JP2000063350A - Method for purifying optically active n-protecting group- having amino acid ester - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for purifying an optically active N-protecting group-having amino acid ester having high optical purity. SOLUTION: This method for purifying an amino acid ester having an optically active N-protecting group is to recrystallize or crystallize by mixing with a poor solvent a N-protecting group-having amino acid ester obtained by reacting an optically active N-protecting group-having amino acid with an alcohol in the presence of a catalyst from a solution prepared by dissolving or extracting the amino acid ester in or with a solvent. The alcohol is methanol, the amino acid is S-phenyl-L-cysteine and the amino-protecting group is a nucleus-substituted or nonsubstituted benzyloxycarbonyl group.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD OF THE INVENTION Optically active N-protecting group amino acid ester, which is widely used as an intermediate for medical and agricultural chemicals, is dissolved or extracted in an organic solvent to recrystallize it or to crystallize it with a poor solvent to obtain an optical compound. The present invention relates to a method for purifying an amino acid ester of N-protecting group for enhancing purity.

[0002]

2. Description of the Related Art As a method for producing an optically active N-protecting group amino acid ester, for example, benzyloxycarbonyl chloride (abbreviated as Z--Cl), which is a typical amino protecting group, is used. Using
In most cases, the Schotten-Baumann method is used. This method is carried out by dissolving an amino acid in an aqueous solution of sodium hydroxide and dropping Z-Cl in an equimolar amount to the amino acid while maintaining alkalinity.

Next, an N-protecting amino acid ester is obtained by reacting with an alcohol in the presence of an acid catalyst. However, in many cases, the N-protecting amino acid ester obtained through such a reaction step cannot be obtained as a product having a high optical purity due to the optical purity of the raw material or racemization in the reaction step.

Particularly, when the amino acid is S-phenyl-L-cysteine, N-carbobenzoxy-S-phenyl-L-cysteine methyl ester is expected as an AIDS drug intermediate and is desired as a product with high optical purity. It is rare.

[0005]

As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that the N-protecting amino acid methyl ester having a high optical purity can be obtained by the reaction.
It was found that the optical purity of the obtained crystal can be improved by mixing and crystallizing the solution obtained by extracting the protecting group amino acid methyl ester with an organic solvent, and completed the present invention.

That is, the present invention is to recrystallize an N-protecting amino acid ester obtained by reacting an optically active N-protecting amino acid with an alcohol in the presence of an acid catalyst in an organic solvent or extract it from a solution obtained by recrystallization or a poor solvent. It is a method for purifying an amino acid ester of N-protecting group that improves optical purity by mixed crystallization.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION In the present invention, an amino acid having a N-protecting group can be dissolved in an organic solvent, an acid catalyst is added thereto, and then an alcohol is added to carry out an esterification reaction.

The amino acid used as a raw material in the present invention may be a natural product or a non-natural product, and may be a racemic compound, an optically active compound or a derivative thereof. Examples of amino acids include alanine, arginine, isoleucine, glycine, glutamine, cystine, cysteine, serine, tyrosine, tryptophan, valine, phenylalanine, S-phenylcysteine, methionine,
Examples thereof include leucine and the like, preferably amino acids having an aromatic ring such as tryptophan, phenylalanine and S-phenylcysteine, and particularly preferably S-phenyl-L.
-Cysteine.

Examples of the amino group-protecting group used in the present invention include a protecting group which is not deprotected under acidic conditions, and examples thereof include a nuclear-substituted or unsubstituted benzyloxycarbonyl group.

Examples of the alcohol used in the esterification reaction of the present invention include methanol, ethanol, benzyl alcohol and the like, with methanol being particularly preferable.

Solvents used in the esterification reaction of the present invention include aliphatic alcohols such as methanol, aromatic hydrocarbons such as toluene and xylene, halogen compounds such as chloroform and dichloromethane, methyl acetate, ethyl acetate and butyl acetate. And the like, such as acetic acid esters.
These organic solvents may be used in combination of two or more. The amount of the organic solvent used is not particularly limited, but is preferably 2 to 20 times by weight, and particularly preferably 3 to 5 times by weight based on the N-protecting group amino acid.

The acid catalyst used in the present invention may be any one as long as it catalyzes esterification, but generally, a mineral acid such as hydrochloric acid, sulfuric acid, nitric acid or phosphoric acid, or a strong cation exchange resin or the like. Solid acid catalysts and the like. When the esterification reaction is carried out with a two-layer reaction medium of water and a poorly water-soluble organic solvent, an acid containing water such as 35% hydrochloric acid can also be used. These acid catalysts can be used in combination of two or more.

After completion of the esterification reaction, the aqueous layer may be separated by a liquid separation operation, and if necessary, washing of the solvent layer with water or a weak alkaline aqueous solution, dehydration of the solvent layer with a desiccant, and the like may be incorporated.

For the isolation and purification of the N-protecting group amino acid ester, the organic solvent layer may be cooled as it is and recrystallized or it may be mixed with a poor solvent. Further, the organic solvent layer may be distilled under reduced pressure or normal pressure to remove the solvent, and the solvent may be replaced with an aliphatic alcohol such as methanol, ethanol, isopropanol, butanol or the like, and then recrystallization may be carried out. There is no problem even if a poor solvent is added to and mixed crystallization is performed.

The poor solvent for the N-protecting group amino acid ester is a solvent capable of precipitating the N-protecting group amino acid ester without removing the organic solvent when a sufficient amount of the N-protecting group amino acid ester solution is added.

Examples of the poor solvent used in the present invention include hexanes such as n-hexane, methyldiethylmethane, dimethylpropylmethane, dimethylisopropylmethane, trimethylethylmethane and cyclohexane, and ethers such as diethyl ether and petroleum ether. To be You may use these in mixture of 2 or more types. The amount of the poor solvent used is preferably 1 to 5 times by weight, more preferably 2 times by weight, the weight of the organic solvent in which the N-protecting group amino acid methyl ester is dissolved.
It is 3 times by weight to 3 times by weight.

[0017]

EXAMPLES The method of the present invention will be described in detail below with reference to examples. Example 1 N-carbobenzoxy-S-phenyl-L-cysteine (35 g) was dissolved in toluene (65 g) to obtain 36% hydrochloric acid (17.2).
g and 13.7 g of methanol were added, and an esterification reaction was performed at 70 ° C. for 6 hours. Most of the produced N-carbobenzoxy-S-phenyl-L-cysteine methyl ester was present in the toluene layer, and the reaction yield was 96%.
In order to remove N-carbobenzoxy-S-phenyl-L-cysteine remaining unreacted from the toluene layer,
It was washed once with 24 g of 7% sodium hydrogencarbonate and once with the same amount of water to obtain 36% concentration of N-carbobenzoxy-
A toluene solution of S-phenyl-L-cysteine methyl ester was obtained. Here, the optical purity of N-carbobenzoxy-S-phenyl-L-cysteine methyl ester was measured and found to be 98.5% ee. 126 g of hexane was added to this, and the mixture was cooled to 5 ° C. to precipitate crystals, which was allowed to crystallize for 1 hour, and the crystals were taken out by filtration. The optical purity of the taken out crystal was analyzed and found to be 99.9% e
It was e. Moreover, when the optical purity of the filtrate side was analyzed, it was 7
It was 2.8% ee, which indicates that optical resolution was performed by crystallization.

Example 2 35 g of N-carbobenzoxy-S-phenyl-L-cysteine methyl ester having an optical purity of 88.8% ee and 93.4% ee was dissolved in 65 g of toluene, and 130 g of hexane was added thereto. The mixture was cooled to 5 ° C., crystals were deposited, the crystals were allowed to stand for 1 hour, and crystals were taken out by filtration. Table 1 shows the optical purity analysis results on the crystal and filtrate sides in each case.

[Table 1]

Example 3 N-carbobenzoxy-S- with an optical purity of 98.5% ee
After dissolving 35 g of phenyl-L-cysteine methyl ester in 65 g of toluene at 50 ° C., the mixture was cooled to 5 ° C. to precipitate crystals, and the crystals were allowed to crystallize for 1 hour. The optical purity of the taken out crystal was analyzed and found to be 99.9% ee. The optical purity of the filtrate was analyzed and found to be 96.4% ee.

Example 4 N-carbobenzoxy-S- with an optical purity of 98.5% ee
Phenyl-L-cysteine methyl ester 35 g 31
After dissolving in 5 g of methanol, ethanol, isopropanol and butanol at 50 ° C., the mixture was cooled to 5 ° C., crystals were deposited and allowed to crystallize for 1 hour, and crystals were taken out by filtration. Table 2 shows the optical purity analysis results of the crystals taken out and the filtrate side.

[Table 2]

Reference Example 1 Table 3 shows the solubilities of the L-form of N-carbobenzoxy-S-phenyl-cysteine methyl ester and the racemate in a hexane / toluene mixed solution.

[Table 3]

Reference Example 2 Same as Example 5 except that the N-carbobenzoxy-S-phenyl-cysteine methyl ester used was changed to N-carbobenzoxy-tryptophan methyl ester and N-carbobenzoxy-phenylalanine methyl ester. The solubility in hexane / toluene (2/1) was measured (Table 4). As a result, N-carbobenzoxy-tryptophan methyl ester and N-carbobenzoxy-phenylalanine methyl ester were L-like as well as N-carbobenzoxy-S-phenyl-cysteine methyl ester.
The solubility of the racemate was higher than that of the body.

[Table 4]

[0023]

INDUSTRIAL APPLICABILITY According to the present invention, an amino acid ester of N-protecting group having high optical purity can be efficiently produced in high yield.

   ─────────────────────────────────────────────────── ─── Continued front page    (72) Inventor Seto Yoshino             30 Asamu-cho, Omuta-shi, Fukuoka Mitsui Chemicals             Within the corporation (72) Inventor Nobuhiro Fukuhara             30 Asamu-cho, Omuta-shi, Fukuoka Mitsui Chemicals             Within the corporation F term (reference) 4H006 AA02 AD15 AD16 BB11 BB12                       BB14 BB17 TA04 TC34

Claims (7)

[Claims] 1. An N-protecting amino acid ester obtained by reacting an optically active N-protecting amino acid with an alcohol in the presence of an acid catalyst is recrystallized from a solution obtained by dissolving or extracting it in an organic solvent or mixed crystallization with a poor solvent. A method for purifying an amino acid ester of N-protecting group, which enhances optical purity. 2. The purification method according to claim 1, wherein the alcohol is methanol. 3. The purification method according to claim 1, wherein the amino acid is an amino acid having an aromatic ring. 4. The purification method according to claim 1, wherein the amino acid is S-phenyl-L-cysteine. 5. The purification method according to claim 1, wherein the amino-protecting group is a nucleus-substituted or unsubstituted benzyloxycarbonyl group. 6. The purification method according to claim 1, wherein the organic solvent is one or more selected from the group consisting of aliphatic alcohols, aromatic hydrocarbons, halogen compounds and acetic acid esters. 7. The purification method according to claim 1, wherein the poor solvent is hexane.