JP2979138B2 - Acrylamide compounds with amino acid residues - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a monomer used for producing a polymer having an amino acid residue in a side chain.

[0002]

2. Description of the Related Art The phase transition of a polymer gel has been receiving much interest from both basic and applied aspects, and research on the control of swelling / shrinking of discontinuous and irreversible gel volume has been conducted on temperature (heat), pH, and the like. It has been actively performed by changing external factors such as electric field, light and the like. Various monomers have been used for the synthesis of such a polymer compound, but there is a demand for the development of a new polymer compound.

[0003]

SUMMARY OF THE INVENTION An object of the present invention is to provide a novel monomer compound used for synthesizing a new thermosensitive polymer or the like.

[0004]

The present invention provides a compound represented by the following formula (I).

[0005]

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Wherein Z is a benzyloxycarbonyl group
And Y represents a benzyl group. )

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION As described above, the compound of the formula (I) of the present invention is characterized in that the hydrogen atom of the amino group bonded to the α-carbon of the amino acid and the hydroxyl group in the carboxyl group are each the aforementioned protecting group
Is protected by

Next, compound (I) of the present invention is converted to N-isopropylacrylamide (hereinafter referred to as "NIPAAm").
And a copolymer represented by the following formula (II) can be obtained.

[0009]

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(Wherein, Z and Y have the same meaning as described above, and m and n each represent a ratio (%).) In this copolymer, the molar ratio of NIPAAm to the compound (I) of the present invention = 9: 1, the optical rotation α and the specific rotation [α] were measured at an optical path length of 10.0 cm using an aqueous solution of 2.00 g / ml, and α = 0.286, respectively.
[Α] = 14.290, indicating that the lysine residue in the polymer was not racemized.

The aqueous solution of the polymer of the formula (II) dissolves in water below the transition temperature, but above the transition temperature causes phase separation and insolubilization in water, and the solution becomes cloudy. It can be used as a molecule. Further, since this copolymer also has different affinity for amino acids, the transition temperature of the complex changes depending on the type of amino acid added. Thus, the copolymer can be used as a reagent for identifying the type of amino acid. This copolymer can be applied to amino acid recognition and optical recognition by a ligand exchange method.

[0012]

Next, the present invention will be described in more detail with reference to examples. Examples Compound (5) of the present invention was synthesized according to the following scheme.

[0013]

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1) ZL-Lys (Boc) -OBzl
A synthetic commercial product of (2), ZL-Lys (Boc) (1), was reacted with benzyl alcohol to protect the α-carboxyl group. ZL-Lys (Boc) (1) (Kokusan Chemical Co., Ltd.)
1.00 g (2.63 mmol), dimethylaminopyridine (DMAP): 0.0321 g (0.263
mmol) and benzyl alcohol (BzlOH):
0.34 g (3.15 mmol) of methylene chloride.
Dissolve in 0 ml, and stir at 0 ° C. while stirring, water-soluble carbodiimide hydrochloride (WSC · HCl): 0.552 g (2.
88 mmol) was added. After stirring at 0 ° C. for 2 hours and at room temperature overnight, the mixture was concentrated under reduced pressure and extracted with ethyl acetate-water (5: 1). The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and then with water, and then dried over anhydrous magnesium sulfate. A large excess of hexane-acetone (9: 1)
Crystals of L-Lys (Boc) -OBzl (2) were precipitated. After drying, a white powder was obtained. 1.0786 g, 80% yield, mp 78.7-8
0.1 ° C. NMR (CDCl ₃ , room temperature, δ): 1.3-1.6
_{(T, (CH 2) 4} , 8H), 7.3-7.4 (s, benzene .10H), Calcd (%) C, 66.
36; H, 7.29; N, 5.95, found (%) C,
H, 7.19; N, 5.87.

2) The combination of ZL-Lys-OBzl (3)
Synthesis, (Removal of Boc group ) ZL-Lys (Boc) -OBzl (2): 0.80
6 g (1.70 mmol) was dissolved in 5.0 ml of ethyl acetate, and 8.5 ml of a 4N hydrochloric acid / ethyl acetate solution was added thereto.
Was added dropwise and stirred for 1 hour. After the reaction solution was concentrated under reduced pressure, ether-petroleum ether was added, and ZL-Lys-OBz was added.
l (3) was precipitated. After drying, an oily product was obtained.
Since the Z group protecting the amino group at the α-position was not removed, only the amino group at the δ-position could be made free.

3) Monomer ZL-Lys-OBzl-A
Synthesis of Am (5) ZL-Lys-OBzl (3): 0.630 g (1.
70 mmol), triethylamine: 0.378 g
(3.74 mmol) was dissolved in 5.0 ml of tetrahydrofuran, and acrylic acid chloride: 0.18 in an ice bath.
5 g (2.04 mmol) were added dropwise. After stirring for 1 hour in an ice bath, the mixture was concentrated under reduced pressure. The precipitate was dissolved in methylene chloride, washed with a 5% aqueous solution of sodium hydrogen carbonate and then with water, and then dried over anhydrous magnesium sulfate. The compound of the present invention, ZL-Lys-OBzl-AAm (5), was precipitated in a large excess of ethyl acetate-petroleum ether (1: 9) solution. After drying, a white powder was obtained. 0.7035 g, yield 76%, mp 105.3-1
07.7 ° C. NMR (CDCl ₃ , room temperature, δ): 1.3-1.6
_{(T, (CH 2) 4} , 8H), 5.5-6.4 (m, C
_{H 2 = CH, 3H),} 7.3-7.4 (s, benzene,
10H) Elemental analysis: Calculated value (%) C, 67.90;
6.66; N, 6.60, found (%) C, 66.6.
0; H, 6.66; N, 6.46.

<Synthesis Example 2> (NIPAAm-L-Lys
Synthesis of Copolymer (8) 1) Acrylamide monomer containing lysine residue (Z-
L-Lys-OBzl-AAm) (5) and N-isopro
When the Z group and the OBzl group are removed in the state of the copolymerized monomer of pyracrylamide (6), the vinyl group reacts and the polymerization reaction becomes impossible. Therefore, copolymerization with NIPAAm was carried out with both protecting groups attached to obtain a polymer, and then the protecting groups were removed. ZL-Lys-OBzl-AAm (5): 0.40 g
(0.94 mmol), N-isopropylacrylamide (NIPAAm) (6): 0.9596 g (8.48)
mmol) (molar ratio; NIPAAm (6): ZLL)
ys-OBzl-AAm (5) = 9: 1)
Butyl alcohol: dissolved in 15.0 ml. Α, α'-azobisisobutyronitrile: 1 as a polymerization initiator
5.4 mg (0.0942 mmol) was added, and the mixture was stirred at 60 ° C. for 20 hours under a nitrogen atmosphere to polymerize. After completion of the reaction, the precipitate was precipitated in a large excess of hexane, and then dried under reduced pressure.
A copolymer (7) was obtained. From the NMR measurement, the constitutional ratio of (7) is a molar ratio, and NIPAAm (6):
It was revealed that OBzl-AAm (5) = 10.6: 1. From this value, the Z-L charged during the polymerization was used.
It was found that 85.0% of -Lys-OBzl-AAm (5) had reacted. 1.2523 g, 92.1% yield

2) NIPA of the present invention by removing a protecting group
Synthesis of Am-L-Lys copolymer (8) Copolymer (7): 0.150 g dissolved in 1M trifluoromethanesulfonic acid-thioanisole (molar ratio: 1: 1) /0.880 ml of trifluoroacetic acid Then, the mixture was stirred in an ice bath under an Ar atmosphere for 90 minutes to remove the protecting group. After completion of the reaction, the product was dissolved in tert-butyl alcohol and precipitated in a large excess of hexane. After drying under reduced pressure, the obtained polymer was dissolved in water and dialyzed under a weak alkali (pH 7 to 8). The dialyzed solution is freeze-dried and the NIPA of the present invention is dried.
An Am-L-Lys copolymer (8) was obtained. NMR measurements confirmed that almost all of the protecting groups had been removed.

[0019]

The compound of the present invention is useful as a monomer used for copolymerization of a polymer compound having a use as a thermoresponsive polymer or the like.

──────────────────────────────────────────────────続 き Continuing on the front page (72) Takao Sato, Inventor 1422-5, Ohira-machi, Shimotsuga-gun, Tochigi Prefecture 6-8-4 Yakushidai, Moriya-cho, Kitasoma-gun (56) References JP-A-11-11639 (JP, A) (58) Fields investigated (Int. Cl. ⁶ , DB name) CA (STN) REGISTRY ( STN)

Claims (1)

(57) [Claims] 1. A compound represented by the following general formula (I). ( Wherein , Z represents a benzyloxycarbonyl group, and Y represents
Represents a jyl group. )