JPH1067699A - Production of 4-substituted-2-butenals - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method capable of producing safely and simply the subject compound low in corrosive properties and toxicity, and useful for an intermediate of medicine and agrochemical in high yield by carrying out a reaction of a substituted acetaldehyde with an aldehyde compound in the presence of an aminocarboxylic acid. SOLUTION: The compound of the formula is obtained by carrying out the reaction of (B) a compound of the formula: X-CH2 -CHO (X is an acyloxy or a halogen) with (C) a compound of the formula: R-CH2 -CHO [R is H, a (OH, an alkoxy, an aryloxy, an acyl or an alkoxycarbonyl substituted) aliphatic or aromatic hydrocaron group], in the presence of (A) an amino acid such as glycine, alanine, glutamic acid, aspartic acid, etc. The reaction is preferably carried out using the component (A) in an amount of 0.1-10mol%, especially 0.5-5mol%, regarding on reaction efficiency and production cost.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing 2-butenals having an acyloxy group or a halogen atom at the 4-position as a substituent (hereinafter referred to as 4-substituted-2-butenals). The 4-substituted-2-butenals obtained by the production method of the present invention are useful as synthetic intermediates for pharmaceuticals, agricultural chemicals and the like. For example, 4-acetoxy-2-methyl- obtained by the production method of the present invention.
2-Butenal is an important compound for producing vitamin A acetate [Pure & Appl. Chem., 63 , 45 (199).
1), Japanese Patent Publication No. 45-18648, etc.]. Further, 4-chloro-2 obtained by the production method of the present invention.
-Methyl-2-butenal can be easily treated with potassium acetate to easily prepare the above-mentioned 4-acetoxy-2-methyl-
Can be converted to 2-butenal [J. Org. Chem., 42 , 164].
8 (1976).

[0002]

2. Description of the Related Art Various methods have been known for producing 4-substituted-2-butenals. For example,
Regarding the above-mentioned 4-acetoxy-2-methyl-2-butenal, its production method is as follows: 1,4-dihydroxy-2-butene is converted to 3,4-dihydroxy-1-butene by a rearrangement reaction, By acetylation, 3,4-diacetoxy-1
-A method of removing one acetoxy group in the molecule after conversion to butene and further hydroformylation (West German Patent No. 1)
No. 941632), ethynylation of methylglyoxal dimethyl acetal followed by partial hydrogenation
Hydroxy-2-methyl-3-butenal dimethyl acetal is acetylated to give 2-acetoxy-2-methyl-
3-butenal dimethyl acetal was obtained and then rearranged in the presence of a copper catalyst to give 4-acetoxy-2-methyl-2-.
A method of deriving butenal dimethyl acetal and further selectively hydrolyzing (see German Patent No. 1297597), reacting propanal with acetoxyacetaldehyde in the presence of a secondary amine and an organic acid, (See JP-A-63-135356), and the like.

In addition, the above-mentioned 4-chloro-2-methyl-2
As a method for producing butenal, 2-methyl-2-vinyloxirane obtained by oxidizing isoprene with an organic peracid such as peracetic acid in an ethyl acetate solvent is chlorinated in the presence of copper chloride and lithium chloride. Method [see J. Org. Chem., 41 , 1648 (1976)], a method of chlorinating the above 2-methyl-2-vinyloxirane with acetyl chloride and alumina under gas phase conditions (West German Patent No. 2620968). Oxidizing prenyl chloride with selenium dioxide [Journal of the Chemical Society of Japan, Vol. 12, p. 2246 (1975)]
Reference], etc. are known.

[0004]

However, the above and the above methods require a number of reaction steps. Also,
Is required to use a secondary amine and an organic acid as a catalyst in an amount of 20 to 100 mol% based on acetoxyacetaldehyde as a raw material in order to obtain a target compound in a high yield. The yield itself is 42 ~
Only 63%. Also, and methods of
When preparing 2-methyl-2-vinyloxirane, there is a problem in that an organic peracid which has a risk of explosion must be used, and the reactor is corroded during halogenation.
Further processes require the use of highly toxic selenium dioxide in equimolar amounts relative to the raw material.

[0005] As described above, all of the conventionally known methods for producing 4-substituted-2-butenals have difficulty in industrial implementation. The present invention has been made in view of the above-mentioned problems of the related art, and is directed to 4-substituted-2-.
It is an object of the present invention to provide a method capable of producing butenals easily, conveniently and industrially with good yield.

[0006]

According to the present invention, the above object is achieved by the following formula (2) X-CH ₂ -CHO (2) wherein X represents an acyloxy group or a halogen atom.
And a substituted acetaldehyde represented by the following formula (3): R—CH ₂ —CHO (3) (wherein R represents a hydrogen atom, an aliphatic hydrocarbon group or an aromatic hydrocarbon group. May be substituted with a hydroxyl group, an alkoxy group, an aryloxy group, an acyl group, or an alkoxycarbonyl group.) In the presence of an aminocarboxylic acid. 1)

[0007]

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The problem is solved by providing a process for producing 4-substituted-2-butenals represented by the formula (wherein X and R are as defined above).

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail.
In the above formula (2) representing a substituted acetaldehyde used as a raw material in the present invention, the acyloxy group represented by X includes, for example, an acetoxy group, a propionyloxy group, a butyryloxy group, an isobutyryloxy group, a valeryloxy group, an isovale Aliphatic acyloxy groups such as a lyloxy group, a pivaloyloxy group, an octoyloxy group, a lauroyloxy group, a myristoyloxy group, a palmitoyloxy group, and a stearoyloxy group; a benzoyloxy group, a p-toluoyloxy group, and a p-chlorobenzoyloxy Examples thereof include aromatic acyloxy groups such as a group, and among them, those having 1 to 20 carbon atoms are preferable.
In the above formula (2), examples of the halogen atom represented by X include a chlorine atom or a bromine atom.

Here, specific examples of the substituted acetaldehyde represented by the formula (2) include acetoxyacetaldehyde, propionyloxyacetaldehyde, isovaleryloxyacetaldehyde, octyloxyacetaldehyde, chloroacetaldehyde and the like.
Among these compounds, in the present invention, acetoxyacetaldehyde and chloroacetaldehyde are preferably used as the substituted acetaldehyde represented by the formula (2).

As the substituted acetaldehyde represented by the formula (2), a commercially available product may be appropriately used, or a product prepared according to a known method described in a literature may be used. For example, acetoxyacetaldehyde corresponding to the case where X represents an acetyl group in the formula (2) is ozonolysis of 1,4-diacetoxy-2-butene (European Patent No. 6148).
69, etc.).

In the above formula (3), which represents an aldehyde used as a raw material in the present invention, examples of the aliphatic hydrocarbon group represented by R include a methyl group, an ethyl group, a propyl group, an isopropyl group and an isoamyl group. , N-
Alkyl groups such as octyl group; alkenyl groups such as allyl group; alkynyl groups such as propargyl group; cycloalkyl groups such as cyclohexyl group and cyclooctyl group; Are preferable, and those having 1 to 12 carbon atoms are more preferable, and a methyl group is further preferable. Examples of the aromatic hydrocarbon group represented by R include an aryl group such as a phenyl group, a tolyl group, and a naphthyl group; and an aralkyl group such as a benzyl group and a phenethyl group. Twelve are preferred. These aliphatic hydrocarbon groups or aromatic hydrocarbon groups include, for example, a hydroxyl group; an alkoxy group such as a methoxy group, an ethoxy group, an isopropoxy group, an isobutoxy group and an isopentyloxy group; an aryloxy group such as a phenoxy group; And an acyl group such as a propionyl group or a benzoyl group; and an alkoxycarbonyl group such as a methoxycarbonyl group or an ethoxycarbonyl group.

Here, specific examples of the aldehyde represented by the formula (3) are as follows: acetaldehyde, propanal, butanal, pentanal, 4-pentenal, 3-methylbutanal, 3-phenylpropanal, 3-aniline Silpropanal, 4-hydroxybutanal, 4-acetoxybutanal, esters of 3-formylpropionic acid, and the like. Among these, in the present invention, the formula (3)
As the aldehyde represented by the formula, propanal is suitably used.

The use amount of the aldehyde represented by the formula (3) is not particularly limited, but from the viewpoint of the yield of the desired 4-substituted-2-butenals, reaction efficiency and production cost,
Usually, the amount is in the range of 1 to 10 mol per 1 mol of the substituted acetaldehyde represented by the formula (2), and preferably the amount is 1 to 2 mol per 1 mol of the substituted acetaldehyde represented by the formula (2). Is the amount of

In the present invention, an aminocarboxylic acid is used as a catalyst. The aminocarboxylic acid referred to in the present invention refers to a compound having an amino group (—NH ₂ ) and a carboxyl group in one molecule, for example, glycine, alanine, β
-Alanine, valine, leucine, isoleucine, serine, cysteine, methionine, threonine, tyrosine,
α-aminobutanoic acid, β-aminobutanoic acid, phenylalanine, aspartic acid, sodium salt of aspartic acid, potassium salt of aspartic acid, glutamic acid, sodium salt of glutamic acid, potassium salt of glutamic acid, and the like. Among these, glycine, alanine, glutamic acid and aspartic acid are particularly suitable compounds. When a compound having a substituted amino group and a carboxyl group is used in place of the aminocarboxylic acid in the present invention, side reactions such as dimerization of the substituted acetaldehyde represented by the formula (2) by self-condensation occur, and The 4-substituted-2-butenals represented by the formula (1) cannot be obtained in good yield.

The amount of the aminocarboxylic acid used in the present invention is usually 0.01 to 50 mol% based on the substituted acetaldehyde represented by the formula (2). From the viewpoint of reaction efficiency and production cost, the amount of aminocarboxylic acid used is
0.1 with respect to the substituted acetaldehyde represented by the formula (2).
The content is preferably 1 to 10 mol%, more preferably 0.5 to 5 mol%.

In the present invention, in addition to the above-mentioned aminocarboxylic acid, a carboxylic acid having no functional group other than a carboxyl group in the molecule (hereinafter abbreviated as carboxylic acid)
Alternatively, it is preferable to use a salt thereof in combination, since the reaction proceeds more smoothly. Such carboxylic acids include monobasic acids,
Any of dibasic acids and polybasic acids may be used. For example, acetic acid, propionic acid, butanoic acid, 2-methylpropanoic acid, pentanoic acid, 3-methylbutanoic acid, oxalic acid, malonic acid, succinic acid, adipine Acids and the like.

As the salt of the carboxylic acid used in the present invention, an alkali metal salt such as sodium or potassium or an alkaline earth metal salt such as calcium of the above carboxylic acid is used.

The amount of the carboxylic acid or a salt thereof to be used is usually 0.01 to 100 mol% based on the substituted acetaldehyde represented by the formula (2), and from the viewpoint of reaction efficiency and production cost, the formula ( It is preferably 0.1 to 10 mol% based on the substituted acetaldehyde represented by 2).

In the present invention, a solvent is not necessarily required, but the use of a solvent may be used as long as the reaction is not inhibited. Examples of the solvent that can be used include water; saturated aliphatic hydrocarbons such as pentane, hexane, heptane, and octane;
Aromatic hydrocarbons such as benzene, toluene and xylene; dichloromethane, dichloroethane, chloroform,
Halogenated hydrocarbons such as carbon tetrachloride; ethers such as diethyl ether and diisopropyl ether;

The amount of the solvent to be used is usually within a range of 0.001 to 2 times the weight of the substituted acetaldehyde represented by the formula (2), and from the viewpoint of reaction efficiency and production cost, 0.01 to 2 times. It is preferable that the weight is within the range of 1 to 1 weight.

The reaction according to the present invention is preferably carried out in an atmosphere of an inert gas such as nitrogen or argon.

In the present invention, although the mechanism of the reaction between the substituted acetaldehyde represented by the formula (2) and the aldehyde represented by the formula (3) is not always clear, as an intermediate, the following formula (4)

[0024]

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It has been confirmed that an aldol condensate represented by the formula (wherein R and X are as defined above) is formed, and the target 4-substituted-2-butenals are obtained from such an intermediate. Is thought to be formed.

The present invention is generally implemented as follows. That is, a substituted acetaldehyde represented by the formula (2), an aldehyde represented by the formula (3), an aminocarboxylic acid, and, if desired, a carboxylic acid or a salt thereof, and, if necessary, a solvent are added to a reaction vessel equipped with a stirrer. Preparation,
It is carried out by maintaining a predetermined reaction temperature. Also,
In a reaction vessel equipped with a stirrer charged with the aldehyde represented by the formula (3), the aminocarboxylic acid, and, if desired, a carboxylic acid or a salt thereof, and if necessary, a solvent,
Alternatively, the reaction may be carried out by adding a substituted acetaldehyde represented by the formula (1) and maintaining the obtained reaction mixture at a predetermined reaction temperature.

The progress of the reaction can be monitored by confirming the disappearance of the starting materials and the disappearance of the produced intermediate using known means such as gas chromatography.

According to the present invention, when the disappearance of the raw material can be confirmed, an excessively substituted substituted acetaldehyde represented by the formula (2) or an aldehyde represented by the formula (3) is distilled off under normal pressure or reduced pressure. Then, the obtained residue may be stirred at a predetermined temperature.

The reaction temperature is generally in the range from 10 to 200 ° C., preferably from 50 to 150 ° C., and the reaction time is generally from 4 to 12 hours. The reaction is generally carried out at atmospheric pressure, but can also be carried out under reduced or elevated pressure.

After completion of the reaction, the target compound is prepared, for example, by pouring the reaction mixture into water, extracting with an organic solvent such as methylene chloride or ethyl acetate, and then distilling off the organic solvent under normal pressure or reduced pressure. It can be isolated by a known method such as The desired product thus obtained can be further purified, if desired, by means such as distillation under reduced pressure or chromatography.

The present invention can also be carried out in a two-stage process in which the intermediate product is once separated and then led to the desired 4-substituted-2-butenals.

The embodiment at this time is as follows. That is, in the same manner as described above, the substituted acetaldehyde represented by the formula (2) is reacted with the aldehyde represented by the formula (3) in the presence of an aminocarboxylic acid. The intermediate product is separated from the reaction mixture by a method such as extraction with an organic solvent. In the extraction, methylene chloride, ethyl acetate and the like can be used as a solvent.

The intermediate product separated from the reaction mixture is
4-substituted easily by heating to 50 to 160 ° C.
It can be converted to 2-butenals. The reaction time at this time is usually 2 to 4 hours. At the time of heating, it is preferable to add the carboxylic acid or a salt thereof to the reaction system.

After completion of the reaction, the target compound can be isolated by treating the reaction mixture in the same manner as described above.

[0035]

EXAMPLES The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples.

Example 1 Propanal 43 was placed in a three-necked flask having an inner volume of 300 ml.
g (0.74 mol), alanine 0.2 g (2 mmol), acetic acid 0.4 g and water 1.6 g were charged, and the internal temperature was raised to 60 ° C. with vigorous stirring. Next, 40 g of acetoxyacetaldehyde (0.
39 mol) was added dropwise over 2 hours. After the addition, the mixture was stirred at the same temperature for 4 hours. During this time, a small amount of the reaction mixture was sampled, and the reaction was followed by gas chromatography under the following analysis conditions to confirm the disappearance of the starting material, acetoxyacetaldehyde. Unreacted propanal was distilled off from the obtained reaction mixture under normal pressure. The resulting residue was stirred at 80 ° C. for 4 hours. During this time, a small amount of the reaction mixture was sampled, and the reaction was followed by gas chromatography under the following analysis conditions, and the disappearance of the intermediate (retention time: 16 minutes) was confirmed. When the reaction was completed, 40.7 g of 4-acetoxy-2-methyl-2-butenal was produced.

After the reaction mixture obtained above was cooled to room temperature, 10 g of a 5% aqueous sodium bicarbonate solution was added, and the mixture was shaken sufficiently to separate an organic layer. The obtained organic layer was subjected to simple distillation under reduced pressure to obtain a crude product, and the obtained crude product was further distilled under reduced pressure to obtain 4-acetoxy-2-methyl-2-butenal (boiling point: 83 to 85 ° C./1 mmHg) (39.2 g, yield 70.5%).

Gas Chromatography Analysis Conditions Column: OV-17 3 m × 4 mmφ (GL Science) Column temperature: 70 → 240 ° C. (heating rate: 5 ° C./min) Detector: FID detector

Example 2 The procedure of Example 1 was repeated, except that 0.2 g (3 mmol) of glycine was used instead of 0.2 g of alanine, to give 4-acetoxy-2-methyl-2-butenal 3
6.9 g were obtained (66.3% yield).

Example 3 0.3 g of glutamic acid (2.
Except that 5 mmol) was used, 33.2 g of 4-acetoxy-2-methyl-2-butenal was obtained by the same operation as in Example 1 (yield: 59.4%).

Comparative Example 1 0.2 g of N-methylalanine instead of 0.2 g of alanine
The reaction was carried out in the same manner as in Example 1 except that (1.4 mmol) was used. The reaction mixture 3 hours after the completion of the dropwise addition of acetoxyacetaldehyde was analyzed by gas chromatography under the same analysis conditions as in Example 1, but no formation of 4-acetoxy-2-methyl-2-butenal was observed. Was.

Examples 4 to 6 The substituted acetaldehyde represented by the formula (2) having X and R shown in Table 1 and the aldehyde represented by the formula (3) were used in the same mole number as in Example 1, and these were used. The reaction was carried out in the same manner as in Example 1, and the corresponding 4-substituted
2-Butenals were obtained. The yield of the target compound (determined by an internal standard method using gas chromatography under the same analysis conditions as in Example 1) is also shown in Table 1. The target compound was isolated by silica gel column chromatography [developing solvent: hexane / ethyl acetate = 9/1 (volume ratio)].

[0043]

[Table 1]

Example 7 Propanal 58 was placed in a three-necked flask having an inner volume of 300 ml.
g (1 mol), alanine 0.2 g, sodium acetate 0.1 g.
4 g and 1.6 g of water were charged, and the internal temperature was raised to 60 ° C. with vigorous stirring. Next, 98.1 g of an aqueous chloroacetaldehyde solution (containing 39 g (0.5 mol) of chloroacetaldehyde) was added dropwise to the obtained mixture over 2 hours. After the addition, the mixture was stirred at the same temperature for 6 hours.
During this time, a small amount of the reaction mixture was sampled and
The reaction was followed by gas chromatography under the same analysis conditions as in Example 1 to confirm the disappearance of the raw material chloroacetaldehyde. Unreacted propanal was distilled off from the resulting reaction mixture under normal pressure. The resulting residue was stirred at 80 ° C. for 8 hours. During this time, a small amount of the reaction mixture was sampled, and the reaction was followed by gas chromatography under the same analysis conditions as in Example 1 to confirm the disappearance of the intermediate (retention time: 12 minutes). At the end of the reaction, 4-chloro-2
28.8 g of -methyl-2-butenal was produced.

After the reaction mixture obtained above was cooled to room temperature, 10 g of a 5% aqueous sodium bicarbonate solution was added, and the mixture was shaken sufficiently to separate an organic layer. The obtained organic layer was subjected to simple distillation under reduced pressure to obtain a crude product, and the obtained crude product was further distilled under reduced pressure to obtain 4-chloro-2-methyl-2-butenal (boiling point of 40 to 40). 26.9 g (42 ° C./0.5 mmHg) (66.3% yield).

Example 8 In a three-necked flask having an inner volume of 300 ml, propanal 43 was placed.
g (0.74 mol), alanine 0.2 g, acetic acid 0.4 g
And 1.6 g of water, and the internal temperature was raised to 60 ° C. while stirring vigorously. Next, 40 g (0.39 mol) of acetoxyacetaldehyde was added dropwise to the obtained mixture over 2 hours. After the addition, the mixture was stirred at the same temperature for 4 hours. During this period, a small amount of the reaction mixture was sampled, and the reaction was followed by gas chromatography under the same analysis conditions as in Example 1 to confirm the disappearance of the starting material, acetoxyacetaldehyde. 10 g of a 5% aqueous sodium bicarbonate solution was added to the obtained reaction mixture, and the mixture was shaken sufficiently to separate an organic layer. The obtained organic layer was subjected to simple distillation, and the boiling point was 100 to 105 ° C./1 mm.
59.2 g of an Hg intermediate product fraction were obtained. When this intermediate product fraction was analyzed by gas chromatography under the same analysis conditions as in Example 1, a single peak at a retention time of 16 minutes was observed.

The infrared absorption spectrum and mass spectrum (GC-Mass) of the intermediate product fraction are shown below.

Infrared absorption spectrum (ν: cm ⁻¹ ): 34
75 (OH), 3000 (CH), 2950 (CH)
H), 2900, 1740 (C = O), 1460, 14
40, 1380, 1240 (C-O), 1160 (C-
O) 1120, 1050, 980, 930, 620

Mass spectrum: 160 (M ⁺ ), 142
_{([M-H 2 O]} +), 83 ([M-H 2 O-CH 3 CO
O] ⁺ )

From the above results, this intermediate product fraction was 4%
It can be seen that it contains -acetoxy-3-hydroxy-2-methylbutanal.

59.2 g of the intermediate product fraction obtained above
0.1 g of acetic acid was added to the mixture, and the mixture was heated to 70 ° C and reacted for 2 hours. The reaction mixture was analyzed by gas chromatography under the same analysis conditions as in Example 1. As a result, the intermediate product had disappeared, and 44.0 g of 4-acetoxy-2-methyl-2-butenal was obtained (yield: 80.80 g). 2%, quantified by the internal standard method using gas chromatography under the same analysis conditions as in Example 1).

[0052]

According to the present invention, 4-substituted-2-butenals can be easily produced with good yield. The present invention is advantageous as an industrial process for producing 4-substituted-2-butenals.

Continuation of the front page (51) Int.Cl. ⁶ Identification number Reference number in the agency FI Technical display location // C07B 61/00 300 C07B 61/00 300

Claims (3)

[Claims] 1. The following formula (2) X—CH ₂ —CHO (2) (wherein, X represents an acyloxy group or a halogen atom)
And a substituted acetaldehyde represented by the following formula (3): R—CH ₂ —CHO (3) (wherein R represents a hydrogen atom, an aliphatic hydrocarbon group or an aromatic hydrocarbon group. May be substituted with a hydroxyl group, an alkoxy group, an aryloxy group, an acyl group, or an alkoxycarbonyl group.) In the presence of an aminocarboxylic acid. 1) (Wherein X and R are as defined above), and a method for producing 4-substituted-2-butenals. 2. The reaction of the substituted acetaldehyde represented by the above formula (2) with the aldehyde represented by the above formula (3) in the presence of an aminocarboxylic acid, to give the following formula (4): (Wherein, X represents an acyloxy group or a halogen atom,
R represents a hydrogen atom, an aliphatic hydrocarbon group or an aromatic hydrocarbon group. These hydrocarbon groups may be substituted by a hydroxyl group, an alkoxy group, an aryloxy group, an acyl group, or an alkoxycarbonyl group. The method according to claim 1, wherein the compound represented by the formula (1) is converted to the 4-substituted-2-butenals represented by the formula (1) by reacting the compound under heating. 3. The following formula (4): (Wherein, X represents an acyloxy group or a halogen atom,
R represents a hydrogen atom, an aliphatic hydrocarbon group or an aromatic hydrocarbon group. These hydrocarbon groups may be substituted by a hydroxyl group, an alkoxy group, an aryloxy group, an acyl group, or an alkoxycarbonyl group. ).