JPS6325580B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to an optical resolution method for DL-serine, and more specifically, a method for optically resolving DL-serine or serine in which either D- or L-active form is present in excess and meta-xylene-4-sulfonic acid (hereinafter referred to as (abbreviated as meta-xylene sulfonic acid);
A serine optical method characterized by inoculating crystals of optically active serine/meta-xylene sulfonate into a solution in which a different type of serine salt coexists to precipitate the same type of serine/meta-xylene sulfonate. It concerns the division method. The L-form of serine is used in nutritional supplements such as amino acid infusions, and cosmetics such as creams and lotions, and it is desired to supply pure L-form in large quantities and at low cost. Conventional methods for obtaining the L-form of serine include fermentation and extraction and separation from natural flea white matter hydrolysates, but the L-form obtained in this way is both expensive and extremely expensive. There are many difficulties because it requires complicated operations. As a method for obtaining the DL-form of serine, there is, for example, a method for producing it from a vinyl compound described in Chem.Ber., 92 , 1081, (1959). As a method for obtaining an optically active form of serine, its derivative is
A method of optical resolution using a diastereomer method using a resolving agent such as aminopropanediol, dibenzoyl-D-tartaric acid, cinchonine, or brucine has been reported. However, these resolving agents are difficult to obtain in large quantities and at low cost, and have poor resolving efficiency, making them difficult to use as an industrial method. Furthermore, these methods require complicated operations, and it is difficult to obtain pure active substances. Also,
DL-serine as metaxylene sulfonate,
An optical resolution method using preferential crystallization has also been reported, in which this is dissolved in water to make it supersaturated, and then crystals of optically active serine meta-xylene sulfonate are inoculated to obtain the same type of active salt. . (Tokuko Showa 46
-29843) However, according to this method, the yield of optically active salt obtained from dissolved DL-serine salt is low, and the supersaturated solution is unstable, so strict operating conditions such as temperature control are required. There are some drawbacks, such as the need for The present inventors hope to improve these shortcomings and improve the DL
- After examining various methods for carrying out the optical resolution of serine more advantageously, we determined that DL-serine was converted into meta-xylene sulfonate, and a different type of DL-serine salt was co-existed in a supersaturated solution of this salt. The present inventors have discovered that optically active serine meta-xylene sulfonate with high optical purity can be crystallized in a stable yield and with a simple operation by carrying out preferential crystallization based on the above results, and have completed the present invention. . In the present invention, serine salts different from serine meta-xylene sulfonate are desirably those that have high solubility in the crystallization solution and therefore have a large stabilizing effect on the crystallization solution, such as DL-
Serine sulfate, hydrochloride, methanesulfonate,
Lactate and the like are preferred. In addition, water, methanol, ethanol, isopropanol, etc. can be considered as a solvent for coexisting and dissolving DL-serine/meta-xylene sulfonate and another type of serine salt, but industrially, water is the most preferable because it is inexpensive. . The present invention is carried out, for example, in the following manner.
A solvent is added to DL-serine metaxylene sulfonate and another type of serine salt in an amount of 1 to 10 times the mole, preferably 2 to 5 times the mole thereof, and the mixture is heated and dissolved, and then cooled to form DL-serine.・Supersaturate the meta-xylene sulfonate, inoculate it with a small amount of optically active serine-metaxylene sulfonate, crystallize the same type of active salt, and separate it from the mother liquor. In addition, DL-serine, metaxylene sulfonic acid, and another type of acid are heated and dissolved in a solvent,
After preparing an aqueous solution in which DL-serine meta-xylene sulfonate and another type of salt coexist, it is cooled to supersaturation in the same manner as above, and optically active serine meta-xylene sulfonate is inoculated to obtain the active form. It is also possible to crystallize crystals. Next, add DL− to the mother liquor.
Replenishing serine meta-xylene sulfonate,
A crystal of serine meta-xylene sulfonate having an optical rotation opposite to that of the previously inoculated active substance is inoculated, crystals of the same type of active substance salt are crystallized, and solid-liquid separation is performed.
By repeating these operations, the DL
- Easily convert serine meta-xylene sulfonate,
And it can be completely optically separated. In addition, in the method of the present invention, after the first crystallization of an optically active compound, the number of optically active compounds having opposite optical rotation to that of the crystallized compound increases in the solution. When meta-xylene sulfonate is replenished, crystallization can occur naturally without inoculating seeds of the optically active salt that is present in large amounts. According to the method of the present invention, the easily soluble serine salt, which has sufficient solubility even when cold, is in equilibrium with the serine metaxylene sulfonate, and acts as a buffer against the crystallization pressure of the enantiomer. Therefore, the crystallized liquid phase maintains a stable phase equilibrium relationship throughout. Therefore, according to the method of the present invention, the instability of supersaturation, which was considered to be a drawback of the conventional preferential crystallization method, is significantly alleviated, and it is possible to crystallize the same amount of the active form as the dissolved racemic form. It has a revolutionary effect. In this way, according to the invention, DL-
Serine metaxylene sulfonate can be easily optically resolved in high yield and purity. Next, the method of the present invention will be explained in more detail with reference to Examples. Example 1 8.41g (80m mol) of DL-serine and 5.33g (24m mol) of metaxylene sulfonic acid dihydrate were mixed in 6N
It was heated and dissolved in 10.26 g (56 mmol) of HCl and 7 ml of water.
As a result, 24 m mol of DL-serine metaxylene sulfonate (hereinafter abbreviated as DL-serine MXS salt) and 56 m mol of DL-serine hydrochloride
This means that an aqueous solution in which these coexist is prepared. Next, after cooling this aqueous solution to room temperature, 50 mg of optically active L-serine MXS salt was inoculated, and the solution was incubated at 2°C for 1.5 min.
After standing for a while, separate the precipitated crystals and 1.80g
(5.6 mmol) of L-serine MXS salt was obtained. [α] ¹⁰ ₄₃₅ +10.6° (c=4, H ₂ O) Specific optical rotation of pure L-serine MXS salt prepared separately [α] ¹⁰ ₄₃₅ +10.65° (c = 4, H ₂ The optical purity calculated from O) was 99.5%. Add DL-serine to the mother liquor obtained by the above procedure.
1.31 g (12.5 m mol), 2.67 g (12 m mol) of metaxylene sulfonic acid dihydrate and 1 ml (0.5 m mol) of 0.5N HCl
mol) and then heated to dissolve. By this operation, 12 mmol of DL-serine MXS salt and DL-
This means that an aqueous solution containing 0.5 m mol of serine/hydrochloride was prepared and replenished. Next, after cooling this aqueous solution to room temperature, 50 mg of D-serine MXS salt was inoculated, and after standing at 2°C for 1 hour, the precipitated crystals were separated and 3.60 g (11.0 m
mol) of D-serine MXS salt was obtained. [α] ¹⁰ ₄₃₅ −10.65゜(c=4, H ₂ O) Optical purity 100% Below, repeat the same operation until the optical purity is 99~
100% L-serine MXS salt and D-serine
3-4 g portions of MXS salt were obtained alternately. Obtained L-serine MXS salt 3.94g (12.0m
1.20 g of L-serine with an optical purity of 99.0% was obtained by treating 1.20 g of L-serine with an optical purity of 99.0%.
(11.4m mol) was obtained. [α] ¹⁴ _D −14.9° (c=2, 1N HCl) Next, the results of the first optical resolution of L-serine metaxylene sulfonate in Example 1 of the present invention and the conventional method of the present specification Table 1 shows a comparison with the optical resolution results of Example 1 of Japanese Patent Publication No. 46-29843, which was explained in the technical description. Here, since the amount of solvent used in both Examples is different, the amount of water used in Example 1 of the present application was converted to 100 ml for comparison.

[Table] *1) Amount of active salt obtained - Amount of seed crystals From the results in Table 1 above, according to the method of the present invention,
It can be seen that the coexistence of DL-serine hydrochloride is superior to known techniques in the following respects. 1 In one operation when the amount of solvent is the same,
Only half the amount of DL-serine metaxylene sulfonate as a raw material is required, and double the amount of active salt can be crystallized. This net crystallization amount is the value obtained by subtracting the amount of seed crystals used from the amount of active salt obtained. 2. Only a very small amount of seed crystals is needed.

Claims (1)

[Scope of Claims] 1 (a) Serine meta-xylene obtained by reacting metaxylene-4-sulfonic acid with DL-serine or serine in which an active form of either D- or L- is present in excess. 4-sulfonate,
and (b) optically active serine meta-xylene-4 in an aqueous solution in which DL-serine hydrochloride coexists and the above (a) serine meta-xylene-4-sulfonate is present in a supersaturated state.
- A method for optical resolution of serine, which comprises inoculating a sulfonate and precipitating crystals of the same type of optically active serine meta-xylene-4-sulfonate.