JP2003277316A - Method for producing derivative of acrylic acid - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an industrially profitable method for producing a derivative of acrylic acid with good yield. <P>SOLUTION: The method produces the objective substance in good yield, in producing the derivative of acrylic acid (II) from an aldehyde (I) and malonic acid in the presence of a base by carrying out the reaction in an aprotic polar solvent not using pyridine solvent which is hardly recovered as a conventional method. The objective substance is inexpensively obtained in good yield with high purity from filtration of precipitated product by mixing water that is a poor solvent, to the reaction liquid to crystallize the product after distilling away low boiling fractions than the reaction solvent. <P>COPYRIGHT: (C)2004,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing an acrylic acid derivative which is useful as a raw material for medicines, agricultural chemicals and the like and intermediates, particularly as an intermediate in the production of amino acid compounds.

[0002]

2. Description of the Related Art A conventional method for producing an acrylic acid derivative, for example, a method for producing 3- (3-pyridyl) acrylic acid is to heat 3-pyridinecarboxaldehyde and malonic acid in a pyridine solvent in the presence of piperidine as a base. It is known that the product is obtained as crystals in a yield of 96% by a method of reacting under the following conditions, adding a poor solvent diethyl ether to precipitate the product as crystals (J. Am. Chem. Soc. (1979). ), 101
(18), 5370). However, in this method, diethyl ether, which has a low boiling point and is easy to generate a peroxide, is used as a crystallization solvent, a pyridine solvent which is difficult to separate by distillation from other solvents is used, and a solvent is used. This is an industrially unsuitable method because, for example, it is impossible to separate pyridine, which is a base, from piperidine, which is a base.

[0003]

SUMMARY OF THE INVENTION It is an object of the present invention to provide an industrially suitable production method capable of producing an acrylic acid derivative with a high yield.

[0004]

Means for Solving the Problems As a result of intensive studies to achieve the above object, the present inventors have found that in the presence of a base,
In a method for producing an acrylic acid derivative (II) from an aldehyde (I) and malonic acid, by reacting in an aprotic polar solvent without using a pyridine solvent which is difficult to recover as in the conventional method. The target product can be obtained in a high yield, and preferably, a component having a boiling point lower than that of the reaction solvent is distilled out of the reaction solution to the outside of the system, and then the product is crystallized from the reaction solution. Therefore, the inventors have found that the target product can be obtained at a low cost in a high yield and a high purity by a method of mixing with a poor solvent such as water and filtering out a precipitated product, and thus completed the present invention.

That is, the present invention provides the following formula (I):

[0006]

Embedded image In the formula, R is an unsubstituted or substituted phenyl group, an unsubstituted or substituted naphthyl group, or an oxygen atom, a nitrogen atom, or sulfur. A 5- or 6-membered aromatic heterocycle containing one or more of any atom or two or more of each atom in combination, and the heterocycle may be substituted). After reacting the aldehydes with malonic acid in the presence of a base in an aprotic polar solvent, preferably after distilling out from the reaction solution a component having a lower boiling point than the reaction solvent to the outside of the system by distillation. , The following formula (II) obtained by filtering the precipitated product by mixing with water

[0007]

Embedded image A method for producing an acrylic acid derivative represented by R—CH═CHCOOH (II) (wherein R has the same meaning as described above).

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION In the present invention, aldehydes represented by the formula (I) and the formula (II) used as raw materials
In the acrylic acid derivative represented by, R is an unsubstituted or optionally substituted phenyl group, an unsubstituted or optionally substituted naphthyl group, or an oxygen atom,
A 5- or 6-membered aromatic heterocycle containing at least one nitrogen atom or sulfur atom or at least two atoms in combination with each atom is shown, and the heterocycle may be substituted. .

The unsubstituted or optionally substituted phenyl group represented by R in the formula is not particularly limited, but specifically, an alkyl group such as a methyl group or an ethyl group, a methoxy group or an ethoxy group. Group such as lower alkoxy group, fluorine atom, chlorine atom, halogen atom such as bromine atom or iodine atom, hydroxy group, amino group, lower alkylamino group such as methylamino group or dimethylamino group, nitro group, cyano group, formyl Group or lower acyl group such as acetyl group, carboxyl group,
Examples thereof include a lower acylamide group such as a formamide group or an acetamido group, and a phenyl group in which 1 to 5 unsubstituted or optionally substituted phenyl groups are substituted at arbitrary positions. Specifically, a 4-methylphenyl group,
4-methoxyphenyl group, 2-fluorophenyl group, 3
-Fluorophenyl group, 4-fluorophenyl group, 2-
Chlorophenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 2-bromophenyl group, 3-bromophenyl group, 4-bromophenyl group, 4-iodophenyl group,
3,4-dibromophenyl group, 2,3,4,5,6-pentafluorophenyl group, 4-hydroxyphenyl group,
4-nitrophenyl group, 3-chloro-4-hydroxyphenyl group, 2-chloro-3,5-dihydroxyphenyl group, 3,4-ethylenedioxyphenyl group, 4-biphenyl group, 4- (2 ', 6 '-Dimethoxybiphenyl) group and the like.

The unsubstituted or optionally substituted naphthyl group represented by R in the formula is not particularly limited, but specifically, an alkyl group such as a methyl group or an ethyl group, a methoxy group or an ethoxy group. Group such as lower alkoxy group, fluorine atom, chlorine atom, halogen atom such as bromine atom or iodine atom, hydroxy group, amino group, lower alkylamino group such as methylamino group or dimethylamino group, nitro group, cyano group, formyl Group or lower acyl group such as acetyl group, carboxyl group,
Examples thereof include a naphthyl group in which 1 to 7 lower acylamide groups such as a formamide group or an acetamido group are substituted at arbitrary positions. Further, an anthryl group, a phenanthryl group, a pyrenyl group, and the like, in which one or more aromatic rings containing two or more carbon atoms on a naphthyl group may be adjacent to each other, may be mentioned. Specifically, 1-naphthyl group, 2-naphthyl group, 2- (6-fluoronaphthyl) group, 2- (6-chloronaphthyl) group, 2- (6-bromonaphthyl) group, 2-
(6-hydroxynaphthyl) group, 2-anthryl group, 9
Examples thereof include anthryl group and 9-phenanthryl group.

The 5- or 6-membered aromatic heterocycle represented by R in the formula includes at least one oxygen atom, nitrogen atom or sulfur atom, or at least two atoms in combination with each atom. Furyl group such as 2-furyl group and 3-furyl group, thienyl group such as 2-thienyl group and 3-thienyl group, 1-pyrrolyl group, 2-pyrrolyl group, pyrrolyl group such as 3-pyrrolyl group, 1-pyrazolyl group Group, 3-pyrazolyl group, 4-pyrazolyl group, pyrazolyl group such as 5-pyrazolyl group, 2-oxazolyl group, 4-oxazolyl group, 5-
Oxazolyl group such as oxazolyl group, 3-isoxazolyl group, 4-isoxazolyl group, isoxazolyl group such as 5-isoxazolyl group, 2-thiazolyl group, 4-
Thiazolyl groups such as thiazolyl group and 5-thiazolyl group, 3
-Isothiazolyl groups such as isothiazolyl group, 4-isothiazolyl group and 5-isothiazolyl group, 3- (1,2,5
-Thiadiazolyl) group and the like, 1,2,5-thiadiazolyl group, 3- (1,2,4-thiadiazolyl) group, 5-
Five-membered aromatic heterocycle such as 1,2,4-thiadiazolyl group such as (1,2,4-thiadiazolyl) group, pyridyl group such as 2-pyridyl group, 3-pyridyl group and 4-pyridyl group, etc. And a six-membered aromatic heterocycle.

Although any substituents may be introduced on these aromatic heterocycles, it is preferable that 1 to 3 substituents be introduced, and the substituents are particularly preferable. Although not limited, specifically, an alkyl group such as a methyl group or an ethyl group, a lower alkoxy group such as a methoxy group or an ethoxy group, a fluorine atom, a chlorine atom,
Halogen atom such as bromine atom or iodine atom, hydroxy group, amino group, lower alkylamino group such as methylamino group or dimethylamino group, lower acyl group such as nitro group, cyano group, formyl group or acetyl group,
Examples thereof include a lower acylamide group such as a carboxyl group, a formamide group or an acetamide group. Further, an aromatic ring containing 2 atoms on the aromatic heterocycle may be adjacent to each other. Specifically, 3-indolyl group, 3-
Examples thereof include (5-chloroindolyl) group, 2-benzoxazolyl group, 2-benzothiazolyl group, and 2- (6-methylpyridyl) group.

The base used in the present invention is an organic base, and examples thereof include primary amines such as ammonia, methylamine, ethylamine, ethanolamine and aniline, dimethylamine, diethylamine, diethanolamine, methylaniline, piperidine, morpholine, Secondary amines such as piperazine and pyrrole, trimethylamine,
Triethylamine, triethanolamine, pyridine,
Examples thereof include tertiary amines such as quinoline, dimethylaniline and isoquinoline, and two or more kinds of these may be used simultaneously. The amount of these bases to be used is arbitrary, but is 0.001 to 0.001 relative to the aldehyde represented by the formula (I).
A 10-fold molar amount is preferable, and a 0.01- to 2-fold molar amount is particularly preferable. Further, the catalyst amount is preferably 0.01 to 0.5 times mol.

The amount of malonic acid used in the present invention is arbitrary, but it is 0.8 to 0.8% of the aldehydes represented by the formula (I).
A 10-fold molar amount is sufficient, and a 1- to 3-fold molar amount is particularly preferable.

The reaction solvent used in the present invention is N,
It is an aprotic polar solvent such as N-dimethylimidazolidinone, N-methyl-2-pyrrolidone, N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide and sulfolane, and the amount thereof is not particularly specified. Is preferably 0.1 to 100 times the amount (weight) of the aldehydes represented by the formula (I), particularly 1 to 20.
Double amount (weight) is preferable.

The reaction temperature in the present invention is within the temperature at which the solvent is refluxed, preferably 20 to 130 ° C, more preferably 50 to 100 ° C. Although the reaction time is optional, it is preferably about 0.5 to 10 hours.

From the reaction solution after completion of the reaction, it is preferable to distill off components having a lower boiling point than the solvent to the outside of the system by distillation. The subsequent reaction solution is mixed with water, which is a poor solvent for precipitating the product. Although the amount of water is arbitrary, it is preferably 0.1 to 10 times the weight (weight) of the whole reaction solution so that 90% or more of the product present in the system is precipitated.
Particularly, the amount (weight) of 0.5 to 5 times is preferable. Mixing of the reaction solution and water and subsequent filtration can be carried out at any temperature, but upon filtration, it is preferable to cool to 0 to 20 ° C. in order to reduce the amount of the product dissolved in the filtrate. . The reaction solvent can be recovered by distillation after water is distilled off from the filtrate by distillation or the like.

[0018]

EXAMPLES The present invention will be specifically described below with reference to examples. [Example 1] 4-chlorobenzaldehyde 7.03 g (50 mmol) and malonic acid 1 were placed in a 100 ml four-necked flask.
1.99 g (115 mmol), piperidine 0.43 g
(5 mmol), N-methyl-2-pyrrolidone 14.3
g was charged, and the mixture was reacted at 83 ° C. for 5 hours. The reaction yield was 97.6 mol% / 4-chlorobenzaldehyde. 70.0 g of water was added to precipitate the product, and 1
After cooling to 0 ° C, the precipitated crystals were filtered. Filter cake 1
It was washed with 72.0 g of water cooled to 0 ° C. Then, it dried and obtained the crystal of 8.84 g (48.4 mmol) of 3- (4-chlorophenyl) -2-propenecarboxylic acid.
The extraction yield was 99.2 mol% / 4-chlorobenzaldehyde.

Example 2 In a 100 ml four-necked flask,
4-fluorobenzaldehyde 6.21 g (50 mmo
1), malonic acid 11.99 g (115 mmol), piperidine 0.43 g (5 mmol) and N-methyl-2-pyrrolidone 43.5 g were charged and reacted at 81 ° C. for 6 hours. The reaction yield was 99.1 mol% / 4-fluorobenzaldehyde. Water 1 to precipitate the product
After adding 40.0 g and cooling to 10 ° C., the precipitated crystals were filtered. The filter cake was washed with 220.0 g of water cooled to 10 ° C. Then, it is dried and 7.60 g (45.7) of 3- (4-fluorophenyl) -2-propenecarboxylic acid.
(mmol) crystals were obtained. Extraction yield is 92.3 mol
% / 4-fluorobenzaldehyde.

Example 3 In a 100 ml four-necked flask,
5.36 g of 3-pyridinecarbaldehyde (50 mmo
1), malonic acid 11.99 g (115 mmol), piperidine 0.43 g (5 mmol) and N-methyl-2-pyrrolidone 26.8 g were charged and reacted at 78 ° C. for 3 hours. The reaction yield was 85.6 mol% / 3-pyridinecarbaldehyde. Water 1 to precipitate the product
After adding 40.0 g and cooling to 10 ° C., the precipitated crystals were filtered. The filter cake was washed with 135.0 g of water cooled to 10 ° C. Then, it is dried and 3- (3-pyridyl)-
2-propenecarboxylic acid 6.27 g (42.1 mmo
Crystals of l) were obtained. The take-out yield was 98.3% / 3-pyridinecarbaldehyde.

Example 4 In a 100 ml four-necked flask,
4-Chlorobenzaldehyde 7.03 g (50 mmo
1), malonic acid 11.99 g (115 mmol), pyridine 1.58 g (20 mmol) and N, N-dimethylimidazolidinone 21.1 g were charged and reacted at 86 ° C. for 5 hours. The reaction yield was 96.3 mol% / 4-chlorobenzaldehyde. Water (110.0 g) was added to precipitate the product, the mixture was cooled to 10 ° C., and the precipitated crystal was filtered. Water 105.0 with filter cake cooled to 10 ° C
washed with g. Then, it was dried and 8.68 g (47.47 g) of 3- (4-chlorophenyl) -2-propenecarboxylic acid.
5 mmol) of crystals were obtained. Extraction yield is 98.7mo
It was 1% / 4-chlorobenzaldehyde.

Example 5 In a 100 ml four-necked flask,
4-Chlorobenzaldehyde 7.03 g (50 mmo
1), malonic acid 11.99 g (115 mmol), piperidine 0.43 g (5 mmol), and N, N-dimethylimidazolidinone 21.1 g were charged and reacted at 83 ° C. for 5 hours. The reaction yield was 97.8 mol% / 4-chlorobenzaldehyde. Before mixing the reaction solution with water, piperidine, acetic acid, and water produced which have lower boiling points than the reaction solution were distilled out of the system by distillation. Then, 86.0 g of water was added to precipitate the product, and the mixture was cooled to 10 ° C., and the precipitated crystal was filtered. Water 1 with filter cake cooled to 10 ° C
It was washed with 05.0 g. Then, it is dried and 3- (4-
Chlorophenyl) -2-propenecarboxylic acid 8.92 g
Crystals of (48.9 mmol) were obtained. Extraction yield is 9
It was 9.9 mol% / 4-chlorobenzaldehyde. The reaction solvent, N, N-dimethylimidazolidinone, was recovered by distilling water off from the filtrate.

Example 6 In a 100 ml four-necked flask,
5.36 g of 3-pyridinecarbaldehyde (50 mmo
1), malonic acid 11.99 g (115 mmol), piperidine 0.43 g (5 mmol) and N-methyl-2-pyrrolidone 21.4 g were charged and reacted at 85 ° C. for 3 hours. The reaction yield was 86.1 mol% / 3-pyridinecarbaldehyde. Before mixing the reaction solution with water, piperidine, acetic acid, and water produced which have lower boiling points than the reaction solution were distilled out of the system by distillation. Then, 100.0 g of water was added in order to precipitate the product, and after cooling to 10 ° C., the precipitated crystal was filtered. Water that cooled the filter cake to 10 ° C 11
It was washed with 0.0 g. Then, it was dried and 6.30 g of 3- (3-pyridyl) -2-propenecarboxylic acid (42.
2 mmol) of crystals were obtained. Extraction yield is 98.3% /
It was 3-pyridinecarbaldehyde. The reaction solvent, N-methyl-2-pyrrolidone, was recovered by distilling and distilling water from the filtrate.

[Comparative Example 1] In a 100 ml four-necked flask,
4-Chlorobenzaldehyde 7.03 g (50 mmo
1), malonic acid 11.99 g (115 mmol), piperidine 0.43 g (5 mmol) and N-methyl-2-pyrrolidone 14.3 g were charged and reacted at 83 ° C. for 5 hours. The reaction yield was 97.2 mol% / 4-chlorobenzaldehyde. 65.0 g of toluene was added to precipitate the product, and the mixture was cooled to 10 ° C. However, almost no product was precipitated, and 3- (4-chlorophenyl) -2-propenecarboxylic acid could not be obtained only by filtration. There wasn't.

[Comparative Example 2] In a 100 ml four-necked flask,
5.36 g of 3-pyridinecarbaldehyde (50 mmo
1), malonic acid 11.99 g (115 mmol), piperidine 0.43 g (5 mmol) and pyridine 45.
0 g was charged and reacted at 85 ° C for 1 hour and then at 100 ° C for 2 hours. Reaction yield is 88.2 mol% / 3
-Pyridine carboxaldehyde. Then, 200.0 g of ether was added to precipitate the product, and 10
After cooling to ° C, the precipitated crystals were filtered. Filter cake 10
It was washed with 120.0 g of ether cooled to ° C. Then, it dried and obtained the crystal of 6.50 g (43.6 mmol) of 3- (3-pyridyl) -2-propenecarboxylic acid.
The extraction yield was 98.9% / 3-pyridinecarbaldehyde. I tried to recover the reaction solvent pyridine from the filtrate, but I could not separate it from piperidine, etc.
It was impossible to recover. Therefore, it is an industrially inappropriate method.

[0026]

INDUSTRIAL APPLICABILITY According to the present invention, an acrylic acid derivative useful as a raw material for medicines, agricultural chemicals and the like, and as an intermediate, particularly as an intermediate in the production of amino acid compounds, is treated with aldehyde in an aprotic polar solvent in the presence of a base. Are produced in high yield from the compounds and malonic acid, and preferably, after the reaction is completed, the components having a lower boiling point than the solvent are distilled out of the system by distillation, and then confused with water to precipitate the precipitated product. By filtering, it became possible to manufacture by an industrially suitable method of obtaining in high yield and high purity.

Claims (2)

[Claims] 1. A compound represented by the following formula (I): R-CHO (I) (wherein R is an unsubstituted or optionally substituted phenyl group, an unsubstituted or optionally substituted naphthyl group. Or a 5- or 6-membered aromatic heterocycle containing one or more oxygen atom, nitrogen atom, or sulfur atom or two or more atoms in combination with each atom. May be substituted) in an aprotic polar solvent in the presence of a base, to react with malonic acid, and then mixed with water,
A precipitate of an acrylic acid derivative represented by the following formula (II): R-CH = CHCOOH (II) (wherein R is as defined above), characterized by being obtained by filtration. Production method. 2. The method according to claim 1, wherein a component having a lower boiling point than the solvent is distilled off before mixing the reaction liquid and water.