JP2001328971A - Method for purifying amino acid amide - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for purifying an optically active amino acid amide. SOLUTION: A basic compound, especially a potassium compound, is added to a solution containing an amino acid and an amino acid amide. Thereby, the amino acid amide can be purified without contaminating the amino acid amide with the amino acid.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a method for purifying an amino acid amide which is an intermediate useful for medical and agricultural chemicals.

[0002]

2. Description of the Related Art In recent years, the demand for optically active amino acids and amides as intermediates for the synthesis of physiologically active substances such as medical and agricultural chemicals has been increasing, and synthetic studies using various techniques have been actively conducted. Methods for producing optically active amino acids and amino acid amides include, for example, methods for producing optically active amino acids and optically active amino acid amides by enzymatic asymmetric hydrolysis of racemic amino acid amides. In this method, one enantiomer undergoes hydrolysis and is converted into an optically active amino acid, but the other enantiomer remains as an optically active amino acid amide, so that it is necessary to separate the amino acid and the amino acid amide. . As a separation method, after performing an enzymatic asymmetric hydrolysis reaction in an aqueous solvent, the reaction solution is concentrated, and an organic solvent such as alcohol, which is a poor solvent for amino acids, is added to take out the crystallized amino acid. A method is conceivable in which the amino acid amide of the reaction is obtained as a filtrate dissolved in a water-alcohol mixed solvent. Further, as a more efficient method for producing, an optically active amino acid and amino acid amide production method combining racemization has been reported. Regarding the racemization method of amino acid amides and the method for obtaining the same, for example, the methods described in JP-A-61-197530 and JP-A-61-293394 are exemplified. The publication describes that racemization proceeds efficiently in an organic solvent under alkaline conditions.

[0003]

However, in the above-mentioned method, it is not always possible to completely crystallize only the amino acid, and the amino acid may be mixed into the amino acid amide. If only one of the optically active substances is required,
For example, it would be extremely advantageous if the optically active amino acid amide could be racemized and reused as a raw material for an asymmetric hydrolysis reaction, but it was feared that the contaminated amino acids would lower the optical purity. An object of the present invention is to provide an effective method for purifying an amino acid amide which has solved the above problems.

[0004]

Means for Solving the Problems The present inventors have conducted intensive studies on a method for purifying an amino acid amide from a solution containing an amino acid and an amino acid amide. As a result, the basic compound was contained in the solution containing the amino acid and the amino acid amide. Is added, the solubility of the amino acid in the organic solvent is improved, and by precipitating the amino acid amide from the solution, the amino acid amide with less contamination of the amino acid can be obtained with high purity. The present invention was found to be very effective for separating amino acids and amino acid amides and for racemizing amino acid amides, and completed the present invention. That is, the present invention is a method for purifying an amino acid amide, which comprises using a basic compound.

[0005]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be specifically described below. Examples of the amino acid amide targeted in the present invention include tert-leucinamide, leucinamide, alaninamide, phenylalanine amide, p-chlorophenylalanine amide, p-hydroxyphenylalanine amide, and the like. When purifying an amino acid amide from a solution containing an amino acid and an amino acid amide, any basic compound to be used may be used as long as the amino acid becomes a salt that is easily soluble in an organic solvent. Particularly, a potassium compound is preferable. For example, when amino acids become potassium salts,
Potassium hydroxide, metal potassium, potassium hydride, tert
-Potassium butoxy, potassium carbonate and the like. The use amount of these basic compounds is 1 to 100% mol, preferably 5 to 50% mol based on the amino acid amide.
In addition, since a solution containing an amino acid and an amino acid amide contains a basic compound, racemization can be performed at the same time. The conditions for the racemization reaction of the amino acid amide vary depending on various factors such as α-amino acid amide, the type of base compound, and concentration, and are not particularly limited.
Generally, the reaction temperature is from 80 to 200 ° C, preferably from 100 to 200 ° C.
Perform at 150 ° C. for 10 minutes to 24 hours. The amino acid amide is obtained by adding a suitable organic solvent to a solution containing the amino acid and the amino acid amide mixed with the basic compound, and precipitating the amino acid amide preferentially. At the time of precipitation, any organic solvent may be used as long as the solvent is one in which the amino acid salt converted to the salt of the basic compound is dissolved and the amino acid amide is hardly dissolved. The amino acid amide can be precipitated from the solution by an operation such as concentration or cooling. The racemic amino acid amide obtained by the method is
For example, it can be used in a method for producing an optically active amino acid by enzymatic asymmetric hydrolysis.

[0006]

The present invention will be described in more detail with reference to the following examples. Example 1 70 g of D-tert-leucinamide (optical purity> 99% ee), L-tert-leucine (optical purity> 9)
2 g of 9% ee) dissolved in 48 g of water and 80 g of isopropyl alcohol A total of 200 g (24% water content)
Was added to 100 g of n-butanol, and the mixture was heated at 60 ° C./80 to
The mixture was concentrated to a total amount of 150 g at rr. 4.9 g of potassium hydroxide (equivalent to amino acid and 20% mol to amide) and 145 g of n-butanol were added thereto and stirred at room temperature for 1 hour to dissolve potassium hydroxide (total amount of 300 g). ). The measured amount of water was 6%. Further, the mixture was concentrated at 80 ° C./80 torr until the total amount became 150 g, and 150 g of n-butanol was added to add a total amount of 3 g.
00 g (water content 0.1%). The solution was stirred at 120 C for 6 hours. As a result, the amino acid ratio was 2.8% (w / w) before the reaction, and was 5.4% (w / w) after the reaction. After the reaction, the reaction mixture was concentrated to a total amount of 100 g, and 100 g of n-heptane was added.
After drying, 63 g of racemic tert-leucinamide was obtained. The concentrations of tert-leucine and tert-leucinamide were analyzed under high performance liquid chromatography (HPLC) analysis condition 1, and the optical purity of each was analyzed under HPLC analysis condition 2.

HPLC analysis conditions 1: Column: Inertosyl ODS-3V (4.6φ × 25
0 mm) Moving layer: 0.1% phosphoric acid aqueous solution Flow rate: 1 mL / min Detection: RI HPLC analysis condition 2: Column: SUMICHIRAL OA-5000 (4.
6φ × 250mm) Moving layer: water-methanol (85:15) Flow rate: 1 mL / min Detection: UV 254 nm

When analyzed by HPLC under the above conditions, the tert-leucine contained in the collected tert-leucinamide was 0.13% (w / w). The yield of amino acid amide was 90%, and the racemization rate was 99%.

Example 2 D-tert-leucinamide 7
0 g (optical purity> 99% ee) and 5.5 g of L-tert-leucine (optical purity> 99% ee) in 44 g of water and 80 g of isopropyl alcohol were used in a total amount of 20 g.
100 g of n-butanol was added to 0 g (water content 22%), and the mixture was concentrated at 60 ° C./80 torr until the total amount became 150 g. Thereto, 9.87 g of potassium hydroxide (equivalent to amino acid and 20% mol to amide) and 140 g of n-butanol were added and stirred at room temperature for 1 hour to dissolve potassium hydroxide ( The total amount is 300 g). The measured amount of water was 4%. Furthermore, 80 ° C / 8
After concentrating at 0 torr until the total amount becomes 150 g, n-
150 g of butanol was added to make the total amount 300 g (water content 0.1%). The solution was stirred at 120 C for 6 hours. As a result, the amino acid ratio before the reaction was 7.3% (w / w), and after the reaction was 11.9% (w / w). After the reaction, the mixture was concentrated to a total amount of 100 g, 100 g of n-heptane was added, and the precipitated crystals were centrifugally filtered and dried to obtain 63 g of racemic tert-leucinamide. Example 1
The tert-leucine contained in the collected tert-leucinamide was analyzed to be 1.07%
(W / w). Acquisition yield of amino acid amide is 89
%, And the racemization rate was 99%.

Example 3 D-tert-leucinamide 7
0 g (optical purity> 99% ee) and 5.5 g of L-tert-leucine (optical purity> 99% ee) dissolved in 44 g of water and 80 g of isopropyl alcohol were used in a total amount of 200 g.
g (water content: 22%), 100 g of n-butanol was added, and the mixture was concentrated at 60 ° C./80 torr until the total amount became 150 g. Then, 150 g of n-butanol was added to obtain a total amount of 300 g.
I made it. The measured amount of water was 4%. Further, the mixture was concentrated at 80 ° C./80 torr until the total amount became 150 g, and 150 g of n-butanol was added to add a total amount of 300 g.
g. The measured amount of water was 0.1%.
To this was added 10.74 g of potassium tert-butoxide (equivalent to amino acid and equivalent to 10% mol to amide), and the mixture was stirred at 120 ° C for 6 hours. As a result, before reaction, 7.
The amino acid ratio of 3% (w / w) is 9.4% after the reaction.
(W / w). After the reaction, the mixture was concentrated to a total amount of 100 g, 100 g of n-heptane was added, and the precipitated crystals were centrifugally filtered and dried to obtain 63 g of racemic tert-leucinamide. When analyzed by HPLC under the conditions of Example 1, the tert-leucine contained in the collected tert-leucinamide was 0.89% (w / w).
The acquisition yield of amino acid amide is 89% and the racemization rate is 96
%Met.

Comparative Example 1 D-tert-leucinamide 7
200 g of a solution prepared by dissolving 0 g (optical purity> 99% ee) and 5.5 g of L-tert-leucine (optical purity> 99% ee) in 44 g of water and 80 g of isopropyl alcohol.
(Moisture content: 22%), 100 g of n-butanol was added, and the mixture was concentrated at 60 ° C./80 torr until the total amount became 150 g. Thereto, 6.00 g of sodium hydroxide (equivalent to amino acid and 20% to amide) and 144 g of n-butanol were added and stirred at room temperature for 1 hour to dissolve sodium hydroxide ( The total amount is 300 g). The measured amount of water was 4%. Furthermore, 80 ° C / 8
After concentrating at 0 torr to a total amount of 150 g, 150 g of n-butanol was added to make a total amount of 300 g (water content).
0.1%). The solution was stirred at 120 C for 6 hours. As a result, the amino acid ratio was 7.3% (w / w) before the reaction, and 12.1% (w / w) after the reaction. After the reaction,
Concentrate until the total amount becomes 100 g, 100 g of n-heptane
Was added, and the precipitated crystals were centrifugally filtered and dried to collect 65 g of racemic tert-leucinamide. When analyzed by HPLC under the conditions of Example 1, the tert-leucine contained in the collected tert-leucinamide was 5.96%.
(W / w). The amino acid amide yield was 87.
%, And the racemization rate was 98%.

[0012]

When the amino acid amide is purified from the amino acid mixture, the solubility of the amino acid in the organic solvent is improved by using a basic compound, particularly a potassium compound, and the amino acid amide can be separated with high purity.

Claims (6)

[Claims] 1. A method for purifying an amino acid amide from a solution containing an amino acid and an amino acid amide, wherein a basic compound is added to the solution, and the amino acid amide is preferentially precipitated from the solution. Purification method. 2. A method for purifying an amino acid amide from a solution containing an amino acid and an amino acid amide, wherein a basic compound is added to the solution, a racemization reaction is performed, and then the amino acid amide is preferentially precipitated from the solution. A method for purifying an amino acid amide, comprising: 3. The method for purifying an amino acid amide according to claim 1, wherein the basic compound is a metal potassium and / or a basic potassium compound. 4. A method for purifying an amino acid amide having an amino acid content of 1.5% or less in an amino acid amide crystal precipitated by the method according to claim 1. Description: 5. The method according to claim 1, wherein the amino acid amide is tert-leucinamide. 6. The method for purifying an amino acid amide according to claim 1, wherein the amino acid amide is a substituted or unsubstituted phenylalanine amide.