JPS61204176A - Production of d-(-)-pantolactone - Google Patents

Abstract

PURPOSE:To obtain the titled compound having optical purity, easily in high yield with simple operation using an inexpensive reagent, on an industrial scale, by reacting DL-pantolactone with an alkali and subjecting the resultant compound to optical resolution with a specific optical resolution agent. CONSTITUTION:DL-pantolactone is made to react with an alkali such as NaOH in a solvent (preferably ethanol, etc.). The obtained alkali metal or alkaline earth metal salt of DL-pantoic acid is subjected to lactonization and optical resolution in a solvent (preferably ethanol, etc.) in the presence of optically active D-10-camphor-sulfonic acid as the optical resolution agent at -100-+25 deg.C, the solvent is distilled out under reduced pressure and the residue is extracted with a solvent such as methylene chloride and dried. The dried product is extracted with a solvent, which is distilled off under reduced pressure to obtain the objective compound. USE:A synthetic intermediate for D-(+)-pantothenic acid Ca salt, etc. useful as medicinal drugs, feed additive for chicken raising or hog raising, or a vitamin complex, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] Part 8A of the present invention relates to a method for producing D-(-)-pantolactone.

L)-(-)-pantolactone produced by the method of the present invention is D-(+)-calcium pantothenate, which is used as a pharmaceutical, a feed additive for poultry and pig farming, a multivitamin, etc. It is useful as a synthetic intermediate for -(+)-pantothenyl alcohol, D-(+)-pantethine, etc. [Prior art] Conventionally, D-(-)-pantolactone has generally been chemically synthesized DL- It is produced by optical resolution of pantolactone. Optical resolution methods for vantolactone include a method of fractional crystallization of diastereomers produced using a resolving agent such as an optically active amine compound (diastereomer method), and a method of inoculating the required optically active form. A method of preferentially crystallizing the optically active substance by doing so (direct crystallization method), a method of utilizing microbial hydrolase (biochemical optical resolution method), etc. are known.

[Problem that the invention seeks to solve]

The conventional diastereomer method described above has drawbacks such as the expensive resolving agent used, difficulty in recovering and reusing the resolving agent, and low resolution yield. The direct crystallization method has the disadvantage that crystallization reproducibility of the desired optically active substance is poor and the resolution rate is low, and the biochemical optical resolution method has the disadvantage that the resolution requires a long time. Therefore, there is currently a need to develop a method for optically resolving QDL-pantolactone and producing D-(-)-pantolactone on an industrial scale using inexpensive reagents and simple operations. be.

Therefore, an object of the present invention is to provide a method for producing D-(-)-pantolactone on an industrial scale by optically resolving DL-pantolactone using inexpensive reagents and with simple operations. be.

[Means for solving problems]

According to the present invention, the above object is achieved by reacting DL-pantolactone with an alkali and converting the resulting alkali metal salt or alkaline earth metal salt of DL-pantoic acid into optically active 10-can-7arsulfonic acid ( Hereinafter, this optically active -10-kan7arsulfonic acid will be referred to as D-C8A)
D-(-
)--by providing a method for producing pantolactone.

By reacting DL-pantolactone with an alkali, an alkali metal salt or alkaline earth metal salt of pDL-pantoic acid can be obtained. Examples of alkalis include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, and lithium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; barium hydroxide, magnesium hydroxide, and calcium hydroxide. Alkaline earth metal hydroxides are used. The amount of alkali used is about 1 mole or more, preferably about 1 to 1 mole, relative to DL-pantolactone.
The range is 1.05 times the mole. This reaction is preferably carried out in the presence of a solvent, such as methanol,
Alcohol such as ethanol and impropatul; Water:
or mixtures thereof are used. It is usually convenient to use alcohol as the solvent, but if the alkali used is difficult to dissolve in 7/l/coal, it is also possible to use water or hydrous alcohol. The amount of the solvent to be used is arbitrarily selected, and is preferably an amount that provides sufficient KI@ for the alkali or more, but may be an amount that does not completely dissolve the alkali. After the reaction is completed, the solvent is distilled off from the reaction mixture under reduced pressure, and then an entrainer such as benzene is added for azeotropic dehydration, and then the entrainer is distilled off under reduced pressure to obtain DL. - An alkali metal salt or alkaline earth metal salt of pantoic acid is obtained as a powder. Next, by lactonizing the alkali metal salt or alkaline earth metal salt of DL-pantoic acid in the presence of D-C8A, D -(-)-pantolactone is obtained. This reaction is preferably carried out in the presence of a solvent, including alcohols such as methanol, ethanol, isopropanol, hexane, benzene, ethyl acetate, tetrahydrofuran, methylene chloride, and other solvents commonly used in organic chemical reactions. can be used. The amount of solvent to be used is about 50 to 1000 t, preferably about 100 to 500 t, and more preferably 150 to 300 t per mole of the alkali metal salt or alkaline earth metal salt of DL-pantoic acid.
It is. The D-C8A used also includes its hydrate.

The amount of D-C8A used is approximately 0.0 per mole of the alkali metal salt or alkaline earth metal salt of DL-pantoic acid.
The amount is 5 to 0.7 mol, preferably 0.075 to 0.4 mol. The reaction is usually carried out at a temperature in the range of about -100 to 25°C, preferably in the range of about -100 to 0°C, more preferably 1-1-7.
The temperature is 8 to -30°C. A preferred embodiment of this reaction operation is shown below. D-C8A dissolved in a solution or suspension obtained by adding a solvent to an alkali metal salt or alkaline earth metal salt of DL-pantoic acid, an alcohol such as methanol, ethanol, isopropanol, or a solvent such as ethyl acetate. After adding the solution little by little while stirring, the solvent is distilled off under reduced pressure, and the residue is extracted with a solvent such as methylene chloride, chloroform, trichloroethylene, benzene, or toluene. After drying, the solvent is distilled off from the extract under reduced pressure to obtain the desired optically active pantolactone.

The residue after extracting optically active pantolactone contains L.
, <There is an alkali metal salt or alkaline earth metal salt of pantoic acid containing an excess of pantoic acid.

Therefore, by dissolving the residue of and heating the resulting aqueous solution in the presence of a mineral acid such as hydrochloric acid or sulfuric acid, L-
After converting an alkali metal salt or alkaline earth metal salt of pantoic acid containing an excess of bantoic acid to bantolactone containing an excess of L-pantolactone, the L-pantolactone can be recovered by solvent extraction or by a conventional method. By racemizing bantoic acid containing excess bantoic acid, 5DL-
After converting into bantoic acid, fiDL-pantolactone can be recovered by treating this DL-bantoic acid under acidic conditions. According to the method of the present invention, by selecting the reaction conditions, 99% or more of the fiDL-pantolactone can be recovered. It is also possible to obtain D-(→-pantolactone with optical purity.Also, by selecting the reaction conditions, the yield of D-(-)-pantolactone can be increased even if the optical purity of the obtained D-(-)-pantolactone is somewhat low at around 5 Ots. D-(-)-pantolactone with high optical purity can be obtained by subjecting the relatively low optical purity pantolactone obtained in high yield to the conventional direct crystallization method. is also possible.

Although D-C8A is commercially available and can be obtained at a low price,
It can also be easily synthesized from D-camphor, sulfuric acid and acetic anhydride. (Org, Syn.

COI, V,] 94 (1973)] [Examples] The present invention will be explained below with reference to Examples, but the present invention is not limited to these Examples. In addition, enantiomeric excess (enantiomeric excess).

%e, e, ) is the specific optical rotation of optically pure L-(+)-pantolactone [α]p=50.9 (methanol)
It was calculated based on.

Example I DL-pantolactone 10.85F was dissolved in 20d of 99.5% ethanol, and 3.0ml of sodium hydroxide was added to this solution.
A solution obtained by dissolving 42 in 99.5 Cetanol 5011JK was added, and the mixture was stirred at room temperature for 2 hours to obtain a white precipitate. After distilling off ethanol from this reaction mixture under reduced pressure, 50 d of benzene was added to the residue to form an ean-
Water was azeotropically distilled off using a 5tark type water separator. After cooling, benzene was distilled off from the residue under reduced pressure, and DL
-Pantoic acid sodium salt 14.1? Obtained.

DL-pantoic acid sodium salt 100 ~ was dissolved in ethanol 1001, and 5.9 m4 of an ethanol solution (10 mrnol solution) of D-C8A was added dropwise to this bath solution with stirring at a temperature of -78°C. The solvent was distilled off from the reaction mixture under reduced pressure, and the residue was extracted with methylene chloride. After drying the organic layer over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain D-(-)-pantolactone 6.1'P. The specific optical rotation of this product was [α] back= -50,6 (methanol) was 99.4% e,e.

Examples 2 to 5 The reaction operation was carried out in the same manner as in Example 1 except that the amount of the ethanol solution of D-C8A used was changed, and D-(
-'I-pantolactone was obtained. The results are shown in Table 1.

Table 1 Example 6 The reaction was carried out in the same manner except that 4.769 potassium hydroxide was used in place of 3.42 sodium hydroxide used in Example 1, and 15.4% of DL-pantoic acid potassium salt was used. I got F.

Next, the reaction was carried out in the same manner as in Example 1, except that 109 mg of DL-pantoic acid potassium salt was used in place of DL-pantoic acid sodium salt 100'P used in Example 1, and %D-(-)-pantolactone 6 was obtained. .0 cape obtained.

The specific optical rotation of this product was 97.8% e, e with [α] Amase-49,8 (methanol).

Example 7 DL-pantolactone 1.30F was dissolved in methanol 10M, and 1.58% of baricum hydroxide octahydrate was added to this solution.
A solution obtained by dissolving 1 in methanol lQd was added, and the mixture was stirred at room temperature overnight. After distilling off methanol from the reaction mixture under reduced pressure, the remaining 4K hair cef 50 tr
The water was azeotropically distilled off using a Dean-5 Tark type water separator. After cooling, benzene was distilled off from the residue under reduced pressure to obtain DL-pantoic acid barium salt 'ft: 2.15f.

DL-Pantoic acid barium salt 126 ~ ethanol 1
00M, and 5.9 m of an ethanol solution (30 mmol solution) of L)-C8A was added to this solution at a temperature of -78°C with stirring. The solvent was distilled off from the reaction mixture under reduced pressure, and the residue was extracted with methylene chloride. After drying the organic layer over anhydrous sodium sulfate, the solvent was removed under reduced pressure and D-(-)-pantolactone 6. Obtained OWq. The specific optical rotation of this substance is [α)j' = -50,
0 (methanol), it was 98.8% e.

Example 8 The reaction operation was carried out in the same manner as in Example 1, except that the temperature during dropping of the dilute solution of D-csA at -78°C was replaced by -20°C, and D-(-) - Pantolactone 6, OWq was obtained. The specific optical rotation of this product is [α)''7 = -23,2 (methanol), 45.6%
It was e, e.

Example 9 DL-pantoic acid sodium salt 1 obtained in Example 1
100 ml of tetrahydrofuran was added to 00119, and 5.9 al of an ethanol solution (1 o mmol solution) of D-C8A was added dropwise to this solution with stirring at a temperature of -78°C.

The solvent was distilled off from the reaction mixture under reduced pressure, and the residue was extracted with methylene chloride.

After drying the organic layer over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and D-(-)-pantolactone 5.9
I got wq. The specific optical rotation of this item is [α] = -50
, 5 (methanol) and 99.2 q6 e,e.

〔Effect of the invention〕

According to the method of the present invention, DL-pantolactone can be optically resolved using inexpensive reagents and by simple operations, and DL-pantolactone can be easily resolved.
-(-)-pantolactone can be produced. Furthermore, since the reagents used in the uninvented method are inexpensive and the filtration and operation are simple, it is not possible to produce L)-(-)-pantolactone on an industrial scale.

Claims (1)

[Claims] D, characterized in that DL-pantolactone is reacted with an alkali, and the obtained alkali metal salt or alkaline earth metal salt of DL-pantoic acid is lactonized in the presence of optically active D-10-camphorsulfonic acid. −(−)
- A method for producing pantolactone.