WO2003097624A1

WO2003097624A1 - Process for preparing (r)-3,4-epoxy-1-butanol

Info

Publication number: WO2003097624A1
Application number: PCT/KR2003/000989
Authority: WO
Inventors: Jongpil Chun; Jae Kwang Hwang; Seung Bum Ha; Yik-Haeng Cho; Ji Uk Yoo
Original assignee: Samsung Fine Chemicals Co., Ltd.
Priority date: 2002-05-20
Filing date: 2003-05-19
Publication date: 2003-11-27
Also published as: KR20030089948A; AU2003228111A1

Abstract

The present invention relates to a novel process for preparing (R)-3,4-epoxy-1-butanol in particular, a process for preparing (R)-3,4-epoxy-1-butanol with relatively high yield and in a cost-effective manner, wherein (S)-3-alkyl or arylsulfonyloxy-butyrolactone used as a starting material is reduced under a mild condition to give 2-alkyl or arylsulfonyloxy-1,4-butanediol as an intermediate, and the intermediate is then epoxidized in the presence of a base to invert a chiral center.

Description

PROCESS FOR PREPARING (R)-3, 4-EPOXY-l-BUTANOL

BACKGROUND OF THE INVENTION FIELD OF THE INVENTION The present invention relates to a novel process for preparing (R)-3,4-epoxy-

1-butanol represented by the following formula (I), in particular, a process for preparing (R)-3,4-epoxy-l-butanol with a relatively high yield and in a cost- effective manner, wherein (S)-3-alkyl or arylsulfonyloxy-butyrolactone as a starting material is reduced under a mild condition to give 2-alkyl or arylsulfonyloxy-l,4-butanediol as an intermediate, and the intermediate is then epoxidized in the presence of a base to invert a chiral center.

DESCRIPTION OF THE RELATED ART

3,4-epoxy-l-butanol having optical activity has been frequently used as a raw material for synthesizing biologically and chemically diverse chiral intermediates. For example, in synthesizing chiral compounds as a raw material for intermediates of biologically important compactin and milbemycin (Tetrahedron Lett. 1984, 25, 2101, and Synthesis 621-623, 1992), an intermediate of neurotransmitter (R)-GABOB (/. Org. Chem. 1984, 49, 3707-3711) and core intermediate of carbapenem antibiotic (Heterocycles, 24, 5, 1986, and WO 88/08845), 3,4-epoxy-l-butanol having optical activity has been considered as a key compound. Therefore, intensive researches have been carried out using 3,4- epoxy-1-butanol with optical activity in the synthesis of chiral compounds. The conventional processes for preparing 3,4-epoxy-l-butanol are described as follows.

It has been suggested that 3,4-epoxy-l-butanol with optical activity could be prepared by using allylic alcohols as a starting material in the presence of a metal catalyst through asymmetric epoxidation (/. Org. Chem. 1984, 49, 3707-3711, U.S.Pat. No. 4,471,130, Tetrahedron: Asymmetry, 9, 3895-3901, 1998, and Macromol. Symp. 156, 125-136, 2000). Such technologies resulted in a relatively low yield and low optical purity of 23-55%ee.

It has been reported that 3,4-epoxy-l-butanol with optical activity may be synthesized from S-malic acid by multi-step process (/. Org. Chem., 1981, 46, 1208,

Tetrahedron, 40, 1208, 1984, and Chem. Lett. 363, 1985). However, this process has a few shortcomings: a requirement of a process consisting of several steps and use of LiAlH , which is not easy to handle from the commercial point of view.

Further, it has been disclosed that 1,2,4-butanetriol may be converted to 3,4- epoxy-1-butanol by using diethoxytriphenylphosphorane through phosphoranylation and cyclodehydration (/. Am. Chem. Soc, 108, 24, 1986).

However, this method requires use of expensive reagents and also generates about 20% of 3-hydroxytetrahydrofuran as a by-product.

There have been also reported other methods for synthesizing (S)-3,4-epoxy- 1-butanol by virtue of reduction of 4-halo-3-hydroxy-butanoate using a reducing agent followed by epoxidation (Japanese Patent Kokai Pyeong 2-174733); the technology comprising several steps from (S)-erythrulose as a starting material (Tetrahedron Lett. 28, 40, 4759-4760, 1987); the hydrolysis of esters using lipase (/. Am. Chem. Soc. 106, 7250-7251, 1984), the asymmetric Michael addition of thiophenol (Chem. Lett. 363-366, 1985); and Asymmetric 1,4-addition to 5-alkoxy- 2(5H)-furanone (Tetrahedron, 44, 23, 7213-7222, 1988).

As one very similar to the present invention, there is also known a process wherein the amino group of D- or L-aspartic acid as a starting material is modified to a halogen group and then reduced with B2H6 reducing agent to give 2-halo-l,4-butanediol, followed by inversion of chiral center through epoxidation, finally producing (R)-3,4-epoxy-l-butanol (Heterocycles, 1986, 24, 5, and Synthesis, 621-623, 1992). However, this method requires B2H6, a reducing agent for yielding 2-halo-l,4-butanediol as a core intermediate, which is very expensive and difficult to handle.

SUMMARY OF THE INVENTION

For these reasons, the present inventors have executed intensive researches to develop a novel process for preparing (R)-3,4-epoxy-l-butanol with commercial facility in a cost-effective manner. As a result, the present inventors have accomplished a process for preparing (R)-3,4-epoxy-l-butanol with relatively high yield and in a cost-effective manner, wherein (S)-3-alkyl or arylsulfonyloxy-butyrolactone as a starting material is reduced by a reducing agent showing commercial facility under a mild condition to give 2-sulfonyloxy- 1,4-butanediol as a novel intermediate, and then the intermediate is epoxidized in the presence of a base to invert a chiral center. Accordingly, it is an object of this invention to provide a simple process for preparing (R)-3,4-epoxy-l-butanol with higher yield under a mild condition compared to those of conventional processes.

DETAILED DESCRIPTION OF THE INVENTION In an aspect of this invention, there is provided a process for preparing (R)- 3,4-epoxy-l-butanol, which comprises the steps of: (a) reducing (S)-3-alkyl or arylsulfonyloxy-butyrolactone represented by the following formula (II) to give 2-sulfonyloxy-l,4-butanediol represented by the following formula (III) as an intermediate; and (b) epoxidizing said intermediate represented by the following formula (III) in the presence of a base to invert a chiral center, whereby (R)-3,4- epoxy-1-butanol represented by the following formula (I) is produced:

(II) (III) (I)

wherein R represents an alkyl, an aryl or a substituted aryl group having 1-12 carbon atoms.

The present invention will be described in more detail hereunder: The present invention is characterized in that (S)-3-alkyl or arylsulfonyloxy- butyrolactone as a starting material is reduced under a mild condition by using a reducing agent that is commercially facile, to obtain 2-sulfonyloxy-l,4-butanediol as an intermediate, and in turn the intermediate is epoxidized in the presence of a base to invert a chiral center, which enables to easily prepare (R)-3,4-epoxy-l- butanol with a higher yield and in a cost-effective manner as compared to conventional ones.

(S)-3-alkyl or arylsulfonyloxy-butyrolactone represented by the formula (II) serving as a starting material in this invention may be readily prepared by the reaction between sulfonic acid derivatives and (S)-3-hydroxy-γ-butyrolactone that is prepared from naturally occurring carbohydrates (U.S. Pat. Nos. 5,292,939, 5,319,110, 5,374,773, 6,124,122 and 6,221,639). Here, the sulfonylating agents include, but are not limited to, anhydrides of alkylsulfonic acid, alkylsulfonyl chloride and arylsulfonyl chloride, in particular, anhydrides of alkylsulfonic acid having 1-12 carbon atoms, alkylsulfonyl chloride having 1-12 carbon atoms and arylsulfonyl chloride having 1-12 carbon atoms. Preferably, methanesulfonyl chloride or p-toluenesulfonyl chloride is employed.

In the present process, the reducing agent for reducing (S)-3-alkyl or arylsulfonyloxy-butyrolactone represented by the formula (II) is a boron metal compound that is commercially facile. Preferably, NaBH₄ or Ca(BH )₂ is employed. The reductant is used in the range of 0.5-5 equivalents, preferably, 0.5- 2 equivalents. The solvent used in reduction is a sole organic solvent or a mixed solvent, and preferably, one selected from the group consisting of methanol, ethanol, isopropylalcohol, dichloromethane, dichloroethane, trichloromethane, tetrahydrofuran, dioxane and a combination of these thereof. The reduction is performed at a temperature of -10 to 40 ^°C, preferably, 0 to 30 ^°C . The reaction time ranges from 1 to 24 hr, preferably, 1 to 4 hr. According to the following step, the compound of interest, (R)-3,4-epoxy-l- butanol, can be obtained in such a manner that 2-alkyl or arylsulfonyloxy-1,4- butanediol is epoxidized in the presence of a base to invert a chiral center. In this step, the base is an inorganic or organic base. The inorganic base refers to alkali metal salt or alkali earth metal salt, in particular, it includes hydroxides, alkoxides and carbonates of alkali metal salt or alkali earth metal salt. The organic base refers to aliphatic or aromatic amines, in particular, it includes alkylamines and arylamines. The base is used in the range of 1-10 equivalents, preferably, 1-3 equivalents. For epoxidation, the reaction solvent includes water, polar organic solvent or a mixture of water and polar organic solvent, preferably, water, low grade alcohols or aqueous alcohol solution. The epoxidation is performed at a temperature of 0 to 50 ^°C, preferably, 10 to 30 TJ . The required time for epoxidation ranges from 1 to 24 hr, preferably, 2 to 5 hr.

The following specific examples are intended to be illustrative of the invention and should not be construed as limiting the scope of the invention.

EXAMPLE 1: Preparation of (S)-2-Methanesulfonyloxy-l,4-Butanediol

Into a 2 L reactor, NaBH₄ (42 g, 1.11 mol) and 300 ml of isopropylalcohol were added, cooled to 5-10 TJ and agitated. (S)-3-methanesulfonyloxy- butyrolactone (200 g, 1.11 mol) was dissolved in 1 L of anhydrous tetrahydrofuran at 50 TJ and the solution was added dropwise to the reactant over 2 hr while maintaining a temperature at 15 °C . Following agitation for 2 hr at the same temperature to complete the reaction, 10% aqueous hydrochloric acid solution (0.7 mol, 283 ml) was added dropwise to the reaction mixture for 1 hr at 5^°C, thereby adjusting pH to 3-3.5. The solution was agitated for 30 min at 5°C and concentrated by evaporation. 800 ml of methanol was added to the concentrate and then concentrated under vacuum. The above process was repeated twice and the concentrate was dissolved in 700 ml of ethylacetate, followed by suction filtration and vacuum concentration, finally yielding 173 g of (S)-2-methanesulfonyloxy-l,4-butanediol (yield 85%): Η-NMR(D₂0, ppm) δl.88(m, 2H), 3.15(s, 3H), 3.52-3.80(m, 4H), 4.85(m, 1H) EXAMPLE 2: Preparation of (S)-2-Methanesulf onyloxy-l,4-Butanediol

The same procedures as Example 1 was carried out except Ca(BH )₂- 2 THF(118.7 g, 0.55 mol) was used as a reducing agent instead of NaBH . 179.9 g of (S)-2-methanesulfonyloxy-l,4-butanediol were given (yield 88%): ¹H- NMR(D₂0, ppm) δl.88(m, 2H), 3.15(s, 3H), 3.52-3.80(m, 4H), 4.85(m, 1H)

EXAMPLE 3: Preparation of (S)-2-/?-Toluenesulfonyloxy-l,4-Butanediol

Into a 2 L reactor, NaBH (32.5 g, 0.86 mol) and 300 ml of isopropylalcohol were added, cooled to 5-10 ^°C and agitated. (S)-3-toluenesulfonyloxy-l,4- butyrolactone (220 g, 0.86 mol) dissolved in 300 ml of dichloromethane was added dropwise to the reactant over 2 hr while maintaining a temperature at

15^°C . Following agitation for 2 hr at the same temperature to complete the reaction, 10% aqueous hydrochloric acid solution (0.7 mol, 219 ml) was added dropwise to the reaction mixture for 1 hr at 5^°C, thereby adjusting pH to 3-3.5.

The solution was agitated for 30 min at 5^°C and concentrated by evaporation.

800 ml of methanol was added to the concentrate and then concentrated under vacuum. The above process was repeated twice and the concentrate was dissolved in 700 ml of ethylacetate, followed by suction filtration and vacuum concentration, finally yielding 194.4 g of (S)-2-p-toluenesulfonyloxy-l,4- butanediol (yield 87%): Η-NMR(D₂0, ppm) δl.65(m, 2H), 2.24(s, 3H), 3.25-

3.49(m, 4H), 4.52(m, 1H), 7.27(d, 2H), 7.63(d, 2H)

EXAMPLE 4: Preparation of (R)-3,4-Epoxy-l-Butanol Into a 2 L reactor, 2-methanesulfonyloxy-l,4-butanediol (173 g, 0.94 mol) and 1 L of methanol were added and dissolved, after that anhydrous K₂C0₃ (129.9 g, 0.94 mol) was added and agitated for 4 hr at room temperature. After the completion of reaction, the reaction mixture was filtered under reduced pressure and methanol was evaporated under vacuum for concentration. The concentrate was dissolved in 1 L of dichloromethane and washed with 100 ml of saturated brine, thereby obtaining dichloromethane layer. In addition, the layer of saturated brine was extracted twice with 600 ml of dichloromethane and the dichloromethane layers obtained were combined, followed by concentration under vacuum to yield the compound of interest as residue. Following the distillation at 65 ^°C under 3 torr, 74.5 g of the compound of interest was yielded as a purified form (yield 90%): Η-NMR(CDC1_3/ ppm) δl.74(m, 1H), 1.89(br, 1H), 2.00(m, 1H), 2.61(m, 1H), 2.82(t, 1H), 3.12(m, 1H), 3.83(t, 2H)

EXAMPLE 5: Preparation of (R)-3,4-Epoxy-l-Butanol The same procedure as Example 4 was carried out except (S)-2-p- toluenesulfonyloxy-l,4-butanediol (160 g, 0.61 mol) as a starting material instead of 2-methanesulfonyloxy-l,4-butanediol. 47.7 g of (R)-3,4-epoxy-l-butanol were given (yield 88%): Η-NMRfCDCls, ppm) δl.74(m, 1H), 1.89(br, 1H), 2.00(m, 1H), 2.61 (m, 1H), 2.82(t, 1H), 3.12(m, 1H), 3.83(t, 2H)

The present invention relates to a process for preparing (R)-3,4-epoxy-l- butanol readily in high yield and cost-effective manner, performed in such a manner that (S)-3-alkyl or arylsulfonyloxy-butyrolactone as a starting material is reduced under mild condition to give 2-alkyl or arylsulfonyloxy-l,4-butanediol as intermediate, and then the intermediate is epoxidized in the presence of a base to invert a chiral center.

Therefore, the present invention allows mass production of (R)-3,4-epoxy-l- butanol in high yield and easy manner. In this regard, this invention is much more effective than the conventional processes in view of production of (R)-3,4- epoxy-1-butanol in industrial scale.

Claims

CLAIMSWHAT IS CLAIMED IS:

1. A process for preparing (R)-3,4-epoxy-l-butanol, which comprises the steps of: (a) reducing (S)-3-alkyl or arylsulfonyloxy-butyrolactone represented by the following formula (II) to give 2-sulfonyloxy-l,4-butanediol represented by the following formula (III) as an intermediate; and

(b) epoxidizing said intermediate represented by the following formula (III) in the presence of a base to invert a chiral center, whereby (R)-3,4-epoxy-l- butanol represented by the following formula (I) is produced:

wherein R represents an alkyl, an aryl or a substituted aryl group having

1-12 carbon atoms.

2. The process according to claim 1, wherein said reducing reaction is performed by using a boron metal compound as a reducing agent

3. The process according to claim 2, wherein said reducing reaction is performed by using said boron metal compound as a reducing agent selected from the group consisting of NaBH₄ and Ca(BH₄)₂.

4. The process according to claim 1, wherein said reducing reaction is performed at a temperature ranging from -10 to 40 TJ .

5. The process according to claim 1, wherein said epoxidizing reaction is performed at a temperature ranging 0 to 50 ^°C .