JPS6039357B2 - 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-carboso acid salts.

More specifically, B-halogenoalanine, its ester, or mineral acid salt thereof can be treated with alkali IJ metal or alkali metal hydroxide or aqueous ammonia in water or a water-containing organic solvent in a high yield. The present invention relates to a method for producing aziridine-2-carboxylic acid salt.

Aziridine-2-carboxylate is a very useful compound as an intermediate for Q-amino acids or agricultural pharmaceuticals, etc.
For example, 15% aziridine-2-carboxylic acid lithium salt
Treatment in sulfuric acid yields serine, a Q-amino acid. Conventionally, as a method for producing aziridine-2-carboxylic acid, for aziridine-2-carboxylic acid sodium salt, 1) Q-chloro-8-alanine hydrochloride is used as a raw material, and this compound is dissolved in water with an aqueous sodium hydroxide solution. After neutralization, a 1N aqueous sodium hydroxide solution is added dropwise under heating under reflux to maintain the pH of the aqueous solution at 7 to 7.5.
er, 93, 1640 (1960)), 2) Isobu Q,8-dibromopropionate.

A method of hydrolyzing aziridine-2-carboxylic acid isopropylester obtained by the reaction of pyruester and liquid ammonia with sodium ethoxide in a mixed solvent of ether-ethanol-water (E. Kyburz, H.
elv. Chim. Acta, 49, 368 (1966
))It has been known. In addition, as a method for producing lithium salt of aziridine-2-carboxylic acid, 3) the hydrochloride of Q-chloro-3-alanine ethyl ester is treated with triethylamine in ethanol to produce ethyl aziridine-2-carboxylic acid ester. A method of producing and hydrolyzing the compound with lithium hydroxide in a mixed solvent of ethanol and water (K.D.
,G plate derman,Chem,morr,,93,16
39 (1960)) is known. However, in these known methods, method 1) limits the initial reaction concentration of Q-chloro-8-alanine hydrochloride as a raw material to a low concentration of about 1% by weight, and requires heating;
In addition, it is necessary to control spots in the reaction solution, and methods 2) and 3) require complicated synthesis of each aziridine-2-carboxylic acid ester, and have low yields. Alternatively, there is a problem in terms of yield, and it cannot be said that this method is necessarily satisfactory from an industrial perspective. The present inventors have completed the present invention as a result of intensive studies on an industrially advantageous manufacturing method for aziridine-2-carboxylate.

That is, the method of the present invention uses 8-halogenoalanine, its ester, or a key salt thereof as a raw material, and treats it with an alkali metal or alkali metal hydroxide, or ammonia in water or a water-containing organic solvent. This is a method for producing an alkali metal or alkali metal salt, or an ammonium salt of aziridine-2-carboxylic acid under very mild conditions and in high yield.

The method of producing aziridine-2-carboxylate from 8-halogenoalanine, its ester, or a mineral acid salt thereof according to the present invention is a novel production method that has not been previously known. Compared to the above-mentioned known methods, the method of the present invention has the following features:
It has various advantages such as easy production of raw materials, simple reaction operation, ability to produce aziridine-2-carponate in high concentration, and high yield, and is suitable for industrial use. It is a highly valuable manufacturing method. Examples of 6-halogenoalanine or its mineral acid salt used in the method of the present invention include 8-chloroalanine, 3-bromoalanine, 8-chloroalanine hydrochloride and sulfate, and 3-fromalanine hydrochloride and sulfate. can be mentioned.

Examples of B-halogenoalanine esters or mineral acid salts thereof include B-chloroalanine esters, B-fromalanine esters, 3-chloroalanine ester hydrochlorides, and 8-fromalanine ester hydrochlorides. The esters used are alkyl esters having 1 to 4 carbon atoms, and methyl ester, ethyl ester, isopropyl ester, tertiary butyl ester, etc. are frequently used. In the method of the invention,
8-halogenoalanine or its key salt used as a raw material, for example, 8-chloroalanine hydrochloride, is prepared by treating chloroacetaldehyde with sodium bisulfite, reacting it with ammonia and then sodium cyanide to form Q-amino-3. -chloropropionitrile, and further hydrolyzing this in hydrochloric acid (Kokai No. 164,661/1983).

Further, the ester of 8-halogenoalanine or its mineral acid salt can be obtained by esterifying 8-halogenoalanine by a conventional method. In the method of the present invention, an alkali metal or alkali metal hydroxide or aqueous ammonia is used in the ring-closing reaction of 8-halogenoalanine, the ring-closing reaction of ester of 3-halogenoalanine, and the hydrolysis reaction.

Specific examples of hydroxides of alkali metals or alkali metals include lithium hydroxide, sodium hydroxide, potassium hydroxide, beryllium hydroxide, magnesium hydroxide, calcium hydroxide, and barium hydroxide. . When using free 8-halogenoalanine or 3-halogenoalanine ester as a raw material, the alkali should be used in an amount of 2 equivalents or more based on the raw material. When an acid salt is used as a raw material, it is used in an amount of 3 equivalents or more based on the raw material. The upper limit of the amount 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 aqueous solution or in a solvent using water as well as organic solvents that are miscible with water. Organic solvents miscible with water include methanol, ethanol, n-
Alcohols such as pro/gnol, isopro/gnol, rt-butanol, cellosolve, methyl cellosolp, acetone, dioxane, tetrahydrofuran, N,N
-dimethylformamide, N,N-diethylformamide or 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 water or water-containing organic solvent used is 3 to 20 needles per 8-halogenoalanine or its ester, or its mineral acid salt, as the raw material.
Preferably the volume is 5 to 10 degrees. To carry out the method of the present invention, a method for preparing raw materials, an alkali and a reaction solvent,
Although there is no particular limitation on the order etc., usually {li8-halogenoalanine or its ester or their stannate is dissolved in water and/or a water-miscible organic solvent to an arbitrary concentration, and in this solution Ammonia water while worshiping the light,
or by adding an alkali metal or alkali metal hydroxide (as an aqueous solution or as a solid);
2} 8-halogenoalanine, its ester, or mineral acid salt thereof may be added to aqueous ammonia, or an aqueous solution or suspension of an alkali metal or alkali metal hydroxide.

The reaction temperature is in the range of 0 to 100°C, preferably 20 to 80°C, and 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 varies depending on various reaction conditions, but 0.5
~5 hours, usually completed in 2.0-3 hours. The end point of the reaction can be quickly and easily determined by thin layer chromatography. The aziridine-2-carboxylic acid produced in the method of the present invention is an alkali metal or alkali metal salt or ammonium salt corresponding to the alkali metal or alkali metal hydroxide or ammonia water used in the reaction. 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 hydrochloric acid salt of Q-chloro-8-aminopropionate ethyl ester in 100M dehydrated ethanol and adding 20 minutes of triethanolamine, the mixture was reacted for 5 hours at 60 to 70°C under a hawk frame. The precipitated trietanoamine hydrochloride is separated from the furnace and washed with a small amount of ethanol.

Combine the furnace washing liquid, gradually add 55 parts of a 1N lithium hydroxide aqueous solution while cooling, and leave in a cool, dark place for 2 hours. Thereafter, the reaction solution is concentrated to dryness under reduced pressure, 30 ml of benzene is added to the resulting residue (syrup-like substance), and water is completely removed by azeotropic distillation. Next, 50' of hot ethanol is added and upon cooling, a precipitate separates out. After adding 100% of ether to sufficiently precipitate the crystals,
The deposited precipitate was separated in a furnace and washed with ether to obtain 1.0 ml of aziridine-2-carboxylic acid lithium salt.

Melting point 260-268°C (decomposition) Elemental analysis value (%) Actual value C: 37.86, H: 4.23, N: 14.71, Li: 7.40 Calculated value C as C8 ratio N02Li: 38. 74, H: 4.33, N: 15.06, Li: 7.46 The purity of the aziridine-2-carboxylic acid lithium salt obtained here is determined by proton NM using dioxane as an internal standard.
It was 97% based on the R spectrum (measurement solvent: ○20, measurement temperature: room temperature).

b High performance liquid chromatography analysis conditions Power ram: Sh
ode×○Hpak B-804 (manufactured by Showa Denko ■) Detector: Differential refractometer RI-2 type (manufactured by Nippon Analytical Industry ■) Moving bar: lxlo-3 mol/day 3P04 aqueous solution flow
Amount: 1.3'/min Measuring temperature: Room temperature The retention time of aziridine-2-carboxylic acid under these conditions is 16.5 to 16.8 minutes.

Example 1 A solution prepared by dissolving 20 parts of sodium hydroxide in 50 parts of water was gradually added dropwise to a solution prepared by dissolving 24 parts of 8-chloroalanine hydrochloride in 70 parts of water.

Thereafter, the mixture was allowed to react at room temperature for 2 hours. As a result of analyzing this reaction solution by high performance liquid chromatography using aziridine-2-carboxylic acid lithium salt as a standard, the production rate of aziridine-2-carboxylic acid sodium salt was 92.6% (8-chloroalanine). The resulting reaction solution was exposed to proton N.
When subjected to MR spectrum, 6-value 1.7 substance pm (quartet;
A signal of methylene proton of aziridine-2-carboxylic acid was detected in ), and a signal of methine proton was detected at 6 value of 2.35 ppm (quartet; IH), and lithium aziridine-2-carboxylate synthesized as a standard product It showed exactly the same signal pattern as the salt. Example 23-0 loalanine hydrochloride 24-g was dissolved in 100 g of water and condensed.
A solution prepared by dissolving 27 parts of potassium hydroxide in 50 parts of water was gradually added dropwise.

Then, the temperature of the reaction solution was raised to 60:00, and the reaction was carried out for 4 hours at 60:00 to 65:00. The reaction solution was analyzed in the same manner as in Example 1, and the production rate of aziridine-2-carboxylic acid potassium salt was 88.3%.

Example 3 The reaction was carried out in the same manner as in Example 1 except that 26.1 days of 3-chloroalanine methyl ester hydrochloride was used instead of 8-chloroalanine hydrochloride.

The production rate of aziridine-2-carboxylic acid sodium salt is
It was 91.3%. Example 4 The reaction was carried out in the same machine as in Example 2, except that 39% of calcium hydroxide was used instead of potassium hydroxide in Example 2, and excess calcium hydroxide was removed from the furnace after the reaction.

The production rate of aziridine-2-carboxylic acid calcium salt is 8
It was 4.7%. Example 24 parts of 8-chloroalanine hydrochloride were dissolved in a mixed solvent of 90 parts of water and 50 parts of methanol, and an aqueous solution of 20 parts of sodium hydroxide dissolved in 80 parts of water was added dropwise to the solution.

Claims (1)

[Claims] 1. Aziridine-2-, which is characterized by treating β-halogenoalanine or its ester, or a mineral acid salt thereof with an alkali metal or alkaline earth metal hydroxide, or aqueous ammonia in water or a water-containing organic solvent.
Method for producing carboxylic acid salts.