JPS61227549A - Optical resolution of (+-)-2-chlorobutanoic acid - Google Patents

Abstract

PURPOSE:To enable the optical resolution of the titled substance useful as a synthetic raw material, by using optically active 1-(1-naphthyl)ethylamine as a resolution agent, reacting (+ or -)-2-chlorobutanoic acid with the resolution agent to form a diastereomer salt and resolving the salt taking advantage of the solubility difference. CONSTITUTION:A hardly soluble diastereomer salt is produced by reacting (+ or -)-2-chlorobutanoic acid with an optically active 1-(1-naphthyl)ethylamine as a resolution agent in a solvent (preferably methanol or 2-propanol) usually at 15-60 deg.C. The amount of the resolution agent is preferably 0.8-1.0 equivalent based on (+ or -)-2-chlorobutanoic acid. The produced salt is separated into solid and liquid, if necessary, the hardly soluble diastereomer salt is recrystallized with a proper amount of methanol, etc., and the salt is treated with a base and extracted with an organic solvent to recover (+) or (-) resolution agent. The mother liquor is made acidic, extracted with an organic solvent and concentrated and dried to obtain the titled (+) or (-) compound.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for optically resolving 2-chlorobutanoic acid. 2-chlorobutanoic acid (hereinafter abbreviated as CBA) has various 2-chlorobutanoic Since it can be converted to -substituted butanoic acid, it is a compound that can be a useful synthetic intermediate.

Currently, the method for obtaining optically active CBA is a method using cinchonidine as a resolving agent (Karl Freu-denb
erg and Walter Lwowaki, L.
iebigsAnn, Chem, 597.141
(1955) ), but this method requires very complicated operations and multiple recrystallizations in order to obtain CBA with high optical purity, and the yield is also low.

As a result of intensive studies on the optical resolution method of CBA from this viewpoint, the present inventors found that optically active 1-
By using (1-naphthyl)ethylamine (hereinafter abbreviated as NEA), it was discovered that (→-CBA) could be easily optically resolved with high purity and high yield, and the present invention was completed.

That is, the present invention is a method in which (1) -CBA is reacted with optically active NEA to form diastereomeric salts, and the solubility difference is utilized for optical resolution.

The optically active NEA used in the present invention can be easily obtained by a method using →-tartaric acid (US Patent No. 2.996.545) or a method using cis-2-benzamidocyclohexanecarboxylic acid (Japanese Patent Laid-Open No. 58-24545). You can get it.

In the present invention, optically active NEA and (-t,
Although the molar ratio with 1-CBA is not particularly limited,
It is preferable to use 0.8 to 1.0 equivalents of the resolving agent relative to (+1)-CBA because (+)-CBA can be resolved efficiently and with high purity.

In the method of the present invention, (→-CBA and optically active NEA are reacted in a solvent, and the solvent used at this time is water, methanol, or ethanol.

1-f lonoPnol, 2-pronognol, 1-7
``Tanol, acetone, methyl ethyl ketone, etc. alone or a mixture thereof may be used, especially methanol, 2-pro- or alcohol.
This is preferable because A can be obtained.

The present invention is carried out, for example, as follows.

2-prono or Nor K(e)-CBA is dissolved, and 0.8 to 1.0 equivalents of an optically active NEA 2-fo panol solution is added dropwise to form a poorly soluble diastereomeric salt. The salt production reaction in this case can be carried out at any temperature between 0 and 80°C, but it is usually preferably carried out at 15 to 60°C. After the sparingly soluble noastereomeric salt precipitated by this operation is removed as a solid overnight, the sparingly soluble diastereomeric salt is recrystallized using an appropriate amount of 2-f ronoenol or methanol, if necessary. The purified poorly soluble diastereomer salt thus obtained was treated with 5.5% sodium hydroxide. Potassium hydroxide.

After treatment with a base such as ammonia and extraction with an organic solvent such as ether or garlic, (g) or (h)-NE
Collect A. Furthermore, the mother liquor is made acidic with a mineral acid such as hydrochloric acid or sulfuric acid, extracted with an organic solvent such as ether, methylene chloride, or chloroform, and dried. ! By condensation, (g) or (h)-CBA is obtained.

Next, the present invention will be explained in more detail with reference to Examples, but the scope of the present invention is not limited thereto.

Example 1 Methanol 3g (((trans)), -cBA3.06f(25
mmol) and (g)-NEA4.28F (25mmol
l) was dissolved and allowed to stand at room temperature for 2 hours, and the precipitated crystals were filtered. c) -CBA・(→-NEA salt 3.74 y
(12°7 mmol) was obtained. This salt was recrystallized twice using 2-f ropanol to produce a purified salt of 2.40 f (8.2 m
mol) was obtained. '/also (f) = (→- in CBA
The yield for CB and A is 65.61 n”7+2.
so(C2,0, MeOH) mpl 32-133
．． 5℃.

This salt 2.40? (8.2 mmol) 3.3-N K3 normal aqueous sodium hydroxide solution was added and extracted with benzene to recover (t)-NEA. Subsequently, 0.67-ml of concentrated sulfuric acid was added to the aqueous layer and extracted with methylene chloride, and the methylene chloride layer was dried over anhydrous magnesium sulfate and concentrated to give H.-
CB A O, 89t (7.3 mmol was obtained. Free yield from salt 89.0t) (→-CBA in (→
-The yield for CBA trap is 582 chi CaJ"3-13
．． 3° (c 4.2, CHCL3) literature value CaJ2
゜5-17.5° (neat) (Karl Fre
Udenberg and Walter L.
wowski, LiebigsAnn, Chem,
Optical purity tIi76.597.141 (1955)). Ochi Example 2 2-Proper tool 11-((transfer)-CBA3.08t
(25.1 mmol) and (-[-N E A 4.2
9t (25.1 mmol) was dissolved while heating at about 80° C., then slowly cooled to room temperature and left to stand for about 3 hours. Filter the precipitated crystals)-CBA-(g)・
-NEA salt 4,07t (13,9 mmol) was obtained.

This salt was reconstituted twice using 2-propanol to obtain 2.489 (8.4 mmol) of purified salt. used ((1
The yield for (+)-CBA in )・-CBA is 67
．． 2% Gin 2.1° (c 2.0, MeOH) mp
132.5-133.5℃ This salt 2.48 ? Add 3.4-3N aqueous sodium hydroxide solution to (8.4mM) and prepare (+)-
NEA was collected. Next, 0.6 ml of concentrated sulfuric acid was added to the water layer at this time.
87! was added and extracted with methylene chloride, and the methylene chloride layer was dried over anhydrous magnesium sulfate and concentrated to give @-CBA0.
91y (7.4 mmol) was obtained. Free yield from salt 88.1. (→-CB in (1)-CBA used
The yield for A is 59.0% Car 2tP-14,
0° (e3.3, CHCLs) optical purity 80
．． 0chi Example 3 2-f Ronognor 20go (1), -CB A 9.
Add 10 f (74,3 mmol) and heat at about 60°C (-[-NEA 12.7 f (74,3
Purified (he)-CBA- was synthesized separately at 45°C by dropping a solution of 2-pro-e-nol 24-mmol) dissolved in 2-pro-e-nol 24-
(g) - After inoculating 10 μ of NEA salt 1. The mixture was cooled to room temperature over 2 hours with stirring. The precipitated crystals were filtered to give (he)-CBA-(t)-NEA salt 9.752 (33
, 2 mmol) was obtained.

5. Recrystallize this salt once from methanol to obtain a purified salt.
53 F (18.8 mmol) was obtained: for t0 (
The yield for (h)-CBA in g)-CBA is 50
, 6% CaJ n + 1.8° (c 2.0
3, MeOH) mp 137.5-138.5°C To 5653 ml (18.8 mmol) of this salt was added 7.5-N sodium hydroxide solution and extracted with benzene.
→-NEA was collected. Next, 0 concentrated sulfuric acid was added to the water layer at this time.
．． By adding 68 m and extracting with methylene chloride (
)-CBA2.0Of (16.4 mmof) was obtained.

Free yield from salt: 87.2 cm. Yohata ((trans)-CBA
(→-CB The yield relative to A is 44.0%.
6.0° (c 4.20, CHCLs) Optical purity 9
1.4% Example 4 The salt-forming mother liquor obtained in Example 3 was dried under reduced pressure,
16.5 ml of a 3N aqueous sodium hydroxide solution (containing 41.1 mmol of CBA as a theoretical amount) was added and extracted with benzene to recover (t)-NEA.

Subsequently, concentrated sulfuric acid (3.3-) was added to the aqueous layer at this time and extracted with methylene chloride, resulting in a concentration of 5.00? (40.8mm
(t)-CBA of ol) was obtained. [:al Amako'7.
7° (Ca, 65, CHCl5) Optical purity 44. Ochiko no ff) -CB A 4.40? (
36 mmol) was dissolved in 2-pro-gunol 10-, and θ-NEA6.16 t (
A solution of 36 mmol) dissolved in 2-pro-e-nol 12- was added dropwise. After cooling to 42°C, separately synthesized smelting (→-CBA-(c)-NEA salt IQ++y
After inoculation, the mixture was cooled to room temperature over 2 hours with stirring. Filter the precipitated crystals to)-CBA-(f)-N
5.89 f (20, Ommol) of EA salt was obtained.

4. Recrystallize this salt once using methanol to obtain a purified salt.
20 f (14.3 mmol) was obtained.

(a12I8)-3,9°(c2.OO,MeOH
) mp136-138℃ This salt 4.20? A 3N aqueous sodium hydroxide solution 5,7- was added to (14,'3 mmol) and extracted with benzene to recover (c).-NEA. Subsequently, concentrated sulfuric acid 1.2- was added to the aqueous layer at this time and extracted with methylene chloride to obtain Cy(t)-cBhl, 64y (13.4 mmol).
I got it. Free yield from salt 93.7%.

@W-zs, o°(c 3.95, CHCts
) Optical purity 91.4chi

Claims (1)

[Claims] (±)-2-chlorobutanoic acid is reacted with optically active 1-(1-naphthyl)ethylamine to produce a (+)-2-chlorobutanoic acid salt and a (-)-2-chlorobutanoic acid salt; Utilizing the difference in solubility of these salts in solvents, they are separated into (+)-2-chlorobutanoate and (-)-2chlorobutanoate, and further, by treating each salt with a basic substance, (+)-2-chlorobutanoate and (-)-2-chlorobutanoate are separated. )-2-chlorobutanoic acid and (-)-2
-Characterized by liberating chlorobutanoic acid (±)
Optical resolution method of -2-chlorobutanoic acid.