KR100469944B1 - Manufacturing Method of Hydroxytetrahydrofuran - Google Patents

Abstract

The present invention relates to a method for preparing hydroxytetrahydrofuran, and more particularly, butane-1,2,4-triol 1,2, -aceto, which is easily purified from butane-1,2,4-triol. The present invention relates to a method of preparing 3-hydroxytetrahydrofuran represented by the following Chemical Formula 1 by synthesizing amide and cyclizing the same.

[Formula 1]

Description

Method for preparing hydroxytetrahydrofuran

The present invention relates to a method for preparing hydroxytetrahydrofuran, and more particularly, butane-1,2,4-triol 1,2, -aceto, which is easily purified from butane-1,2,4-triol. The present invention relates to a method of preparing 3-hydroxytetrahydrofuran represented by the following Chemical Formula 1 by synthesizing amide and cyclizing the same.

[Formula 1]

3-hydroxytetrahydrofuran represented by Formula 1 is used as a key chiral intermediate in the field of AIDS, antibiotics and chiral pharmaceuticals. 3-hydroxytetrahydrofuran has (R)-or (S) -stereoisomers due to the hydroxy group orientation of the C3-position, and each of these stereoisomers is relatively difficult to synthesize and compared to racemates. It is sold at a very high price.

Methods for preparing 3-hydroxytetrahydrofuran represented by the formula (1) are known in the literature.

For example, a method of synthesizing (S) -3-hydroxytetrahydrofuran from a 2,5-dihydrofuran using a chiral boron reducing agent [Journal of American Chemical Society Vol 108. No 8. 2049 (1986)], And asymmetrical silylation from 2,5-dihydrofuran with a chiral palladium catalyst and oxidative cleavage to synthesize (S) -3-hydroxytetrahydrofuran [Tetrahedron Letters Vol 34. No 14. 2335 (1993)].

As another method, (S) -butane-1,2,4-triol obtained by using (S) -malic acid as a starting material, esterifying it and reducing with lithium aluminum hydride, is converted into p-toluene as an intermediate. There is a method of synthesizing (S) -3-hydroxytetrahydrofuran by cyclization under a sulfonic acid monohydrate catalyst (Journal of Organic Chemistry Vol 48. No 16. 2767 (1983)). At this time, the cyclization reaction of (S) -butane-1,2,4-triol is described in the conventional literature [Organic Synthesis collect. Vol. Ⅳ. 534 (1963), using the synthesis of 3-hydroxytetrahydrofuran from butane-1,2,4-triol.

Scheme 1

The cyclization reaction according to Scheme 1 is carried out under reduced pressure and warming conditions using p-toluenesulfonic acid monohydrate as an acid catalyst, whereby the same amount of water is produced as a by-product. In many reactions using water-containing 3-hydroxytetrahydrofuran as a raw material, side-reaction occurs because water causes side reactions, and dehydration must be accompanied to increase the value of commodity as 3-hydroxytetrahydrofuran as an intermediate. . However, it is not easy to remove water completely and loss of 3-hydroxytetrahydrofuran is followed during the dehydration process, especially when the expensive (R)-or (S) -3-hydroxytetrahydrofuran is produced. There is a lot of loss.

Therefore, the inventors of the present invention while studying a method for producing anhydrous 3-hydroxytetrahydrofuran, intermediate compounds in the process for producing 3-hydroxytetrahydrofuran from butane-1,2,4-triol The present invention was completed by preparing anhydrous butane-1,2,4-triol 1,2-acetonide and cyclizing them.

Accordingly, the present invention has a low boiling point of butane-1,2,4-triol 1,2-acetonide, which is produced as an intermediate, without the risk of generating water during the manufacturing process, and thus has an excellent purification process of the intermediate. In addition, when the stereoisomer is used as a starting material, racemization does not occur during the reaction, and thus there is another superiority in obtaining hydroxytetrahydrofuran stereoisomer having high optical and chemical purity.

The present invention provides a method for preparing 3-hydroxytetrahydrofuran from butane-1,2,4-triol,

The butane-1,2,4-triol is stirred in the presence of an acid catalyst and acetone to prepare butane-1,2,4-triol 1,2-acetonide, which is then prepared by cyclization under an acid catalyst. It is characterized by a method for producing anhydrous 3-hydroxytetrahydrofuran.

Referring to the present invention in more detail as follows.

The present invention provides anhydrous butane-1,2,4-triol 1,2-acetonide intermediate instead of the conventional method for preparing 3-hydroxytetrahydrofuran directly from butane-1,2,4-triol. The present invention relates to a method for directly recovering high-purity 3-hydroxytetrahydrofuran from a reactant without performing a separate dehydration process.

The manufacturing process of hydroxytetrahydrofuran represented by the formula (1) from butane-1,2,4-triol represented by the formula (2) according to the present invention is briefly shown in the following scheme 2.

Scheme 2

First, butane-1,2,4-triol represented by the formula (2) is stirred at room temperature under acetone solvent and acid catalyst conditions to synthesize butane-1,2,4-triol 1,2-acetonide. After completion of the reaction, the reaction mixture was neutralized with sodium bicarbonate and evaporated to remove excess acetone to obtain butane-1,2,4-triol-1,2-acetonide. Butane-1,2,4-triol-1,2-acetonide is dissolved in 1 to 2 times the mass of acetonide, and then extracted 2 or 3 times with 1 to 3 times the mass of ethyl acetate to acetonide. After separating the acetonide from the water-soluble impurities of the acetonitrile, to obtain a high purity acetonide, distilled under reduced pressure to obtain anhydrous acetonide represented by the formula (3) having a purity of 99% or more in a high yield of about 90% or more. Butane-1,2,4-triol 1,2-acetonide, which is synthesized as an intermediate in the present invention, has a relatively low boiling point, thereby facilitating a purification process, and greatly improves the purity of the target product.

When the high-purity acetonide obtained above is subjected to the cyclization reaction under an acid catalyst, 3-hydroxytetrahydrofuran, which is the object of the present invention, is synthesized. The cyclization reaction temperature is 80 to 120 ° C, more preferably 110 to 120 ° C.

Acid catalysts used during the synthesis of acetide intermediates and the cyclization reaction according to the present invention are organic or inorganic acids that are commonly used, and preferably p-toluenesulfonic acid or sulfuric acid is used. The acid catalyst may be used in an amount of 0.005 to 0.1 equivalents, preferably 0.005 equivalents.

In particular, the acid catalyst used during the cyclization reaction is preferably anhydrous to synthesize anhydrous targets. In the case of p-toluenesulfonic anhydride, p-toluenesulfonic acid monohydrate is heated and stirred with benzene or toluene to obtain water by azeotropic distillation.

As described above, in the preparation method according to the present invention, butane-1,2,4-triol-1,2-acetonide is cyclized using anhydrous acid catalyst under anhydrous conditions to produce anhydrous 3-hydroxytetrahydrofuran. As a new method of synthesizing acetone, the acetone produced as a reaction by-product has a low breaking point and is easily removed during the reaction, so that anhydrous 3-hydroxytetrahydrofuran of high purity can be easily prepared by simple first distillation after the reaction is completed. There is this.

In addition, butane-1,2,4-triol represented by the formula (2) used as a starting material in the present invention is prepared by a method disclosed in the literature. For example, malic acid is reduced with lithium aluminum hydride to produce butane-1,2,4-triol. Butane-1,2,4-triol has a high polarity and a high breaking point, which is very difficult to purify with high purity, but the butane-1,2,4-triol containing impurities is broken by the manufacturing method according to the present invention. Purification is facilitated by conversion to low-point acetonide compounds, which results in high purity butane-1,2,4-triol-1,2 using low purity butane-1,2,4-triol as starting material Acetonide can be easily produced.

In addition, the steric orientation of 3-hydroxytetrahydrofuran represented by the general formula (1), which is the object of the present invention, is determined by the steric orientation of butane-1,2,4-triol used as a starting material. The production method according to this invention can be applied irrespective of such three-dimensional orientation. In particular, when the production method of the present invention is applied to the production of expensive (R)-or (S) -3-hydroxytetrahydrofuran with high optical purity, there is an advantage that a high purity product can be obtained. .

Hereinafter, the present invention will be described in more detail with reference to the following Examples, but the present invention is not limited by the Examples.

Example 1: Preparation of (R, S) -3-hydroxytetrahydrofuran

Acetone (92 ml) and p-toluenesulfonic acid monohydrate (0.9 g) were added to (R, S) -butane-1,2,4-triol (92.0 g), followed by stirring at room temperature under nitrogen atmosphere for 5 hours. g of sodium bicarbonate was added. The mixture was stirred for 20 minutes, saturated sodium bicarbonate solution was added to adjust pH to 7, and acetone was removed under reduced pressure. Ethyl acetate (100 ml) was added to the reaction mixture, the impurities were washed with distilled water (150 ml), and ethyl acetate was removed by distillation under reduced pressure to obtain 98.1% pure butane-1,2,4-triol 1,2-acetonide. 113.1 g was obtained. This was further distilled under reduced pressure at 60 to 108 ° C. under a pressure of 0.3 to 20 torr to give 107.7 g of (R, S) -butane-1,2,4-triol 1,2-acetonide (purity: 99.5%, yield: 85.0%). )

In a round flask equipped with a condenser, distilled butane-1,2,4-triol 1,2, -acetonide (107.7 g) and p-toluenesulfonic anhydride (0.9 g) were reacted at 110 ° C. for 3 hours. The obtained residue was vacuum distilled (68-70 degreeC / 12mmHg), and 58.4g (chemical purity: 99.5%, yield: 90.0%) of (R, S) -3-hydroxy tetrahydrofuran were obtained.

Example 2 Preparation of (S) -3-hydroxytetrahydrofuran

(S) -maleic dimethyl ester (dimethyl (S) using (S) -maleic acid (99% ee) as a starting material by a known method (Journal of American Chemical Society Vol 108. No 8. 2049, 1986). ) -malate), followed by reduction using lithium aluminum hydride, was added to a Soxhlet extractor and the organics were extracted with anhydrous ethanol. After removing the organic solvent, acetone (500 ml) and p-toluenesulfonic acid monohydrate (0.5 g) were added to (S) -butane-1,2,4-triol (50.0 g) having a purity of 86.0%, and a nitrogen atmosphere was obtained. After stirring for 5 hours at room temperature, sodium bicarbonate (10 g) was added.

After neutralizing in the same manner as in Example 1 and removing the acetone solvent under reduced pressure, distilled water (100 mL) was added to the reaction mixture, extracted twice with ethyl acetate (150 mL), and ethyl acetate was removed by distillation under reduced pressure. 52.2 g of (S) -butane-1,2,4-triol 1,2-acetonide were obtained. This was further distilled under reduced pressure at 60 to 108 ° C. under a pressure of 0.3 to 20 torr in the same manner as in Example 1 to obtain 49.7 g of (S) -butane-1,2,4-triol 1,2-acetonide (chemical Purity 99.5%, yield 84.0%). 49.7 g of distilled (S) -butane-1,2,4-triol 1,2-acetonide and 0.3 g of anhydrous p-toluenesulfonic acid were placed in a round flask equipped with a condenser and reacted at 110 ° C. for 3 hours. The obtained residue was vacuum distilled (68-70 degreeC / 12mmHg), and 27.9g (chemical purity: 99.5%, optical purity: 99% ee, yield: 93.1%) of (S) -3-hydroxy tetrahydrofuran were obtained. .

Example 3 Preparation of (R, S) -3-hydroxytetrahydrofuran

In a round flask equipped with a condenser, (R, S) -butane-1,2,4-triol 1,2-acetonide (50 g) and sulfuric acid (0.17 g) having a purity of 99.5% obtained in Example 1 were prepared. The mixture was reacted at 110 DEG C for 4 hours, and then the obtained residue was vacuum distilled (68-70 DEG C / 12 mm) to give (R, S) -3-hydroxytetrahydrofuran (chemical purity: 99.3%, yield: 94.0%). Got.

Example 4 Preparation of (S) -3-hydroxytetrahydrofuran

In a round flask equipped with a condenser, sulfuric acid (0.17 g) was added to (S) -butane-1,2,4-triol 1,2-acetonide (50 g) obtained in Example 2, at 110 ° C for 4 hours. After the reaction, the obtained residue was vacuum distilled (68-70 ° C./12 mm) to give (S) -3-hydroxytetrahydrofuran (chemical purity: 99.5%, optical purity: 99% ee, yield: 93.0%). Got it.

Example 5: Preparation of (S) -3-hydroxytetrahydrofuran

(S) -butane-1,2,4-triol (chemical purity: 82%, optical purity) containing 1,4-butanediol, boric acid, glycolic acid, formic acid, 3,4-dihydroxybutyric acid as impurities : (9.0)% ee) was carried out in the same manner as in Example 1 (S) -butane-1,2,4-triol 1,2-acetonide (chemical purity: 99.5%, yield: 82.0%) Got. Then, the same procedure as in Example 1 was performed to obtain (S) -3-hydroxytetrahydrofuran (chemical purity: 99.5%, optical purity: 99% ee, yield: 93.1%).

As described above, in the production method of 3-hydroxytetrahydrofuran according to the present invention, by preparing anhydrous butane-1,2,4-triol 1,2-acetonide intermediate, side reactions are suppressed as much as possible. The boiling point of butane-1,2,4-triol 1,2-acetonide, which is produced as an intermediate, is low and the purification process is easy. In particular, the production method of the present invention is effective for producing high value-added (R)-or (S) -3-hydroxytetrahydrofuran.

Claims (4)

In the process for producing 3-hydroxytetrahydrofuran from butane-1,2,4-triol under an acid catalyst, The butane-1,2,4-triol is converted into butane-1,2,4-triol 1,2-acetonide by stirring with acetone under normal temperature and acid catalyst conditions,  3-hydroxytetrahydro, characterized in that 3-hydroxytetrahydrofuran is prepared by cyclization of butane-1,2,4-triol 1,2-acetonide at 80-120 ° C. and acid catalyst conditions. Method for producing furan. The method for preparing 3-hydroxytetrahydrofuran according to claim 1, wherein the cyclization reaction is carried out in the presence of anhydrous acid catalyst. The method for producing 3-hydroxytetrahydrofuran according to claim 1 or 2, wherein the acid catalyst is p-toluenesulfonic acid or sulfuric acid. The method for preparing 3-hydroxytetrahydrofuran according to claim 1, wherein the 3-hydroxytetrahydrofuran is made of (R) -isomer, (S) -isomer or racemate.