JP2001151768A - Method for producing 1,3-dioxolan derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing a 1,3-dioxolan derivative (2) useful as an intermediate for a medicine simply in a high yield. SOLUTION: A compound of general formula (1) (R1 and R2 are each independently an alkyl group which may contain a substituent or an aryl group which may contain a substituent) is subjected to an intramolecular ring formation in a solvent in the presence of a Broensted acid.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for producing a 1,3-dioxolane derivative. More specifically, the present invention relates to a method for producing a 1,3-dioxolane derivative by intramolecularly closing a 1,2-diol dialkoxymethyl ether derivative in the presence of a specific catalyst. This compound is useful as a raw material for synthesis of pharmaceuticals, agricultural chemicals, etc. For example, in the formula (2), 4,5-bis (benzoyloxymethyl) -1,3-dioxolane in which R ¹ is a benzoyl group is useful for radiation (±)-(2RS, 3SR) -3- which is a sensitizer
[(2-Nitroimidazol-1-yl) -methoxy]
Butane-1,2,4-triol (JP-A-10-287)
657) is useful as an intermediate.

[0002]

2. Description of the Prior Art Methods for producing 1,3-dioxolanes from 1,2-diol dialkoxymethyl ethers have been known. For example, JP-A-6-2281
No. 23 discloses a reaction of the formula (3) using phosphorus pentoxide.

[0003]

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Japanese Patent Application Laid-Open No. 10-287657 discloses a formula (4) using BF ₃ .Et ₂ O which is a Lewis acid.
Reaction is shown.

[0005]

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[0006]

However, in order to obtain the desired 1,3-dioxolane derivative in high yield also from the reaction mechanism, phosphorus pentoxide or Lewis acid is required for the above-mentioned method. However, these reagents are very hygroscopic and difficult to handle, and if a large amount of phosphorus pentoxide is used, the phosphorus wastewater must be treated, and There are various problems as a typical manufacturing method. An object of the present invention is to provide a method for producing a 1,3-dioxolane derivative of the formula (2) simply and in a high yield from a compound of the formula (1).

[0007]

Means for Solving the Problems The inventors of the present invention have made intensive studies in view of the above circumstances, and have found that a 1,2-diol dialkoxymethyl ether derivative is intramolecularly ring-closed in a solvent in the presence of a specific acid catalyst. By doing so, they have found that a 1,3-dioxolane derivative can be easily produced at a high yield, and have completed the present invention.

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

[0009]

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(Wherein, R ¹ and R ² each independently represent an alkyl group which may have a substituent or an aryl group which may have a substituent)

Wherein the compound represented by the general formula (2) is subjected to intramolecular cyclization in a solvent in the presence of a Bronsted acid catalyst.

[0012]

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

A method for producing a 1,3-dioxolane derivative represented by the formula:

[0015]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail.
The method of the present invention is characterized in that a compound of the formula (1) is intramolecularly cyclized in a solvent in the presence of a Bronsted acid catalyst to produce a 1,3-dioxolane derivative of the formula (2). .

(1,2-diol dialkoxymethyl ether) The 1,2-diol dialkoxymethyl ether used as a raw material in the present invention is a compound represented by the formula (1).

[0017]

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(Wherein, R ¹ and R ² each independently represent an alkyl group which may have a substituent or an aryl group which may have a substituent)

In the formula (1), when R ¹ and R ² are an alkyl group which may have a substituent, the alkyl group may be linear, branched or cyclic, Is preferably 1 to 8, and 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 ¹ and R ² are an aryl group which may have a substituent, the aryl group preferably has 6 to 10 carbon atoms, and specific examples thereof include, for example, a phenyl group, a tolyl group, a cumyl group, p-
Examples include a tert-butylphenyl group, a methoxyphenyl group, a chlorophenyl group, a bromophenyl group, and a naphthyl group.

Among them, R ¹ is preferably a phenyl group, and R ² is preferably a methyl group or a benzyl group. The compound of the formula (1) is, for example,
1,4-bis (acyloxy) -2,3-butanediol is converted to an alkyl halide such as R ² Cl or R ² Br (R ² is as defined in the formula (1)), tetrahydrofuran, ethyl acetate, chloroform, In a solvent such as dichloromethane in the presence of a base such as sodium hydride, triethylamine, diisopropylethylamine,
It is obtained by reacting at 150 ° C. for 1 to 12 hours and etherifying.

Also, 1,4-bis (acyloxy)-
For example, 2,3-butanediol is prepared by reacting 1,2,3,4-butanetetraol with acyl chloride and a non-polar polar solvent such as amide at 0 to 100 ° C. for 30 minutes to 15 hours. It is obtained by selectively acylating a primary hydroxyl group in tetraol. The configuration of the compound of the formula (1) 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. .

(Brønsted acid catalyst) The Bronsted acid used in the present invention is not particularly limited, but specific examples thereof include sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, and propane. Sulfonic acids such as sulfonic acid, butanesulfonic acid, pentanesulfonic acid, hexanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 1-naphthalenesulfonic acid, and 2-naphthalenesulfonic acid; polyphosphoric acid; formic acid, acetic acid, and trifluorocarbon Carboxylic acids such as acetic acid, propionic acid and benzoic acid; and hydrohalic acids such as hydrochloric acid, hydrobromic acid and hydroiodic acid. Of these, sulfonic acids and polyphosphoric acid are preferred. The amount of the acid to be used is 0.001 to 2 times, preferably 0.01 to 0.5 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 (1) as a raw material, but an aprotic solvent is preferable. Specific examples thereof include, for example, benzene, toluene, xylene,
Aromatic hydrocarbons such as chlorobenzene and 1,2-dichlorobenzene; hydrocarbons such as hexane, heptane and octane; diethyl ether, di-n-propyl ether;
Diisopropyl ether, di-n-butyl ether, T
Ethers such as HF; dichloromethane, chloroform,
Halogenated hydrocarbons such as 1,2-dichloroethane; and esters such as ethyl acetate, n-propyl acetate, isopropyl acetate, and n-butyl acetate. Of these, toluene is particularly preferred. The solvent may be used in such an amount that at least a part of the compound (1) as a raw material can be dissolved and can be stirred, and it is not necessary to completely dissolve the raw material. Usually, 2 to 10 with respect to compound (1)
0 times by weight is used, preferably 5 to 50 times by weight.

(Reaction Conditions) The ring closure reaction is carried out by charging a compound of the formula (1), a Bronsted acid and a solvent into a reactor, and reacting the mixture preferably at a predetermined temperature at a predetermined temperature for a predetermined time. The reaction temperature is usually in the range of 0 to 200 ° C, preferably 50 to 150 ° C. The reaction time varies depending on the type of the Bronsted acid and the solvent and the reaction temperature, but is usually 30 minutes to 8 hours. The reaction pressure is usually normal pressure, but may be increased or decreased as necessary. The reaction may be carried out in air or in an inert gas such as nitrogen.

(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.

[0026]

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

Example 1 1,4-Di-O-benzoyl-2,3-di-O-methoxymethylerythritol
5 g, 26.5 mg of 98% sulfuric acid, and 5.0 ml of toluene were charged into an eggplant-shaped flask, and were heated at 50 ° C. for 4 hours and at 70 ° C. for 2 hours.
Stirred for hours. When the reaction solution was quantitatively analyzed by high performance liquid chromatography (HPLC), the conversion was 95.9.
%, 4,5-bis (benzoyloxymethyl) -1,3
The reaction yield of dioxolane was 40.8%.

Example 2 1,4-Di-O-benzoyl-2,3-di-O-methoxymethylerythritol
5 g, 40.2 mg of 75% polyphosphoric acid, toluene 5.0
ml was charged into an eggplant-shaped flask and stirred at 50 ° C. for 2 hours. The reaction solution was quantitatively analyzed by HPLC.
00%, 4,5-bis (benzoyloxymethyl)-
The reaction yield of 1,3-dioxolane was 73.5%.

Example 3 1,4-Di-O-benzoyl-2,3-di-O-methoxymethylerythritol
5 g, p-toluenesulfonic acid monohydrate 22.6 mg,
5.0 ml of toluene was charged into an eggplant-shaped flask,
For 1 hour and at 70 ° C. for 3 hours. HPLC the reaction solution
As a result, the conversion was 100%, and the reaction yield of 4,5-bis (benzoyloxymethyl) -1,3-dioxolane was 61.8%.

Example 4 1,4-Di-O-benzoyl-2,3-di-O-methoxymethylerythritol
5 g, 34.0 mg of trifluoromethanesulfonic acid and 5.0 ml of toluene were charged into an eggplant-shaped flask and stirred at 50 ° C. for 2 hours. When the reaction solution was quantitatively analyzed by HPLC, the conversion was 100%, and the reaction yield of 4,5-bis (benzoyloxymethyl) -1,3-dioxolane was 58.8.
%Met.

Example 5 0.1 g of 1,4-di-O-benzoyl-2,3-di-O-benzyloxymethylerythritol, 5.0 mg of 98% sulfuric acid, and 5.0 m of toluene
was charged into an eggplant-shaped flask and stirred at 50 ° C. for 1 hour. The reaction solution was quantitatively analyzed by HPLC.
00%, 4,5-bis (benzoyloxymethyl)-
The reaction yield of 1,3-dioxolane was 62.6%.

[0032]

According to the present invention, a 1,3-dioxolane derivative (2) useful as a pharmaceutical intermediate can be easily produced in a high yield.

Claims (6)

[Claims] [Claim 1] The following general formula (1) Wherein R ¹ and R ² each independently represent an alkyl group which may have a substituent or an aryl group which may have a substituent. Intramolecular cyclization in the presence of a Sted acid catalyst is represented by the following general formula (2): (Wherein R ¹ has the same meaning as in formula (1))
A method for producing a 3-dioxolane derivative. 2. The method for producing a 1,3-dioxolane derivative according to claim 1, wherein the Bronsted acid is sulfonic acid or polyphosphoric acid. 3. The method according to claim 1, wherein the solvent is an aprotic solvent.
Or the method for producing a 1,3-dioxolane derivative according to 2. 4. The method for producing a 1,3-dioxolane derivative according to claim 3, wherein the aprotic solvent is an aromatic hydrocarbon. 5. The compound according to claim 1, wherein R ¹ is a phenyl group and R ¹ is a methyl group.
A method for producing a 3-dioxolane derivative. 6. The method for producing a 1,3-dioxolane derivative according to claim ¹ , wherein R ¹ is a phenyl group and R ¹ is a benzyl group.