JPS59116250A - Optical resolution of alpha-p-tolylethylamine - Google Patents

Abstract

PURPOSE:To obtain an optically active substance of the titled compound useful as an optically resolving agent in high purity in high yield easily, by crystallizing preferentially an optically active p-hydroxybenzoate from a solution of a p-hydroxybenzoate of alpha-p-tolylethylamine. CONSTITUTION:A salt of (+ or -)-alpha-p-tolylethylamine of alpha-p-tolylethylamine containing an excess of one of the optically active forms of it and p-hydroxybenzoic acid is dissolved in a liquid diluent under heating to give a supersaturated solution. A small amount of optical active salt of alpha-p-tolylethylamine and p- hydroxybenzoate is seeded to the supersaturated solution, and the same optically active salt as the seeded optically active salt is crystallized and separated to give the desired compound. Methanol or ethanol may be cited as the liquid duluent. This process shows buffer actuon on crystallization pressure of antipode, and always keeps a crystallization solution and a crystal phase in a stabilized phase equilibrium relationship.

Description

DETAILED DESCRIPTION OF THE INVENTION Among certain heel medicines, agricultural chemicals, and food additives, there are many optically active compounds. And such a compound V/
In the case of 1-6, where J is a chemical method, it is called + optical resolution.
There are many cases where a continuation is necessary. Traditionally, for the optical resolution of such compounds, natural optical resolving agents such as quinine and brucine were often used, or a-methylbenzylamine and l-phenyl-2-(p-tolylethylamine) were used. The requirements for synthetic optical resolution agents such as these have been increasing.

The present invention can be expected to open up new uses as one of such synthetic optical resolution agents.
-p-1-1) It relates to a method for ethically producing an optically active form of ruethylamine, and is described in more detail (
・Simplified version of tz-p-tolylethylamine (7b regarding further optical resolution method)

An example of a well-known optical resolution method for tz-p-)lylethylamine is the method using d-camphoric acid as a resolving agent (AW, Ingersoll).
, F., B-Burns, J., Al11. Chei
.

Soc, 54, 4.712 (1932)), etc.
According to method C, the resolving agent, d-camphoric acid, is expensive and one of the enantiomers is difficult to obtain, so the resolving agent is the resolving agent (only one enantiomer of 1-p-tolylethylamine is used). It can be obtained efficiently, and when salt is produced, 4
There are 5 points, which involve complicated operations such as the need for concentration of Maki.

The present inventors conducted extensive research on the optical resolution method of σ-p-)IJ-ruethylamine, and found that ti, -p
- IJ ethylamine, its p-hydro-ethylamine,
By using a quartz salt, it is possible to apply a preferential crystallization method, and σ-p, -t! They discovered that J-ruethylamine could be easily optically resolved with high purity and high yield, and completed the present invention.

In carrying out the misfire test, (±)-a-p-tolylethylamine or a salt of α-p-tolylethylamine and p-hydroxybenzoic acid containing an excess of one optically active substance is used. Supersaturation and f
6 o this optically active 0. - Inoculate a small amount of crystals of a salt of p-tolylethylamide and p-hydroxyammonium, -, folic acid, and crystallize and separate the salt of the ytS chemically active form of the same type as the inoculated 9'C chemically active form. reactor. In this case, ap-to! J
p-Hydroxybenzoate of tolylethylamine may be prepared separately using a diluent IC, or directly prepared using σ-1)~tolylethylamine and p-hydroginebenzoic acid as a diluent. In addition, salts may be generated in the adult diluted AIJ for further understanding.

Optical resolution σ-p-1-1) When ethylamine contains an excess of one of the optically active substances, it is preferable to inoculate 1% of the same type of optically active substance salt; It is also possible to obtain active salts from natural products without inoculating them with active salts.

Next, after the early crystallization, (±)-d-p-tolylethylamine p-hydroxybenzoate was supplemented, and α-p-), which has the opposite optical rotation to the optically active substance inoculated last time, was added.
! By inoculating crystals of J-ruethylamine p-hydroxybenzoate, crystals of a salt of the same optically active substance are crystallized, and this is separated. , racemic σ-p-) with low optical purity
Lylethylamine can be easily and completely optically resolved with p-hydroxybenzoate.

As the liquid diluent and brightener described above, diluents such as methanol, ethanol, etc., or a mixture of these and water may also be used, but optical resolution can be carried out efficiently enough with water alone. It will be done.

History'Ltt -p-t') p-Hydroxybenzoate of ethylamine has sufficient compatibility even when cold. Create a filter that efficiently and stably crystallizes optically active salts. This is because the coexisting σ-p-tolylethylamine acetate is (Z-p-
There is an equilibrium state tζ with tolylethylamine/p-hydroxybenzoate, which acts as a buffer against the crystallization pressure of the enantiomer, so the crystal phase of the crystallization solution and the inoculated active biological salt is stable from beginning to end. This is to maintain the phase equilibrium relationship.

Moreover, when crystallizing an optically active salt, it is also possible to significantly shorten the crystallization time by stirring the crystallization liquid.

The thus obtained optical compound, L-p-tolylethylamine p-hydroxybenzoate (soil, if necessary, is crystallized in sodium hydroxide or hydroxide 1
'It is decomposed by the action of an alkaline water bath solution such as hypotassium,
When the liberated optically active tt -p -) l) ethylamine is extracted with an organic hot medium such as ether or benzene and distilled, optically pure tt -p - and IVl-σ-p - are obtained.
ethylamine can be obtained.

Hereinafter, the method of the present invention will be explained in more detail with reference to Examples, but the present invention is not limited thereby.

Example 1
) Ruethylamine acetate 17.57 ? 120 tons of water was added to the mixture, heated, and then cooled to room temperature. A crystal of gauze frame r←)-σ-p-tolylethylamine p-hydroxybenzoate (mp.

204-2'05 o, [a]25-14.
5゜(c 1.0, MeOH) ) 7
07n9 was stirred at a rate of 90 times/min for 1 hour, and the precipitated crystals were collected by P←) v
11-1- IJ ethylamine p-hydroxybenzoate 0.64? [Vl e OH) Optical purity 81.4% +] j
Add 0.779 ton of a-p-tolylethylamine/p-hydroxybenzoate, dissolve in a heating bath, cool to room temperature, and add separately prepared pure (t)-α-p-tolylethylamine/p- Crystals of hydroxyammonium, p, folic acid salt (mp,
203-204C.

[α]? :Z + 14.3° (c 1.
0 , M e Oi('))7 (l ry
RG was inoculated and similarly stirred for 50 minutes. The precipitated crystals were collected as 0→-(j,-p-)lylethylamine/p-
Hydroxybenzoate fL 729 yen was obtained. [a]”
+lx,o0(c],,0,MeOI-1)
) Optical purity of 75.9% or more ＼ Repeat the same operation to obtain 0 → - and C-1-v -p- with optical purity of 72 to 86%.
Tolylethylamine/p-hydroxyammonium salt monochloride (1,5~), 2? They take turns taking advantage of each other.

Example 2 (1) Contains a large amount of monomer (optical purity 14.2 cl)
)a-1)-)Lylethylamine °p-Hydroxybenzoic acid 2.81 f and (±)-a-p-1Lylethylamine 21.67? Add 120 g of water to the solution, cool the bath solution to about 10'C, and cool the solution (pure H- prepared separately) -u -p
-IJ ethylamine p-hydroxybenzoate σ)
Inoculate crystal 707n'i, stir at a speed of 90 times/min for 3 hours under ice cooling, collect the precipitated crystals and make a juice) -
tx -p-tolylethylamine p-hydroxybenzoate (1,78S' was obtained. [a ] 20-" +
12.00 (c 1.0, Me OH) Optical purity 82.8%
Add 0.50 ft' of ±)-α-p-tolylethylamine/p-hydroxybenzoate, heat for 6 days, cool to about 10C, and prepare separately prepared pure ←)-(L
-p-Tolylethylamine/p-hydroxybenzoate crystals 7Qrrrg were inoculated and stirred in the same manner for 13 hours. After removing the precipitated crystalline F←)-σ-p-1-
IJ ruethylamine p-hydroxybenzoin, -tf,
Salt 0.41? I got 17. [a118・5-12.5
° (c 1.L), MeOH) Optical purity 8 6
．． 2' Repeat the same operation to obtain (g) ~ and ←) -a -p~tolylethylamine/p-hydroxybenzoic Hi'ff+ with an optical purity of 82 to 86 from 0.4 to 1.1.
7 were obtained alternately.

Example: 3 0-)-σ-p-)lylethylamine p-hydroquine benzoate with an optical purity of 79.9 was mixed with 3.837 of water and 657
nI! ,! The mixture was removed from the L heating bath, left to stand for several hours, and the precipitated crystals were collected to obtain 2.79 y of (t)-a-p-tolylethylamine/p-hydroxybenzoate. [a
] 21.5 +] :3. c+ ° (c
1.0, MeOH). The yield per 1C of the total (+) contained in a-phlylethylamine is 8%, 1%. 1 Thus obtained U) Ot0-)-σ-p-tolylethylamine/p-hydrogyamine, Iα, 2, f'i 8 ii' of the salt was added to 15 m of 2N sodium hydroxide water bath solution. /! The liberated e-)-α-p-tolylethylamine was extracted with benzene and dried over potassium hydroxide. After f1, the benzene was distilled off under reduced pressure, and by distillation, 0-)-α~I )-tolylethylamide 71.1
3 f was obtained. bp, 94-95-1: (21,5 mm
H? ) a'D8-t-36,5°(ldm.

neat), optical purity ioo%. From salt 0) Yuko 1t
The 11-fold ratio 'L was 85.0%.

Example 4 Optical purity: 80.2 ←) -tx-p~Tolylethylamine/p-hydroxybenzoic salt 5.77 P7 P7 Water 90 ml was placed in a heating bath and left to stand for several hours, then the precipitated crystals were collected. (-)-α-p-tolylethylamine.
3.82 P of p-hydroxybenzoate was obtained. [a]”
-13,7° (c 1.L), ap-tolylethylamine using MeOH) containing sulfur, filtered ←)
The yield was 73.5%.

Thus the samurai created ←)-d-p-tolylethylamine.
5 et al.3.72 ii' of p-hydroxy7benzoate 2
Specified water j Sodium sulfide water bath Enemy 157, Tulle decomposition,
After extracting the liberated (1)-α-1]-tolylethylamine with benzene and drying it with monohypotassium hydroxide,
Benzene was distilled off under reduced pressure, and by distillation -C←)-α-p
-1-1) Ruethylamine 1.73f Fudo 21@Iko.

bp, I O3'C (26111m H9) a
','' 35.6° (l di.

neat), optical purity was 97.5 units, and free yield from salt (', f: 94.0 units).

% Applicant: Hiroshi Nohira 4461

Claims (1)

[Claims] In optically resolving σ-p-)lylethylamine, α
- If the bath solution of p-hydroxybenzoate of p-tolylethylamine is optically active, the p-hydroxybenzoate of p-tolylethylamine will be crystallized as soon as possible! Optical resolution method of ap-) IJ ethylamine.