JPS6064950A - Method for purifying optically active alpha-(1-aminoethyl)- benzenemethanol - Google Patents

Abstract

PURPOSE:To purify and separate an optically active substance from a mother liquor, by cruystallizing racemic modification from a solution of alpha-(1-aminoethyl--benzenemethanol rich in the optically active substance, and separating and removing the resultant racemic modification. CONSTITUTION:The (+ or -)-isomer is crystallized from a solution of alpha-(1-aminoethyl)-benzenemethanol rich in the (+)- or (-)-isomer, separated and removed from the mother liquor. Thus, the (+)- or (-)-alpha-(1-aminoethyl)-benzenemethanol is obtained from the mother liquor. According to the above-mentioned method, the aimed compound having a high optical purity is obtained from the mother liquor simply by crystallizing the (+ or -)-isomer if the alpha-(1-aminoethyl)-benzenemethanol having a certain optical activity is obatined and led to diastereomer salts with an optical resolving agent.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for purifying optically active α-(l-aminoethyl)-benzene methanol.

(＠-〇-(1-Aminoethyltobenzene methanol is used as a sympathomimetic stimulant and is also important as an intermediate raw material for manufacturing various pharmaceutical products.On the other hand, (
l-)-α-(1-aminoethyl)-benzene methanol is useful as an optical resolution agent and a raw material for asymmetric reactions.

α-(1-Aminoethyl)-benzene methanol, which is usually synthesized by chemical methods, is a racemate, and it is necessary to optically resolve it in order to obtain the optical standard as described above.

Conventionally, as a method for optically resolving racemic α-(I-aminoethyl-benzene methanol), the optically active te1
．． How to use monolithic acid as a 1'l drug (Pharmacy Miscellaneous R)
i, Volume 98, Page 947 and J, Org,
Cbem, vol. 25, p. 1929), a method using optically active pantoic acid or its alkali salt as a resolving agent (JP-A-51-98281), optically active (S
) -(Carboxymethyl)-cysteine as a resolving agent (Japanese Unexamined Patent Publication No. 11858-46045)
It has been known.

However, even in these methods, in order to obtain optically highly pure α-(I-aminoethyl)-benzene methanol, it is necessary to combine the α-(1-aminoethyl)-benzene methanol with each resolving agent. It is necessary to purify the diastereomeric salt by repeated recrystallization operations, and a relatively expensive resolving agent with high optical purity is required.
In particular, as a method for obtaining optically high-purity α-(1-aminoethyl)-benzene methanol for industrial inspections, it is necessary to use precise and complicated separation operations. (It is hard to say that 7 is sufficient.

The present inventors have conducted intensive studies on a method for obtaining optically high-purity α-(l-aminoethyl)-benzene methanol.
In the method of directly crystallizing (-1-1 monomer or (→ monomer itself) from a solution of -aminoethyl)-benzene methanol, the improvement in optical purity is coupled with lfi <, on the contrary, (
We discovered that α-(l-aminoethyl)-benzene methanol of extremely high optical purity (-1-1 or (@)) can be obtained as the mother liquor by crystallizing ±). This led to the invention.

That is, the present invention provides (1→integrity or (-)integrity-rich α-
From a solution of (l-aminoethyl)-benzene methanol, (±) monocle is crystallized, and after separating and removing the crystals of (±) monocle, α of (−F) monocle or Optical activity α-(1-aminoethyl)- by obtaining -(l-aminoethyl)-benzene methanol
This article provides 117 methods for producing benzene methanol.

According to the method of the present invention, as long as α-(l-aminoethyl)-benzene methanol having a certain degree of optical activity is obtained by the optical resolution method as described above, it can be subjected to optical resolution again. By simply crystallizing the (±) monomer of the diastereomer salt without separation and purification, α- with extremely high optical purity can be obtained from the mother liquor.
(l-Aminoethyl)-benzene methanol is obtained, which is extremely advantageous in terms of economy and operability.

The method of the present invention will be described in detail below.

In the method of the present invention, the optical purity of α-(l-aminoethyl)-benzene methanol rich in (+) monomer or (polymer) used as a compound is not particularly limited; However, from the viewpoint of the efficiency of the method of the present invention, it is preferable to use 50% e, e or more.

In addition, as a solvent for crystallizing the (±) monomer from the solution of α-(l-aminoethyl)-benzene-methanol, methanol, ethanol, n-propanol,
1so-propertool, n-butyl alcohol, sec
, -butyl alcohol, tel"t-butyl alcohol, is.

5 le -Butyl alcohol, amyl alcohol, is.

-Amyl alcohol, benzyl alcohol, caffryl alcohol, diacetone alcohol, diethylene glycol, fukifuryl alcohol, natonoalcoholic solvents, acetone, ketone solvents such as methyl isobutyl ketone, ethyl romate, acetic acid/r-soprovir, etc. ester solvents, hydrocarbon solvents such as n-hexane, n-pentane, benzene, toluene, xylene, ether, diisopropylede! Examples include ether solvents such as salt, halogenated hydrocarbon solvents such as menalene chloride, ice, etc., and mixed solvents thereof, ester solvents, hydrocarbon solvents, and O. Preference is given to using mixed solvents. There are no particular restrictions on the paper used for these solvents, but they are about 5 to 10 times (heavy capacity) the amount of normally used α-(l-aminoethyl)-non-methanol.

The operation for crystallization is similar to the general recrystallization operation (-1 → monolithic or (=) monolithic α-(l
-Aminoethyl)-benzene methanol is dissolved in the above solvent to prepare a saturated or nearly saturated solution, and the solution is cooled or concentrated to bring it to a supersaturated state (±j) This is done by crystallization.

In the above operation, (+l integral or (@ integral rich α
The temperature at which -(l-aminoethyl)-benzene methanol is dissolved in the solvent is arbitrary as long as α-(l-aminoethyl-benzene methanol is not decomposed), but it is generally in the range of 50 to 150 °C, and The crystallization temperature is also not particularly limited, but the purpose can be sufficiently achieved within the range of room temperature to -10°C.In addition, in the above crystallization,
Although it is possible to inoculate (±) integral crystals as seed crystals, it is not essential, and either a static method or a stirring method can be adopted.

After removing the needles from the mother liquor by filtration, decantation, etc., the crystallized (±) monomer as described above is subjected to e-condensation of the mother liquor.
m) integral or (→ integral α-(l-aminoethyl)-
Benzene methanol can be obtained. In addition, obtained in this way is (-+1 unitary or (→ unitary extension -(1
-aminoethyl)-benzene methanol can be further improved in optical purity by repeating the above-mentioned operation, if necessary.

Hereinafter, the present invention will be explained in detail with reference to ζ Examples.

Example 1 (-H-enriched α-(l-aminoethyl)-benzene methanol (hereinafter referred to as NEP) ([α)D=12
．． 7° (ethanol) 1. (-F+/H=94.715
．． 3) 1. Add ethyl acetate/L/2me and n-hexane lme to Oy and heat to about 60°C to dissolve the crystals. The solution was kept at room temperature overnight, the resulting crystals were removed to remove P (P = 0.07 P), and the mother liquor was concentrated under reduced pressure to obtain (+)-N E P O,9Of as crystals. ([α]D=+14.2°(ethanol), (-H
/[-1=10010).

Example 2 (-)-i integrally enriched N E P ([Q!]ゎ-10
, 70 (ethanol), (profit/H = 87.7/12.
Add ethyl acetate 6af' and 2me hexane to 8L2.25F and heat to about 60°C to dissolve the crystals.

The solution was allowed to stand at room temperature for 6 hours, and the resulting crystals were quenched (crystal yield: 0.8 By). Let's wait as a mouse item ([O'Jゎ = +13.4° (ethanol), (-(
→/(-1=97.3/2.7).

￥Example: 3 (-1 → -i NE/P rich in books ([αJ,, =+l
1.40 (ethanol), J edition / (-1 = 90.1 /
9.9) 52.99 to ethyl acetate 141. (and n-hexane 47?ll11. Then, 0 ”C
The resulting crystals were cooled to 4.9 s and kept warm for 2.5 hours, and the resulting crystals were removed from the crystals (4.9 s), and the mother liquor was concentrated under reduced pressure.
NEP48.0y was obtained as a crystal. ([/)I), J
= 10' 13.10 (ethanol), (-→/H= 9
6.2/8.8>.

Furthermore, this crystal was treated with ethyl acetate l 28 me and then,
Incubate at 0°C overnight. Remove the generated crystals and leave the crystals in place:
lr), the mother liquor was concentrated under reduced pressure and (+l N E P
46.1 F was obtained as a crystal ((b)]D=+14.
2° (ethanol), (+)/(-1 x 10010).

Example 4 (±integrally rich Nl coP((b)].=+10.50(
ethanol) ((+)/l→= 87.0/13.0
) 1. Of diisopropyl ether8. Od;'
j;- was added and heated to about 60°C to dissolve the crystals. Let the solution stand overnight at room temperature, remove the P and leave the crystals in place:
0.20y), the mother liquor was concentrated under reduced pressure and
, 80y was obtained as a crystal ([αJD= + 14.1
'(ethanol), (+l/(-1=99.61
0.4).

Example 5 (N E P rich in punishment ([Z]D = -1-10
,5°(ethanol),(''→/(-1=87.0/
18.0 ) 1. OF isopropyl diacetate 2.0
=t was added and heated to about 60°C to dissolve the crystals. The solution was left at room temperature overnight = +18.8' (ethanol), (
−+−1/(→=98.6/1.4).

Example 6 (-)1 integrally enriched N E P ((Ql]D+l O
, 5° (ethanol), (-1-1/(-1=87.
0/18.0) Toluene 2.0- was added to 1.09 and heated to about 60°C to dissolve the crystals. The solution was left overnight.
Leave to stand at room temperature and remove P to obtain crystals g: 0.2
1y), the mother liquor was concentrated under reduced pressure to form (-H-NE PO
, 79ry was obtained as a crystal ([αJD=+ta, g°
(ethanol) , (-)-1/(-1=98.9/
1.1).

Example 7 (+NEP rich in monomer ((b)) D+lO,6 (ethanol), (+3/H= 87.0/l 3.0)
1. Oy to methylene chloride-ether 1. :L mixture 4 and Od were added and heated to about 35°C to dissolve the crystals.

The solution was allowed to stand at room temperature overnight, and the resulting crystals were filtered off to obtain crystals (ML: O, lB), and the mother liquor was concentrated under reduced pressure to crystallize (-1-1-NE PO, 879). ( (ffJD= + 18.50 (ethanol),
(-+-1/(-1=97.5/2.5).

Claims (1)

[Claims] (The mother liquor part after crystallizing (±) unite from a solution of α-(l-aminoethyl)-benzene methanol rich in one unit or (=) unit, and separating and removing the crystals of (±) unit) From, (-I-1 integral or (-) integral α-(l
1. A method for purifying optically active U-(1-aminoethyl)-hensenmethanol, which comprises obtaining Hensenmethanol (aminoethyl)-benzene.