JPS5849357A - N-carboxyiminomethylation of aminoacids - Google Patents

Abstract

PURPOSE:The reaction of an alkali metal salt of an aminoacid with an alkoxyiminoacetic acid ester is followed by treatment with an acidic aqueous solution to produce the titled compound used as a medicine simply in high yield. CONSTITUTION:The reaction between an alkali metal salt of an aminoacid and an alkoxyiminoacetic acid ester of formulaI(R<1>, R<2> are 1-4C alkyl) is carried out in an aqueous medium and the product is treated with an acidic aqueous solution such as hydrochloric acid to give the objective compound in which the carboxyiminomethyl group is introduced to the amino group in the aminoacid. The reaction temperature is 0-30 deg.C and the time for the treatment is sufficiently 1hr in general. EFFECT:The utilization of the difference in solubility enables the pure isolation of the objective compound.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for N-carboximinomethylation of amino acids. More specifically, the present invention provides an alkali metal salt of an amino acid with the formula R'oc-cooR2! INH...[f] (wherein R1 and R2 each represent an alkyl group having 1 to 4 carbon atoms) is reacted with an alkoxyniminoacetate in water, and then the reaction obtained This method of N-carboximinomethylation of amino acids is characterized by introducing a carboxyiminomethyl group represented by into the amine group of the amino acid by treating the product with an acidic aqueous solution.

According to this invention, the formula [[) which is a physiologically active group
The carboxyiminomethyl group represented by can be easily introduced into the amine group of an amino acid with good yield. By the method of this invention.

Compounds useful as agricultural chemicals, medicines, and even raw materials for these can be obtained.

Specific examples of amino acids include chrysine, phenylglycine, valine, leucine, phenylalanine, aspartic acid, asparagine, glutamic acid, glutamine,
Histidine, tryptophan 1 proline, β-alanine, ε-aminocaproic acid.

Examples include 6-aminopenicillanic acid and 7-aminosephalosboranic acid.

The alkali metal salt of an amino acid is a salt of the amino acid with an alkali metal such as lithium, sodium, or potassium.

Specific examples of the alkoxyiminoacetic acid ester represented by formula [I] include 4-tyl methoxyiminoacetate, ethyl methoxyiminoacetate, methyl ethoxyiminoacetate, ethyl ethoxyiminoacetate, ethyl methoxyiminoacetate, ethyl ethoxyiminoacetate, metal salts of amino acids and alcoquines in the method of the present invention. Although there are no particular restrictions on the reaction format with the iminoacetic ester, a method of adding an amino acid metal salt or water containing the same to water containing the alkokeine iminoacetic ester and reacting is preferred. Water containing an alkali metal salt of an amino acid may be prepared by adding the amino acid to water containing the amount of carbo/acid in the amino acid and the hydroxide of the alkali metal. Since acetic acid ester reacts in equimolar amounts, both are generally used in approximately equimolar amounts.

There is no particular restriction on the amount of water used, but it is preferably 0.s to 5 t per mole of alkoxyiminoacetic ester.

The reaction temperature is preferably in the range of 0 to 40°C from the viewpoint of preventing hydrolysis of the raw material alkoxyniminoacetic ester.

The reaction proceeds rapidly and is usually completed within 1 to 5 hours.

By treating the reaction product obtained after the reaction with an acidic aqueous solution, a product in which the amino group of the desired amino acid is N-carboquiniminomethylated can be obtained.

Examples of acidic aqueous solutions include dilute acidic aqueous solutions of mineral acids such as hydrochloric acid and sulfuric acid, and organic acids such as para-toluenesulfonic acid, but are not limited to these, and may include aqueous solutions containing cation exchange resins. The amount is 0.2 to 5 ml of an aqueous solution containing 1 milligram equivalent of acid per milligram equivalent.

The reaction temperature when treating the reaction product is usually 2 O to 30C.
In addition, the treatment time is usually 1 hour. Through the treatment, a treatment solution containing a product in which the amine 7 group of the amino acid, which is the target product of the present invention, is N-carboquiniminomethylated, is produced. can get.

The treatment solution containing N-L (carboximinomethyl) amino acid contains, in addition to N-(carboximinomethyl) amino acid, an alkali metal used as an alkali metal salt of the amino acid and an acidic water @ solution. Although a salt with the acid used exists, the N-(carboquiniminomethyl)amino acid can be isolated in a pure form by taking advantage of the difference in solubility.

A compound in which the amino group of an amino acid obtained by this invention is N-carboquiniminomethylated, that is, N-(
Specific examples of carboquiniminomethyl) amino acids include:
N-(carboximinomethyl)chrysine, N-(carboximinomethyl)phenylglinone, N-(carboximinomethyl)valine, N-(carboximinomethyl)leucine, N-(carboximinomethyl)phenylalanine, N-(carboximinomethyl)aspartic acid IN-(carboximinomethyl)asparagine, N-(carboximinomethyl)glutamic acid, N
-(carboquiniminomethyl)glutamine, N-(carboquiniminomethyl)histidine, N-(carboquiniminomethyl)tryptophan, N-(carboquiniminomethyl)proline, β-[N-(carboquiniminomethyl) ]Alanine, ε-[N-(carboquiniminomethinolycyaminocaproic acid), 6-(N-(carboximinomethyl)]aminobeny7lanic acid, 7-(N-(carboximinomethyl))aminocephalosporanic acid Examples include.

Examples are shown below.

Example 1 0 cursin in 10me of 1N sodium hydroxide aqueous solution
．． After adding 7!11 and then adding 51ne of water, the resulting solution was added dropwise to water+5me containing 1.452 ethyl ethyl quinoiminoacetate at room temperature, and the mixture was reacted for 6 hours with stirring at room temperature.

After the reaction, 5 ml of 2N hydrochloric acid was added to the 2 reaction product mixture,
The mixture was concentrated under reduced pressure. 1 ome of water was added to the residual crystals and filtered to obtain 1,02 y (yield near 0 y) of N-(carboquiniminomethyl)glinone crystals. This was recrystallized with water to obtain colorless needle crystals with a decomposition point of 181°C. The elemental analysis values are shown below.

CHN Analysis value 33,15 4.1i i8.89 calculated value 5
2,89 4.1419.17 (C4)' (6NZ ”
4) Example 2 1N sodium hydroxide aqueous Q10me paste.

L-valine 1. Add +7y, then 5m/? of water? Add ethyl ethyl iminoacetate +,
After dropping 15 meK of water containing 45@, the mixture was reacted for 3 hours with stirring at room temperature.

After the reaction, 5 ml of 2N hydrochloric acid was added to the resulting reaction product mixture at room temperature and filtered to obtain 1.16 SF (yield: 62 SF) of N-(carbothenediiminomethyl)varisi crystals. This was recrystallized with water to obtain colorless bulk crystals with a decomposition point of 169°C. The elemental analysis values are shown below.

CHN Analysis value 44,786.3814,9.9 Calculated value 46
, 686.4314.88 (as c7HI2N2o4) Solution F was concentrated under reduced pressure, and 5 mJ of water was added to the resulting residue. Example 3 10 ml of 1N aqueous sodium hydroxide solution 1 KL-leucine 1,319 was added, and then 5 me of water was added. The resulting solution was added dropwise to 15 m/' of water containing 1.455' of ethyl ethoxyiminoacetate at room temperature, and the mixture was reacted for 3 hours with stirring at room temperature.

After the reaction, 2N hydrochloric acid (55%) was added to the resulting reaction product mixture at room temperature.
ml was added and filtered to obtain 1°17v (yield: 58%) of + N Ocarboximinomethyl)leucine crystals. This was recrystallized with water to obtain colorless needle crystals with a decomposition point of 167°C. Its elemental analysis value analysis value 47.54.6.
8814.02 Calculated value 47.526°9813.85
(C4H14N+04) 5 ml of water was added to the residue obtained by concentrating the p liquid under reduced pressure.

Example 4 A solution obtained by adding 10 m of a 1N aqueous sodium hydroxide solution to 1,655 F of KL-7 enylalanine and 5 ml of water was added dropwise to 15 m of water containing 1.452 ethyl ethoxyiminoacetate at room temperature. While stirring the mixture at room temperature,
The reaction was allowed to proceed for 3 hours.

After the reaction, 5 m/2N hydrochloric acid was added to the resulting reaction product mixture at room temperature, and the mixture was filtered to obtain 2.09 f (yield: 85 g) of crystals of N-(carboximinomethyl)phenylalanine. This was recrystallized from water to obtain pale yellow crystals (+ hydrate) with a decomposition point of 2 at 160°C. The elemental analysis values are shown below.

CHN Analysis value 5ro, 845.32 '11.29 Calculation value 5
3.875. 411, 42 (as C2□H26N40u) Example 5 A solution obtained by adding 1.65 f of D-phenylalanine and 5 m of water to 1 part of a 1N aqueous sodium hydroxide solution was diluted with 1.452 ml of ethyl ethoxyiminoacetate at room temperature. was added dropwise to 15 ml of water, and the mixture was reacted for 3 hours with stirring at room temperature.

After the reaction, 5+++/2N hydrochloric acid was added to the resulting reaction product mixture at room temperature and filtered to obtain 1.542 crystals of t N (carboximinomethyl)phenylalanine (yield: 61%). Recrystallize this with water to give 9 decomposition points of 15
Colorless crystals (-beon monohydrate) at 7°C were obtained. The elemental analysis values are shown below.

CHN Analysis value 5ro, 465.4311.18 Calculation value 53,
875.34 M, 42 (as C22H26N409) To the residue obtained by concentrating solution F under reduced pressure, 1 ame of water was added, filtered, and crystals of N-(carboquiniminomethyl)phenylalanine o, 5sr (harvested) were added. rate: 22%).

Example 6 20ml of 1N aqueous sodium hydroxide solution, 1.4y'y of KL-glutamic acid and 5ml of water were added to make the resulting solution,
Ethyl ethoxyiminoacetate at room temperature +, 4! After dropping into 10 ml of water containing IFk, while stirring the mixture at room temperature,
The reaction was allowed to proceed for 3 hours.

After the reaction, 10ml of 2N hydrochloric acid was added to the reaction product mixture at room temperature and filtered to obtain crystals of N-(carboximinomethyl)glutamic acid (yield: 40%).
%) was obtained. This was recrystallized from water to obtain colorless needle-like crystals with a 2 decomposition point of 170°C. The elemental analysis values are shown below.

CHN Analysis value 38,504.6112.87 Calculated value 38,
544.6212.84 (as C7H4oN206) 5 ml of water was added to the residue obtained by concentrating the P solution under reduced pressure,
After filtration, further crystals of N-(carboximinomethyl)glutamic acid were obtained.1. o ay (yield: 48%) was obtained.

Example 7 A solution was obtained by adding 1.55 f of 1N sodium hydroxide aqueous solution 1 om JKL-histidine and 5 ml of water.

The mixture was added dropwise to 15 ml of water containing 1.451 i+ of ethoxyiminoacetate at room temperature, and the mixture was allowed to react for two hours while stirring at room temperature.

After the reaction, 5 ml of 2N hydrochloric acid was added to the resulting reaction product mixture at room temperature, and the mixture was concentrated under reduced pressure. 20 ml of water was added to the residue and filtered to obtain crystals of N-(carboximinomethyl)histidine. s 3 y (yield: 63%) was obtained. This was recrystallized from water to obtain slightly purple massive crystals (monohydrate) with a decomposition point of 174°C.

The elemental analysis values are shown below.

CHN Analysis value 9.664.9323.00 Calculated value 39.
35 j9522.94 (Cs Hl 2 N40S
5 m of water was added to the residue obtained by concentrating the P solution under reduced pressure.
1 was added and filtered to further obtain crystals of N-(carboximinomethyl)histidine o, 51y (yield: 21%).

Example 8 A solution obtained by adding 10 ml of 1N aqueous sodium hydroxide solution, 2.04 y of KL-tryptophan, and 5 ml of water was added to 15 ml of water containing Etquin 19F7 at room temperature. After adding VC dropwise, the mixture was allowed to react for 3 hours while stirring at room temperature.

After the reaction, 2N hydrochloric acid 5ME was added to the resulting reaction product mixture at room temperature and filtered to give N-(carboquiniminomethyl)tryptophan crystals 2,58y (yield: 94%).
I got it. This was recrystallized from water to obtain light brown needle-shaped crystals with a two-decomposition point of 181°C. The elemental analysis values are shown below.

C H N analysis value 56
．． 4ro 4, 7ro 15, 15 calculated value 56,73 4,7
6 15.27 (as Cl5H13 N304) Example 9 1N hydroxide) IJum aqueous solution 1orrte b
- A solution obtained by adding proline 1', 151i' and 5 me of water was prepared at room temperature with ethyl ethoxyiminoacetate 1, 4 5
After dropping the mixture into 1.5 rne of water containing f, the mixture was reacted at room temperature for 3 hours with stirring.

After the reaction, 5 ml of 2N hydrochloric acid was added to the resulting reaction product mixture at room temperature, and the mixture was filtered to obtain 1.08y (yield: 58%) of N-(carboximinomethyl)proline crystals. This was recrystallized from water to obtain colorless needle crystals with a decomposition point of 162°C. The elemental analysis values are shown below.

CH,N Analysis value 44.835. s215j 7 calculated value 45.
165.4j 15. o5 (as C7HION204) 5 tnl of water was added to the residue obtained by expanding and contracting the p solution under reduced pressure, and the mixture was filtered to obtain further crystals of N-(carboximinomethyl)prog/a, 32y (yield: 17g6) I got it.

Example 10 β-alani 10. (A solution obtained by adding 39? and 5 m of water.

The mixture was added dropwise to 15 Wll of water containing 1.45 f of ethyl ethoxyiminoacetate at room temperature, and the mixture was reacted for 3 hours with stirring at room temperature.

After the reaction, 2 N hydrochloric acid was added to the resulting reaction product mixture at room temperature, and the mixture was filtered to give 1.27 f crystals of β-[N-(carboximinomethyl)]aminopropionic acid (yield near 9%). ) was obtained. This was recrystallized with water and the decomposition point was 18.
Colorless massive crystals at 0°C were obtained. The elemental analysis values are shown below.

CH'N Analysis value 37,565.0017.56 Calculated value 37.
515°0317°49 (as C5H8N204) Example 11 1.312 ε-aminocaproic acid and 5 ml of water were added to a 1N aqueous sodium hydroxide solution (JOrttl) to obtain a solution containing 1.451 ethyl ethoxyiminoacetate at room temperature. After dropping the mixture into 15 ml of water, the mixture was reacted at room temperature for 3 hours with stirring.

After the reaction, 5 Wtl of 2N hydrochloric acid was added to the resulting reaction product mixture at room temperature and filtered to obtain 1.5 t of crystals of ε-[N-(carboximinomethyl)]amitsukagulonic acid (
Yield near 4%) was obtained. This was recrystallized from water to obtain colorless massive crystals with a 2-decomposition point of 173°C.

Sozuno Ordinary Analysis (di is shown at the end) CHN Analysis value 47.456.9613.80 Calculation value 47.
526.981385 (as 08H14N204) Patent applicant Ube Industries Co., Ltd. = 493

Claims (1)

[Scope of Claims] An alkali metal salt of an amino acid is an alkoxyniminoacetic acid ester represented by the formula RLO-C-COOR2 1 NH (wherein R1 and R2 each represent an alkyl group having 1 to 4 carbon atoms). An amino acid characterized in that a carboquiniminomethyl group represented by the formula HO-C0\1N is introduced into the amino group of the amino acid by reacting the reaction product with an acidic aqueous solution in water and then treating the resulting reaction product with an acidic aqueous solution. N-carboximinomethylation method of