JPH0586025A - Production of pyrrole derivative - Google Patents

Abstract

PURPOSE:To obtain a 3-acylpyrrole useful as an intermediate for drugs and agricultural chemicals or as a raw material for functional high-molecular materials in high yield and purity without requiring complicated separation and purification processes because the reaction has remarkably high position selectivity. CONSTITUTION:When an N-aromatic sulfonated pyrrole of the formula (Z is aromatic sulfone) is acylated with a carboxylic chloride as an acylating agent in the presence of a Lewis acid, preferably aluminum chloride, by a Friedel.crafs reaction, a nitroalkane and/or a nitroaryl compound such as nitromethane, nitroethane, 1-nitropropane, 2-nitropropane of nitrobenzene is used as a solvent to remarkably improve the position selectivity of the reaction and to selectively introduce an acyl group to the 3-position. The reaction product is hydrolyzed with an alkali for the removal of the sulfone group to profitably obtain a 3- acylpyrrole in an industrial scale.

Description

Detailed Description of the Invention

[0001]

The present invention relates to a synthetic intermediate for pharmaceuticals,
The present invention relates to a method for producing 3-acylpyrrole which is useful as a raw material of a functional polymer material or a synthetic intermediate for agricultural chemicals.

[0002]

BACKGROUND OF THE INVENTION Pyrrole is an aromatic compound having a π-electron excess structure, so that it can be easily reacted by a so-called Friedel-Crafts reaction in which it is reacted with a carboxylic acid chloride in the presence of a suitable Lewis acid. Is acylated. However, the resulting compound usually has an acyl group of 2
It was difficult to selectively obtain 3-acylpyrrole which was 2-acylpyrrole which was in the position of 3-position and which was acylated in 3-position. For this reason, methods for obtaining some 3-acylpyrroles have been conventionally proposed, for example, BL
As shown by Bray et al. In J. Org. Chem., 55 , 6317 (1990), a method of controlling the regioselectivity of the reaction by introducing a bulky triisopropylsilyl group on the nitrogen atom has been tried. However, none of them is said to be suitable for industrial implementation, and the yield was very poor. M. Kakushima et al. Have proposed, as a more economical method, a method for producing 3-acylpyrrole by using N-sulfonated pyrrole in which a sulfone group is introduced on a nitrogen atom and acylating this (J. Org. . Chem.,
48 , 3214 (1983). According to this method, regioselectivity is improved, but it cannot be said to be sufficiently high, and the 2-acyl compound is always produced as a by-product in several%. Therefore, in order to obtain 3-acylpyrrole, it is necessary to separate and purify by column chromatography or the like. There is
It was very inefficient. An object of the present invention is to overcome the problem of by-products in the production of 3-acylpyrrole and to provide a method for producing high-purity 3-acylpyrrole.

[0003]

In the reaction of such N-aromatic sulfonated pyrrole with carboxylic acid chloride in the presence of Friedel-Crafts catalyst, the solvent used in the literature is 1 , 2-dichloroethane was only one kind. As a result of detailed examination of the conditions of the Friedel-Crafts acylation reaction of N-aromatic sulfonated pyrrole, the present inventor surprisingly found that when nitroalkanes or nitroaryls were used as a solvent, the position of the reaction was surprising. It was found that the selectivity is dramatically improved, and as a result, an acyl group is highly selectively introduced at the 3-position,
The present invention has been completed based on this finding.

That is, the present invention is based on the formula

[Chemical 2] (N in the formula, Z represents an aromatic sulfone group.)
-In the acylation of aromatic sulfonated pyrrole and carboxylic acid chloride by the Friedel-Crafts reaction in the presence of Lewis acid, the reaction is carried out in a solvent selected from nitroalkanes and nitroaryls, followed by alkaline hydrolysis. The present invention provides a method for producing 3-acylpyrrole, which comprises desulfonation with.

In the method of the present invention, the aromatic sulfone group on the nitrogen atom of the pyrrole represented by the general formula (I) used as a starting material acts as a protective group, which is present in the presence of a base such as sodium hydride. It is easily introduced by reacting with a suitable aromatic sulfonating agent. Examples of the aromatic sulfonating agent include benzenesulfonic acid chloride, p-toluenesulfonic acid chloride, α-naphthalenesulfonic acid chloride, β-naphthalenesulfonic acid chloride, mesitylenesulfonic acid chloride and 2,4,6-triisopropylbenzenesulfonic acid. Although aromatic sulfonic acid chlorides such as chloride can be mentioned, p-toluenesulfonic acid chloride is preferable from the economical point of view.

Examples of the carboxylic acid chloride used as the acylating agent in the method of the present invention include pentanoyl chloride, hexanoyl chloride, heptanoyl chloride, octanoyl chloride, dodecanoyl chloride, benzoyl chloride and 3-chloropropionyl chloride. , Cyclopropane carbonyl chloride, cyclohexane carbonyl chloride and the like,
It is not limited to these. Friedel
Examples of the Lewis acid as a Krafts catalyst include aluminum chloride, zinc chloride, stannic chloride, titanium tetrachloride, ferric chloride and the like, but aluminum chloride is preferably used from the viewpoint of catalytic activity and selectivity.

In the method of the present invention, the amount of carboxylic acid chloride used is equimolar or more, and preferably 1.1 to 1.5 times the molar amount of pyrrole as the raw material. Examples of the nitroalkanes and nitroaryls include, but are not limited to, nitromethane, nitroethane, 1-nitropropane, 2-nitropropane, and nitrobenzene. The amount of these used is preferably 5 to 15 times (volume) of the raw material pyrrole. The amount of Lewis acid used may vary depending on its type, but in the case of aluminum chloride, it is usually 150 to 25 with respect to the compound of general formula (I).
0 mol% is preferable.

The reaction temperature is not particularly limited as long as it is up to the boiling point of the solvent, but it is preferably carried out in the range of substantially 20 to 40 ° C., and the reaction time of 2 to 3 hours is sufficient.

The N- (aromatic sulfonated) acylpyrrole thus produced is easily desulfonated by alkaline hydrolysis, for example, by treating with an equivalent amount of sodium hydroxide in methanol, resulting in high yield and high purity. Gives acylpyrrole. The obtained 3-acylpyrrole is used as a synthetic intermediate for pharmaceuticals, a raw material for functional polymer materials, and a synthetic intermediate for agricultural chemicals without particular purification, but can be purified by recrystallization or the like, if necessary. But 3
In most cases, the amount of 2-acyl contained in the acylpyrrole is 0.5% or less, which is a substantially negligible amount, and it is not usually necessary to perform troublesome separation means such as conventional column chromatography.

[0010]

EXAMPLES Next, the present invention will be described more specifically with reference to Examples and Comparative Examples, but the present invention is not limited to these Examples.

Example 1 2.93 g (22.0 mmol) of anhydrous aluminum chloride
Is charged into a reaction vessel and cooled with ice under a nitrogen stream. 5 ml of nitromethane was added, followed by 5 ml of n-hexanoyl chloride (1.53 g, 11.4 mmol) of nitromethane.
Add the solution and stir for 15 minutes. Return to room temperature, N- (p
-Toluenesulfonyl) pyrrole 2.21 g (10.0
A solution of 25 mmol of nitromethane in 25 ml is added dropwise and the mixture is stirred for 3 hours. The reaction solution is poured into 40 g of ice, and the organic layer is washed 3 times with water. Once the solvent is distilled off, the remaining oil is diluted with 25 ml of methanol. A solution of 0.48 g (11.4 mmol) of sodium hydroxide in 1 ml of water is added, and the mixture is stirred at 50 ° C. for 1 hour. The solvent was distilled off, the residue was extracted with 1,2-dichloroethane, washed with water and dried over anhydrous magnesium sulfate, and then the solvent was distilled off to give 1.43 g.
(86.3%) crude crystals were obtained. When this product was analyzed by gas chromatography, it contained 0.006% of a 2-acyl compound (this is α) and 99.132% of a 3-acyl compound (this is β). The production ratio α / β ratio was 1/1525.

Example 2 The same operation as in Example 1 was carried out except that the solvent was changed to nitrobenzene. As a result, n-hexanoylpyrrole was obtained with a yield of 93.2%, and its α / β ratio was 1/545. Met.

Comparative Examples 1 to 5 The same conditions as in Example 2 were used except that the kind of solvent was changed. The results are shown in Table 1.

[0014]

[Table 1]

Example 3 The same operation as in Example 1 was carried out except that n-pentanoyl chloride was used as the carboxylic acid chloride, and n-pentanoylpyrrole was obtained in a yield of 95.8%.
The β ratio was 1/768.

Example 4 When n-dodecanoyl chloride was used as the carboxylic acid chloride and the same conditions as in Example 1 were used, the yield was 9
N-dodecanoylpyrrole was obtained at 6.3% and its α / β
The ratio was 1/1990.

Example 5 The same procedure as in Example 1 was carried out except that N- (α-naphthalenesulfonyl) pyrrole was used as the N-sulfonated pyrrole and benzoyl chloride was used as the carboxylic acid chloride to obtain benzoylpyrrole. Obtained at 96.4%.
The α / β ratio was 1/619.

Example 6 N- (mesitylenesulfonyl) pyrrole was used as the N-sulfonated pyrrole and 3-carboxyl chloride was used as the carboxylic acid chloride.
The same operation as in Example 1 was carried out except that chloropropionyl chloride was used, to obtain (3-chloropropionyl) pyrrole with a yield of 92.8%. The α / β ratio is 1/1127
Met.

[0019]

According to the method of the present invention, regioselectivity is so high that 3-acylpyrrole can be obtained in high yield and high purity. Therefore, it is not necessary to perform the conventional complicated separation and purification, and its industrial significance is great.

Claims (1)

[Claims] 1. The formula: (N in the formula, Z represents an aromatic sulfone group.)
-In the acylation of aromatic sulfonated pyrrole and carboxylic acid chloride by the Friedel-Crafts reaction in the presence of Lewis acid, the reaction is carried out in a solvent selected from nitroalkanes and nitroaryls, followed by alkaline hydrolysis. A method for producing 3-acylpyrrole, which comprises desulfonation with