JP2001158782A - Method for producing 1,3-dioxolane derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing a 1,3-dioxolane derivative simply in a high yield. SOLUTION: In this method for producing a 1,3-dioxolane derivative of general formula (2) (R is a hydrocarbon group which may contain a substituent) by subjecting a 1,4-bis(acyloxy)-2,3-butanediol of general formula (1) (R is as shown for the formula (2)) and paraformaldehyde to ring formation reaction in the presence of an acid catalyst, this method is characterized in that the reaction is carried out in the presence of a dehydrating agent.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for producing a 1,3-dioxolane derivative. Specifically, 1,4-bis (acyloxy) -2,3-butanediol (hereinafter, referred to as 1,4-bis (acyloxy) -2,3-butanediol)
(Sometimes referred to as "1,2-diol derivative (1)")
To an intramolecular cyclization reaction with paraformaldehyde in a solvent with an acid catalyst to produce a 1,3-dioxolane derivative. This compound is useful as a raw material for synthesizing pharmaceuticals, agricultural chemicals, and the like. For example, in the formula (2), 4,5-bis (benzoyloxymethyl) -1,3-dioxolane in which R is a benzoyl group is useful for increasing radiation. (±)-(2RS, 3SR) -3-[(2-nitroimidazol-1-yl) -methoxy] butane-
It is useful as an intermediate of 1,2,4-triol (JP-A-10-287657).

[0002]

2. Description of the Related Art There have been proposed several methods for producing a 1,3-dioxolane derivative (2) from 1,2-diols as represented by the formula (1). For example, EP 72027 describes the reaction of formula (3).

[0003]

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Japanese Patent Application Laid-Open No. Hei 10-287657 discloses a reaction represented by the formula (4).

[0005]

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[0006]

However, in the former method, at least a stoichiometric amount of a Lewis acid is required due to the reaction mechanism in order to obtain a 1,3-dioxolane derivative in a high yield. For the latter method,
As an industrial production method, for example, phosphorus pentoxide, which has high hygroscopicity, is difficult to handle, and has a problem of wastewater treatment, and at least a stoichiometric amount of Lewis acid is required at the time of ring closure. There are various problems. The present invention relates to 1,3
-An object of the present invention is to provide a method for producing a dioxolane derivative in a simple and high yield.

[0007]

Means for Solving the Problems The inventors of the present invention have made intensive studies in view of the above circumstances and found that the 1,2-diol derivative (1) was subjected to a cyclization reaction in a solvent in the presence of paraformaldehyde and an acid catalyst in a solvent. 1,3-dioxolane derivative (2)
Found that the yield of the target product (2) was significantly improved by performing the reaction in the presence of a dehydrating agent when producing
The present invention has been completed.

That is, the gist of the present invention is that the following general formula (1)

[0009]

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(Wherein, R represents a hydrocarbon group which may have a substituent)

1,4-bis (acyloxy) represented by
Cyclization reaction of -2,3-butanediol in the presence of paraformaldehyde and an acid catalyst in a solvent to give the following general formula (2)

[0012]

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(Wherein R has the same meaning as in formula (1))

In the method for producing a 1,3-dioxolane derivative represented by the formula (1), the reaction is carried out in the presence of a dehydrating agent.

[0015]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail.
The production method of the present invention includes the steps of: producing a 1,3-dioxolane derivative (2) by subjecting a 1,2-diol derivative (1) to a cyclization reaction with paraformaldehyde in a solvent in the presence of an acid catalyst; The reaction is carried out in the presence of a dehydrating agent.

(1,2-diol derivative (1)) 1,2-diol derivative (1) used as a raw material in the present invention
Is a compound represented by the formula (1).

[0017]

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(Wherein, R represents a hydrocarbon group which may have a substituent)

In the formula (1), the hydrocarbon group is not particularly limited, but specific examples thereof include an alkyl group, an alkenyl group, an alkynyl group and an aryl group. Groups and aryl groups are preferred. In the formula (1), when R is an alkyl group which may have a substituent, the alkyl group is linear,
It may be branched or cyclic, and preferably has 1 to 8 carbon atoms. Specific examples thereof include a methyl group, an ethyl group, a propyl group, a butyl group, a benzyl group, and an ethylphenyl group. .

When R is an aryl group which may have a substituent, the aryl group preferably has 6 to 10 carbon atoms. Specific examples thereof include a phenyl group, a tolyl group, a cumyl group and a p-type group. -Tert-butylphenyl group, methoxyphenyl group, chlorophenyl group, bromophenyl group, naphthyl group and the like. Among them, R is preferably a phenyl group.

The 1,4-bis (acyloxy) -2,3-butanediol of the formula (1) is, for example, 1,2,2
3,4-butanetetraol is reacted with acyl chloride in a basic polar solvent such as an amide at 0 to 100 ° C. for 30 minutes to 15 hours to selectively acylate a primary hydroxyl group in butanetetraol. To be obtained. The steric configuration of the compound of the formula (1) as a raw material is not particularly limited, that is, it may be any of a meso form, a racemic form and an optically active form, and may be an arbitrary mixture thereof. Absent.

(Paraformaldehyde) Paraformaldehyde is used as a source of formaldehyde. Therefore, in addition to paraformaldehyde, trioxane which is a trimer of formaldehyde or gaseous formaldehyde can also be used. However, paraformaldehyde is particularly preferred in terms of handling and price.
The amount of paraformaldehyde to be used is generally 0.5 to 20 times, preferably 1.0 to 10 times, the molar amount of the 1,2-diol derivative (1).

(Acid) With regard to the acid used in the present invention,
Although not particularly limited, specific examples thereof include, for example,
Sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, propanesulfonic acid, butanesulfonic acid, pentanesulfonic acid, hexanesulfonic acid,
Sulfonic acids such as benzenesulfonic acid, p-toluenesulfonic acid, 1-naphthalenesulfonic acid, and 2-naphthalenesulfonic acid; phosphoric acids such as phosphoric acid and polyphosphoric acid; formic acid;
Carboxylic acids such as acetic acid, trifluoroacetic acid, propionic acid and benzoic acid; and hydrohalic acids such as hydrochloric acid, hydrobromic acid and hydroiodic acid. Of these, sulfonic acids are preferred, and sulfuric acid is particularly preferred. The amount of the acid used is 0.01 to 2 times, preferably 0.1 to 1.0 times the molar amount of the raw material.

(Solvent) The solvent used in the present invention is not particularly limited as long as it can dissolve the compound of the formula (1) as a raw material, but usually an aprotic solvent is used. Specifically, benzene, toluene, xylene,
Aromatic hydrocarbons such as chlorobenzene and 1,2-dichlorobenzene; aliphatic hydrocarbons such as hexane, heptane and octane; diethyl ether, di-n-propyl ether, diisopropyl ether, di-n-butyl ether, THF and the like Ethers; halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; and esters such as ethyl acetate, n-propyl acetate, isopropyl acetate and n-butyl acetate. Among them, toluene, heptane and 1,2-dichloroethane are particularly preferred. The amount of the solvent used may be such that at least a part of the 1,2-diol derivative (1) and the paraformaldehyde as the raw materials are dissolved and can be stirred, and it is not necessary to completely dissolve the raw materials. Usually, 2 to 10 with respect to the 1,2-diol derivative (1).
0 times by weight is used, and preferably 5 to 30 times by weight.

(Dehydrating agent) The dehydrating agent used in the present invention includes:
It is a halide of an alkaline earth metal. Examples of the halide include chloride, bromide, and iodide.
Of these, chlorides are preferred, and their anhydrides are particularly preferred. Specific examples of the alkaline earth metal halide include magnesium chloride, calcium chloride, strontium chloride, barium chloride, calcium bromide, calcium iodide and the like. Of these, calcium chloride and magnesium chloride are preferred. The amount of dehydrating agent used is as follows:
0.1 to 20 times by mole, preferably 1.
It is in the range of 0 to 5.0 molar times.

(Reaction conditions) The ring closure reaction is carried out by charging a compound of the formula (1), paraformaldehyde, an acid and a solvent into a reactor and reacting the mixture at a predetermined temperature, preferably under stirring, for a predetermined time. . The reaction temperature is usually in the range of 0 to 200 ° C, preferably 50 to 120 ° C, and the reaction time varies depending on the type of the acid, dehydrating agent, solvent and the reaction temperature, but is usually 1 to 12 hours. And the reaction pressure is usually normal pressure, but may be under pressure or under reduced pressure as required. The reaction may be carried out in air or in an inert gas such as nitrogen.However, in order to prevent a decrease in yield due to moisture absorption of the dehydrating agent, it is particularly preferable to carry out the reaction in an inert gas such as nitrogen. preferable.

(Purification method) The product can be separated and purified from the reaction solution by a conventional method. For example, after washing the reaction solution with water, the organic layer is concentrated, and a solvent is added to the residue, whereby the residue can be taken out as crystals. Further, the product can be further purified by recrystallization, reprecipitation, column chromatography or the like to obtain a high-purity target product.

[0028]

EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples and comparative examples, but the present invention is not limited to the examples unless it exceeds the gist thereof.

Example 1 0.5 g of 1,4-di-O-benzoylerythritol, 0.252 g of 90% paraformaldehyde, 0.335 g of calcium chloride, 0.1 g of sulfuric acid.
091 g and toluene 10 ml were charged into an eggplant-shaped flask and stirred at 80 ° C. for 7 hours. When the reaction solution was quantitatively analyzed by high performance liquid chromatography (HPLC), the conversion was 99.0%, and the reaction yield of 4,5-bis (benzoyloxymethyl) -1,3-dioxolane was 86.0%. Was.

(Example 2) 0.5 g of 1,4-di-O-benzoylerythritol, 0.252 g of 90% paraformaldehyde, 0.289 g of magnesium chloride, 0.091 g of sulfuric acid and 10 ml of toluene were charged into an eggplant type flask. Stirred at 80 ° C. for 5 hours. HPLC the reaction solution
The conversion was 96.0%, and the reaction yield of 4,5-bis (benzoyloxymethyl) -1,3-dioxolane was 75.0%.

Comparative Example 1 0.5 g of 1,4-di-O-benzoylerythritol, 0.252 g of 90% paraformaldehyde, 0.091 g of sulfuric acid and 10 ml of toluene
Was charged into an eggplant-shaped flask and stirred at 80 ° C. for 5 hours.
The reaction solution was quantitatively analyzed by HPLC.
8.0%, 4,5-bis (benzoyloxymethyl)-
The reaction yield of 1,3-dioxolane was 47.0%.

[0032]

According to the present invention, a 1,3-dioxolane derivative useful as a pharmaceutical intermediate can be easily produced.

Continued on the front page (72) Inventor Josef Yuneman 1-1 Kurosaki Castle Stone, Yawata-nishi-ku, Kitakyushu F-term in Mitsubishi Chemical Co., Ltd. Kurosaki Office (reference) 4H039 CA42 CH20

Claims (5)

[Claims] [Claim 1] The following general formula (1) (Wherein, R represents a hydrocarbon group which may have a substituent)
A 1,4-bis (acyloxy) -2,3-butanediol represented by the following formula is subjected to a cyclization reaction in a solvent in the presence of paraformaldehyde and an acid catalyst to give a compound represented by the following general formula (2): (Wherein R has the same meaning as in formula (1))
-A method for producing a dioxolane derivative, wherein the reaction is carried out in the presence of a dehydrating agent. 2. The method for producing a 1,3-dioxolane derivative according to claim 1, wherein the dehydrating agent is an alkaline earth metal halide. 3. The method for producing a 1,3-dioxolane derivative according to claim 1, wherein the acid catalyst is a sulfonic acid. 4. The method according to claim 1, wherein the solvent is an aprotic solvent.
4. The method for producing a 1,3-dioxolane derivative according to any one of claims 1 to 3. 5. The method according to claim 1, wherein R is a phenyl group.
The method for producing a 1,3-dioxolane derivative according to any one of the above.