JPH11158174A - Production of 1,3-dioxane compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To industrially and advantageously produce the subject compound useful as a synthetic intermediate for medicines, etc., in a good yield at a low cost by reacting a specific aldehyde with a specified butanediol in the presence of an acidic substance. SOLUTION: (A) An aldehyde represented by the formula R-CHO (R is a hydrocarbon) (e.g. isobutyraldehdye) is reacted with (B) 2 hydroxymethyl-1,4- butanediol represented by formula I in the presence of (C) an acidic substance such as p-toluenesulfonic acid, preferably at 20-100 deg.C usually under 0.1-10 atm pressure to produce the objective compound represented by formula II [e.g. 2-isopropyl-5-(2-hydroxyethyl)-1,3-dioxane]. The amounts of the components used are preferably 0.5-3 mol component A based on 1 mol component B and 0.1-1 wt. % component C based on the component B.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to the formula (1)

[0002]

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[0003] The present invention relates to a method for producing a 1,3-dioxane compound represented by the formula (wherein R represents a hydrocarbon group). The 1,3-dioxane compound obtained by the method of the present invention is
It is useful as a synthetic intermediate for pharmaceuticals and the like.

[0004]

2. Description of the Related Art One of the 1,3-dioxane compounds represented by the above formula (1), 2-isopropyl-5- (2
-Hydroxyethyl) -1,3-dioxane [formula (1)
Wherein R is an isopropyl group is a known substance, and can be produced by reducing the corresponding carboxylic acid (2-isopropyl-1,3-dioxan-5-yl) acetic acid with lithium aluminum hydride. (See J. Org. Chem., 42 , 1533 (1977)).

[0005]

However, in the above-mentioned production method, it is difficult to obtain a carboxylic acid as a raw material, and the lithium aluminum hydride used is a compound which is easily decomposed when exposed to water. Need attention, and there is a difficulty in using it on an industrial scale. In addition, since lithium aluminum hydride is expensive, the production cost increases. The present invention has been made to solve such a problem, and has been made in consideration of the following.
Isopropyl-5- (2-hydroxyethyl) -1,3
1, which includes dioxane and has the formula (1),
It is an object of the present invention to provide a method for producing a 3-dioxane compound inexpensively and industrially advantageously.

[0006]

According to the present invention, an object of the present invention is to provide an aldehyde represented by the formula R-CHO (2) (wherein R represents a hydrocarbon group);

[0007]

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2-hydroxymethyl-1,4 represented by
Reacting butanediol in the presence of an acidic substance, formula (1)

[0009]

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The problem is solved by providing a method for producing a 1,3-dioxane compound represented by the formula (wherein R is as defined above).

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION In the present invention, in the formula (2) representing a starting material and the formula (1) representing a target compound, examples of the hydrocarbon group represented by R include a methyl group, an ethyl group, and a propyl group. Alkyl group such as isopropyl group, isopropyl group, butyl group, pentyl group, hexyl group and heptyl group; cycloalkyl group such as cyclopentyl group and cyclohexyl group; aryl group such as phenyl group and naphthyl group; aralkyl group such as benzyl group. No.

Here, specific examples of the aldehyde represented by the formula (2) include acetaldehyde, propionaldehyde, butyraldehyde, isobutyraldehyde, pentanal, n-octanal, cyclopentanecarbaldehyde, cyclohexanecarbaldehyde, benzaldehyde, and naphthyl. Aldehyde, phenylacetaldehyde and the like can be mentioned.

Further, 2-hydroxymethyl-1,4-butanediol as another starting material is, for example, 2-formyl obtained by hydroformylating 2-butene-1,4-diol which is easily available. -1,4-
It can be easily produced on an industrial scale by hydrogenating butanediol (JP-A-6-34056).
No. 9).

In the present invention, the amount of the aldehyde represented by the formula (2) is usually in the range of 0.1 to 10 mol, and preferably 1 to 2 mol of 2-hydroxymethyl-1,4-butanediol. , 2-hydroxymethyl-1,4
-In the range of 0.5 to 3 mol per 1 mol of butanediol.

The reaction according to the present invention is a reaction for producing an acetal from 2-hydroxymethyl-1,4-butanediol which is a triol compound and an aldehyde represented by the formula (2).

[0016]

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The 1,3-dioxane compound represented by the formula (1) is selectively produced with almost no formation of the 7-membered ring compound represented by the formula (1). The selective formation of a 6-membered cyclic 1,3-dioxane compound as described above indicates that when a ketone is used in place of the aldehyde represented by the formula (2), as shown in Reference Examples described later. Although a similar acetalization reaction proceeds, it is unexpected in view of the fact that a relatively large amount of a 7-membered cyclic compound is produced.

As the acidic substance used in the present invention, those generally used as a catalyst for an acetalization reaction can be used. For example, inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid; Carboxylic acids such as fluoroacetic acid; sulfonic acids such as methanesulfonic acid, p-toluenesulfonic acid and trifluoromethanesulfonic acid; acidic salts such as pyridinium p-toluenesulfonate; solid acids such as acidic ion exchange resins; aluminum chloride And Lewis acids such as zinc chloride, titanium chloride and stannic chloride dihydrate; and titanium compounds having acetylacetone as a ligand. Among these, p-toluenesulfonic acid is preferred. As the acidic substance, one kind may be used, or two or more kinds may be used in combination.

The amount of the acidic substance used is not particularly limited, but is preferably in the range of 100 ppm to 10% by weight based on 2-hydroxymethyl-1,4-butanediol. More preferably, it is in the range of 0.1 to 1% by weight based on methyl-1,4-butanediol.

The reaction according to the present invention is carried out by mixing the aldehyde of the formula (2) and 2-hydroxymethyl-1,4-butanediol in the presence of an acidic substance. Here, the mixture of the aldehyde represented by the formula (2) and 2-hydroxymethyl-1,4-butanediol is obtained by adding 2-hydroxymethyl- to the aldehyde represented by the formula (2).
It may be carried out by adding 1,4-butanediol or by adding an aldehyde represented by the formula (2) to 2-hydroxymethyl-1,4-butanediol. The reaction according to the present invention may be carried out in any of a batch system and a continuous system.

In the reaction according to the present invention, a solvent is not essential, but a solvent can be used as long as the reaction is not adversely affected. Examples of usable solvents include aliphatic hydrocarbon solvents such as pentane, hexane and heptane; aromatic hydrocarbon solvents such as benzene, toluene and xylene; halogenated hydrocarbon solvents such as methylene chloride, dichloroethane and chloroform. Ether solvents such as diethyl ether, diisopropyl ether and tetrahydrofuran; The amount of the solvent used is not particularly limited, but is preferably in a range that does not impair the volumetric efficiency of the reaction, and is 0.1 to 100 times the weight of 2-hydroxymethyl-1,4-butanediol. And more preferably 1 to 10 times the weight of 2-hydroxymethyl-1,4-butanediol.

The reaction according to the present invention is usually carried out at 0 ° C to 200 ° C.
C., but preferably at a temperature in the range of 20.degree. C. to 100.degree. The reaction according to the present invention is usually carried out under a pressure in the range of 0.1 to 10 atm.

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, since water is by-produced with the progress of the reaction, it is preferable to remove the water and suppress the hydrolysis of the target compound in order to obtain the target compound in good yield. As a method of removing water, a known method such as a method of distilling water out of the reaction system by azeotropic distillation, a method of using a dehydrating agent such as molecular sieve, anhydrous magnesium sulfate, and anhydrous sodium sulfate may be used. it can.

As a method of distilling water out of the reaction system by azeotropy, a method of distilling water as an azeotrope with an aldehyde represented by the formula (2) as a raw material is simple. In this case, it is desirable to separate water from the distillate using a water separator such as a Dean-Stark trap, and to return the distillate after the water separation to the reaction system again. In addition, water can be distilled out of the reaction system using a solvent that can azeotrope with water, such as toluene.

After completion of the reaction, the desired 1,3-dioxane compound can be converted into unreacted starting materials by a conventional method such as, for example, neutralizing acidic substances in the reaction mixture if necessary and then distilling the reaction mixture. Can be easily separated and obtained. The purity of the thus obtained 1,3-dioxane compound represented by the formula (1) can be further increased, if necessary, by means such as distillation and column chromatography.

[0027]

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 [2-isopropyl-5- (2-
Production of hydroxyethyl) -1,3-dioxane] In a 300 ml three-necked flask equipped with a water separator,
-Hydroxymethyl-1,4-butanediol (50
g, 0.41 mol), p-toluenesulfonic acid (0.0
5 g) and 80 g of toluene were charged and heated to 80 ° C. under a nitrogen atmosphere. Next, isobutyraldehyde (35.5 g, 0.49 mol) was added to the obtained mixture over 1 hour, and the generated water was removed from the reaction system by azeotropic distillation at 80 ° C. and normal pressure under stirring. While reacting for 2 hours.
At this time, water was separated from the distillate in the water separator, and the distillate from which the water had been separated was returned to the reaction system.
When the obtained reaction solution was analyzed by gas chromatography under the following conditions, a peak corresponding to 2-isopropyl-5- (2-hydroxyethyl) -1,3-dioxane was observed. No peak corresponding to 2-isopropyl-5-hydroxymethyl-1,3-dioxacycloheptane, which is a compound of the formula (1), was observed.

The reaction mixture obtained above was cooled to room temperature, neutralized by adding 0.5 g of triethanolamine, and then the solvent was distilled off under reduced pressure. -Isopropyl-5- (2-hydroxyethyl)
-1,3-dioxane (boiling point: 98 to 108 ° C./2To
rr) to 53.6 g (0.31 mol, yield: 76%)
Obtained.

Gas chromatography analysis conditions Column: PEG-HT [length: 3 m, manufactured by GL Sciences Corporation] Column temperature: 100 → 245 ° C. (heating rate: 7 ° C. /
Min) Detector: FID detector

Reference Example A reaction was conducted in the same manner as in Example 1 except that 28.4 g (0.49 mol) of acetone was used instead of isobutyraldehyde. As a result of analyzing the obtained reaction solution by gas chromatography, the product was found to be a 2-membered cyclic compound, 2,2-dimethyl-5- (2-hydroxyethyl) -1,3-dioxane, and a 7-membered cyclic compound. 2,2-dimethyl-5-hydroxymethyl-1,3
-A mixture of dioxacycloheptane [ratio: former / latter = 40/60 (molar ratio)].

Examples 2 to 4 In Example 1, n-octanal [Example 2, R: nC ₇ H ₁₅ in the formula (2)] and benzaldehyde [Example 3, Formula 3] were substituted for isobutyraldehyde. Using R: Ph in (2) or phenylacetaldehyde [Example 4, R: PhCH ₂ in formula (2)] in the same mole number as in Example 1, the reaction was carried out in the same manner as in Example 1 below. , Respectively, 2-heptyl-5- (2-
(Hydroxyethyl) -1,3-dioxane (Example 2), 2-phenyl-5- (2-hydroxyethyl)-
1,3-dioxane (Example 3) and 2-benzyl-
5- (2-Hydroxyethyl) -1,3-dioxane (Example 4) was obtained. Here, the isolation of the product was performed by adding triethanolamine to the obtained reaction mixture and then distilling off the solvent and distilling the obtained residue under reduced pressure as in Example 1. Table 1 shows the yield and the physical properties of the product (mass spectrum: m / z).

[0033]

[Table 1]

[0034]

According to the present invention, the 1,3-dioxane compound represented by the above formula (1) can be produced industrially and advantageously at a low cost and a high yield.

 ──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Hideharu Iwasaki 2045 Sakurazu, Kurashiki City, Okayama Prefecture 1 Kuraray Co., Ltd.

Claims (1)

[Claims] 1. An aldehyde represented by the formula R-CHO (2) wherein R represents a hydrocarbon group, and an aldehyde represented by the formula (3): Which comprises reacting 2-hydroxymethyl-1,4-butanediol represented by the formula (1) in the presence of an acidic substance. (Where R is as defined above)
-A method for producing a dioxane compound.