JPH11292832A - Production of optically active amide of amino acid - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing an optically active amide of an amino acid, having a high optical purity by reacting a neutralized salt of an optically active amino acid ester with an amine, bringing the product into contact with an aqueous solution of an alkali compound after finishing the reaction, and carrying out an isolation treatment of the alkali-treated product. SOLUTION: (A) A neutralized salt of an optically active amino acid ester (e.g. a hydrochloric acid salt of ethyl ester of L-alanine, and a hydrochloric acid salt of methyl ester of L-phenylalanine) is reacted with (B) an amine (e.g. benzylamine and aniline) preferably without a solvent at 10-60 deg.C, and after the reaction, the reaction product is brought into contact with (C) an alkali compound (e.g. sodium hydroxide and potassium hydroxide) preferably at 0-40 deg.C for 5-60 min. The obtained alkali-treated product is subjected to isolation treatment to provide the objective optically active amide of the amino acid in the method for producing the optically active amide of the amino acid. The component B preferably has >=80 deg.C boiling point at a normal pressure, and the excess amount thereof over the amount of the component A is preferably used. The concentration of the component C is preferably <=10 wt.%.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for producing an optically active amino acid amide maintaining a high optical purity by reacting a neutralized salt of an optically active amino acid ester with an amine.

[0002]

2. Description of the Related Art As a method for producing an optically active amino acid amide maintaining a high optical purity, (1) an amino group of an optically active amino acid is protected with an acetoacetate ester and converted into an imide derivative, and then -15% in anhydrous tetrahydrofuran. ~ 2
A method in which a carboxyl group is activated with ethyl chlorocarbonate under cooling at 0 ° C. and then reacted with an amine (Japanese Patent Publication No.
No. 39583) and a method of directly reacting (2) a neutralizing salt of an optically active amino acid ester with an excess of an amine (Nobuo Izumiya, Tetsuo Kato, Higashihiko Aoyagi, Michinori Waki, "Basic and Experimental Peptide Synthesis" Maruzen Co., Ltd. ) Issued January 20, 1985, 4th
4 pages) are known. However, although (1) is excellent as a method for producing an optically active amino acid amide maintaining high optical purity, a low-temperature reaction is essential to suppress racemization, and it is an anhydrous reaction;
There are problems such as complicated operations. Further, (2) is an excellent method in that an optically active amino acid amide can be produced by a simple operation, but it is necessary to remove excess amine. Therefore, low-boiling amines such as ammonia and methylamine can achieve the objective with little decrease in optical purity, but amines having a high boiling point have problems such as racemization occurring in isolation operation.

[0003]

That is, an object of the present invention is to provide a method for producing an optically active amino acid amide maintaining a high optical purity by a simple operation.

[0004]

Means for Solving the Problems The inventors of the present invention aimed to produce an optically active amino acid amide having a high optical purity by reacting a neutralized salt of an optically active amino acid ester with an amine. As a result of intensive studies on a method for removing amines, the present invention has been achieved.

That is, in the present invention, in producing an optically active amino acid amide by reacting a neutralized salt of an optically active amino acid ester with an amine, an isolating operation is carried out after the reaction is brought into contact with an aqueous solution of an alkali compound. A process for producing an optically active amino acid amide characterized by the following.

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION The optically active amino acid ester used as a raw material is unstable in a free state, and is usually stored in a neutralized state with an acid, that is, in a neutralized salt state. The optically active amino acid ester used herein means a compound having both an amino group and a carboxylic acid ester group. For example, L-alanine ethyl ester, L-lysine ethyl ester, D-phenylalanine methyl ester, L-
Optically active α-amino acid esters such as tyrosine butyl ester and optically active β-amino acid esters such as methyl D-3-aminobutyrate can be used.

[0007] The usual storage form is a neutralized salt, but an optically active amino acid ester released immediately before use can also be used in the present invention. Use is more advantageous.
Here, any acid may be used for neutralization, but in general, mineral acids such as hydrochloric acid and sulfuric acid, and organic carboxylic acids such as acetic acid are generally preferable.

The amine used as the other raw material is
Although alkylamines such as pentylamine and dibutylamine, aralkylamines such as benzylamine and phenethylamine, and phenylamines such as aniline, amines having a boiling point of 80 ° C. or more at normal pressure are more effective.

In the reaction, it is preferable to use an excess of amine with respect to the optically active amino acid ester neutralized salt. This is because the optically active amino acid ester neutralized salt is neutralized into a free optically active amino acid ester, and the free optically active amino acid ester is easily racemized, so that it can be rapidly amidated. The amount used is preferably from 2 to 20 mol, more preferably from 3 to 6 mol, per mol of the free optically active amino acid ester, in addition to the necessary amount to neutralize the optically active amino acid ester in a free state. By setting such a range, the amidation reaction can be accelerated, and the optical purity of the generated amino acid amide can be increased. Further, it does not require a long time to remove the excess amine, and does not lower the optical purity of the produced amino acid amide. Although a reaction solvent may be used, it is preferable not to use it from the viewpoint of reaction efficiency and reaction rate. The reaction temperature is preferably 10 to 60
° C, more preferably 20 to 40 ° C. By setting the temperature within such a temperature range, the reaction speed can be increased and the reaction can be completed in a short time. In addition, racemization can be prevented. The reaction time varies depending on the molar ratio of the amine used and the reaction temperature, but is substantially when the reaction is completed.

In the reaction, the neutralized salt of the optically active amino acid ester may be added to the stirred amine, or the neutralized salt of the optically active amino acid ester and the amine may be mixed at once, followed by stirring to effect the reaction. However, the temperature of the reaction solution is preferably maintained at 60 ° C. or lower.

Here, it is preferable to remove amines used in excess under mild conditions. By doing so, racemization of the generated optically active amino acid amide can be effectively prevented. When the optically active amino acid ester neutralized salt is completely reacted with the amine, the optically active amino acid amide becomes a mixture of a free state and a neutralized salt. The raw material amine is also a mixture of a free amine and a neutralized salt. When low-boiling amines such as ammonia are used as raw materials, these mixtures are concentrated under reduced pressure at a low temperature, and the low-boiling amine is distilled out of the system to cause an equilibrium shift, and the residue becomes a neutralized salt of an optically active amino acid amide. It is preferable because it can be isolated as an optically and chemically stable compound. On the other hand, when an amine having a high boiling point is used, racemization occurs at the time of concentration under reduced pressure, and the equilibrium is not easily shifted. So, in such a case,
It is preferable that the reaction solution of the optically active ester neutralized salt and excess amine is brought into contact with an aqueous solution of an alkali compound to convert all of the neutralized salt into an alkali salt, and the optically active amino acid amide and excess amine are released. .

The alkali used here is preferably an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or lithium hydroxide, or an alkaline earth metal hydroxide such as calcium hydroxide. The amount of the alkali used is preferably in the range of 2 equivalents to 2 equivalents, and more preferably in the range of 1 equivalent to 1.2 equivalents required for neutralizing the neutralized salt contained in the raw material to make the alkali salt. In this case, the optically active amino acid amide can be completely released. In addition, racemization is not likely to be promoted due to the added alkali compound. The concentration of the aqueous solution of the alkali compound is preferably dilute, preferably 10% by weight or less. More preferably, it is 2 to 5 wt%. With such a range, the alcohol and excess amine generated by the reaction are not distributed to both the aqueous layer and the organic layer, and the interface does not become difficult to appear. Also, the production efficiency can be increased.

The contact method may be such that the reaction solution is added to the aqueous solution of the alkali compound while stirring, or an aqueous solution of the alkali compound is added to the reaction solution. The temperature of the reaction solution during stirring is preferably from 0 to 40 ° C, more preferably from 10 to 30 ° C.
° C. The contact time is preferably from 5 to 60 minutes, more preferably from 10 to 30 minutes.

When the reaction solution is brought into contact with an aqueous solution of an alkali compound and allowed to stand, the organic layer is separated. Here, when the reaction is immature and the raw material amino acid ester remains, the amino acid ester is hydrolyzed by contact with an aqueous solution of an alkali compound to be converted into an amino acid. As it migrates to the layer, substantially only the optically active amino acid amide and excess amine are present in the organic layer. In order to recover the optically active amino acid amide from the organic layer, usually, a solvent for separating water and a liquid is added to the separated organic layer. The organic layer is diluted with a solvent that separates from water, so that the mixed water comes to separate, and the aqueous layer is separated and discarded.

The solvent used for liquid separation with water used herein may be any organic solvent having a solubility of the optically active amino acid amide at 30 ° C. of 5% or more. Although it depends on the type of the optically active amino acid amide, usually, aromatic hydrocarbons such as toluene and halogenated hydrocarbons such as dichloromethane can be preferably used. Next, this organic layer is concentrated under reduced pressure usually at 40 ° C. or lower. If the amine used as the raw material has a relatively low boiling point, it is considerably removed from the system at this point, but if the boiling point is relatively high, the amine used as the raw material together with the target optically active amino acid amide is contained in the concentrated solution. The amine remains. From the viewpoint of preventing racemization of the optically active amino acid amide, the time is preferably 20 hours or less, more preferably 10 hours or less.

The optically active amino acid amide is not dissolved in this concentrated solution, and a solvent for dissolving the amine is added to dilute the concentrate to crystallize the desired optically active amino acid amide. Optically active amino acid amide does not dissolve, the solvent that dissolves the amine,
Depending on the type of the compound, for example, an aliphatic hydrocarbon such as heptane or cyclohexane can be used.

Next, by filtering and drying the crystallized optically active amino acid amide, an optically active amino acid amide having high optical purity can be obtained. By using the method of the present invention, an optically active amino acid amide having a high optical purity of 95% ee or more can be produced.

[0018]

EXAMPLES The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples.

Example 1 1 equipped with a thermometer, a Dimroth condenser and a stirrer
A 2,000 ml flask was charged with 236 g of parachloroaniline and stirred at 10 to 15 ° C. In this, liquid temperature is 25
While keeping the temperature at not more than 0 ° C., 52 g of L-alanine ethyl ester hydrochloride (L-alanine ethyl ester was obtained by ethyl esterifying L-alanine (manufactured by Mion, food grade) with ethanol / HCl) was added, and 20 was added. Stirred at 〜25 ° C. overnight. Next, 440 g of a 5 wt% aqueous sodium hydroxide solution was added dropwise while stirring at 25 ° C. or lower, and the mixture was further stirred for 1 hour. The organic layer was separated, 200 g of toluene was added, and the mixture was stirred for 1 hour. After removing the separated aqueous layer, the toluene layer was concentrated under reduced pressure at 40 ° C. or lower. While stirring the concentrated solution, 1500 g of hexane was added dropwise to precipitate crystals. The precipitated crystals were filtered and dried under reduced pressure to obtain 59 g of L-alanine parachloroanilide. Melting point 71-74
° C, optical purity 98.9% ee Example 2 As in Example 1, 300 g of paramethoxyaniline
And 67 g of D-phenylglycine methyl ester hydrochloride were reacted. Next, 500 g of a 4 wt% aqueous potassium hydroxide solution was added dropwise with stirring at a temperature of 25 ° C. or lower, and the mixture was further stirred for 1 hour. Separate the organic layer and add toluene 2
00g was added and stirred for 1 hour. After removing the separated aqueous layer, the toluene layer was concentrated under reduced pressure at 40 ° C. or lower. While stirring the concentrated liquid, 1500 g of cyclohexane was added dropwise to precipitate crystals. The precipitated crystals were filtered and dried under reduced pressure to obtain 59 g of D-phenylglycine paramethoxyanilide. Melting point 85-87 ° C, optical purity 99.0% ee Example 3 In the same manner as in Example 1, 270 g of benzylamine and L-
136 g of phenylalanine methyl ester hydrochloride were reacted. Then, while stirring, 759 g of a 4 wt% aqueous sodium hydroxide solution was added dropwise while maintaining the temperature at 25 ° C. or lower,
The mixture was further stirred for 1 hour. The organic layer is separated, and toluene 450
g was added and stirred for 1 hour. After removing the separated aqueous layer, the toluene layer was concentrated under reduced pressure at 40 ° C. or lower. While stirring the concentrated liquid, 1200 g of cyclohexane was added dropwise to precipitate crystals. The precipitated crystals were filtered and dried under reduced pressure to obtain 112 g of L-phenylalanine benzylamide. Melting point 67
６８68 ° C., optical purity 99.1% ee.

Comparative Example 1 In the same manner as in Example 3, 270 g of benzylamine and L-
136 g of phenylalanine methyl ester hydrochloride were reacted. Next, 152 g of a 20 wt% aqueous sodium hydroxide solution was added and stirred, but no clear interface was formed. When toluene was added until the interface appeared, 100
0 ml or more of toluene was required. The optical purity of L-phenylalanine benzylamide isolated from the toluene solution was as low as 93.9% ee.

[0021]

According to the present invention, an optically active amino acid amide having a high optical purity can be produced from an optically active amino acid ester neutralized salt and an amine.

Claims (5)

[Claims] 1. A method for producing an optically active amino acid amide by reacting a neutralized salt of an optically active amino acid ester with an amine, comprising the steps of: contacting an aqueous solution of an alkali compound after completion of the reaction; A method for producing an optically active amino acid amide. 2. The method for producing an optically active amino acid amide according to claim 1, wherein the optically active amino acid ester neutralized salt is an optically active α-amino acid ester neutralized salt. 3. An optically active α-amino acid ester neutralized salt represented by the general formula (1): ## STR1 ## (Where R is unsubstituted or substituted with a straight-chain or branched alkyl group having 1 to 6 carbon atoms or substituted with a hydroxyl group, an alkoxyl group, a carboxyl group or a carbamoyl group, or a phenyl group, or a hydroxyl group, an alkoxyl group, Aralkyl group substituted with carbamoyl group, unsubstituted or hydroxyl group,
It represents a phenyl group substituted with an alkoxyl group or a carbamoyl group. R ¹ represents a lower alkyl group having 1 to 6 carbon atoms or an aralkyl group. 3. The method for producing an optically active amino acid amide according to claim 2, wherein the optically active α-amino acid ester represented by the formula (1) is a salt of a mineral acid or an organic carboxylic acid. 4. The optically active compound according to claim 1, wherein the amine to be reacted with the optically active amino acid ester neutralizing salt is an amine having a boiling point of 80 ° C. or more at normal pressure. Method for producing amino acid amide. 5. The process for producing an optically active amino acid amide according to claim 1, wherein the concentration of the aqueous solution of the alkali compound is 10% by weight or less.