KR19980059286A - Method for preparing D-(-)-pantolactone - Google Patents

Abstract

The present invention relates to a method for preparing optically active pantolactone, and more particularly, to D-(-)-pantolactone represented by the following Chemical Formula 1 and rotating the direction of polarization in the negative direction to the following Chemical Formula 2. Synthesized diastereomers of racemic DL-pantolactone using α-arylamino acids prepared from the indicated 3,3-dimethyl-2,4-dihydroxy butanenitrile, but with optical activity, were prepared as diastereomers of the diastereomers. The present invention relates to a method for preparing D-(-)-pantolactone of D-stereoisomers in high yield and high optical purity by using solubility difference.

Description

Method for preparing D-(-)-pantolactone

The present invention relates to a method for preparing optically active pantolactone, and more particularly, to D-(-)-pantolactone represented by the following Chemical Formula 1 and rotating the direction of polarization in the negative direction to the following Chemical Formula 2. Synthesized diastereomers of racemic DL-pantolactone using α-arylamino acids prepared from the indicated 3,3-dimethyl-2,4-dihydroxy butanenitrile, but with optical activity, were prepared as diastereomers of the diastereomers. The present invention relates to a method for preparing D-(-)-pantolactone of D-stereoisomers in high yield and high optical purity by using solubility difference.

[Formula 1]

[Formula 2]

D-(-)-pantolactone with optical activity is an important intermediate used in the preparation of D-(+)-pantothenic acid and D-(+)-panthetin.

Therefore, research on the manufacturing method of D-(-)-pantolactone has been actively conducted, and the typical manufacturing method is as follows.

Industrially available manufacturing methods include the process of optically dividing racemic DL-pantolactone into diastereomers of α, γ-dihydroxy-β, β-dimethylbutyl acid using an optically active amine. have.

This preparation method is disclosed in US Pat. No. 2,319,545 for optical division using quinine, a natural alkaloid, and in East German Patent No. 32,628, L-(+)-1- (p-nitrophenyl) -2-amino -1,3-propanediol was used.

However, the quinine used in the above method is very expensive and the molecular weight is large, the amount used in the equivalent amount is disadvantageous in the industrial method. In addition, L-(+)-1- (p-nitrophenyl) -2-amino-1,3-propanediol also forms a high price and cannot secure a sufficient amount for industrial use. .

Meanwhile, according to German Patent No. 1,568,755, a method of optically dividing racemic DL-pantolactone using dihydroabiethylamine has been introduced. Dihydroabiethylamine is synthesized from abiethyl acid, which has a disadvantage in that the amount obtained from nature is limited and expensive, and it is very difficult to be purified in pure form.

A further improved process is described in US Pat. No. 3,996,246, which uses (+)-3-aminomethylpinene as an optical splitting agent. However, this method using (+)-3-aminomethylpinene has a lot of problems in practical applicability, such as the reaction proceeds from (-)-α-pinene under 100 atm of carbon monoxide and the use of liquid ammonia.

In addition, Japanese Patent Publication No. 43-12149 discloses a method of optically dividing racemic DL-pantolactone using optically active amino acids. However, this method poses a danger by using sodium metal in the process of converting acid functionalities to sodium salts to give nucleophilicity to amino acid functionalities of amino acids. In particular, sodium metal requires an explosive handling because it causes an explosive reaction upon contact with moisture.

Therefore, in the present invention, as a result of trying to solve the problems occurring during the conventional manufacturing process of D-(-)-pantolactone, α-arylamino acid and 3,3-dimethyl-2,4- having optical activity The present invention has been completed by developing a new method for optically dividing from dihydroxy butanenitrile into D-diastereomers to obtain D-(-)-pantolactone in high yield and high purity.

This method of the present invention can be carried out in the reaction of the hydrolysis, lactonation reaction and DL-pantolactone in the conventional production process in one reaction, while simplifying the preparation of D-(-)-pantolactone It is to provide a method for producing the target product in yield and high purity.

In the present invention, in preparing D-(-)-pantolactone, α-arylamino acid represented by the following formula (3) from 3,3-dimethyl-2,4-dihydroxy butanenitrile represented by the following formula (2) It is characterized by a method for producing D-(-)-pantolactone represented by the following formula (1) by optical splitting technique.

[Formula 1]

[Formula 2]

[Formula 3]

In the above formulas,

R is H,

X is H or OH.

Referring to the present invention in more detail as follows.

The method for preparing D-(-)-pantolactone according to the present invention is a compound of Formula 2 used as an intermediate when synthesizing racemic DL-pantolactone by optical splitting technique using an α-arylamino acid having optical activity. No attempt has been made to optically split 3,3-dimethyl-2,4-dihydroxy butanenitrile into D-stereoisomers, and its novelty, applicability and ease of use are very dominant, especially in industrial applications. It is a high new technology.

The optical splitting agent used in the present invention is α-arylamino acid represented by Chemical Formula 3.

α-arylamino acids have excellent crystallinity due to aromatic rings compared to amines used as conventional optical splitting agents, and have excellent physical properties that crystallization occurs very well during optical splitting. In addition, there is an advantage in that the spatially bulky and aromatic ring advantageous for crystal formation, the resulting diastereomers easily form crystals and precipitate in solution.

Referring to the reaction mechanism used in the present invention in detail, 1 equivalent of racemic 3,3-dimethyl-2,4-dihydroxy butanenitrile of Formula 2 and 1 equivalent thereof in α in distilled water The reaction is carried out by refluxing with arylamino acid and hydrochloric acid to make diastereomers and recovering the desired D-(-)-pantolactone by the difference in solubility of the two diastereomers.

That is, the present invention provides an optical splitting agent and hydrochloric acid of 3,3-dimethyl-2,4-dihydroxy butanenitrile represented by the formula (2) and α-arylamino acid represented by the formula (3) having optical activity in a water solvent. Reflux for 15 hours to form DL-pantoyl-L-arylglycine, and then selectively precipitate D-pantoyl-L-arylglycine using the difference in solubility of the two diastereomers and hydrolyze it to D-plate It can be described as a method of preparing tolactone.

According to the present invention, in preparing D-(-)-pantolactone, C ₁ to C ₂ alcohols and distilled water were used as reaction solvents, and the α-arylamino acids used were L-phenylglycine and Lp-hydride. Hydroxyphenylglycine, L-3,4-dihydroxyphenylglycine can be used.

In the reaction conditions of the present invention, 1 equivalent of racemic 3,3-dimethyl-2,4-dihydroxy butanenitrile and α-arylamino acid and concentrated hydrochloric acid corresponding to 1 equivalent thereof are added to methanol, ethanol and distilled water solvent. Reflux for 15 hours to form diastereomers in the amide form. The obtained reaction mixture is diluted with water and treated with caustic soda to adjust the pH of the aqueous solution to 2 to 4 to precipitate the desired diastereomer of D-pantolactone. This is recovered and heated in an acid solution of hydrochloric acid for 0.5 to 1 hour to liberate D-pantolactone, and then extracted with 1,2-dichloroethane using a continuous extraction device to obtain the desired D-pantolactone. The yield of _D- pantolactone obtained at this time is 90-96%, and [alpha] _D value is -50 degrees --50.3 degrees.

Hereinafter, the present invention will be described in detail with reference to Examples, but the present invention is not limited by Examples.

Example 1

In a 1 L flask equipped with a reflux condenser and stirrer, 300 ml of distilled water, 129 g of 3,3-dimethyl-2,4-dihydroxy butanenitrile, 151 g of L-phenylglycine and 240 ml of concentrated hydrochloric acid were added thereto, and the mixture was refluxed for 10 hours with stirring. . After the reaction, the mixture is cooled to room temperature and diluted with 500 ml of water in the obtained reaction mixture. When the pH of the reaction solution is adjusted to 4 by adding 50% caustic soda solution to this solution, 133 g (95% yield) of crystals are precipitated. The precipitated crystal is D-pantoyl-L-phenylglycine.

The dried D-pantoyl-L-phenylglycine was dissolved in 500 ml of water, and 10 g of concentrated hydrochloric acid was added thereto and refluxed for 30 minutes. The reaction solution was placed in a continuous extraction apparatus and extracted with 500 ml of 1,2-dichloroethane for 5 hours. D-pantolactone can be obtained by distilling the extracted 1,2-dichloroethane solution under reduced pressure.

D- patno lactone is obtained 61.8g (yield 95%), [α] _D is a _{-50.2˚ (c = 1, H 2} O).

Example 2

In a 1 L flask equipped with a reflux condenser and a stirrer, 300 ml of distilled water, 129 g of 3,3-dimethyl-2,4-dihydroxy butanenitrile, 167 g of L-hydroxyphenylglycine and 240 ml of concentrated hydrochloric acid were added thereto, followed by stirring for 15 hours. Reflux. After the reaction, the mixture is cooled to room temperature and diluted with 500 ml of water in the obtained reaction mixture. When the pH of the reaction solution is adjusted to 4 by adding 50% caustic soda solution to this solution, 138 g (93% yield) of crystals are precipitated. The precipitated crystal is D-pantoyl-L-hydroxyphenylglycine.

D-pantolactone obtained by the same method as in Example 1 was 59.8 g (yield 92%), and [α] _D was -50.1 ° (c = 1, H ₂ O).

As can be seen from the manufacturing results of Examples 1 and 2, the manufacturing method according to the present invention shows that the yield and optical purity are improved as compared with Japanese Patent Publication No. 43-12149.

Therefore, the present invention has the effect of synthesizing the target substance in high yield and high purity by producing the target substance in a continuous precipitation method and hydrolysis method more efficient than the conventional.

Claims (2)

In preparing D-(-)-pantolactone, using an α-arylamino acid represented by the following formula (3) from 3,3-dimethyl-2,4-dihydroxy butanenitrile represented by the formula (2) A process for producing D-(-)-pantolactone, which comprises producing D-(-)-pantolactone represented by the following formula (1) by dividing: [Formula 1] [Formula 2] [Formula 3] In the above formulas, R is H, X is H or OH. The method of claim 1, wherein the optical splitting is performed by refluxing the reactant and concentrated hydrochloric acid in a water solvent for 10 to 15 hours to form DL-pantoyl-L-arylglycine, and then selectively using the solubility difference between the two diastereomers. A method for producing D-(-)-pantolactone, which is obtained by depositing D-pantoyl-L-arylglycine and hydrolyzing it.