JPS60126257A - Optical resolution of dl-n-acetylphenylalanine alkyl ester - Google Patents

Abstract

PURPOSE:Either of the two-optically active isomers is inoculated to effect optically resolving crystallization from oversaturated solution containing the DL- isomer of N-acetyl-phenylalanine alkyl ester of the formula (R is lower alkyl) or a mixture in which one isomer is included more than the other isomer without limitation in selection of the solvent for resolution. CONSTITUTION:Optical resolution of the DL-isomer of N-acetylphenylalanine alkyl ester of the formula (R is lower alkyl) or an isomer mixture in which one is included more than the other isomer is effected by inoculating either of the two optically active isomer to a supersaturated solution thereof and carrying out crystallization. Since the DL-isomer of the compound represented by the formula is solubled in almost all of the organic solvent, non-polar solvents can be used advantageously.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for the optical resolution of DIN-acetyl-phenylalanine alkyl esters by preferential crystallization. Resolved D- or L-N-acetyl-phenylalanine alkyl ester Ll: Since it can lead to rho- or L-phenylalanine, respectively, by hydrolysis, the method of the present invention is useful as a method for optical resolution of phenylalanine.

Optical resolution using preferential crystallization is known as an industrially advantageous optical resolution method because it does not require an expensive resolving agent and also allows for mass synthesis.

However, this method cannot be applied unless the racemate is a crystalline compound that forms a racemic mixture.

For phenylalanine derivatives, racemic compounds often form which cannot be preferentially crystallized. So far, the derivatives that can be preferentially crystallized include the ammonium salt of N-acetyl-phenylalanine (see Japanese Patent Publication No. 39-24440) and the cyclohexylammonium salt of N-acetyl-phenylalanine (Japanese Patent Publication No. 1987-24440).
Only three types are known: monosulfate of phenylalanine methyl ester (see JP-A-48-75540). However, all of these are salts, and therefore, in terms of solubility, the dividing solvent has been limited to polar solvents such as water and alcohol.

As a result of various studies on the possibility of preferential crystallization of phenylalanine derivatives, the present inventors found that -N-acetyl-phenylalanine alkyl ester, which is a completely different type of compound from conventional examples, preferentially crystallizes. We have discovered that it is a compound that can be That is, DL-N-acetyl-phenylalanine alkyl ester is a covalent compound and is superior to salts in terms of stability, solubility, and the like. In particular, the present compound is advantageous in that it is soluble in most organic solvents and can also be used in non-polar solvents.

It has become clear from the following fact that DL-N-acetyl-phenylalanine alkyl ester forms a racemic 1M compound. That is, the infrared absorption spectra of the racemic form and the optically active form match, and the solubility of the racemic form is greater than that of the optically active form. Furthermore, the racemic form and the optically active form showed melting points as shown in Table 1, and the melting point diagram showed that they were a typical caries mixture.

Table 1. Melting point (℃) of N-acetyl-phenylalanine alkyl ester. It can be synthesized by a method such as acetylation of phenylalanine alkyl ester.

To divide these by the preferential crystallization method of the present invention,
This is achieved by adding a seed crystal of D- or L to a supersaturated solution of the racemate and preferentially crystallizing an optically active substance of the same type. Also, partially divided (i.e.
Supersaturated solutions of mixtures (in which one optically active form is more present) can also be used for resolution; in this case,
It is not necessarily necessary to add seed crystals from the outside (splitting proceeds by spontaneous crystallization.

These supersaturated solutions can be prepared using lightning methods, such as heating and dissolving the racemate or partially resolved mixture in a suitable solvent, cooling it, concentrating the solution, or adding a solvent that reduces solubility. Can be cleaved.

The solvent used for the separation is one in which DL-N-acetyl-phenylalanine alkyl ester has an appropriate solubility, such as petroleum ether, benzine, ligroin, n
- aliphatic hydrocarbons such as hexane or cyclohexane, aromatic hydrocarbons such as benzene or toluene, ethers such as ethyl ether or isopropyl ether, halogenated hydrocarbons such as carbon tetrachloride, chloroporum or dichloromethane; esters such as ethyl acetate, alcohols such as methanol, ethanol, isopropanol, n-propanol or t-butanol, acetone, methyl ethyl ketone, D
Examples include aprotic polar solvents such as MF or DM'SO, and mixed solvents thereof.

Unlike conventional salts that can be preferentially crystallized, DL-N-acetyl-phenylalanine alkyl ester is a covalent compound, so non-polar solvents such as hydrocarbons can also be used, and various types of solvents can be used as needed. solvent systems can be selected.

There are no particular restrictions on the amount or particle size of seed crystals added, but usually 1 to 100 ml of seed crystals are added to the racemic product or partially separated mixture in the solution.
It is appropriate to use a powder containing about 20% by weight of crushed crystals.

The operating temperature is not particularly limited and can be up to the boiling point of the solvent, but it must be adjusted according to the solubility of DL-N-acetyl-phenylalanine alkyl ester in the solvent used so that a stable supersaturated solution can be obtained.

The separation methods include a batch method in which opposite optically active substances are separated alternately, a continuous method in which a seed crystal is present in the column and a supersaturated solution is continuously introduced, and a method in which one optically active substance is separated from the other optically active substance. Various methods known as preferential crystallization methods can be used, such as soaking the body as seed crystals at spaced locations and growing each seed crystal at the same time.

D- or L-N-acetyl- thus obtained
If the optical purity of the phenylalanine alkyl ester is insufficient, the optical purity can be further increased by recrystallization or the like.

The present invention will be explained in more detail with reference to Examples below. Note that the present invention is not limited to these Examples.

Example 1 2.72 g of DL-N-acetyl-phenylalanine methyl ester is heated and melted in 100 g of isopropyl ether. The solution was cooled to 20 °C and L-N-acetyl-phenylalanine methyl ester < [cxf: + t
6. 1° (c = 1, M e OH), 1
After inoculating 143 mg of powdered crystals of 00% e, e, ) and stirring for 1 hour, the crystals were filtered, washed, and dried. Yield of L 320■ [αζ+14.1' (c=l, Me
OH>, 87.6% e, e,.

When the solvent of the filtrate was distilled off, 2.54 g of raw material was recovered.

(α), -0, go (c=1.MgO old.

Example 2 20 g (O
L-r, h-acetyl-phenylalanine methyl ester (2.82 g), and the DL unit 307
was added and heated to dissolve. The solution was cooled to 17°C and L
-N-acetyl-phenylalanine methyl ester powder crystals (152 cm) were inoculated, stirred for 50 minutes, and then the crystals were filtered, washed, and dried. Yield of L 214■ [α]
. +100°6° (c=1.ClCl5), 96.6
%e, eExample 3° Partially split N-acetyl-phenylalanine ethyl ester ([α column +2.3° (C=0.5.CHC
13), 25.8% e, e,) 625■ was heated and melted in a mixed solvent of 55 g of isopropyl ether and 0.5 g of methanol. The solution was cooled to 17°C and L-N-acetyl-
Phenylalanine ethyl ester ([αri+89.0
' (C=0.3.CHCl3), 100% e, e,)
After stirring for 40 minutes, the crystals were filtered, washed and dried. Yield of L 102+ni+
(α +71.9° ((= Q , 5 , CHC
l 3), 80.8% e, e,.

Example 4 1.11 g of DL-N-acetyl-phenylalanine methyl ester was dissolved in 75 g of isopropyl ether. The solution was cooled to 20°C and L-N-acetyl-phenylalanine methyl ester ([α] and +104.1"
(c=1.CHCl3)) uncrystallized 59cm was inoculated and stirred for 40 minutes, and then the crystals were filtered off, washed, and dried. Yield of L 167■ [α+103.4° (C
=1. CHCl3), 99.3% e, e.

A total of 159 cm of 01 was added to the filtrate, and the mixture was heated and melted. The solution was cooled to 20°C, and 82 cm of powder crystals ([α]
Gokawa 05.5° (C = 1. CHCl3)) was inoculated,
After stirring for 40 minutes, the crystals were filtered off and dried. Yield of 2
29■ (α)? −105,1” (C=1.CHCl3
), 99.6% e, e,.

156 mg of DL was added to the filtrate, and the same operation was carried out using 82 cm of L as a seed crystal. l, total storage N215■
[αζ+104.2° <c=1. ClICl5),
100% e, e,.

Patent applicant: Nissan Chemical Industries, Ltd.

Claims (4)

[Claims] (1) N- represented by formula (1) (in the formula, R represents a lower alkyl group)
Acetyl-phenylalanine alkyl ester DL
or a mixture in which one optically active form is present in excess of the other optically active form, by inoculating either one of the optically active forms to a supersaturated solution of the crystallization and resolution. An optical resolution method for the DL form of N-acetyl-phenylalanine alkyl ester represented by (■) or a mixture in which one optically active form is present in excess of the other optically active form. (2) The optical resolution method according to claim (1), wherein R in the formula (+) represents a methyl group or an ethyl group. (3) N- represented by formula (1) (in the formula, R represents a lower alkyl group)
Formula (1), characterized in that crystallization separation is carried out by spontaneous crystallization of a supersaturated solution of a mixture in which one optically active form of acetyl-phenylalanine alkyl ester is present in excess of the other optically active form. An optical resolution method for a mixture in which one optically active form of N-acetyl-phenylalanine alkyl ester represented by is present in excess of the other optically active form. (4) The optical resolution method according to claim (3), in which R in formula (1) represents a methyl group or an ethyl group.