JP2002145847A - Acrylic acid derivative bearing amino acid residue - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a novel monomer that is used in the synthesis of heat- sensitive polymers. SOLUTION: The objective novel compound is represented by the following general formula (I) (R is H or methyl; n is an integer of 1 -4; Z is a protecting group of the amino group).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel acrylic acid derivative which is useful as a starting monomer for acrylic polymers such as acryloyl polymers and methacryloyl polymers having amino acid residues and stimuli-responsive polymer compounds such as methacryloyl polymers. (Hereinafter referred to simply as acrylic acid derivative).

[0002]

2. Description of the Related Art Stimuli-responsive polymer compounds and their gels reversibly change their solubility in solvents and gel volume by changing external factors such as temperature (heat), pH, electric field, and light. Because of these unique properties, in recent years, there has been much interest in both basic and applied aspects, and a number of studies have been conducted with the aim of applying them to a wide range of fields. Various monomers are known as a raw material monomer for such a polymer compound, and the present inventors have also proposed an amino acid such as L-lysine in which a carboxy group and an amino group at the α-position have been protected. Acrylic acid derivative (Japanese Patent No. 2979138) which forms an amide bond with an amino group in the side chain of the above, and acryl which forms an amide bond with the amino group of the side chain of an amino acid such as L-lysine in which the carboxy group and the amino group at the α-position are not protected. An acid derivative (Japanese Patent Application No. 11-250891) has been proposed. The monomer described in the former Patent No. 2979138 is copolymerized with another vinyl monomer and the like, and then subjected to a deprotection reaction, whereby the carboxyl group and the amino group at the α-position become free and exhibit the properties of an amphoteric electrolyte. become. The latter monomer disclosed in Japanese Patent Application No. 11-250891 has an amphoteric electrolyte component only by copolymerization with another vinyl monomer since the carboxyl group and the amino group at the α-position are not protected by a protecting group. The resulting polymer material is obtained.

[0003]

DISCLOSURE OF THE INVENTION The present invention has been further devised by modifying the structure of the above-mentioned monomer, and is useful as a raw material monomer for a stimuli-responsive polymer or gel showing a sharp response due to a pH change. It is another object of the present invention to provide a novel acrylic acid derivative which forms an amide bond with the amino group at the α-position of an amino acid.

[0004]

According to the present invention, there is provided an acrylic acid derivative having an amino acid residue represented by the following general formula (I).

Embedded image (In the formula, R is a hydrogen atom or a methyl group, n is an integer of 1 to 4, and Z is a protecting group for an amino group.)

[0005]

BEST MODE FOR CARRYING OUT THE INVENTION The compound represented by the general formula (I) of the present invention is an acrylic acid derivative having an amide bond with the amino group at the α-position of an amino acid in which the amino group in the side chain is protected. In the general formula (I), R is hydrogen or a methyl group, n is an integer of 1 to 4, and Z is a protecting group for an amino group. Examples of the amino-protecting group Z include all conventionally known protecting groups, and include, for example, benzyloxycarbonyl, m-chlorobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, t-butoxycarbonyl and the like. Of these, protecting groups such as benzyloxycarbonyl and m-chlorobenzyloxycarbonyl are preferably used.

The compound represented by the general formula (I) is prepared, for example, by reacting an amino acid having a protected side-chain amino group with an alkali salt such as sodium hydroxide to synthesize the amino acid salt first. And acrylic acid chloride, methacrylic acid chloride, etc. are reacted in a solvent,
It is produced by an amide bond with the amino group at the α-position. As the raw material amino acids, N-β-ZL-α,
β-diaminopropionic acid, N-γ-ZL-α, γ-
Diaminobutyric acid, N-δ-ZL-α, δ-ornithine,
L-amino acid compounds such as N-ε-Z-L-α, ε-lysine, N-β-ZD-α, β-diaminopropionic acid, N-γ-ZD-α, γ-diaminobutyric acid , N-δ-
ZD-α, δ-ornithine, N-ε-ZD-α, ε
As a solvent such as a D-amino acid compound such as -lysine and a racemic compound, for example, a mixed solvent of water and an organic solvent such as dioxane, tetrahydrofuran and acetone is used. There is no particular restriction on the reaction temperature, but about 0 to 5 ° C. is sufficient.

The compound represented by the general formula (I) according to the present invention is obtained by homopolymerizing or copolymerizing it with another monomer such as an acrylamide or methacrylamide derivative, followed by deprotection. And an amphoteric electrolyte polymer having a carboxyl group and an amino group in a monomer unit.

For example, when the compound (I) according to the present invention is homopolymerized by an appropriate method, a homopolymer having a repeating unit represented by the following general formula (II) can be obtained.

[0009]

Embedded image In the general formula (II), Z, R and n have the same meaning as described above. m indicates the degree of polymerization and is generally 50 to 10,000.
0, preferably 100 to 5,000.

The compound (I) of the present invention can
When copolymerized with a substituted acrylamide derivative or an N-substituted methacrylamide derivative, a copolymer having a repeating unit represented by the following general formula (III) can be obtained.

[0011]

Embedded image In the general formula (III), n, Z, R and n have the same meaning as described above. Q1 and Q2 represent a hydrogen atom or n-
Propyl group, isopropyl group, n-butyl group, sec-
And a lower alkyl group such as a butyl group and a tert-butyl group. Of these, a combination of Q1 as a hydrogen atom, Q2 as a lower alkyl group, and Q1 as an ethyl group and Q2 as an ethyl group are preferred. x and y indicate the mole fraction of each component in the copolymer, and generally, x is 0.5 to
0.95, preferably 0.8 to 0.95, and y is 0.05 to 0.5, preferably 0.05 to 0.2. The molecular weight of this copolymer is generally between 10,000 and 2,
00000, preferably 20,000 to 1,000
It is 0000.

An aqueous solution of a homopolymer having a repeating unit represented by the above general formula (II) is used as a stimulus-responsive polymer because its viscosity and electrical properties are reversibly changed by a change in pH. be able to.

The gelled product swells greatly in an aqueous solution, swells at a temperature lower than the transition temperature, and contracts at a temperature higher than the transition temperature, and thus exhibits a phase transition phenomenon, so that it can be used as a thermoresponsive polymer.

An aqueous solution of a copolymer having a repeating unit represented by the above general formula (III) dissolves in water and becomes transparent below the transition temperature, but becomes insoluble in water above the transition temperature. However, since the solution becomes cloudy, it can be used as a thermoresponsive polymer. Furthermore, since this copolymer contains a specific amino acid group, the phase separation behavior changes depending on the pH, and the aqueous solution does not undergo phase separation in the range of pH 4 to 10 over both acidic and alkaline regions. Maintains transparency and exhibits a unique behavior of causing phase separation and turbidity in the vicinity of acidity of pH 4 or less and alkalinity of pH 10 or more. In addition, this copolymer has a relatively low phase transition temperature,
In addition, the phase transition occurs in both acidic and alkaline regions, and the transparent pH region is relatively wide. Further, since the boundary between the transparent pH region and the opaque pH region is clear, a sharp thermal response is obtained. And pH responsiveness.

Further, since the gelled product of the copolymer having the repeating unit represented by the general formula (III) contains a unique amino acid group, the phase transition behavior changes depending on pH, and p
In the vicinity of H4-10, it is in a contracted state.
At a pH below that, the gel swells sharply and greatly.

Therefore, the polymer obtained by polymerizing the monomer of the present invention and the gelled product thereof have a temperature,
It can be used as a sensor or actuator that recognizes pH or the like, or as a separation material such as a column filler.

[0017]

Next, the present invention will be described in more detail with reference to examples.

Example According to the following scheme 1, compound (4) of the present invention was synthesized.

[0019]

Embedded image

[Acrylic acid derivative having amino acid residue]
(Synthesis of Compound (4)) Compound (1) (3.0 g, 1
0.7 mmol) in 0.1N aqueous sodium hydroxide solution
(108ml, 10.8mmol)
An aqueous solution of (2) was obtained. 53.5 ml of dioxane, 1N
-Sodium hydroxide aqueous solution (10.7 ml, 10.7 m
mol)) and stirred vigorously. This solution is called solution A.
Was. Acryloyl chloride (compound (3)) (1.21 g,
13.4 mmol) in 12 ml of dioxane
Was prepared. 1N-sodium hydroxide aqueous solution (12.3
ml, 12.3 mmol).
Was. In an ice bath, liquid B and liquid C were divided into four times, and every 10 minutes, A
The solution was added and stirred for 7 hours. After completion of the reaction, 1N hydrochloric acid aqueous solution
The reaction solution was adjusted to pH 5 using the solution. Dioxane
The product was dissolved in methylene chloride under reduced pressure. Water 10
The organic phase was washed with 0 ml. Anhydrous magnesium sulfate
Dehydration was performed by adding sodium, and the mixture was concentrated under reduced pressure.
In the roloform mixture (180 ml: 20 ml (= 9:
Crystals were precipitated in 1)). After standing at low temperature, decane
And dried under reduced pressure to obtain a white compound (4).
Was. Yield: 1.8 g, Yield: 50.3% 1H-NMR (DMSO, room temperature, δ): 1.2-1.8
(M, (CH₂)₄, 8H), 4.2-4.3 (m, C
H, 1H), 5.0 (s,) 5.0 (s, CH) ₂, 1
H), 5.6 (d, CH₂= CH, 1H), 6.0-
6.4 (m, CH₂= CH, 2H), 7.3-7.4.
(M, benzene, 5H), elemental analysis: calculated values
(%): C, 61.1; H, 6.63; N, 8.38,
Found (%): C, 60.2; H, 6.74; N, 8.
14

Application Example 1 [Polymerization of Compound (4)] According to the following Scheme 2, a homopolymer (6) of the compound (4) was synthesized.

[0022]

Embedded image

The compound (4) (4.7 g,
14 mmol) was dissolved in 20 ml of dimethyl sulfoxide. Α, α′-azobisisobutyronitrile (23.3 mg, 0.14 mmol) was added as a polymerization initiator, and the mixture was reacted at 60 ° C. for 24 hours under a nitrogen atmosphere. After returning to room temperature, the mixture was precipitated with water and freeze-dried to obtain a white polymer (5). Yield: 4.11 g, Yield: 87.4% [Removal of protecting group (Z group) from polymer] Polymer (5), wherein R = H, n = 4 was dissolved in 25 ml of acetic acid and 25%
Hydrogen bromide / acetic acid solution (25 ml) was added. After stirring at room temperature for 3 hours, the mixture was concentrated under reduced pressure. The product was dissolved in water and dialyzed. Lyophilized, white flocculent polymer (6)
(M = 1,500) was obtained. Yield: 1.20 g, yield: 80.7%

Application Example 2 [Copolymerization of N-isopropylacrylamide (compound (7)) and compound (4)] A copolymer (9) of compound (7) and compound (4) was synthesized according to the following scheme 3.

[0025]

Embedded image

Compound (7) (1.45 g, 12.8 mm
ol) and compound (4) (0.47 g, 1.42 mmol)
l) (molar ratio; compound (7): compound (4) = 9: 1)
Was dissolved in 20 ml of dimethyl sulfoxide. Α, α'-azobisisobutyronitrile (23.
3 mg, 0.14 mmol) and add 60 under nitrogen atmosphere.
The reaction was performed at 24 ° C. for 24 hours. After returning to room temperature, the mixture was precipitated with water and freeze-dried to obtain a white copolymer (8) of the compound (7) and the compound (4). Yield: 1.71 g, Yield: 89.2% [Removal of protecting group (Z group) from copolymer] Copolymer (8)
(0.8 g) in 25% hydrogen bromide / acetic acid solution (25.6 m
1), left at room temperature for 3 hours, and concentrated under reduced pressure. The product was dissolved in water and dialyzed. By freeze-drying, a white flocculent copolymer (9) (x = 0.9, y = 0.
1; molecular weight 350,000). Yield: 0.64 g, Yield: 85.2%

[0027]

(1) An aqueous solution of a homopolymer having a repeating unit represented by the general formula (II) obtained by homopolymerizing the compound represented by the general formula (I) of the present invention is reversible by a change in pH. Viscosity and electrical properties change,
It can be used as a responsive polymer material. (2) The gelled product swells greatly in an aqueous solution, swells at a temperature lower than the transition temperature, and exhibits a phase transition phenomenon of contraction at a temperature higher than the transition temperature, so that it can be used as a thermoresponsive polymer. (3) An aqueous solution of a copolymer having a repeating unit represented by the general formula (III) obtained by copolymerizing the compound represented by the general formula (I) of the present invention dissolves in water at a transition temperature or lower. Although it becomes transparent, at a temperature higher than the transition temperature, it causes phase separation and becomes insoluble in water, and the solution becomes cloudy, so that it can be used as a thermoresponsive polymer. Furthermore, since this copolymer contains a specific amino acid group, the phase separation behavior changes depending on the pH, and the aqueous solution does not undergo phase separation in the range of pH 4 to 10 over both acidic and alkaline regions. Maintains transparency and exhibits a unique behavior of causing phase separation and turbidity in the vicinity of acidity of pH 4 or less and alkalinity of pH 10 or more. Also,
This copolymer has a relatively low phase transition temperature, has a phase transition over both acidic and alkaline regions, has a relatively wide transparent pH region, and further has a transparent pH region and a opaque pH region. Since the boundaries of the regions are clear, they exhibit sharp, thermo-responsive and pH-responsive. (4) Since the gelled product of the copolymer contains a unique amino acid group, the phase transition behavior changes depending on pH, and p
In the vicinity of H4-10, it is in a contracted state.
At a pH below that, the gel swells sharply and greatly. (5) Accordingly, such an acrylic acid derivative having an amino acid regret represented by the general formula (I) according to the present invention is a thermoresponsive polymer material that recognizes ampholyte, temperature, pH, etc., It is useful as a polymer material or a monomer used for polymerization of a polymer compound having a use as a separation material such as a column packing material.

Claims (1)

[Claims] 1. An acrylic acid derivative having an amino acid residue represented by the following general formula (I). Embedded image (In the formula, R is a hydrogen atom or a methyl group, n is an integer of 1 to 4, and Z is a protecting group for an amino group.)