KR100910645B1 - Process for (R_-3,4-Epoxybutyric acid salt/(R)-3,4-Epoxybutyric acid - Google Patents

Abstract

The present invention is to prepare (R) -3-hydroxy-gamma-butyrolactone by using the racemic 3-acyloxy-gamma-butyrolactone as a raw material or to obtain an alkyl (R)- (R) -3-hydroxy-gamma-butyrolactone was prepared by hydrolysis from 4-chloro-3-hydroxybutyrate, followed by halogen from (R) -3-hydroxy-gamma-butyrolactone. (R) -3-acyloxy-4-halobutyl acid represented by the general formula (5) was prepared through a ring-opening reaction using an acid and a carboxylic acid, and the (R) -3-acyloxy-4-halobutyl acid was prepared. (R) -3,4-epoxybutyl acid and its salts are prepared by carrying out an epoxidation in the presence of a base.

3-hydroxy-gamma-butyrolactone, 3-acyloxy-gamma-butyrolactone, enzyme, hydrolysis reaction, optical activity, ring opening reaction, epoxy reaction, (R) -3-acyloxy-4-halobutyl Acid, (R) -3-acetoxy-4-bromobutyl acid, (R) -3,4-epoxybutyl acid

Description

Process for preparing (al) -3,4-epoxybutyric acid and salts thereof {Process for (R_-3,4-Epoxybutyric acid salt / (R) -3,4-Epoxybutyric acid}

The present invention relates to a method for producing (R) -3,4-epoxybutyl acid and salts thereof, and more particularly, by improving the manufacturing process of (R) -3-hydroxy-gamma-butyrolactone. The present invention relates to a method for producing (R) -3,4-epoxybutyl acid and its salts, which are capable of providing this simple, high optical purity raw material.

Carnitine contains an asymmetric center and there are two stereo enantiomers of L-carnitine and D-carnitine. One of these isomers, L-carnitine, is an essential part of fatty acid metabolism in the human body and transports fatty acids through cell membranes. It is a natural product that plays a key role in and is being used to improve energy metabolism and heart function. L-carnitine and its derivatives are also used as serum lipid lowering agents, anticonvulsants and blood product supplements.

Although D, L-carnitine racemate has been used in various applications of medicines and food additives, D-carnitine is known to play a competitive interfering role in the physiological role of L-carnitine in vivo. Therefore, much research on the production of L-carnitine has been conducted.

The prior art related to the production of L-carnitine may be as follows.

First, L-tartaric acid (European Patent No. 157,315), dibenzyl-D-tartaric acid (U.S. Patent No. 4,933,490), Dibenzoyl-L-Tartic Acid (US Patent No. 4,610,828), Optical resolution reagents such as D-mandelic acid (Japanese Patent No. 59-231,048) and N-acetyl-D-glutamate (Japanese Patent No. 1-31,143). Isomers are used to form isomers from racemates of D, L-carnitine or derivatives thereof, and then only the isomers of the desired type are obtained by using the difference in solubility in a suitable solvent. There is a way to get it. However, the above manufacturing method is not easy to recrystallization process, using an expensive optical splitting agent has a disadvantage of high unit cost.

Second, there is a method of obtaining L-carnitine by stereospecific hydration of crotonobetain or gamma-butyrobetain using microorganisms or enzymes (US Pat. No. 4,708,936, US Pat. No. 4,371,618). , U.S. Patent 4,650,759.

Third, there is a method of preparing (R) -4-chloro-3-hydroxybutyrate by reducing 4-chloro-3-oxobutyrate and synthesizing L-carnitine therefrom. In this case, microorganisms may be used for the reduction reaction, in which case a coenzyme is required and involves the process of culturing the microorganisms (Journal of American Chemical Society, 1985,107,4028-4031). Alternatively, L-carnitine may be prepared by a general method after synthesizing (R) -4-chloro-3-hydroxybutyrate derivative from 4-chloro-3-oxobutyrate derivative by stereoselective reduction reaction of ruthenium catalyst. (US Pat. No. 4,895,979, EP-A-339764, Tetahedron Letters, 1998, 29: 1555). However, the above method has a disadvantage in that the preparation cost of the (R) -4-chloro-3-hydroxybutyrate derivative is expensive and the reaction must be performed at high hydrogen pressure.

Fourth, there is a method for producing L-carnitine from chiral raw materials easily obtained from natural products. L-carnitine can be prepared through several reaction steps using D-mannitol as a raw material (US Pat. No. 4,413,142). However, the reaction step is complicated and heavy metals such as tetraacetyl lead are used. In addition, a method for preparing L-carnitine from D- (R) -tartrate is known (Tetrahedron Letters, 31, 7323-7326,1990), but in this case, the manufacturing process is long and very complicated.

Fifth, a method of preparing a three-dimensional pure compound as a starting material. (S) -3-hydroxy-gamma-butyrolactone as a starting material, ring opening, epoxy reaction including reversed chiral center, and nucleophilic substitution of trimethylamine -There is a method for producing carnitine (Korean Patent No. 0255039). In addition, there is a ring-opening reaction using trimethylamine using (R) -epibromohydrin, and a method of preparing by continuously reacting acetonitrile and crown ether under acidic conditions (Korea Patent Publication 10-2005-0010203). However, the above method has a problem that the three-dimensional pure starting material is expensive, and thus is not a useful process.

* Despite such studies, it is difficult to maintain high yields and high optical purity, and it is difficult to apply them to actual processes due to complicated processes or high manufacturing costs due to high temperature and high pressure reactions.

In the production of L-carnitine, the raw material of the process for preparing L-carnitine through ring-opening reaction and epoxy reaction from (S) -3-hydroxy-gamma-butyrolactone described above (Korean Patent No. 0255039) Since it is a substance having a (S) coordination, which is the opposite of the coordination of the (R) form of L-carnitine, a reverse conversion process of the chiral center is necessary during the manufacturing process. To this end, the hydroxy group of (S) -3-hydroxy-gamma-butyrolactone is activated, and then ring-opening reaction is performed in the presence of an acid. Only about 63% of the ring-opening reactions are performed and the remaining 37% of the hydroxy group activating material is Epoxy reaction with base, the next reaction, is easily converted into unnecessary materials and must be separated in advance.

Korean Patent No. 032703 discloses a method for preparing (S) -3,4-epoxybutylate through ring-opening reaction and epoxy reaction using (S) -3-hydroxy-gamma-butyrolactone, but L Since it has a coordination with carnitine, it is not suitable as a raw material for producing L-carnitine.

Accordingly, the present inventors have prepared (R) -3-hydroxy-gamma-butyrolactone from racemic 3-acyloxy-gamma-butyrolactone by enzymatic method (Korean Patent Application No. 10-2005-0089119) (R) using an alkyl catalyst (Liebigs Ann. IRecueil, 1877-1879, 1997) or a resin catalyst (H + resin, Korean Patent Application No. 10-2005-0010927) in alkyl (R) -4-chloro-3-hydroxybutyrate ) -3-hydroxy-gamma-butyrolactone was prepared, and (R) -3-acyloxy-4-halobutyric acid was prepared by ring-opening reaction using carboxylic acid containing halogen acid and epoxidized in the presence of a base. A new method for preparing (R) -3,4-epoxybutyl acid was developed.

The present invention includes a process for preparing (R) -3-hydroxy-gamma-butyrolactone, wherein chiral centers in the existing process using (S) -3-hydroxy-gamma-butyrolactone are reversed. Since the epoxy compound can be manufactured as it is without a process, it is possible to establish a simpler manufacturing process. In addition, it is possible to prepare an intermediate of 99 ee% by the hydrolysis reaction using the enzyme, it is possible to produce L-carnitine of high optical purity.

The method for preparing (R) -3,4-epoxybutyl acid and salts thereof described in the present invention is economical by using low-cost reagents without using any reagents that are expensive or difficult to handle as compared with conventional manufacturing methods. The aim is to provide a new, simple and new method of manufacturing.

In order to achieve the above object, (R) -3,4-epoxybutyl acid and a method for preparing the salt thereof according to the present invention, (a) the alkyl represented by the general formula (4) in the following [Scheme 1] ( (R) -3-hydroxy-gamma-butyrolactone represented by the general formula (3) using an acid catalyst or a cation exchange resin catalyst in R) -4-chloro-3-hydroxybutyrate

(b) (R) -3-acyloxy-4-halobutyl acid represented by the general formula (5) through ring-opening reaction using halogen acid and carboxylic acid from (R) -3-hydroxy-gamma-butyrolactone Preparing a; And

(C) performing the epoxy reaction of the (R) -3-acyloxy-4-halobutyl acid in the presence of a base; characterized in that it comprises a.

[Scheme 1]

Here, the substituent R ₁ is an alkyl group having 1 to 8 carbon atoms substituted with a halogen compound, an alkyl group having 1 to 8 carbon atoms not substituted with a halogen compound, an alkenyl group having 1 to 8 carbon atoms substituted with a halogen compound, and not substituted with a halogen compound And an alkenyl group having 1 to 8 carbon atoms, a benzyl group, and a cycloalkyl group having 3 to 6 carbon atoms.The substituent R ₂ is a halogen group (F, Cl, Br, I) that facilitates the epoxidation reaction. And R ₃ represents an acyl group (COC _n H _{2n + 1} , n = 1 to 4), and substituent R ₄ represents an alkyl group having 1 to 8 carbon atoms.

As described above, the preparation method of (R) -3,4-epoxybutyl acid and its salt according to the present invention may be optically divided by enzymatic method using racemic 3-acyloxy-gamma-butyrolactone as a raw material. (R) -3-hydroxy-gamma-butyrolactone was prepared by hydrolysis from alkyl (R) -4-chloro-3-hydroxybutyrate, followed by ring-opening reaction, epoxy reaction, sulfuric acid, The reaction is carried out using cheap compounds such as sodium hydroxide, which is economical and industrially useful, and has been reported previously (R) -3,4-epoxybutyl acid and salts thereof.

Hereinafter, a method of preparing (R) -3,4-epoxybutylate / (R) -3,4-epoxybutyl acid according to an embodiment of the present invention will be described in detail with reference to [Scheme 1]. As follows.

(a) (R) -3-hydroxy-gamma-butyrolactone represented by General Formula (3) in the following [Scheme 1] was prepared. At this time, there are various methods for preparing (R) -3-hydroxy-gamma-butyrolactone, which will be described below.

(b) (R) -3-acyloxy-4-halobutyl acid represented by the general formula (5) through ring-opening reaction using halogen acid and carboxylic acid from (R) -3-hydroxy-gamma-butyrolactone To prepare.

(c) (R) -3,4-epoxybutylate or (R) -3,4-epoxybutyl acid by carrying out an epoxy reaction of (R) -3-acyloxy-4-halobutyl acid in the presence of a base. To prepare.

Here, the substituent R ₁ of (R) -3-acyloxy-gamma-butyrolactone represented by the general formula (2) is an alkyl group having 1 to 8 carbon atoms substituted with a halogen compound, and 1 to C carbon not substituted with a halogen compound. An alkyl group of 8, an alkenyl group of 1 to 8 carbon atoms substituted with a halogen compound, an alkenyl group of 1 to 8 carbon atoms unsubstituted with a halogen compound, a benzyl group, and a cycloalkyl group of 3 to 6 carbon atoms. In (R) -3-acyloxy-4-halobutyl acid represented by the general formula (5), the substituent R ₂ represents a halogen group (F, Cl, Br, I) which facilitates the epoxy reaction, and R ₃ represents The actual group (COC _n H _{2n + 1} , n = 1 to 4) is shown. In general formula (4), substituent R <_4> represents a C1-C8 alkyl group.

In addition, the method of preparing (R) -3-hydroxy-gamma-butyrolactone in the step (a) is as follows.

In the first method, an aqueous solution containing racemic 3-acyloxy-gamma-butyrolactone (3-acyloxy-gamma-butyrolactone) represented by the general formula (1) in the above [Scheme 1] or an aqueous solution containing a solvent (R) -3-hydroxy-gamma-butyrolactone is prepared by stereoselective hydrolysis with an enzyme in the phase.

As a second method, an aqueous solution containing racemic 3-acyloxy-gamma-butyrolactone represented by the general formula (1) in [Scheme 1] or an aqueous solution or solvent Stereoselective hydrolysis using an enzyme on the phase to obtain (R) -3-acyloxy-gamma-butyrolactone represented by formula (2) (R) -3-hydroxy-gamma-butyrolactone is prepared by decomposition.

As a third method, (R) -3- using an acid catalyst or a cation exchange resin catalyst in alkyl (R) -4-chloro-3-hydroxybutyrate represented by the general formula (4) in the above [Scheme 1] Hydroxy-gamma-butyrolactone is prepared.

Commercially prepared immobilized lipase CAL B (Novozyme 435, Novozyme) can be used in the preparation of the optically active intermediate through the stereoselective hydrolysis reaction, and PS-D (Amano) or these hydrolases can be used instead of this enzyme. Good results can be obtained by using strains containing the same.

In the ring-opening reaction, the halogen acid used includes hydrofluoric acid, hydrochloric acid, bromic acid and iodic acid, and the carboxylic acid uses an alkyl carboxylic acid having 1 to 4 carbon atoms containing acetic acid. The epoxidation reaction is carried out in a single solvent of water or a mixed solvent of water and an organic solvent using a base. Examples of the base used include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide; Alkaline earth metal hydroxides such as magnesium hydroxide, potassium hydroxide and barium hydroxide; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, and potassium t-butoxide; NHR ₅ R ₆ (where R ₅ And R ₆ is an alkylamine represented by each of 2 to 7 carbon atoms) or NH ₂ R ₇ (R ₇ is an alkyl group having 3 to 9 carbon atoms); tetrabutylammonium hydroxide and benzyltrimethylammonium hydroxide. It is used, selecting from quaternary amine hydroxides, such as a hydroxide.

(R) -3,4-epoxybutylate produced through the reaction or a product (R) -3,4-epoxybutyl acid, which is converted to acid by acidification, is added to an aqueous solution of triethylamine according to a known fact. It can be prepared from carnitine.

In the present invention, the reactants and products used in the reaction were identified by FT-NMR (Burker, Model DPX300), in particular 3-hydroxy-gamma-butyrolactone, 3-acyloxy-gamma-butyro Lactone, ethyl 4-chloro-3-hydroxybutyrate, and 3-acetoxy-4-bromobutyl acid were gas chromatographed with capillary column HP-FFAP (Agilent, 30 m X 0.53 mm) (Donan Instruments). 4, model DS6200). Optical purity of (R) -3-hydroxy-gamma-butyrolactone and (R) -3-acyloxy-gamma-butyrolactone is equipped with chiral column AD-H (Daicel, 0.446 cm x 25 cm) Hexane and isopropanol were flown at a rate of 90:10 at 0.7 ml / min per minute using an HPLC (LAB Alliance, Model 201), and analyzed under conditions of a UV absorbance of 220 nm. In addition, the optical purity of L-carnitine was dissolved in pure water at a concentration of 1% (w / v) and confirmed by a polarimeter (ATAGO, model AP-100).

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

Example 1. Preparation of 3-butoxy-gamma-butyrolactone (1)

30 g of racemic 3-hydroxy-gamma-butyrolactone was added to 300 ml of chloroform, 35 g of pyridine and 47 g of butyryl chloride were slowly added thereto while stirring at 0 ° C., followed by reaction at room temperature. After extraction into an organic layer, the product obtained by removing the solvent through distillation under reduced pressure was purified (33 g), and identified by nuclear magnetic resonance analysis to 3-butoxy-gamma-butyrolactone.

¹ H-NMR (300 MHz, CDCl ₃ ): 0.9 (t, 3H), 1.5-1.7 (dd, 2H), 2.2 ~ 2.3 (t, 2H), 2.5 ~ 2.9 (m, 2H), 4.3 ~ 4.5 ( m, 2H), 5.4 (m, 1H) ppm

Example 2. Preparation of (R) -3-hydroxy-gamma-butyrolactone (3)

To 0.2 M phosphate buffer (pH 7.0), racemic 3-butoxy-gamma-butyrolactone produced by the method of Example 1 was added to 5% (v / v) and CAL B lipase ( 0.2%) was used to carry out the reaction at 30 ° C. The reaction is carried out until the optical purity of (R)-3-butyloxy-gamma-butyrolactone according to the reaction becomes 99% (conversion rate 80%) and from the organic solvent layer through organic solvent layer separation (R)- 3-butoxy-gamma-butyrolactone was isolated and the butyl group was removed with sulfuric acid solution to give (R) -3-hydroxy-gamma-butyrolactone, 99 ee% of material according to the analytical method described above. It was confirmed that.

Example 3. Preparation of (R) -3-hydroxy-gamma-butyrolactone (3)

Ethyl (R) -4-chloro-3-hydroxybutyrate 5% (w / v) was added to the vial containing distilled water, Amberlite IR-120 was added to 5% (w / v), and the reaction was carried out at 60 ° C. Was performed. After the reaction for 32 hours, the reaction solution was extracted with ethyl acetate and analyzed. At this time, the conversion was 99%, and the optical purity of the produced (R) -3-hydroxy-gamma-butyrolactone was maintained at the optical purity of the substrate and the production rate was 99%.

Example 4. Preparation of (R) -3-acetoxy-4-bromobutyl acid (5)

6.6 g of (R) -3-hydroxy-gamma-butyrolactone and 30% bromic acid / acetic acid solution (20 ml) were mixed and reacted at 60 ° C. for 4 hours. After distillation under reduced pressure, the mixture was separated using methylene chloride and water to obtain a product (7.8 g) from the organic solvent layer.

¹ H-NMR (300 MHz, CDCl ₃ ): 2.08 (m, 3H), 2.83 (m, 2H), 3.53-3.74 (dd, 2H), 5.35 (m, 1H)

Example 5. Preparation of (R) -3,4-epoxybutyl acid (6)

3N NaOH was added dropwise to (R) -3-acetoxy-4-bromobutyl acid prepared in Example 4, followed by stirring for 2 hours to prepare (R) -3,4-butylate. Acidified to 3-4, followed by extraction with ethyl ether and distillation under reduced pressure to prepare (R) -3,4-epoxybutyl acid. (R) -3,4-epoxybutyl acid was analyzed by nuclear magnetic resonance analysis.

¹ H-NMR (300 MHz, CDCl ₃ ): 2.3 ~ 2.8 (m, 2H), 2.6 ~ 2.9 (m, 2H), 3.3 ~ 3.4 (m, 1H)

Claims (4)

(a) represented by the general formula (3) using an acid catalyst or a cation exchange resin catalyst in the alkyl (R) -4-chloro-3-hydroxybutyrate represented by the general formula (4) R) -3-hydroxy-gamma-butyrolactone (b) (R) -3-acyloxy-4-halobutyl acid represented by the general formula (5) through ring-opening reaction using halogen acid and carboxylic acid from (R) -3-hydroxy-gamma-butyrolactone Preparing a; And (c) carrying out an epoxidation of (R) -3-acyloxy-4-halobutyl acid in the presence of a base; (R) -3,4-epoxybutyl acid and salts thereof Manufacturing method. [Scheme 1]

Here, the substituent R ₁ is an alkyl group having 1 to 8 carbon atoms substituted with a halogen compound, an alkyl group having 1 to 8 carbon atoms not substituted with a halogen compound, an alkenyl group having 1 to 8 carbon atoms substituted with a halogen compound, and not substituted with a halogen compound And an alkenyl group having 1 to 8 carbon atoms, a benzyl group, and a cycloalkyl group having 3 to 6 carbon atoms.The substituent R ₂ is a halogen group (F, Cl, Br, I) that facilitates the epoxidation reaction. And R ₃ represents an acyl group (COC _n H _{2n + 1} , n = 1 to 4), and substituent R ₄ represents an alkyl group having 1 to 8 carbon atoms. The method of claim 1, The halogen acid used in the ring-opening reaction is selected from hydrofluoric acid, hydrochloric acid, bromic acid and iodic acid, and the carboxylic acid is an alkylcarboxylic acid having 1 to 4 carbon atoms containing acetic acid, (R) -3,4-epoxy. Butyric acid and its salt manufacturing method. The method of claim 1, The epoxy reaction is characterized by using water alone or a mixed solvent of water and an organic solvent in the presence of a base selected from alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal alkoxides, alkylamines and quaternary amine hydroxides. Method for producing 3,4-epoxybutyl acid and salts thereof. The method of claim 3, wherein The alkali metal hydroxide is selected from sodium hydroxide, potassium hydroxide and lithium hydroxide, The alkaline earth metal hydroxide is selected from magnesium hydroxide, potassium hydroxide and barium hydroxide, The alkali metal alkoxide is selected from sodium methoxide, sodium ethoxide and potassium t-butoxide, The alkylamine is NHR ₅ R ₆ (where R ₅ And R ₆ is each selected from an alkyl group having 2 to 7 carbon atoms) and NH ₂ R ₇ (R ₇ is an alkyl group having 3 to 9 carbon atoms), The quaternary amine hydroxide is selected from tetrabutyl ammonium hydroxide and benzyltrimethyl ammonium hydroxide, the method for producing (R) -3,4-epoxybutyl acid and salts thereof.