JPS648008B2 - - Google Patents

Description

[Detailed description of the invention]

This invention relates to a method for producing a vinyl polymer having a cyclic peptide in its side chain. Although it is known that various cyclic compounds form specific complexes with metal ions in living organisms and are involved in the transport of metal ions, the present inventors have attempted to utilize such properties of cyclic compounds industrially. The present invention was completed through repeated research with the aim of obtaining a substance in a form that could be obtained. That is, the gist of the present invention is to polymerize cyclo(N〓-acryloyl-L-lysylsarcosine) or a mixed monomer containing cyclo(N〓-acryloyl-L-lysylsarcosine) and a vinyl monomer having a substituent that is easily conjugated with a double bond in the presence of a radical polymerization catalyst. The present invention relates to a method for producing a vinyl polymer having a cyclic peptide as a side chain. The present invention will be explained in detail below. Cyclo(N-acryloyl-L-lysylsarcosine), which is a monomer used in the method of the present invention, is synthesized, for example, as follows. First, this synthesis reaction is expressed by the following formula. A specific example of synthesis according to the above reaction formula will be described below. (1) Synthesis of N〓-tert-butyroxycarbonyl-N〓-carbobenzoxy-L-lysine (); N〓-carbobenzoxy-L-lysine ()
14 g (0.05 mol) was suspended in 300 ml of 50% dioxane, (C ₂ H ₅ ) ₃ N (10.5 ml) (0.075 mol) and 2-tert-butyloxycarbonyloxyimino-
Add 13.55 g (0.055 mol) of 2-phenylacetonitrile and stir at room temperature for 3 hours. After concentrating under reduced pressure to remove dioxane, water (75 ml) is added and the mixture is washed with ethyl acetate (100 ml). Add citric acid to this aqueous solution to adjust the pH to 2-3. After extraction with ethyl acetate, dehydration with Na ₂ SO ₄ and concentration under reduced pressure, an oily N〓-tert-butyloxycarbonyl-N〓
-Carbobenzoxy-L-lysine () is obtained. The yield was 83%. (2) Synthesis of N〓-tert-butyloxycarbonyl-N〓-carbobenzoxy-L-lysylsarcosine ethyl ester (); 9.5 g (0.025 g) of the compound () obtained in (1) above
mol) in CH ₂ Cl ₂ (250 ml) and, under stirring,
Add 5 g (0.025 mol) of dicyclohexylcarbodiimide while cooling on ice. After about 20 minutes, acid anhydride and dicyclohexyl urea, which are reaction intermediates, precipitate. Then 3.85 g (0.025 mol) of sacosine ethyl ester hydrochloride and (C ₂ H ₅ ) ₃ N (3.5
ml) (0.025 mol) in CH ₂ Cl ₂ (20 ml) was added, and the mixture was stirred for 3 hours while cooling on ice. The mixture is left at room temperature for a day and night to remove the precipitated dicyclohexyl urea. The liquid was washed three times in the order of saturated saline, 10% citric acid aqueous solution, saturated saline, 4% NaHCO ₃ aqueous solution, and saturated saline,
After drying with Na ₂ SO ₄ and concentration under reduced pressure, an oil was obtained. The yield of the obtained N〓-tert-butyroxycarbonyl-N〓-carbobenzoxy-L-lysylsarcosine ethyl ester () was 68%. (3) Synthesis of cyclo(N〓-carbobenzoxy-L-lysylsarcosine) (); 4.79 g (0.01
mol) in 4N HCl-dioxane solution (37.5 mol)
ml) (15 equivalents) and leave for 30 minutes. After concentration under reduced pressure and washing with hexane, oily N-carbobenzoxy-L-lysylsarcosine hydrochloride is obtained. The yield was 75%. The resulting oil was then dissolved in NH ₃ saturated ethanol solution (100
ml) and left overnight at room temperature, ethanol was removed under reduced pressure, the resulting oil was washed with hexane, dissolved in ethyl acetate, and dissolved in saturated brine, 10% citric acid aqueous solution, saturated brine, 4%
Wash with NaHCO ₃ aqueous solution and saturated saline,
After drying with Na ₂ SO ₄ and concentrating under reduced pressure, cyclo(N〓
-carbobenzoxy-L-lysylsarcosine)
Crystals of () are obtained. The yield of this is 81
%, and the melting point was 114.5-115.5°C. The results of elemental analysis were as follows. Measured value C, 61.42%; H, 6.96%; N, 12.62% Calculated value as C ₁₇ H ₂₃ N ₃ O ₄ C, 61.25%; H, 6.95%; N, 12.60% (4) Cyclo(L-lysyl Synthesis of sarcosine) hydrochloride (); 3.33 g (0.01
mol) in 0.5N HCl-methanol solution (24ml)
(1.2 equivalents), add palladium black powder, and pass hydrogen through with stirring for 8 hours. After confirming the completion of the reaction by thin layer chromatography,
Palladium black is removed and methanol is distilled off under reduced pressure to obtain oily cyclo(L-lysylsarcosine) hydrochloride (). The yield was 100%. (5) Synthesis of cyclo(N〓-acryloyl-L-lysylsarcosine) (); Dissolve 0.495 g (0.00175 mol) of cyclo(L-lysylsarcosine) hydrochloride obtained in (4) above in 3.2 ml of water. After neutralizing with 1N-NaOH, 10μ of acrylic acid chloride was added dropwise in 26 portions over 3 hours while stirring and cooling on ice.
Maintain pH at 8.5-9 with 2N-NaOH. After the dropwise addition was completed, the mixture was further stirred for 1 hour, neutralized with 1N-HCl, concentrated under reduced pressure, and when it became syrupy, cyclo(N-acryloyl-L-lysylsarcosine) was extracted with ethyl acetate and extracted with Na ₂ SO. ₄ for a day and night, and the acetate insoluble part was left in methanol for a day and night to remove the remaining cyclo(N〓
-acryloyl-L-lysylsarcosine) was extracted with methanol, concentrated under reduced pressure, and dried under reduced pressure. Attempts were made to crystallize cyclo(N-acryloyl-L-lysylsarcosine) using various solvents, but the result was an oily substance. The yield was 84%. The results of elemental analysis are as follows. Note that this was calculated assuming that 1/2 molecule of H ₂ O was included. Measured value C, 55.54%; H, 7.80%; N, 15.43%; O,
21.23% Calculated value C, 54.95%; H, 7.69%; N, 16.02%; O,
21.35% The present invention provides the above cyclo(N〓-acryloyl-
L-lysylsarcosine) is homopolymerized in the presence of a radical polymerization catalyst, or a mixed monomer containing this monomer and a vinyl monomer having a substituent that is easily conjugated with a double bond is radically polymerized. This invention relates to a method for producing a novel polymer by conducting polymerization in the presence of a catalyst. As the polymerization catalyst used in the method of the present invention, any catalyst that is normally used in radical polymerization reactions can be used. Specifically, azobisisobutyronitrile (hereinafter referred to as AIBN) can be used.
Examples include aliphatic azo compounds such as, organic peroxides such as benzoyl peroxide, inorganic peroxides such as potassium persulfate and hydrogen peroxide, and redox polymerization catalysts using these catalysts in combination with reducing compounds. In the method of the present invention, cyclo(N〓-acryloyl-L
Comonomers to be copolymerized with styrene, nuclear-substituted styrene; acrylic acid, methacrylic acid or alkyl esters of these acids (e.g. methyl, ethyl, n-propyl n-butyl ester), amides, alkylamides; ; acrylonitrile, methacrylonitrile; vinylpyridine and the like. Next, examples of homopolymerization of the above monomers will be described. Example 1 0.328 g of cyclo(N〓-acryloyl-L-lysylsarcosine) was added to 0.348 ml of dimethylformamide.
0.0197g of AIBN was added thereto, the tube was sealed under reduced pressure, and polymerized at 80°C for 42 hours, poured into 20 times the volume of acetone, filtered, dried, washed with methanol and then acetone, and cyclo( A polymer of N-acryloyl-L-lysylsarcosine) was obtained. The yield was 64%. This polymer is estimated to consist of repeating units of the following formula. This polymer can be used in water, methanol, ethanol,
It is easily soluble in chloroform, methylene chloride, and dimethylformamide, soluble in dioxane and benzene, slightly soluble in acetone and tetrahydrofuran, and insoluble in ethyl ether. The IR spectrum of this polymer is shown in the accompanying drawing. Figure 1 shows the IR spectrum measured with the monomer cyclo(N-acryloyl-L-lysylsarcosine) applied to the surface of a KBr tablet.
The figure shows the IR spectrum of the polymer obtained in the above example by the KBr tablet method. In Figure 1,
Amide is present near 1650 cm ^-1 (indicated by arrow A in the figure).
Amide absorption is observed near 1530 cm ^-1 (arrow B) and C=C absorption is observed near 985 cm ^-1 (arrow C), but in contrast, in the IR spectrum of the polymer in Figure 2, absorption is observed near 985 cm ^-1 . The fact that no C=C absorption was observed indicates that a polymer was obtained. Next, an example of producing a copolymer of cyclo(N-acryloyl-L-lysylsarcosine) will be shown. Example 2 2.67 g (0.0105 mol) of cyclo(N〓-acryloyl-L-lysylsarcosine) and 1.10 styrene
Dissolve g (0.0106 mol) in 3.19 ml of dimethylformamide, and add 0.090 g (0.00055 mol) of AIBN to this.
was added and polymerized in a vacuum-sealed tube at 80°C for 42 hours, and then the polymerization solution was poured into 80 ml (20 times the volume) of acetone to precipitate the polymer. It was collected with a glass filter (without suction), dried under reduced pressure, washed several times with acetone and water, and dried. Yield: 2.72g
It is. The resulting copolymer is dimethylformamide,
Easily soluble in methanol, ethanol, chloroform, methylene chloride, soluble in benzene and dioxane, slightly soluble in acetone, tetrahydrofuran, water,
It was insoluble in ether. Dissolve 3.77 g of the copolymer obtained above in approximately 20 ml of dimethylformamide, and dissolve approximately 10 ml of the copolymer.
of diethyl ether was added little by little with stirring, and when it became cloudy, the mixture was warmed to form a homogeneous clear solution, and equilibrium was reached at room temperature. I got a fraction. Diethyl ether was added to the supernatant and fractionated in the same manner as above to obtain second and third fractions. The copolymer recovery rate is 72%. Data such as fractionation amount and physical properties of each fraction are shown below.

【table】 .
** 〓η〓＝3.3×10 ⁻⁵ M ^{0 85}
Calculate according to
Figure 3 shows the IR spectra of each of the above fractions measured by the KBr tablet method. That is, Figure 3 A, B and C represent the first, second and third fractions, respectively.
This is an IR spectrum. In these IR spectra, the absorption around 995 cm ^-1 (CH bending vibration of vinyl group) common to styrene and cyclo(N〓-acryloyl-L-lysylsarcosine) is not observed in the reaction product. Indicates that the product is a polymer.
Also, around 700cm ^-1 (arrow D) and 750cm ^-1 (arrow E)
The absorption is due to the C-H bending vibration of the monosubstituted phenyl group, indicating that the reaction product is a styrene copolymer. The absorption near 1650 cm ^-1 (arrow A) is an amide absorption band, and the absorption near 1530 cm ^-1 (arrow B) is an amide absorption band, and the reaction product is cyclo(N〓
-acryloyl-L-lysylsarcosine) copolymer. The repeating units of these copolymers are considered as follows. The homopolymers and copolymers obtained by the method of the present invention are utilized in the following fields due to the cyclic peptides in their side chains. For example, it can be used for the removal of various metal ions (light metal ions, heavy metal ions), halogen molecules such as iodine, homopolymers in aqueous solutions and organic solvents, and copolymers for the removal of substances that can form complexes in organic solvents. .
In addition, homopolymers and copolymers with copper ions coordinated serve as catalysts for oxidation reactions (e.g., epoxide production by oxidation of olefins, aldehyde production by alcohol oxidation, etc.), and those with rhodium ions coordinated can be used for reduction. It can be used as a catalyst for reactions (such as the production of alkanes by the reduction of olefins and the production of alcohols by the reduction of ketones). In this case, as a catalyst supported on an asymmetric polymer, it can be expected to serve as a catalyst for asymmetric, substrate-selective oxidation and reduction reactions. What has been explained above and shown in the examples relates to typical examples to help the understanding of the present invention, and the present invention is not limited to these examples, but may include other modifications within the gist of the invention. It is something that can be taken.

[Brief explanation of drawings]

Figure 1 is the IR spectrum of cyclo(N〓-acryloyl-L-lysylsarcosine), Figure 2 is the IR spectrum of the homopolymer of cyclo(N〓-acryloyl-L-lysylsarcosine), Figure 3 is A,
B and C are each cyclo(N〓-acryloyl-L
This is an IR spectrum of a copolymer of styrene (-lysylsarcosine) and styrene that was fractionated using a solvent. In Figures 1 to 3, the vertical axis is transmittance (%) (left)
and absorbance (right), the horizontal axis is the wavelength (10 ^-6 m) (top) and the wave number (cm ^-1 ) (bottom), where A is the amide absorption band, B is the amide absorption band, and C is the vinyl type CH. , and D and E indicate the absorption part due to CH bending vibration of the monosubstituted phenyl group.

Claims (1)

[Claims] 1 Polymerization of cyclo(N〓-acryloyl-L-lysylsarcosine) or a mixed monomer containing this and a vinyl monomer having a substituent that is easily conjugated with a double bond in the presence of a radical polymerization catalyst. A method for producing a vinyl polymer with a characteristic cyclic peptide in its side chain.