JPH0318629B2 - - Google Patents

Description

Detailed Description of the Invention (Technical Field of the Invention) The present invention relates to (±)-trans-oxirane-2,
The present invention relates to a method for optical resolution of 3-dicarboxylic acid.

(Prior Art) Racemic trans-oxirane-2,3-dicarboxylic acid derivatives are known to irreversibly inhibit thiol proteases such as papain [Protein Nucleic Acid Enzymes Vol. 25, p. 483 (1980
Year)〕. However, trans-oxirane-2,3-
Since dicarboxylic acids have optical isomers (+) and (-), it is well predicted that compounds that specifically react with enzymes are limited to one of the enantiomers. It is about to be done. Therefore, obtaining this active form is extremely important in developing new pharmacologically active compounds.

A conventional method for obtaining an optically active form of trans-oxirane-2,3-dicarboxylic acid is a method using ephedrin [J.OH-HASHI and K.
HARADA.Bull.Chem.Soc.Jpn. Vol. 40, p. 2977 (1967)], but the resolving agent used in this method requires complicated legal procedures to obtain. Therefore, it is difficult to use it in large quantities, and the yield of optically active trans-oxirane-2,3-dicarboxylic acid obtained by resolution is not very high (the yield in the salt formation step is
The yield of the salt decomposition step was 97.5%, and the total yield was 0.476 x 0.975 = 0.463 or 46.3%).

Therefore, it has been a technical challenge to develop an optical resolution method with a good total yield using substances that can be easily obtained and easily managed.

(Structure of the Invention) As a result of repeated studies in order to overcome the above-mentioned difficulties, the present inventors have found that (±)- trans-oxirane-2,3
-We have discovered that dicarboxylic acids can be optically resolved with high purity and high yield, and have completed the present invention.

That is, the present invention provides (±)-trans-oxirane-2,3-dicarboxylic acid with optically active 1-(1
-naphthyl)ethylamine to form diastereomer salts, and the difference in solubility is utilized for optical resolution.

The above configuration of the present invention will be explained in detail below.

(Resolving agent) In the present invention, as optically active 1-(1-naphthyl)ethylamine, dextrorotatory 1-(1-naphthyl)
Even in ethylamine, levorotatory 1-(1-naphthyl)
Ethylamine can optionally also be used.

Optically active 1-(1-naphthyl)ethylamine can be produced by the diastereomer method using natural (+)-tartaric acid as a resolving agent (U.S. Pat. No. 2,996,545, U.S. Pat. No. 3,000,947) or by the optically active method. Cis-2-benzamidocyclohexanecarboxylic acid Diastereomer method using as a resolving agent
No. 24545), it can be easily obtained by optical resolution.

In the present invention, optically active 1-
Although the molar ratio of (1-naphthyl)ethylamine to (±)-trans-oxirane-2,3-dicarboxylic acid is not particularly limited, When substantially 1.5 to 2 equivalents of resolving agent are used, (±)-
This method is preferable because trans-oxirane-2,3-dicarboxylic acid can be resolved efficiently and with high purity.

(Procedure method) The method of the present invention comprises (±)-trans-oxirane-2,3-dicarboxylic acid and 1-(1-naphthyl).
Ethylamine is reacted in a solvent, and the solvents used at that time include methanol, ethanol, 1-propanol, 2-propanol, 1-propanol,
Butanol, 2-butanol, acetone, methyl ethyl ketone, etc. alone or a mixture thereof;
Alternatively, a water-containing substance may be used, and methanol is particularly preferable because highly purified optically active trans-epoxysuccinic acid can be obtained. Therefore, a preferred method for using methanol as a solvent will be described below.

(±)-trans-oxirane- in methanol
Dissolve 2,3-dicarboxylic acid and add 1.5 to 2
An equivalent amount of a methanol solution of optically active 1-(1-naphthyl)ethylamine is added dropwise to generate a sparingly soluble diastereomeric salt. Although the salt production reaction in this case can be carried out at any temperature between 0 and 50°C, it is generally preferable to carry out the reaction at room temperature of 15 to 25°C for ease of operation.

After solid-liquid separation of the sparingly soluble diastereomer salt precipitated by this operation, sodium hydroxide,
Treatment with a base such as potassium hydroxide or ammonia recovers (+) or (-) 1-(1-naphthyl)ethylamine. Furthermore, it is passed through a strongly acidic ion exchange resin to obtain (-) or (+)-trans-oxirane-2,3-dicarboxylic acid.

(Effects of the Invention) According to the present invention, as shown in the following example, a good product can be obtained with a total yield of 83.3% and an optical purity of 97.9% (Example 1).

Furthermore, optically active 1-(1-naphthyl)ethylamine as a resolving agent used in the present invention is
It is easily available, and there are no special legal regulations regarding its storage or use.

Therefore, the present invention is an excellent method for the optical resolution of (±)-trans-oxirane-2,3-dicarboxylic acid that can be implemented on an industrial scale.

(Examples) In order to make the present invention easier to understand, examples are shown below, but the present invention is not limited in any way by the following examples.

Example 1 Add 13.21 g (100.0 mmol) of (±)-trans-oxirane-2,3-dicarboxylic acid [hereinafter abbreviated as (±)-] to 70 ml of methanol, dissolve it, and then dissolve (-)-1 at room temperature. -(1-naphthyl)ethylamine [hereinafter abbreviated as (-)-] 25.69g
(150.0 mmol) in 30 ml of methanol solution was added dropwise,
It was left at room temperature overnight. By filtering the precipitated crystals, 20.00g of (+)--(-)-salt
(42.1 mmol) was obtained. Used (±) - middle (+)
- yield is 84.3%. [α] ²⁵ ₅₈₉ +30.0゜(C1.0, 1NHCl), mp214−215℃, elemental analysis value
_Calculated values _as C70.5% _, H6.26%, N5.83%, _C28H30N2O5 C70.87%, H6.37%, N5.90%.

42 ml of 2N aqueous sodium hydroxide solution was added to 18.98 g (40.0 mmol) of this salt, and the mixture was extracted with benzene. The aqueous layer at this time was added to an ion exchange resin (Amberlite IR120B, H type), and the eluate was dried under reduced pressure to obtain 5.22 g of (+)-
(39.5 mol) was obtained. Yield 98.9%.

[α] ²⁸ ₅₈₉ +115.5° (C2.60, ethanol), optical purity 97.9%.

Example 2 The mother liquor obtained in Example 1 was dried under reduced pressure (57.9 mmol as theoretical acid amount), 120 ml of water and 58 ml of 2N sodium hydroxide were added, and extracted with benzene. The aqueous layer is removed using ion exchange resin (Amberlite).
IR120B, H type) and the eluate was dried under reduced pressure to obtain 7.60 g (57.5 mmol) of (-)-. Yield 99.2%. [α] ²⁶ ₅₈₉ −86.6° (C1.0, ethanol), optical purity 73.5%.

Example 3 After dissolving 1.65 g (12.5 mmol) of the acid obtained in Example 2 (theoretical amounts (-)-10.8 mmol, (+)-1.7 mmol) in 8 ml of methanol, the (+)-
A solution of 4.00 g (23.4 mmol) in 12 ml of methanol was added dropwise. After standing overnight at room temperature, 4.28 g of (-)--(+)-salt was obtained by filtering the precipitated crystals.
(9.0 mmol) was obtained. The yield for (-)- in acid is 83.3%. [α] ²⁶ ₅₈₉ −31.8゜(C1.0, 1N−
HCl), mp214-215℃, elemental analysis value C70.68%,
Calculated _{values as} H6.30%, _N5.93 %, _C28H30N2O5
C was 70.87%, H was 6.37%, and N was 5.90%.

8.5 ml of 2N aqueous sodium hydroxide solution was added to 3.80 g (8.0 mmol) of this salt, and the mixture was extracted with benzene. Water with ion exchange resin (Amberlite)
IR120B, H type) and the eluate was dried under reduced pressure to obtain 1.05 g of (-)-.
(7.95 mmol) was obtained. Yield 99.4%, [α] ²⁶ ₅₈₉ −
The temperature was 117.5° (C2.60, ethanol), and the optical purity was 99.6%.

Example 4 6.60 g of (±)- in 35 ml of methanol
After adding and dissolving (50.0 mmol), (+) at room temperature.
A solution of 12.84 g (75.0 mmol) of - in 15 ml of methanol was added dropwise, and the mixture was left overnight at room temperature. By filtering the precipitated crystals, 9.66 g (20.4 mmol) of (-)--(+)-salt was obtained. Used (±)−
The yield for (-)- in the sample was 81.4%. [α]
²⁵ ₅₈₉ −30.4゜(C1.0, 1N−HCl), mp214−215℃, elemental analysis value C70.72%, H6.30%, N5.92%,
Calculated value _{as C28H30N2O5} C70.87%, _{H6.37 %} ,
M5.90%.

21 ml of 2N aqueous sodium hydroxide solution was added to 9.49 g (20.0 mmol) of this salt, and the mixture was extracted with benzene. The aqueous layer at this time was added to an ion exchange resin (Amberlite IR120B, H type), and the eluate was dried under reduced pressure to obtain 2.62 g of (-)-.
(19.8 mmol) was obtained. Yield 99.2%.

[α] ²⁵ ₅₈₉ −116.7゜ (C2.60, ethanol), optical purity
It was 98.9%.

Claims (1)

[Claims] 1 (±)-Trans-oxirane-2,3-dicarboxylic acid is reacted with optically active 1-(1-naphthyl)ethylamine to form a salt of (+)-trans-oxirane-2,3-dicarboxylic acid and (- )-trans-oxirane-2,3-dicarboxylic acid salts are produced, and (+)-trans-oxirane-2,
By separating the 3-dicarboxylate and the (-)-trans-oxirane-2,3-dicarboxylate and further treating each salt with a strong basic substance, (+)-trans-oxirane-2, 3-dicarboxylic acid and (-)-trans-oxirane-2,3-
A method for producing optically active trans-oxirane-2,3-dicarboxylic acid, which comprises liberating dicarboxylic acid.