KR20000065995A - A process for preparing chiral 3-hydroxy-gamma-butyrolacton - Google Patents

Abstract

PURPOSE: A process for producing 3-hydroxy-γ-butyrolactones by halogenating chiral 3,4-epoxybutyric acid or its salt using water in place of an expensive solvent and cyclization without any special purification processes in one reactor is provided which produces 3-hydroxy-γ-butyrolactones in high yield and any low cost. CONSTITUTION: Chiral 3,4-epoxybutyric acid or its salt of formula 2 is halogenated and cycled in the presence of a water solvent to give 3-hydroxy-γ-butyrolactones of formula 1. In the halogenation, a halogenating agent alone or a mixture of the halogenating agent and acid are used in which the halogenating agent is halogen acid selected from chloric acid, bromic acid, or halogenated alkali metal salt selected from sodium chloride, sodium bromide, sodium iodide, potassium chloride and potassium bromide. In formula, a chiral center (*) represents (R)- or (S)-; M is hydrogen ion, metal ion or organic amine; X is a halogen atom.

Description

Process for preparing chiral 3-hydroxy-gamma-butyrolacton

The present invention relates to a method for preparing chiral 3-hydroxy-γ-butyrolactone represented by the following Chemical Formula 1, and more specifically, to a chiral 3,4-epoxybutyric acid or a salt thereof as a raw material, The present invention relates to a method for economically preparing chiral 3-hydroxy-γ-butyrolactone by carrying out a cyclization reaction.

Formula 1

Chiral 3-hydroxy-γ-butyrolactone is a useful chiral intermediate used in the preparation of chiral compounds for various uses. Examples of the compound synthesized using chiral 3-hydroxy-γ-butyrolactone as an intermediate are as follows: Aplysistatin, a natural product having an anticancer effect; Shieh, H., Prestwich, G. D., Tetrahedron Letters, (1982) 23, 4643, Multistriatin, a group of insect pheromones; Larcheveque, M., Henrot, S., Tetrahedron, (1987) 43, 2303], β-lactam antibiotics (Japanese Patent Laid-Open No. 64-13,069 (1989)), as intermediates of HMG-CoA reductase inhibitors for the treatment of hyperlipidemia 5,6-dihydroxy-3-keto-hexyl acid used (Japanese Patent Laid-Open No. 4-173,767 (1992)).

On the other hand, as a well-known manufacturing method of manufacturing a chiral 3-hydroxy- (gamma) -butyrolactone, there exist the following methods.

Although a method of preparing in two steps from dimethylmalic acid has been reported [Chemistry Letters, (1984) 1389], expensive and difficult to handle reagents such as borolein, sodium borohydride, trifluoroacetic acid, etc. have been reported. In addition, it has a disadvantage in that an anhydrous organic solvent must be used, and thus has a disadvantage in that it is difficult to mass produce industrially.

Synthesis (1987) 570 has been reported to produce a multistage from L-ascorbic acid or D-isoascovinic acid, but has a disadvantage in that the total yield is low, multistage, and an organic solvent must be used.

Although a method for producing inexpensive caustic soda and hydrogen peroxide from polysaccharides (US Pat. No. 5,292,939 (1994)) has been reported, only (S) -3-hydroxy-γ-butyrolactone is produced due to the nature of the raw materials used. It has a disadvantage.

In addition, there has been reported a method of preparing by reacting D-carnitine under a polar organic solvent at a high temperature of about 150 ° C. for several hours (US Pat. No. 5,714,619 (1998)).

In the present invention, research efforts have been made to develop a method for producing chiral 3-hydroxy-γ-butyrolactone economically using a cheap reagent, and as a result, halogenated chiral 3,4-epoxybutyric acid or salts thereof in an aqueous solvent. The present invention was completed by preparing the chiral 3-hydroxy-γ-butyrolactone more easily and economically by performing the reaction and the cyclization reaction in one reactor without additional purification.

The present invention is very economical because water is used as a solvent in place of the expensive organic solvent used in the conventional manufacturing method, inexpensive reagents are used, and various reactions are continuously performed in one reactor without a separate purification process. Such a method for preparing a chiral 3-hydroxy-γ-butyrolactone derivative of the present invention has not been attempted in the literature to date.

Accordingly, an object of the present invention is to provide a method for preparing chiral 3-hydroxy-γ-butyrolactone in high yield using cheap compounds without using expensive or difficult to handle compounds.

The present invention provides a 3-hydroxy-γ-butyrolactone represented by the following Chemical Formula 1 by halogen addition and cyclization of chiral 3,4-epoxybutyric acid or a salt thereof in an aqueous solvent. The method is characterized by that.

Formula 1

In the above formulas: chiral center (*) represents (R) -form or (S) -form; M is hydrogen ion, metal ion, organic amine, or the like; X represents a halogen atom.

Referring to the present invention in more detail as follows.

The present invention is very economical to produce chiral 3-hydroxy-γ-butyrolactone by continuously carrying out halogenation and cyclization reaction using chiral 3,4-epoxybutyric acid or a salt thereof as a raw material. It relates to a novel manufacturing method.

Chiral 3,4-epoxybutyric acid represented by the formula (2) used as a starting material in the present invention can be prepared by a variety of methods, looking at representative methods as follows.

Method of preparing an epoxy group through an asymmetric epoxidation reaction followed by an oxidative reaction. Org. Chem., Vol. 49, 3707-3711 (1984)], and another method is to prepare a racemic 3,4-epoxybutyric acid ester by a chemical method and then optically divide it by (R) -3 having a desired chiral center. A method for selectively obtaining 4,4-epoxybutyric acid ester [Helvetica Chimica Acta, vol. 70, 142-152 (1987); European Patent No. 237,983 (1987). In addition, the applicant has recently reported a method for preparing a salt of chiral 3,4-epoxybutyric acid whose chiral center is reversed from chiral 3-activated hydroxy-γ-butyrolactone [PCT / KR 98/00166.

In the present invention, a salt of chiral 3,4-epoxybutyric acid prepared by the method mentioned in PCT / KR 98/00166 is mainly used as a starting material, and the type of cation (M) is also existing patent PCT / As mentioned in KR 98/00166, a representative cation is sodium ion.

Scheme 1 below briefly illustrates a method for preparing chiral 3-hydroxy-γ-butyrolactone according to the present invention.

In Scheme 1: chiral center (*) represents (R) -form or (S) -form; M is derived from the reaction step of preparing the raw material 3,4-epoxybutyric acid and represents hydrogen ions, metal ions, organic amines, and the like; X represents the halogen atom derived from the halide used for halogenation reaction.

In the preparation method of the present invention according to Scheme 1, the halogen addition reaction of 3,4-epoxybutyric acid or a salt thereof represented by Chemical Formula 2 and 4-halo-3-hydroxybutyric acid represented by Chemical Formula 3 synthesized as an intermediate It consists of a cyclization reaction.

This halogen addition reaction and cyclization reaction are carried out in one reactor (one-pot reaction). In order to perform the halogen addition reaction of this invention, a halogenating agent is used individually, or a halogenating agent and an acid are used together. Specific examples of the halogenating agent include various halogenated alkali metal salts such as sodium chloride, sodium bromide, sodium iodide, potassium chloride, potassium bromide and the like; Various halogen acids such as hydrochloric acid, bromic acid, iodic acid and the like are included. According to the experimental results of the researchers, when using a halogenated alkali metal salt as a halogenating agent in the halogenation reaction, it is more preferable to use an acid together. In addition, concrete examples of the acid that can be used with the halogenating agent include inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid; Organic acids such as acetic acid, propionic acid, butyric acid, fumaric acid, formic acid, tartaric acid, lactic acid, malic acid, oxalic acid, citric acid, methanesulfonic acid, toluenesulfonic acid and camphorsulfonic acid.

The cyclization reaction according to the invention proceeds continuously after the halogen addition reaction described above. In the above halogenation reaction, when the halogenating agent is combined with an acid and the acid used is a weak acid of pK 4.5 or more, the cyclization reaction proceeds continuously after the halogenation reaction, whereas the acid used in the halogenation reaction is a strong acid of pK 4.5 or less. In this case, it is preferable to add a small amount of base in order to perform a more smooth cyclization reaction. Specific examples of the base that can be used in the cyclization reaction include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate and sodium bicarbonate; Various organic bases such as sodium acetate, potassium acetate, triethylamine, and the like. The base is preferably used in an amount of 1.0 equivalent less than the amount of acid used in the halogenation reaction. When the excess base is used, 3-hydroxy-γ-butyrolactone, which is a final substance, is formed by the base. This is because the yield is lowered due to decomposition.

Looking at the specific example of the reaction according to the present invention as described above are as follows.

3.0 equivalents of bromic acid was added to an aqueous solution of sodium salt of 3,4-epoxybutyric acid and stirred at room temperature for 1 hour, followed by nuclear magnetic resonance analysis. As a result, 4-bromo-3-hydroxybutyric acid was confirmed to be formed with a conversion rate of 90% or more. Could. Subsequently, 2.0 equivalents of sodium bicarbonate were added to the reaction solution, and stirred for 1 hour. Nuclear magnetic resonance analysis showed that 4-bromo-3-hydroxybutyric acid was almost quantitatively converted to 3-hydroxy-γ-butyrolactone. I could confirm it. After distillation under reduced pressure to remove water from the reaction solution, the mixture was extracted twice with ethyl acetate solvent, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography to obtain pure 3-hydroxy-γ-buty in 81% yield. Lactone could be obtained.

In addition, even when 2.0 equivalents of sodium acetate was used as the base in the reaction, pure 3-hydroxy-γ-butyrolactone was obtained in a similar yield.

On the other hand, unlike the reaction described above, halogenated compounds such as neutral sodium iodide, sodium bromide, sodium chloride, etc. are used instead of strong acids such as bromic acid, using acetic acid which is a weak acid, and instead of strong acidic halogen acids such as bromic acid and hydrochloric acid as halogenating agents. When the alkali metal salt is used, it can be observed that the halogenation reaction and the cyclization reaction proceed continuously without using a base separately, which is considered to be due to the generation of sodium acetate as a base after the halogenation reaction as follows.

The reaction iodide (I ^-), bromide (Br ^-), chloride (Cl ^-) in order to was the reaction rate to determine the faster of which is determined to be due to the nucleophilic ease Castle strength and release resistance of halogen ions do.

For example, 1.0 equivalent of sodium iodide and 2.0 equivalents of acetic acid were added to an aqueous solution of sodium salt of 3,4-epoxybutyric acid, and stirred at 30 ° C. for 3 hours, followed by nuclear magnetic resonance analysis. It was confirmed that oxy-γ-butyrolactone was formed. After distillation under reduced pressure to remove water from the reaction solution, the mixture was extracted twice with ethyl acetate solvent, and the solvent was distilled off under reduced pressure to remove the solvent, and then purified by column chromatography to obtain pure 3-hydroxy-γ-buty in 85% yield. Lactone could be obtained. In addition, even when sodium bromide or sodium chloride was used instead of sodium iodide, the reaction rate was relatively slow, but 3-hydroxy-γ-butyrolactone was obtained in high yield.

As described above, the preparation of chiral 3-hydroxy-γ-butyrolactone according to the present invention is carried out using a halogenation reaction and a cyclization reaction using chiral 3,4-epoxybutyric acid or a salt thereof represented by Chemical Formula 2 as a raw material. It can be seen that it is carried out in turn, but in the aqueous solution state without the need for a separate purification process continuously carried out in one reactor to produce industrially useful chiral 3-hydroxy-γ-butyrolactone.

When the present invention is described in more detail based on the following examples, the present invention is not limited thereto.

Example 1 Preparation of (S) -3-methanesulfonylhydroxybutyrolactone

(S) -3-hydroxy-γ-butyrolactone (10.2 g, 0.10 mol), methanesulfonyl chloride (13.7 g, 0.12 mol) and dichloromethane (150 mL) were placed in a 250 mL reactor. 50% triethylamine-dichloromethane solution (22.2 g, 0.11 mol) was added dropwise at 1 ° C for 1 hour. Stir for an additional 30 minutes. The reaction solution was extracted twice with saturated NaCl solution (70 mL) to remove salts, the dichloromethane solution was dried over magnesium sulfate and filtered, and the solvent was concentrated slowly under reduced pressure using a reduced pressure distillation to give a solid. The obtained solid was recrystallized from dichloromethane and isopropanol, and the crystals were filtered and dried to obtain pure (S) -3-methanesulfonylhydroxybutyrolactone (17.1 g, 95% yield).

¹ H-NMR (acetone-d ₆ , ppm) δ2.7-3.2 (m, 2H, -CH ₂ CO-), 3.2 (s, 3H, CH ₃ SO _3- ), 4.5-4.8 (m, 2H, O-CH ₂ CH (OMs)-), 5.5-5.6 (m. 1H, O-CH ₂ CH (OMs)-); ¹³ C-NMR (acetone-d ₆ , ppm) δ 35.31 (-CH ₂ CO-), 37.97 (CH ₃ SO _3- ), 73.41 (-CH ₂ CH (OMs)-), 77.39 (O-CH ₂ CH (OMs)-), 174.45 (-CH ₂ CO-)

Example 2 Preparation of (S) -4-hydroxy-3-methanesulfonylhydroxybutyric acid

(S) -3-methanesulfonylhydroxybutyrolactone (1.0 g, 5.6 mmol), D ₂ O (10 mL) and methanesulfonic acid (0.538 g, 5.6 mmol) were placed in a 25 mL reactor, and then at 45 ° C. Stir for 2.5 hours. The reaction solution was cooled to room temperature and extracted twice with dichloromethane (10 mL) to recover unreacted (S) -3-methanesulfonylhydroxybutyrolactone. It was confirmed using nuclear magnetic resonance analysis that the desired (S) -4-hydroxy-3-methanesulfonylhydroxybutyric acid was present in a very pure state in the D ₂ O layer.

¹ H-NMR (D ₂ O, ppm) δ 2.6 to 2.8 (m, 2H, -CH ₂ CO ₂ H), 3.1 (s, CH ₃ SO _3- ), 3.6 to 3.9 (m, 2H, HOCH ₂ -9, 4.9 to 5.1 (m, 1H, -CH (OMs)-); ¹³ C-NMR (D ₂ O, ppm) δ 36.27 (-CH ₂ CO ₂ H), 38.15 (CH ₃ SO _3- ), 62.94 (-CH (OMs)-), 80.81 (HOCH _2- ), 174.04 (-CH ₂ CO ₂ H)

Example 3: Preparation of (R) -3,4-epoxybutyrate sodium salt

To a reaction solution containing (S) -4-hydroxy-3-methanesulfonylhydroxybutyric acid (3.9 mmol) obtained in Example 2 was added 3N aqueous sodium hydroxide solution (4.43 ml, 13.3 mmol), and then at room temperature. Stir for 10 minutes. It was confirmed by nuclear magnetic resonance analysis that the desired (R) -3,4-epoxybutyric acid sodium salt was present in a very pure state in the reaction solution.

¹ H-NMR (D ₂ O, ppm) δ 2.3 to 2.5 (m, 2H, CH ₂ -CO ₂ Na), 2.6 to 2.9 (m, 2H), 3.2 to 3.3 (m, 1H); ¹³ C-NMR (D ₂ O, ppm) δ 40.87 (-CH ₂ -CO ₂ Na), 48.24 (4-CH ₂ ), 51.08 (3-CH), 179.41 (-CO ₂ Na)

Example 4: Preparation of (R) -3,4-epoxybutyrate calcium salt

Calcium hydroxide (518 mg, 7.0 mmol) was added to the D ₂ O reaction solution containing (S) -4-hydroxy-3-methanesulfonylhydroxybutyric acid prepared in Example 2, followed by stirring at room temperature for 30 minutes. It was. It was confirmed by nuclear magnetic resonance analysis that the desired calcium salt (R) -3,4-epoxybutyrate was present in the reaction solution layer.

¹ H-NMR (D ₂ O, ppm) δ 2.3 to 2.4 (m, 2H, CH ₂ -CO ₂ Ca), 2.5 to 2.8 (m, 2H), 3.2 to 3.3 (m, 1H, 3-H) ; ¹³ C-NMR (D ₂ O, ppm) δ 40.78 (-CH ₂ -CO ₂ Ca), 48.23 (4-CH ₂ ), 51.05 (3-CH), 179.52 (-CO ₂ Ca)

Example 5: Preparation of (R) -3,4-epoxybutyric acid triethylamine salt

Triethylamine (1.35 g, 13.5 mmol) was added to the D ₂ O reaction solution containing (S) -4-hydroxy-3-methanesulfonylhydroxybutyric acid prepared in Example 2, followed by 30 at room temperature. Stir for minutes. It was confirmed by nuclear magnetic resonance analysis that the desired (R) -3,4-epoxybutyric acid triethylamine salt was present in the reaction solution layer.

¹ H-NMR (D ₂ O, ppm) δ 2.2 to 2.4 (m, 2H, CH ₂ -CO ₂ HNEt ₃ ), 2.5 to 2.8 (m, 2H), 3.1 to 3.2 (m, 1H, 3-H ); ¹³ C-NMR (D ₂ O, ppm) δ 40.94 (-CH ₂ -CO ₂ HNEt ₃ ), 48.15 (4-CH ₂ ), 51.04 (3-CH), 178.97 (-CO ₂ HNEt ₃ )

Example 6 Preparation of (R) -3-hydroxy-γ-butyrolactone

(S) -3-methanesulfonylhydroxybutyrolactone (10.0 g, 55.6 mmol), water (100 mL) and methanesulfonic acid (5.38 g, 55.6 mmol) were added to a 250 mL reactor, and then 2.5 hours at 45 ° C. Was stirred. The reaction solution was cooled to room temperature and then extracted twice with dichloromethane (50 mL) to recover unreacted (S) -3-methanesulfonylhydroxybutyrolactone (2.99 g, 16.6 mmol). To a solution containing (S) -4-hydroxy-3-methanesulfonylhydroxybutyric acid (39.0 mmol) was added 3N aqueous sodium hydroxide solution (44.7 mL, 134 mmol), followed by stirring at room temperature for 10 minutes (S An aqueous solution containing the sodium salt of) -3,4-epoxybutyric acid was obtained.

48% aqueous bromic acid solution (19.7g, 117mmol) was added to the aqueous solution, followed by stirring at room temperature for 1 hour, sodium bicarbonate (6.5g, 77.4mmol) was added thereto, followed by further stirring for 1 hour to remove water by distillation under reduced pressure, and ethyl acetate (80ml Extracted twice), the extract was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography to give pure (R) -3-hydroxy-γ-butyrolactone (3.22 g, 81% yield).

¹ H-NMR (CDCl ₃ , ppm) δ 2.4 to 2.5 (d, 1H, CH ₂ -CO), 2.6 to 2.8 (m, 1H, CH ₂ -CO), 4.2 to 4.3 (d, 1H, -OCH _{2 -), 4.4~4.5 (m,} 1H, -OCH 2 -), 4.6~4.7 (m, 1H, -CH (OH) -); ¹³ C-NMR (CDCl ₃ , ppm) δ 37.74 (CH ₂ -CO), 67.37 (-CH (OH)-), 76.25 (-OCH _2- ), 176.9 (-CO-)

Example 7 Preparation of (R) -3-hydroxy-γ-butyrolactone

In the same manner as in Example 6 to obtain an aqueous solution containing the sodium salt of (S) -3,4-epoxybutyric acid, sodium iodide (5.85 g, 39.0 mmol) and acetic acid (4.68 g, 77.9 mmol) After addition and stirring at 30 ° C. for 3 hours, the resultant was worked up and purified in the same manner as in Example 6 to obtain pure (R) -3-hydroxy-γ-butyrolactone (3.38 g, yield 85%).

Example 8 Preparation of (R) -3-hydroxy-γ-butyrolactone

In the same manner as in Example 6 to obtain an aqueous solution containing the sodium salt of (S) -3,4-epoxybutyric acid, sodium bromide (24.1 g, 234 mmol) and acetic acid (3.51 g, 58.5 mmol) were added thereto. After stirring at 35 ° C. for 6 hours, work up and purification were carried out in the same manner as in Example 6 to obtain pure (R) -3-hydroxy-γ-butyrolactone (3.18 g, yield 80%).

The method for preparing chiral 3-hydroxy-γ-butyrolactone according to the present invention uses an inexpensive compound in an aqueous solution, and is very industrially useful because the preparation method is simple and can be continuously performed in one reactor. .

Claims (9)

Next, 3-hydroxy-γ-butyrolactone represented by the following Chemical Formula 1, which is prepared by halogenation and cyclization of chiral 3,4-epoxybutyric acid or a salt thereof in an aqueous solvent. Manufacturing method. Formula 2 Formula 1 In the above formulas: chiral center (*) represents (R) -form or (S) -form; M is hydrogen ion, metal ion or organic amine; X represents a halogen atom. The method for producing 3-hydroxy-γ-butyrolactone according to claim 1, wherein the halogenation reaction comprises a halogenating agent alone or a halogenating agent and an acid in combination. 3. The chiral halogen compound according to claim 2, wherein the halogenating agent is a halogen acid selected from hydrochloric acid, bromic acid and iodic acid or a halogenated alkali metal salt selected from sodium chloride, sodium bromide, sodium iodide, potassium chloride and potassium bromide. Method for preparing 3-hydroxy-γ-butyrolactone. [Claim 3] The 3-hydroxy- [gamma] -butyrolactone according to claim 1, wherein a halogenated reaction and a cyclization reaction are performed at a time by adding a halogenated alkali metal salt and a weak acid of pK 4.5 or more to the compound represented by Formula 2. Manufacturing method. 5. The method of claim 4, wherein the weak acid having a pK of at least 4.5 is selected from acetic acid, propionic acid, and butyric acid. 6. According to claim 1 or 2, wherein after the halogen addition reaction using a halogenating agent and a strong acid of less than pK 4.5 in combination with the compound represented by the formula (2), a base is added to perform a cyclization reaction Method for producing 3-hydroxy-γ-butyrolactone. The chiral 3-hydride according to claim 6, wherein the strong acid of less than pK 4.5 is selected from tartaric acid, lactic acid, malic acid, oxalic acid, citric acid, fumaric acid, methanesulfonic acid, toluenesulfonic acid, sulfuric acid, phosphoric acid and hydrochloric acid. Method for preparing oxy-γ-butyrolactone. The method of claim 6, wherein the base is selected from sodium carbonate, sodium bicarbonate, sodium hydroxide, and sodium acetate. The method of claim 7 or 8, wherein the base is used in an amount of less than 1 equivalent based on the amount of acid used.