JP2002128735A - Method for manufacture of high purity hydroxymalonic acid diester - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for manufacturing high purity diester of hydroxymalonic acid from crude diester of chloromalonic acid on an industrial scale in high yield. SOLUTION: This manufacturing method comprises reacting a betaine or a lower fatty acid salt to the diester of chloromalonic acid, extracting/removing a hydrophobic impurity by using an aliphatic hydrocarbon or an alicyclic hydrocarbon and then extracting the objective compound by using a solvent immiscible with water and dissolving the objective compound.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for industrially and advantageously producing a high-purity hydroxymalonic acid diester.

[0002]

2. Description of the Related Art Hydroxymalonic acid diester, especially diethyl hydroxymalonic acid, is a compound useful as an intermediate material for fine chemicals such as pharmaceuticals and agricultural chemicals. Heretofore, several methods for producing hydroxymalonic diester from malonic diester are known.
One of the methods is to react hydroxymalonic acid with ethanol in the presence of concentrated sulfuric acid (J, Am. Chem, Soc.
83, 4231 (1961)). Hydroxymalonic acid in this method is usually synthesized in two steps from diethyl malonate, but the yield is low and not practical. In addition, malonic acid diester which is mixed in the production process of raw material hydroxymalonic acid,
Since it is not easy to separate hydroxymalonic acid from chloromalonic acid diester, dichloromalonic acid diester and by-products derived from them, crude hydroxymalonic acid containing these as raw materials will be used,
These impurities are also mixed in the hydroxymalonic acid diester, which lowers the purity of the target product.

[0003] Further, a method of reacting acetoxymalonic acid diester with potassium bicarbonate or an acid (J. Org.
Chem., 55, 4515-4516 (1990)). In this method, the raw material acetoxymalonate diester is obtained by reacting bromomalonate diester obtained by bromination of malonate diester with potassium acetate in acetic acid, but also malonic diester mixed in the raw material. Since it is difficult to remove impurities such as bromomalonic acid diester and dibromomalonic acid diester, these impurities are also contaminated in the target hydroxymalonic acid diester, which lowers the yield and purity of the target product. However, there is no description in any of the documents regarding the method for removing these contaminants. In addition, a method for synthesizing hydroxymalonic acid diester by a two-step reaction using malonic acid diester as a starting material and chloromalonic acid diester is not known.

[0004]

Therefore, the present inventors started from inexpensive malonic diesters and obtained high-purity hydroxymalonic diesters even if the intermediate raw material chloromalonic diester was crude. Research has been conducted to develop a method that can be used.

[0005]

As a result, the present inventors have made betaine or an alkali metal acetate act on a chloromalonic acid diester obtained by chlorinating a malonic acid diester, and the reaction mixture was subjected to a specific extraction solvent. Thus, the above-mentioned problem of industrially and advantageously producing the target hydroxymalonic acid diester with high purity and high yield was solved by extracting and removing impurities first and then extracting the target product. That is, the present invention provides (1) a reaction of betaine or a lower fatty acid salt with chloromalonic acid diester in the presence of water or a hydrophilic solvent, and after distilling off the solvent from the resulting reaction mixture, optionally removing water. In addition, carbon number 5-1
The hydrophobic impurities are extracted and removed with an impurity extraction solvent selected from aliphatic hydrocarbons and alicyclic hydrocarbons of 0, and then a target substance selected from halogenated hydrocarbons, fatty acid esters, aromatic hydrocarbons and ethers (2) a method for producing a high-purity hydroxymalonic acid diester by extracting a target substance with an extraction solvent, (2) the production method according to (1), wherein the impurity extraction solvent is at least one selected from hexane, heptane, octane and cyclohexane; 3) The production method according to (1), wherein the target solvent is a fatty acid ester, and (4) betaine is represented by the general formula (1). (Wherein R ¹ , R ² and R ³ are the same or different and each represent a hydrocarbon group having 1 to 18 carbon atoms, and R ⁴ represents an alkylene group having 1 to 4 carbon atoms which may have a substituent. The method according to any one of (1) to (3), wherein the lower fatty acid salt is a compound represented by the general formula (2): R ⁵ COOM (2) wherein R ⁵ is Wherein the alkyl having 1 to 3 carbon atoms and M represents an alkali metal or ammonium group), the production method according to any one of (1) to (4),
(6) the chloromalonic acid diester is chloromalonic acid diethyl ester, the hydrophilic solvent is ethanol,
The production method according to any one of (1) to (4), wherein the impurity extraction solvent is hexane or heptane and the target substance extraction solvent is ethyl acetate, and (7) the chloromalonic acid diester is obtained by adding chlorine to malonic acid diester. The method according to (1), which is obtained by reacting a gas.

[0006]

DESCRIPTION OF THE PREFERRED EMBODIMENTS In the present invention, first, betaine or a lower fatty acid salt is reacted with chloromalonic acid diester in the presence of a hydrophilic solvent. The ester portion of the chloromalonic acid diester is not particularly limited, and usually includes the same or different hydrocarbon residues. Preferred examples of the ester moiety include, for example, an aliphatic hydrocarbon residue having 1 to 3 carbon atoms, and specific examples include methyl, ethyl, n-propyl, and isopropyl. Most typical are methyl and ethyl. As a method for producing this chloromalonic acid diester, chlorination of malonic acid diester and esterification of chloromalonic acid are known.
The chlorination of malonic diester is carried out, for example, by using chlorine gas (Cl
₂ ), sulfuryl chloride (SO ₂ Cl ₂ ), phosphorus pentachloride (PCl ₅ ), ethyl trichloroacetate (Cl ₃ CC)
It can be carried out by a method known per se using a chlorinating agent such as OOC ₂ H ₅ ). In the method of the present invention, the reaction mixture obtained by reacting the chlorinating agent with a malonic acid diester or an organic solvent solution thereof is optionally washed with water, and the crude chloromalonic acid diester obtained by distilling off the solvent is used as a raw material. Since it can be used, it is extremely advantageous as an industrial production method of hydroxymalonic acid diester.
The chlorination of the malonic acid diester can be carried out by dissolving the malonic acid diester in a solvent such as toluene, and reacting the reaction system with a chlorinating agent at normal or elevated temperature. The obtained reaction mixture is washed with water, an aqueous alkali solution, an aqueous saturated salt solution or the like as necessary, and the solvent is distilled off to obtain a chloromalonic acid diester which can be used as a raw material in the method of the present invention.

Next, chloromalonic diester is reacted with betaine or a lower fatty acid salt in the presence of water or a hydrophilic solvent to produce hydroxymalonic diester. Solvents that can be used are water or hydrophilic solvents. Examples of the hydrophilic solvent include methanol, ethanol, 1-
Propanol, 2-propanol, 1-butanol, 2
Alcohols having 1 to 5 carbon atoms such as butanol, 2-methyl-1-propanol and 2-methyl-2-propanol; alcoholic solvents such as mixed solvents thereof; and carbon atoms having 2 to 3 carbon atoms such as acetic acid and propionic acid. Fatty acids. Among them, methanol, ethanol, 1-propanol and the like are preferable. The amount of water or hydrophilic solvent used is not particularly limited, but is usually about 0.1 to 10 times, preferably about 1 to 5 times the weight of chloromalonic acid diester. The betaine used in the present invention may be any one having a carboxyl group as an anion part and a quaternary ammonium group as a cation part in the molecule, but usually, the general formula (1) (Wherein R ¹ , R ² and R ³ are the same or different and each represent a hydrocarbon group having 1 to 18 carbon atoms, and R ⁴ represents an alkylene group having 1 to 4 carbon atoms which may have a substituent. ) Are preferably used.

(1) wherein R ¹ and R ² are methyl,
Alkyl having 1 to 3 carbon atoms such as ethyl and propyl is preferable, and a methyl group is particularly preferable. R ³ has 1 to 18 carbon atoms
Is preferred, and a linear alkyl group having 1 to 3 carbon atoms is particularly preferred. R ⁴ is an alkylene having 1 to 4 carbon atoms such as methylene, ethylene, propylene, and butylene, and may have a substituent that does not participate in the reaction. As the lower fatty acid salt, preferably, a compound represented by the formula (2) R ⁵ COOM (2) (wherein R ⁵ is an alkyl having 1 to 3 carbons and M represents an alkali metal or ammonium group) is mentioned. Can be (2) wherein the number of carbon atoms represented by R ⁵ is 1
Examples of the alkyl groups (1) to (3) include methyl, ethyl and propyl, and examples of the alkali metal represented by M include sodium, potassium and lithium. Representative compounds represented by formula (2) are potassium acetate, potassium propionate, sodium acetate, ammonium acetate, and the like, with potassium acetate being particularly preferred. The amount of the betaine and lower fatty acid salt used is usually 1 to 6 times mol, preferably 1.2 to 4 times mol of chloromalonic acid diester.
It is twice the mole.

The reaction between the chloromalonic acid diester and betaine or a lower fatty acid salt is carried out at 50 ° C. to the reflux temperature of the reaction solvent, preferably at the reflux temperature. The reaction time varies depending on the type and amount of each raw material and the solvent used, the reaction temperature and the like, but is usually 1 hour to 100 hours, preferably about 4 to 48 hours. By this reaction, the desired hydroxymalonic acid diester is formed in the reaction mixture. In order to isolate the target substance from the reaction mixture, it is preferable to first distill off the solvent in the reaction mixture. The distillation can be performed under normal pressure or reduced pressure. If necessary, water is added to the obtained residue, and an impurity extraction solvent, that is, a solvent which does not dissolve the target substance as much as possible, dissolves hydrophobic impurities, and is insoluble in water, lower alcohols and lower fatty acids, is contained in the residue. Hydrophobic impurities such as raw material chloromalonic acid diester, chloromalonic acid diester, dichloromalonic acid diester and the like are extracted and removed. Examples of the solvent for extracting impurities include aliphatic hydrocarbons having 5 to 10 carbon atoms and alicyclic hydrocarbons having 5 to 7 carbon atoms.

Examples of the aliphatic hydrocarbon having 5 to 10 carbon atoms include pentane, hexane, heptane, octane,
Isohexane, isoheptane, isooctane, petroleum ether and the like can be mentioned, and hexane, heptane and octane are particularly preferred. Examples of the alicyclic hydrocarbon include cyclopentane, cyclohexane, and cycloheptane, and cyclohexane is particularly preferable. The amount of the impurity extraction solvent used is 0.1 to 10 times the weight of the theoretical yield of hydroxymalonic acid diester, preferably 0.2 to 10 times.
It is three times the weight. The extraction temperature is usually in the range from 0 ° C to the boiling point of the solvent, preferably from 10 to 35 ° C. Extraction is 2
It can be performed in several times. The extract may be washed with water if necessary, and the wash may be combined with the original hydrophilic layer. In this way, the target substance is dissolved in the hydrophilic layer containing the target substance after the hydrophobic impurities are extracted and removed, and the water-soluble compounds such as betaine and lower fatty acid salts are dissolved without mixing with water. Extract the desired product with a difficult target extraction solvent.

Examples of the solvent for extracting the target substance include halogenated hydrocarbons such as dichloromethane, chloroform and dichloroethane, fatty acid esters such as methyl acetate, ethyl acetate, isopropyl acetate, methyl propionate and ethyl propionate, benzene, toluene, and the like. Examples thereof include aromatic hydrocarbons such as xylene, and ethers such as diethyl ether, dipropyl ether and diisopropyl ether, and ethyl acetate can be conveniently used. The amount of these target extraction solvents used is 0.1 to 10 times the theoretical yield of hydroxymalonic acid diester,
Preferably it is 0.2 to 3 times the amount. Extraction temperature is usually 0 ° C
To the boiling point of the solvent from 10 to 3
It can conveniently be performed at room temperature of 5 ° C. The extraction may be performed in two to several times. The standing time for separating the hydrophilic layer and the oil layer is about 5 seconds to 3 hours, preferably 1 minute to 1 hour. The oil layer in which the target product thus obtained is dissolved is washed with a salt solution such as water or saline, if necessary, and the extraction solvent is distilled off to obtain a high-purity target hydroxymalonic acid diester in high yield. Can be

[0012]

EXAMPLES The present invention will be specifically described below with reference to examples. Example 1 Toluene (166) of diethyl malonate (96.1 g)
g) Chlorine gas (4.0 g) was blown into the solution and heated to 60 ° C. The solution was stirred for 10 minutes, and after confirming the progress of the reaction, chlorine gas (54.0 g) was further blown in at room temperature for 3 hours. After stirring for an additional hour, water (90 g) was added. The organic layer was separated and washed sequentially with a 6.3% aqueous sodium hydrogen carbonate solution (160 g), water (50 g), and saturated saline (60 g). The toluene was distilled off by distillation to obtain crude diethyl chloromalonate. To this, ethanol (948 g), betaine (N, N, N-
Trimethyl-N-carboxymethylammonium betaine) (211 g) was added, and the mixture was stirred with heating under reflux for 48 hours. After the reaction, the solvent was distilled off by distillation, water (100 g) was added to the residue, and the mixture was extracted twice with heptane (80 g). The heptane layer was extracted with water (40 g) and combined with the previous aqueous layer. To this aqueous layer was added sodium chloride (30 g), and the mixture was extracted five times with ethyl acetate (70 g). The ethyl acetate layer was washed with saturated saline and dried over anhydrous sodium sulfate (100 g). After concentrating the organic layer by atmospheric distillation, diethyl hydroxymalonate (81.5 g, yield 77%, purity 98%) was obtained by vacuum distillation. bp. 104-108 ° C (8.0-8.5 mmHg) IR (NaCl): 3480, 1750, 1236,1
116 cm ^-1

Example 2 Diethyl malonate (96.1 g) in toluene (166)
g) Chlorine gas (4.0 g) was blown into the solution and heated to 60 ° C. This solution was stirred for 10 minutes, and after confirming the progress of the reaction, chlorine gas (54.3 g) was further blown in at room temperature for 3 hours. After stirring for another hour, water (9
0 g) was added. The organic layer was separated and washed sequentially with a 6.3% aqueous sodium hydrogen carbonate solution (160 g), water (50 g), and saturated saline (60 g). The toluene was distilled off by distillation to obtain crude diethyl chloromalonate. to this,
Ethanol (948 g) and betaine (211 g) were added, and the mixture was stirred for 48 hours under heating and reflux. After the reaction, the solvent was distilled off by distillation, water (100 g) was added to the residue, and the mixture was extracted twice with hexane (80 g). The hexane layer was extracted with water (40 g) and combined with the previous aqueous layer. This aqueous layer was extracted three times with toluene (85 g). Further, sodium chloride (30 g) was added to the aqueous layer, and the extraction was repeated in the order of toluene (85 g), ethyl acetate (85 g), and ethyl acetate (40 g). The toluene layer and the ethyl acetate layer were combined, washed with saturated saline, and dried over anhydrous sodium sulfate (100 g). Removal of the solvent under reduced pressure gave diethyl hydroxymalonate (86.4 g, 82% yield, 98% purity).
%).

Example 3 A chlorine gas (3.0 g) was blown into a toluene (64 ml) solution of diethyl malonate (32 g) and heated to 65 ° C. The solution was stirred for 5 minutes, and after confirming the progress of the reaction, chlorine gas (15.0 g) was further blown in at 31 to 35 ° C. for 1 hour. After stirring for another hour, water (3
0 ml) was added. The organic layer was separated and washed with a 10% aqueous sodium hydrogen carbonate solution (50 ml), water (30 ml), and saturated saline (30 ml) in this order. The toluene was distilled off by distillation to obtain crude diethyl chloromalonate. To this, ethanol (117 ml) and potassium acetate (39
g) was added and the mixture was stirred under reflux for 7 hours. After the reaction, the solvent was distilled off by distillation, water (70 g) was added to the residue, and the mixture was extracted twice with hexane (50 g). This hexane layer was extracted with water (30 g) and combined with the previous aqueous layer. Salt (20 g) was added to the aqueous layer, and the mixture was extracted three times with ethyl acetate (50 g). The ethyl acetate layer was washed with a saturated saline layer and dried over anhydrous sodium sulfate (70 g). After concentrating the organic layer by atmospheric distillation, diethyl hydroxymalonate (18 g, yield 51%, purity 98%) was obtained by vacuum distillation.

Example 4 A solution of diethyl chloromalonate (94 g) obtained in the same manner as in Example 3 and potassium acetate (108 g) in ethanol (323 ml) was stirred under heating and reflux for 23 hours.
After the reaction, the solvent was distilled off by distillation, and water (1
50 ml) and extracted twice with heptane (60 g). The heptane layer was extracted with water (30 g) and combined with the previous aqueous layer. To this aqueous layer was added sodium chloride (22 g), and the mixture was extracted three times with ethyl acetate (150 ml once, 100 ml twice). The organic layer was washed with water and a saturated saline layer, and dried over anhydrous sodium sulfate. After concentrating the organic layer by atmospheric distillation, diethyl hydroxymalonate (59.7 g, yield 70%, purity 98%) was obtained by vacuum distillation.

[0016]

The physical and chemical properties of hydroxymalonic diester are mixed with the raw material, impurities produced as a by-product during the reaction, and unreacted raw materials such as dichloromalonic diester and chloromalonic diester. Therefore, it is difficult to separate them from each other, and it is difficult to obtain a high-purity target product and a high yield. According to the present invention, even if a crude intermediate material is used, a high-purity target product can be obtained in a high yield by a relatively simple operation, which is an industrially extremely advantageous method.

Claims (7)

[Claims] 1. A chloromalonic acid diester is reacted with betaine or a lower fatty acid salt in the presence of water or a hydrophilic solvent, and the solvent is distilled off from the resulting reaction mixture. Extract and remove hydrophobic impurities with an impurity extraction solvent selected from 5 to 10 aliphatic hydrocarbons and alicyclic hydrocarbons, and then selected from halogenated hydrocarbons, fatty acid esters, aromatic hydrocarbons and ethers. A method for producing a high-purity hydroxymalonic acid diester by extracting a target substance with a target substance extraction solvent. 2. The method according to claim 1, wherein the solvent for extracting impurities is at least one selected from hexane, heptane, octane and cyclohexane.
2. The method according to claim 1, which is a seed. 3. The method according to claim 1, wherein the target solvent is a fatty acid ester. 4. A betaine having the general formula (1) (Wherein R ¹ , R ² and R ³ are the same or different and each represent a hydrocarbon group having 1 to 18 carbon atoms, and R ⁴ represents an alkylene group having 1 to 4 carbon atoms which may have a substituent. The method according to any one of claims 1 to 3, which is a compound represented by the formula: 5. The lower fatty acid salt is represented by the general formula (2) R ⁵ COOM (2) (wherein R ⁵ is alkyl having 1 to 3 carbon atoms and M represents an alkali metal or ammonium group). The method according to any one of claims 1 to 3, which is a compound. 6. The chloromalonic acid diester is chloromalonic acid diethyl ester, the hydrophilic solvent is ethanol, the impurity extraction solvent is hexane or heptane, and the target substance extraction solvent is ethyl acetate. The production method according to any one of the above. 7. The method according to claim 1, wherein the chloromalonic diester is obtained by reacting malonic diester with chlorine gas.