JP4191008B2 - Method for producing aminocarboxylic acid ester - Google Patents

Description

  The present invention relates to a method for producing aminocarboxylic acid esters useful as surfactants, surfactant intermediates, pharmaceuticals, agricultural chemical intermediates and the like.

  As an example of synthesizing an aminocarboxylic acid ester, Patent Document 1 and Non-Patent Documents 1 to 3 use a secondary amine such as diethylamine or dipropylamine and ethyl chloroacetate in a large amount of a reaction solvent such as benzene or acetone. In this method, the salt produced as a by-product is removed by alkaline water washing or filtration, and optionally distilled.

  However, since this method uses a large amount of reaction solvent, the yield and productivity are low, and operations such as solvent removal and solvent recovery are also required. For this reason, there are problems such as an increase in manufacturing equipment, a complicated manufacturing process, and inability to manufacture at low cost.

  In addition, the method of reacting bromoacetic acid and dimethylamine described in Patent Document 2 and the hydrolysis by reacting formalin, sodium cyanide and dimethylamine described in Patent Document 3 in the presence of sodium bisulfite. The aminocarboxylic acid ester can also be produced by applying a method of synthesizing an aminocarboxylic acid by extraction, crystallization, and esterifying with an alcohol.

However, these methods have a large number of steps, a large amount of impurities are generated as a by-product in the reaction, require complicated operations such as purification, and there are restrictions on the material of the device. It could not be manufactured at a low cost.
Japanese Patent Publication No.31-72 Japanese Patent Publication No.58-34478 USP 4,968,839 Farmaco (Pavia), Ed.Pract. 16, 190-3 (1961) J. Pharm. Pharmacol. 16 (9), 618-26 (1964) J. f. Praktische Chem. (1990), 332 (3), 325-30

  An object of the present invention is a method for producing an aminocarboxylic acid ester useful as a surfactant, a surfactant intermediate, a pharmaceutical and an agrochemical intermediate, etc., and a high-quality product can be obtained in a high yield. It is to provide an industrially valuable production method with high productivity and excellent economic efficiency.

  As a means for solving the problems, the present invention provides a secondary amine represented by the following general formula (I):

[Wherein, R ¹ may be unsubstituted or substituted, a linear or branched alkyl group having 2 to 6 carbon atoms, or an alkenyl group, a hydroxyalkyl group, or R ² may be unsubstituted or substituted. A linear or branched alkyl group having 1 to 6 carbon atoms, an alkenyl group, or a hydroxyalkyl group is shown, and R ¹ and R ² may be bonded to each other to form a ring. ]
And a halocarboxylic acid ester represented by the following general formula (II)

[Wherein, X is a halogen atom, R ³ is hydrogen or a linear or branched alkyl group having 1 to 6 carbon atoms, R ⁴ is an unsubstituted or substituted linear chain having 1 to 6 carbon atoms or A branched alkyl group or an alkenyl group is shown. ]
To an aminocarboxylic acid ester represented by the following general formula (III)

[Wherein R ¹ , R ² , R ³ , and R ⁴ have the same meaning as described above. ]
Is a method of manufacturing
The reaction of the secondary amine represented by the general formula (I) and the halocarboxylic acid ester represented by the general formula (II) is performed without a solvent, or the solvent is 1 mass times or less with respect to the mass of the halocarboxylic acid ester. A process for producing an aminocarboxylic acid ester represented by the general formula (III) is provided.

  According to the production method of the present invention, since the target product can be obtained with no solvent or in a small amount of solvent, the purity and yield of the target aminocarboxylic acid ester can be increased. This eliminates or greatly reduces the burden required for removal and recovery of the product, so that productivity can be improved and manufacturing costs can be reduced.

  In the production method of the present invention, the amination reaction of the secondary amine represented by the general formula (I) and the halocarboxylic acid ester represented by the general formula (II) is carried out without a solvent, or the halocarboxylic acid ester It is carried out using a small amount of solvent not more than 1 mass times the mass.

In the secondary amine represented by the general formula (I) used in the present invention, the meaning of each symbol is as described above, but R ¹ is preferably a linear or branched alkyl having 2 to 6 carbon atoms. R ² is preferably a linear or branched alkyl group having 1 to 6 carbon atoms.

  Examples of the secondary amine represented by the general formula (I) include methylethylamine, methylpropylamine, methylisopropylamine, methylbutylamine, methylisobutylamine, methyl-t-butylamine, methylamylamine, methylisoamylamine, methylcyclohexane. Propylamine, methylcyclobutylamine, methylcyclopentylamine, methylcyclohexylamine, methylethanolamine, diethylamine, ethylpropylamine, ethylisopropylamine, ethylbutylamine, ethylisobutylamine, ethyl-t-butylamine, ethylamylamine, ethylisoamylamine , Ethylcyclopropylamine, ethylcyclobutylamine, ethylcyclopentylamine, ethylcyclohexylamine, ethylethanolamine , Dipropylamine, diisopropylamine, propylbutylamine, isopropylbutylamine, propylisobutylamine, isopropylisobutylamine, propyl-t-butylamine, isopropyl-t-butylamine, propylamylamine, isopropylamylamine, propylisoamylamine, propylisoamylamine , Propylcyclopropylamine, isopropylcyclopropylamine, propylcycloptylamine, isopropylcycloptylamine, propylcyclopentylamine, isopropylcyclopentylamine, propylcyclohexylamine, isopropylcyclohexylamine, propylethanolamine, isopropylethanolamine, dibutylamine, diisobutylamine J-t-Buchi Amine, diethanolamine, pyrrolidine, pyrrole, piperidine and the like, especially methyl ethyl amine, diethylamine, dipropylamine, diisopropylamine, pyrrolidine are preferable.

In the halocarboxylic acid ester represented by the general formula (II) used in the present invention, the meaning of each symbol is as described above, but X is preferably Cl, Br, or I, and particularly preferably Cl; R ³ is Hydrogen or a linear or branched alkyl group having 1 to 3 carbon atoms is preferable, particularly hydrogen or a methyl group is preferable; R ⁴ is preferably a linear or branched alkyl group having 1 to 6 carbon atoms, particularly carbon. A linear or branched alkyl group of 1 to 3 is preferable.

  Examples of the halocarboxylic acid ester represented by the general formula (II) include methyl chloroacetate, ethyl chloroacetate, propyl chloroacetate, isopropyl chloroacetate, methyl 2-chloropropionate, ethyl 2-chloropropionate, and 2-chloropropionic acid. Propyl, isopropyl 2-chloropropionate, methyl 2-chlorobutanoate, ethyl 2-chlorobutanoate, propyl 2-chlorobutanoate, isopropyl 2-chlorobutanoate, methyl bromoacetate, ethyl bromoacetate, propyl bromoacetate, isopropyl bromoacetate, 2 -Methyl bromopropionate, ethyl 2-bromopropionate, propyl 2-bromopropionate, isopropyl 2-bromopropionate, methyl 2-bromobutanoate, ethyl 2-bromobutanoate, propyl 2-bromobutanoate, 2 Isopropyl bromobutanoate, ethyl iodoacetate, propyl iodoacetate, isopropyl iodoacetate, methyl 2-iodopropionate, ethyl 2-iodopropionate, propyl 2-iodopropionate, isopropyl 2-iodopropionate, methyl 2-iodobutanoate, Examples include ethyl 2-iodobutanoate, propyl 2-iodobutanoate, and isopropyl 2-iodobutanoate.

  Among these, methyl chloroacetate, ethyl chloroacetate, propyl chloroacetate, isopropyl chloroacetate, methyl 2-chloropropionate, ethyl 2-chloropropionate, propyl 2-chloropropionate, isopropyl 2-chloropropionate, methyl bromoacetate , Ethyl bromoacetate, propyl bromoacetate, isopropyl bromoacetate, methyl 2-bromopropionate, ethyl 2-bromopropionate, propyl 2-bromopropionate, isopropyl 2-bromopropionate, particularly methyl chloroacetate, chloroacetic acid Ethyl, propyl chloroacetate, isopropyl chloroacetate, methyl 2-chloropropionate, ethyl 2-chloropropionate, propyl 2-chloropropionate, and isopropyl 2-chloropropionate are preferred.

  The halocarboxylic acid ester represented by the general formula (II) may be produced by any method. For example, a method in which a halocarboxylic acid and an alcohol are reacted with a solvent if necessary in the presence of an acid catalyst such as sulfuric acid, methylsulfuric acid, p-toluenesulfonic acid, nitric acid, phosphoric acid, if necessary, a halocarboxylic acid halide After obtaining the corresponding halocarboxylic acid ester by, for example, a method of reacting alcohol with alcohol as necessary, a method of obtaining a high-purity halocarboxylic acid ester by distillation or solvent distillation is applied as necessary. it can.

  The amination reaction of the secondary amine of the general formula (I) and the halocarboxylic acid ester of the general formula (II) is preferably carried out without solvent, but with respect to the mass of the halocarboxylic acid ester of the general formula (II) used. In addition, it can be carried out using a small amount of a solvent of 1 times by weight or less, preferably 0.3 by weight or less.

  The type of solvent in the case of using a reaction solvent is not particularly limited. However, when water is used as a reaction solvent, a halogenated carboxylic acid ester or an aminocarboxylic acid ester may be hydrolyzed, and a solvent other than water is preferable. Include methanol, ethanol, propanol, isopropanol, benzene, toluene, chlorobenzene, xylene, methyl acetate, ethyl acetate, diethyl ether, petroleum ether, acetone and the like.

  The ratio of the secondary amine of the general formula (I) and the halocarboxylic acid ester of the general formula (II) is not particularly limited, but the secondary amine is preferably 0.9 to 5 with respect to 1 equivalent of the halocarboxylic acid ester. Equivalent, more preferably 1.0 to 3.0 equivalents are reacted.

  The reaction temperature and reaction time are not particularly limited, but the reaction temperature is preferably 0 to 100 ° C, more preferably 10 to 80 ° C, and the reaction time is preferably 1 to 30 hours, more preferably 2 to 20 hours.

  After the reaction, an alkali metal hydroxide can be added as necessary, and may be added as an aqueous solution of an alkali metal hydroxide. Alkali metal hydroxides neutralize secondary amine hydrohalides by-produced in the amination reaction to make secondary amines free. Specifically, NaOH, KOH, etc. Can be mentioned. When using an alkali metal hydroxide, it is preferable to add 0.9-1.5 equivalent with respect to 1 equivalent of halocarboxylic acid ester.

  Moreover, in order to suppress the deterioration of the hue of the product due to the amination reaction, the reaction system can be replaced with nitrogen gas, inert gas, or the like, if necessary.

  In the production method of the present invention, it is preferable to provide a step of performing water washing after the amination reaction and further distilling for the purpose of removing salts and impurities by-produced in the amination reaction.

  The amount of water for the water washing treatment is not particularly limited, but is preferably 0.1 to 5 times by mass with respect to the mass of the aminocarboxylic acid ester of the general formula (III) produced from the viewpoint of economy and removal efficiency of salts and the like. 0.2-2 mass times is more preferable.

  The temperature of the washing water is not particularly limited, but is preferably 100 ° C. or less and more preferably 10 ° C. to 80 ° C. from the viewpoint of enhancing the salt removal efficiency. The number of washings is preferably 1 to 5 times, more preferably 1 to 3 times. After the water washing treatment, residual water can be removed by dehydrating after separation and separation.

  Although distillation conditions are not specifically limited, It can carry out in nitrogen gas or an inert gas atmosphere as needed under a normal pressure or pressure reduction.

  Water is further added to the aminocarboxylic acid ester of the general formula (III) obtained by the production method of the present invention, and hydrolyzed using a catalyst as necessary to produce the corresponding aminocarboxylic acid or a salt thereof. Even in this case, a very high purity material containing almost no impurities can be obtained. For this reason, the aminocarboxylic acid obtained by this method or a salt thereof is useful as a surfactant, a surfactant intermediate, a pharmaceutical and an agrochemical intermediate or the like.

Example 1
Into a four-necked flask equipped with a stirrer, thermometer, dropping funnel, Dimroth condenser, and nitrogen inlet, 182.9 g of diethylamine was introduced, and 122.6 g of ethyl chloroacetate was introduced while introducing nitrogen at a temperature of 30 ° C. to 40 ° C. The solution was added dropwise in 20 minutes, and reacted for 6 hours at 55 ° C. without solvent.

  After completion of the reaction, 79.6 g of water was added, followed by washing with water twice to stir at 50 ° C. for 30 minutes and then stand for 30 minutes to discard the aqueous layer. Next, after removing initial fractions such as water and diethylamine remaining at a temperature of 55 ° C. to 150 ° C. under normal pressure, distillation was performed to obtain 145.0 g of the desired ethyl N, N-diethylaminoacetate ( Yield 91%, purity 99.9%). The productivity obtained from the following formula of the target product obtained with respect to the total amount of raw materials charged was 48%.

Example 2
In the same apparatus as in Example 1, 122.6 g of ethyl chloroacetate was added, 119.1 g of methylethylamine was added dropwise at a temperature of 22 ° C. to 35 ° C. over 1 hour, and the reaction was carried out at a temperature of 35 ° C. for 10 hours without solvent. .

  After completion of the reaction, 57.7 g of water was added, followed by washing with water twice to stir at 25 ° C. for 30 minutes and then stand for 30 minutes to discard the aqueous layer. Next, after removing initial fractions such as water and methylethylamine remaining at a temperature of 50 ° C. to 140 ° C. under normal pressure, distillation is performed to obtain the target N-ethyl-N-methylaminoethyl acetate. 132.0 g (yield 91%, purity 99.6%) was obtained. The productivity of the target product was 55%.

Example 3
In the same apparatus as in Example 1, 122.6 g of methyl 2-chloropropionate was added, 160.9 g of diethylamine was added dropwise at a temperature of 20 ° C. to 50 ° C. over 1 hour, and the reaction was carried out at a temperature of 60 ° C. for 8 hours without solvent. I let you.

  After completion of the reaction, 79.6 g of water was added, and after 30 minutes of stirring at 30 ° C., the mixture was allowed to stand for 30 minutes and the water layer was discarded. Next, after removing initial fractions such as water and diethylamine remaining at a temperature of 50 ° C. to 160 ° C. under normal pressure, distillation was performed to obtain 147.7 g of the desired methyl 2-diethylamino-propionate ( Yield 93%, purity 99.7%). The productivity of the target product was 52%.

Example 4
After putting 182.9 g of diethylamine in the same apparatus as in Example 1 and dropping 136.58 g of isopropyl chloroacetate at a temperature of 30 ° C. to 40 ° C. over 1 hour and reacting at a temperature of 60 ° C. for 6 hours without solvent. After cooling to 30 ° C., 83.3 g of 48% NaOH aqueous solution was added and stirred for 10 minutes.

  After completion of the reaction, 104.0 g of water was added, followed by washing with water twice to stir at 50 ° C. for 30 minutes and then stand for 30 minutes to discard the aqueous layer. Next, after removing initial fractions such as water and diethylamine remaining at a vacuum degree of 26 kpa and a temperature of ~ 110 ° C., distillation was performed to obtain 163.1 g (concentration) of the target isopropyl N, N-diethylaminoacetate. 94%, purity 99.4%). The productivity of the target product was 51%.

Comparative Example 1
The reaction was carried out using the same apparatus and reaction conditions as in Example 1 except that 305.5 g of acetone was used as the reaction solvent and the reaction time was 10 hours. After completion of the reaction, 79.6 g of water was added, and the mixture was stirred at 50 ° C. for 30 minutes and allowed to stand for 30 minutes. However, the intended ethyl N, N-diethylaminoacetate and water did not separate. When a large amount of a water-soluble reaction solvent was used, the by-produced salt could not be removed by washing with water, so that distillation could not be performed and the desired ethyl N, N-diethylaminoacetate could not be obtained.

Comparative Example 2
The reaction was carried out using the same apparatus and reaction conditions as in Example 1 except that 305.5 g of acetone was used as the reaction solvent and the reaction time was 10 hours. After completion of the reaction, filtration was performed at a temperature of 25 ° C. using a Nutsche type filter to remove by-produced salts. Next, after removing initial fractions such as reaction solvent, water, and diethylamine at a temperature of 55 to 150 ° C. under normal pressure, distillation was performed. The target ethyl N, N-diethylaminoacetate had a purity of 98.8%, a yield of 122.5 g (yield 76%), and the productivity of the target product was 20%.

  In Examples 1 to 4, since no reaction solvent was used, the yield and purity of the target product were high, and the productivity was also good. In addition, since removal and recovery of the reaction solvent is unnecessary, the manufacturing cost can be reduced.

On the other hand, in Comparative Examples 1 and 2, since a large amount of the reaction solvent was used, the loss of the target product due to the residual liquid in the filter cake, and a part of the target product distills together with the solvent when separating the reaction solvent. Yield is low. In addition, when a solvent is used, productivity is very low, and a large manufacturing facility, a filter, a solvent recovery facility, and the like are required, resulting in an increase in manufacturing cost and poor economic efficiency.

Claims (4)

Secondary amine represented by the following general formula (I)

[Wherein, R ¹ is a linear or branched alkyl group having 2 to 6 carbon atoms, or an alkenyl group, a hydroxyalkyl group, and R ² is a linear or branched alkyl group having 1 to 6 carbon atoms, or alkenyl. A hydroxyalkyl group, R ¹ and R ² may be bonded to each other to form a ring; ]
And a halocarboxylic acid ester represented by the following general formula (II)

[Wherein, X is a halogen atom, R ³ is hydrogen or a linear or branched alkyl group having 1 to 6 carbon atoms, R ⁴ is a linear or branched alkyl group having 1 to 6 carbon atoms, or an alkenyl group. Indicates. ]
To an aminocarboxylic acid ester represented by the following general formula (III)

[Wherein, R ¹ , R ² , R ³ and R ⁴ have the same meaning as described above. ]
Is a method of manufacturing
Process for producing aminocarboxylic acid ester represented by general formula (III), wherein the reaction of secondary amine represented by general formula (I) and halocarboxylic acid ester represented by general formula (II) is carried out without solvent . Formula respect halocarboxylic acid ester 1 equivalent represented by (II), secondary process according to claim 1 Symbol placement equivalent using 0.90 to 5 amine represented by the general formula (I). The production method according to claim 1 or 2 , further comprising a step of washing and distilling the produced aminocarboxylic acid ester represented by the general formula (III). The water washing step is a step of washing with water of 0.1 to 5 times the mass of the aminocarboxylic acid ester represented by the general formula (III), and the water washing treatment is performed 1 to 5 times. The manufacturing method of Claim 3 .