JPS6141339B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for racemizing optically active α-amino acid esters in a short time and efficiently. Optically active amino acid esters are useful as raw materials for the synthesis of various peptides, but since amino acid esters produced by general synthetic methods are racemic, it is difficult to obtain the desired optically active form by means such as appropriate optical resolution. Is required. By the way, it is desired to effectively utilize the other undesired optically active substance obtained by optical resolution, and one way to do this is to racemize it again, optically resolve it, and gradually convert it into the desired optically active substance. There are many ways to use it. For this purpose, the present invention provides a method for racemizing optically active α-amino acid esters. Conventionally, as methods for racemizing amino acids themselves, methods such as heating an optically active amino acid in water or contacting it with acetic anhydride have been developed and widely used. On the other hand, racemization technology for optically active amino acid esters is still not well known.
For example, a method in which D-methionine ester is reacted with an aldehyde to form a Schiff base and then hydrolyzed (Japanese Patent Publication No. 33-1775), an optically active amino acid ester is reacted with a catalyst consisting of an alkali metal and an aromatic hydrocarbon, or an alkali is converted into a porous base. A method of bringing the catalyst into contact with a catalyst dispersed in a carrier
49226, Japanese Patent Application Laid-Open No. 50-50302) are known. In addition, as a method for racemizing optically active phenylalanine ester, a method is known in which the racemization is carried out by heating in alcohol using an alkali metal alcoholate (US Pat. No. 3,941,831). However, among these known methods, in the case of the method via Schiff's base, sufficient purification is required because side reactions occur, and in the case of the catalytic method using alkali metals or alkali metal alcoholates, This is not an industrially advantageous method because of problems in catalyst production and cost. Furthermore, one ester of the α-amino acid enantiomer is reacted with an optically active acid in the presence of an aldehyde or a ketone,
A method of obtaining a desired α-amino acid enantiomer by separating it in the form of a salt at the same time as racemization is also known (Japanese Patent Application Laid-open No. 48-97801). However, this method requires the use of an optically active acid in an equimolar amount as the desired enantiomer as an optical resolving agent, and requires a long reaction time, so it is not suitable for industrial implementation. It has the disadvantage of being appropriate. The present inventors discovered that optically active α-
As a result of extensive research into the racemization of amino acid esters, we have found that racemization occurs simply by heating in a ketone or an organic solvent containing a ketone, and that the corresponding amino acid and by-products such as diketopiperazine are present during the reaction. The racemate can be recovered in a high yield with almost no reaction.Furthermore, when the racemate is produced in the presence of an acid, the reaction is accelerated, the reaction temperature and reaction time are reduced, and by-products are eliminated. The inventors have discovered that ketones are extremely suitable solvents for racemization reactions, such as by reducing the amount of products produced, and have completed the present invention based on these findings. That is, the present invention provides a racemic optically active α-amino acid ester, which is characterized in that the optically active α-amino acid ester is heated in a ketone at a temperature of 90°C or higher in the presence of an acid catalyst of 0.05 to 0.5 times the molar amount of the optically active α-amino acid ester. It provides a method of conversion. The optically active α-amino acid ester used as a raw material in the method of the present invention is not particularly limited, and esters of neutral, basic or acidic amino acids having hydrogen at the α-carbon can be used without any problem. The amino acid in this case is preferably an α-amino acid having 15 or less carbon atoms, such as alanine, valine, leucine, isoleucine, serine, threonine, cystine, cysteine, methionine, phenylalanine, tyrosine, dopa, proline, hydroxyproline. , neutral amino acids such as tryptophan, basic amino acids such as lysine, δ-hydroxylysine, arginine, and histidine, and acidic amino acids such as aspartic acid and glutamic acid. Even if these amino acids have functional groups such as hydroxyl groups, amino groups, thiol groups, and amide groups in their amino acid skeletons, they cannot be used in the solvent components used in this racemization method or the acids added to the solvent as necessary. There is no particular problem as long as it is stable. however,
If a free carboxyl group is present, it may not dissolve in the solvent used in the present invention. In that case, it is desirable to use the carboxyl group after esterifying it. Furthermore, the alcohol residue constituting the ester moiety of the optically active α-amino acid ester as a raw material is not particularly limited, and any residue may be used as long as it does not react with the solvent component or the acid used if necessary.
For example, methyl alcohol, ethyl alcohol,
Lower aliphatic alcohols having about 1 to 7 carbon atoms, such as allyl alcohol, propyl alcohol, butyl alcohol, crotyl alcohol, amyl alcohol, hexyl alcohol, heptyl alcohol and their isomers; octyl alcohol;
Nonyl alcohol, lauryl alcohol, stearyl alcohol, eicosyl alcohol, higher aliphatic alcohols having about 8 to 22 carbon atoms such as isomers thereof, alicyclic alcohols such as cyclopentanol and cyclohexanol, benzyl alcohol, and cinnamyl alcohol Examples include residues derived from aromatic alcohols such as, or heterocyclic alcohols such as furfuryl alcohol. Furthermore, in addition to the monohydric alcohols mentioned above, residues of polyhydric alcohols such as ethylene glycol, propylene glycol, glycerin, and trimethylolpropane can also be used. The optically active α-
The amino acid ester need not be a single component, but may be a mixture with a racemate or a mixture of different α-amino acid esters. In the method of the present invention, it is necessary to use a ketone as a solvent, but this does not necessarily have to be pure and may be used in combination with other solvents as desired. Since the reaction temperature of the ketones used in the present invention needs to be 90°C or higher, those having a boiling point of 90°C or higher are preferable, such as acetone, ethyl methyl ketone, methyl propyl ketone, butyl methyl ketone, and isobutyl methyl. Ketones, aliphatic saturated ketones such as pinacolone, diethyl ketone, butylon, diisopropyl ketone, amyl methyl ketone, hexyl methyl ketone, diisobutyl ketone, aliphatic unsaturated ketones such as mesityl oxide, methyl hepranone, holone, cyclopentanone, cyclohexanone, etc. Aliphatic saturated ketones, especially 4-carbon ketones such as isobutyl methyl ketone and diisobutyl ketone, can be used.
The aliphatic saturated ketones of 1 to 11 are advantageous because they can raise the reaction temperature and are easily available. Other organic solvents that can be mixed with ketones include optically active α-amino acid esters as raw materials or solvents that are stable against acids used as necessary, and whose mixture with ketones has a boiling point of 90°C or higher. There are no particular restrictions as long as it is. For example, alcohols such as methyl alcohol, ethyl alcohol, propyl alcohol, and butyl alcohol similar to the alcohol residues constituting the raw material ester, hydrocarbons such as toluene, benzene, and hexane, ethylene dichloride, tetrachlorethylene, carbon tetrachloride, and chloroform. halogenated hydrocarbons, such as
Alternatively, esters of methyl, ethyl, propyl, butyl, and pentyl esters of fatty acids such as acetic acid, propionic acid, butyric acid, valeric acid, and hexanoic acid may be mentioned. The combined use of these other organic solvents may be advantageous in promoting the solubility of the acid used or in recovering the desired racemate, if necessary.
It can be effectively applied in the process. but,
When alcohol or alcohol derivatives such as fatty acid esters are used as other organic solvents, there is a risk of transesterification with the optically active α-amino acid ester as a raw material. Recommended. In the method of the present invention, it is necessary to use the above-mentioned solvent containing at least a ketone and to add an acid catalyst to the solvent in order to promote the racemization reaction. This acid catalyst includes hydrohalic acids such as hydrochloric acid and hydrobromic acid, sulfuric acid, sulfurous acid,
Inorganic acids such as phosphoric acid, pyrophosphoric acid, boric acid, acetic acid, propionic acid, butyric acid, oxalic acid, malonic acid,
Sebacic acid, maleic acid, fumaric acid, tartaric acid, citric acid, aliphatic carboxylic acids such as N-protected amino acids, aromatic carboxylic acids such as phthalic acid, isophthalic acid, benzenesulfonic acid, xylene sulfonic acid, dodecylbenzenesulfonic acid, Protic acids such as organic sulfonic acids such as nonylsulfonic acid, organic phosphoric acids such as ethyl phosphoric acid and phytic acid are used, but aluminum chloride, magnesium chloride, titanium chloride, copper chloride, zinc chloride, ammonium salts of protic acids are used. Lewis acids such as organic amine salts such as monoethylamine salts, isopropylamine salts, diethylamine salts, and triethylamine salts can also be used. Therefore, the protonic acid may be introduced into the reaction system in a free form, but even when introduced as an ammonium salt or an organic amine salt, it exhibits the effect of an acid catalyst. It is advantageous to introduce the protonic acid salt as a protonic acid salt, for example, a hydrogen halide salt of a raw material amino acid ester, since the raw material and the acid can coexist in the reaction system at the same time. The concentration of the amino acid ester during racemization in the method of the present invention is not particularly limited, but when a ketone is used alone, the raw material ester concentration is usually 2 to 30 g/
dl, preferably 5 to 20 g/dl.
On the other hand, when other organic solvents are used in combination, the overall raw material ester concentration is selected from the above range, but the amount of ketone used in this case is at least equimolar, preferably 3 molar to the raw material ester. It is more than double the mole. The amount of acid used in the method of the present invention needs to be selected within the range of 0.05 to 0.5 moles relative to the raw material ester. If this amount is less than 0.05 times the mole, sufficient effect of promoting racemization cannot be obtained;
Even if the amount is increased by more than twice the mole, no particular improvement in the effect is observed and it is uneconomical. Next, the method of the invention can be carried out very easily as described below. For example, after dissolving or suspending the raw material amino acid ester in a mixed solvent with ketone or other organic solvent, if necessary, the acid may be directly or briefly dissolved in another organic solvent, and then introduced into the raw material solution and heated. . Furthermore, since this reaction involves racemization by heating, the raw materials only need to be dissolved at a desired reaction temperature, and do not necessarily need to be dissolved at room temperature. In addition, since this reaction involves heating the raw material ester, it is important to carry out the reaction in a substantially anhydrous state in order to prevent decomposition of the ester and improve the yield. Also,
The reaction temperature varies depending on the type of raw material ester and ketone used, but if it is too low, racemization will take a long time, while if it is too high, side reactions will occur, which is undesirable, so it should be 90℃ or higher. , preferably temperatures up to 140°C are used. The reaction time required to complete racemization varies depending on the reaction conditions, especially the reaction temperature and the presence or absence of an acid. Generally, as the reaction temperature increases, the reaction time may be shorter, and by using an acid, the reaction time can be reduced by approximately 1. It can be shortened to /2 to 1/10. Since the racemization reaction solution obtained in this way has almost no coloration or presence of by-products, it can be used as a racemic amino acid ester solution without purification after separating the acid if necessary. . Furthermore, if it is necessary to isolate a racemate, it may be concentrated as necessary and then isolated as a crystalline derivative such as a hydrochloride. As is clear from the above description, the present invention provides a method for extremely efficiently racemizing optically active α-amino acid esters, and greatly contributes to various peptide synthesis industries. Hereinafter, the present invention will be explained in more detail with reference to Examples. Comparative Example 1 50 g of D-phenylalanine methyl ester was dissolved in isobutyl methyl ketone 1, and the boiling point (approx.
The mixture was heated under reflux at 116°C for 24 hours. Next, the reaction solution was concentrated under reduced pressure, and the residue was dissolved in 280 ml of 1N hydrogen chloride-methanol solution, and concentrated under reduced pressure until the total volume became 100 ml. 300 ml of ethyl ether was gradually added to the residue, and the precipitated phenylalanine methyl ester hydrochloride crystals were collected by filtration and dried. The yield of the obtained crystals was 55 g (yield
91%), and the specific optical rotation is [α] _D = 0° (c =
1, methanol). Comparative Example 2 In Example 1, diisobutylketone 1 was used instead of isobutylmethylketone, and the boiling point (approximately
The mixture was heated under reflux at 168°C for 4 hours. The reaction solution was diluted 5 times with diisobutyl ketone and its optical rotation was measured and found to be 0°. In addition, the reaction solution was developed on silica gel thin layer chromatography and colorimetrically determined using ninhydroly.
% or more remained in the reaction solution without decomposition (residual rate of 71% or more). Example 1 50 g of L-phenylalanine methyl ester was dissolved in ketone 1 listed in Table 1 and heat treated in the presence of an acid. The optical rotation of the reaction solution and the residual rate of phenylalanine methyl ester obtained in the same manner as in Example 2 are also shown in Table 1.

【table】

[Table] Example 4 After dissolving 50 g of D-phenylalanine methyl ester in isobutyl methyl ketone 1, 27.8 ml of 1N hydrogen chloride-methanol solution was added, and the mixture was heated under reflux for 6 hours. The reaction solution was diluted with isobutyl methyl ketone.
It was diluted twice and its optical rotation was measured and found to be 0°. Moreover, the residual rate of phenylalanine methyl ester was 95% or more. Example 5 50 g of various amino acid esters were dissolved in Solvent 1 listed in Table 2, and heat racemization was performed. The optical rotation of the reaction solution and the residual rate of the raw material ester are both
Shown in the table.

【table】

【table】

Claims (1)

[Claims] 1 optically active α-amino acid ester, its 0.05
90°C in ketones in the presence of ~0.5x molar acid catalyst
A method for racemizing an optically active α-amino acid ester, which comprises heating at a temperature above.