JP2971291B2 - Production method of optically active 2-aminobutyric acid - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel process for producing optically active 2-aminobutyric acid, which is useful as a raw material for various pharmaceuticals or agricultural chemicals, and more particularly, to a process using a novel 2-aminobutyric acid / p-toluenesulfonate. And a method for industrially producing high-purity optically active 2-aminobutyric acid using a preferential crystallization method.

[0002]

2. Description of the Related Art Optically active 2-aminobutyric acid is a kind of α-amino acid, and its importance as a raw material for a chiral pool agent or a catalyst for asymmetric synthesis has been increasing in recent years. The D-form is a substance that has attracted attention as a raw material for various pharmaceuticals, including antibiotic modifiers. As a method for producing optically active 2-aminobutyric acid, a method for diastereomeric optical resolution of racemic 2-aminobutyric acid using optically active trans-1,2-cyclohexanedicarboxylic anhydride as an optical resolving agent has been reported. (Chemical Society of Japan, (6) 765 (19
79)). However, this method requires preparation since the optical resolving agent is not commercially available as a special reagent, and also requires an amidation bond to perform optical resolution, so that a free optically active 2-aminobutyric acid can be obtained after the resolution. Must be hydrolyzed with hydrochloric acid, and there is a risk of troublesome racemization,
This is not always an advantageous method.

Further, a method has been reported for preferential crystallization optical resolution as an ammonium salt of racemic N-acetyl-2-aminobutyric acid (Bull. Chem. Soc. Jp.).
n. , 60 (3), 947 (1987)). However, in this method, once free 2-aminobutyric acid is once N-acetylated, it must be further derivatized to an ammonium salt.
Moreover, these must be removed after the division and the division efficiency is not good, so that it is not industrially advantageous. Therefore, a new method for producing optically active 2-aminobutyric acid which can be produced industrially advantageously has been demanded.

[0004]

SUMMARY OF THE INVENTION The present inventors have made intensive studies to overcome the above-mentioned drawbacks, and as a result, have been able to efficiently produce optically active 2-aminobutyric acid by a simple operation economically and industrially. A preferred crystallization optical resolution method that can be well prepared has been found. The principle of the preferential crystallization method is well known, for example, as described in J. Jesques, E. Colette, S., and Et Wylen, enantiomers, racemates, and resolution, J. Willie and Sun, New York (1981); Usually, one of the racemic supersaturated solutions is inoculated with one optically active substance, and the same optically active substance as inoculated is separated and obtained. This method is said to be industrially advantageous because it does not require a special and expensive optically active resolving agent unlike the diastereomer method. However, this method is advantageously applicable only generally when the racemic crystals form a racemic mixture. However, it is not known what compounds crystallize to form a racemic mixture and whether preferential crystallization can be achieved, and there is no regularity. That is, in order to find a racemic mixture to which this optical resolution method can be applied, it is necessary to prepare and identify crystals of a salt of 2-aminobutyric acid one by one. Usually, the probability of forming a racemic mixture is extremely low, and formation can be interpreted as a rather special case. Therefore, great effort must be made to find a compound that satisfies such conditions.

[0005]

The present inventors have conducted various studies on an efficient optical resolution method of 2-aminobutyric acid and found that 2-aminobutyric acid is simply converted into a salt with p-toluenesulfonic acid. Alone, and found that the salt forms a racemic mixture. Furthermore, a preferential crystallization optical resolution method capable of efficiently separating the optically active salt and the racemic salt from the solubility properties of the racemic salt and the optically active salt was found. completed. That is,
The present invention provides a novel method for producing optically active 2-aminobutyric acid, which is useful as a raw material for pharmaceuticals and agricultural chemicals, at a lower cost and in an industrially advantageous manner than the conventional method, and a novel 2-aminobutyric acid / p-toluene used therefor. It provides a sulfonate.

According to the present invention, 2-aminobutyric acid to be optically resolved is first introduced into a novel 2-aminobutyric acid / p-toluenesulfonate, which is optically resolved using a preferential crystallization method. The desired optically active 2-aminobutyric acid is produced in high purity and high yield by decomposing the obtained optically active 2-aminobutyric acid / p-toluenesulfonic acid salt.

The 2-aminobutyric acid / p-toluenesulfonate used in the present invention is p-toluene in water or a water-soluble organic solvent.
It can be easily obtained by dissolving toluenesulfonic acid, gradually adding 2-aminobutyric acid thereto, concentrating the solution to an appropriate concentration, and separating and collecting the precipitated crystals. At this time, p-toluenesulfonic acid can be used as its alkali metal salt or alkaline earth metal salt, in which case the above operation may be performed in the presence of a mineral acid such as hydrochloric acid or sulfuric acid in the solution. . The 2-aminobutyric acid / p-
Toluenesulfonic acid salt is separated and collected as crystals as described above, but it is not always necessary to isolate it as crystals in industrial practice, and a solution of 2-aminobutyric acid / p-toluenesulfonic acid salt is directly subjected to optical resolution. In such a case, it is preferable to use as a supersaturated solution of the salt. As the 2-aminobutyric acid / p-toluenesulfonate, racemic 2-aminobutyric acid / p-toluenesulfonate, or an optically active 2-aminobutyric acid in which either one is more excessively contained There can be mentioned 2-aminobutyric acid / p-toluenesulfonic acid salt obtained from a mixture of active 2-aminobutyric acids, in which either one of the optically active salts is present in excess.

In order to carry out the optical resolution of the present invention, first, a supersaturated solution of racemic 2-aminobutyric acid / p-toluenesulfonic acid salt or 2-aminobutyric acid in which one of the optically active salts is present in excess. Prepare a supersaturated solution of p-toluenesulfonic acid salt. Usually, a racemic 2-aminobutyric acid / p-toluenesulfonate salt or a mixture of salts containing one of the optically active salts in excess is converted into a saturated solution at a high temperature, and then cooled or concentrated. Industrially, it is preferable to gradually cool a material saturated at a high temperature to obtain a supersaturated solution.

The solvent used is water or alcohols such as methanol, ethanol, propanol, isopropanol, butanol, cyclohexanol, acetone,
Ketones such as methyl ethyl ketone, acetic acid, propionic acid, lower fatty acids such as halogenoacetic acid, acetonitrile,
Aprotic polar solvents such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, N, N'-dimethylimidazolidinone, N-methylpyrrolidone,
A mixed solvent of water and a water-soluble organic solvent of ethers such as dioxane can be used. The concentration of 2-aminobutyric acid / p-toluenesulfonate in the supersaturated solution varies depending on the temperature at the time of division, but when the solvent is water, 8 to 15 W /
About V%, and when a mixed solvent is used, 15 to 35 W
/ V% is good.

The optically active 2-aminobutyric acid / p-toluenesulfonate is usually obtained by inoculating a supersaturated solution of the racemic salt prepared as described above with a seed crystal.
The seed crystal used for this inoculation is naturally preferably of optically high purity. The larger the inoculation amount, the better, but usually 1 to 5% of the dissolved mass is sufficient. When the same optically active salt is inoculated into a supersaturated solution in which one optically active salt is present in excess, and the same type of optically active salt is preferentially crystallized, the optical rotation of the solution is determined by the preferential crystallization of the optically active salt. Gradually decreases, and eventually the direction is reversed. Therefore, it is usually preferable that the amount of crystallization is usually cut off at 1.5 to 2.5 times the amount of the dissolved optically active salt. Inoculation amount in this case is 0.1% of dissolved mass
The following is sufficient. The remaining mother liquor from which the precipitated crystals were collected,
A racemic salt is added to make a supersaturated solution, and the same optically active salt as the optically active salt present in excess in the mother liquor is inoculated, and the preferential crystallization is performed in the same manner as described above to thereby obtain the other optically active salt. Salt can be obtained. In addition, as is generally known, coexisting salts suitable for stabilizing a supersaturated solution state, for example, mineral salts of 2-aminobutyric acid (hydrochloride, sulfate, etc.) and organic acid salts of 2-aminobutyric acid ( Addition of benzenesulfonate, alkylbenzenesulfonate, substituted benzenesulfonate, etc.) may allow more efficient optical resolution. The above-mentioned preferential crystallization can be carried out by a batch system or a continuous system.

When the optically active 2-aminobutyric acid / p-toluenesulfonate obtained in this way is not optically pure, it is re-used from water or the above-mentioned mixed solvent of water-soluble organic solvent and water. By crystallizing, an optically active salt with higher purity can be easily obtained. The optically active 2-aminobutyric acid / p-toluenesulfonate thus obtained is dissolved or dispersed in water or a water-soluble organic solvent or a mixed solvent thereof, and is dissolved in a conventional manner, for example, sodium hydroxide, triethylamine. If the salt is decomposed by a method such as neutralization or passage through an ion exchange resin, optically active 2-aminobutyric acid can be easily obtained.

[0012]

The present invention will be described in detail with reference to the following examples. Example 1 48.4 g of p-toluenesulfonic acid monohydrate was added to 50 parts of water.
dissolved in 50 ml, and added with 25 g of DL-2-aminobutyric acid.
The solution was completely dissolved by heating to ° C. The solution was concentrated under reduced pressure to dry solid, 150 ml of acetone was added, the precipitated crystal was filtered, washed with acetone and dried to obtain 62.4 g of DL-2-aminobutyric acid / p-toluenesulfonic acid salt. . Yield 93.6% m. p. : 153 to 156 ° C IR (KBr) cm ^-1 : 3420, 2950, 174
_{5,1600,1520,1170,1040,810 NMR (DMSO-d 6)} δ: 0.93 (t, 3H, J
= 7.5), 1.73-1.87 (m, 2H), 2.2
9 (s, 3H), 3.87 (s, 1H), 7.12
(D, 2H, J = 8.2), 7.49 (d, 2H, J =
8.0), 8.20 (s, 3H ) as elemental analysis _{(C 11 H 17 O 5 NS} ): Calculated C: 47.99, H: 6.22, N: 5.09 measurements C: 48 .03, H: 6.20, N: 5.11

Example 2 18.8 g of p-toluenesulfonic acid monohydrate was added to 30 parts of water.
dissolved in 50 ml, and added with 10 g of D-2-aminobutyric acid at 50 ° C.
Completely dissolved under heating. This solution was treated in the same manner as in Example 1 to obtain 26.1 g of D-2-aminobutyric acid / p-toluenesulfonic acid salt. Yield 99.3% m.p. p. : 186 to 188 ° C [α] _D ²⁵ : -11.6 ° (c = 1, methanol) IR (KBr) cm ^-1 : 3420, 2950, 174
_{5,1600,1520,1170,1040,810 NMR (DMSO-d 6)} δ: 0.93 (t, 3H, J
= 7.5), 1.73-1.87 (m, 2H), 2.2
9 (s, 3H), 3.87 (s, 1H), 7.12
(D, 2H, J = 8.2), 7.49 (d, 2H, J =
8.0), 8.20 (s, 3H ) as elemental analysis _{(C 11 H 17 O 5 NS} ): Calculated C: 47.99, H: 6.22, N: 5.09 measurements C: 48 .11, H: 6.19, N: 5.09

Example 3 9.4 g of p-toluenesulfonic acid monohydrate was added to 30 m of water.
and heated to 50 ° C. and completely dissolved. This solution was treated in the same manner as in Example 1 to obtain 12.4 g of L-2-aminobutyric acid / p-toluenesulfonic acid salt. Yield 94.3% m.p. p. : 186 to 188 ° C [α] _D ²⁵ : + 11.6 ° (c = 1, methanol) IR (KBr) cm ^-1 : 3420, 2950, 174
_{5,1600,1520,1170,1040,810 NMR (DMSO-d 6)} δ: 0.93 (t, 3H, J
= 7.5), 1.73-1.87 (m, 2H), 2.2
9 (s, 3H), 3.87 (s, 1H), 7.12
(D, 2H, J = 8.2), 7.49 (d, 2H, J =
8.0), 8.20 (s, 3H ) as elemental analysis _{(C 11 H 17 O 5 NS} ): Calculated C: 47.99, H: 6.22, N: 5.09 measurements C: 48 .01, H: 6.20, N: 5.07

Example 4 DL-2-aminobutyric acid / p-toluenesulfonic acid salt 1
5.84 g, 0.80 g of D-2-aminobutyric acid / p-toluenesulfonate, and 10 ml of water were charged into a triangular Meyer and dissolved by heating at 50 ° C., and the solution was stirred slowly.
Cooled to ° C. Thereto was added 0.01 g of a seed crystal of D-2-aminobutyric acid / p-toluenesulfonate, and after cooling gradually to 25 ° C., the precipitated crystal was separated by filtration, washed with acetone, dried and dried. 1.44 g of 2-aminobutyric acid / p-toluenesulfonate ([α] _D ²⁵ : -8.9 ° (c =
1, methanol) and optical purity: 76.7%). Further, 1.44 g of DL-2-aminobutyric acid / p-toluenesulfonate was added to the filtered mother liquor and dissolved by heating at 50 ° C., and the solution was slowly stirred and cooled to 30 ° C.
At the same temperature, 0.01 g of a seed crystal of L-2-aminobutyric acid / p-toluenesulfonate was added, and the mixture was gradually cooled to 25.5 ° C., and the precipitated crystal was separated by filtration and washed with acetone. After drying, 0.67 g of L-2-aminobutyric acid / p-toluenesulfonic acid salt was obtained ([α] _D ²⁵ : + 9.3 ° (c =
1, methanol) and optical purity: 80.2%). Hereinafter, in the same manner as described above, the D-form salt and the L-form salt are alternately added by a method of adding DL-2-aminobutyric acid / p-toluenesulfonic acid salt corresponding to the obtained optically active form salt to the split mother liquor. The solution was optically resolved once, and 0.89 g of D-2-aminobutyric acid / p-toluenesulfonate ([α] _D ²⁵ : −8.
1 ° (c = 1, methanol), optical purity: 69.8%)
And 0.69 g of L-2-aminobutyric acid / p-toluenesulfonate ([α] _D ²⁵ : + 9.0 ° (c = 1, methanol), optical purity: 77.5%).

Example 5 D-2-aminobutyric acid / p-toluenesulfonate 1.4
4 g ([α] _D ²⁵ : -8.9 ° (c = 1, methanol), optical purity: 76.7%) was recrystallized from aqueous acetone to give D-2-aminobutyric acid / p-toluenesulfonate. 1.01 g ([α] _D ²⁵ : −11.6 ° (c = 1, methanol)) was obtained. The optical purity of this salt was 100%, and the melting point, IR and NMR were identical to those of the standard D-form salt obtained in Example 2. Further, 0.9 g of this salt was dissolved by heating in 3 ml of methanol, and triethylamine was added at 50 ° C.
33 g were added. Then, after stirring at room temperature for 2 hours, the precipitated crystals were collected by filtration, washed with methanol, and dried to obtain D-2.
-0.30 g of aminobutyric acid was obtained. Yield 90.0% m. p. : 302 to 306 ° C [α] _D ²⁵ : -7.9 ° (c = 4, H ₂ O) IR (KBr) cm ^-1 : 3440, 3070, 160
_{0,1420,1310,810 NMR (DMSO-d 6 +} D 2 O) δ: 0.88 (t,
3H, J = 7.5), 1.66-1.75 (m, 2
H), 3.16 (t, 1H , as J = 5.5) Elementary analysis _{(C 4 H 9 O 2 N} ): Calculated C: 46.59, H: 8.80, N: 13.5
8 measured values C: 46.50, H: 8.75, N: 13.6
1

[0017]

According to the present invention, racemic 2-aminobutyric acid / p- is easily produced from racemic 2-aminobutyric acid.
High-purity optically active 2-aminobutyric acid / p-toluenesulfonate can be efficiently obtained by performing preferential crystallization optical resolution using toluenesulfonate as a raw material, as compared with the conventional method. Moreover, the split optically active 2-aminobutyric acid / p-toluenesulfonic acid salt can be easily led to optically active 2-aminobutyric acid simply by desalting. Therefore, the present invention can produce optically active 2-aminobutyric acid cheaply and easily as compared with the conventional method, and can be an excellent industrial production method.

──────────────────────────────────────────────────の Continued on the front page (58) Field surveyed (Int. Cl. ⁶ , DB name) C07C 227/34 C07B 57/00 365 C07C 229/06 CA (STN) REGISTRY (STN)

Claims (2)

(57) [Claims] 1. A process for producing optically active 2-aminobutyric acid, which comprises optically resolving 2-aminobutyric acid / p-toluenesulfonate by preferential crystallization and decomposing the salt. 2. 2-aminobutyric acid / p-toluenesulfonic acid salt.