JPS62192355A - Stabilization of aziridine-2-carboxylic acid salt - Google Patents

Abstract

PURPOSE:To stabilize an aziridine-2-carboxylic acid salt having a specific range of alkali(ne earth) metal hydroxide content, by adding a stabilizing agent consisting of a base to the above carboxylic acid salt, thereby exposing the acid to an atmosphere having stronger basicity than the basicity of the carboxylic acid. CONSTITUTION:The known aziridine-2-carboxylic acid salt of formula [R<1>-R<4> are H or 1-10C hydrocarbon residue; M is cation selected from (substituted) ammonium ion and metallic ion; n is valence of cation]having an alkali(ne earth) metal hydroxide content of <=0.1wt% and exhibiting physiological activity such as antitumor activity can be stabilized by the addition of a stabilizing agent consisting of a base. The stabilizing agent is e.g. metal hydroxide, carbonate, phosphate, borate or acetate, NH3, organic amine, etc. EFFECT:The deterioration of a solution or solid containing the compound during the storage or transportation can be suppressed even at high temperature or at large quantities or over a long period. The process has high industrial value owing to the increased stability of the compound.

Description

DETAILED DESCRIPTION OF THE INVENTION [Background of the Invention] The present invention relates to a method for stabilizing aziridine-2-carboxylic acid salts.

Aziridine-2-carboxylate itself and its derivatives are compounds that have antitumor and other physiological activities, and
It is a compound useful as a raw material for reagents, agricultural chemicals, intermediates such as amino acids, and functional resins.

°C: Tozu aziridine-2-carboxylate is generally produced using an alkali metal or alkaline earth metal hydroxide as one of the raw materials, but if the produced aziridine-2-carboxylate is used in excess. When these hydroxides are separated and removed,
This is a surprisingly unstable compound, and the problem is that it undergoes deterioration and a significant drop in purity when subjected to reaction operations, storage, or transportation, especially in acidic, neutral, or heated conditions. It turned out that there was a point.

In particular, deterioration due to cleavage of the aziridine ring may proceed in a chain manner, which not only causes a decrease in purity but also may be dangerous in some cases.

[Unexamined] Generally, in the case of aziridine (ethyleneimine), it is known that adding an alkali such as caustic soda increases the stability against polymerization.
There are no reports regarding the stabilization of 2-carboxylate salts.

[Summary of the invention]

Therefore, the present inventors developed aziridine-2- which does not substantially contain alkali metal or alkaline earth metal hydroxide.
As a result of various studies on ways to suppress the deterioration of carboxylic acid salts and increase their stability, we found that by bringing aziridine-2-carboxylic acid salts into a more basic atmosphere than the basicity, deterioration can be suppressed even at high temperatures. The present inventors have discovered that the stability can be significantly increased, and have completed the present invention.

Therefore, the method for stabilizing aziridine-2-carboxylate according to the present invention is to stabilize aziridine-2-carboxylate with a content of alkali metal or alkaline earth metal hydroxide of 0.1% or less.
- A stabilizer consisting of a base is added to the carboxylic acid salt to bring the aziridine-2-carboxylic acid salt into a more basic atmosphere than its basicity.

Effects The method of the present invention is effective against allidine-2, which exists in a solution or solid state, during reaction steps that require heating such as concentration and purification of liquids containing allidine-2-carboxylate, and during long-term storage and transportation. - It is extremely effective in preventing deterioration of carboxylic acid salts and has extremely great industrial value.

In general, it is known that aziridine ring compounds cause isomerization or ring-opening reactions with ammonia and organic amines (Japan Chemical Industry Association Monthly Report May 1984 issue p.
, 15), it must be said that the stabilizing effect of the present invention is truly surprising.

[Detailed description of the invention]

Silidine-2-carboxylic acid salt The aziridine-2-carboxylic acid salt to be stabilized in the present invention is a known compound and is represented by its general formula.

Here, R1, R2, R3, and R4 each independently represent a hydrogen atom or a hydrocarbon residue having 1 to 10 carbon atoms, and M
represents a cation selected from substituted or unsubstituted ammonium ions and metal ions, and n is the valence of the cation.

R1, R2, R3 and R4 are each preferably a hydrogen atom, or a hydrocarbon residue having 1 to 7 carbon atoms (for example, a methyl group, an ethyl group, a propyl group, a butyl group, an amyl group, a hexyl group, a cyclohexyl group, phenyl group, benzyl group, etc.). Particularly preferably, R1-R4 are all hydrogen atoms, or R1 is a methyl group and R2-R4 are hydrogen atoms. Especially preferably,
R1-R4 are all hydrogen atoms.

Preferred examples of M include alkali metal ions such as lithium, sodium, and potassium, and alkaline earth metal ions such as beryllium, magnesium, calcium, and strontium. Particularly preferred are lithium, sodium, potassium and calcium ions.

This compound may be obtained by any method of preparation, but one such method is to prepare an aziridine-2-carboxylic acid ester or an aziridine-2-carboxylic acid amide with an alkali metal or alkaline earth metal. This method involves reaction of metal with hydroxide.

In the present invention, the aziridine-2-carboxylic acid salt, which is a reaction product obtained by such a method, is stabilized during a reaction step that involves heating such as concentration, fi'lJ, or Does it contain alkali metal or alkaline earth metal hydroxides in solution or solid state, during long-term storage or transportation, etc.? is 0.1
It has a weight h'i% or less (including O). Here, the alkali metal or alkaline earth metal hydroxide is usually derived from the alkali metal or alkaline earth metal hydroxide used in the above typical manufacturing method, and its residual Even if the amount is 0.1% by weight or less or exceeds 0.1% by weight, it also includes those that have been subjected to processing such as refining and have been reduced to 0.1% by weight or less. It also includes cases where even if other basic substances are contained, they hardly contribute to the stabilization of aziridine-2-carboxylic hydrochloric acid.

That is, for example, aziridine-2-carboxylate containing a small amount of basic by-products (such as oligomers of aziridine-2-carboxylic acid) during the production of aziridine-2-carboxylic acid salt.
-carboxylic acid salts fall into the category of aziridine-2-carboxylic acid salts to be stabilized which are the object of the present invention.

Stabilizer Compound In the present invention, a base is used as a stabilizer. Specifically, selected from the group consisting of (a) alkali metal and alkaline earth metal hydroxides, carbon MfA, phosphates, borates, and acetates, (b) ammonia, and (c) organic amines. Retc 1 type or these 2
It is a combination of more than just species.

Hydroxides of alkali metals and alkaline earth metals include lithium hydroxide, mono-lithium hydroxide, potassium hydroxide, rubidium hydroxide, cesium hydroxide, beryllium hydroxide, magnesium hydroxide, calcium hydroxide, and water. Carbonates such as strontium oxide, barium hydroxide, etc.
Lithium carbonate, sodium carbonate, potassium carbonate, sodium potassium carbonate, rubidium carbonate, cesium carbonate, magnesium carbonate, calcium carbonate, magnesium calcium carbonate, strontium carbonate, barium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, etc., phosphoric acid As salts, lithium phosphate, lithium dihydrogen phosphate, sodium phosphate, sodium hydrogen phosphate,
Sodium dihydrogen phosphate, potassium phosphate, potassium hydrogen phosphate, potassium dihydrogen phosphate, magnesium phosphate, magnesium hydrogen phosphate, calcium phosphate, calcium hydrogen phosphate, calcium dihydrogen phosphate, strontium phosphate, Strontium hydrogen phosphate, barium phosphate, barium hydrogen phosphate, barium dihydrogen phosphate, etc.; borates include lithium borate, sodium borate, potassium borate, magnesium borate, calcium borate, borate; Examples of acetates such as barium acetate include lithium acetate, sodium acetate, potassium acetate, rubidium acetate, cesium acetate, magnesium acetate, calcium acetate, strontium acetate, barium acetate, and the like. In addition, organic amines include methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, propylamine, dipropylamine, tripropylamine, isopropylamine, diisopropylamine, triisopropylamine, butylamine, dibutylamine, and tributylamine. , isobutylamine, shibdelamine, tripropylamine, 2-ethylhexylamine, di(2-ethylhexyl)amine, tri(2-ethylhexyl)amine, ocdylamine, dioctylamine, triethylamine, benzylamine, dibenzylamine, N, N-dimethylbenzylamine, piperidine, N-dimethylbiperidine, N
-Ethylpiperidine, N-propylpiperidine, hexamethyleneimine, N-medylhexylmebuleneimine, N
-hexylhexamethyleneimine, pipecoline, N-methylpipecoline, N-ethylpipecoline, pyrrolidine,
N-methylpyrrolidine, N-ethylpyrrolidine, N,N
, N', N'-tetramethylethylenediamine,
Examples include N, N, N', N'-tetramethylhexamethylene diamine, pyridine, picoline, lutidine, collidine monoethanolamine, jetanolamine, triethanolamine, and the like.

Preferred among these are alkali metal and alkaline earth metal hydroxides, ammonia, and organic amines, and more preferred are ammonia, trimedelamine, triethylamine, tripropylamine, triisopropylamine, and tributylamine. , trioctylamine, tri(2-ethylhexyl)amine, trioctylamine, N,N-dimethylbenzylamine, N-methylpiperidine, N-propylpiperidine, N-methylhexamethyleneimine, N-ethylhexamethyleneimine,
N-methylpipecoline, N-ethylpipecoline, N-methylpyrrolidine, N-ethylpiperine, N, N, N'
, N'-tetramethylethylenediamine, N, N,
These are tertiary amines such as N', N'-tetramethylhexamethylene diamine, pyridine, picoline, lutidine, collidine, and triethanolamine.

The compounds exemplified above as stabilizers are readily available and are shown as practical representative examples, but the present invention is not necessarily limited to these.

The amount of these stabilizers used is at least 0.0001 times the amount of aziridine-2-carboxylic acid salt, and the greater the amount, the greater the stabilizing effect. However, as a matter of course, the effect of the stabilizer has its own limits, and even if it is used in too large a quantity, an effect proportional to the quantity cannot necessarily be obtained. In addition, in some cases, the presence of a stabilizer may have an adverse effect, so in reality, it is recommended to use the minimum amount necessary, taking into account the usage situation and stabilizing effect of aziridine-2-carboxylate. preferable.

Therefore, in practice, the stabilizer is aziridine-2-
The range is 0.0001 to 100 times the weight of the carboxylic acid salt, or 0.001 to 10 times, more preferably 0.01 to 1 times by weight. used in

As a method for adding the stabilizer, aziridine-2-carboxylate is present in a solution state in water, alcohols such as methanol and ethanol, or other solvents that can dissolve aziridine-2-carboxylate. In some cases, a stabilizer may be added thereto so that the stabilizer compound is present in solution or suspension. On the other hand, in the case of aziridine-2-carboxylate that exists in a solid state,
A solution of the stabilizer compound may be added, or gaseous ammonia or an organic amine may be introduced into the container of the aziridine-2-carboxylic acid salt. On the other hand, in the case of the aziridine-2-carboxylate salt existing in the solid state, a solution containing a stabilizer compound may be added, or gaseous ammonia or organic Just introduce an amine.

There is no particular restriction on the applicable temperature range of the stabilizer used in the present invention. Since aziridine-2-carboxylate undergoes deterioration even below room temperature, adding a stabilizer is effective.
Furthermore, at high temperatures of 50° C. or higher, the aziridine-2-carboxylic acid salt undergoes significant deterioration, so the effect of adding the stabilizer becomes even greater.

Experimental Example ■ Snoring Calcium aziridine-2-carboxylate 3.0g 10
Pour into a 0 ml Erlenmeyer flask, replace the inside of the container with ammonia gas, seal it tightly and let it stand at 30°C. After 100 days, open the cap, dissolve calcium aziridine-2-carboxylate in water, and perform liquid chromatography. When analyzed,
The survival rate was 100.0%.

Comparative Example 1 Calcium aziridine-2-carboxylate 3.03 to 10
The mixture was placed in an On+l Erlenmeyer flask, sealed tightly and allowed to stand at 30°C. After 100 FJ, the bottle was opened, and calcium aziridine-2-carboxylate was dissolved in water and analyzed by liquid chromatography, and the residual rate was 88.7%.

Omisen Niasiridine - 2-calcium carboxylate as aziridine -
Example 1 was repeated, substituting 1-lium 2-carboxylate and trimethylamine gas for ammonia gas.

The residual rate of sodium aziridine-2-carboxylate is 10
It was 0%.

Lithium aziridine-2-carboxylate 3 was added to a solution of 011 g of triethylamine dissolved in 501 dehydrated ether.
．． Added 0g. Ether was distilled off from this slurry at room temperature under reduced pressure to form a solid. This solid was placed in a 1001 flask, the flask was tightly stoppered, and the flask was left standing at 30°C. The residual rate of aziridine-2-carboxylic acid lithium after 10 days was 98.
It was 1%.

Example 3 was repeated without using triethylamine. The residual rate of aziridine-2-carboxylic acid lithium is 88
．． It was 7%.

Sodium hydroxide o, ig in dehydrated methanol 501
3.0 g of calcium 3-methylaziridine-2-carboxylate was added to the solution.

Methanol was distilled off from this solution at room temperature under reduced pressure to form a solid. Put this solid into a 100a+l flask,
The container was sealed tightly and allowed to stand at 30°C. The residual rate of calcium 3-methylaziridine-2-carboxylate after 100 days is 95
．． It was 9%.

Comparative Example 3 Example 4 was repeated without using mono-lithium hydroxide. The residual rate of 3-methylaziridine-2-carboxylic acid cardim was 87.3%.

1 straight ■ 1 1.09 of calcium aziridine-2-carboxylate to 3 3 of water
09, 25% aqueous ammonia-15 = 0.51 was added, the mixture was placed in a 1001 Erlenmeyer flask, the flask was tightly stoppered, and the mixture was allowed to stand at 30°C. After 90 days, the bottle was opened and analyzed by liquid chromatography, and it was found that aziridine-2-
The residual rate of calcium carboxylate was 100.0%.

Comparative Example 4 Calcium aziridine-2-carboxylate 1.09% water
Dissolve 0g, put it in a 100ml Erlenmeyer flask, and seal it tightly.
It was left standing at 30°C. After 90 days, the bottle was opened and analyzed by liquid chromatography, and it was found that aziridine-2-
The residual rate of calcium carboxylate was 85.0%.

Examples 6 to 9 and ratio 5 Example 5 by changing the type of stabilizer, hanging and storage temperature
repeated. The results are not shown in Table 1.

In place of calcium aziridine-2-carboxylate, 3
Example 7 was repeated using sodium -methylaziridine-2-carboxylate. 3-methylaziridine-2-
The residual rate of sodium carboxylate was 99.9%.

Comparative Example 6 Example 10 was repeated without using sodium hydroxide as a stabilizer. The residual rate of sodium 3-methylaziridine-2-carboxylate was 82.6%.

Claims (1)

[Claims] 1. A stabilizer consisting of a base is added to aziridine-2-carboxylic acid salt having an alkali metal or alkaline earth metal hydroxide content of 0.1% by weight or less to produce aziridine. −
1. A method for stabilizing aziridine-2-carboxylate, which comprises bringing the 2-carboxylate into an atmosphere that is stronger than its basicity. 2. The stabilizer is a group consisting of (a) hydroxides, carbonates, phosphates, borates, and acetates of alkali metals and alkaline earth metals, (b) ammonia, and (c) organic amines. The method according to claim 1, wherein the method is at least one selected from the following. 3. The method according to claim 1, wherein the stabilizer is at least one selected from ammonia and organic amines. 4. The method according to claim 3, wherein the stabilizer is a tertiary amine. 5. The method according to claim 2, wherein the stabilizer is one selected from hydroxides of alkali metals and alkaline earth metals.