JPS62164646A - Optical resolution of (+-)-2-methylpentanoic acid - Google Patents

Abstract

PURPOSE:To separate (+ or -)-2-methylpentanoic acid into the titled (+)- or (-)- compound with a solvent, by reacting a specific optical resolving agent with (+ or -)-2-methylpentanoic acid to carry out optical resolution in high purity and yield and utilizing the solubility difference of the resultant salts. CONSTITUTION:(+ or -)-2-Methylpentanoic acid is reacted with optically active 1-phenyl-2-(p-tolyl)ethylamine as an optical resolving agent to carry out optical resolution and form a salt of (+)-2-methylpentanoic acid and salt of (-)-2- methylpentanoic acid. The solubility difference between them is utilized to separate the titled compound into the salt of the (+)-2-methylpentanoic acid and salt of the (-)-2-methylpentanoic acid. The optical active substances can be utilized as an optical resolving agent and is capable of readily synthesizing optically active 2-methylpentanol by reduction or various optically active derivatives by ester bonds or amide bonds, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION This invention relates to division. Optically active 2-methylpentanoic acid (hereinafter abbreviated as MPA) can not only be used as a synthetic acidic optical resolution agent, but also can be easily reduced to optically active 2-methylpentanol (hereinafter abbreviated as MPL). Various optically active derivatives can be easily synthesized from optically active MPA through ester bonds, amide bonds, etc., and optically active MPL through ester bonds, ether bonds, urethane bonds, carbonate bonds, etc. This is a compound that is expected to have a very wide range of uses.

At present, the methods for obtaining optically active MPA'% are as follows:
Method of optical resolution using quinine (P, A.
Levene and R. E. Marker *
J. Biol. Cherrb+98 1 (p
-Toryl 932)) has been reported, but it has the disadvantage that it requires recrystallization several times and the operation is complicated.

Based on these facts, the present inventors have determined that ((p-tolyl)
As a result of various studies regarding the optical resolution method of 1-MPA, we found that optically active 1-phenyl-2-(p-tolyl)
The present invention was completed by discovering that (p-tolyl)-MPA can be optically resolved with high purity and high yield by using ethylamine (hereinafter abbreviated as PTE).

That is, the present invention provides (g) optically active PT in MPA.
In this method, diastereomeric salts are formed by the action of E, and the difference in solubility is utilized for optical resolution.

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

In the present invention, dextrorotatory PTE is used as the optically active PTE.
However, even levorotatory PTE can optionally be used.

Optically active PTE is synthesized in two steps from benzylamine, benzaldehyde, and p~methylbenzyl chloride, and then optically resolved using optically active mandelic acid (JP-A-5
9-110656) can be obtained relatively easily.

In the present invention, the molar ratio of optically active PTE as a resolving agent and (t)-MPA is not particularly limited;
(g) The amount of resolving agent for MPA is substantially 0.8 to 1.
It is preferable to use 0 equivalent because (g)-MPA can be separated efficiently (and with high purity).The method of the present invention
- MPA and optically active PTE are allowed to interact in a solvent, and the solvents used at this time include water, methanol, ethanol, 1-propanol, 2-propanol, l-butanol, acetone, methyl ethyl ketone, etc. Either one or a mixture of these may be used (especially ethanol is preferable since highly pure optically active MPA can be obtained).

To implement the method of the present invention, for example, the following may be performed.

Dissolve (t)-MPA in ethanol, and add O18~
Add 1.0 equivalent of optically active PTE to generate a poorly soluble diastereomeric salt. The salt production reaction in this case is
Although it is possible to carry out the reaction at any temperature between 0 and 80°C, it is usually preferable to carry out the reaction at a temperature of 20 to 60°C.

After solid-liquid separation of the sparingly soluble diastereomer salt precipitated by this operation, it is recrystallized using an appropriate amount of ethanol, if necessary. The purified poorly soluble diastereomer salt thus obtained is treated with a base such as sodium hydroxide, potassium hydroxide, or ammonia, and extracted with an organic solvent such as ether or benzene to recover the resolving agent. Further, the mother liquor is made acidic with a mineral acid, extracted with an organic solvent such as ether or methylene chloride, dried, concentrated (+) or (→-MP
get an A.

Next, the present invention will be specifically explained with reference to Examples.

Example 1゜(d-MPA5.80r, zp/-k 30-
(+)-pTEs, 44r was added to this solution, heated to 60°C to dissolve, and then slowly cooled to form (→-MPA・(+)
-PTE salt was inoculated with 20 μm, and after 3 hours, a crystalline mass was formed and dried to obtain crude ←)-MPA-(e)-PTE salt. Yield 5.31f(α)6°+79, も(c
2. Methanol) mploo ~ 104℃ This crude salt was dissolved in 8d of ethanol by heating at 60℃, stirred and slowly cooled, and the crystalline P that precipitated after 2 hours was collected and dried to give purified (+)-MPp, -( +) -PTE salt was obtained. Yield 3.78f, [α7 also +801° (c2. methanol), mp, 108-110°C.

After heating and dissolving 3.77 t of this purified salt in 6 g of 4N aqueous sodium hydroxide solution, it was extracted with benzene (→-PT
E was collected, 1 rnt of concentrated sulfuric acid was added to the aqueous layer, and the mixture was extracted with ether. After drying the ether layer with magnesium sulfate, the solvent was distilled off to obtain (→-MpAt24r.
15.47° (c23.hexane), optical purity 84% Example 2 (T)-MPA18f was dissolved in ethanol 92-, and (→-PTE26.24F was added to this solution, heated and dissolved at 60°C, then stirred. Slowly cool, (-)-MPA・←)-PT
Inoculated with 20 μ of E salt, and after 3 hours, the crystals formed were inoculated with F.
After removing and drying, crude (→-MPA・(-)-PTE salt was obtained. Yield: 13.20?, [α seat -76.0° (c
2. methanol).

After dissolving Kono crude salt in ethanol 18-18°C by heating at 70°C, it was slowly cooled with stirring, and after 3 hours, the precipitated crystals were collected.
When dried, purified ←) -MPA・←) -P T E
Salt was obtained. Yield 9.639 (α) Total 76.7° (c
2. methanol).

After heating and dissolving 9.43f of this purified salt in 4N aqueous sodium hydroxide solution 14-, it was extracted with benzene ←) -
After collecting PTE and adding concentrated sulfuric acid 2.2- to the aqueous layer,
Extracted with ether. After drying the ether layer with magnesium sulfate, the solvent was distilled off to obtain ←)-MPA3.43f.

[α] 2-crystal-knee 14.5°eat) Optical purity 78.8
%.

Example 3 (p-tolyl)-MPA30.90f, (+)-PTE
44.962 was mixed with 150% of ethanol, dissolved by heating, and then cooled to 35°C. (+) -M P A・(10)
- After inoculating 0.02F of P T E salt and stirring for 3 hours, the precipitated crystals were collected at 20°C and dried.
27.77 f of MPA·(+)-PTE salt was obtained.

[α]p+ 78.8F' (e 2. methanol)
mp, 102-108°C.

The obtained salt was recrystallized twice with ethanol (35-125-) to obtain purified (→-MPA・(+)-PTE salt 18.
Obtained 28F. [α) p+79.8° (C2°methanol) mp, 106-110°C.

After adding 27.8 m of a 4N aqueous sodium hydroxide solution to this purified salt 18.18F and dissolving it under heating, extraction with benzene was performed to recover (+)-PTE, and concentrated hydrochloric acid 11.8 m was added to the aqueous layer.
1- was added and extracted with ether.

After drying the ether layer with magnesium sulfate, the solvent was distilled off to obtain (+)-MP A 6.28 f.

Claims (1)

[Claims] By reacting optically active 1-phenyl-2-(p-tolyl)ethylamine with (±)-2-methylpentanoic acid, (
+)-2-Methylpentanoic acid salt and (-)-2-methylpentanoic acid salt are generated, and by using the difference in solubility of these salts, (+)-2-methylpentanoate and (+)-2-methylpentanoate are generated using a solvent. , (-)-2-methylpentanoic acid is separated.