JPH08127564A - N-vinyloxycarbonyl-leucine alkyl ester, its production and polymer therefrom - Google Patents

Abstract

PURPOSE: To obtain a novel N-vinyloxycarbonyl-leucine alkyl ester which is useful as a starting substance of a novel polymer having liquid crystal properties, biocompatibility, biodegradability and the like. CONSTITUTION: This compound is represented by formula I (R<1> is a 1-3C alkyl), for example, N-vinyloxycarbonyl-L-leucine methyl ester. The compound of formula I is obtained by reaction of a leucine-alkyl ester of formula II with a vinyl chloroformate in a solvent such as methylene chloride, preferably in the presence of a base such as sodium hydrogen carbonate at -20-40 deg.C for 1-24 hours. The compound of formula I is polymerized with a polymerization initiator such as azobisisobutyronitrile to give N-vinyloxycarbonyl-leucine alkyl ester polymer. This polymer has a combination of the optical activity with the physiological activity due to the leucine alkyl ester structure.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel compound, N-vinyloxycarbonyl-leucine alkyl ester, a method for producing the same, and a (co) polymer of the compound.

[0002]

2. Description of the Related Art Various vinyl monomers having an α-amino acid structure as a side chain are known, and there is interest in the polymerization behavior based on the chirality of the side chain and the structure and properties of the produced polymer.

However, there has been no report so far on the synthesis of a vinyloxycarbonyl compound having a leucine alkyl ester structure in its side chain and its polymer. The inventors of the present invention have diligently studied to obtain a novel polymer that exhibits optical activity derived from a leucine alkyl ester structure, physiological activity, liquid crystallinity, biocompatibility, and biodegradability. The present invention has been completed based on the idea of introducing a leucine alkyl ester structure into the side chain of a vinyloxycarbonyl compound.

[0004]

OBJECT OF THE INVENTION It is an object of the present invention to provide a novel polymer expected to have properties such as liquid crystallinity, biocompatibility and biodegradability. Another object of the present invention is to provide a monomer compound as a starting material for such a novel polymer and a method for producing the same.

[0005]

SUMMARY OF THE INVENTION The novel compound N-vinyloxycarbonyl-leucine alkyl ester according to the present invention has a structure represented by the following formula (I).

[0006]

Embedded image

(In the formula, R ¹ represents an alkyl group having 1 to 3 carbon atoms.) Here, L-leucine or D-leucine is specifically used as leucine.

The N-vinyloxycarbonyl-leucine alkyl ester according to the present invention can be obtained by reacting a leucine-alkyl ester represented by the following formula (II) with vinyl chloroformate.

[0009]

[Chemical 6]

The N-vinyloxycarbonyl-leucine alkyl ester polymer according to the present invention comprises a repeating unit represented by the following formula (III). N- according to the present invention
Vinyloxycarbonyl-leucine alkyl ester /
The alkyl (meth) acrylate copolymer has the following (II
It comprises a repeating unit represented by the formula (I) and a repeating unit represented by the following formula (IV).

[0011]

[Chemical 7]

(In the formula, R ¹ represents an alkyl group having 1 to 3 carbon atoms, R ² represents a hydrogen atom or a methyl group, and R ³ represents an alkyl group having 1 to 10 carbon atoms.) N-vinyloxycarbonyl according to the present invention
Leucine alkyl ester (co) polymers are expected to have properties such as liquid crystallinity, biocompatibility, and biodegradability.

[0013]

DETAILED DESCRIPTION OF THE INVENTION The N-vinyloxycarbonyl-leucine alkyl ester according to the present invention has a structure represented by the following formula (I).

[0014]

Embedded image

Here, R ¹ represents an alkyl group having 1 to 3 carbon atoms, specifically, a methyl group, an ethyl group, an n-propyl group or an i-propyl group, preferably a methyl group. The leucine in the N-vinyloxycarbonyl-leucine alkyl ester may be in the L-form or the D-form, and may be a mixture thereof (racemic form). From the viewpoint of the above, it is preferable to be either one of the L-form and the D-form, and from the viewpoint of biocompatibility, the L-form is preferable.

The structure of such N-vinyloxycarbonyl-leucine alkyl ester according to the present invention can be determined by nuclear magnetic resonance analysis (NMR), infrared absorption analysis (IR), elemental analysis and the like.

The N-vinyloxycarbonyl-leucine alkyl ester of the present invention can be obtained by reacting a leucine-alkyl ester with vinyl chloroformate. The leucine-alkyl ester as a starting material can be obtained by reacting leucine with an alcohol (R ¹ OH, where R ² represents an alkyl group having 1 to 3 carbon atoms) by a known method. Leucine may be in the L-form, the D-form, or a mixture thereof (racemic form). As the alcohol, methanol, ethanol or propanol is used, and methanol is particularly preferable. The leucine-alkyl ester obtained by such a reaction is usually present in the form of a hydrochloride or TosOH salt. In the present invention, leucine-alkyl ester may be used in the form of these salts,
It is also possible to use a desalted and isolated leucine-alkyl ester.

The N-vinyloxycarbonyl-leucine alkyl ester according to the present invention can be obtained by reacting a leucine-alkyl ester with vinyl chloroformate. This reaction is performed using halogenated hydrocarbon solvents such as methylene chloride and chloroform; THF, acetonitrile, DM
In a solvent such as an aprotic polar solvent such as F, -20 to 4
It is carried out at about 0 ° C. for about 1 to 24 hours. Also, during the reaction, triethylamine, t-BuOK, K ₂ C
It is particularly preferable to add a base such as O ₃ , Na ₂ CO ₃ and NaHCO ₃ . This reaction is represented by the following equation.

[0019]

[Chemical 9]

(In the formula, R ¹ is an alkyl group having 1 to 3 carbon atoms.) The N-vinyloxycarbonyl-leucine alkyl ester polymer according to the present invention is the above-mentioned N-vinyloxycarbonyl-leucine alkyl ester. Is obtained in the presence of a polymerization initiator.

As the polymerization initiator, azobisisobutylnitrile (AIBN), benzoyl peroxide (BPO),
Conventionally known radical polymerization initiators such as acetyl peroxide are preferably used.

The polymerization reaction may be carried out in a solid phase (bulk polymerization) or in a liquid phase using chlorobenzene, dimethylformamide, methanol or the like as a reaction solvent.

The amount of the polymerization initiator used is preferably about 0.1 to 10 mol% based on 1 mol of all the monomers. In the case of liquid phase polymerization, the monomer concentration in the reaction system is usually preferably about 0.1 to 10 mol / liter. The polymerization temperature is appropriately set according to the type of polymerization initiator used. Polymerization time is usually 1
It is about 72 hours. After the reaction for a predetermined time, the polymerization is stopped, washed and dried to obtain an N-vinyloxycarbonyl-leucine alkyl ester polymer. The molecular weight of the obtained N-vinyloxycarbonyl-leucine alkyl ester polymer is usually 5,000 to 1.0.
It is about 0,000, preferably 10,000 to 5
It is about 0,000. This polymerization reaction is represented by the following formula.

[0024]

[Chemical 10]

(In the formula, R ¹ is the same as above.) The polymer thus obtained has optical activity and physiological activity derived from the leucine alkyl ester structure, and has liquid crystallinity, biocompatibility and biodegradability. It is expected to exhibit characteristics such as sex.

The N-vinyloxycarbonyl-leucine alkyl ester / alkyl (meth) acrylate copolymer according to the present invention is an N-vinyloxycarbonyl-leucine alkyl ester represented by the above formula (I) and an alkyl (meth). It is obtained by radical copolymerization with an acrylate in the presence of a radical polymerization initiator.

Here, as the alkyl group of the alkyl (meth) acrylate, specifically, methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, t- C1-C1 such as butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group and decyl group
Examples thereof include an alkyl group of 0, and among these, particularly preferable ones are a methyl group and an ethyl group. Therefore,
Particularly preferred alkyl (meth) acrylates include
Examples thereof include methyl acrylate, methyl methacrylate, ethyl acrylate and ethyl methacrylate.

The copolymerization of N-vinyloxycarbonyl-leucine alkyl ester and alkyl (meth) acrylate is carried out under the same conditions as in the above-mentioned homopolymerization of N-vinyloxycarbonyl-leucine alkyl ester.

Such an N-vinyloxycarbonyl-leucine alkyl ester / alkyl (meth) acrylate copolymer according to the present invention comprises a structural unit (III) derived from N-vinyloxycarbonyl-leucine alkyl ester, And a structural unit (IV) derived from alkyl (meth) acrylate.

[0030]

[Chemical 11]

(In the formula, R ¹ is the same as above, R ² represents a hydrogen atom or a methyl group, and R ³ has 1 to 10 carbon atoms.
Is an alkyl group. ) In the copolymer of the present invention, the ratio of the structural unit (III) derived from N-vinyloxycarbonyl-leucine alkyl ester to the structural unit (IV) derived from alkyl (meth) acrylate is Although not limited, it is usually (III) / (IV) (molar ratio), 99/1 to 1
/ 99, preferably about 95/5 to 5/95. The composition of such a copolymer is appropriately set depending on the application, and, for example, from the viewpoint of biocompatibility and biodegradability, the proportion of structural units derived from N-methacryloyl-L-leucine alkyl ester is Larger copolymers are preferred. The molecular weight of such a copolymer according to the present invention is usually 5,0.
It is about 0 to 1,000,000, preferably 1
It is about 50,000 to 500,000.

Further, the N-vinyloxycarbonyl-leucine alkyl ester / alkyl (meth) acrylate copolymer of the present invention is copolymerized with various monomers within a range not impairing the object of the present invention. Good.

[0033]

EXAMPLES The present invention will be described more specifically below based on examples, but the present invention is not limited to these examples.

[0034]

Example 1 [Synthesis of N-vinyloxycarbonyl-L-leucine methyl ester] L-leucine methyl ester hydrochloride (9.08 g,
50 mmol), NaHCO ₃ (8.4 g, 100 mmol) and methylene chloride (100 ml) were added dropwise with chloroform chloroformate (5.1 ml, 56 mmol) at 0 ° C. under a nitrogen stream.
Stir overnight at room temperature. After filtering the inorganic salts, the solvent of the filtrate was distilled off under reduced pressure, and the residue was purified by distillation under reduced pressure (0.9 mmHg / 100 ° C).
Vinyloxycarbonyl-L-leucine methyl ester (hereinafter sometimes abbreviated as VOCLM) was obtained in an amount of 18.1 g (yield 56%). ¹ H-NMR and ^{1 3} C-N of VOCLM
The MR spectrum is shown in FIGS. 1 and 2. The analysis results are shown below. ¹ H-NMR (CDCl ₃ ) (δ in ppm): 7.12-7.48
(m, 1H), 5.80 (d, J = 17Hz, 1H), 4.70-4.95 (m, 2H),
4.25-4.60 (m, 1H), 3.80 (s, 3H), 1.43-1.92 (m, 3
H), 0.71-1.15 (m, 6H) ¹³ C-NMR (CDCl ₃ ) (δ in ppm): 173.4, 15
4.6, 142.5, 95.2, 53.0, 52.9, 41.7, 24.9, 22.5, 21.
7 Specific optical rotation [α] ²⁷ _D , IR spectrum of the obtained VOCLM,
The results of elemental analysis are shown below. [Α] ²⁷ _D : + 3.5 ° (c 1.00 g / dl, CHCl ₃ ) IR (KBr): 3341, 2959, 1744, 1649, 1530, 1223, 1046
cm ^-1 Elemental analysis (calculated): C, 55.80; H, 7.96; N, 6.51 Elemental analysis (measured): C, 55.61; H, 8.37; N, 6.54

[0035]

Example 2 [Polymerization of N-vinyloxycarbonyl-L-leucine methyl ester (VOCLM)] VOCLM obtained in Example 1
1 mol% of 2,2'-azobisisobutyronitrile (AIBN) was added to 3 mmol (0.65 g), and the tube was degassed and sealed.
Solid phase polymerization was performed at 20 ° C. for 20 hours.

After 20 hours, the obtained polymer was washed with n-hexane and dried under reduced pressure to recover the polymer. The conversion rate of VOCLM measured by ¹ H-NMR is
It was 63%.

The molecular weight and molecular weight distribution of the polymer obtained were determined by polystyrene conversion by GPC. Further, the glass transition temperature (Tg) of the polymer was measured by DSC. The Td ₁₀ (10% weight loss temperature) of the polymer was measured by thermogravimetric analysis in a nitrogen stream. 27 ℃ (c 1.00 g
The specific rotation [α] _D was measured with / dl, CHCl ₃ ). Table 1 shows the results.

¹ H-NMR of the obtained VOCLM polymer
Is shown in FIG. ¹ H-NMR (CDCl ₃ ) (δ in ppm): 6.48-6.94
(m, 1H), 4.60-5.18 (m, 1H), 4.09-4.45 (m, 1H), 3.58
-3.90 (m, 3H), 1.30-2.31 (m, 5H), 0.64-1.08 (m, 6H)

[0039]

Examples 3 to 5 VOCLM (3 mmol) was added to chlorobenzene (Example 3), dimethylformamide (Example 4) and methanol (Example 5) as a polymerization solvent at a concentration of 1
The same operation as in Example 2 was carried out except that the solution was dissolved so that the amount became mol / liter and the liquid phase polymerization was carried out. The results are shown in Table 1.

[0040]

[Table 1]

[0041]

The N-vinyloxycarbonyl-leucine alkyl ester (co) polymer according to the present invention has optical activity and physiological activity derived from the leucine alkyl ester structure, and has liquid crystallinity, biocompatibility, and bioactivity. Expected to develop properties such as degradability.

[Brief description of drawings]

FIG. 1 shows the ¹ H-NMR spectrum of N-vinyloxycarbonyl-L-leucine methyl ester.

FIG. 2 shows a ¹³ C-NMR spectrum of N-vinyloxycarbonyl-L-leucine methyl ester.

FIG. 3 shows a ¹ H-NMR spectrum of an N-vinyloxycarbonyl-L-leucine methyl ester polymer.

Claims (6)

[Claims] 1. An N-vinyloxycarbonyl-leucine alkyl ester represented by the following formula (I). Embedded image (In the formula, R ¹ represents an alkyl group having 1 to 3 carbon atoms.) 2. The N-vinyloxycarbonyl-group according to claim 1, wherein leucine is L-leucine.
Leucine alkyl ester. 3. The N-vinyloxycarbonyl-group according to claim 1, wherein leucine is D-leucine.
Leucine alkyl ester. 4. A N-vinyloxycarbonyl-leucine alkyl ester represented by the above formula (I), which comprises reacting a leucine alkyl ester represented by the following formula (II) with vinyl chloroformate. Production method. Embedded image (In the formula, R ¹ represents an alkyl group having 1 to 3 carbon atoms.) 5. An N-vinyloxycarbonyl-leucine alkyl ester polymer comprising a repeating unit represented by the following formula (III). Embedded image (In the formula, R ¹ represents an alkyl group having 1 to 3 carbon atoms.) 6. An N-vinyloxycarbonyl-leucine alkyl ester / alkyl (meth) acrylate copolymer comprising a repeating unit represented by the following formula (III) and a repeating unit represented by the following formula (IV). [Chemical 4] (In the formula, R ¹ represents an alkyl group having 1 to 3 carbon atoms, and R ²
Represents a hydrogen atom or a methyl group, and R ³ has 1 to 1 carbon atoms.
And represents an alkyl group of 0. )