JP3221151B2 - Method for producing pyrrole derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a process for producing a pyrrole-3-carboxylic acid derivative having improved yield, simplicity and safety.

[0002]

2. Description of the Related Art Several methods for producing derivatives of 4-methylpyrrole-3-carboxylic acid have been known so far. However, as a direct synthesis method, tosylmethyl isocyanide and crotonic acid ester are used as raw materials. Is the most frequently used method. (References, AMv Leus
en. et al. , Tetrahedron Let
t. However, this reaction is significantly disadvantageous from an industrial point of view in the following respects. 1) It is extremely dangerous because it is necessary to use ignitable sodium hydride in an equivalent amount or more. 2) It is necessary to dehydrate the reaction solvent used, which is complicated. 3) Tosyl methyl isocyanide is very expensive as a reagent.

[0003] Next, as a past production method similar to the present invention, 2-carboxy-4-methylpyrrole-3-acid was prepared by reacting a 0.535 M aqueous solution of sodium oxalate ethyl acetate with aminoacetone in water. Methods for producing ethyl carboxylate are known. (R. La
ncaster et al. , J. et al. Org. Che
m. , 23 , 1208, 1958) According to this method, it is safe because water is used as a solvent,
In addition, since each reagent can be obtained or manufactured at low cost, it has industrially advantageous characteristics. However, when we strictly repeated the example reported in this paper, it was found that there were the following problems. 1) The yield of ethyl 2-carboxy-4-methylpyrrole-3-carboxylate was 52.8%, but it was 45% or less in our additional test. 2) It is described that 4-methylpyrrole-3-carboxylic acid was quantitatively obtained by decarboxylation of the pyrrole using potassium hydroxide, but in our additional test, the yield was very small,
The product was mostly 4-methylpyrrole-2,3-dicarboxylic acid.

Further, as for the decarboxylation of 2-pyrrolecarboxylic acids such as pyrrole, a method using a copper-quinoline system is known as the most general method.
However, the reaction temperature is rather high (usually 170 ° C
In the case of mass synthesis, special equipment must be used, which is disadvantageous from an industrial point of view. Also, the reaction is not necessarily a high yield.

As described above, there is no method for producing a pyrrole-3-carboxylic acid derivative which is satisfactory in terms of safety, simplicity and yield.

[0006]

SUMMARY OF THE INVENTION An object of the present invention is to produce a pyrrole-3-carboxylic acid derivative safely, simply, stably and in good yield.

[0007]

Means for Solving the Problems Constitution of the Invention The production method of the present invention comprises the following reactions.

Reaction A: Formula [II] R ¹ COCH ₂ NH ₂ [II] wherein R ¹ has the same meaning as described above. The solution of the compound represented by the formula (III)

Embedded image [Wherein, R ² represents an alkyl group which may have a substituent, an alkenyl group which may have a substituent, or an alkynyl group which may have a substituent, and Z is an alkali metal or an alkaline earth. Represents a metal. 0.05 to 0.5 of the compound represented by
Molar solution and reacting to give the formula (IV)

Embedded image [Wherein, R ¹ and R ² represent the same meaning as described above. Is produced.

Reaction B: Formula [IV]

Embedded image [Wherein, R ¹ and R ² represent the same meaning as described above. The compound represented by the formula [V]

Embedded image [Wherein, R ¹ and R ² represent the same meaning as described above. Is produced.

Reaction C: Formula [V]

Embedded image [Wherein, R ¹ and R ² represent the same meaning as described above. The compound represented by the formula [I]

Embedded image [Wherein, R ¹ has the same meaning as described above. Is produced.

DETAILED DESCRIPTION Next, the present invention will be described in detail.

An alkyl group or alkenyl group for R ¹ and R ² ,
Examples of the substituent of the alkynyl group include halogen, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, dialkylamino, amide and the like.

Description of Reaction A The compound represented by the formula [II] is produced, for example, by the following reaction.

Embedded image In the formula, R ¹ has the same meaning as described above. In the reaction A, first, a hydrochloric acid solution of the compound represented by the formula [II] is prepared (at this time, the pH is set to 0.5 to 5, preferably 1 to 3). Examples of the solvent include water or a mixture of water and an inert solvent such as alcohol and DMF. next,
A solution of the compound represented by the formula [III] (Z is preferably an alkali metal, more preferably lithium or sodium) (the concentration is 0.05 to 0.5 M,
Preferably, it is 0.05-0.4M, more preferably 0.
The solvent is water or a mixture of water and an inert solvent such as alcohol and DMF. )
Is heated to 70 to 85 ° C., preferably 75 ± 3 ° C., and the solution of the compound represented by the formula [II] prepared above is added thereto. At this time, when the pH value becomes 0.3 to 0.5 lower than the pH value (usually 5 to 6) at the time when crystals start to precipitate, an alkaline solution (preferably lithium hydroxide,
Or sodium hydroxide) to bring the pH back within 0.5. After the addition, depending on the scale, it is usually heated for 0 to 2 hours, preferably for 20 minutes to 1 hour.
Cool to around room temperature and filter the resulting crystals. The desired product can be obtained by washing with water or a diluted acidic aqueous solution and then drying.

Description of Reaction B Pyrrole of the formula [IV] and an organic base (for example, primary amines such as ethanolamine and ethylenediamine,
Di-n-propylamine, morpholine, 2,2,6,6
Secondary amines such as tetramethylpiperidine, N-methylmorpholine, tertiary amines such as diazabicyclo [2,2,2] octane (DABCO), N, N-dimethylethanolamine, DBU, DBN, guanidine Organic bases having a boiling point of 100 ° C. or higher, such as natural amidines, preferably morpholine, DABCO, DBU, etc.)
Is used in an amount of 1 to 3 equivalents to the pyrrole [IV]. At this time, the organic base may be used alone or in combination with an appropriate organic solvent. The reaction temperature is 100 to 150 ° C, and the reaction time is 3
0-5 hours. The completion of the reaction can be confirmed by tracking the consumption of pyrrole [IV] using thin layer chromatography or the like. After completion of the reaction, the reaction solution is cooled to around room temperature to make the reaction solution acidic and then subjected to ordinary post-treatment.
Purification can be carried out in a conventional manner, for example, by column chromatography to obtain the desired product.

Description of Reaction C Using a 2-6M alkaline solution at 70-reflux temperature, 3
React for 0 minutes to 5 hours. After standing to cool, the reaction solution is made acidic, and the precipitated crystals are filtered, washed and dried to obtain the desired product. In the present invention, the structure of the compound was confirmed by IR, NMR, MASS, melting point and the like.

[0016]

【Example】

 Next, the present invention will be described more specifically with reference to examples. Example 1

Embedded image 45 ml of water and 90 ml of concentrated hydrochloric acid were added to 30 g of N-acetonylphthalimide, and the mixture was heated under reflux for 4 hours. After cooling, 3
A 0% NaOH aqueous solution was added to adjust the pH to about 1.5, and an aminoacetone hydrochloric acid aqueous solution (400 ml) was adjusted. Next, 30 g of an aqueous solution (960 ml) of ethyl sodium acetate macaque (Tokyo Chemical, purity 90%) was added to about 7 ml.
The mixture was heated to 5 ° C., and the aminoacetone solution prepared above was added dropwise over 30 minutes. During the dropping, when the pH reached 4.9, the pH was adjusted to 5.1 by adding a 1N aqueous solution of NaOH. After completion of the dropwise addition, the mixture was directly heated for 30 minutes and allowed to cool to room temperature. The precipitated crystals were filtered, washed with water, and dried to obtain 13.7 g of 2-carboxy- as primary crystals.
Ethyl 4-methylpyrrole-3-carboxylate was obtained. The filtrate was adjusted to pH 8 by adding a dilute aqueous solution of NaOH, and again at 75 ° C.
And stirred for 30 minutes. After standing to cool, concentrated hydrochloric acid was added to acidify (pH 3 or less), and the precipitated crystals were filtered,
After washing with water and drying, 1.1 g as a secondary crystal was obtained.
I got Total yield 14.8 g (65% yield) mp. 19
6-198 ° C

Embodiment 2

Embedded image A mixture of 19.7 g of ethyl 2-carboxy-4-methylpyrrole-3-carboxylate and 13 g of morpholine was added to 12 g
The mixture was heated to 0 to 130 ° C. and stirred for 5 hours. After cooling, 150 ml of water and 150 ml of methylene chloride were added, and 5 ml of concentrated hydrochloric acid was slowly added while cooling. The aqueous layer was further extracted with methylene chloride (150 ml, twice), and the combined organic layers were washed with 150 ml of water. After drying over sodium sulfate, the solvent was distilled off, and the residue was subjected to silica gel column chromatography (developing solvent: hexane-ethyl acetate v / v).
v = 7/3) to obtain 11.4 g of ethyl 4-methylpyrrole-3-carboxylate. (75% yield)
mp. 75-77 ° C

Embodiment 3

Embedded image A mixture of 19.7 g of ethyl 2-carboxy-4-methylpyrrole-3-carboxylate and 13 g of morpholine was reacted in the same manner as in Example 2, and post-treatments such as extraction were also performed in the same manner. To the obtained residue, 5.3 M KOH aqueous solution (50 ml)
Was added and the mixture was heated under reflux for 4 hours. After standing to cool, 50 ml of water was added, and under cooling, 20 ml of concentrated hydrochloric acid was slowly added. The precipitated crystals were filtered, washed with water, and dried to obtain 8.7 g of 4-methylpyrrole-3-carboxylic acid. (70% yield) mp. 153 ° C

[0019]

In reaction A, as can be seen from Example 1, by reducing the concentration of the solution of the compound represented by the formula [III], by-products can be suppressed and the desired product can be obtained in good yield. it can. Also, as is clear from other examples,
For the first time, it has become possible to produce the pyrrole-3-carboxylic acid derivative [I] safely, simply and stably in good yield.

Claims (4)

(57) [Claims] 1. A compound of the formula [I], which comprises the following steps a to c: [In the formula, R ¹ represents an alkyl group which may have a substituent, an alkenyl group which may have a substituent, or an alkynyl group which may have a substituent. ] The manufacturing method of the compound represented by this. Step a: Formula [II] R ¹ COCH ₂ NH ₂ [II] wherein R ¹ has the same meaning as described above. And a solution of the compound represented by the formula [III] [Wherein, R ² represents an alkyl group which may have a substituent, an alkenyl group which may have a substituent, or an alkynyl group which may have a substituent, and Z is an alkali metal or an alkaline earth. Represents a metal. 0.05 to 0.5 of the compound represented by
The reaction is carried out by adding the solution to a molar solution. [Wherein, R ¹ and R ² represent the same meaning as described above. Step b: decarboxylating a compound represented by the formula [IV] in the presence of an organic base to give a compound represented by the formula [V]: [Wherein, R ¹ and R ² represent the same meaning as described above. Step c: hydrolyzing the compound represented by the formula [V] to give a compound represented by the formula [I] [Wherein, R ¹ has the same meaning as described above. A process for producing the compound represented by the formula 2. Formula [II] R ¹ COCH ₂ NH ₂ [II] wherein R ¹ has the same meaning as in claim 1 . And a solution of the compound represented by the formula [III] [Wherein R ² and Z have the same meanings as in claim 1] . ]
Wherein the compound represented by the formula (IV) is reacted by adding to a 0.05 to 0.5 molar solution of the compound represented by the formula: [Wherein, R ¹ and R ² represent the same meaning as described above. ] The method for producing the compound represented by the formula: 3. A compound represented by the formula [V], wherein the compound represented by the formula [IV] is decarboxylated in the presence of an organic base. Wherein R ¹ and R ² have the same meaning as in claim 1 . ]
A method for producing a compound represented by the formula: 4. A compound represented by the formula [IV] is decarboxylated in the presence of an organic base to give a compound of the formula [V] Wherein R ¹ and R ² have the same meaning as in claim 1 . ]
Wherein the compound represented by the formula (I) is produced and then hydrolyzed. [Wherein, R ¹ represents the same meaning as described above. ] The method for producing the compound represented by the formula: