JP2003096037A - Production method of alanine ester hydrochloride - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a production method of an amino acid ester hydrochloride which can industrially be carried out. SOLUTION: The production method of an alanine ester hydrochloride comprises a step of reacting alanine with an alcohol in the presence of thionyl chloride. In this case, characteristically, after the reaction is finished, the reaction solution is concentrated at 40 to 100 deg.C to remove sulfur dioxide and free hydrogen chloride, and the content of the alcohol in the concentration solution is adjusted to be 0.05 to 25 wt.% to the content of the alanine ester hydrochloride, and then an organic solvent except the above alcohol is added to the adjusted solution to conduct the crystallization of the alanine ester hydrochloride.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing alanine ester hydrochloride.

[0002]

BACKGROUND OF THE INVENTION Alanine ester hydrochloride is useful as a synthetic intermediate for medicines, agricultural chemicals, etc. As a method for producing it, for example, thionyl chloride is added to a mixed solution of alanine and alcohol at a low temperature of 0 ° C. or lower, Then keep it warm at 40 ℃,
A method is known in which after the completion of heat retention, the mixture is concentrated, and tetrahydrofuran is added for crystallization (Liebigs Ann.
Chem. , 641 , 176 (1961)). However, during the concentration, the crystals of alanine ester hydrochloride may be suddenly precipitated and solidified, which is not always an industrially viable method for producing alanine ester hydrochloride.

[0003]

Under these circumstances,
The present inventors have examined the industrially feasible method for producing amino acid ester hydrochloride, after the reaction,
The reaction solution is concentrated at an internal temperature of 40 to 100 ° C. to remove by-produced sulfur dioxide and free hydrogen chloride, and
The concentration of alcohols after concentration is adjusted to 0.05 to 25% by weight with respect to alanine ester hydrochloride, and then crystallization treatment is performed to prevent precipitation of alanine ester hydrochloride during concentration treatment. The inventors have found that crystals of alanine ester hydrochloride can be obtained in high yield, and have completed the present invention.

[0004]

That is, the present invention is a method for producing an alanine ester hydrochloride by reacting alanine with an alcohol in the presence of thionyl chloride. Concentration treatment is performed at 40 to 100 ° C. to remove sulfur dioxide and free hydrogen chloride, and the amount of alcohols in the concentrated liquid is adjusted to 0.05 to 25% by weight based on alanine ester hydrochloride. After that, add an organic solvent other than the alcohols,
In the method for producing alanine ester hydrochloride, which comprises performing a crystallization treatment of alanine ester hydrochloride, and in the presence of thionyl chloride, alanine and alcohols are reacted to produce alanine ester hydrochloride,
After the completion of the reaction, the reaction solution is concentrated in the presence of an organic solvent other than the alcohols to remove sulfur dioxide and free hydrogen chloride, and the organic solvent remains in the concentrated solution, and is concentrated. The method for producing an alanine ester hydrochloride is characterized in that the amount of alcohols in the liquid is adjusted to 25% by weight or less with respect to the alanine ester hydrochloride, and then the alanine ester hydrochloride is crystallized. It is provided.

[0005]

BEST MODE FOR CARRYING OUT THE INVENTION First, in the presence of thionyl chloride,
The step of reacting alanine with alcohols to obtain a reaction solution containing alanine ester hydrochloride will be described.

Alanine may be an optically active substance or a mixture of optically active substances. Further, it may be used as an alanine mineral acid salt such as hydrochloride or sulfate.

Examples of alcohols include methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, tert-butanol, n-pentanol, 2-
Examples thereof include lower alcohols having 1 to 5 carbon atoms such as pentanol.

The amount of alcohol used is usually 1 mol times or more with respect to alanine, but a large excess may be used also as a reaction solvent. The amount of alcohols used as a reaction solvent is not particularly limited, but if it is too large, it tends to be disadvantageous in terms of cost and volume efficiency. Is. Such alcohols are usually used by mixing the entire amount thereof with alanine in advance.

The amount of thionyl chloride used is usually 1 mol times or more with respect to alanine, and the upper limit is not particularly limited, but if it is too much, it is economically disadvantageous, and the treatment after the reaction is also performed. Since it tends to be complicated, it is practically 2 mol times or less, preferably 1.5 mol times or less with respect to alanine. In addition, thionyl chloride may be used as a mixture with the reaction solvent when the reaction solvent described later is used.

In this reaction, thionyl chloride is usually added to a mixed solution of alanine and alcohols, but it is preferable to add thionyl chloride continuously or intermittently.

The addition temperature of thionyl chloride is usually -10 ° C.
It is above, and preferably 20 ° C. or above. There is no particular upper limit, but if it is too high, the stability of the alanine ester hydrochloride will deteriorate, and thionyl chloride will easily volatilize, so it is usually 80 ° C. or lower, preferably 60 ° C. or lower.
The addition time may be appropriately set depending on the treatment capacity of the generated gas, the heat removal capacity of the reaction heat, etc., and is usually about 0.5 to 20 hours.

In this reaction, alcohols are usually used also as a reaction solvent as described above, but solvents other than alcohols may be used as reaction solvents. As the reaction solvent other than alcohols, for example, aromatic hydrocarbon solvents such as toluene and xylene, for example, aliphatic hydrocarbon solvents such as hexane, heptane, and cyclohexane, such as diethyl ether, methyl tert-butyl ether, and tetrahydrofuran. Ethereal solvents such as dichloromethane,
Examples thereof include halogenated hydrocarbon solvents such as dichloroethane and chlorobenzene, and single or mixed solvents such as ester solvents such as ethyl acetate, and the amount thereof is not particularly limited. Specifically, the amount is 50 times or less the weight of the amino acid. Such a solvent may be mixed with any of alanine, alcohols and thionyl chloride.

After the addition of thionyl chloride is completed, the reaction solution containing alanine ester hydrochloride can be obtained by keeping the temperature at a predetermined temperature, if necessary. Insulation temperature is usually 20-8
It is in the range of 0 ° C. In order to proceed the reaction more efficiently, it is preferable to carry out the reaction with sufficient stirring so that alanine is dispersed in the reaction solution almost uniformly.

After completion of the reaction, the reaction solution containing alanine ester hydrochloride is first concentrated to remove sulfur dioxide and free hydrogen chloride produced as a by-product of the reaction, but the obtained reaction solution is directly concentrated. The case of performing crystallization treatment by adding an organic solvent other than the alcohols and the case of performing concentration treatment in the presence of an organic solvent other than the alcohols and performing crystallization treatment will be separately described below.

First, the case where the obtained reaction solution is concentrated as it is, and an organic solvent other than the alcohols is added for crystallization is described.

The obtained reaction liquid contains alanine ester hydrochloride, unreacted alcohols, sulfur dioxide produced as a by-product, free hydrogen chloride and the like. And free hydrogen chloride is removed. In such concentration treatment, unreacted alcohols are simultaneously removed together with the sulfur dioxide and hydrogen chloride. However, if unreacted alcohols are removed too much, crystals of alanine ester hydrochloride will precipitate during the concentration treatment. In addition, since the amount of unreacted alcohols remaining is too large, crystals of alanine ester hydrochloride do not precipitate, so the amount of alcohols in the concentrated solution is greater than the amount of alanine ester hydrochloride in the concentrated solution. Therefore, it is necessary to carry out a concentration treatment so that an amount of alcohol of 0.05 to 25% by weight, preferably 0.5 to 25% by weight, remains. As a method of adjusting the amount of alcohols in the concentrated liquid to the above range, for example, a method of concentrating while analyzing the amount of alcohols in the concentrated liquid over time, the temperature of the concentrated liquid in which the amount of alcohols falls within the above range Is measured in advance, and the concentration treatment is performed while measuring the temperature of the concentrated liquid during concentration with time.

Further, depending on the amount of thionyl chloride used,
Unreacted thionyl chloride may remain in the reaction solution. In this case, it is preferable to remove unreacted thionyl chloride by concentration treatment.

When the reaction solution is directly concentrated, the concentration is 40 to 100 ° C., preferably 50 to 90.
It is performed at ℃. If the internal temperature is lower than 40 ° C, crystals of alanine hydrochloride are likely to precipitate during the concentration treatment, which may deteriorate the operability. If the internal temperature is higher than 100 ° C, decomposition of the alanine ester hydrochloride occurs. It is not preferable because it becomes easy.

The operating pressure may be atmospheric pressure, or
It may be performed under reduced pressure.

After the concentration treatment, the alanine ester hydrochloride is crystallized by adding an organic solvent other than the alcohols. The organic solvent other than the alcohols, for example, hexane, heptane, cyclohexane and other aliphatic hydrocarbon solvents, for example, toluene, xylene and other aromatic hydrocarbon solvents, for example, dichloromethane, dichloroethane, chlorobenzene and other halogenated hydrocarbons. System solvents such as diethyl ether, tetrahydrofuran, methyl t
Examples thereof include ether solvents such as ert-butyl ether and single or mixed solvents such as ester solvents such as ethyl acetate, and the amount thereof is not particularly limited, and is appropriately selected in consideration of slurry property during crystallization treatment and the like. do it.

The temperature at which such an organic solvent is added may be appropriately selected depending on the type of solvent and the like, and is usually 20 to 80 ° C.
It is preferably 40 to 70 ° C.

Crystals of alanine ester hydrochloride are obtained by adding such a solvent and then cooling with stirring. The cooling temperature is usually -10 to 40 ° C. A seed crystal may be added to facilitate the precipitation of crystals.

After the crystallization treatment, the precipitated alanine ester hydrochloride can be collected by filtration to take out the alanine ester hydrochloride. The taken out alanine ester hydrochloride may be washed, dried, etc., if necessary.

Next, the case where the concentration treatment and the crystallization treatment are performed in the presence of an organic solvent other than the alcohols will be described.

When the concentration treatment is carried out in the presence of an organic solvent other than the alcohols, for example, the reaction obtained when the reaction between the alanine and the alcohols is carried out in the presence of the organic solvent other than the alcohols. In the case of concentrating the liquid, a case where an organic solvent other than the alcohols is added to the reaction liquid obtained by the reaction of the alanine and the alcohols and the liquid is concentrated can be mentioned.

In either case, unreacted alcohols, by-produced sulfur dioxide and free hydrogen chloride contained in the reaction solution are removed by a concentration treatment. The concentration treatment is carried out under normal pressure conditions or reduced pressure. Performed under conditions. When a solvent having a high boiling point is used as the solvent other than the alcohols, it is preferable to carry out the concentration treatment under a reduced pressure condition. Also,
Depending on the amount of thionyl chloride used, unreacted thionyl chloride may remain in the reaction solution.
Unreacted thionyl chloride is preferably removed by concentration treatment.

In the concentration treatment, an organic solvent other than the alcohols may be removed, but it is necessary that the organic solvent remains in the concentrated liquid. Furthermore, if the amount of alcohols in the concentrated liquid exceeds 25% by weight with respect to the alanine ester hydrochloride in the concentrated liquid, crystals of alanine ester hydrochloride do not precipitate, so the amount of alcohols in the concentrated liquid It is also important to perform a concentration treatment of 25% by weight or less with respect to the alanine ester hydrochloride in the concentrated liquid.

In order to make it easier to adjust the amount of alcohols, it is preferable to use a solvent that is azeotropic with the alcohols.

After the concentration treatment, the alanine ester hydrochloride can be obtained by performing the crystallization treatment as it is. The precipitated alanine ester hydrochloride can be taken out by a normal filtration operation.

[0030]

The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples. In addition,
Chemical purity (content; weight%) and optical purity were determined by high performance liquid chromatography analysis method.

Example 1 A flask was charged with d-alanine (ratio of d-form: 99.8% or more).
14.5 g and 40 g of ethanol were added and suspended at room temperature, and then the internal temperature was raised to 50 ° C. At the same temperature, 22.8 g of thionyl chloride was added dropwise over 2 hours. After the dropping is completed,
The mixture was stirred and reacted at the same temperature for 3 hours. Then, under reduced pressure conditions, while maintaining an internal temperature of 50 to 70 ° C., from the reaction solution,
By-produced sulfur dioxide, free hydrogen chloride, unreacted thionyl chloride and unreacted ethanol were distilled off, and the amount of ethanol in the concentrate was relative to d-alanine ethyl ester hydrochloride in the concentrate. A concentrate of 2% by weight was obtained. To this concentrated liquid was added 51.7 g of toluene, and the internal temperature was 70 ° C.
After confirming that it is a homogeneous liquid, the internal temperature is 20 ° C.
Until cooled over 2 hours. The precipitated d-alanine ethyl ester hydrochloride was collected by filtration and dried under reduced pressure. The obtained amount was 24.0 g. Chemical purity (content): 100% by weight, optical purity: d-form ratio of 99.8% or more.

Comparative Example 1 The same operation as in Example 1 was carried out, and the amount of ethanol was 30% by weight based on d-alanine ethyl ester hydrochloride in the concentrated solution.
To obtain a concentrated liquid. To the concentrated liquid, 51.7 g of toluene
Was added, the internal temperature was raised to 70 ° C., and after confirming that it was a uniform liquid, the internal temperature was cooled to 5 ° C., but no precipitation of crystals was observed.

Example 2 The procedure of Example 1 was repeated except that methanol was used instead of ethanol to obtain 22.0 g of d-alanine methyl ester hydrochloride. Chemical purity (content): 100% by weight, optical purity: d-form ratio of 99.8% or more.

Example 3 In a flask, d-alanine (d-form ratio of 99.8% or more) 4 was added.
9.9 g and ethanol (modified with 1% hexane) 13
1.7 g was added and suspended at room temperature, and the internal temperature was raised to 50 ° C. At the same temperature, 79.9 g of thionyl chloride was added dropwise over 100 minutes, and the mixture was stirred and reacted at the same temperature for 200 minutes. Then, under reduced pressure, while maintaining an internal temperature of 60 to 70 ° C,
From the reaction solution, sulfur dioxide, free hydrogen chloride, unreacted thionyl chloride and unreacted ethanol were distilled off, and the amount of ethanol in the concentrate was relative to d-alanine ethyl ester hydrochloride in the concentrate. A concentrated liquid having a concentration of 1.6% by weight was obtained. To the concentrated solution, 200 g of tetrahydrofuran was added at an internal temperature of 50 to 60 ° C., the mixture was cooled to an internal temperature of 35 to 40 ° C. over 1 hour, 20 mg of seed crystals were added, and then the internal temperature was 0 ° C.
Until cooled over 2 hours. The precipitated d-alanine ethyl ester hydrochloride was collected by filtration and dried under reduced pressure. The obtained amount was 83.1 g. Chemical purity (content): 99.3
% By weight, optical purity: d-form ratio of 99.8% or more.

Example 4 In a flask, d-alanine (d-form ratio: 99.8% or more) 5 was added.
0.0 g and 149.8 g of ethanol were added and suspended at room temperature, and then the internal temperature was raised to 50 ° C. At the same temperature, 74.5 g of thionyl chloride was added dropwise over 90 minutes, and the mixture was stirred and reacted at the same temperature for 3 hours. Then, while maintaining the internal temperature of 50 ° C., sulfur dioxide, free hydrogen chloride, unreacted thionyl chloride and ethanol were removed from the reaction solution at an operating pressure of 100 Torr (equivalent to 13.3 kpa), and the amount of ethanol in the concentrated solution was A concentrated liquid having a concentration of 27% by weight based on d-alanine ethyl ester hydrochloride in the concentrated liquid was obtained. The operating pressure was set to 20 Torr (equivalent to 2.67 kpa), and the concentration operation of ethanol was performed again to obtain a concentrated solution in which the amount of ethanol was 9% by weight based on d-alanine ethyl ester hydrochloride. Tetrahydrofuran 77 g was added to the concentrated solution at an internal temperature of 50 to 60 ° C., and the operation of distilling off 77 g of the solvent at an internal temperature of 50 to 60 ° C. was repeated 4 times. The amount of ethanol in the concentrated solution was d-alanine ethyl ester. For the hydrochloride salt, 1.
A concentrate of 2% by weight was obtained. An internal temperature of 5
200 g of tetrahydrofuran was added at 0 to 60 ° C., and the internal temperature was cooled to 20 ° C. over 2 hours. The precipitated d-alanine ethyl ester hydrochloride was collected by filtration and dried under reduced pressure. The amount acquired was 83.0 g. Chemical purity (content): 99.9% by weight, optical purity: d-form ratio of 99.8% or more.

[0036]

According to the present invention, alanine ester hydrochloride can be industrially produced.

Claims (3)

[Claims] 1. A method for producing an alanine ester hydrochloride by reacting alanine with an alcohol in the presence of thionyl chloride, which comprises:
Concentration treatment at 100 ° C removes sulfur dioxide and free hydrogen chloride, and the amount of alcohols in the concentrate is
The alanine ester is characterized in that it is adjusted to 0.05 to 25% by weight with respect to the alanine ester hydrochloride, and then an organic solvent other than the alcohols is added to carry out a crystallization treatment of the alanine ester hydrochloride. Method for producing hydrochloride. 2. A method for producing an alanine ester hydrochloride by reacting alanine with an alcohol in the presence of thionyl chloride, wherein the reaction solution is in the presence of an organic solvent other than the alcohol after completion of the reaction. Concentration treatment is performed to remove sulfur dioxide and free hydrogen chloride, the organic solvent remains in the concentrate, and the amount of alcohols in the concentrate is 25% by weight based on alanine ester hydrochloride.
A method for producing alanine ester hydrochloride, which comprises performing crystallization treatment of alanine ester hydrochloride after adjusting as follows. 3. The method for producing an alanine ester hydrochloride according to claim 1 or 2, wherein thionyl chloride is continuously or intermittently added to the mixed solution of alanine and alcohol at an internal temperature of 20 ° C. or higher to react.