JP2728891B2 - Method for producing amino acid ester mineral salts - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention improves the operability of dehydration, desolvation, liquid transfer, and the like by obtaining an amino acid methyl ester mineral salt as a non-crystalline oily substance. How to do it. 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.

[Prior art and problems]

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, the alcohol in which amino acids are suspended is saturated with hydrogen chloride, and after the reaction, excess methanol is removed, and the alcohol used in the reaction is repeatedly added and concentrated, and then crystallized using ether or petroleum ether. Thus, the intended product is obtained. However, if this method is to be carried out industrially, it is very difficult to completely remove alcohol and water from the lump of precipitated crystals when the target crystals precipitate during concentration. In addition, when an operation is performed at a high temperature for a long time to completely remove the solvent or dehydrate, ester hydrolysis or racemization of the amino acid proceeds. If the alcohol used does not azeotrope with water like methanol, water remains after removing the alcohol, and hydrolysis is promoted.

In addition, a special device must be used in order to remove crystals precipitated in the reactor after desolvation and dehydration. In addition, complicated operations such as slurrying with a solvent, filtration, and drying are required.

As described above, the conventional methods for producing methyl esters of amino acids have industrial problems.

[Means for solving the problem]

The inventors of the present invention react an amino acid with methanol in the presence of a mineral acid to esterify, then partially remove the methanol by concentration, add an organic solvent capable of azeotroping with water, and azeotropically dehydrate the amino acid methyl. It has been found that mineral salts of esters can be produced in high yields and has already been filed.

As a result of further studies, the present inventors have found that when the methyl ester of an amino acid is produced by the above method, the desired amino acid methyl ester is converted into a mixture of two or more salts of a mineral acid to remove solvent and dehydrate. The present inventors have found that the operation can be performed efficiently without crystallization even in the inside, and that the operations such as mixing and liquid transfer can be easily performed, and the present invention has been completed.

That is, the present invention provides a method for producing a mineral acid salt of an amino acid methyl ester, the method comprising the step of converting the ester into two or more kinds in which at least one of the mineral salts is in the range of 20 to 80 mol% of the total amount of the mineral salts. A method for producing an amino acid methyl ester mineral acid salt characterized by being isolated as a non-crystalline mixture of the mineral acid salt and producing a mineral acid salt of a methyl ester of two or more amino acids, excluding excess methanol, Subsequently, an azeotropic dehydration is performed by adding an organic solvent capable of azeotropic distillation with water.

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. Generally, mineral acids such as hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid are used. Used in combinations of more than one type. The combination is not particularly limited, but it is preferable to use, as one of the mineral acids, hydrochloric acid capable of easily removing an excessively used mineral acid after the esterification reaction.

The total amount of these mineral acids must be at least equivalent to the amino acids used. The amount of the mineral acid used in the mixture is preferably such that at least one or more of the amino acid methyl ester mineral salts accounts for 20 to 80 mol% based on the total amount of the mineral salts.

More or less than this is not preferred because the ester precipitates as a mineral salt. Further, various mineral acids may be added before esterification, or may be added after esterification is completed and before removing methanol.

The conditions for the esterification in the method of the present invention are not particularly limited, and the temperature, the time, the molar ratio of the raw materials, and the like can be appropriately selected in consideration of the difficulty of the esterification with the amino acid used. Usually, the reaction is carried out by leaving the mixture at room temperature for several days, or by heating it to near the reflux temperature of methanol for several hours.

Methanol is usually used in excess, but is removed by concentration under reduced pressure after the reaction. Further, water generated by the reaction can be removed by repeating the operation of adding methanol and evaporating a single solvent. However, a method of removing most of methanol and then adding an organic solvent to carry out azeotropic dehydration is preferable.

The organic solvent used in this case is one that forms an azeotrope with water and may be anything that is inert to the components of the reaction mixture. For example, benzene, toluene, n
-Hydrocarbons such as hexane and cyclohexane, halogenated hydrocarbons such as chloroform, dichloroethane, carbon tetrachloride, 1,2-dichloroethane, 1,1,2-trichloroethane and chlorobenzene, ethyl ether, butyl ether, tetrahydrofuran, dioxane Ethers such as
Esters such as methyl acetate and methyl propionate are exemplified.

The methanol concentration and azeotropic operation can be performed under normal pressure or reduced pressure, but it is preferably performed at 80 ° C. or lower because racemization of amino acids and hydrolysis of esters occur at high temperatures.

The thus obtained non-crystalline amino acid methyl ester mineral acid salt can be used as it is or dissolved in a solvent for the next step, or after the solvent is added, the remaining solvent is distilled off and removed. Can be used in the next step.

[Action and effect]

In the conventional method, when concentrated and isolated as a mineral acid salt of amino acid methyl ester, water incorporated in the crystallized amino acid methyl ester promotes hydrolysis, whereas according to the method of the present invention, It can be concentrated and isolated as a mixture of mineral salts, and can be efficiently desolventized and dehydrated in an oily state at a low temperature and in a short period of time. Can be manufactured. Moreover, since the obtained ester is a non-crystalline fluid, it is an industrially superior method that does not require complicated operations such as slurrying, filtration, and drying.

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

[Example] Example 1 165.2 g of L-phenylalanine is added to 660 g of methanol containing 146 g of hydrogen chloride, and the mixture is stirred at 40 ° C for 4 hours. As a result of analysis of the reaction solution by high performance liquid chromatography, L-
The conversion to phenylalanine methyl ester reached over 99%. Here, 50.1 g of 98% sulfuric acid (50 mol% of sulfuric acid added later) is added, and methanol is distilled off at 50 ° C. or less under a reduced pressure of 50 mmHg for 30 minutes, and the mixture is concentrated to a weight of 253.7 g. next,
Toluene (300 g) was added, and toluene and water were distilled off under the same conditions as above for 30 minutes to obtain 15.8 g of an oily substance (50 mol% of sulfate).

This was analyzed by high performance liquid chromatography to find that the purity was 92.6%, the unreacted L-phenylalanine was 2.2%, and the water was 1.1%. 97.8% yield.

Comparative Example 1 After the same reaction as in Example 1 was performed, the reaction was performed under reduced pressure of 50 mmHg.
When methanol is distilled off at a temperature lower than or equal to 30 ° C., crystals precipitate. The weight of the distillate residue at this time was 298.4 g. When 300 g of toluene was further added and toluene and water were distilled off under the same conditions as above, 238.9 g of crystals were obtained.

The product was analyzed by high performance liquid chromatography, and as a result, the purity was 87.4%, the unreacted L-phenylalanine was 3.2%, and the water was 5.1%. Yield 96.8% Examples 2-5 Instead of L-phenylalanine, L-alanine, L
-Aspartic acid, L-serine and L-lysine hydrochloride were subjected to esterification in the same manner as in Example 1 using 146 g of hydrogen chloride and 660 g of methanol. After the reaction, each of the mineral acids shown in Table 1 was added, and the mixture was concentrated and dehydrated to obtain an oily substance. The results obtained from the analysis by these high performance liquid chromatography are shown in Table 1.

Comparative Examples 2-5 Instead of L-phenylalanine, L-alanine, L
-Aspartic acid, L-serine, and L-lysine hydrochloride were subjected to esterification, concentration, and dehydration in the same manner as in Comparative Example 1 using 146 g of hydrogen chloride and 660 g of methanol to obtain crystals, respectively. Table 1 shows the results of the analysis by high performance liquid chromatography.

 ────────────────────────────────────────────────── ─── Continuation of the front page (56) References JP-A-50-53323 (JP, A) JP-B-45-29488 (JP, B1) Edited by The Chemical Society of Japan New Experimental Chemistry Lecture 14, “Synthesis of Organic Compounds Reaction ▲ II ▼ ”Volume 14, Page 1002, Maruzen Co., Ltd.

Claims (2)

(57) [Claims] 1. A process for producing a mineral acid salt of an amino acid methyl ester, the method comprising the step of removing at least one of the mineral acid salts from at least one of the at least one mineral acid salt in the range of 20 to 80 mol% of the total amount of the mineral acid salt. A method for producing an amino acid methyl ester mineral acid salt, which is isolated as a non-crystalline mixture of the mineral acid salt. 2. The method according to claim 1, wherein after the production of two or more kinds of amino acid methyl ester mineral salts, excess methanol is removed, followed by adding an organic solvent capable of azeotroping with water to effect azeotropic dehydration. Production method as described.