding an alkylaluminum chloride of the general formula [2], for example, isobutylaluminum dichloride, the following formula The reaction can be carried out by changing triisobutylaluminum to diisobutylaluminum chloride as in (1).

Embedded image

When pure diisobutylaluminum hydride is used, the amount of alkylaluminum chloride added is preferably 3 mol% or more, more preferably 5 mol% or more, of the alkylaluminum chloride of the general formula [1] based on diisobutylaluminum hydride. When diisobutylaluminum hydride containing a small amount of triisobutylaluminum is used, the amount of the alkylaluminum chloride of the general formula [2] is not less than the amount sufficient to convert triisobutylaluminum to alkylaluminum chloride. Equivalent amount or more, and preferably 3 mol% or more of diisobutylaluminum hydride, more preferably 5 mol% or more. Although the upper limit of the addition amount is not particularly limited, adding too much lowers the concentration of diisobutylaluminum hydride and increases the total amount of alkylaluminum compounds, resulting in a decrease in reaction rate and an increase in reaction vessel volume. However, this is not preferable because the industrial disadvantages such as an increase in the amount of heat used increase.

When diisobutylaluminum hydride containing a small amount of triisobutylaluminum is used, the effect of addition of alkylaluminum chloride is greater when the ratio Cl / Al of chlorine and aluminum is larger, if the number of moles is the same. Specifically, the order is aluminum chloride> alkyl aluminum dichloride> alkyl aluminum sesquichloride. However, alkylaluminum dichloride is most preferable because aluminum chloride is a solid and therefore difficult to handle and mix.

The reason why the compound having a higher Cl / Al ratio has a larger addition effect may be a solvent effect, a catalytic effect, and a change in the intermolecular ring structure formed by the alkylaluminum compound in the solvent, but it is not clear. . In the method of adding the alkylaluminum chloride of the general formula [1] or [2] to diisobutylaluminium hydride, both may be mixed directly or diluted with a solvent and mixed. In most cases, heat is generated by mixing, so it is necessary to be careful about overheating.

As the solvent used in the reaction and mixing, aliphatic hydrocarbons such as hexane, heptane, octane and liquid paraffin, aromatic hydrocarbons such as benzene, toluene and xylene, and ethers such as Examples thereof include ethyl ether, butyl ether, ethylene glycol dimethyl ether and the like. The reaction is carried out by adding [1] to the raw material carboxylic acid or carboxylic ester.
Alternatively, diisobutylaluminum hydride added with [2] alkylaluminum chloride may be added dropwise. Conversely, diisobutylaluminum hydride added with [1] or [2] alkylaluminum chloride may be added with carboxylic acid or carboxylic acid. The acid ester may be added dropwise.

If the reaction temperature is too low, the reaction will not proceed, and if it is too high, the isobutylaluminum will self-decompose or a side reaction will occur. Therefore, the reaction temperature is generally -30 to 100 ° C, preferably Is used in the range of 0 to 60 ° C. After completion of the reaction, any generally known reaction may be used to decompose the formed complex. For example, it can be decomposed with methanol and water. After decomposing the complex, the aluminum compound is filtered, the filtrate is concentrated, and then the alcohol can be separated by a method such as distillation or recrystallization.

According to the method of the present invention, in the reaction of reducing a carboxylic acid or a carboxylic acid ester with diisobutylaluminum hydride to obtain an alcohol, when pure diisobutylaluminum hydride is used as a reducing agent, the selectivity and the yield are improved. Not only the reduction, but even when using diisobutylaluminum hydride containing a small amount of triisobutylaluminum, the reduction proceeds completely, reducing the generation of impurities and producing the corresponding alcohol with high selectivity and high yield. can do.

[0018]

EXAMPLES Hereinafter, the present invention will be described more specifically with reference to Examples, but the scope of the present invention is not limited thereto. Example 1 In a 500 ml flask which had been sufficiently replaced with nitrogen, 13.6 g (0.10 mol) of methyl benzoate and 200 m of toluene were added.
1 was added and stirred. Pure diisobutylaluminum hydride (hereinafter abbreviated as DIBAH) /
93.7 g of a 30% solution of toluene (2 as DIBAH
9.07 g (0.20 mol) of diisobutylaluminum chloride 1.77 g (0.010 mol, DIBAH)
(5 mol%) was added dropwise over 2 hours. The temperature inside the flask rose to 47 ° C. After the dropping was completed, stirring was continued for another 2 hours while maintaining the temperature at 45 ° C., and then the mixture was allowed to cool to room temperature, and 32.0 g of methanol was added thereto.
(1.0 mol) / toluene 40 ml, then water 18.0
g (1.0 mol) / methanol (30 ml) was added dropwise to decompose the complex. The reaction mixture was filtered using a glass filter, concentrated, and then distilled under reduced pressure to obtain 10.2 g (0.094 mol) of benzyl alcohol. The yield is 94
%Met.

Comparative Example 1 Synthesis was carried out in the same manner as in Example 1 except that pure DIBAH / toluene solution was used without adding diisobutylaluminum chloride. The amount of benzyl alcohol obtained was 9.08 g (0.084 mol), and the yield was 84%.

Examples 2 to 4 The amount of diisobutylaluminum chloride added to DIBAH was examined. The synthesis was carried out according to Example 1. The results are shown in Table 1 (Table 1).

[0021]

[Table 1]

Example 5 As a reducing agent, 107.0 g of a 30% toluene solution of a mixture of 90 wt% DIBAH and 10 wt% triisobutylaluminum (28.9 g of DIBAH (0.20 mol), 3.2 g of triisobutylaluminum (0. 01
6 mol)) was added according to Example 1 except that 2.48 g (0.016 mol, 8 mol% based on DIBAH) of isobutylaluminum dichloride was added. The benzyl alcohol obtained was 10.
With 3 g (0.095 mol), the yield was 95%.

Comparative Example 2 Synthesis was carried out according to Example 2 except that the reducing agent was used without adding isobutylaluminum dichloride. The amount of benzyl alcohol obtained was 8.11 g (0.075 mol), and the yield was 75%.

[0024]

Industrial Applicability According to the method of the present invention, an alcohol useful in organic synthesis of pharmaceuticals and the like can be produced from a carboxylic acid or a carboxylic acid ester with few impurities and at a low cost.

Claims (4)

[Claims] 1. In a reaction of reducing a carboxylic acid or a carboxylic acid ester with diisobutylaluminum hydride to obtain an alcohol, a compound of the general formula [1] (Chemical Formula 1) (Wherein R represents an alkyl group having 1 to 6 carbon atoms and n represents 1, 1.5, 2 or 3), and the reduction reaction is carried out in the presence of an alkylaluminum chloride. A method for reducing a carboxylic acid or a carboxylic ester. 2. The reduction method according to claim 1, wherein the amount of the alkylaluminum chloride of the general formula [1] present is 3 mol% or more of diisobutylaluminum hydride. 3. When the diisobutylaluminum hydride contains triisobutylaluminum, a sufficient amount of the general formula [2] (Chemical formula 2) [Chemical formula 2] to convert the triisobutylaluminum to alkylaluminum chloride is obtained. The reduction method according to claim 1, wherein an alkylaluminum chloride represented by the formula (wherein R represents an alkyl group having 1 to 6 carbon atoms and m represents 1.5, 2 or 3) is added. 4. The reduction method according to claim 3, wherein the amount of the alkylaluminum chloride of the general formula [2] to be added is 3 mol% or more of diisobutylaluminum hydride.