JP2000355589A - Method for obtaining 3-methylthiophene-2-carbaldehyde - Google Patents

Abstract

(57) [Summary] [Problems] 3- useful as a synthetic intermediate for pharmaceuticals, agricultural chemicals, etc.
Provided is a method for industrially and advantageously obtaining methylthiophene-2-carbaldehyde with high purity and high yield. SOLUTION: A mixture of 3-methylthiophene-2-carbaldehyde and 3-methylthiophene-5-carbaldehyde is represented by the following general formula (I): (In the formula, R represents an alkyl group, an alkenyl group, an aryl group which may have a substituent or an aralkyl group which may have a substituent.) Formula (II) (Wherein R is as defined above)
-Methylthiophen-2-imine derivative and general formula (III) (Wherein R is as defined above)
A mixture of -methylthiophen-5-imine derivatives,
Separating a 3-methylthiophen-2-imine derivative from the mixture, and hydrolyzing the obtained 3-methylthiophen-2-imine derivative in the presence of an acid.
A method for obtaining methylthiophene-2-carbaldehyde.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a method for obtaining 3-methylthiophene-2-carbaldehyde. The 3-methylthiophene-2-carbaldehyde produced according to the present invention is a compound useful as a synthetic intermediate for pharmaceuticals, agricultural chemicals and the like.

[0002]

2. Description of the Related Art As a method for producing 3-methylthiophene-2-carbaldehyde, 3-methylthiophene is
A method of reacting phosphorus oxychloride with a Vilsmeier reagent prepared from N, N-dimethylformamide [Journal of the American Chemical Society (Journal of American Chem.)
ical Society), Vol. 75, p. 989 (1
953)] is known.

[0003]

According to the above method, the desired 3-methylthiophene-2-carbaldehyde can be obtained in good yield. However, in this method, it is inevitable that the isomer 3-methylthiophene-5-carbaldehyde is by-produced at a rate of about 10%. Since the physical properties of 3-methylthiophene-2-carbaldehyde and 3-methylthiophene-5-carbaldehyde are similar, it is very difficult to directly separate them by ordinary separation means such as distillation. For example, even if the crude product obtained by the above method is subjected to distillation purification,
-Methylthiophene-2-carbaldehyde has a purity of 9
Since it remains at about 0% and contains 3-methylthiophene-5-carbaldehyde, it may be insufficient when used as it is for pharmaceutical and agricultural chemical applications. -There is a need for a method for obtaining carbaldehyde. Thus, an object of the present invention is to separate 3-methylthiophene-2-carbaldehyde and 3-methylthiophene-5-carbaldehyde, which are difficult to separate by ordinary separation means such as distillation, to obtain highly pure 3-methylthiophene. An object of the present invention is to provide a method for industrially and advantageously obtaining 2-carbaldehyde in good yield.

[0004]

According to the present invention, the above object is achieved by preparing a mixture of 3-methylthiophene-2-carbaldehyde and 3-methylthiophene-5-carbaldehyde of the general formula (I)

[0005]

Embedded image

Wherein R is an alkyl group, an alkenyl group,
Represents an aryl group which may have a substituent or an aralkyl group which may have a substituent. ) (Hereinafter abbreviated as primary amine (I)) to form a compound of the general formula (II)

[0007]

Embedded image

(Wherein R is as defined above)
(Hereinafter referred to as a 3-methylthiophen-2-imine derivative (I)
I)) and the general formula (III)

[0009]

Embedded image

(Wherein, R is as defined above.)
3-methylthiophen-5-imine derivative represented by the following formula (hereinafter referred to as 3-methylthiophen-5-imine derivative (I
II), from which the 3-methylthiophen-2-imine derivative (II) is separated,
The obtained 3-methylthiophen-2-imine derivative (I
3-) characterized in that I) is hydrolyzed in the presence of an acid.
This is achieved by providing a method for obtaining methylthiophene-2-carbaldehyde.

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION In the above general formula, examples of the alkyl group represented by R include a methyl group, an ethyl group, a propyl group,
Isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, hexyl group, heptyl group, octyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, etc. Examples of the alkenyl group include a vinyl group, an allyl group, a methallyl group, a butenyl group, a prenyl group, and an octenyl group.

The aryl group represented by R includes, for example, a phenyl group and a naphthyl group, and the aralkyl group includes, for example, a benzyl group. These aryl group and aralkyl group may have a substituent. Examples of such a substituent include a methyl group, an ethyl group, a propyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, and the like. An alkyl group; a halogen atom such as a fluorine atom, a chlorine atom and a bromine atom; an alkoxyl group such as a methoxy group, an ethoxy group, a propoxy group and a butoxy group; a nitro group and the like, and an aryl group and an aralkyl having these substituents. Specific examples of the group include, for example, a fluorophenyl group, a chlorophenyl group,
Bromophenyl, methoxyphenyl, nitrophenyl, tolyl, xylyl, isopropylphenyl, methoxybenzyl, chlorobenzyl, bromobenzyl, nitrobenzyl and the like can be mentioned.

A feature of the present invention is that 3-methylthiophene is obtained by reacting 3-methylthiophene with Vilsmeier reagent prepared from N, N-dimethylformamide with phosphorus oxychloride and 3-methylthiophene-2-carbaldehyde. -Methylthiophene-5-carbaldehyde is dehydrated and condensed with a primary amine (I) to give a 3-methylthiophene-2-imine derivative (II) and
After obtaining a mixture of the methylthiophen-5-imine derivative (III) and separating only the 3-methylthiophen-2-imine derivative (II) from the mixture, the obtained 3-methylthiophen-2-imine derivative (II) ) Is hydrolyzed in the presence of an acid.
-Methylthiophene-2-carbaldehyde and 3-methylthiophene-5-carbaldehyde were separated in an indirect manner, making it possible to obtain 3-methylthiophene-2-carbaldehyde with high purity. is there.

A mixture of 3-methylthiophen-2-carbaldehyde and 3-methylthiophen-5-carbaldehyde is dehydrated and condensed with a primary amine (I) to give a 3-methylthiophen-2-imine derivative (II) The reaction for obtaining a mixture of and a 3-methylthiophene-5-imine derivative (III) can be carried out in the same manner as the method generally used for obtaining an imine from an aldehyde and a primary amine.

Examples of the primary amine (I) include fatty acids such as methylamine, ethylamine, propylamine, n-butylamine, n-hexylamine, n-octylamine, cyclopropylamine, cyclobutylamine, cyclopentylamine and cyclohexylamine. Aromatic amines;
Examples thereof include aromatic amines such as aniline, p-toluidine, p-anisidine, p-fluoroaniline, p-chloroaniline, p-bromoaniline, p-nitroaniline, and naphthylamine. Among them, aniline, p
-Toluidine, p-anisidine, p-chloroaniline are preferred, and aniline is particularly preferred. The amounts of the primary amines (I) used are 3-methylthiophene-2-carbaldehyde and 3-methylthiophene-5.
-0.5 mol times based on the mixture with carbaldehyde
The range is preferably 2 mole times, more preferably 1 mole to 1.5 mole times.

The reaction is preferably performed in the presence of a solvent. Solvents that can be used include, for example, aliphatic hydrocarbons such as pentane, hexane, cyclohexane, heptane and ligroin; aromatic hydrocarbons such as benzene, toluene, xylene and chlorobenzene; ethers such as diethyl ether, tetrahydrofuran and dioxane; Alcohols such as methanol and ethanol; esters such as methyl acetate, ethyl acetate and butyl acetate. Among them, it is preferable to use an aliphatic hydrocarbon such as pentane, hexane, cyclohexane, heptane, and ligroin, and it is particularly preferable to use hexane. The amount of the solvent used is preferably 1 to 50 times by weight, more preferably 2 to 5 times by weight based on the mixture of 3-methylthiophene-2-carbaldehyde and 3-methylthiophene-5-carbaldehyde used as raw materials. Is more preferred.

The reaction is carried out, for example, with 3-methylthiophene-2
Mixture of a mixture of carbaldehyde and 3-methylthiophene-5-carbaldehyde, primary amine (I) and a solvent, silica gel, molecular sieves, alumina, sodium sulfate, magnesium sulfate, copper sulfate, sodium hydroxide, hydroxide The reaction is carried out in the presence or absence of a dehydrating agent such as potassium. When a solvent azeotropic with water is used, the reaction can be carried out while removing water by azeotropic dehydration.

The thus obtained mixture of the 3-methylthiophen-2-imine derivative (II) and the 3-methylthiophen-5-imine derivative (III) is separated from the reaction mixture by a conventional method. be able to.
For example, after the completion of the reaction, the reaction solution is concentrated, and the residue is subjected to distillation, recrystallization, chromatography and the like. Further, the mixture of the 3-methylthiophen-2-imine derivative (II) and the 3-methylthiophen-5-imine derivative (III) can be directly subjected to the next separation operation without being separated from the reaction mixture.

3-Methylthiophen-2-imine from a mixture of 3-methylthiophen-2-imine derivative (II) and 3-methylthiophen-5-imine derivative (III)
The imine derivative (II) can be separated, for example, by recrystallization utilizing the difference in solubility in the solvent. Further, the mixture can be separated by distillation or chromatography to obtain a 3-methylthiophen-2-imine derivative (II). In a particularly preferred embodiment of the practice of the invention, 3-methylthiophene-2
A solvent in which the mixture of 3-carboxyaldehyde and 3-methylthiophene-5-carbaldehyde is reacted with the primary amine (I) such that the 3-methylthiophen-2-imine derivative (II) is hardly soluble Is used, after the reaction, the resulting solution is cooled to precipitate the 3-methylthiophen-2-imine derivative (II) as crystals. Also, a small amount of the 3-methylthiophen-2-imine derivative (II) may be added as a seed crystal to the solution to precipitate the 3-methylthiophen-2-imine derivative (II). As a method for separating the precipitated 3-methylthiophen-2-imine derivative (II), a normal separation method such as filtration and centrifugation can be used. For example, when aniline is used as the primary amine (I), if hexane is used as a solvent, the resulting 3-methylthiophene-2-carbaldehyde-
Of the mixture of N-phenylimine and 3-methylthiophen-5-carbaldehyde-N-phenylimine, 3
Since -methylthiophen-2-carbaldehyde-N-phenylimine is hardly soluble in hexane, the reaction solution containing the mixture is cooled and filtered to give 3-methylthiophen-2-carbaldehyde-N-phenylimine. Can be easily separated.

Next, the step of hydrolyzing the 3-methylthiophen-2-imine derivative (II) separated as described above in the presence of an acid to obtain 3-methylthiophen-2-carbaldehyde will be described. .

The hydrolysis reaction is preferably performed in the presence of a solvent. The solvent is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include aliphatic hydrocarbons such as pentane, hexane, cyclohexane, heptane, and ligroin; aromatic hydrocarbons such as benzene, toluene, and xylene; diethyl ether , Tetrahydrofuran,
Ethers such as dioxane; halogenated hydrocarbons such as methylene chloride, 1,2-dichloroethane and chlorobenzene; esters such as methyl acetate, ethyl acetate and butyl acetate; or a mixed solvent thereof can be used. Among them, it is preferable to use aromatic hydrocarbons such as benzene, toluene and xylene. The amount of the solvent used is not particularly limited, but is usually 3-methylthiophene-2.
-It is preferable to use the imine derivative (II) in a range of 1 to 10 times by weight.

Examples of the acid include hydrofluoric acid, hydrochloric acid,
Mineral acids such as hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, and hexafluorophosphoric acid; oxo acids such as perchloric acid and periodic acid; methanesulfonic acid, ethanesulfonic acid;
Organic sulfonic acids such as benzenesulfonic acid, toluenesulfonic acid, and trifluoromethanesulfonic acid are included. Among these, it is preferable to use hydrochloric acid. The amount of the acid used is the 3-methylthiophen-2-imine derivative (I
It is preferably in the range of 0.5 to 10 times the mole of I), and
The range of about to 5 mole times is more preferable.

The amount of water used is 3-methylthiophene-2
-The range is preferably 1 to 20 times by weight, more preferably 3 to 10 times by weight, relative to the imine derivative (II).

The reaction temperature is preferably in the range of -50 to 100 ° C, more preferably in the range of 0 to 50 ° C.

The thus obtained 3-methylthiophene-2-carbaldehyde can be separated from the reaction mixture by a conventional method. For example, the reaction mixture is washed with a basic aqueous solution such as a saturated aqueous sodium hydrogen carbonate solution, the solvent is distilled off, and the obtained crude product is purified by distillation, chromatography, or the like.

[0026]

EXAMPLES The present invention will be described in more detail with reference to the following Examples, which should not be construed as limiting the present invention.

REFERENCE EXAMPLE N, N-dimethylformamide (84.9 g, 1.16 mol) was placed in a 2000 ml three-necked flask, and while maintaining the internal temperature at 25 ° C. or less, 177.6 g of phosphorus oxychloride.
(1.16 mol) was added dropwise over 1 hour to prepare a Vilsmeier reagent. Next, the internal temperature of this solution was adjusted to 20 to 2
91.5 g of 3-methylthiophene while keeping at 5 ° C
(0.903 mol) was added dropwise over 2 hours. After completion of the addition, the mixture was further stirred at the same temperature for 21 hours. 192 g of toluene was added to the reaction mixture, and 498 g of water was added dropwise over 1 hour while maintaining the internal temperature at 25 ° C. or lower.
After 672 g of an N-sodium hydroxide aqueous solution was added little by little, the organic layer was separated by standing still. 96 g of toluene in the aqueous layer
, And the solvent was distilled off under reduced pressure together with the organic layer. The obtained concentrate was purified by distillation under reduced pressure to obtain 107.1 g of a mixture of 3-methylthiophene-2-carbaldehyde and 3-methylthiophene-5-carbaldehyde (yield 94%, 3-methylthiophene). Thiophene-2-carbaldehyde / 3-methylthiophen-5-carbaldehyde = 90.1 / 9.9).

Example 8 A mixture of 3-methylthiophene-2-carbaldehyde and 3-methylthiophene-5-carbaldehyde obtained in Reference Example 82.0 was placed in a 500 ml three-necked flask.
g (0.651 mol, 3-methylthiophen-2-carbaldehyde / 3-methylthiophen-5-carbaldehyde = 90.1 / 9.9, 3-methylthiophen-2
-Carboxaldehyde content 73.9 g, 3-methylthiophene-5-carbaldehyde content 8.1 g) and hexane 240 g, and at room temperature, 63.5 g of aniline
(0.682 mol) was added dropwise over 15 minutes. After completion of the dropwise addition, the mixture was heated to 65 to 75 ° C., and stirred for 6 hours while removing water generated by azeotropic dehydration. The resulting solution was allowed to cool, and when the temperature of the solution reached 50 ° C, 3-
A small amount of methylthiophene-2-carbaldehyde-N-phenylimine was added as seed crystals, followed by 20 ° C.
And kept at 15-20 ° C. for 6 hours to precipitate crystals. The precipitated crystals were filtered and hexane 127 was removed.
g, and then dried under reduced pressure to give a purity of 99.7.
% 3-methylthiophene-2-carbaldehyde-N
97.7 g of -phenylimine were obtained (yield based on 3-methylthiophene-2-carbaldehyde: 83%). Next, the 3-methylthiophene-2-carbaldehyde-N obtained above was placed in a three-necked flask having a capacity of 1000 ml.
50.2 g (0.249 mol) of phenylimine and 200 g of toluene were added thereto, and 249 m of 2N hydrochloric acid was added at room temperature.
1 (0.498 mol) was added slowly, and then 5
Stirred for hours. The obtained mixture was allowed to stand, and the organic layer was separated. The aqueous layer was extracted with 100 g of toluene, and the extract was combined with the organic layer to obtain 100 g of a saturated aqueous sodium hydrogen carbonate solution.
After washing with, the solvent was distilled off under reduced pressure. The obtained concentrate was purified by distillation under reduced pressure to give 99.4% pure 3-methylthiophene-2-carbaldehyde 28.1.
g was obtained (yield based on 3-methylthiophene-2-carbaldehyde-N-phenylimine: 89%).

[0029]

Industrial Applicability 3-Methylthiophene-2-carbaldehyde, which is useful as a synthetic intermediate for pharmaceuticals, agricultural chemicals, etc., can be obtained with high purity and high yield in an industrially advantageous manner.

Claims (1)

[Claims] 1. A mixture of 3-methylthiophen-2-carbaldehyde and 3-methylthiophen-5-carbaldehyde is represented by the general formula (I): (In the formula, R represents an alkyl group, an alkenyl group, an aryl group which may have a substituent or an aralkyl group which may have a substituent.) Formula (II) (Wherein R is as defined above)
-Methylthiophen-2-imine derivative and general formula (III) (Wherein R is as defined above)
A mixture of -methylthiophen-5-imine derivatives,
Separating a 3-methylthiophen-2-imine derivative from the mixture, and hydrolyzing the obtained 3-methylthiophen-2-imine derivative in the presence of an acid.
A method for obtaining methylthiophene-2-carbaldehyde.