JP2928564B2 - Method for producing amino acid methyl ester mineral acid salt - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a method for producing an amino acid methyl ester mineral acid salt. More specifically, methanol, water,
The present invention relates to a method for efficiently producing an amino acid methyl ester mineral salt having few impurities such as amino acids.

The amino acid methyl ester mineral salt of the present invention is important as an intermediate for peptide synthesis, and is useful as a raw material for synthesizing a dipeptide sweetener aspartame or a raw material for medicine.

[Conventional technology]

The esterification method of amino acids has been known for a long time, and basically the method developed by Curtius et al. In 1888 is still used today. In this method, dehydration is performed by saturating hydrogen chloride in methanol in which amino acids are suspended, reacting, removing excess methanol, further adding methanol and concentrating the mixture, and then using ether or petroleum ether. The desired product is obtained by crystallization. However, in this method, a large amount of alcohol needs to be used in order to remove water generated by the reaction, and hydrolysis proceeds in a process of repeating concentration. For this reason, the yield of the esterified product obtained by filtration and drying is at most about 90%. Further, when the obtained ester contains a large amount of the starting amino acid produced by hydrolysis, there is a problem that it is difficult to separate the ester from these impurities.

In addition, since ethers are used for crystallization, industrial implementation is difficult due to problems in handling and collecting them.

In addition, the amino acid is heated with p-toluenesulfonic acid, ethanol and carbon tetrachloride to remove the generated water out of the system as an azeotrope, and the amino acid ethyl ester p-
Method for obtaining toluenesulfonate (Nikka Chemical 83,1151,
1962) is also known, but it is necessary to use a non-volatile acid, and when methanol is used as the alcohol, methanol and carbon tetrachloride azeotropically remove methanol from the system, There is an industrial problem such as the need to use a large amount of methanol.

Japanese Patent Application Laid-Open No. 1-165560 discloses a method of producing an amino acid ester by reacting an amino acid with an alcohol and esterifying the water produced by the reaction together with the starting alcohol while distilling the water out of the system. Have been. However, this method is the same as the above method in that a large amount of alcohol is required to remove water, and is very inefficient.

Also, even if crystals precipitate after esterification by these methods and can be separated by filtration as they are, these filter cakes contain water produced by the reaction and a considerable amount of methanol. If these amino acid esters containing water or alcohol are used as a reaction raw material as they are, the reaction results are often adversely affected. Therefore, it is an important problem to remove water and alcohol from the amino acid ester used as a raw material. However, long-term operation at high temperature in order to completely dehydrate the reaction mixture and dehydrated alcohol causes hydrolysis of the ester or racemization of the amino acid, which results in isolation and purification under mild conditions. Operation has to be performed, and the efficiency is poor and the yield is high, which is industrially problematic.

[Problems to be solved by the invention]

An object of the present invention is to provide a method for producing an amino acid methyl ester mineral salt from an amino acid and ethanol in the presence of a mineral acid. An object is to provide a method for efficiently manufacturing.

[Means for solving the problem]

In a method for producing a mineral acid salt of an amino acid methyl ester from an amino acid and methanol in the presence of a mineral acid, the present inventors filtered the amino acid methyl ester mineral acid salt which crystallized as a result of cooling after completion of the esterification reaction. The wet crystals containing the amino acid methyl ester mineral acid salt can be dried without hydrolysis, and the amino acid methyl ester mineral acid salt containing almost no methanol and water can be obtained. Was found.

In addition, they have found that the filtrate can efficiently produce amino acid methyl ester mineral acid salt in high yield by using the esterification reaction again.

Furthermore, the present inventors have found that washing the wet crystals containing the amino acid methyl ester mineral salt with an organic solvent yields an amino acid methyl ester mineral salt having a low methanol content, thereby completing the present invention.

That is, the present invention provides a highly pure and highly pure amino acid methyl ester salt from a reaction solution of esterifying an amino acid with methanol in the presence of a mineral acid in 0.5 to 2 times the weight of methanol. In a cyclic production method for producing and separating in a yield, 1) a mineral acid salt of an amino acid esterified by cooling is precipitated as a crystal from a reaction solution obtained by the esterification reaction, and 2) the precipitated crystal is separated by filtration, 3) The methanol and water are removed from the separated wet crystals by drying or washing with an organic solvent. 4) The filtrate or a solid obtained by concentrating the filtrate is reduced to a water content of 20% by weight or less in the reaction solution. This is a process for producing an amino acid methyl ester mineral acid salt, which is circulated through a reaction system so as to be maintained and used again in the esterification reaction.

The amino acid used in the present invention may be a natural product or a non-natural product, and may be any of a racemic form and an optically active form. For example, glycine, alanine, valine, leucine,
Examples include neutral amino acids such as isoleucine, phenylalanine, serine, and threonine, basic amino acids such as lysine and arginine, acidic amino acids such as aspartic acid and glutamic acid, and derivatives in which their functional groups are protected.

The mineral acid used in the present invention forms a salt with the amino group of the amino acid and serves as a catalyst for esterification. In general, mineral acids such as hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid are used. Preferably, hydrochloric acid, which can easily remove excess mineral acid after the esterification reaction, is suitable.

The mineral acid used is at least equimolar to the amino acid. Usually, a small excess to about 5 times the molar amount is used, but if it is too large, the amount of the mineral acid attached to the obtained amino acid methyl ester mineral salt increases, and the amount of alkali required for neutralization increases.

The methanol used for the esterification is preferably used in an amount of 0.5 to 2 times the weight of the starting amino acid including the solvent. If the amount is too large, the yield of the target amino acid methyl ester mineral acid salt is low when cooled after the completion of esterification. Therefore, it is preferable to use as little as possible and carry out the reaction at a high concentration. However, if the amount is too small, the slurry viscosity of the precipitated crystals increases, and operations such as stirring and liquid transfer become difficult.

The reaction can be diluted by adding an inert organic solvent. Examples of the organic solvent used include hydrocarbon solvents such as toluene, xylene, and hexane; ether solvents such as tetrahydrofuran and dioxane; and aliphatic halogenated hydrocarbons such as methylene chloride, ethylene chloride, trichloroethylene, and tetrachloroethylene. Examples thereof include solvents, aliphatic ester solvents such as methyl acetate and methyl propionate, and phosphate ester solvents such as trimethyl phosphate.

Other conditions for esterification are not particularly limited, and conditions such as temperature and time can be appropriately selected in consideration of the difficulty of esterification of the amino acid to be used. Usually, a method is used in which a large excess of a mineral acid is used and left at room temperature for several days, or the mixture is heated to near the reflux temperature of methanol and reacted for several hours.

After the reaction, the amino acid methyl ester mineral salt precipitated by cooling to 20 ° C. or lower, preferably 10 ° C. or lower, is filtered by a usual method to obtain a filter cake to which a small amount of water and methanol are attached. Subsequently, by drying, a high-purity amino acid methyl ester mineral salt can be obtained.

If drying is carried out at a high temperature for a long time, the amino acid methyl ester is hydrolyzed. Usually, it is dried at 20 to 80 ° C, preferably at 60 ° C or less.
Drying is preferably performed under reduced pressure of 100 mmHg or less.

The filtrate is used for the esterification reaction by adding methanol, mineral acid and amino acid as they are. When recycling is repeated, the water generated by the esterification accumulates in the reaction solution, but some of the generated water adheres to the filter cake and is removed from the system. It can be kept below. The amount of this accumulation is the amount that adheres to the filter cake and is removed,
The amount of water that accumulates can be reduced by determining the ratio of the amount recycled together with the filtrate, performing the reaction at a high concentration, and reducing the amount of filtrate circulated.

By repeating the recycling of the filtrate in this way,
By keeping the water accumulated in the reaction solution at 20% or less, the reaction rate of the esterification reaction can be kept high.

However, it is usually preferable to concentrate the filtrate before recycling to remove the contained water. In this case, even if the filtrate is concentrated at a relatively high temperature to hydrolyze the amino acid methyl ester, the reaction is carried out again under esterification conditions, so there is no problem at all. Therefore, the concentration temperature may be any temperature at which amino acid racemization does not occur. Preferably, it is performed under reduced pressure at 20 to 60 ° C.

In the method of the present invention, after the esterification reaction, the precipitated crystals are filtered by cooling to 20 ° C. or lower, preferably 10 ° C. or lower, and then washed with an organic solvent to reduce the amino acid methyl ester mineral acid salt having a low methanol content. You can get a wet cake.

Examples of the organic solvent include hydrocarbon solvents such as toluene, xylene and hexane; ether solvents such as tetrahydrofuran and dioxane; aliphatic halogenated hydrocarbon solvents such as methylene chloride, ethylene chloride, trichloroethylene and tetrachloroethylene; and ethyl acetate. And aliphatic ester solvents such as methyl acetate, propyl acetate and methyl propionate, and phosphate ester solvents such as trimethyl phosphate and tri-n-butyl phosphate. However, if the solubility of the amino acid methyl ester mineral salt in these solvents is high, the yield will be reduced by the washing operation, so that hydrocarbon solvents such as toluene, xylene and hexane are preferred. Particularly preferably, toluene is used.

The amount of the solvent is not particularly limited, but usually the same volume or more as the amino acid methyl ester mineral salt wet cake is used, and the solvent is washed several times. The allowable amount of methanol in the amino acid methyl ester mineral acid salt obtained by such an operation varies depending on the purpose of use of the amino acid methyl ester, but is generally 5% or less based on the amino acid methyl ester mineral acid salt. no problem.

 Hereinafter, the method of the present invention will be described in detail with reference to examples.

〔Example〕

Example 1 165.2 g of L-phenylalanine was added to 165.2 g of methanol containing 79 g of hydrogen chloride, and the mixture was stirred at 40 ° C for 4 hours. As a result of analysis of the reaction solution by high performance liquid chromatography, L
-Conversion to phenylalanine methyl ester reached more than 99%.

After the reaction, the mixture was cooled to 3 ° C. and filtered to obtain 258.6 g of a filter cake. As a result of analysis of this cake, the moisture was 3.
At 6% methanol was 13.0%.

This filter cake is dried by ventilation at 50 ° C. for 10 hours to give a purity of 96.8%, a water content of 0.2%, and L-phenylalanine 1.2%.
L-phenylalanine methyl ester hydrochloride containing 197.
6 g were obtained.

88.7% yield.

On the other hand, 150.8 g of the filtrate was concentrated at 60 ° C. under reduced pressure of 100 mmHg to obtain 43.9% of a solid containing 19.8% of L-phenylalanine methyl ester hydrochloride, 23.3% of L-phenylalanine hydrochloride, and 10.3% of water. . 136.
Dissolve in 3 g of methanol and add L-phenylalanine
Add 150.2 g and absorb 79 g of hydrochloric acid gas at 40 ° C or less. Four
After reacting at 0 ° C. for 4 hours, the mixture was cooled to 3 ° C., and the precipitated crystals were filtered. The obtained filter cake was air-dried at 50 ° C for 10 hours to obtain 199.5 g of L-phenylalanine methyl ester hydrochloride having a water content of 0.1% containing 1.1% L-phenylalanine and a purity of 97.2%. The yield based on the newly added L-phenylalanine was 98.9%.

The filtrate contains 14.9 g of phenylalanine methyl ester hydrochloride and phenylalanine hydrochloride in terms of phenylalanine, and is used again in the esterification reaction.

Example 2 An esterification reaction was carried out in the same manner as in Example 1, and the crystals precipitated by cooling were filtered and dried to give a purity of 9%.
193.3 g of L-phenylalanine methyl ester hydrochloride containing 7.3%, water 0.1% and L-phenylalanine 1.1% was obtained.

Yield 87.2%.

On the other hand, L-phenylalanine methyl ester hydrochloride 1
1 containing 6.3%, L-phenylalanine 0.5%, water 4.4%
49.7 g of the filtrate is used without concentration, 64.8 g of methanol and 145.8 g of L-phenylalanine are newly added, and 49.1 g of hydrochloric acid gas is absorbed at 40 ° C. or lower. After reacting at 40 ° C. for 4 hours, the mixture was cooled to 5 ° C., and the precipitated crystals were filtered. By air-drying the obtained filter cake at 50 ° C for 10 hours,
0.1% water containing 1.1% L-phenylalanine, purity 9
8.2% L-phenylalanine methyl ester hydrochloride 19
0.1% was obtained. The yield based on the newly added L-phenylalanine was 98.1%.

The operation of recycling the filtrate obtained as it is without concentration was repeated.
Met. The conversion after the esterification reaction reached 97%, and the crystals obtained by cooling, filtering and drying contained 2.3% L-phenylalanine, 0.1% water, and had a purity of 96.3%.
The yield based on the newly added L-phenylalanine was 97.1%.

Comparative Example 1 After performing an esterification reaction in the same manner as in Example 1,
The operation of concentrating methanol at a temperature of 50 ° C. under reduced pressure, adding 200 g of methanol, and concentrating the methanol is repeated twice. Ethyl ether was added to the obtained oily residue for crystallization, followed by filtration and drying to obtain 93.3% pure L-phenylalanine methyl ester hydrochloride (211.1 g). The yield was 91.3% and contained 0.3% of water and 5.1% of L-phenylalanine.

Example 3 L-alanine 89.1 g instead of L-phenylalanine
The esterification reaction was carried out in the same manner as in Example 1 except that methanol was changed to 89.1 g and hydrochloric acid to 42.6 g, and the precipitated crystals were filtered and dried to obtain a purity of 97.7 g.
%, Water 0.1%, L-alanine methyl ester hydrochloride 120.5 g containing L-alanine 1.2%.

Yield 84.3%.

On the other hand, 70.2 g of the filtrate was concentrated at 60 ° C. under a reduced pressure of 100 mmHg to give L-alanine methyl ester hydrochloride 26.5 g.
%, L-alanine hydrochloride 30.5%, solid 30.3% containing 8.5% water. This solid is dissolved in 71.0 g of methanol, and 76.5 g of L-alanine is newly added to absorb 42.6 g of hydrochloric acid gas at 40 ° C. or lower. After reacting at 40 ° C for 4 hours, 3
After cooling to ℃, the precipitated crystals were filtered. The resulting filter cake is dried by air at 50 ° C. for 10 hours to give 0.9%
120.4 g of L-alanine methyl ester hydrochloride having a water content of 0.1% and a purity of 98.7% containing L-alanine was obtained. The yield based on the newly added L-alanine was 99.1%. The filtrate contains 12.2 g of alanine methyl ester hydrochloride and alanine hydrochloride in terms of phenylalanine, and is used again in the esterification reaction.

Example 4 L-aspartic acid instead of L-phenylalanine
Using 133.1 g, the esterification reaction was performed in the same manner as in Example 1 except that methanol was changed to 133.1 g and hydrochloric acid was changed to 64 g.
The crystals precipitated by cooling were filtered and dried to give a purity of 96.5%, a water content of 0.2%, and a total of L-aspartic acid and α- and β-monomethyl esters of L-aspartic acid of 2.
L-aspartic acid dimethyl ester hydrochloride 1 containing 6%
60.5 g were obtained.

Yield 78.4%.

On the other hand, 116.2 g of the filtrate was concentrated at 60 ° C. under reduced pressure of 100 mmHg to obtain L-aspartic acid dimethyl ester hydrochloride 5.6%, L-aspartic acid hydrochloride 55.2%, water content
61.1 g of a solid containing 6.4% were obtained. This solid was dissolved in 100.7 g of methanol, and 104.4 g of L-aspartic acid was newly added.
To absorb 64 g of hydrochloric acid gas at 40 ° C. or lower. After reacting at 40 ° C. for 4 hours, the mixture was cooled to 3 ° C., and the precipitated crystals were filtered. The obtained filter cake was air-dried at 50 ° C. for 10 hours to give L-aspartic acid and L-aspartic acid α- and β-monomethyl esters containing a total of 2.8% of water containing 0.2% of water and a purity of 97.1%. 156.4 g of aspartic acid dimethyl ester hydrochloride was obtained. The yield based on the newly added L-aspartic acid was 98.0%. The filtrate contains 18.6 g of aspartic acid methyl ester hydrochloride and aspartic acid hydrochloride in terms of aspartic acid, and is used again in the esterification reaction.

Example 5 An esterification reaction was carried out in the same manner as in Example 1 except that 105.6 g of L-serine was used in place of L-phenylalanine, and 105.6 g of methanol and 50.5 g of hydrochloric acid were used. The crystals were filtered and dried to give a purity of 97.0.
%, Water 0.2%, L-serine methyl ester hydrochloride 134.4 g containing L-serine 0.7% was obtained.

Yield 83.8%.

On the other hand, 84.9 g of the filtrate was concentrated at 60 ° C. under a reduced pressure of 100 mmHg to give L-serine methyl ester hydrochloride 12.1 g.
%, L-serine hydrochloride 39.5%, water containing 12.8% water
43.9 g was obtained. This solid is dissolved in 78.2 g of methanol, and 89.1 g of L-serine is newly added to absorb 50.5 g of hydrochloric acid gas at 40 ° C. or lower. After reacting at 40 ° C. for 4 hours, the mixture was cooled to 3 ° C., and the precipitated crystals were filtered. The obtained filter cake was blow-dried at 50 ° C. for 10 hours to give 0.9% L.
133.6 g of L-serine methyl ester hydrochloride having a water content of 0.1% containing serine and a purity of 97.2% was obtained. The yield based on the newly added L-serine was 98.4%. The filtrate contains 16.2 g of serine methyl ester hydrochloride and serine hydrochloride in terms of serine, and is used again in the esterification reaction.

Example 6 Instead of L-phenylalanine, L-phosphodihydrochloride 18
Using 6.2 g, the esterification reaction was performed in the same manner as in Example 1 except that methanol was changed to 182.6 g and hydrochloric acid was changed to 87.3 g.
The crystals precipitated by cooling are filtered and dried to obtain a L-containing solution containing 96.6% pure, 0.2% water and 1.3% L-lysine hydrochloride.
-134.4 g of lysine methyl ester dihydrochloride were obtained. Yield 8
1.3%.

On the other hand, 190.9 g of the filtrate was concentrated at 60 ° C. under a reduced pressure of 100 mmHg to give L-lysine methyl ester dihydrochloride 2
52.0 g of a solid containing 3.3%, L-lysine dihydrochloride 51.0% and water 12.3% was obtained. This solid was dissolved in 162.2 g of methanol, and 151.0 g of L-lysine hydrochloride was newly added thereto.
The following absorbs 87.3 g of hydrochloric acid gas. After reacting at 40 ° C. for 4 hours, the mixture was cooled to 3 ° C., and the precipitated crystals were filtered. The obtained filter cake was air-dried at 50 ° C. for 10 hours to give water containing 0.2% of L-lysine hydrochloride and a purity of 96.3%.
% L-lysine methyl ester dihydrochloride 197.0 g was obtained.
The yield based on the newly added L-lysine hydrochloride was 98.4%. The filtrate contains 31.0 g of lysine methyl ester hydrochloride and lysine hydrochloride in terms of lysine acid, and is used again in the esterification reaction.

Example 7 L-Phenylalanine (165.2 g) and methanol (165.2 g) were used, and instead of hydrochloric acid, 98% sulfuric acid (120.1 g) was added.
Allowed to react for hours. The crystals precipitated by cooling in the same manner as in Example 1 were filtered and dried to give a purity of 95.7% and a water content of 0.3.
%, L-phenylalanine methyl ester hydrochloride 184.9 g containing 2.4% L-phenylalanine was obtained.

Yield 63.8%.

On the other hand, the filtrate of 200.7 g was concentrated at 50 ° C. under reduced pressure of 100 mmHg to obtain 120.3% of a solid containing 24.0% of L-phenylalanine methyl ester hydrochloride, 50.5% of L-phenylalanine sulfate and 16.5% of water. . 15 of this solid
Dissolve in 3.7 g of methanol, and newly add 109.9 g of L-phenylalanine and 66.6 g of 98% sulfuric acid. After reacting at 60 ° C. for 8 hours, the solution was cooled to 3 ° C. and the precipitated crystals were filtered. The resulting filter cake was air-dried at 50 ° C. for 10 hours to give L-phenylalanine methyl ester sulfate having a water content of 0.2% containing 3.0% L-phenylalanine and a purity of 95.4%.
181.9 g were obtained. The yield based on the newly added L-phenylalanine was 94.1%. The filtrate contains 56.3 g of phenylalanine methyl ester sulfate and phenylalanine sulfate in terms of phenylalanine, and is used again in the esterification reaction.

Example 8 165.2 g of L-phenylalanine and 165.2 g of methanol were used, and 132.1 g of 89% phosphoric acid was added in place of hydrochloric acid.
Allowed to react for hours. The crystals precipitated by cooling in the same manner as in Example 1 were filtered and dried to give a purity of 95.1% and a water content of 0.3.
%, L-phenylalanine methyl ester phosphate (169.4 g) containing 3.0% L-phenylalanine.

Yield 58.1%.

On the other hand, 227.2 g of the filtrate was concentrated at 60 ° C. under a reduced pressure of 100 mmHg to obtain 138.9% of a solid containing 18.8% of L-phenylalanine methyl ester phosphate, 55.7% of L-phenylalanine phosphate and 16.3% of water. . 15 of this solid
Dissolve in 5.1 g of methanol, and newly add 101.1 g of L-phenylalanine and 67.4 g of 89% phosphoric acid. After reacting at 60 ° C. for 8 hours, the solution was cooled to 3 ° C. and the precipitated crystals were filtered. The obtained filter cake was air-dried at 50 ° C. for 10 hours to give L-phenylalanine methyl ester sulfate having a water content of 0.2% containing 3.2% L-phenylalanine and a purity of 95.1%.
169.8 g were obtained. The yield based on the newly added L-phenylalanine was 95.2%. The filtrate contains 63.6 g of phenylalanine methyl ester phosphate and phenylalanine phosphate in terms of phenylalanine, and is used again in the esterification reaction.

Example 9 165.2 g of L-phenylalanine was added to 165.2 g of methanol containing 98 g of hydrogen chloride, and the mixture was stirred at 40 ° C for 4 hours. As a result of analysis of the reaction solution by high performance liquid chromatography,
Conversion to L-phenylalanine methyl ester is 99%
Reached.

After the reaction, the mixture was cooled to 3 ° C. and filtered to obtain 252.4 g of a filter cake. As a result of analysis of this cake, the moisture was 3.
At 5% methanol was 13.8%.

This filter cake was redispersed in 200 g of toluene, stirred for 30 minutes, and then filtered to obtain 215.6 g of a cake. As a result of the analysis,
88.7% purity, 2.2% L-phenylalanine, 2.6% moisture,
Methanol was 4.2%. 88.7% yield.

Example 10 165.2 g of L-phenylalanine was added to a mixed solvent of 165.2 g of methanol containing 98 g of hydrogen chloride and 80 g of toluene.
Stir at 0 ° C. for 4 hours. As a result of analysis of the reaction solution by high performance liquid chromatography, the conversion to L-phenylalanine methyl ester reached 99% or more.

After the reaction, the reaction mass was cooled to 3 ° C., and the reaction mass separated into three layers was filtered as it was to obtain 223.7 g of a filter cake.
Analysis of this cake showed that the water content was 2.3% and methanol was
It was 5.9%.

This filter cake was re-dispersed in 200 g of toluene, stirred for 30 minutes, and filtered to obtain 213.4 g of a cake. As a result of the analysis,
87.4% purity, 2.4% L-phenylalanine, 1.9% moisture,
Methanol was 2.3%. 86.5% yield.

〔The invention's effect〕

According to the method of the present invention, the amino acid methyl ester produced in methanol can be isolated in the form of a filter cake with low water content without performing a methanol concentration step involving a hydrolysis reaction. It can be used as a reaction raw material, and a high-purity amino acid methyl ester mineral salt can be obtained without hydrolysis even when dried. In addition, if the filter cake is washed with an organic solvent without drying, a wet cake of amino acid methyl ester mineral salt containing less methanol can be obtained, and can be used as it is as a reaction raw material depending on the purpose.

In addition, the method of the present invention is a method for producing amino acid methyl esters, which is capable of minimizing the loss of the raw material amino acid because the filtrate is reused as it is or by concentrating it, and has a high yield and is industrially efficient. is there.

────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification symbol FI C07C 229/36 C07C 229/36 // C07B 61/00 300 C07B 61/00 300 (56) References JP-A-62-96453 ( JP, A) JP-A-58-52252 (JP, A) JP-A-57-159746 (JP, A) JP-A-53-127412 (JP, A) JP-A-50-71642 (JP, A) 1939-6656 (JP, B1) U.S. Pat. No. 4,684,745 (US, A) U.S. Pat. No. 4,173,562 (US, A) (58) Fields investigated (Int. Cl. ⁶ , DB name) C07C 229 / 08,229 / 22,229 / 24 C07C 229 / 26,229 / 36,227 / 18 C07B 61/00 CA (STN) CAOLD (STN) REGISTRY (STN)

Claims (3)

(57) [Claims] (1) In the presence of a mineral acid, an amino acid is reduced to a weight of 0.
In a cyclic production method for producing and separating a mineral acid salt of an amino acid methyl ester with high purity and high yield from a reaction solution esterified with methanol in 5 to 2 times the weight of methanol, 1) esterification reaction The mineral acid salt of an amino acid esterified by cooling is precipitated as crystals from the reaction solution obtained by 2), 2) The precipitated crystals are separated by filtration, and 3) Methanol and methanol are removed from the separated wet crystals by drying or washing with an organic solvent. 4) The filtrate or a solid obtained by concentrating the filtrate is circulated to the reaction system so that the water accumulated in the reaction solution is kept at 20% by weight or less, and is used again in the esterification reaction. A method for producing an amino acid methyl ester mineral acid salt, which comprises: 2. The method according to claim 1, wherein the drying is performed at a temperature of 60 ° C. or less. 3. The method according to claim 1, wherein the organic solvent is toluene.