JP2002128738A - Method for producing tartaric acid lower alkyl diester - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing a tartaric acid lower alkyl diester having high quality at a low cost and to provide a method for producing a tartaric acid lower alkyl diester having high optical purity while suppressing the lowering of optical purity in the case of using an optically active tartaric acid as a raw material. SOLUTION: A tartaric acid lower alkyl diester obtained by reacting tartaric acid with a lower alkyl alcohol is subjected to thin film distillation to obtain the objective diester having high quality.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for producing a lower alkyl ditartaric acid ester which is useful as an intermediate for agricultural chemicals and pharmaceuticals.

[0002]

2. Description of the Related Art Lower alkyl tartaric acid diesters are useful as intermediates in the production of agricultural chemicals and medicaments, and particularly, optically active lower alkyl tartaric acid diesters are useful as asymmetric catalysts. As a method for producing a lower alkyl diester of tartaric acid by reacting tartaric acid and an alcohol, a method using an esterifying agent such as orthoformate in the presence of an acid catalyst (Synthetic Communications (Synth. Comn.), 14, 1087, (1
984)), a method in which a lower alkyl alcohol is removed from the system by azeotropic dehydration in the presence of an acid catalyst in the presence of an organic solvent azeotropic with water, for example, chloroform, and by-product azeotropic dehydration.
elv. Chim. Acta 62, 1710 (197
9)) and the like are known. The method using orthoformate has a high reaction yield and is excellent as a method for obtaining a high-purity diester, but orthoformate is expensive and disadvantageous in price for use in industrial production. Further, a method of removing water produced as a by-product in the coexistence of chloroform outside the system by azeotropic dehydration is not preferable because chloroform may contaminate the environment. In addition, in any of the methods, the lower intermediate monoalkyl tartrate as a reaction intermediate remains in the product. As a method of reducing the residual amount of lower alkyl tartaric acid monoester, there is a method of using a large amount of alcohol, but alcohol cost is increased and economic efficiency is poor. Further, there is a method in which the reaction conditions are strict, but a dimer, a trimer, or the like, which is a polymer of tartaric acid, is formed, and the yield is reduced. Further, if mild reaction conditions such as a dilute solution are employed, the amount of tartaric acid polymer produced can be reduced, but this is not only economical, but also increases the residual amount of monoester. In addition, the lower alkyl tartaric acid diester is isolated through a step of concentrating the reaction solution, but the quality of the isolated lower alkyl tartaric diester also deteriorates due to an increase in the amount of the tartaric acid polymer in the enrichment process. I do.

[0003]

SUMMARY OF THE INVENTION An object of the present invention is to provide a process for producing high quality lower alkyl ditartaric acid ester at low cost. Further, when optically active tartaric acid is used, it is an object of the present invention to provide a method for producing a lower alkyl diester of tartaric acid having a high optical purity while suppressing a decrease in optical purity.

[0004]

Means for Solving the Problems The present inventors have made intensive studies to solve the above-mentioned problems, and as a result, have reached the present invention.

That is, there is provided a method for producing a lower alkyl tartaric diester, which comprises subjecting a lower alkyl ditartaric acid ester obtained by an esterification reaction of tartaric acid and a lower alkyl alcohol to thin-film distillation.

[0006]

DESCRIPTION OF THE PREFERRED EMBODIMENTS In the present invention, tartaric acid used as a raw material includes L-tartaric acid, D-tartaric acid, DL-tartaric acid,
Any of the meso-tartaric acids can be used. The present invention is particularly effective when tartaric acid is an optically active substance and the resulting lower alkyl ditartaric acid ester is an optically active substance.

[0007] The lower alkyl alcohol as the other raw material is preferably an alcohol having 1 to 6 carbon atoms, and any of a straight-chain or branched alcohol can be used. Specifically, methanol, ethanol, isopropanol,
Tertiary butanol and 1-pentanol are preferred, and may be used according to the purpose. The use amount of the lower alcohol is preferably 2 to 30 times, more preferably 3 to 6 times the molar amount of tartaric acid. Within this range, the economic efficiency is good and the yield of lower alkyl tartaric diester is high.

The esterification reaction preferably uses an acid catalyst. For example, mineral acids such as hydrochloric acid and sulfuric acid, benzenesulfonic acid, aromatic sulfonic acids such as toluenesulfonic acid,
Aliphatic sulfonic acids such as methanesulfonic acid, and H-type cation exchange resins such as Nafion (manufactured by DuPont) and Diaion PK208 (Mitsubishi Chemical Corporation)
Manufactured). The amount of the acid catalyst to be used is preferably 0.001 to 1 mol, more preferably 0.005 to 0.1 mol, per mol of tartaric acid.

The reaction proceeds by heating tartaric acid and a lower alcohol, preferably in the presence of an acid catalyst. Here, in order to enhance the economic effect, it is advantageous to use a lower alcohol in a small amount.
The amount is preferably from 2 to 6 mol per mol. By performing the reaction in this range, a high-purity lower alkyl diester of tartaric acid can be obtained economically. However, if the amount of the lower alcohol is small, the concentration of the slurry becomes high and there may be a problem in stirring or the like. Therefore, it is preferable to add a diluent in order to make the reaction proceed smoothly. As the diluent added here, an organic solvent that does not react with tartaric acid or a lower alcohol and azeotropes with water can be preferably used. 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.

The amount of the diluent to be added may be such that the reaction mixture has a slurry concentration at which the reaction mixture can be stirred, and it depends on the amount of the lower alcohol used. It is 10 times the weight. Within this range, economic efficiency is good and workability is good. Further, the diluent may be used in the concentration step. It is preferable to concentrate and remove excess lower alcohol and by-produced water after completion of the esterification reaction, but by reducing the volume change in the concentration step, the thermal efficiency of the reaction vessel is reduced and the concentration time is extended. It is possible to prevent the problem and the problem that the quality of the lower alkyl tartaric acid diester is reduced by the local heating.

[0011] Therefore, if a diluent corresponding to the amounts of the lower alcohol, water and diluent distilled out in the concentration step is added to the system, the azeotropic dehydration efficiency can be increased and the quality deterioration due to local heating can be prevented. Can be prevented.

Also, thionyl chloride can be used in the esterification reaction. Proceed by adding thionyl chloride to tartaric acid and lower alcohol. The addition amount of thionyl chloride is preferably from 0.2 to 5 moles, more preferably from 0.5 to 2 moles, per mole of unreacted carboxyl groups. The reaction temperature is preferably from 0 to 120C, more preferably from 20 to 9C.
0 ° C. By performing the reaction in this range, the yield of the lower alkyl ditartaric acid diester can be increased. At the time of the reaction, hydrogen chloride and sulfur dioxide are generated as exhaust gas. However, if the amount of added thionyl chloride is large, the amount of exhaust gas is large and the load of exhaust gas treatment is increased, which may cause a problem. In this case, when an acid catalyst is used in combination, the load of exhaust gas treatment is reduced, and the reaction can also proceed smoothly. Specifically, tartaric acid and a lower alcohol are allowed to undergo an esterification reaction in the presence of an acid catalyst, and then water produced as a by-product is removed by concentration.
It is preferable to add 0.5 to 2.0 moles of thionyl chloride to the mixture of the lower alcohol and the remaining carboxyl group to the mixture of the lower alkyl tartaric acid monoester and the lower alkyl tartaric diester.

If the above reaction is employed, the optical purity of the optically active tartaric acid used as a raw material during the reaction does not decrease.

After the esterification reaction, the acid catalyst is preferably deactivated and then concentrated. If the concentration is performed without deactivating the acid catalyst, impurities such as a polymer of a lower alkyl tartaric diester are generated in the concentration step, and the quality of the lower alkyl tartaric diester may be degraded.

Here, in order to inactivate the acid catalyst, it is preferable to neutralize with a tertiary amine and / or an inorganic alkali. As the tertiary amine, a trialkylamine such as triethylamine can be used. In addition, hydroxides, carbonates of alkali metals and alkaline earth metals as inorganic alkalis,
Bicarbonate and the like can be used. For example, sodium hydroxide,
Potassium hydroxide, calcium hydroxide, sodium hydrogen carbonate, potassium carbonate and the like can be mentioned. When it is added to the reaction system, it can be used as a solid or dissolved in the used lower alcohol, diluent or water. The amount used is preferably 0.9 to 1.5 equivalents, more preferably 1.0 to 1.2 equivalents, based on the acid catalyst in the system. By adding in this range, the yield of the lower dialkyl tartaric acid ester can be increased and the purity can be improved.

In the concentration, it is preferable to carry out azeotropic concentration using an organic solvent which does not react with tartaric acid or lower alcohol and azeotropes with water. By performing azeotropic concentration, generation of impurities can be reduced.

In order to reduce the amount of lower alcohol used, shorten the time, increase the yield, and reduce by-products such as polymers of lower alkyl ditartaric acid diester, an esterification step
A method in which the neutralization step and the azeotropic concentration step are repeated is preferable. Specifically, for example, a lower alcohol is mixed twice with respect to tartaric acid (equimolar with respect to a carboxyl group), a diluent is mixed with 4 times by weight, and an acid catalyst is mixed with 0.03 times by mole, and 70 to 8 moles are mixed.
When the reaction is carried out at 0 ° C. for 1 to 2 hours, an equilibrium composition (carboxyl group conversion: about 60 to 70%) is reached. Here, after neutralizing the acid catalyst, by-product water, unreacted lower alcohol, and diluent are concentrated to remove free water in the system, but the diluent is added so that the amount of solution in the system does not change significantly. It is preferred to concentrate while concentrating. Next, a lower alcohol and an acid catalyst are added again, the reaction is similarly performed for 1 to 2 hours to obtain an equilibrium composition, and the neutralization and concentration of the catalyst are repeated to shorten the total esterification reaction time. Usually, the lower alkyl ditartaric acid diester can be synthesized almost quantitatively by repeating the process three to four times. When such a repetitive reaction method is employed, the amount of lower alcohol used is small, the formation of by-products can be suppressed, and the yield of lower alkyl tartaric acid diester is also improved.

In order to isolate a lower alkyl ditartaric acid ester from a reaction solution obtained by repeating the reaction, neutralization and concentration operations several times, water is added to the concentrated solution and a very small amount of tartaric acid or lower alkyl tartaric acid residue remains. By transferring the ester, neutralized salt and the like to the aqueous layer and concentrating the diluent solution, the desired lower alkyl ditartaric acid diester can be isolated. However, the lower alkyl ditartaric acid ester has a high affinity for water, and the yield decreases when washed with water. If the lower alkyl diester of tartaric acid transferred to the aqueous layer is back-extracted with an organic solvent, the yield can be recovered, but the operation becomes complicated.

A crude product containing impurities such as tartaric acid, a lower alkyl tartaric acid monoester and a lower alkyl tartaric acid diester polymer can be purified by vacuum distillation, but the lower alkyl tartaric acid diester is thermally decomposed. Because it is easy to use a high-vacuum distillation facility and distilling in a short period of time, the product yield is reduced, and it is difficult to commercialize the product by ordinary vacuum distillation. In particular, in the case of the optically active lower alkyl ditartaric acid ester, not only the chemical purity is reduced, but also the optical purity is reduced, so that it is difficult to employ the distillation purification method, and the isolation and purification are complicated. Operation is required.

Therefore, in the present invention, thin film distillation is employed in order to obtain industrially high yield and high quality lower alkyl ditartaric acid diester.

Here, the thin film temperature during thin film distillation is 80 to 2
The temperature is preferably 00 ° C, more preferably 100 to 150 ° C. Further, the internal pressure is preferably from 30 to 1330 Pa, and more preferably from 60 to 665 Pa. The feed rate to the thin film depends on the temperature of the thin film, the internal pressure, the size and equipment specifications of the thin film distillation equipment, or the type of lower alkyl ditartaric acid diester, but when using a thin film still having a heat transfer area of 50 to 100 cm ² , , 50-600 g / cm ²
Hr is preferred, and more preferably 100 to 400 g /
cm ² · Hr.

By subjecting the crude optically active lower alkyl diester to thin-film distillation under the above conditions, a high-quality and high-quality optically active tartaric acid diester can be industrially produced.

[0023]

The present invention will be described in more detail with reference to the following Examples and Comparative Examples, but the present invention is not limited by these ranges.

The optical purity of the optically active lower alkyl ditartaric diester was analyzed by the following capillary gas chromatography. Column: Chrome Pack CP-Chirasil-DEX-CB 25m *
0.32mmφ (WCOT fused silica capillary column) Temperature: 150 ° C Injection and detection temperature: 200 ° C Detection method: FID Carrier gas and column pressure: Helium gas, 100
kPa split flow rate: ５０50 ml / min Purity analysis of the lower alkyl tartaric diester was performed by the following capillary gas chromatography. Column: TC-17 (manufactured by GL Science Co., Ltd.) 0.53 mm × 15 m in diameter Column temperature: 50 to 280 ° C. (heated at a rate of 10 ° C./min) Injection and detection temperature: 250 ° C. Detection method: FID carrier Gas and column pressure: helium gas, 60k
Pa split flow rate: 100 ml / min Example 1 D-tartaric acid (manufactured by Toray Industries, Inc., optical purity 99.9% ee or more) was placed in a 1 L three-necked flask equipped with a thermometer, a condenser, a dropping funnel, and a stirrer. 0.1 g (0.8 mol), ethanol (Katayama Chemical Co., Ltd., special grade reagent) 7
3.7 g (1.6 mol), toluene (Katayama Chemical Co., Ltd.)
432.3 g was added and stirred. to this,
8.8 g (24 mmol) of a 10% ethanol solution of hydrogen chloride prepared by blowing hydrogen chloride gas into ethanol was added, and the mixture was heated at 80 ° C. for 2 hours. Then, 2.0 g of a 48% aqueous solution of caustic soda (caustic soda 2) prepared by dissolving caustic soda (a first-class reagent manufactured by Katayama Chemical Co., Ltd.) in water.
4 mmol), a simple distillation apparatus was attached, and water and ethanol in the flask were mixed with toluene under reduced pressure while adding 180.1 g of toluene with a dropping funnel.
Distilled under ° C. After distilling out about 240 g of a mixture of water, ethanol and toluene, the mixture was cooled, and the concentration of D-tartaric acid and D-tartaric acid monoethyl ester in the liquid was analyzed. Rate is 14%, D-tartaric acid monoethyl ester formation rate is 34%
Met. 64.5 g (1.4 mol) of ethanol was added, and thionyl chloride (Katayama Chemical Co., Ltd.) was added at 30 to 40 ° C.
61.9 g (0.52 mol) were added dropwise in about 30 minutes. After stirring for 2 hours, water and ethanol in the flask were evaporated at 50 ° C. together with toluene under reduced pressure while adding 72.0 g of toluene with a dropping funnel.
About 108 g of a mixture of water, ethanol and toluene was distilled off to obtain about 650 g of a concentrate. The yield of D-tartaric acid diethyl ester in the concentrate was almost 100%. After cooling the concentrate to 35 ° C. or lower, 6.7 g (0.08 mol) of sodium hydrogencarbonate (Katayama Chemical Co., Ltd., primary reagent)
Was added thereto, and the mixture was stirred at room temperature for 1 hour to neutralize hydrochloric acid remaining in the system. The reaction solution was filtered under reduced pressure to remove inorganic substances, and then the toluene layer was concentrated under reduced pressure to obtain about 300 g of a concentrate. 65cm ² (φ30mm × 10m
m) and fed to a still having a thin film area in about 3 hours to perform thin film distillation. The temperature of the thin film part is 100-110
° C, and the degree of reduced pressure in the system was 133 Pa. As a result, 157.2 g of diethyl D-tartaric acid was obtained. The isolation yield of D-tartaric acid diethyl ester was 95.3%. The optical purity was 99.9% ee or more, and the optical purity was not reduced. Chemical purity was 99.6%, D-tartaric acid monoethyl ester was 0.3% or less, and D-tartaric acid diethyl ester dimer was 0.1% or less.

Comparative Example 1 The reaction was carried out in the same manner as in Example 1 to obtain about 650 g of a concentrate. The concentrate is allowed to cool to 35 ° C. or lower, and 6.7 g (0.08%) of sodium hydrogen carbonate (a first-class reagent manufactured by Katayama Chemical Co., Ltd.)
Mol) and sodium chloride (Katayama Chemical Co., Ltd., primary reagent) were dissolved in water, and 33 g of 8% saline solution was added to the reaction solution. After 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. Then, the organic layer was concentrated to dryness under reduced pressure at 40 ° C., the solvent was distilled off, and the residue was filtered to obtain 156.7 g of diethyl D-tartaric acid. The yield of D-tartaric acid diethyl ester based on the charged D-tartaric acid is 95.0%.
Met. The optical purity was 99.9% ee or more, and the optical purity did not decrease. Chemical purity is 98.5%, D-tartaric acid monoethyl ester is 0.1% or less, D
-1.2% of dimer of tartaric acid diethyl ester was contained.

Example 2 In a 1 L three-necked flask equipped with a thermometer, a condenser, a dropping funnel and a stirrer, 120.1 g of D-tartaric acid (manufactured by Toray Industries, Inc., optical purity of 99.9% ee or more) was added. .8 mol), ethanol (Katayama Chemical Co., Ltd., special grade reagent) 7
3.7 g (1.6 mol), toluene (Katayama Chemical Co., Ltd.)
432.3 g was added and stirred. to this,
8.8 g (0.024 mol of hydrogen chloride) of a 10% ethanol solution of hydrogen chloride prepared by blowing hydrogen chloride gas into ethanol was added, and the mixture was heated at 80 ° C. for 2 hours. Then, 2.0 g of a 48% aqueous solution of caustic soda (0.024 mol of caustic soda) prepared by dissolving caustic soda (Katayama Chemical Co., Ltd., first-class reagent) in water was added, and then a simple distillation apparatus was attached. Water and ethanol in the flask were distilled off at 70 ° C. together with toluene under reduced pressure while adding 180.1 g of toluene. After distilling out about 240 g of a mixture of water, ethanol and toluene, 73.7 g of ethanol
(1.6 mol) 10% hydrogen chloride ethanol solution 4.4
g (0.012 mol of hydrogen chloride) was added, and the mixture was heated at 80 ° C. for 2 hours. Next, 1.0 g of a 48% aqueous sodium hydroxide solution
(0.012 mol of caustic soda), and while adding 120.1 g of toluene with a dropping funnel, the water and ethanol in the flask were mixed with toluene at 70 ° C. under reduced pressure.
Evaporated below. After distilling out about 145 g of a mixture of water, ethanol and toluene, 36.9 g of ethanol (0.
(8 mol), 4.4 g of a 10% ethanol solution of hydrogen chloride (0.012 mol of hydrogen chloride) was added, and the mixture was heated at 80 ° C. for 2 hours. Next, after adding 1.0 g of 48% aqueous sodium hydroxide solution (0.012 mol of sodium hydroxide), water and ethanol in the flask were evaporated together with toluene at 70 ° C. under reduced pressure while adding 72.0 g of toluene with a dropping funnel. About 108 g of a mixture of water, ethanol and toluene was distilled to obtain about 650 g of a concentrate. The yield of D-tartaric acid diethyl ester in the concentrate was about 92%. 3 concentrates
After cooling to 5 ° C. or lower, 6.7 g (0.08 mol) of sodium hydrogencarbonate (Katayama Chemical Co., Ltd., first grade reagent) was added, and the mixture was stirred at room temperature for 1 hour to remain in the system. The existing hydrochloric acid was neutralized. The reaction solution was filtered under reduced pressure to remove inorganic substances, and then the toluene layer was concentrated under reduced pressure to obtain about 300 g of a concentrate. Thereafter, the concentrate was subjected to thin-film distillation in the same manner as in Example 1 to obtain 146.7 g of D-tartaric acid diethyl ester.
The isolation yield of D-tartaric acid diethyl ester was 88.9%. The optical purity was 99.9% ee or more, and the optical purity did not decrease. Chemical purity is 99.6%, D-tartaric acid monoethyl ester is 0.3% or less, D
-Dimer of tartaric acid diethyl ester was 0.1% or less.

Comparative Example 2 The reaction was carried out in the same manner as in Example 2 to obtain about 650 g of a concentrate.
After cooling the concentrate to 35 ° C. or lower, 6.7 g of sodium hydrogen carbonate (a first-class reagent manufactured by Katayama Chemical Co., Ltd.) (0.08 g)
Mol) and sodium chloride (a first-order reagent manufactured by Katayama Chemical Co., Ltd.) were added to the reaction solution, and 33 g of 8% saline solution was added to the reaction solution. The mixture was stirred well, and 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. Then, the organic layer was concentrated to dryness under reduced pressure at 40 ° C., the solvent was distilled off, and the residue was filtered to obtain 140.2 g of diethyl D-tartaric acid. The dimer in the obtained D-tartaric acid diethyl ester was 0.4%,
The yield of D-tartaric acid diethyl ester relative to tartaric acid is 8
5%. The optical purity was 99.9% ee or more, and the optical purity did not decrease.

Comparative Example 3 The reaction was carried out in the same manner as in Example 2 to obtain about 650 g of a concentrate.
After cooling the concentrate to 35 ° C. or lower, 6.7 g of sodium hydrogen carbonate (a first-class reagent manufactured by Katayama Chemical Co., Ltd.) (0.08 g)
Mol), and the mixture was stirred at room temperature for 1 hour to neutralize hydrochloric acid remaining in the system. The reaction solution was filtered under reduced pressure to remove inorganic substances, and then the toluene layer was concentrated under reduced pressure. As a result of vacuum simple distillation of the concentrate, 0.7 kPa, 130 to 140
105 g of D-tartaric acid diethyl ester was obtained as a fraction at ° C. The isolation yield was 63.7%. The optical purity is 9
It was 8.3% ee, and the optical purity was lowered. The chemical purity was 98.5%, and the content of the D-tartaric acid diethyl ester dimer was 1.5%.

[0029]

According to the present invention, a high-purity lower alkyl ditartaric acid diester can be efficiently produced. When optically active tartaric acid is used, it can be produced without lowering optical purity.

Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat II (reference) C07B 61/00 300 C07B 61/00 300 C07M 7:00 C07M 7:00

Claims (4)

[Claims] 1. A process for producing a lower alkyl tartaric diester, comprising subjecting a lower alkyl ditartaric acid obtained by an esterification reaction of tartaric acid and a lower alkyl alcohol to thin-film distillation. 2. The method for producing a lower alkyl ditartaric acid ester according to claim 1, wherein thionyl chloride is present in the esterification reaction. 3. The method for producing a lower diester of tartaric acid according to claim 1, wherein the tartaric acid is optically active tartaric acid. 4. The method for producing a lower alkyl ditartaric acid ester according to claim 1, wherein the lower alcohol is an alcohol having 1 to 6 carbon atoms.