WO2008093955A1

WO2008093955A1 - Process for the efficient preparation of 3-hydroxytetrahydrofuran

Info

Publication number: WO2008093955A1
Application number: PCT/KR2008/000395
Authority: WO
Inventors: Long Guo Quan; Chang Jin Boo; Mei Hua Hong; Jae Kwan Lee; Jong Min Lee; Seong-Jin Kim
Original assignee: Rstech Corporation
Priority date: 2007-02-01
Filing date: 2008-01-22
Publication date: 2008-08-07
Also published as: KR20080072206A; KR100877849B1

Abstract

Disclosed is a process for the efficient preparation of 3-hydroxytetrahydrofuran. In particular, the present invention provides a process for the preparation of 3-hydroxytetrahydrofuran by performing cyclization of 4-halo-1,3-butanediol either neat or in an organic solvent by heating to 75°C to 18O°C. In the present invention, acidic solution is not used in the cyclization and, thus, the reaction environment is improved. Further, the cyclization product 3-hydroxytetrahydrofuran is purified by a simple process. In addition, according to the present invention, chirality of the starting material is substantially maintained. Consequently, chiral 3-hydroxytetrahydrofuran with a high optical purity of 99.0% ee or better can be prepared economically, in high yield.

Description

PROCESS FOR THE EFFICIENT PREPARATION OF 3-HYDROXYTETRAHYDROFURAN

Technical Field

[1] The present invention relates to a process for the preparation of chiral

3-hydroxytetrahydrofuran. More particularly, the present invention relates to a process for the commercial- scale preparation of chiral 3-hydroxytetrahydrofuran with high optical purity, without sacrificing optical purity of the starting material. Background Art

[2] 3 -Hydroxy tetrahydrofuran is useful as synthesis intermediate of medicines, agri- chemicals, and the like. Especially, it is used as key intermediate in the synthesis of amprenavir, a protease inhibitor used to treat HIV infection. Currently known preparation processes of 3-hydroxytetrahydrofuran are as follows.

[3] There was proposed a process for preparing 3-hydroxytetrahydrofuran through cyc- lodehydrogenation of 1,2,4-butanetriol in the presence of a catalyst such as p - toluenesulfonic acid or strongly acidic cation exchange resin having a sulfate group as ion-exchange group [J. Org. Chem. 1983, vol. 48, p. 2767-2769; Korean Patent Publication No. 10-2006-0067620; Japanese Patent Laid-open No. 2006-36710]. However, the starting material 1,2,4-butanetriol has many problems in synthesis. Generally, 1,2,4-butanetriol was obtained from malic diester, 3-hydroxy- -butyrolactone, tetrahy- drofuran-2,4-diol, and the like. Typically, 1,2,4-butanetriol was prepared from reduction of the malic diester. But, the reduction is undesirable in reaction yield and the purification process of the product is complicated. Alternatively, 1,2,4-butanetriol may be prepared by reducing 3-hydroxy- -butyrolactone or chiral tetrahydrofuran- 2,4-diol in the presence of a reducing agent such as sodium borohydride. However, this method is economically unfavorable because 3-hydroxy- -butyrolactone or tetrahy- drofuran-2,4-diol is relatively expensive [J. Org. Chem. 1983, vol. 48, p. 2767-2769; WO 99/44976; Japanese Patent Laid-open No. 2006-36710].

[4] As an alternative, a process for the preparation of chiral 3-hydroxytetrahydrofuran by protecting the hydroxy group of malic diester with ?-butyl, reducing the same using lithium aluminum hydride (LAH) to obtain 2-?-butoxybutane-l,4-diol, deprotecting the resultant compound in the presence of an acid catalyst, and then performing cyclode- hydrogenation has been proposed [Org. Biomol. Chem. 2004, vol. 2, p. 2061-2070]. However, this process is complicated and difficult to handle. And, since expensive lithium aluminum hydride is used as reducing agent, it seems to be inapplicable to commercial- scale production. [5] U.S. Patent No. 5,780,649 discloses a process for the preparation of

3 -hydroxy tetrahydrofuran from easily available and inexpensive 4-halo-3-hydroxybutyric ester. This method comprises the steps of reducing 4-halo-3-hydroxybutyric ester in an water-miscible organic solvent such as tetrahydrofuran, using sodium borohydride, to obtain 4-halo-l,3-butanediol, and cyclizing the resultant compound in an acidic solution to obtain chiral 3-hydroxytetrahydrofuran. However, this process is not satisfactory in yield (58 to 68%).

[6] As an improvement of the above method, U.S. Patent No. 6,359,155 discloses a process comprising the steps of reducing chiral 4-halo-3-hydroxybutyric ester in an water-immiscible organic solvent such as toluene and ethyl acetate, using sodium borohydride, treating the resultant reaction mixture with water and an acid to obtain an aqueous solution of 4-halo-l,3-butanediol, and then cyclizing 4-halo-l,3-butanediol to obtain chiral 3-hydroxytetrahydrofuran. Although this method provides relatively high reaction yield (80 to 82%), it required long reaction time (40 hours or longer) and a complicated extraction (continuous extraction at 7O⁰C) for the purification. For this reason, this method has a low productivity, on the whole.

[7] In both U.S. Patent Nos. 5,780,649 and6,359, 155, cyclization is performed under acidic solution condition. Acid is harmful to the human body and the use thereof needs to be restricted as much as possible. Particularly, in large-scale production, an acidic condition is difficult to handle. In addition, cyclization in aqueous solution makes the purification of 3-hydroxytetrahydrofuran complicated.

[8] To conclude, the methods disclosed in U.S. Patent Nos. 5,780,649 and 6,359,155 involve at least one of the following problems: i) unsatisfactory yield, ii) long reaction time (40 hours or longer), iii) unfavorable working condition due to use of acid, and iv) difficulty in purification of the target compound due to use of aqueous solution. Disclosure of Invention Technical Problem

[9] An object of the present invention is to provide a process for the efficient preparation of 3-hydroxytetrahydrofuran.

[10] Another object of the present invention is to provide a process for the efficient preparation of chiral 3-hydroxytetrahydrofuran with a high optical purity of 99.0% ee or better, without sacrificing optical purity of the starting material. According to a preferred embodiment of the present invention, the targeted chiral 3-hydroxytetrahydrofuran is prepared in high yield and with high optical purity of 99.0% ee or better, without sacrificing chirality of the starting material. Technical Solution

[11] In one aspect, the present invention provides a process for the preparation of 3 -hydroxy tetrahydrofuran comprising cyclizing 4-halo-l,3-butanediol either neat or in an organic solvent, by heating to 75⁰C to 18O⁰C.

[12] In a preferred embodiment, the present invention provides a process for the preparation of 3 -hydroxy tetrahydrofuran wherein the cyclization is performed in the presence of a base.

[13] In another preferred embodiment, the present invention provides a process for the preparation of 3 -hydroxy tetrahydrofuran wherein the cyclization is performed at 9O⁰C to 15O⁰C.

[14] In still another preferred embodiment, the present invention provides a process for the preparation of 3 -hydroxy tetrahydrofuran wherein the cyclization is performed at 100⁰C to 13O⁰C.

[15] In yet another preferred embodiment, the present invention provides a process for the preparation of 3 -hydroxy tetrahydrofuran wherein the organic solvent used in the cyclization has a boiling point in the range from 75⁰C to 15O⁰C or from 21O⁰C to 600⁰C, more preferably from 9O⁰C to 15O⁰C or from 25O⁰C to 600⁰C, most preferably from 100⁰C to 15O⁰C or from 28O⁰C to 600⁰C.

[16] In still yet another preferred embodiment, the present invention provides a process for the preparation of 3 -hydroxy tetrahydrofuran wherein the chirality of the starting material is preserved during the cyclization and the resultant 3 -hydroxy tetrahydrofuran has a high optical purity of 99.0% ee or better.

[17] In a further preferred embodiment, the present invention provides a process for the preparation of 3 -hydroxy tetrahydrofuran which comprises a) reducing 4-halo-3-hydroxybutyric ester to obtain chiral 4-halo-l,3-butanediol, b) cyclizing the resultant compound either neat or in an organic solvent, by heating to 75⁰C to 18O⁰C, and c) recovering 3 -hydroxy tetrahydrofuran from the resultant reaction mixture.

[18] In another further preferred embodiment, the present invention provides a process for the preparation of 3 -hydroxy tetrahydrofuran wherein the 4-halo-3-hydroxybutyric ester is ethyl-4-halo-3-hydroxybutyrate or methyl-4-halo-3-hydroxybutyrate.

[19] In still another further preferred embodiment, the present invention provides a process for the preparation of 3 -hydroxy tetrahydrofuran wherein the reduction in the step a) is performed in the presence of M(BH₄)_n (where M is an alkali metal or an alkaline earth metal, and n is 1 or 2) or a mixture thereof with methanol.

[20] In yet another further preferred embodiment, the present invention provides a process for the preparation of 3 -hydroxy tetrahydrofuran wherein said M is sodium and the proportion of M(BH₄)_n : methanol is from 1:0.5 to 1:2.

[21] In still yet another further preferred embodiment, the present invention provides a process for the preparation of 3 -hydroxy tetrahydrofuran wherein the cyclization is performed neat without using a solvent. Advantageous Effects

[22] According to the process for the preparation of chiral 3 -hydroxy tetrahydrofuran of the present invention, 3 -hydroxy tetrahydrofuran can be prepared with high optical purity, without sacrificing optical purity of the starting material. Specifically, from the starting material represented by the formula 2 and/or formula 3, 3 -hydroxy tetrahydrofuran having high optical purity of 99% ee or better can be prepared in high yield, without sacrificing chirality. And, chiral 4-halo-l,3-butanediol represented by the formula 2 can be used in the following cyclization process in crude form, without any purification. Further, since the cyclization is performed either neat or in an organic condition, instead of using an acidic solution, the complicated procedure of extraction or concentration of aqueous solution can be avoided. In addition, by performing the cyclization in neat condition and using an organic solvent having a boiling point higher than that of the target compound, chiral 3 -hydroxy tetrahydrofuran can be purified simply through distillation under reduced pressure. Accordingly, the process for the preparation of 3 -hydroxy tetrahydrofuran according to the present invention is carried out conveniently in mild condition. This means that the process for the preparation of 3 -hydroxy tetrahydrofuran with high optical purity in accordance with the present invention can be applied for commercial- scale production. Mode for the Invention

[23] The present inventors performed various experiments in order to find an alternative to the cyclization of 3 -hydroxy tetrahydrofuran in an acidic solution. As a result, they found out that 4-halo-l,3-butanediol can be cyclized into 3 -hydroxy tetrahydrofuran either in the presence of an organic solvent or neat without using a solvent. They confirmed that yield and reaction time of the cyclization of 4-halo-l,3-butanediol are greatly dependent on reaction temperature. Specifically, cyclization was hardly carried out below 75⁰C. The reaction was initiated at 75⁰C to 9O⁰C and activated at 9O⁰C or higher, most preferably at 100⁰C or higher. Surprisingly, the chirality of 3 -hydroxy tetrahydrofuran was preserved during the cyclization. As a result, it was confirmed that 3 -hydroxy tetrahydrofuran can be prepared with high optical purity (99.0% ee or better).

[24] In order to evaluate the effect of HCl on the cyclization of 4-halo-l,3-butanediol, the present inventors performed the cyclization in the presence of a base. Surprisingly enough, the rate of the cyclization increased to some extent, instead of decreasing. Such a result indicates that the HCl produced during the cyclization does not have a significant effect on the reaction. In other words, this contradicts the theory that the HCl produced during the cyclization of 4-halo-l,3-butanediol changes the reaction solution into acidic condition and thereby accelerates the cyclization. [25] The process for the preparation of 3 -hydroxy tetrahydrofuran represented by the formula 1 below according to the present invention comprises cyclizing

4-halo-l,3-butanediol represented by the formula 2 either neat or in an organic solvent, by heating to 75⁰C to 18O⁰C: [26] Formula 1

[30] wherein * represents a chiral center and X is a halogen atom (F, Cl, Br or I).

[31] The preparation of 3 -hydroxy tetrahydrofuran through cyclization of

4-halo-l,3-butanediol represented by the formula 2 is summarized in the following

Scheme 1: [32] Scheme 1

[34] wherein * represents a chiral center and X is a halogen atom (F, Cl, Br or I).

[35] 4-Halo-l,3-butanediol may be prepared in high yield by reducing chiral

4-halo-3-hydroxybutyric ester represented by the formula 3. The reduction is also performed with high yield, without sacrificing optical purity. [36] Formula 3

[38] In the formula 3, * represents a chiral center, X is a halogen atom (F, Cl, Br or I) and

R is an ester forming group, preferably Ci-C₄ alkyl. [39] The entire process of preparing 3 -hydroxy tetrahydrofuran from

4-halo-3-hydroxybutyric ester comprises: [40] a) reducing 4-halo-3-hydroxybutyric ester represented by the formula 3 to obtain

4-halo-l,3-butanediol represented by the formula 2; [41] b) cyclizing the resultant compound represented by the formula 2 either neat or in an organic solvent, by heating to 75⁰C to 18O⁰C; and [42] c) recovering 3 -hydroxy tetrahydrofuran represented by the formula 1 from the resultant reaction mixture. [43] The entire process of preparing 3 -hydroxy tetrahydrofuran from

4-halo-3-hydroxybutyric ester represented by the formula 3 is summarized in the following Scheme 2: [44] Scheme 2 heating in organic or neat condition to perform cyclization

[46] wherein * represents a chiral center, X is a halogen atom (F, Cl, Br or I) and R is an ester forming group, preferably Ci-C₄ alkyl.

[47] During the reduction of the 4-halo-3-hydroxybutyric ester and the cyclization by heating, no substantial degradation of chirality was observed. Accordingly, the process according to the present invention is particularly useful for the preparation of chiral 3-hydroxytetrahydrofuran. According to a preferred embodiment of the present invention, the target compound 3 -hydroxy tetrahydrofuran is prepared from chiral 4-halo-3-hydroxybutyric ester with a high optical purity of 99.0% ee or better.

[48] Hereinafter, the present invention is described in further detail.

[49] 4-Halo-3-hydroxybutyric ester represented by the formula 3 is reduced to

4-halo- 1 ,3-butanediol.

[50] Examples of a reducing agent that can used for the reduction include borane-methyl sulfide complex, borane-tetrahydrofuran complex, diborane, lithium aluminum hydride, metal salt of boron hydride, and a mixture of metal salt of boron hydride and methanol. A mixture of alkali metal salt of boron hydride and methanol or a mixture of alkaline earth metal salt of boron hydride and methanol is more preferred. A mixture of sodium borohydride and methanol is further more preferred. A mixture of metal salt of boron hydride and methanol forms a metal salt of methoxy borohydride in the reaction solution, in situ. A mixture of sodium borohydride and methanol is the most preferred. The metal salt of boron hydride is used in 0.5 to 2.0 equivalents, preferably in 0.8 to 1.2 equivalents, based on compound represented by the formula 3. Methanol is used in 0.5 to 2.0 equivalents, preferably in 0.8 to 1.5 equivalents, based on the metal salt of boron hydride. According to experimental results, when sodium borohydride was used alone in 1 equivalent based on the compound represented by the formula 3, about 48 hours of reaction time was required. But, when a mixture of 1 equivalent of sodium borohydride and 1 equivalent of methanol was used, the reaction was completed in about 20 hours.

[51] The solvent used for the reduction is not particularly limited, but one commonly used in the related art may be used. Specifically, an aliphatic or aromatic hydrocarbon solvent, a halogenated hydrocarbon solvent, an ether, an ester or an alcohol may be used. Among them, a less toxic and inexpensive organic solvent is preferred. For example, toluene, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, 1,4-dioxane, etc. may be used. The solvent may be used in an amount of 1 to 10 equivalents, preferably 2 to 5 equivalents, based on the weight of the compound represented by the formula 3. The reaction is performed normally at 0 to 100⁰C, preferably at 20 to 7O⁰C.

[52] In the 4-halo-3-hydroxybutyric ester represented by the formula 3, the ester protecting group R is not particularly limited, but may be a general protecting group. Alkyl is preferred, Ci-C₄ alkyl is more preferred, and ethyl or methyl is further more preferred.

[53] 4-Halo-l,3-butanediol represented by the formula 2 obtained from the reduction of

4-halo-3-hydroxybutyric ester can be used in the following cyclization in crude form without special purification. In addition to simplified process, this contributes to improvement of yield.

[54] The cyclization of 4-halo-l,3-butanediol represented by the formula 2 is performed at a temperature of about 75⁰C or higher. Considering that the target compound 3 -hydroxy tetrahydrofuran has a boiling point of about 18O⁰C, the cyclization is performed in the temperature range from 75⁰C to 18O⁰C. More preferably, the cyclization is performed in the temperature range from 9O⁰C to 15O⁰C. Most preferably, the cyclization is performed in the temperature range from 100⁰C to 13O⁰C.

[55] The cyclization may be performed either in the presence of an organic solvent or neat without using a solvent. The organic solvent has a boiling point of at least 75⁰C. Preferably, the organic solvent has a boiling point of at least 9O⁰C. Most preferably, the organic solvent has a boiling point in the range from 100 to 15O⁰C or from 21O⁰C to 600⁰C. Use of an organic solvent having a boiling point in the range from 15O⁰C to 21O⁰C is recommended to be avoided, if possible. It is because the purification of the target compound 3 -hydroxy tetrahydrofuran (boiling point = ~180°C) by distillation may become difficult. Accordingly, as described above, an organic solvent having a boiling point in the range from 100 to 15O⁰C or from 21O⁰C to 600⁰C is the most preferred, in view of reaction rate, reaction yield and separation of the solvent from the target compound. Specific examples of available organic solvent include an aliphatic or aromatic hydrocarbon solvent, a halogenated hydrocarbon solvent, an ether, an ester and an alcohol. For example, benzene, toluene, xylene, C₂-C₄ alcohols (e.g., ethanol, propanol, isopropanol, 1-butanol, 2-butanol and ?-butanol), 1,2-dichloroe thane, ethyl acetate, 1,4-dioxane, etc., may be used. Also, a mixture solvent of the above- mentioned solvents may be used. Preferable solvents are toluene, xylene and C₃-C₄ alcohols. When an organic solvent having a boiling point in the range from 100 to 150⁰C is used, the organic solvent is first recovered by distillation under reduced pressure, and then the target compound 3 -hydroxy tetrahydrofuran is obtained at higher temperature. Use of an organic solvent having a boiling point higher than 210⁰C provides the advantage that the target compound can be recovered first through distillation under reduced pressure. Examples of organic solvent 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 and phenyl sulfoxide. The organic solvent is used in 0.5 to 20 equivalents, preferably in 2 to 5 equivalents, based on the weight of the compound represented by the formula 2.

[56] The cyclization can also be performed neat without using an organic solvent. After performing cyclization in neat condition, the target compound 3 -hydroxy tetrahydrofuran can be obtained simply through distillation under reduced pressure.

[57] As described earlier, the cyclization may be performed in the presence of a base. The addition of a base increases reaction rate to some extent. Available bases are not particularly limited, but various inorganic and organic bases may be used. Examples of inorganic base include an alkali metal salt. For example, an alkali carbonate, an alkali bicarbonate or an alkali phosphate may be used. Specifically, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, lithium phosphate, sodium phosphate, potassium phosphate, cesium phosphate, etc. may be used. Preferred examples of organic base include alkyl- or aryl-substituted amine. Specifically, tri- methylamine, triethylamine, tripropylamine, tributylamine, triphenylamine, diisopro- pylethylamine, dicyclohexylamine, dibenzylamine, benzylamine, etc. may be used. The base is used in 0.5 to 10 equivalents, preferably in 1.0 to 2 equivalents, based on the weight of the 4-halo-l,3-butanediol compound represented by the formula 2.

[58] The following examples illustrate the present invention and are not intended to limit the same.

[59] Example 1

[60] 61.5 g (1.626 mol) of sodium borohydride was dissolved in 694 mL of toluene, and

52 g (1.626 mol) of methanol was added drop wise at room temperature for 1 hour. Subsequently, 300 g (1.807 mol, 99.3% ee) of ethyl (S)-4-chloro-3-hydroxybutyrate was added, and stirring was performed at room temperature for 12 hours. The reaction mixture was cooled below 10⁰C and, after adding 183 g of 36% HCl dropwise, the solvent was removed by distillation under reduced pressure below 40⁰C. Using 800 mL of methanol, concentration under reduced pressure was performed for 3 times below 40 C. 800 mL of dichloromethane was added to the resultant residue. After filtering off solid inorganic materials and removing the solvent under reduced pressure, 220 g of (S )-4-chloro-l,3-butanediol was obtained as oil (yield = 98%).

[61] Example 2

[62] 800 mL of toluene was added to 220 g ( 1.774 mol) of (S)-4-chloro- 1 ,3-butanediol prepared in Example 1, and stirring was performed for 16 hours under reflux. The reaction mixture was cooled to room temperature and, after adding 37.6 g (0.355 mol) of Na₂CO₃ and 1 g (0.055 mol) of water, stirring was further performed for 30 minutes. After removing solid by filtering, the solvent was recovered by concentration under reduced pressure, and the residue was further distilled under reduced pressure. 138 g of colorless (S)-3-hydroxytetrahydrofuran was obtained (yield = 88%, optical purity = 99.55% ee).

[63] Example 3

[64] 61.5 g (1.626 mol) of sodium borohydride was dissolved in 694 mL of toluene, and

52 g (1.626 mol) of methanol was added drop wise at room temperature for 1 hour. Subsequently, 300 g (1.807 mol, 99.3% ee) of ethyl (#)-4-chloro-3-hydroxybutyrate was added, and stirring was performed at room temperature for 12 hours. The reaction mixture was cooled below 1O⁰C and, after adding 183 g of 36% HCl dropwise, the solvent was removed by distillation under reduced pressure below 4O⁰C. Using 800 mL of methanol, concentration under reduced pressure was performed for 3 times below 4O⁰C. 800 mL of dichloromethane was added to the resultant residue. After filtering off solid inorganic materials and removing the solvent under reduced pressure, 218 g of (R )-4-chloro-l,3-butanediol was obtained as oil (yield = 97%).

[65] Example 4

[66] 800 mL of toluene was added to 218 g (1.758 mol) of (#)-4-chloro-l,3-butanediol prepared in Example 3, and stirring was performed for 16 hours under reflux. The reaction mixture was cooled to room temperature and, after adding 37.3 g (0.352 mol) of Na₂CO₃ and 1 g (0.055 mol) of water, stirring was further performed for 30 minutes. After removing solid by filtering, the solvent was recovered by concentration under reduced pressure, and the residue was further distilled under reduced pressure. 137 g of colorless (/?)-3-hydroxytetrahydrofuran was obtained (yield = 88%, overall yield = 85%, optical purity = 99.52% ee).

[67] Example 5

[68] 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 dissolved in 400 g of tetrahydrofuran, and 34.7 g (1.084 mol) of methanol was added dropwise at room temperature for 1 hour. After stirring at room temperature for 10 hours, the reaction mixture was cooled below 1O⁰C. Then, after adding 122 g of 36% HCl dropwise, the solvent was removed by distillation under reduced pressure below 4O⁰C. Using 550 mL of methanol, concentration under reduced pressure was performed for 3 times below 4O⁰C. 550 mL of di- chloromethane and 20 g of Na₂SO₄ were added to the resultant residue, and stirring was performed for 30 minutes. After filtering off solid inorganic materials and removing the solvent under reduced pressure, 144 g of (S)-4-chloro-l,3-butanediol was obtained as oil (yield = 96%).

[69] Example 6

[70] 550 mL of toluene was added to 144 g (1.161 mol) of (S)-4-chloro-l,3-butanediol prepared in Example 5, and stirring was performed for 16 hours under reflux. The reaction mixture was cooled to room temperature and, after adding 24.6 g (0.232 mol) of Na₂CO₃ and 0.5 g (0.028 mol) of water, stirring was further performed for 30 minutes. After removing solid by filtering, the solvent was recovered by concentration under reduced pressure, and the residue was further distilled under reduced pressure. 91 g of colorless (S)-3-hydroxytetrahydrofuran was obtained (yield = 89%, overall yield = 85%, optical purity = 99.45% ee).

[71] Example 7

[72] 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 dissolved in 400 g of isopropanol, and 34.7 g (1.084 mol) of methanol was added dropwise at room temperature for 1 hour. After stirring at room temperature for 12 hours, the reaction mixture was cooled below 1O⁰C. Then, after adding 122 g of 36% HCl dropwise, the solvent was removed by distillation under reduced pressure below 4O⁰C. Using 500 mL of methanol, concentration under reduced pressure was performed for 3 times below 4O⁰C. Stirring was performed after adding 550 mL of isopropanol to the resultant residue. After filtering off solid inorganic materials, 147 g of (S)-4-chloro-l,3-butanediol was obtained as oil (yield = 98%).

[73] Example 8

[74] An isopropanol solution containing 147 g (1.182 mol) of (S)-4-chloro-l,3-butanediol obtained in Example 7 was stirred for 22 hours under reflux. After cooling the reaction mixture to room temperature, 24.6 g (0.232 mol) of Na₂CO₃ and 0.5 g (0.028 mol) of water were added, and stirring was performed for 30 minutes. After filtering, the solvent was recovered by concentration under reduced pressure, and the residue was further distilled under reduced pressure. 89 g of colorless (S)-3-hydroxytetrahydrofuran was obtained (yield = 87%, overall yield = 85%, optical purity = 99.43% ee).

[75] Example 9

[76] 400 mL of 1,4-dioxane was added to 100 g (0.806 mol) of (S

)-4-chloro-l,3-butanediol obtained in Example 1, and stirring was performed for 20 hours under reflux. After cooling the reaction mixture to room temperature, 24.6 g (0.232 mol) of Na₂CO₃ and 0.5 g (0.028 mol) of water were added, and stirring was performed for 30 minutes. After filtering, the solvent was concentrated under reduced pressure. The resultant residue was distilled under reduced pressure to obtain 58 g of colorless (S)-3-hydroxytetrahydrofuran (yield = 82%, optical purity = 99.42% ee).

[77] Example 10

[78] While stirring 220 g (1.774 mol) of (S)-4-chloro-l,3-butanediol prepared in Example

1 at 11O⁰C in neat condition without a solvent, distillation under reduced pressure was performed for 6 hours. The resultant compound was diluted in 200 mL of toluene and, after adding 37.6 g (0.355 mol) Of Na₂CO₃ and 1 g (0.055 mol) of water, stirring was performed for 30 minutes. After filtering, distillation under reduced pressure was performed to obtain 130 g of colorless (S)-3-hydroxytetrahydrofuran (yield = 83%, overall yield = 82%, optical purity = 99.45% ee).

[79] Example 11

[80] 200 g (1.613 mol) of (S)-4-chloro-l,3-butanediol prepared in Example 1 was added to 600 g of polyethylene glycol, and distillation under reduced pressure was performed at 11O⁰C for 4 hours, while stirring. The resultant compound was diluted in 200 mL of toluene and, after adding 34.2 g (0.323 mol) of Na₂CO₃ and 0.6 g (0.033 mol) of water, stirring was performed for 30 minutes. After filtering, distillation under reduced pressure was performed to obtain 125 g of colorless (S)-3-hydroxytetrahydrofuran (yield = 88%, optical purity = 99.61% ee).

[81] Example 12

[82] 200 g (1.613 mol) of (S)-4-chloro-l,3-butanediol prepared in Example 1 was added to 600 g of polyethylene glycol dimethyl ether, and distillation under reduced pressure was performed at 11O⁰C for 5 hours, while stirring. The resultant compound was diluted in 200 mL of toluene and, after adding 34.2 g (0.323 mol) of Na₂CO₃ and 0.6 g (0.033 mol) of water, stirring was performed for 30 minutes. After filtering, distillation under reduced pressure was performed to obtain 126 g of colorless (S )-3-hydroxytetrahydrofuran (yield = 90%, optical purity = 99.46% ee).

[83] Example 13

[84] 200 g (1.613 mol) of (S)-4-chloro-l,3-butanediol prepared in Example 1 was added to 600 g of polypropylene glycol monobutyl ether, and distillation under reduced pressure was performed at 11O⁰C for 4 hours, while stirring. The resultant compound was diluted in 200 mL of toluene and, after adding 34.2 g (0.323 mol) of Na₂CO₃ and 0.6 g (0.033 mol) of water, stirring was performed for 30 minutes. After filtering, distillation under reduced pressure was performed to obtain 123 g of colorless (S )-3-hydroxytetrahydrofuran (yield = 86%, optical purity = 99.45% ee).

[85] Example 14

[86] 800 mL of toluene and 197.5 g (1.951 mol) of triethylamine were added to 220 g

(1.774 mol) of (S)-4-chloro-l,3-butanediol prepared in Example 1, and stirring was performed for 16 hours under reflux. The reaction mixture was cooled to room temperature and filtered to remove solid. After recovering the solvent by concentrating under reduced pressure, the residue was further distilled under reduced pressure to obtain 136 g of colorless (S) -3 -hydroxy tetrahydrofuran (yield = 87%, optical purity = 99.5% ee).

[87] Example 15

[88] 700 mL of toluene and 149 g (1.774 mol) of NaHCO₃ were added to 200 g (1.613 mol) of (S)-4-chloro-l,3-butanediol prepared in Example 1, and stirring was performed for 16 hours under reflux. The reaction mixture was cooled to room temperature and filtered to remove solid. After recovering the solvent by concentrating under reduced pressure, the residue was further distilled under reduced pressure to obtain 121 g of colorless (S)-3-hydroxytetrahydrofuran (yield = 85%, overall yield = 83%, optical purity = 99.54% ee).

[89] Example 16

[90] 61.5 g (1.626 mol) of sodium borohydride was dissolved in 694 mL of toluene, and

275.6 g (1.807 mol, 99.3% ee) of methyl (S)-4-chloro-3-hydroxybutyrate was added. After adding 52 g (1.626 mol) of methanol drop wise at room temperature for 1 hour, stirring was performed at room temperature for 12 hours. The reaction mixture was cooled below 1O⁰C and, after adding 183 g of 36% HCl dropwise, the solvent was removed by distillation under reduced pressure below 4O⁰C. Using 800 mL of methanol, concentration under reduced pressure was performed below 4O⁰C for 3 times. 800 mL of dichloromethane was added to the resultant residue. After filtering off solid inorganic materials, the solvent was removed under reduced pressure to obtain 220 g of (S)-4-chloro-l,3-butanediol as oil (yield = 98%).

[91] Example 17

[92] 800 mL of toluene was added to 22O g (1.774 mol) of (S)-4-chloro- 1 ,3-butanediol prepared in Example 16, and stirring was performed for 16 hours under reflux. The reaction mixture was cooled below 1O⁰C and, after adding 37.6 g (0.355 mol) of Na₂ CO₃ and 1 g (0.055 mol) of water, stirring was further performed for 30 minutes. After filtering off solid inorganic materials, the solvent was recovered by distillation under reduced pressure. The residue was further distilled under reduced pressure to obtain 136 g of colorless (S)-3-hydroxytetrahydrofuran (yield = 87%, optical purity = 99.5% ee).

[93] The invention has been described in detail with reference to preferred embodiments thereof. However, it will be appreciated by those skilled in the art that changes may be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.

Claims

[1] A process for the preparation of 3 -hydroxy tetrahydrofuran represented by formula 1, which comprises cyclizing 4-halo-l,3-butanediol represented by formula 2 either neat or in an organic solvent, by heating to from 75⁰C to 18O⁰C: formula 1

wherein, * represents a chiral center and X is a halogen atom (F, Cl, Br or I).

[2] The process of claim 1, wherein the cyclization is performed in the presence of a base.

[3] The process of claim 1, wherein the cyclization is performed at 9O⁰C to 15O⁰C.

[4] The process of claim 1, wherein the cyclization is performed at 100⁰C to 13O⁰C.

[5] The process of claim 1, wherein the organic solvent used in the cyclization has a boiling point in a range of from 75⁰C to 15O⁰C or from 21O⁰C to 600⁰C.

[6] The process of claim 1, wherein the 4-halo-3-hydroxybutyric ester represented by formula 2 is optically active.

[7] The process of claim 1, wherein the organic solvent used in the cyclization is benzene, toluene, xylene, C₂-C₄ 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.

[8] The process of claim 7, wherein the organic solvent used in the cyclization is toluene, xylene, C₃-C₄ alcohol, 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.

[9] The process of claim 1, wherein the cyclization is performed neat without using a solvent.

[10] The process of claim 1, which comprises: a) reducing 4-halo-3-hydroxybutyric ester represented by formula 3 to obtain 4-halo-l,3-butanediol represented by formula 2; b) cyclizing the compound represented by formula 2 either neat or in an organic solvent, by heating to from 75⁰C to 18O⁰C; and c) recovering 3 -hydroxy tetrahydrofuran represented by formula 1 from a reaction mixture of the step b): formula 1

formula 3

OH X^^^C°^0R wherein * represents a chiral center, X is a halogen atom (F, Cl, Br or I) and R is an ester forming group.

[11] The process of claim 10, wherein the reduction in the step a) is performed in the presence of M(BH₄)_n (where M is an alkali metal or an alkaline earth metal, and n is 1 or 2) or a mixture thereof with methanol.

[12] The process of claim 11, wherein said M is sodium and the proportion of M(BH₄

)_n : methanol is from 1:0.5 to 1:2.

[13] The process of claim 10, wherein said R is Ci-C₄ alkyl.

[14] The process of claim 13, wherein said R is ethyl or methyl.