JPH11152280A - Preparation of 3-methyl-4-hydroxy-2-butenolide - Google Patents

Abstract

PROBLEM TO BE SOLVED: To industrially, advantageously and cheaply obtain the subject compound by using a compound available in an industrial scale and carrying out the reaction of a specific compound with an acid in the presence of water. SOLUTION: (A) A compound of the formula (R<1> is an alkyl or an aralkyl; R<2> is a >=2C acyl), (e.g. 1-methoxycarbonyl-2-formylpropyl acetate) is reacted with (B) an acid (e.g. hydrochloric acid) of 0. 0001-10 mol, preferably 0.005-1.2 mol based on 1 mol of the component A in the presence of (C) water of not less than the equal weight, preferably of not less than the weight equal to and not more than five times as much as that of the component A preferably in an inert gas (e.g. nitrogen) atmosphere at >=30 deg.C preferably 40-120 deg.C, if necessary, while removing a carboxylic acid and an alcohol of by-products from a reaction system as a mixture with the component C by means of distillation or the like to provide the objective compound.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to 3-methyl-methacrylate, which is useful as an intermediate for the synthesis of 13-cis retinoic acids such as 13-cis retinoic acid used for the treatment of acne and the like.
The present invention relates to a method for producing 4-hydroxy-2-butenolide.

[0002]

2. Description of the Related Art As a method for producing 3-methyl-4-hydroxy-2-butenolide, for example, the following methods are known. A method of reacting glyoxylic acid and propanal in the presence of morpholine hydrochloride [J. Org. Chem., 46 , 4889 (1
981). A method in which an acid such as hydrochloric acid is allowed to act on 3-formyl-2-butenoic acid or an ester derivative thereof [J. Chem. Soc., 5
94 (1964)].

[0003]

[Problems to be solved by the invention] However, J. Or
g. Chem., 46 , 4889 (1981) describes a 2-N-morpholino-3 which is a condensate obtained by a Mannich reaction.
Since the reaction proceeds via -methyl-4-hydroxybutanolide, it is necessary to use morpholine hydrochloride in an equimolar amount with glyoxylic acid in order to obtain the desired compound in good yield. This leads to an increase in manufacturing costs. J. Org. Chem., 46 , 4889 (1981) states that the reaction of glyoxylic acid and propanal directly in the presence of hydrogen chloride without the use of morpholine hydrochloride leads to the reaction of complex composition. A mixture was obtained and the yield of 4-hydroxy-3-methyl-2-butenolide was disclosed to be 8%. Meanwhile, J. Chem. Soc., 594 (1964)
In the method described in (1), 3-formyl-2-butenoic acid or an ester derivative thereof is used as a starting material. However, according to the production methods known so far, the synthesis is complicated and the yield is low. Because the rate is not high [Tetrahedron Le
tters, 22 , 1595 (1981); Synthesis, 297 (1983);
Org.Chem., 51 , 256 (1986); Helv. Chim. Acta., 45 ,
541 (1962) etc.], and are not inexpensive and readily available compounds on an industrial scale. Thus, none of the above and the above methods is suitable for industrial implementation. Thus, the present invention provides an industrially advantageous method capable of producing 4-hydroxy-3-methyl-2-butenolide at a lower cost than before using a compound available on an industrial scale. As an issue.

[0004]

According to the present invention, the above object is achieved by the following equation (1).

[0005]

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(Wherein, R ¹ represents an alkyl group or an aralkyl group, and R ² represents an acyl group having 2 or more carbon atoms)
Is solved by providing a method for producing 3-methyl-4-hydroxy-2-butenolide, which comprises reacting a compound represented by the formula with an acid in the presence of water.

[0007]

DETAILED DESCRIPTION OF THE INVENTION Formula (1) representing the starting material of the present invention
In the above, examples of the alkyl group represented by R ¹ include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a t-butyl group, a pentyl group, and a hexyl group. Examples of the aralkyl group represented by R ¹ include a benzyl group and a phenethyl group. Further, in the formula (1), examples of the acyl group having 2 or more carbon atoms represented by R ² include an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a valeryl group, an isovaleryl group, a pivaloyl group, a hexanoyl group,
Examples include a heptanoyl group and a benzoyl group.

Here, specific examples of the compound represented by the formula (1) include 1-methoxycarbonyl-2-formylpropyl acetate, 1-ethoxycarbonyl-2-formylpropyl acetate, and 1-butoxycarbonyl. 2-formylpropyl acetate, 1-benzyloxycarbonyl-2-formylpropyl acetate,
1-methoxycarbonyl-2-formylpropyl = propionate, 1-ethoxycarbonyl-2-formylpropyl = isovalerate, 1-methoxycarbonyl-2
-Formylpropyl = pivalate, 1-methoxycarbonyl-2-formylpropyl = benzoate and the like.

The compound represented by the formula (1) can be obtained, for example, by converting acrolein to cyanohydrin and then methanol,
After alcoholysis using alcohols such as ethanol and butanol, and then reacting with carboxylic anhydrides such as acetic anhydride (see West German Patent No. 3634151), the following can be produced on an industrial scale. Equation (2)

[0010]

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(Wherein R ¹ and R ² are as defined above), for example, 3-butenoic acid esters [eg, 1-methoxycarbonyl-2-propenyl acetate, 1-methoxycarbonyl-2 -Propenyl propionate, 1-ethoxycarbonyl-2-propenyl benzoate, 1-t-butoxycarbonyl-2-propenyl acetate, etc.) with hydrogen and carbon monoxide in the presence of a rhodium compound and a tertiary organophosphorus compound. It is a compound that can be produced by reacting (hydroformylation) and is available at low cost on an industrial scale.

Examples of the acid used in the present invention include inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid; and organic acids such as p-toluenesulfonic acid and methanesulfonic acid.
Bronsted acids are preferred, and hydrochloric acid is more preferred. The amount of the acid used is usually in the range of 0.0001 to 10 mol with respect to 1 mol of the compound represented by the formula (1). 005 ~
More preferably, it is within the range of 1.2 mol.

In the present invention, the amount of water used is not particularly limited, but is usually equal to or more than the weight of the compound represented by the formula (1), preferably the compound represented by the formula (1) Within the range of not less than equal weight and not more than 5 times weight.

The reaction according to the present invention is usually carried out in the absence of an organic solvent, provided that the reaction is not adversely affected.
It can be carried out in the presence of an organic solvent. Examples of usable solvents include aromatic hydrocarbon solvents such as benzene, toluene, and xylene; and ether solvents such as isopropenyl ether, tetrahydrofuran, and 1,3-dioxane. The reaction according to the present invention is preferably carried out in an atmosphere of an inert gas such as nitrogen or argon.

The reaction according to the present invention is usually carried out in a reaction vessel equipped with a stirrer, by mixing the compound represented by the formula (1), an acid, water and, if desired, an organic solvent. The reaction according to the present invention can also be carried out by adding water to a mixture of the compound represented by the formula (1) and the acid. In this case, water may be added in a desired amount at a time,
It may be added in several small portions and may be added continuously.

In the present invention, the reaction may be carried out while removing the carboxylic acid and alcohol by-produced as the reaction proceeds as a mixture with water from the reaction system by means such as distillation.

The reaction temperature is usually 30 ° C. or higher, but preferably in the range of 40 to 120 ° C. In addition, the reaction according to the present invention is generally performed under normal pressure, but can be performed under reduced pressure or under increased pressure.

After completion of the reaction, the desired compound, 3-methyl-4-hydroxy-2-butenolide, is neutralized with an acid in the reaction mixture using, for example, sodium hydrogen carbonate or potassium carbonate, if desired. ) Method of distillation, or b)
It can be separated and obtained from the reaction mixture according to a conventional method such as an extraction method using an organic solvent. When hydrochloric acid is used as the acid, instead of the above neutralization operation,
Excess acid (hydrogen chloride) can be removed by placing the reaction solution under reduced pressure. In the above, as the extraction solvent, for example, ethyl acetate, chloroform, dichloromethane, diethyl ether and the like can be used.

The thus obtained 3-methyl-4-hydroxy-2-butenolide is optionally subjected to distillation, recrystallization,
Purity can be further increased by means such as column chromatography.

[0020]

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

Reference Example Production of 1-methoxycarbonyl-2-formylpropyl acetate: 3.9 mg of dicarbonylacetylacetonatotrodium was placed in a 300 ml stainless steel electromagnetically stirred autoclave equipped with a gas inlet and a sampling port. 485 mg of tris (2,4-di-t-butylphenyl) phosphite, 30 ml of 1-methoxycarbonyl-2-propenyl acetate (31.8 g,
0.201 mol) and 120 ml of toluene were charged in a nitrogen atmosphere without contacting air, and the atmosphere in the autoclave was replaced with a mixed gas of hydrogen / carbon monoxide = 1/1 (molar ratio). The pressure inside the autoclave was adjusted to 90 atm with the gas of
° C. A mixed gas of hydrogen / carbon monoxide = 1/1 (molar ratio) was supplied to the autoclave, and the reaction was carried out for 2 hours while maintaining the pressure in the autoclave at 90 atm. The obtained reaction mixture is subjected to gas chromatography [column: G-300 (trade name, manufactured by Chemical Inspection Association), column temperature: 100 ° C. → 200 ° C. (heating rate: 10 ° C./min)].
As a result, it was found that 18.2 g of 1-methoxycarbonyl-2-formylpropyl acetate and 8.4 g of 1-methoxycarbonyl-4-oxobutyl acetate, which is a linear aldehyde, were produced. Was. The conversion of 1-methoxycarbonyl-2-propenyl acetate was 99% and the selectivity for hydroformylation was 98%.

The resulting reaction mixture was distilled under reduced pressure to obtain 28.5 g of 1-methoxycarbonyl-2-formylpropyl acetate as a fraction having a boiling point of 87 ° C. to 89 ° C./1 mmHg (purity 89%). )Obtained. This compound was a mixture of two diastereomers (threo form and erythro form). The physical properties are shown below.

Diastereomer (1) ¹ H-NMR (270 MHz, CDCl ₃ , TMS) δ (ppm): 1.21 (d, 3H, J = 6.5H)
z), 2.16 (s, 3H), 2.96-2.99
(M, 1H), 3.78 (s, 3H), 5.38 (d,
1H, J = 4.2 Hz), 9.69 (s, 1H)

Diastereomer (2) ¹ H-NMR (270 MHz, CDCl ₃ , TMS) δ (ppm): 1.22 (d, 3 H, J = 6.5 H)
z), 2.13 (s, 3H), 2.96-2.99
(M, 1H), 3.79 (s, 3H), 5.59 (d,
1H, J = 3.0 Hz), 9.67 (s, 1H)

The ratio of diastereomers calculated from the ¹ H-NMR spectrum was as follows: diastereomer (1)
/ Diastereomer (2) = about 59/41 (molar ratio).

Example 1 20.0 g (purity 89%, 94.7 mmol) of 1-methoxycarbonyl-2-formylpropyl acetate obtained in Reference Example was placed in a 100 ml three-necked flask equipped with a distillation column, and the concentration was 9%. 40 g of 1% hydrochloric acid (hydrogen chloride in 0.1 g).
After stirring, the pressure in the flask was reduced to 13.33 kPa under a nitrogen atmosphere, and then the internal temperature was increased to 50 ° C. At the same time as the water containing methanol and acetic acid began to distill from the upper part of the distillation column, water was fed into the flask so that the liquid volume in the flask was kept constant. The reaction was continued for 5 hours in this state. The amount of water fed during this time was 40 g. The resulting reaction mixture was cooled to room temperature and neutralized by adding 2.0 g of sodium hydrogen carbonate.
Extracted twice with 00 ml. After combining the obtained extracts, methylene chloride was distilled off under reduced pressure, and the precipitated salt was filtered to obtain 12.5 g of a filtrate. The obtained filtrate was analyzed by gas chromatography [column: G-100 (trade name, manufactured by Chemical Inspection Association), column temperature: 100 → 240 ° C. (heating rate: 10 ° C./min)]. Methyl-
9.8 g of 4-hydroxy-2-butenolide (yield: 9
1%).

[0027]

According to the present invention, 4-hydroxy-3-
Methyl-2-butenolide can be produced at lower cost than before using a compound available on an industrial scale.

Claims (1)

[Claims] (1) Formula (1) (Wherein, R ¹ represents an alkyl group or an aralkyl group;
R ² represents an acyl group having 2 or more carbon atoms) with an acid in the presence of water.
A method for producing methyl-4-hydroxy-2-butenolide.