JPS6038381B2 - Method for producing aziridine-2-carboxylate - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing aziridine-2-carboxylic acid salts.

More specifically, Q-halogeno-8-aminopropionitrile or its mineral acid salt in water or a water-containing organic solvent,
The present invention relates to a method for producing aziridiso-2-carboxylate in high yield by treatment with an alkali metal or alkali metal hydroxide.

The reaction for producing the aziridiso-2-carboxylic acid of the present invention is shown as formula '1). or (wherein, X represents a chlorine or bromine atom, M represents an alkali IJ metal or an alkali IJ± group metal, and m and n represent an integer of 1 or 2.

) Aziridine-2-carboxylic acid salt is a compound useful as an intermediate for Q-amino acids or agricultural pharmaceuticals, etc. For example, when aziridine-2-carboxylic acid lithium salt is treated in 15% sulfuric acid, Q-amino acid One type of serine is obtained.

Conventionally, the method for producing aziridiso-2-carboxylic acid is as follows:
About aziridine-2-carbosic acid sodium salt,'
1} Using Q-chloro-P-alanine hydrochloride as a raw material, neutralize the compound in water with an aqueous sodium hydroxide solution, and then heat to reflux to maintain the pH of the aqueous solution at 1N to 7-7.5. A method for producing by dropping an aqueous solution of sodium hydroxide (K.D. Gundermann, Chem. Be
r. , 93, 1640 (1960)), [2} Q, 8
Hydrolysis of isopropyl aziridine-2-carboxylate obtained by the reaction of isopropyl dipropionate and liquid ammonia with sodium ethoxide in a mixed solvent of ether, ethanol, and water. How to (E.KyburZ, Helv.Chim.A
cta, 49, 3 Iso (1966)) is known.

In addition, as a method for producing lithium salt of aziridine-2-carboxylic acid, '31 aziridine-2-carboxylic acid was prepared by treating hydrochloride of -chloro-3-alanine ethyl ester with triethanolamine in ethanol. A method of producing ethyl ester and hydrolyzing the compound with lithium hydroxide in a mixed solvent of ethanol and water (K.D.C skin derma
nn, Chem, Ber, 93, 1639 (1960
))It has been known. However, in these known methods, method 1 requires that the reaction system concentration of the raw material Q-chloroB-alanine hydrochloric acid be carried out at a low concentration of about 1% by weight, and at the same time, attention must be paid to the pH of the reaction solution. In addition, methods '2) and {3' have complicated synthesis of aziridine-2-carboxylic acid ester and have low yields. Both methods have problems in terms of raw materials or yield. However, this method is not necessarily satisfactory from an industrial perspective.
The present inventors have conducted extensive studies on an industrially advantageous production method for aziridine-2-carboxylate, and have discovered that Q-halogeno-3-
By treating aminopropionitrile or its key salt in water or a water-containing organic solvent with an alkali metal or alkaline earth metal hydroxide, heating as necessary, the nitrile group is hydrolyzed. It was found that an alkali metal or alkali metal salt of aziridine-2-carboxylic acid was generated almost selectively through an intramolecular dehydrochlorination reaction (ring-closing reaction) with almost no by-products generated. , and arrived at the present invention.

The method of producing aziridine-2-carboxylic acid in one step using Q-halogeno-8-aminopropionitrile or its key salt as a raw material, as in the method of the present invention, is a novel production method that has not been previously known. It is the law. Compared to the above-mentioned known methods, the method of the present invention has the following advantages: the production of raw materials is easy, the reaction operation is simple, aziridine-2-carboxylic acid can be produced in high concentration, and the yield is high. It is an industrially extremely advantageous manufacturing method with various advantages. Q-halogeno-3-aminopropionitrile or its mineral acid salt used in the method of the present invention is Q-chloro-8-aminopropionitrile, Q-prom-8-aminopropionitrile, Q-chloro-0-aminopropionitrile. These include nitrile hydrochloride and sulfate, and Q-from-8-aminopropionitrile hydrochloride and sulfate.

These Q-halogeno-8-aminopropionitriles or their nutrient salts are obtained by reacting Q,8-dihalogenopropionitrile or Q-halogenoacrylonitrile with ammonia in water or an organic solvent.

If necessary, extract the reaction product from the reaction solution with an organic solvent immiscible with water, and distill it under reduced pressure to obtain free Q-halogeno-8.
-Aminopropionitrile is obtained, and when the reaction solution is treated with hydrogen chloride or sulfuric acid, Q-halogeno-8-aminopropionitrile hydrochloride or sulfate is obtained.
For example, Q-chloroacrylonitrile is added dropwise to a solution of ammonia gas dissolved in isopropanol at around 0°C, reacted at the same temperature for 2 to 4 hours, and then a solution of hydrogen chloride in isopropanol is added. By entering Q-
Chloro-3-aminopropionitrile hydrochloride can be produced in a single unit with a yield of 80% or more. The alkali metal or alkali metal hydroxide used in the method of the present invention is a hydroxide of an alkali metal such as lithium, sodium, potassium, or rubidium, or an alkali metal hydroxide such as beryllium, magnesium, calcium, strontium, or barium. hydroxides of similar metals, specifically lithium hydroxide, sodium hydroxide, potassium hydroxide, beryllium hydroxide,
Magnesium hydroxide, calcium hydroxide, barium hydroxide, etc., and usually sodium hydroxide, potassium hydroxide, calcium hydroxide, etc. are frequently used.

In the method of the present invention, the amount of alkali metal or alkali metal hydroxide used is free Q-Ha.

When geno-8-aminopropionitrile is used as a raw material, 2 equivalents or more based on the raw material, and Q-halogeno-8-
When using aminopropionitrile mineral salt as raw material,
It is 3 equivalents or more based on the raw material. The upper limit of the amount to be used is not particularly limited, but it is not necessary to use a significantly excessive amount, and it is usually sufficient to use up to 5 equivalents. The method of the invention is carried out in water or a water-containing organic solvent.

That is, the reaction can be carried out in an aqueous solution or in a solvent in combination with water and an organic solvent miscible with water. Organic solvents miscible with water include methanol, ethanol, n-
Alcohols such as pro/benol, isopro/gunol, rt-butanol, cellosolve, methyl cellosolve, acetone, dioxane, tetrahydrofuran, N,
Examples include N-dimethylformamide, N,N-diethylformamide, and dimethylsulfoxide.

When water and an organic solvent are used together in the reaction, the ratio of water to organic solvent can be arbitrarily selected. The amount of these solvents to be used is 3 to 200 times, preferably 5 to 1 times the amount of Q-halogeno-3-aminopropionitrile or its stannate as the raw material.
The volume is zero. In carrying out the method of the invention, raw materials,
There are no particular limitations on the method or order of adding the alkali and reaction solvent, but usually '1) Q-halogeno-6-aminopropionitrile or its key salt is added to water and/or a water-miscible organic compound at an arbitrary concentration. Either the alkali metal or alkali metal hydroxide is dissolved in a solvent and the alkali metal or alkali metal hydroxide is added (as an aqueous solution or as a solid) to this solution; Q-halogeno B-aminopropionitrile or its key salt may be added to the aqueous solution or suspension.

The reaction temperature is 0 to 100 pm, preferably 20 to 80 pm.
The reaction is usually carried out under normal pressure, but the reaction may be carried out under reduced pressure or increased pressure if necessary. The reaction time is
Although it varies depending on various reaction conditions, the reaction is completed in 0.5 to 5 hours, usually 2.0 to 3 feeding hours. The end point of the reaction can be quickly and easily determined by thin layer chromatography. Aziridine-2 produced in the method of the present invention
- The carboxylic acid is obtained in the form of an alkali metal or alkali metal salt depending on the alkali used in the reaction, and if necessary, the organic solvent is removed under reduced pressure to obtain an aqueous solution.

The method of the present invention will be explained below using Examples.

The synthesis method of the standard aziridine-2-carboxylic acid lithium salt used in the examples and the analytical conditions of high performance liquid chromatography are as follows.

a Production method 1 of aziridine-2-carboxylic acid lithium salt
After dissolving the hydrochloride of female Q-chloro P-aminopropionic acid ethyl ester in 100 ml of dehydrated ethanol, and adding 2 ml of triethanolamine, the mixture was reacted for 5 hours at 60 to 70 ml under the net. The precipitated trietanoamine hydrochloride is separated from the furnace and washed with a small amount of ethanol.

Combine the furnace washing liquid, gradually add 1N lithium hydroxide aqueous solution 55' while cooling, and leave in a cold room for 2 hours.
Thereafter, the reaction solution was concentrated to dryness under reduced pressure, and the obtained residue (
Add 30 ml of benzene to the syrup-like substance and completely remove water by co-nutrient distillation. Next, 50 ml of hot ethanol was added, and upon cooling, a precipitate was deposited. 10
After adding ether above 0 to sufficiently precipitate the crystals, the precipitated precipitate was separated in a furnace and washed with ether to obtain 1. Female aziridine-2-carboxylic acid lithium salt was obtained.

Melting point 260-28 0 (decomposition) Elemental analysis value (%) Actual value C: 37.80 H: 4.23 N: 14.71, Li
: Calculated value as 7.40C3 day N02Li C: Spot. 74 H: 4.3 pieces N: 15.00 Li: 7
．． 46 The purity of the aziridine-2-carboxylic acid lithium salt obtained here was 97% based on proton NMR spectrum using dioxane as an internal standard (measurement solvent: D20, measurement temperature: room temperature).

b High performance liquid chromatography analysis conditions Column: Sh
odexOHPakB-804 (manufactured by Showa Denko) Detector: Differential refractometer RI-2 type (manufactured by Nippon Analytical Industry) Mobile phase:
1×10-3 mol/day 3POK solution flow rate: 13 min Measurement temperature: room temperature The retention time of aziridine-2-carboxylic acid under these conditions is 16.5 to 16.8 minutes.

Example 1 Q-chloro3-aminopropinitrile hydrochloride 28.m in water 8 eyes. Add him and melt scales.

Next, an aqueous solution prepared by dissolving 25.6 g of sodium hydroxide in 8 pipes of water was gradually added dropwise to the bottom of the oak casserole, and then reacted at room temperature for 2 hours. As a result of analyzing this reaction solution by high performance liquid chromatography using lithium salt of aziridine-2-carboxylate as a standard, the production rate of sodium aziridine-2-carboxylate was 95.5% (relative to Q-chloro- 8-aminopropionitrile hydrochloride). When the obtained reaction solution was subjected to proton NMR spectrum, the 6-value 1.7 p
m (quartet; 2H) of methylene proton of aziridine-2-carboxylic acid, and 8 value 2.35 ppm (quartet;
A methine proton signal was detected in IH), and all showed the same signal pattern as the aziridine-2-carboxylic acid lithium salt synthesized as a standard product.

Example 2 After adding and dissolving 14.1 g of Q-chloroB-aminopropionitrile hydrochloride in 16 g of water, 22 g of potassium hydroxide was added under water. An aqueous solution of nine female bees dissolved in water is gradually added dropwise.

Then, the temperature of the reaction solution was raised to 60 qo, and 4
Allow time to react. As in Example 1, this reaction solution was analyzed by high performance liquid chromatography, and the results showed that aziridine-2-
The production rate of potassium carboxylate was 92.3%. Example 3 In Example 2, free Q-chloro-8-aminopropionitrile was used instead of Q-chloro-6-aminopropionitrile hydrochloride.10. Example 2 except that a gunwale was used and 13 g of lithium hydroxide was used instead of potassium hydroxide.
By reacting in exactly the same manner as above, the production rate of lithium aziridine-2-carboxylate was 90.8%.

Example 4 Example 2 except that 15.3 g of Q-chloro-8-aminopropionitrile sulfate was used instead of Q-chloro-8-aminopropionitrile hydrochloride in Example 2.
By reacting in exactly the same manner as aziridine-2
-The production rate of lithium carboxylate is Shigeru. It was 2%.

Example 5 Add 14.1 g of Q-chloro8-aminopropionitrile hydrochloride to 16 cups of water, dissolve, and then gradually add one base of calcium hydroxide under the rope.

Then, the temperature of the reaction solution was raised to 60:00, and the temperature was increased to 8:00 from 60 to 65:00.
Allow time to react. After the reaction, excess calcium hydroxide was removed by furnace, and the reaction solution was analyzed using high performance liquid chromatography in the same manner as in Example 1. As a result, Aziridine-2-
The production rate of calcium carboxylate was 92.5%.
Example 6 14.1 g of Q-chloro-8-aminopropionitrile hydrochloride was added and dissolved in 15 g of methanol, and 12 g of sodium hydroxide was added to the solution while stirring. An aqueous solution of 7 parts of water is added dropwise.

Then, the reaction solution was heated to 60° C. and reacted at the same temperature for 1 hour. Thereafter, methanol in the reaction solution was removed under reduced pressure, and analysis was performed using high performance liquid chromatography in the same manner as in Example 1. As a result, the production rate of sodium aziridine-2-carboxylate was 89.2%. . Example 7 The reaction was carried out in exactly the same manner as in Example 6 except that 15 parts of isopropanol was used instead of methanol, and the production rate of sodium aziridine-2-carboxylate was 93.5%.

Claims (1)

[Claims] 1. An aziridine-2-carboxylate salt characterized by treating α-halogeno-β-aminopropionitrile or its mineral acid salt with an alkali metal or alkaline earth metal hydroxide in water or a water-containing organic solvent. manufacturing method.