JPH06321916A - Production of 3,6-bis((4-hydroxyphenyl)methyl)-2,5-diketopiperazine - Google Patents

Abstract

PURPOSE:To produce 3,6-bis[(4-hydroxyphenyl)methyl]-2,5-diketo-piperazine from tyrosine alkyl ester in an organic solvent, and isolate and purify the compound easily. CONSTITUTION:This invention provides a production process for 3,6-bis [(4- hydroxyphenyl)methyl]-2,5-diketo-piperazine from tyrosine alkyl ester by heating it in a non-protonic organic solvent and a purification process for 3,6-bis[(4- hydroxyphenyl)methyl]-2,5-diketo-piperazine through crystallization by adding an organic solvent of 1.5 to 2.7 dipole moment to the solution containing the diketopiperazine.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a method for producing 3,6-bis [(4-hydroxyphenyl) methyl] -2,5-diketopiperazine (hereinafter abbreviated as Tyr-DKP). More specifically, a method for producing Tyr-DKP by heating a tyrosine alkyl ester in an organic solvent, and T from the reaction solution thus obtained,
The present invention relates to a method for separating and purifying yr-DKP.
2,5-Diketopiperazines such as Tyr-DKP are cyclic dimers of amino acids and are generally known as by-products during peptide synthesis. However, those compounds have physiological activity and are used as fungicides for agriculture and horticulture, or composed of amino acids having a functional group in the side chain.
-Diketopiperazines are used as raw materials for polymers as bifunctional monomers.

[0002]

2. Description of the Prior Art 2,5-Diketopiperazines are generally obtained by heating an amino acid alkyl ester or a dipeptide ester. Tyr
Also for DKP, a method of heating tyrosine methyl ester without solvent (US Pat. No. 3,763,091) or tyrosyl-tyrosine methyl ester with 0.1 M acetic acid / 2-
Method of heating in butanol (Chem. Pharm.
Bull. 29 (1) 1981) and the like are known. However, the method of heating a dipeptide ester such as tyrosyl-tyrosine methyl ester requires several steps for synthesizing the starting dipeptide ester and is not economical. On the other hand, in the method of heating tyrosine methyl ester without a solvent, there is a problem in operation because the reaction mixture solidifies, and since a large amount of tyrosine is by-produced, the separation operation is difficult. In addition, in the method of heating the tyrosine alkyl ester in an ordinary organic solvent, Tyr-DK produced
There is almost no solubility of P and the reaction rate is very low.

[0003]

Therefore, it is an object of the present invention to easily produce Tyr-DKP with high yield and high purity.

[0004]

Means for Solving the Problems The present inventors obtained Tyr-DKP from an tyrosine alkyl ester in an organic solvent, and conducted extensive studies to find a method for easily isolating it. As a result, a special solvent was used. It has been found that a high reaction rate can be obtained by reacting the above. Further, it was found that Tyr-DKP can be isolated with high purity by crystallizing Tyr-DKP from the obtained reaction solution using a special organic solvent, and completed the present invention.

That is, the present invention is characterized in that the aprotic polar organic solvent is used for the tyrosine alkyl ester, which is 3,6-bis [(4-hydroxyphenyl) methyl].
-Method for producing 2,5-diketopiperazine and 3,6-bis [(4-hydroxyphenyl) methyl] containing at least tyrosine or a tyrosine derivative as a contaminant
-2,5-Diketopiperazine is dissolved in an aprotic organic solvent, and the solvent has a dipole moment of 1.5-2.
Crystallization of 3,6-bis [(4-hydroxyphenyl) methyl] -2,5-diketopiperazine using an organic solvent of 7D 3,6-bis [(4-hydroxyphenyl) This is a method for purifying methyl] -2,5-diketopiperazine. The tyrosine alkyl ester used in the present invention is preferably an alkyl ester having 1 to 4 carbon atoms, and particularly preferably tyrosine methyl ester. Also, these hydrochlorides can be used after being neutralized with an organic base such as triethylamine or N-methylmorpholine in the reaction solution. Further, these can be used regardless of the optically active form or the racemic form.

The aprotic polar organic solvent which is a feature of the present invention is N-methylpyrrolidone (NMP), N, N'-
Examples thereof include amide solvents such as dimethylimidazolidinone (DMI), N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMAc), and dimethyl sulfoxide (DMSO). The reaction temperature is not particularly limited, but the higher the temperature, the faster the reaction, and preferably 140 ° C to 180 ° C. The concentration of tyrosine alkyl ester in the reaction solution is not particularly limited, but the higher the concentration, the faster the reaction and the higher the reaction rate. Usually 10 to 50 wt%
However, 40 to 50 wt% is preferable.

The dipole moment used as a solvent for precipitating Tyr-DKP is 1.5 to 2.7D.
The organic solvent, ethyl acetate, methyl acetate, ester solvents such as butyl acetate, alcohol solvents such as methanol, ethanol, propanol, isopropanol, acetone, ketone solvents such as methyl isobutyl ketone, ether solvents such as tetrahydrofuran, Examples thereof include halogenated hydrocarbon solvents such as dichloromethane, chloroform and 1,2-dichloroethane. If the dipole moment is smaller than this, the miscibility with the aprotic polar organic solvent is reduced. On the other hand, if it is larger than this, the solubility of Tyr-DKP increases and the yield decreases. A particularly preferred solvent is ethyl acetate. These organic solvents may be added to the Tyr-DKP solution, or conversely, they may be added to Tyr-DKP solution.
You may add a solution. The amount of the solvent added is preferably 2 to 5 times (w / w) with respect to the aprotic polar organic solvent. If it is less than this, the yield becomes low. Further, if the amount is larger than this, the amount of impurities in the obtained crystal increases.

When Tyr-DKP is crystallized, the concentration of Tyr-DKP in the aprotic polar organic solvent is 5-40 wt.
% Is preferable, but 10 to 30 wt% is particularly preferable. At lower concentrations, the yield will be lower. If the concentration is higher than this, crystals will be precipitated before performing the crystallization operation, and this crude crystal contains a large amount of tyrosine, and further separation and purification are required. Therefore, after the Tyr-DKP formation reaction, it is preferable to add an aprotic polar organic solvent to the reaction solution to adjust the Tyr-DKP concentration to 10 to 30 wt% and then perform the crystallization operation. The temperature for performing the crystallization operation is not particularly limited, but is usually 20 to 70.
It is performed at ℃. Particularly preferably, the temperature is 40 to 70 ° C.

[0009]

The present invention will be described in detail below with reference to examples, but the present invention is not limited to the examples. Example 1 4.5 g of tyrosine methyl ester was dissolved in 4.8 g of N-methylpyrrolidone (NMP) and heated to 180 ° C. for 4 hours. High performance liquid chromatography (hereinafter HP)
When analyzed by LC), the production rate of Tyr-DKP is 8
It was 5.8%. After adding 8.0 g of NMP to this reaction solution, 48.5 g of ethyl acetate was added dropwise at 60 ° C. The obtained precipitate was collected by filtration and dried to give a yield of 64.5% and a purity of 9%.
Crystals of 9.5% Tyr-DKP were obtained.

Example 2 5.0 g of tyrosine methyl ester was added to 5.2 g of N, N '.
-Dissolved in dimethyl imidazolidinone (DMI),
Heated to 80 ° C. When the reaction liquid after 6 hours was analyzed by HPLC, the production rate of Tyr-DKP was 82.5%.
After adding 4.0 g of DMI to this reaction liquid, 36.0 g of ethyl acetate was added dropwise. The obtained precipitate was collected by filtration and dried to give Tyr-DKP having a yield of 62.2% and a purity of 98.8%.
Was obtained.

Example 3 5.0 g of tyrosine methyl ester hydrochloride was suspended in 11.0 g of NMP, neutralized with an equivalent amount of triethylamine, and then heated to 180 ° C. HPLC for 6 hours
Analysis revealed that Tyr-DKP was produced at a production rate of 72.5%.

Example 4 3.0 g of tyrosine methyl ester was dissolved in 3.0 g of dimethyl sulfoxide and heated to 140 ° C. When the reaction solution after 22 hours was analyzed by HPLC, Tyr-DKP was found to be 7
It was produced at a production rate of 2.1%.

Comparative Example 1 Mesitylene 27.0 was obtained by adding 3.0 g of tyrosine methyl ester.
g and suspended at 168 ° C. When the reaction solution after 4 hours was analyzed by HPLC, the production rate of Tyr-DKP was 10.
4% and did not progress thereafter.

Comparative Example 2 3.0 g of tyrosine methyl ester was added to 27 g of m-xylene.
It was suspended in 0 g and refluxed at 139 ° C. When the reaction solution after 4 hours is analyzed by HPLC, the production rate of Tyr-DKP is 1
0.7% and did not progress thereafter.

Comparative Example 3 3.0 g of tyrosine methyl ester was added to 3.0 g of m-xylene.
g, and refluxed at 139 ° C. When the reaction liquid after 4 hours was analyzed by HPLC, the production rate of Tyr-DKP was 37.
9% and did not progress thereafter.

Comparative Example 4 3.35 g of tyrosine methyl ester was added to 135-35 without solvent.
The mixture was heated to 140 ° C. and reacted under a reduced pressure of 70 mmHg. After 7 hours, the product solidified and stirring became impossible. The obtained 3.0 g of crystals were washed 3 times with 33 ml of 0.3N hydrochloric acid. The crystals were dissolved in 85 ml of 28% aqueous ammonia, heated to remove the ammonia, and the resulting precipitate was collected by filtration, washed with water and dried. When the obtained crystals were analyzed by HPLC, the purity was 90.8% and the yield was 44.4%.

[0017]

INDUSTRIAL APPLICABILITY According to the present invention, tyrosine alkyl ester is heated in an organic solvent to obtain a high reaction rate of Tyr-DK.
Pyr is obtained, and Tyr-DKP can be easily isolated by crystallization.

Front page continuation (72) Inventor Akihiro Yamaguchi 1190 Kasama-cho, Sakae-ku, Yokohama-shi, Kanagawa Mitsui Toatsu Chemical Co., Ltd.

Claims (7)

[Claims] 1. A tyrosine alkyl ester is reacted in an aprotic polar organic solvent,
3,6-bis [(4-hydroxyphenyl) methyl]-
A method for producing 2,5-diketopiperazine. 2. The aprotic polar organic solvent used is
The production method according to claim 1, which is N-methylpyrrolidone or N, N'-dimethylimidazolidinone. 3. The tyrosine alkyl ester has 1 to 1 carbon atoms.
4. The method according to claim 1, which is an alkyl ester of No. 4. 4. The method according to claim 3, wherein the tyrosine alkyl ester is tyrosine methyl ester. 5. A solution of 3,6-bis [(4-hydroxyphenyl) methyl] -2,5-diketopiperazine containing at least tyrosine or a tyrosine derivative as a contaminant in an aprotic organic solvent and used as a solvent. , 6-using an organic solvent having a dipole moment of 1.5 to 2.7D
Bis [(4-hydroxyphenyl) methyl] -2,5-
3,6- characterized by crystallization of diketopiperazine
Bis [(4-hydroxyphenyl) methyl] -2,5-
Purification method of diketopiperazine. 6. The concentration of 3,6-bis [(4-hydroxyphenyl) methyl] -2,5-diketopiperazine is 10.
7. The purification method according to claim 6, which is ˜30 wt%. 7. A 3,6-bis [(4-hydroxyphenyl) methyl] -2,5-diketopiperazine containing tyrosine or a tyrosine derivative as at least a contaminant is obtained by the production method according to claim 1. The purification method according to claim 5, which has been obtained.