JP4314600B2 - Method for producing tartaric acid lower alkyl diester - Google Patents

Description

[0001]
BACKGROUND OF THE INVENTION
The present invention relates to an efficient process for producing tartaric acid lower alkyl diesters.
[0002]
[Prior art]
Tartaric acid lower alkyl diesters are useful as intermediates and asymmetric catalysts for agricultural chemicals and pharmaceuticals. The tartaric acid lower alkyl diester can be produced by reacting tartaric acid and a lower alcohol in the presence of an acid catalyst. Since the reaction is an equilibrium reaction, in principle, a large amount of dehydrated lower alcohol can be used to produce tartaric acid lower alkyl diester in a high yield. Complicated work is required. As a method not using a large amount of dehydrated lower alkyl alcohol, an esterifying agent such as orthoformate is used in the presence of an acid catalyst (Synth. Comn., 14, 1087, (1984)). Method, a lower alkyl alcohol is reacted in the presence of an acid catalyst, and by-product water is removed from the system by azeotropic dehydration in the presence of an organic solvent that is azeotroped with water, such as chloroform (Helvetica, Chemica, Actor (Helv Chim. Acta.) 62, 1710 (1979)) and the like are known.
[0003]
[Problems to be solved by the invention]
Although the method using orthoformate ester has a high reaction yield and is excellent as a method for obtaining tartaric acid lower alkyl diester, orthoformate ester is expensive and disadvantageous in price for use in industrial production. Also, the method of azeotropic dehydration using chloroform is not preferred because the reaction takes a long time and there is a risk of chloroform being contaminated with the environment.
[0004]
An object of the present invention is to minimize the amount of lower alcohol used in the process for producing tartaric acid lower alkyl diesters and achieve a high yield in a short time. It is another object of the present invention to provide a method for producing an optically active tartaric acid lower alkyl diester without reducing optical purity when optically active tartaric acid is used as a raw material.
[0005]
[Means for Solving the Problems]
As a result of intensive studies to achieve the above object, the present inventors have found that by adding thionyl chloride to tartaric acid and an alcohol having 4 or less carbon atoms , a lower alkyl diester of tartaric acid can be produced in a high yield in a short time. The present invention has been completed.
[0006]
That is, the present invention provides a process of esterifying tartaric acid and an alcohol having 4 or less carbon atoms in the presence of an acid catalyst, a concentration process for removing by-product water in the system, and a process of adding an alcohol having 4 or less carbon atoms and thionyl chloride. A process for producing lower alkyl diesters of tartaric acid, characterized in that
[0007]
DETAILED DESCRIPTION OF THE INVENTION
The tartaric acid which is the raw material of the present invention can be any of L-tartaric acid, D-tartaric acid, DL-tartaric acid and meso-tartaric acid.
[0008]
The other raw material, lower alcohol, is an alkyl alcohol having 4 or less carbon atoms , and one modified with an inert solvent can be used (in this specification, lower alcohol means an alcohol having 4 or less carbon atoms) . Specifically, it is a linear or branched alkyl alcohol such as methanol, ethanol, propanol, isobutanol and the like. In the case of ethanol, those modified by adding an inert solvent that does not react with tartaric acid or lower alcohol such as toluene can be used as well.
[0009]
The amount of the lower alcohol used is preferably 2 to 30 times mol, more preferably 2 to 6 times mol with respect to tartaric acid. Within this range, economic efficiency is good and the yield of tartaric acid lower alkyl diester is also high.
[0010]
The reaction proceeds by adding thionyl chloride to tartaric acid and lower alcohol. The addition amount of thionyl chloride is preferably 0.2 to 5 times mol, more preferably 0.5 to 2 times mol for the unreacted carboxyl group. 0-120 degreeC of reaction temperature is preferable, More preferably, it is 20-90 degreeC. By carrying out the reaction in this range, the yield of tartaric acid lower alkyl diester can be increased.
[0011]
During the reaction, hydrogen chloride and sulfur dioxide are generated as exhaust gas. However, if the amount of thionyl chloride added is large, the amount of exhaust gas is large and the load of exhaust gas treatment increases, which may cause problems. Therefore, the esterification reaction of tartaric acid and lower alcohol proceeds in the presence of an acid catalyst, and then water produced as a by-product of the reaction is removed by concentration, and then a small amount of unreacted tartaric acid, tartaric acid lower alkyl monoester, and tartaric acid lower It is preferable to add 0.5 to 2.0 times moles of thionyl chloride with respect to the lower alcohol and the remaining carboxyl group in the mixture of alkyl diesters. When esterification is performed in the presence of an acid catalyst, heating is preferably performed. A preferable heating temperature is 30 to 120 ° C, and more preferably 50 to 90 ° C. By performing the reaction within this range, the generation of impurities can be reduced.
[0012]
Here, the acid catalysts used are mineral acids such as hydrochloric acid and sulfuric acid, aromatic sulfonic acids such as benzenesulfonic acid and toluenesulfonic acid, aliphatic sulfonic acids such as methanesulfonic acid, and H-type cation exchange resins. Examples thereof include Nafion (manufactured by DuPont), Diaion PK208 (manufactured by Mitsubishi Kasei Co., Ltd.), and the like. The amount of the acid catalyst used is preferably 0.001 to 1 mole, more preferably 0.005 to 0.1 mole relative to tartaric acid.
[0013]
In the esterification reaction of tartaric acid and lower alcohol in the presence of an acid catalyst, it is advantageous that the amount of lower alcohol used is small, and the amount of lower alcohol used is 2 to 6 moles per mole of tartaric acid. preferable. By carrying out the reaction in this range, a highly pure lower alkyl diester of tartaric acid can be obtained economically. However, if the amount of the lower alcohol used is small, the slurry concentration becomes high and a problem may occur in stirring and the like. Therefore, it is preferable to add a diluent in order to make the reaction proceed smoothly there. The diluent added here is preferably an organic solvent that does not react with tartaric acid or lower alcohol and azeotropes with water. Specific examples include aliphatic hydrocarbons such as hexane, alicyclic hydrocarbons such as cyclohexane, aromatic hydrocarbons such as toluene and xylene, and ethers such as diisopropyl ether.
[0014]
The addition amount may be a slurry concentration that can be stirred, and varies depending on the amount of lower alcohol used, but is usually 1 to 20 times the weight of tartaric acid, more preferably 2 to 10 times the weight. Within this range, economic efficiency is good and workability is also good. The diluent may be used in the concentration step. Excess lower alcohol and by-product water are concentrated and removed after the esterification reaction is completed, but the volume change in the concentration process is reduced, which reduces the thermal efficiency of the reaction can and extends the concentration time. Moreover, the problem that the quality of tartaric acid lower alkyl diester is deteriorated by local heating can be prevented. Therefore, by adding a lower alcohol, water, and a diluent commensurate with the amount of diluent in the concentration process, the azeotropic dehydration efficiency can be improved and quality deterioration due to local heating can be prevented. Can do.
[0015]
The reaction temperature for esterification is preferably 30 to 120 ° C, more preferably 50 to 90 ° C.
[0016]
While the reaction time varies depending on the type and amount of the lower alcohol and acid catalyst used, and the reaction temperature, it is usually preferably 0.5 to 20 hours, more preferably 1 to 6 hours.
[0017]
In the method of the present invention, a normal method can be employed to isolate the tartaric acid lower alkyl diester from the reaction solution obtained by reaction, dehydration, and thionyl chloride addition. For example, tartaric acid or tartaric acid lower alkyl monoester that remains slightly after addition of water to the reaction solution is transferred to the aqueous layer, and the target lower tartaric acid dialkyl diester can be isolated by concentrating the diluent solution. . Alternatively, it can be purified by vacuum distillation.
[0018]
【Example】
Next, the present invention will be specifically described with reference to examples and the like. The concentration analysis of tartaric acid and tartaric acid lower alkyl diester was performed by the following high performance liquid chromatography.
Equipment: Shimadzu LC-10AT
Column: YMC-Pack ODS-AM303 (manufactured by YMC) diameter 4.6 mm × 250 mm
Column temperature: 40 ° C
Detection method: UV (215 nm)
Solvent: 20 mM NaH 2 SO 4 aqueous solution / acetonitrile = 9/1 (V / V)
Flow rate: 0.5ml / min
Example 1
In a 1 L three-necked flask equipped with a thermometer, a condenser, a dropping funnel and a stirrer, D-tartaric acid (manufactured by Toray Industries, Inc., optical purity 99.9% ee or more) 120.1 g (0.8 mol), ethanol 73.7 g (1.6 mol) manufactured by Katayama Chemical Co., Ltd. (special grade reagent) and 432.3 g of toluene (first grade reagent manufactured by Katayama Chemical Co., Ltd.) were added and stirred. To this was added 8.8 g of a 10% ethanol solution of hydrogen chloride prepared by blowing hydrogen chloride gas into ethanol (0.024 mol of hydrogen chloride), and the mixture was heated at 80 ° C. for 2 hours. Next, after adding 2.0 g (caustic soda 0.024 mol) of 48% aqueous caustic soda solution prepared by dissolving caustic soda (Katayama Chemical Co., Ltd., first grade reagent) in water, a simple distillation apparatus was attached, and a dropping funnel was used. While adding 180.1 g of toluene, water and ethanol in the flask were distilled together with toluene at 70 ° C. under reduced pressure. After distilling about 240 g of a mixture of water, ethanol and toluene, the mixture was cooled and analyzed for the concentrations of D-tartaric acid and D-tartaric acid monoethyl ester in the liquid. As a result, D-tartaric acid remained with respect to the charged D-tartaric acid. The rate was 14%, and the production rate of D-tartaric acid monoethyl ester was 34%. 64.5 g (1.4 mol) of ethanol was added, and 61.9 g (0.52 mol) of thionyl chloride (made by Katayama Chemical Co., Ltd., special grade reagent) was added dropwise at about 30 to 40 ° C. in about 30 minutes. After stirring for 2 hours, while adding 72.0 g of toluene with a dropping funnel, water and ethanol in the flask were evaporated together with toluene at 50 ° C. under reduced pressure to distill about 108 g of a mixture of water, ethanol and toluene. It was. The reaction solution is allowed to cool to 35 ° C. or lower, and sodium hydrogen carbonate (Katayama Chemical Co., Ltd., first grade reagent) 6.7 g (0.08 mol), sodium chloride (Katayama Chemical Co., Ltd., first grade reagent) After adding 33 g of 8% saline prepared by dissolving in water to the reaction solution and stirring well, the organic layer was separated. The organic layer was washed twice with 33 g of saturated saline again. The separated aqueous layer was extracted again with 350 g of toluene and added to the previously separated organic layer. Next, the organic layer was concentrated to dryness under reduced pressure at 40 ° C., and the solvent was distilled off, followed by filtration to obtain 156.7 g of D-tartaric acid diethyl ester. The yield of D-tartaric acid diethyl ester relative to the charged D-tartaric acid was 95.0%. The optical purity was 99.9% ee or higher, and the optical purity was not lowered.
[0019]
Example 2
The same operation as in Example 1 was carried out except that the amount of thionyl chloride added was 31.0 g (0.26 mol) to obtain 152.2 g of D-tartaric acid diethyl ester. The yield of D-tartaric acid diethyl ester relative to the charged D-tartaric acid was 92.3%. The optical purity was 99.9% ee or higher, and the optical purity was not lowered.
[0020]
Example 3
In the method of Example 1, the addition temperature of thionyl chloride was 70 ° C., and L-tartaric acid (made by Katayama Chemical Co., Ltd., special grade reagent, optical purity 99.5% ee or more) was used instead of D-tartaric acid. The same operation was performed to obtain 153.7 g of L-tartaric acid diethyl ester. The yield of L-tartaric acid diethyl ester relative to the charged L-tartaric acid was 93.2%. The optical purity was 99.9% ee or higher, and the optical purity was not lowered.
[0021]
Example 4 In the method of Example 1, 2-propanol (manufactured by Katayama Chemical Co., Ltd., primary reagent) was used instead of ethanol, and the addition amount was 96.0 g (at the initial charge), 84.0 g (thionyl chloride). The same operation was carried out except that the addition was carried out to obtain 179.8 g of D-tartaric acid diisopropyl ester. D- tartaric acid yield of di-isopropyl ester on the charged D- tartaric acid was 96.0%. The optical purity was 99.9% ee or higher, and the optical purity was not lowered.
[0022]
Comparative Example Except that the addition of thionyl chloride was omitted in the method of Example 1, 67.6 g of D-tartaric acid diethyl ester was obtained. The yield of D-tartaric acid diethyl ester relative to the charged D-tartaric acid was as low as 41.0%. The optical purity was 99.9% ee or higher, and there was no decrease in optical purity.
[0023]
【The invention's effect】
According to the present invention, by adding thionyl chloride to tartaric acid and lower alcohol, the amount of lower alcohol used can be minimized, and a high-purity tartaric acid lower alkyl diester can be produced in high yield in a short time. It can greatly contribute to the production cost reduction of lower alkyl diesters.

Claims (4)

It comprises a step of esterifying tartaric acid and an alcohol having 4 or less carbon atoms in the presence of an acid catalyst, a concentration step for removing by-product water in the system, and a step of adding alcohol having 4 or less carbon atoms and thionyl chloride. A method for producing tartaric acid lower alkyl diesters. When removing the product water in the system, tartaric also does not react with having 4 or less of the alcohol carbon, and tartaric acid lower alkyl diester of claim 1, wherein the use of organic solvent azeotropic with water Manufacturing method. The amount of alcohol having 4 or less carbon atoms is 2 to 6 moles per 1 mole of tartaric acid, and does not react with tartaric acid or alcohol having 4 or less carbon atoms , and an organic solvent azeotropic with water is used as a diluent. preparation of tartaric acid lower alkyl diester according to claim 1 or 2, characterized that you added to the step of reduction. The method for producing a tartaric acid lower alkyl diester according to any one of claims 1 to 3 , wherein tartaric acid is an optically active substance.