JPS59128364A - Preparation of optically active alanine - Google Patents

Abstract

PURPOSE:To prepare the titled compound in one step and high yield, by simultaneously carrying out the preferential crystallization of DL isomer and the racemization of the isomer of alanine p-chlorobenzenesulfonic acid salt dissolved in a solution in a supersaturated state under racemization condition, thereby effecting the optical resolution of the salt. CONSTITUTION:An optically active alanine is prepared from DL-alanine p-chlorobenzenesulfonic acid salt by optical resolution using preferential crystallization process. In the above process, the preferential crystallization is carried out under the condition to racemize the alanine p-chlorobenzenesulfonic acid salt dissolved in the solution to effect the simultaneous preferential crystallization and the racemization. The preferential crystallization operation is performed in acetic acid solution in the presence of an aldehyde (e.g. salicyl aldehyde) and a free amino acid (e.g. alanine).

Description

[Detailed description of the invention] The present invention relates to a novel method for producing optically active alanine.

Since alanine obtained by chemical synthesis is in the DL form, optical resolution is required to obtain optically active alanine. D
As a method for optically resolving L-alanine, a method is known in which D'L-alanine is optically resolved as P-chlorobenzenesulfonesulfonate by a preferential crystallization method (Japanese Patent Publication No. 47-1436 Lin. However, although this preferential crystallization method is industrially advantageous, it still has various technical limitations.

For example, since only one optically active form is crystallized from a supersaturated solution of the DL form by a preferential crystallization method, the other optically active form is dissolved in the liquid phase while remaining in a supersaturated state. Therefore, the precipitate must be separated and obtained before the spontaneous crystallization of the other optically active substance occurs. In addition, the inoculation of crystals of one optically ancient form and the crystallization of the same crystal and the same type of active form were carried out under conditions in which the optically active form that was not inoculated was stably dissolved in a supersaturated state in the liquid phase. Because it has to be done 1
Naturally, the amount of optically active substance obtained in one operation is small (,
It is about 10 times for DL body lζ. Historically, even when only one of the optically active forms is required, the other optically active form is still present in a supersaturated state in the obtained hindlimb phase. Unless this is taken out of the system, the next optical resolution of the desired optically active substance cannot be carried out.

As a result of extensive research in view of the current situation, the present inventors found that (tll optical properties of 7-nin P chlorobenzene sulfonate were determined by the presence of aldehyde and free amide/acid in acetic acid solution). (2) The optically active alanine P-chlorobenzene sulfonate in the solid state is sufficiently stable without being racemized even under the racemization conditions of the 7-lanine salt dissolved in the above solution. To see irises; and (3
) It was discovered that the alanine salt can be obtained by preferential crystallization under the conditions of the racemization reaction to obtain optically active alanine P-chlorobenzenesulfone Iw! m
The liquid phase during the preferential crystallization, in which the preferential crystallization and racemization reaction 7 proceed in parallel, is always obtained as a solution of the ζDL form, as a result. All of the supersaturated DL form was converted to one optically active form, ζ. It has been found that the drawbacks associated with conventional preferential crystallization methods can be successfully overcome.

Based on this knowledge, the present invention was completed by optically resolving DL-alanine p-chlorobenzene sulfonate by a preferential crystallization method to prepare optically active arnine.
A method for producing optically active alanine characterized in that a preferential crystallization operation is carried out under conditions that racemize alanine p-chlorobenzenesulfonate dissolved in a solution, and preferential crystallization and racemization are carried out simultaneously. , i:, 7..

That is, according to the present invention, crystals of either optically active alanine P-chlorobenzene sulfonate are present in a supersaturated solution of oL-Ryonin P-chlorobenzene sulfonate, and the dissolved alanine P-chlorobenzene is Under the racemization conditions of the sulfonate, the optically active salt of the same type as the above crystals is extracted from the supersaturated solution by extracting the optically active salt P-chlorobenzenesulfone. It can be converted into P-chlorobenzenesulfonate, and then the salt can be deoxidized to produce optically active alanine.

There has been no known method for producing optically active alanine in which such preferential product selection and racemization are simultaneously carried out to convert the 05 salt into an optically active salt.

DL-Rinin P-chlorobenzenesulfonic acid salt used in the present invention can be easily prepared from DL'--rlanin and P-chlorobenzenesulfonic acid, but it is possible to prepare the salt in advance and use it. Alternatively, alanine and P-chlorobenzenesulfonic acid may be added separately to the reaction system.
You may. In the latter case, it is possible to form a salt in the reaction system during the operation of preferential crystallization, and the formed salt becomes supersaturated, allowing subsequent preferential crystallization and racemization to occur. Become.

0) Conditions for priority production and racemization of alanine p-chlorobenzene sulfonate are as follows: 1
There are no particular limitations on this, but it is preferable to use DL-alanine P-chlorobenzenesulfonate (hereinafter referred to as Inoculation is carried out by inoculating a supersaturated solution of optically active phosphoryl P-chlorobenzene sulfonate (hereinafter simply referred to as optically active salt) of the raw material DL salt and stirring under heating. The same type of optically active salt as the optically active salt f precipitates, and the other optically active salt; Further crystallization is carried out using the crystals in which salts of the optically active substance of the same type have already been precipitated from the supersaturated solution formed in 9. In other words, according to the method of the present invention, preferential crystallization and racemization are simply carried out simultaneously. Not only that, but also 1. The ability to continue to obtain the desired optically active salt while the non-crystallized optically active salt dissolved in the liquid phase is racemized and converted into the raw material DL salt. can.

Operations to simultaneously carry out priority product listing and racemization of the present invention (
The toy car number conversion operation (hereinafter referred to as the toy car number conversion operation) is carried out by first mixing raw materials DL aldehyde, free amino acid 2, and acetic acid in the desired order and dissolving them in heated water. Next, seed crystals of an optically active salt are inoculated into a supersaturated solution obtained by cooling or concentrating this, and the optically active salt of the same type as the inoculated optically active salt is crystallized, and the other optically active salt is crystallized. Racemization of the active salt proceeds suitably. Naturally, the optically active salt to be inoculated is preferably of high purity due to its intended use.

In addition, since many types of wax are used, and the relationship between crystallization and crystallization is unknown, it is appropriate to use 0.5 to 5 w/w% of the raw material UL1. This drying operation can be carried out in the range of -Ai from room temperature to the reflux temperature of supersaturated mM, but generally it is about 50 ~
Preferably, the temperature is 100°C.

Examples of the aldehydes present in the acetic acid solution are evaformaldehyde, acet-1'aldehyde, propionaldehyde, n-butyraldehyde, i-butyraldehyde, n-valerylaldehyde, capronaldehyde, n-
Hydrocarbons with a carbon number of 1 to 7, such as heptylaldehyde, chlorolein, or methachlorin/in, can also be used [7! O-unsaturated aliphatic aldehyde or benzaldehyde; benzaldehyde having a nitro residue and a hydroxyl group such as a 5-nitroyl group; benzaldehyde having a Y-hydroxyl group such as a 5-nitroyl group;
1 llI], substituted or non-substituted benzaldehyde with hydroxyl group and alkoxy group, 7 tollaldehyde, phenyl chloride, 7
1b7ral, nitrofurfural, etc. can be used.

Among these, it is particularly preferable to use salicylaldehyde. It is appropriate to use these aldehydes in an amount of about 1 to 6 w/w% based on the body weight of the raw material DL. 0 again
In the present invention, the amino acids added to further promote the racemization of the supersaturated optically active salt in the liquid phase include:
Any amino acid can be used, including the i'lt amino acid, and can be used even if it is an optically active form or a racemic form. Generally, when Y-lanin is used, there is an advantage that there is no possibility that the t-species amino acid will be mixed into the optically active salt obtained. It is appropriate to use the free amino acid in an amount of about 0.1 to 15 w/w% based on the body weight of the raw material OL.

In order to lower the solubility of the DL body in the conversion operation, the above-mentioned raw material DL body weight aldehyde, free amino acid, and acetic acid salt are inert to preferentially crystallize the optically active body salt,
For example, benzene.

It is possible to add toluene or the like to the anti-1'F) system.

In this way, all of the DL body weight corresponding to the supersaturation can be converted into the desired optically active salt. In order to carry out the experiment effectively, it is necessary to continue to give supersaturation by DL body weight.For example, add the raw material DL body weight corresponding to the allowable degree of supersaturation to the reaction solution after the completion of the conversion operation, and add only this DI and body weight. The conversion operation described above may be carried out after warm dissolving (y) to prepare a supersaturated solution.Also, while performing the conversion operation, the reaction system may be freed (t111).
The L-isomer may be added in advance, and an acid may be added to the a4 to impart supersaturation. If the conversion operation is not completed, the above conversion operation can be continued by cooling the reaction solution again, concentrating it, or adding a solvent to supersaturate the concentration of dissolved raw material DL body weight in the reaction solution. You can do it.

In any of the above methods, the optically active salt crystals that have already been precipitated become organic crystals as they are, which is advantageous.

The optically active salt thus obtained can be collected by known methods such as filtration and centrifugation. The obtained optically active alanine P-rubenzene sulfonate was treated with an alkali. Or ion exchange! M! Free optically active alanine can be obtained by carrying out a conventional deoxidizing treatment such as treatment. The acid that has been further separated can be used again as a raw material for the raw material OL body.

As described above, the method of the present invention converts unnecessary optically active salts into desired optically active salts and also produces optically active salts. The raw material can be continuously produced as a desired optically active salt by simply adding the raw material. Therefore, in the conventional method, - gives priority to the desired optically active substance. The method of the present invention does not require such complicated treatment at all.

In addition, according to the present invention, racemization proceeds at the same time as the desired optically active salt is preferentially produced. It also has the advantage of not being subject to the technical constraints of conventional lμ, such as having to prioritize the selection of desired optically active salts. As mentioned above, the method U of the present invention is extremely useful industrially in that it can produce a desired optically active salt in high yield in just one step without requiring any complicated treatment. be.

EXAMPLES Hereinafter, the present invention will be roughly explained in detail with reference to Examples.

Example 1 DL-Rinonin P-chlorobenzene sulfonate 4
5.09. or, -alanine 2. OSI and salicylaldehyde 1.07) Wood vinegar m> b Ornl was added and dissolved by heating at 120°C, then maintained at 100°C. D- to this
γ-lanin p-ll lorbenzenesulfonate crystal 0°b
Inoculate the seeds with the following ingredients and stir for 90 minutes at the same crystallinity. The precipitated crystals were quickly collected, washed with a small amount of glacial acetic acid, and then dried to obtain D-chonin P-chlorobenzenesulfonate 8.
．． I got 97.

[α] Precious -3,5° (C, = 'l, water), optical purity 97
% On the other hand, the mother liquor has no optical rotation, so when 15 m/m of water was added to the mother liquor and the precipitated product was taken off after cooling and stirring, it was found that DL-alanine p
-Chlorbenzenesulfone e 1m 12-2' fi
was gotten.

Cc1! l: 0-05 (C=2, therefore, it is clear that the non-inoculated L isomer was completely racemized in the liquid phase after the above reaction.

45.0 g of 1-D-chlorobenzene sulfonic acid obtained by this reaction was dissolved in 60% of water, and the mixture was heated under ion-exchange resin with Emperlite IR-120 (H type) 2
It was poured into a tower filled with 5 m/ml. Next, the resin was washed with water, and alanine was eluted with 30 ml of 2N aqueous ammonia. After the eluate was reduced to dryness, the residue was recrystallized from aqueous methanol to obtain 1.4P of D-alanine.

[α] Meat-14,4° (C-” 2 , 58-HCI
) Example 2 DL-Ryounin P-chlorobenzenesulfonate 31 (
jg, 'JL--f Rani 715W and salicylaldehyde 4.57 to glacial acetic acid 100. After heating and melting nt at 120°C, keep it at 100°C. L-alanine P here
-Chlorbenzene sulfone e fJM crystal 2, (1
/ was inoculated. Same temperature 1! After stirring at J for 90 minutes, a solution of P-clotebenzenesulfone monohydrate (23.85") dissolved in 12.7 ml of acetic anhydride was added to the reaction mixture at a rate of 74 hours for about 4 hours. system to generate the pre-existing DL-alanine and salt for 2 hours (2.0 g of salicylaldehyde added to I).

Ta. After inoculation, the precipitated product was immediately taken off and washed with a small amount of glacial acetic acid 16, and then dried to obtain L-chlorobenzene sulfonate 36
．． 31i' was obtained.

[α+3.5°t C=2, water), optical purity 97%
On the other hand, not a single sample of the mother liquor had any optical rotation, and when 30 mZ of water was added to i&M and the precipitated crystals were collected after cooling and stirring, DL-γlanin P was found.
-Chlorbenzene sulfonic acid! 53.5Ii was obtained.

[: 11/lj; 0.0° (C=, 2. water) This reaction yields t'+1 L-chlorobenzenesulfonic acid 430F. + As with 1, processing SL,
L-alanine9. I got an O.

Claims (1)

[Claims] 1. When producing optically active alanine by optically resolving DL-alanine p-chlorobenzene sulfonate, the preferential crystallization operation is performed using a method for producing optically active alanine. P-chlorobensene sulfonate was subjected to actual firing under the conditions of racemization, and preferential crystal W and racemization occurred simultaneously.
7. A method for producing optically active alanine, characterized by: 2. Patent claim 41j +, jJ in which the preferential crystallization operation is dependent on the presence of aldehyde B and free amino acids in the acetic acid solution
J, the manufacturing method described in Section 1. 3. The production method according to claim 2, wherein the aldehyde is ~salicylaldehyde and the free amino acid is alanine.