KR100449750B1 - Process for the preparation of racemic alkyl 4-chloro-3-hydroxy butyrate - Google Patents

Abstract

The present invention relates to a method for preparing alkyl 4-chloro-3-hydroxytyrate used as a core intermediate of oxacetam, and more particularly, using alkyl 4-chloroacetoacetate as a starting material, alkyl 4 In preparing -chloro-3-hydroxybutyrate, alkyl 4-chloro- represented by the following Chemical Formula 2 in high yield by reacting with alkyl 4-chloroacetoacetate in the presence of an organic acid with sodium borohydride activated It is to provide a method for producing 3-hydroxybutyrate inexpensively high yield.

In the formula, R is a lower alkyl group having 1 to 4 carbon atoms.

Description

Process for the preparation of racemic alkyl 4-chloro-3-hydroxy butyrate

The present invention relates to a method for preparing alkyl 4-chloro-3-hydroxybutyrate, which is used as a core intermediate of oxyracetam widely used as a memory enhancer. More specifically, alkyl 4-chloroacetoacetate, which has never been used in the preparation of 4-chloro-3-hydroxybutyric acid, is used as a starting material, and in the presence of an organic acid, alkyl is activated while sodium borohydride is activated. It relates to a method for producing alkyl 4-chloro-3-hydroxybutyrate represented by the following formula (2) in high yield by reacting 4-chloroacetoacetate.

The material represented by the formula (2) is an important intermediate for preparing oxacetam with no optical activity. Until now, a simple chemical method has not been known. There are several known methods for preparing (S) -oxyracetam having optical activity. have.

For example, International Patent Publication Nos. 93-06826 and Tetrahedron, Vol. 46, 4277 (1990), et al. (A) -3-hydroxybutyrolactone as a starting material, followed by an amination reaction and a ring reaction after iodine esterification. It is known to produce (S) -oxyracetam having optical activity by the oxidation reaction.

It is well known that racemic oxyracetam without optical activity has the effect of restoring the cognitive function of brain damaged by aging and various diseases in humans and animals [Banfi et al, Pharm Res. Commun. 16, 67, 1984 and Drug Development Res. 2, 447, 1984], and research on the manufacturing method has been actively conducted.

Representative manufacturing methods are well described in US Pat. Nos. 4,788,300, 4,124,594 and 4,797,496.

In such a conventional manufacturing method, the industrial process value is low due to the low utilization and the difficult reaction conditions as an economical manufacturing method using a long manufacturing process and expensive starting materials or reagents.

Accordingly, the inventors of the present invention have long conducted studies on the production of alkyl 4-chloro-3-hydroxybutyrate having high industrial value and high yield, and easily reduce the cheap ethyl 4-chloroacetoacetate to give alkyl 4 The present invention has been completed by developing a novel process for mass production of -chloro-3-hydroxybutyrate.

The method for preparing alkyl 4-chloro-3-hydroxybutyrate described in the present invention has not been attempted as a chemical conversion technique yet, and thus, its novelty and applicability can be said to be very leading.

The present invention provides a method for preparing alkyl 4-chloro-3-hydroxybutyrate, which is a key intermediate of oxracetam,

Reacting with alkyl 4-chloroacetoacetate of Formula 1 in the presence of an acid to activate sodium borohydride to produce alkyl 4-chloro-3-hydroxybutyrate of Formula 2 do.

In the formula, R is a lower alkyl group having 1 to 4 carbon atoms.

Organic acids used here include adipic acid, succinic acid, maleic acid, malic acid, tartaric acid, fumaric acid, glutaric acid, and the like.

The temperature for activating sodium borohydride in the presence of an acid is 50 ℃ to 110 ℃, when reacting it with alkyl 4-chloroacetoacetate, the reaction temperature is carried out in the temperature range of -35 ℃ to +45 ℃ but preferably It is recommended to perform at -20oC to + 25oC.

The reaction solvent is tetrahydrofuran (THF), toluene, xylene, ethylene glycol dimethyl ether, dioxane, dimethyl sulfoxide, diglyme, dimethyl formamide, acetonitrile and the like.

Although this invention is demonstrated in detail based on an Example, this invention is not limited by an Example.

Example 1

Sodium borohydride (8.34 g, 220 mmol), succinic acid (26 g, 220 mmol) and toluene (140 mL) were placed in a 250 mL three-necked flask equipped with a thermometer, a reflux cooler, and a stirrer. Heated to 90 ° C. and stirred for 4 h at the same temperature. After the reaction was completed, the reaction mixture was cooled to 10 ° C., ethyl 4-chloroacetoacetate (22 g, 133.7 mmol) was added dropwise, and stirred at 20 ° C. for 20 hours to complete the reaction.

Ethyl acetate (100 mL) was added to the reaction solution, and water (30 mL) was slowly added dropwise thereto. Then 5N-hydrochloric acid solution was added to adjust the pH to 6.0.

The organic layer was separated, dehydrated by adding anhydrous magnesium sulfate, filtered and concentrated. The concentrated residue was distilled under vacuum (5 mmHg) to obtain the target compound (16.1 g, 72.5%).

H1-NMR (CDCl3, ppm): 1.28 (t, 3H), 2.55-2.70 (m, 2H), 3.17 (br, 1H), 3.55-3.65 (m, 2H), 4.18 (q, 2H), 4.20- 4.30 (m, 1 H).

Boiling Point: 88 ℃-91 ℃ / 5mmHg

Example 2.

Into a 250 ml three-necked flask equipped with a thermometer, a reflux cooler, and a stirrer were added sodium borohydride (4.1 g, 108.37 mmol), DL-malic acid (15.7 g, 117 mmol), and tetrahydrofuran (105 ml). Heated to 66 ° C. and stirred for 4 h at the same temperature. After the reaction was completed, the mixture was cooled to -10 ° C, ethyl 4-chloroacetoacetate (17.6 g, 106.4 mmol) was added dropwise, and stirred at the same temperature for 18 hours to complete the reaction.

Ethyl acetate (200 mL) was added to the reaction solution, and water (40 mL) was slowly added dropwise thereto. Then 5N-hydrochloric acid solution was added to adjust the pH to 6.0.

The organic layer was separated, dehydrated by adding anhydrous magnesium sulfate, filtered and concentrated. The concentrated residue was distilled under vacuum (5 mmHg) to obtain the target compound (14.7 g, 82.5%).

H1-NMR (CDCl3, ppm): 1.28 (t, 3H), 2.55-2.70 (m, 2H), 3.17 (br, 1H), 3.55-3.65 (m, 2H), 4.18 (q, 2H), 4.20- 4.30 (m, 1 H).

Boiling Point: 88 ℃-91 ℃ / 5mmHg

Example 3.

Into a 250 ml three-necked flask equipped with a thermometer, a reflux cooler, and a stirrer were placed sodium borohydride (3.1 g, 81.9 mmol), DL-tartrate (11 g, 73.29 mmol), and tetrahydrofuran (105 ml). Heated to 66 ° C. and stirred for 4 h at the same temperature. After the reaction was completed, the reaction mixture was cooled to −10 ° C., ethyl 4-chloroacetoacetate (10.2 g, 68 mmol) was added dropwise, and stirred at 10 ° C. for 15 hours to complete the reaction.

Ethyl acetate (200 mL) was added to the reaction solution, and water (40 mL) was slowly added dropwise thereto. Then 5N-hydrochloric acid solution was added to adjust the pH to 6.0.

The organic layer was separated, dehydrated by adding anhydrous magnesium sulfate, filtered and concentrated. The concentrated residue was distilled under vacuum (5 mmHg) to obtain the target compound (9.7 g, 90%).

H1-NMR (CDCl3, ppm): 1.28 (t, 3H), 2.55-2.70 (m, 2H), 3.17 (br, 1H), 3.55-3.65 (m, 2H), 4.18 (q, 2H), 4.20- 4.30 (m, 1 H).

Boiling Point: 74 ℃-75 ℃ / 1mmHg

Example 4.

Sodium borohydride (2.58 g, 68.2 mmol), adipic acid (9.94 g, 68.2 mmol) and toluene (160 mL) were placed in a 250 mL three-necked flask equipped with a thermometer, a reflux cooler, and a stirrer. Heated to 95 ° C. and stirred at the same temperature for 4 hours. After the reaction was completed, the reaction mixture was cooled to 10 ° C., ethyl 4-chloroacetoacetate (11.2 g, 68 mmol) was added dropwise, and stirred at 25 ° C. for 15 hours to complete the reaction.

Ethyl acetate (150 mL) was added to the reaction solution, and water (40 mL) was slowly added dropwise thereto. Then 5N-hydrochloric acid solution was added to adjust the pH to 6.0.

The organic layer was separated, dehydrated by adding anhydrous magnesium sulfate, filtered and concentrated. The concentrated residue was distilled under vacuum (5 mmHg) to give the target compound (9.7 g, 85.6%).

H1-NMR (CDCl3, ppm): 1.28 (t, 3H), 2.55-2.70 (m, 2H), 3.17 (br, 1H), 3.55-3.65 (m, 2H), 4.18 (q, 2H), 4.20- 4.30 (m, 1 H).

Boiling Point: 74 ℃-75 ℃ / 1mmHg

Example 5.

Into a 250 ml three-necked flask equipped with a thermometer, a reflux cooler, and a stirrer were added sodium borohydride (4.1 g, 108.37 mmol), DL-malic acid (15.7 g, 117 mmol), and tetrahydrofuran (105 ml). Heated to 66 ° C. and stirred for 4 h at the same temperature. After the reaction was completed, the reaction mixture was cooled to -10 ° C, ethyl 4-chloroacetoacetate (44.2 g, 268.5 mmol) was added dropwise, and stirred at the same temperature for 18 hours to complete the reaction.

Ethyl acetate (450 mL) was added to the reaction solution, and water (90 mL) was slowly added dropwise thereto. Then 5N-hydrochloric acid solution was added to adjust the pH to 6.0.

The organic layer was separated, dehydrated by adding anhydrous magnesium sulfate, filtered and concentrated. The concentrated residue was distilled under vacuum (5 mmHg) to obtain the target compound (39.3 g, 87.8%).

H1-NMR (CDCl3, ppm): 1.28 (t, 3H), 2.55-2.70 (m, 2H), 3.17 (br, 1H), 3.55-3.65 (m, 2H), 4.18 (q, 2H), 4.20- 4.30 (m, 1 H).

Boiling Point: 88 ℃-91 ℃ / 5mmHg

Example 6.

Sodium borohydride (4.1 g, 108.37 mmol) and tetrahydrofuran (105 mL) were placed in a 250 mL three-necked flask equipped with a thermometer, a reflux cooler, and a stirrer. After cooling to 0 ° C., ethyl 4-chloroacetoacetate (44.2 g, 268.5 mmol) was added dropwise and stirred at the same temperature for 25 hours to complete the reaction.

Ethyl acetate (450 mL) was added to the reaction solution, and water (90 mL) was slowly added dropwise thereto. Then 5N-hydrochloric acid solution was added to adjust the pH to 6.0.

The organic layer was separated, dehydrated by adding anhydrous magnesium sulfate, filtered and concentrated. The concentrated residue was distilled under vacuum (5 mmHg) to obtain the target compound (28.6 g, 63.9%).

H1-NMR (CDCl3, ppm): 1.28 (t, 3H), 2.55-2.70 (m, 2H), 3.17 (br, 1H), 3.55-3.65 (m, 2H), 4.18 (q, 2H), 4.20- 4.30 (m, 1 H).

Boiling Point: 88 ℃-91 ℃ / 5mmHg

According to the present invention, it is possible to inexpensively mass-produce alkyl 4-chloro-3-hydroxybutyrate as an intermediate of oxyracetam, thereby providing an industrially useful method.

Claims (3)

A method for preparing alkyl 4-chloro-3-hydroxybutyrate of formula (2) by reducing the alkyl 4-chloroacetoacetate represented by the following formula (1) in an organic solvent in the presence of sodium borohydride and an acid catalyst. In the formula, R is a lower alkyl group having 1 to 4 carbon atoms. The method of claim 1, wherein as an acid catalyst, an organic acid selected from succinic acid, DL-malic acid, DL-tartrate, and adipic acid is used to prepare alkyl 4-chloro-3-hydroxybutyrate. Way. The method for preparing alkyl 4-chloro-3-hydroxybutyrate according to claim 1 or 2, wherein the organic solvent is one or two or more mixed solvents selected from toluene, tetrahydrofuran and isopropyl alcohol. .