JP3160605B2 - Amino acid acrylamide monomer and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an amino acid acrylic
The present invention relates to an amide monomer and a method for producing the amide monomer.

[0002]

2. Description of the Related Art Synthesizing amino acid vinyl polymers, which are raw materials for biodegradable plastics and biomimetic materials, which are trying to replace synthetic polymer plastics that have permeated the chemical industry, plastic processing industry, and everyday life. Is considered to be the best method if the amino acid can be directly vinylized and polymerized.

However Do La, to direct acryloyl amino acids, since the amino acid has a plurality of same functional group in the molecule, by selectively protecting group reagent site to fully express the properties of the amino acid It must be protected and then the protic functional groups of the amino acid side chains have to be acryloylated or methacryloylated.

FIGS. 4 to 10 are schematic views showing the steps of a conventional synthesis method, in which an amino acid and copper carbonate are reacted to form an amino acid copper complex, the amino group is weakly protected, and then copper is removed with hydrogen sulfide. I do.

A benzyloxycarbonyl group is bonded to the amino group bonded to the asymmetric carbon, and a benzyl group is bonded to the carboxyl group to sufficiently protect the amino acid. An acryloyl group is chemically bonded to the acidic functional group to synthesize an N-benzyloxycarbonylated benzylcarboxylated amino acid acryloyl monomer, and the N-benzyloxycarbonylated benzylcarboxylated amino acid acryloyl monomer is polymerized with ultraviolet light, and then a protecting group is added. The protecting group is selectively removed from the amino acid vinyl polymer with a super strong acid to synthesize the amino acid vinyl polymer.

[0006]

In the production of the conventional amino acid vinyl polymer, as described above, the amino acid has a plurality of the same functional groups in the molecule for directly acryloylating the amino acid. The site to be fully expressed must be selectively protected by expensive protecting group reagents.

[0007] In addition, a benzyloxycarbonyl group is bonded to an amino group bonded to an asymmetric carbon and a benzyl group is bonded to a carboxyl group to sufficiently express the properties of amino acids, and the acryloyl group is chemically protected with the benzyl group. Although attached, these protecting groups cannot be removed under mild conditions.

Usually, a super-strong acid, catalytic reduction, alkali or the like is used to remove an amino acid protecting group. However, if an attempt is made to remove the protecting group using these, an acryloyl moiety which is a polymer group will be destroyed. Therefore, after polymerization, the protecting group must be selectively cleaved with a super strong acid, catalytic reduction, alkali or the like.

Further, after the polymerization, the polymer may be decomposed even if the protecting group is removed by a super strong acid, catalytic reduction or alkali.

[0010] In order to solve the above-mentioned problems, the present invention protects an optically active site that sufficiently expresses the properties of amino acids by forming a copper complex, and can safely and safely carry out acrylamide conversion in water at low cost. Another object of the present invention is to provide an amino acid acrylamide monomer which can be resinified by a radical polymerization method similar to a method for synthesizing polyvinyl chloride or polystyrene, and a method for producing the same.

[0011]

Means for Solving the Problems The amino acid acrylic of the present invention
The luamide monomer prepares a copper complex in which a copper ion is coordinated between a carboxyl group bonded to the α-carbon of an α-amino acid and an amino group, and the acryloyl group is added to a side chain protic polar group in a water-containing solvent. It is obtained by attaching a group to acrylamidation and removing copper with a chelating agent.

[0012]

DESCRIPTION OF THE PREFERRED EMBODIMENTS FIGS. 1 to 3 are schematic views showing a part of the steps of the synthesis method of the present invention.

An amino acid-copper complex is formed by using an amino acid and copper ion in water (FIG. 1) to form an acrylamide (FIG. 2), and then a chelating agent such as 8-
Copper is desorbed using quinolinol and amino acid acrylic
An amide monomer is obtained (FIG. 3). This method allows the synthesis of amino acid acrylamide monomers under mild conditions.

Α-amino acids are lysine, ornithine, 2,4-diaminobutyric acid,
There are 2,3-diaminopropionic acids and the like having the following structural formula.

[0015]

Embedded image

As a method of forming a copper complex, the above-mentioned hydrochloride of an amino acid is dissolved in hot water, a predetermined amount of copper carbonate is added and the mixture is boiled, and then filtered quickly to obtain an amino acid-copper complex aqueous solution. A cyclic ether such as dioxane or tetrahydrofuran is added to the aqueous solution of the amino acid-copper complex, and an alkali such as sodium hydroxide or potassium hydroxide is added under ice cooling in an equivalent amount to the amino acid. While stirring vigorously under ice cooling, a solution of acrylic acid chloride in dioxane or tetrahydrofuran is divided into four equivalents of the amino acid amount in four times, and an equivalent alkali such as sodium hydroxide or potassium hydroxide is further divided in four times. their respective added every 10 minutes alternately, stirring for several hours, further stirred at room temperature overnight. At room temperature, collect the precipitate in the solution,
It wash | cleans in order with water, ethanol, and ether, and is dried as it is, and an amino acid acrylamide -copper complex is obtained.

For removing copper from the amino acid acrylamide -copper complex, a chelating agent such as a chelating agent or a chelating resin is used.

Examples of the chelating agent include 8-quinolinol, bis (8-quinolyl) malonamide derivative, 2-carboxyphenyl-azo-β-naphthylamine, dihydroxyazobenzene, diphenylthiocarbazone, ethylenediaminetetraacetic acid and metal salts thereof, and ammonium. Salt, trans-1,2-diaminocyclohexane N,
N, N ', N'-4 acetic acid monohydrate, diethylenetriamine-N, N, N', N ", N" -5 acetic acid, ethylenediamine acetic acid, ethylenediamine-2-propionic acid dihydrochloride, hydroxyethylenediamine triacetic acid, Glycol ether diamine tetraacetic acid, diaminopropane tetraacetic acid, triethylenetetramine hexaacetic acid, N, N-bis (2-hydroxybenzyl) ethylenediamine-N, N-2acetic acid, anisidine blue, azomethine H, bathocuproine, N-
Benzoyl-N-phenylhydroxylamine, N-Benzoyl-N- (2-methylphenyl) hydroxylamine, N-cinamoyl-N-phenylhydroxylamine, Promovirogallol Red, Eriochrome Black T, Chlorohydroxyphenylazo Naphthol, diantipyrmethane, oo'-dihydroxyazobenzene,
Dipyridyl, glyoxal Lou bis (2-hydroxy anil), murexide, neocuproine, o- nitro phenylarsonic acid, nitro Ferro-in, 2- (5-bromo-2-Hoon Rijiruazo) -5-diethylamino phenol, 1- (2- Pyridylazo) -2-naphthol, 4-
(2-pyridylazo) resorcinol, porphyrin group, Shin - phenyl-2-kink Silke Toki shim, Sari dust Denji aminobenzofuran, o- salicylideneamino phenol, salicylideneamino-2-thiophenol, sodium bicinchoninic acid, 4-methyl-2- (2
-Thiazolylazo) phenol, 4- (2-thiazolylazo) resorcinol, 2,4,6-tris (2-pyridyl) -1,3,5-triazine, acetylacetone,
Benzoyl trifluoroacetone, tenoyl trifluoroacetone and the like can be used.

Examples of the chelate resin include an iminodiacetic acid type chelate resin, a polyamine type chelate resin, a methylglucan type chelate resin, a chelate resin carrying a formazan compound, a thiol impregnated chelate resin, an aminopolycarboxylic acid type chelate resin, and the like. Available. When a chelating reagent is used, the obtained amino acid acrylamide -copper complex is dispersed in water, and copper is extracted with a 1% solution of the chelating reagent in chloroform or the like. Then, after washing with chloroform or the like, the aqueous phase is frozen and freeze-dried as it is to obtain the target amino acid acrylamide monomer. At this time, as a solvent for dissolving the chelating reagent, a solvent such as chloroform, methylene chloride, ethane dichloride, carbon tetrachloride, hexane, benzene, toluene, or xylene which is phase-separated from water is used.

When a chelate resin is used, the obtained amino acid acrylamide -copper complex is dispersed in water, and copper is extracted with the chelate resin. Then, after filtration, an amino acid A of interest and frozen filtrate was lyophilized directly
A acrylamide monomer can be obtained.

In the case of a polar-charged side chain amino acid acrylamide -copper complex, the amino acid and the functional group via the polymer group form an amide bond.

Amino acid acryl synthesized according to the present invention
Specific examples of the amide monomer include, for example, those represented by the following structural formula.

[0023]

Embedded image

Embedded image In addition, the amino acid acrylamide monomer synthesized according to the present invention can be used to synthesize an optically active polymer because a vinyl polymer is obtained by radical polymerization and an optically active site is present in a side chain, similarly to a conventional vinyl monomer. Can be.

Further, a telomer can be obtained by telomerization using a sulfur compound, and not only homopolymerization but also copolymerization can be carried out. As well as the functionality of one of the monomers.

[0025]

EXAMPLES Example 1: Synthesis of lysine acrylamide Preparation of lysine-copper complex aqueous solution 10.0 g, 55 mmol of lysine hydrochloride was added to 120 m of hot water
1 and copper carbonate CuCO ₃ Cu (OH) ₂ 4.0
3 g and 30.5 mmol were gradually dissolved so as not to be bumped, boiled for 10 minutes, and then quickly filtered while hot. The precipitate collected by filtration was washed with 20 ml of hot water to obtain a lysine-copper complex aqueous solution.

2. Synthesis of lysine acrylamide-copper complex 70 ml of dioxane was added to the obtained aqueous solution of lysine-copper complex, and the mixture was stirred with a three-one motor. A solution of 2M-sodium hydroxide and an amino acid equivalent in an amount of 28 ml, 55 mmol was added, and while vigorously stirring, a solution prepared by dissolving acrylic acid chloride of 1.25 times the amount of lysine in an amount of 6.22 g, 68.75 mmol of acrylic acid chloride in 30 ml of dioxane was divided into four portions.
Further, 31.5 ml of 2M sodium hydroxide was divided into four portions and added alternately every 10 minutes. Stir for 3.5 hours and overnight at room temperature. The resulting precipitate was collected by filtration, washed with water, ethanol, and ether in that order, and dried under reduced pressure to obtain a lysine acrylamide-copper complex 11.06.
g (87.1% yield).

3. Removal of copper from lysine acrylamide-copper complex by chelating reagent To remove copper from the obtained lysine acrylamide-copper complex, lysine acrylamide copper complex was dispersed in water, and 8-% quinolinol as a chelating reagent in chloroform 1% The copper was extracted with the solution. Thereafter, the mixture was washed with chloroform, and the chloroform dissolved in the aqueous phase was completely distilled off. Then, the aqueous phase was frozen and freeze-dried to obtain 6.85 g of lysine acrylamide (yield: 71.5%).

This 1H-NMR (D ₂ O, room temperature, δpp
m) is 1.2-1.3 (m, β-CH ₂ , 2H),
1.4-1.5 (m, γ-CH ₂ , 2H), 1.6-
1.8 (m, δ-CH ₂ , 2H), 3.1-3.2
(M, ε-CH ₂ , 2H), 3.6-3.7 (t, α-
_{CH 2, 1H), 5.6 (} d, CH 2 = CH, 1H),
_{6.0-6.3 (m, CH 2 = CH} , 2H) was.

4. Removal of copper from lysine acrylamide-copper complex by a chelating resin In order to remove copper from the obtained lysine acrylamide-copper complex, lysine acrylamide copper complex is dispersed in water, and copper is removed with an iminodiacetic acid type chelating resin as a chelating resin. Was extracted. Then, after filtration, the filtrate was frozen and freeze-dried to obtain 5.0 g of lysine acrylamide (yield 52.5%).

[Synthesis of lysine acrylamide homopolymer] At room temperature, 5 g and 25 mmol of lysine acrylamide were dissolved in 50 ml of water, and the atmosphere was replaced with nitrogen for 20 minutes. Then, 28.5 mg of ammonium persulfate and 0.5 mol% were added, and the mixture was added under a nitrogen atmosphere. The reaction was performed for 20 hours. The polymer was purified by dialysis to remove unreacted monomers (yield 4.5 g, 90.0%).

[Synthesis of Copolymer Using Lysine Acrylamide] At room temperature, 3 g of lysine acrylamide, 15.0 mmol
And 1.70 g of N, N-isopropylacrylamide, 1
5.0 mmol was dissolved in 50 ml of water,
Minutes, ammonium persulfate 36.7 mg, 0.5
mol%, and reacted under a nitrogen atmosphere for 20 hours. To remove unreacted monomers, the polymer was purified by dialysis (yield 3.76 g, 80.0%).

[Synthesis of Telomer by Lysine Acrylamide] At room temperature, 3 g of lysine acrylamide, 15.0 mmol
1, 0.295 g of 3-mercaptotrimethoxysilane,
Dissolve 1.50 mmol in 50 ml of water,
After 0 minutes, 18.80 mg of ammonium persulfate,
0.5 mol% was added, and the reaction was performed for 20 hours under a nitrogen atmosphere. In order to remove unreacted monomers, telomers were purified by dialysis (yield 2.64 g, 80.0 g).
%).

Example 2 [Synthesis of Ornithine Acrylamide] Preparation of Ornithine-Copper Complex Aqueous Solution Ornithine hydrochloride (10.0 g, 59 mmol) was dissolved in hot water (12).
0 ml, and copper carbonate CuCO ₃ Cu (OH) 22
4.33 g, 32.8 mmol were slowly dissolved so as not to bump and boiled for 10 minutes, and then quickly filtered while hot. The precipitate collected by filtration was washed with 20 ml of hot water to obtain an ornithine-copper complex aqueous solution.

2. Synthesis of Ornithine-Copper Complex Dioxane 70 m
l and stirred with a three-one motor. 2M-sodium hydroxide equivalent to ornithine 30.0ml, 59m
mol and add vigorously while stirring ornithine.
A solution obtained by dissolving 25.67 equivalents of 6.67 g, 73.75 mmol of acrylic acid chloride in 30 ml of dioxane was added.
Divide into 3 times, 33.8 ml of 2M sodium hydroxide
Is divided into four times and added alternately every 10 minutes.
Stir for 5 hours and stir at room temperature overnight. The generated precipitate is collected by filtration, washed with water, ethanol and ether in this order,
It was dried under reduced pressure as it was to obtain 10.39 g of an ornithine acrylamide-copper complex (yield: 87.1%).

3. Removal of copper from ornithine acrylamide-copper complex To remove copper from the obtained ornithine acrylamide-copper complex, the ornithine acrylamide-copper complex is dispersed in water, and a chelating reagent, 8-quinolinol, in a 1% chloroform solution. Copper was extracted. Thereafter, the mixture was washed with chloroform, and the chloroform dissolved in the aqueous phase was completely distilled off. Then, the aqueous phase was frozen and freeze-dried to obtain 4.55 g of ornithine acrylamide (yield: 71.5).
%).

[Synthesis of Ornithine Acrylamide Homopolymer] Ornithine acrylamide 5 g, 26.8 mm at room temperature
was dissolved in 50 ml of water, and the atmosphere was replaced with nitrogen for 20 minutes. Then, 30.5 g of ammonium persulfate was added, and the mixture was reacted under a nitrogen atmosphere for 20 hours. The polymer was purified by dialysis to remove unreacted monomers (yield 4.25).
g, yield 85.0%).

[Synthesis of Copolymer with Ornithine Acrylamide] At room temperature, 3 g of ornithine acrylamide, 16.1 mm
ol and N, N-isopropylacrylamide 1.82
g, 16.1 mmol was dissolved in 50 ml of water, and after purging with nitrogen for 20 minutes, 36.7 mg of ammonium persulfate was added.
0.5 mol% was added, and the reaction was performed for 20 hours under a nitrogen atmosphere. To remove unreacted monomers, the polymer was purified by dialysis (yield 3.86 g, yield 81.0).
%).

[Synthesis of Telomer with Ornithine Acrylamide] At room temperature, 3 g of ornithine acrylamide, 16.1 mm
ol, 3-mercaptotrimethoxysilane 0.316
g, 1.61 mmol were dissolved in 50 ml of water, and after purging with nitrogen for 20 minutes, 18.3 g of ammonium persulfate was added and reacted under a nitrogen atmosphere for 20 hours. To remove unreacted monomers, telomers were purified by dialysis (yield 2.65 g, 80.0%).

[0039]

The same radicals as in the method of synthesizing a general-purpose resin such as polyethylene, polypropylene, polystyrene, polyacrylamide, and an acrylic resin using a vinyl monomer to which an amino acid which is also a constituent unit of a protein obtained by the present invention is bonded. By the polymerization reaction, it becomes possible to synthesize biodegradable plastics and biomimetic materials, and can be expected to be applied to alternative general-purpose resins and medical materials. In addition, since it is an optically active polymer, application to a separation material using the same can be expected.

Furthermore, according to the present invention, there is no need to use expensive protecting groups as in the conventional synthesis method, and there is no need for a step associated with the protecting groups. / 20 can be greatly reduced.

[Brief description of the drawings]

FIG. 1 is a schematic diagram showing a part of the steps of the synthesis method of the present invention.

FIG. 2 is a schematic view showing a part of the steps of the synthesis method of the present invention.

FIG. 3 is a schematic diagram showing a part of the steps of the synthesis method of the present invention.

FIG. 4 is a schematic view showing a part of the steps of a conventional synthesis method.

FIG. 5 is a schematic view showing a part of steps of a conventional synthesis method.

FIG. 6 is a schematic view showing a part of the steps of a conventional synthesis method.

FIG. 7 is a schematic view showing a part of the steps of a conventional synthesis method.

FIG. 8 is a schematic view showing a part of the steps of a conventional synthesis method.

FIG. 9 is a schematic view showing a part of the steps of a conventional synthesis method.

FIG. 10 is a schematic view showing a part of steps of a conventional synthesis method.

──────────────────────────────────────────────────続 き Continuing on the front page (72) Ryoichi Kishi 1-1-1, Higashi, Tsukuba, Ibaraki Pref., National Institute of Materials Science and Technology (72) Inventor Katsuhiko Ueno 1-1-1, Higashi, Tsukuba, Ibaraki, Japan Examiner, Institute of Engineering, Industrial Technology Research Institute Hideji Sasaki (56) References JP-A-10-251209 (JP, A) JP-A-11-11639 (JP, A) JP-A-11-124360 (JP, A) Technol. Rep. Osak a. Univ. , 26 (1976), p. 363-371 (58) Fields investigated (Int. Cl. ⁷ , DB name) C08F 20/60 C07C 231/02 C07C 233/49 C07D 233/64 106 CA, REGISTRY (STN)

Claims (2)

(57) [Claims] 1. A copper complex in which a copper ion is coordinated between a carboxyl group bonded to the α-carbon of an α-amino acid and an amino group, and the copper complex is converted into a side chain protic polar group in a water-containing solvent. An amino acid acrylamide monomer obtained by bonding an acryloyl group to form acrylamide and removing copper with a chelating agent. 2. A copper complex in which a copper ion is coordinated between a carboxyl group bonded to an α-carbon of an α-amino acid and an amino group is prepared in a water-containing solvent to form a side chain protic polar group. A method for producing an amino acid acrylamide monomer, comprising bonding an acryloyl group to form acrylamide, and removing copper with a chelating agent.