KR20080072206A - Process for the efficient preparation of 3-hydroxytetrahydrofuran - Google Patents

Abstract

A method for preparing 3-hydroxytetrahydrofuran is provided to keep chirality of a starting material substantially and produce a chiral 3 hydroxytetrahydrofuran having high optical purity of at least 99.0% with high yield economically. A method for preparing 3-hydroxytetrahydrofuran represented by a formula(1) comprises a step of heating 4-halo-1,3-butanediol represented by a formula(2) at a temperature of 75-180 deg.C in the presence of an organic solvent such as benzene, toluene, xylene, C2-4 alcohol, 1,2-dichloroethane, ethylacetate, 1,4-dioxane, polyethyleneglycol, polyethyleneglycol butyl ether, polyethyleneglycol dimethylether, polyethyleneglycol methyl ether, polypropylene glycol, propropyleneglycol monobutyl ether, diphenylether, dibenzylether, phenyl sulfone and phenyl sulfoxide or without using any solvent to perform cyclization. In the formulae, * is a chiral center, and X is halogen such as F, Cl, Br and I. Further, the cyclization is performed under condition comprising additionally a base.

Description

       Efficient preparation method of 3-hydroxytetrahydrofuran {PROCESS FOR THE EFFICIENT PREPARATION OF 3-HYDROXYTETRAHYDROFURAN}

The present invention relates to a process for the preparation of chiral 3-hydroxytetrahydrofuran. More specifically, the present invention relates to a process for preparing chiral 3-hydroxytetrahydrofuran suitable for commercial mass production in high optical purity without degrading the optical purity of the starting material.

3-hydroxytetrahydrofuran is useful as a synthetic intermediate for medicines and pesticides, and in particular, as one of the AIDS therapeutics, it is used as a key intermediate in the synthesis of Amprenavir, an HIV protease inhibitor. The conventional manufacturing method of the 3-hydroxytetrahydrofuran known so far is as follows.

1,2-4-butanetriol (1-, 2,4-Butanetriol) is subjected to cyclization dehydration under a catalyst of a strongly acidic cation exchange resin having a paratoluenesulfonic acid or a sulfuric acid group as an exchange group, thereby reacting with 3-hydroxytetrahydro. A method for preparing furan has been proposed (J. Org. Chem. 1983, vol. 48, p2767-2769; Korean Patent Publication No. 10-2006-0067620, Japanese Patent Application Laid-Open No. 2006-36710). However, there are many problems in the synthesis of starting materials 1,2,4-butanetriol. 1,2,4-butanetriol can be normally obtained from a malic acid diester, 3-hydroxy- (gamma) -butyrolactone, or tetrahydrofuran-2,4-diol. More specifically, the 1,2,4-butanetriol may be prepared by the reduction reaction of malic acid diester, and the yield of the reduction reaction is not satisfactory, and the purification of the target product is difficult. The 1,2,4-butanetriol may be prepared by reduction of 3-hydroxy-γ-butyrolactone or chiral tetrahydrofuran-2,4-diol in the presence of a reducing agent such as sodium borohydride or the like. Can be. However, since 3-hydroxy- [gamma] -butyrolactone or tetrahydrofuran-2,4-diol is a relatively expensive raw material, the reaction is less economical (J. Org. Chem. 1983, vol. 48, p2767-2769; WO 99/44976; Japanese Patent Laid-Open No. 2006-36710).

As another method, the hydroxyl group of the malic acid diester is protected with a t-butyl group, and then reduced using lithium aluminum hydride (LAH) to obtain 2-t-butoxybutane-1,4-diol, thereby obtaining a compound. A method for preparing chiral 3-hydroxytetrahydrofuran by carrying out deprotection and cyclodehydration in the presence of an acid catalyst is described (Org. Biomol. Chem. 2004, vol 2, p2061-2070). However, it is believed that the process is not suitable for commercial mass production because the overall process is long, and also difficult to use and expensive lithium aluminum hydride as reducing agent.

US Pat. No. 5,780,649, on the other hand, discloses a process for preparing 3-hydroxytetrahydrofuran from commercially available and inexpensive 4-halo-3-hydroxybutyric acid esters. In the above method, 4-halo-3-hydroxybutyric acid ester is subjected to a reduction reaction using sodium borohydride in a water-soluble organic solvent such as tetrahydrofuran to obtain 4-halo-1,3-butanediol, Cyclizing the obtained compound in an acidic aqueous solution to obtain the desired chiral 3-hydroxytetrahydrofuran. However, this method does not provide the desired compound in a satisfactory yield (58-68%).

As an improvement of the above-mentioned manufacturing method, US Patent No. 5,780, 649, A method for reducing chiral 4-halo-3-hydroxybutyric acid ester using sodium borohydride in an organic solvent which is not mixed with toluene or ethyl acetate and water, Treating the obtained reaction mixture with water and an acid to obtain an aqueous solution of 4-halo-1,3-butanediol, and then cyclizing the aqueous 4-halo-1,3-butanediol aqueous solution to obtain the desired chiral 3-hydroxytetrahydro Preparing furan. The process has a relatively high overall reaction yield of 80-82% throughout the process, but requires a long reaction time (more than 40 hours) and an extraction process that is difficult in the purification process (continuous extraction at 70 ° C.). Due to these factors, the method has low overall productivity.

Further, the US Patent Nos. 5,780,649 and 5,780,649 are both performing a cyclization reaction under acidic aqueous solution conditions. Acid is harmful to the human body and should be avoided if possible. In mass production, in particular, acidic conditions are difficult to control. And cyclization under aqueous solution makes it difficult to purify the final target of 3-hydroxytetrahydrofuran.

In conclusion, the methods described in US Pat. Nos. 5,780,649 and 5,780,649 present one or more of the following problems: i) unsatisfactory yield, ii) long reaction time (40 hours or more), iii) use of acid Violation of the working environment by iv) difficulty in purifying the target compound caused by the aqueous solution.

It is an object of the present invention to provide an efficient method for preparing 3-hydroxytetrahydrofuran.

Another object of the present invention is to provide an efficient method for preparing chiral 3-hydroxytetrahydrofuran having a high optical purity of 99.0% ee or higher, without lowering the optical purity of the starting material. According to an embodiment of the present invention, there is provided a method for producing a desired chiral 3-hydroxytetrahydrofuran with high yield and high optical purity of 99% ee or more, while maintaining the chirality of the starting material.

According to a preferred embodiment of the invention, the 4-halo-1,3-butanediol is cyclized by heating to a temperature of 75 ° C.-180 ° C. in the presence of an organic solvent or in a neat without a solvent. There is provided a method of preparing 3-hydroxytetrahydrofuran comprising the step of:

According to another preferred embodiment of the invention, there is provided a process for preparing 3-hydroxytetrahydrofuran, wherein the cyclization reaction is carried out under conditions further comprising a base.

According to a more preferred embodiment of the present invention, there is provided a method for preparing 3-hydroxytetrahydrofuran, wherein the cyclization reaction is carried out at a temperature of 90 ℃-150 ℃.

According to a further preferred embodiment of the present invention, there is provided a process for preparing 3-hydroxytetrahydrofuran, wherein the cyclization reaction is carried out at a temperature of 100 ℃-130 ℃.

According to another preferred embodiment of the present invention, when the cyclization reaction is carried out in the presence of an organic solvent, the organic solvent is 75 ℃-150 ℃ or 210 ℃-600 ℃, more preferably 90 ℃-150 ℃ Or a process for producing 3-hydroxytetrahydrofuran, having a boiling point of 250 ° C.-600 ° C., most preferably 100 ° C.-150 ° C. or 280 ° C.-600 ° C.

According to another preferred embodiment of the present invention, the cyclization reaction is to preserve the chirality of the starting material in the reaction zone, the method is 3-hydroxytetrahydro having a high optical purity of 99.0% ee or more Provide furan.

According to a most preferred embodiment of the invention, the process comprises the steps of a) reducing 4-halo-3-hydroxybutyric acid ester to obtain chiral 4-halo-1,3-butanediol, b) obtaining the compound, Performing cyclization by heating to a temperature of 75 ° C.-180 ° C. in the presence of a solvent or in a neat without a solvent, and c) recovering 3-hydroxytetrahydrofuran from the obtained reaction mixture. Provided is a method of preparing 3-hydroxytetrahydrofuran, comprising the steps of:

According to a more preferred embodiment of the present invention, the 4-halo-3-hydroxybutyrate is ethyl-4-halo-3-hydroxybutyrate or methyl-4-halo-3-hydroxybutyrate. , 3-hydroxytetrahydrofuran is provided.

According to another preferred embodiment of the invention, the reduction reaction of step a) is M (BH ₄ ) n (wherein M means an alkali metal or alkaline earth metal, n means 1 or 2), or this A process for the preparation of 3-hydroxytetrahydrofuran, which is carried out in the presence of a methanol mixture of is provided.

According to another preferred embodiment of the present invention, there is provided a method for preparing 3-hydroxytetrahydrofuran, wherein M is sodium and M (BH ₄ ) n: methanol = 1: 0.5-2.

According to another preferred embodiment of the present invention, there is provided a process for preparing 3-hydroxytetrahydrofuran, wherein the step cyclization reaction is carried out in a neat without using a solvent.

The inventors of the present invention conducted various experiments that could replace the cyclization of 3-hydroxytetrahydrofuran in an acidic aqueous solution, in which 4-halo-1,3-butanediol was used in the presence of an organic solvent or in the absence of a solvent. Also in neat, it was confirmed that the cyclization reaction can be progressed and converted to 3-hydroxytetrahydrofuran. The cyclization of the 4-halo-1,3-butanediol was confirmed that the yield and the reaction time were significantly dependent on the reaction temperature. Specifically, the cyclization reaction hardly proceeds at temperatures below 75 ° C., the initial initiation of the reaction takes place at 75 ° C.-90 ° C., and the reaction is activated at a temperature above 90 ° C., most preferably at least 100 ° C. Furthermore, it was confirmed that the chirality of 3-hydroxytetrahydrofuran was maintained as it was in the section where the reaction was activated. As a result, it was confirmed that 3-hydroxytetrahydrofuran can be prepared with high optical purity (99.0% or more).

The inventors also carried out the cyclization reaction in the presence of a base to see the effect of HCl produced by cyclization of 4-halo-1,3-butanediol on the reaction. Surprisingly, the cyclization did not reduce the rate of reaction in the presence of a base, but rather increased the rate of reaction to some extent. These results indicate that HCl produced by the cyclization reaction has little effect on the reaction. In other words, these results indicate that HCl produced by the cyclization of 4-halo-1,3-butanediol converts the reaction solution into acidic conditions, thereby denying that the cyclization can be accelerated. The result is.

The preparation method of 3-hydroxytetrahydrofuran represented by the general formula (1) according to the present invention is the 4-halo-1,3-butanediol represented by the general formula (2), in the presence of an organic solvent or without using a solvent ( neat), heating to a temperature of 75 ° C.-180 ° C. to perform a cyclization reaction.

In Chemical Formulas 1 and 2, * denotes a chiral center, and X denotes a halogen atom (F, Cl, Br or I).

The process for preparing 3-hydroxytetrahydrofuran by cyclization of 4-halo-1,3-butanediol represented by Formula 2 is summarized in Scheme 1 below:

In Scheme 1, * means chiral center, and X means halogen atom (F, Cl, Br or I).

 Furthermore, 4-halo-1,3-butanediol can be prepared in high yield by reduction of chiral 4-halo-3-hydroxybutyric acid ester having formula (3). This reduction reaction also proceeds in high yield without deteriorating optical purity.

In Chemical Formula 3, * means a chiral center, X means a halogen atom (F, Cl, Br or I), R is an ester forming group, preferably a C ₁ -C ₄ alkyl group.

The overall process for preparing 3-hydroxytetrahydrofuran from 4-halo-3-hydroxybutyric acid ester is as follows:

a) reducing 4-halo-3-hydroxybutyric acid ester represented by Formula 3 to obtain 4-halo-1,3-butanediol having Formula 2,

b) performing a cyclization reaction by heating the obtained compound of Formula 2 to a temperature of 75 ° C-180 ° C in the presence of an organic solvent or in a neat without a solvent,

c) recovering 3-hydroxytetrahydrofuran represented by the formula (1) from the obtained reaction mixture.

The overall process of preparing 3-hydroxytetrahydrofuran from 4-halo-3-hydroxybutyric acid ester represented by Formula 3 is summarized in Scheme 2 below.

In Scheme 2, * means chiral center, X means halogen atom (F, Cl, Br or I), R is an ester forming group, preferably a C ₁ -C ₄ alkyl group.

During the reduction reaction of the 4-halo-3-hydroxybutyric acid ester and the cyclization reaction by heating, the deterioration of chirality was not found substantially. Thus, the process according to the invention is particularly useful for the preparation of chiral 3-hydroxytetrahydrofuran. According to a specific embodiment of the present invention, the desired 3-hydroxytetrahydrofuran is prepared from chiral 4-halo-3-hydroxybutyric acid ester with high optical purity of 99.0% ee or more.

Hereinafter, the manufacturing method according to the present invention will be described in more detail.

By the reduction reaction, 4-halo-3-hydroxybutyric acid ester represented by the formula (3) is converted to 4-halo-1,3-butanediol.

Examples of reducing agents that may be used in the reduction reaction include borane-methylsulfide complex, borane-tetrahydrofuran complex, borane-tetrahydrofuran complex, diborane, lithium aluminum hydride (lithium aluminum hydride), a boron hydride metal salt, a mixture of a boron hydride metal salt and methanol. More preferably, it is a mixture of a boron hydride alkali metal salt and methanol, or a mixture of a boron hydride alkaline earth metal salt and methanol. Even more preferred is a mixture of sodium borohydride salt and methanol. The mixture of boron hydride metal salt and methanol forms, in situ, a methoxy borohydride metal salt in the reaction solution. Most preferably a mixture of sodium borohydride and methanol. The boron hydride metal salt is used in an amount of 0.5-2.0 equivalents, preferably 0.8-1.2 equivalents, based on the compound of formula (3). Methanol is used in an amount of 0.5-2.0 equivalents, preferably 0.8-1.5 equivalents, relative to the boron hydride metal salt. According to the specific experimental results of the present inventors, when using 1 equivalent of sodium borohydride alone with respect to the compound of Formula 3, the reaction time of about 48 hours was required, but a mixed composition of 1 equivalent of sodium borohydride and 1 equivalent of methanol The reaction was terminated in about 20 hours.

The solvent used for the reduction reaction is not particularly limited, and a solvent usually used in the art is used. Specifically, aliphatic or aromatic hydrocarbon solvents, halogenated hydrocarbon solvents, ethers, esters and alcohols can be used. Among these, an organic solvent having low toxicity and low cost may be employed. For example, toluene, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, 1,4-dioxane, etc. are mentioned. The amount of the solvent used may be used within a range of 1 to 10 times by weight based on the compound of the formula (3). Preferably it is 2-5 times. The reaction temperature is usually carried out at 0-100 占 폚, preferably 20-70 占 폚.

As the 4-halo-3-hydroxybutyric acid ester represented by the formula (3), R which is an ester type protecting group is not particularly limited and may be a general protecting group, but is preferably an alkyl group, more preferably C ₁ -C ₄ It is an alkyl group, More preferably, it is an ethyl group or a methyl group.

The 4-halo-1,3-butanediol of the formula (2) produced by the reduction of 4-halo-3-hydroxybutyric acid ester, in the form of a crude product, in the form of a crude product, without a special purification step It may be used for the reaction. This additionally provides the effect of yield increase with simplification of the process.

The cyclization of 4-halo-1,3-butanediol of formula (2) is carried out at a temperature of at least 75 ° C or higher. Given that the boiling point of the final product, 3-hydroxytetrahydrofuran, is about 180 ° C, the cyclization reaction is carried out in the range of 75 ° C-180 ° C. More preferably, the cyclization is carried out at a temperature of 90 ℃-150 ℃. Most preferably, the cyclization is carried out at a temperature of 100 ℃-130 ℃.

The cyclization can be carried out in the presence of an organic solvent or in a nit where no solvent is used. The organic solvent should have a boiling point of at least 75 ° C or higher. Preferably, the organic solvent has a boiling point of 90 ° C or higher. Most preferably, the organic solvent has a boiling point in the range of 100-150 ° C or 210 ° C-600 ° C. The use of organic solvents in the range of 150 ° C. to 210 ° C. is preferably avoided. This is because purification of the final target 3-hydroxytetrahydrofuran (boiling point: about 180 ° C.) by distillation is difficult. Therefore, in order to facilitate the reaction rate, the reaction yield and the separation of the solvent and the final object, it is most preferably carried out under the organic solvent in the range of 100-150 ℃ or 250 ℃-600 ℃. Specific examples of organic solvents that can be used include aliphatic or aromatic hydrocarbon solvents, halogenated hydrocarbon solvents, ethers, esters and alcohols. For example benzene, toluene, xylene, C ₂ -C ₄ alcohols (e.g. ethanol, propanol, isopropanol, 1-butanol, 2-butanol and t-butanol), 1,2-dichloroethane, ethyl acetate, 1, 4-dioxane etc. can be mentioned, A mixed solvent of these solvent can also be used. Preferably, it is toluene, xylene or C ₃ -C ₄ alcohol. When an organic solvent having a boiling point of 100 to 150 ° C. is used, the organic solvent is first recovered by distillation under reduced pressure, and then the temperature is further increased to obtain 3-hydroxytetrahydrofuran as a final target. Organic solvents having a boiling point of 210 ° C. or higher provide the advantage that the target compound can be preferentially recovered by distillation under reduced pressure. Examples thereof include polyethylene glycol, polyethylene glycol butyl ether, polyethylene glycol dimethyl ether, polyethylene glycol methyl ether, polypropylene glycol, polypropylene glycol monobutyl ether, diphenyl ether, dibenzyl ether, phenyl sulfone, phenyl sulfoxide Can be mentioned. The organic solvent is used in the range of 0.5 to 20 times, preferably 2 to 5 times by weight relative to the compound of the formula (2).

The cyclization reaction may be performed even under neat conditions without using an organic solvent. After carrying out the cyclization reaction in the nit condition, the desired 3-hydroxytetrahydrofuran can be easily obtained by distillation under reduced pressure.

As mentioned above, the cyclization may be carried out in the presence of a base. The reaction rate is increased by some addition of base. The base that can be used is not particularly limited, and various inorganic bases and organic bases can be widely used. Examples of the inorganic bases include alkali metal salts. For example, alkali carbonates, alkali bicarbonates or alkali phosphates can be used. Specifically, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate and cesium bicarbonate, lithium phosphate, sodium phosphate, potassium phosphate, cesium phosphate, and the like may be used. Preferred examples of the organic base are alkyl or aryl substituted amines. Specifically, trimethylamine, triethylamine, tripropylamine, tributylamine, triphenylamine, diisopropylethylamine, dibenzylamine, dicyclohexylamine, dibenzylamine, benzylamine, etc. are mentioned. The base is used in the range of 0.5-10 equivalents, preferably 1.0-2 equivalents, based on the 4-halo-1,3-butanediol compound of formula (2).

The present invention will be described in more detail with reference to the following examples. These examples are presented for the understanding of the present invention, and the scope of the present invention is not limited to these examples.

Example 1

61.5 g (1.626 mol) of sodium borohydride were placed in 694 mL of toluene, and 52 g (1.626 mol) of methanol were added dropwise at room temperature over 1 hour. Subsequently, 300 g (1.807 mol, 99.3% ee) of ethyl (S) -4-chloro-3-hydroxybutyrate was added, followed by stirring at room temperature for 12 hours. After the reaction mixture was cooled to 10 ° C. or lower, 183 g of 36% hydrochloric acid was added dropwise, and the solvent was distilled under reduced pressure at 40 ° C. or lower. 800 mL of methanol was used three times, and the resultant was concentrated under reduced pressure continuously at 40 占 폚. 800 mL of dichloromethane was added to the obtained residue, the solid inorganic substance was filtered off, and the solvent was distilled off under reduced pressure to obtain 220 g (yield 98%) of (S) -4-chloro-1,3-butanediol as oil.

Example 2

To 220 g (1.774 mol) of (S) -4-chloro-1,3-butanediol obtained in Example 1 was added 800 mL of toluene and stirred under reflux for 16 hours. After lowering the temperature of the reaction mixture to room temperature, 37.6 g (0.355 mol) of Na ₂ CO ₃ and 1 g (0.055 mol) of water were added thereto, and the mixture was further stirred for 30 minutes. After filtration to remove the solid, the solvent was concentrated under reduced pressure to recover the residue, and the residue was further distilled under reduced pressure to give 138 g of colorless (S) -3-hydroxytetrahydrofuran (yield 88%, optical purity 99.55% ee). ) Was obtained.

Example 3

61.5 g (1.626 mol) of sodium borohydride were placed in 694 mL of toluene, and 52 g (1.626 mol) of methanol were added dropwise at room temperature over 1 hour. Subsequently, 300 g (1.807 mol, 99.3% ee) of ethyl (R) -4-chloro-3-hydroxybutyrate was added, followed by stirring at room temperature for 12 hours. After the reaction mixture was cooled to 10 ° C. or lower, 183 g of 36% hydrochloric acid was added dropwise, and the solvent was distilled under reduced pressure at 40 ° C. or lower. Concentrated under reduced pressure three times under 40 ℃ using 800 mL of methanol. 800 mL of dichloromethane was added to the obtained residue, the solid inorganic substance was filtered off, and the solvent was distilled off under reduced pressure to obtain 218 g (yield 97%) of (R) -4-chloro-1,3-butanediol as oil.

Example 4

To 218 g (1.758 mol) of (S) -4-chloro-1,3-butanediol obtained in Example 3, 800 mL of toluene was added and stirred under reflux for 16 hours. After lowering the temperature of the reaction mixture to room temperature, 37.3 g (0.352 mol) of Na ₂ CO ₃ and 1 g (0.055 mol) of water were added thereto, and the mixture was further stirred for 30 minutes. After filtration to remove the solid, the solvent was concentrated under reduced pressure to recover the residue, and the residue was further distilled under reduced pressure to give 137 g of colorless (S) -3-hydroxytetrahydrofuran (yield 88%, overall yield 85%, Optical purity 99.52% ee) was obtained.

Example 5

To 400 g of tetrahydrofuran, 41.0 g (1.084 mol) of sodium borohydride and 200 g (1.205 mol, 99.3% ee) of ethyl (S) -4-chloro-3-hydroxybutyrate were added, and 34.7 g of methanol 1.084 mol) was added dropwise at room temperature over 1 hour, followed by stirring at room temperature for 10 hours. The reaction mixture was cooled to 10 DEG C or lower, 122 g of 36% hydrochloric acid was added dropwise, and the solvent was distilled under reduced pressure at 40 DEG C or lower. 550 mL of methanol was concentrated under reduced pressure three times in succession at 40 占 폚. 550 mL of dichloromethane and 20 g of Na ₂ SO ₄ were added to the obtained residue, followed by stirring for 30 minutes. The solid inorganic material was filtered out, and the solvent was removed under reduced pressure to obtain an oily (S) -4-chloro-1,3-butanediol. 144 g (96% yield) were obtained.

Example 6

550 mL of toluene was added to 144 g (1.161 mol) of (S) -4-chloro-1,3-butanediol obtained in Example 5, followed by stirring under reflux for 16 hours. After lowering the temperature of the reaction mixture to room temperature, 24.6 g (0.232 mol) of Na ₂ CO ₃ and 0.5 g (0.028 mol) of water were added thereto, followed by stirring for 30 minutes. After filtration, the solvent was concentrated under reduced pressure and recovered first, and the residue was further distilled under reduced pressure to give 91 g of colorless (S) -3-hydroxytetrahydrofuran (yield 89%, overall yield 85%, optical purity 99.45). % ee) was obtained.

Example 7

To 400 g of isopropanol, 41.0 g (1.084 mol) of sodium borohydride and 200 g (1.205 mol, 99.3% ee) of ethyl (S) -4-chloro-3-hydroxybutyrate were added and methanol 34.7 g (1.084 mol) was added. Was added dropwise at room temperature over 1 hour, and then stirred at room temperature for 12 hours. The reaction mixture was cooled to 10 DEG C or lower, 122 g of 36% hydrochloric acid was added dropwise, and the solvent was distilled under reduced pressure at 40 DEG C or lower. 500 mL of methanol was concentrated under reduced pressure three times in succession at 40 ° C or less. 550 mL of isopropanol was added to the obtained residue, followed by stirring, and then a solid inorganic material was filtered to give 147 g (yield 98%) of an organic phase of (S) -4-chloro-1,3-butanediol.

Example 8

The isopropanol solution containing 147 g (1.182 mol) of (S) -4-chloro-1,3-butanediol obtained in Example 7 was stirred at reflux for 22 hours. After lowering the temperature of the reaction mixture to room temperature, 24.6 g (0.232 mol) of Na ₂ CO ₃ and 0.5 g (0.028 mol) of water were added thereto, followed by stirring for 30 minutes. After filtration, the solvent was concentrated under reduced pressure, and the residue was recovered. The residue was further distilled under reduced pressure to give 89 g of colorless (S) -3-hydroxytetrahydrofuran (yield 87%, overall yield 85%, optical purity 99.43%). ee) was obtained.

Example 9

400 mL of 1,4-dioxane was added to 100 g (0.806 mol) of (S) -4-chloro-1,3-butanediol obtained in Example 1, and stirred under reflux for 20 hours. After lowering the temperature of the reaction mixture to room temperature, 24.6 g (0.232 mol) of Na ₂ CO ₃ and 0.5 g (0.028 mol) of water were added thereto, followed by stirring for 30 minutes. After filtration, the residue obtained by concentrating the solvent under reduced pressure was distilled under reduced pressure to obtain 58 g of a colorless (S) -3-hydroxytetrahydrofuran (yield 82%, optical purity 99.42% ee).

Example 10

220 g (1.774 mol) of (S) -4-chloro-1,3-butanediol obtained in Example 1 were stirred at 110 ° C. under a solvent-free neat condition and distilled under reduced pressure for 6 hours. . After diluting the obtained compound in 200 mL of toluene, 37.6 g (0.355 mol) of Na ₂ CO ₃ and 1 g (0.055 mol) of water were added thereto, followed by stirring for 30 minutes. After filtration, distillation under reduced pressure afforded 130 g of a colorless (S) -3-hydroxytetrahydrofuran (yield 83%, total yield 82%, optical purity 99.45% ee).

Example 11

200 g (1.613 mol) of (S) -4-chloro-1,3-butanediol obtained in Example 1 was put in 600 g of polyethylene glycol, stirred at 110 ° C, and distilled under reduced pressure over 4 hours. After diluting the obtained compound in 200 mL of toluene, 34.2 g (0.323 mol) of Na ₂ CO ₃ and 0.6 g (0.033 mol) of water were added thereto, followed by stirring for 30 minutes. After filtration, distillation under reduced pressure yielded 125 g of colorless (S) -3-hydroxytetrahydrofuran (yield 88%, optical purity 99.61% ee).

Example 12

200 g (1.613 mol) of (S) -4-chloro-1,3-butanediol obtained in Example 1 was put in 600 g of polyethylene glycol dimethyl ether, and stirred at 110 ° C., and distilled under reduced pressure over 5 hours. After diluting the obtained compound in 200 mL of toluene, 34.2 g (0.323 mol) of Na ₂ CO ₃ and 0.6 g (0.033 mol) of water were added thereto, followed by stirring for 30 minutes. After filtration, distillation under reduced pressure afforded 126 g of a colorless (S) -3-hydroxytetrahydrofuran (yield 90%, optical purity 99.46% ee).

Example 13

200 g (1.613 mol) of (S) -4-chloro-1,3-butanediol obtained in Example 1 was placed in 600 g of polypropylene glycol mono butyl ether, and stirred at 110 ° C., and distilled under reduced pressure over 4 hours. . After diluting the obtained compound in 200 mL of toluene, 34.2 g (0.323 mol) of Na ₂ CO ₃ and 0.6 g (0.033 mol) of water were added thereto, followed by stirring for 30 minutes. After filtration, the solvent was concentrated under reduced pressure to recover the residue, and the residue was further distilled under reduced pressure to yield 123 g of a colorless (S) -3-hydroxytetrahydrofuran (yield 86%, optical purity 99.45% ee). .

Example 14

To 220 g (1.774 mol) of (S) -4-chloro-1,3-butanediol obtained in Example 1 was added 800 mL of toluene and 197.5 g (1.951 mol) of triethylamine, followed by stirring under reflux for 16 hours. The reaction mixture was cooled to room temperature, filtered to remove solids, and then the solvent was concentrated under reduced pressure to recover the residue. The residue was further distilled under reduced pressure to give 136 g of colorless (S) -3-hydroxytetrahydrofuran. (Yield 87%, optical purity 99.5% ee) were obtained.

Example 15

To 200 g (1.613 mol) of (S) -4-chloro-1,3-butanediol obtained in Example 1, 700 mL of toluene and 149 g (1.774 mol) of NaHCO ₃ were added and stirred under reflux for 16 hours. The reaction mixture was cooled to room temperature, filtered to remove solids, and then the solvent was concentrated under reduced pressure to recover the residue. The residue was further distilled under reduced pressure to give 121 g of colorless (S) -3-hydroxytetrahydrofuran. (Yield 85%, Total Yield 83%, Optical Purity 99.54% ee) were obtained.

Example 16

61.5 g (1.626 mol) of sodium borohydride was placed in 694 mL of toluene, followed by 275.6 g (1.807 mol, 99.3% ee) of methyl (S) -4-chloro-3-hydroxybutyrate. 52 g (1.626 mol) of methanol were added dropwise at room temperature over 1 hour, followed by stirring at room temperature for 12 hours. After the reaction mixture was cooled to 10 ° C. or lower, 183 g of 36% hydrochloric acid was added dropwise, and the solvent was distilled under reduced pressure at 40 ° C. or lower. 800 mL of methanol was used three times, and the resultant was concentrated under reduced pressure continuously at 40 占 폚. 800 mL of dichloromethane was added to the obtained residue, the solid inorganic substance was filtered off, and the solvent was distilled off under reduced pressure to obtain 220 g (yield 98%) of (S) -4-chloro-1,3-butanediol as oil.

Example 17

To 220 g (1.774 mol) of (S) -4-chloro-1,3-butanediol obtained in Example 16 was added 800 mL of toluene and stirred under reflux for 16 hours. After lowering the temperature of the reaction mixture to room temperature, 37.6 g (0.355 mol) of Na ₂ CO ₃ and 1 g (0.055 mol) of water were added thereto, and the mixture was further stirred for 30 minutes. After removing the solid by filtration, the solvent was distilled off under reduced pressure to recover the residue, and the residue was further distilled under reduced pressure to give 136 g of colorless (S) -3-hydroxytetrahydrofuran (yield 87%, optical purity 99.5% ee). ) Was obtained.

According to the method for preparing chiral 3-hydroxytetrahydrofuran according to the present invention, 3-hydroxytetrahydrofuran can be prepared with high optical purity while maintaining the optical purity of the starting material completely. Specifically, the chiral compound of formula (2) and / or formula (3) used as starting material has 3-hydroxytetrahydro having high optical purity of 99% ee or more, while maintaining optical purity without any deterioration of chirality. Furan can be prepared in high yields. In addition, chiral 4-halo-1,3-butanediol having the formula (2) may be applied as it is to the next cyclization reaction without undergoing purification. In addition, since the cyclization reaction is not performed in an acidic aqueous solution, but is carried out in an organic solvent or a knitted condition, a complicated extraction process or an aqueous solution concentration process can be avoided. In addition, when the cyclization reaction uses a neat condition and an organic solvent higher than the boiling point of the target compound, chiral 3-hydroxytetrahydrofuran can be easily purified through distillation under reduced pressure. Thus, the process for producing 3-hydroxytetrahydrofuran according to the present invention is carried out under simple and mild conditions throughout the whole process. This means that the method according to the invention can be usefully applied for commercial mass production of 3-hydroxytetrahydrofuran with high optical purity.

Claims (14)

In the process for producing 3-hydroxytetrahydrofuran represented by the formula (1), the method is a 4-halo-1,3-butanediol represented by the formula (2), in the presence of an organic solvent or using no solvent at neat, heating to a temperature of 75 ° C.-180 ° C. to carry out the cyclization reaction: Formula 1

Formula 2

In Chemical Formulas 1 and 2, * denotes a chiral center, and X denotes a halogen atom (F, Cl, Br or I). The method of claim 1, wherein said cyclization is carried out under conditions further comprising a base. The method of claim 1, wherein the cyclization is carried out at a temperature of 90 ° C.-150 ° C. 7. The method of claim 1, wherein the cyclization is carried out at a temperature of 100 ° C.-130 ° C. 7. The method according to claim 1, wherein the organic solvent used for the cyclization has a boiling point of 75 ° C-150 ° C or 210 ° C-600 ° C. The method of claim 1, wherein the 4-halo-3-hydroxybutyric acid ester having Formula 2 is an optically active substance. The method of claim 1, wherein the organic solvent used for the cyclization is benzene, toluene, xylene, C ₂ -C ₄ alcohol, 1,2-dichloroethane, ethyl acetate, 1,4-dioxane, polyethylene glycol, polyethylene Glycol butyl ether, polyethylene glycol dimethyl ether, polyethylene glycol methyl ether, polypropylene glycol, polypropylene glycol monobutyl ether, diphenyl ether, dibenzyl ether, phenyl sulfone or phenyl sulfoxide. The method of claim 7, wherein the organic solvent used for the cyclization is toluene, xylene, C ₃ -C ₄ alcohol, polyethylene glycol, polyethylene glycol butyl ether, polyethylene glycol dimethyl ether, polyethylene glycol methyl ether, polypropylene glycol, poly Propylene glycol monobutyl ether, diphenyl ether, dibenzyl ether, phenyl sulfone or phenyl sulfoxide. The process of claim 1 wherein said cyclization is carried out in a neat without using a solvent. The method of claim 1, wherein the method comprises: a) reducing 4-halo-3-hydroxybutyric acid ester to obtain 4-halo-1,3-butanediol having the formula (2), b) performing a cyclization reaction by heating the obtained compound of Formula 2 to a temperature of 75 ° C-180 ° C in the presence of an organic solvent or in a neat without a solvent, c) recovering 3-hydroxytetrahydrofuran represented by Formula 1 from the reaction mixture obtained: Formula 1

Formula 2

Formula 3

In Chemical Formulas 1 to 3, * denotes a chiral center, X denotes a halogen atom (F, Cl, Br or I), and R denotes an ester forming group. The process of claim 10, wherein the reduction of step a) comprises M (BH ₄ ) n where M means an alkali or alkaline earth metal and n means 1 or 2, or a methanol mixture thereof. Method carried out in the presence. 12. The method of claim 11, wherein M is sodium and M (BH ₄ ) n: methanol = 1: 0.5-2. The method of claim 10, wherein R is a C ₁ -C ₄ alkyl group. The method according to claim 13, wherein R is an ethyl group or a methyl group.