JP2662610B2 - N- (2-hydroxyethyl) -N-substituted acrylamide and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

FIELD OF THE INVENTION The present invention relates to a polymer or copolymer monomer having excellent antithrombotic and cell proliferating properties.
The present invention relates to-(2-hydroxyethylene) -N-substituted acrylamide and a method for producing the same.

[0002]

The best known of the derivatives of acrylamide are N-hydroxyalkylacrylamide and N-hydroxyalkylmethacrylamide as monomers for the preparation of water-soluble polymers, In addition, N-isopropylacrylamide and N-cyclopropylacrylamide are used as monomers for producing a reversible heat-sensitive polymer, that is, a polymer that exhibits a behavior of dissolving / insoluble in a solvent depending on temperature. And the like (JP-A-58-174408, JP-A-60-110709).

[0003] However, acrylamide or methacrylamide in which a nitrogen atom is simultaneously substituted with a hydrophilic group and a hydrophobic group has not been known.

[0004]

SUMMARY OF THE INVENTION The object of the present invention is to provide a novel acrylamide derivative which has a wide range of use as a raw material for producing a useful polymer.

[0005]

The present inventors have conducted intensive studies to develop a novel acrylamide derivative. As a result, one of the two hydrogen atoms in the NH2 group of acrylamide is a hydrophilic group. -Hydroxyethylene-substituted and hydrophobic-substituted ones are novel monomers that, when polymerized, produce polymers or copolymers with excellent antithrombotic and cell-proliferating properties This led to the present invention based on this finding.

That is, the present invention provides a compound represented by the general formula

Embedded image (Wherein R is an alkyl or aralkyl group).

The N-hydroxyethyl-N-substituted acrylamide is, for example, an N-hydroxyethyl-N-substituted acrylamide represented by the general formula R-NHCH2CH2OH (wherein R has the same meaning as described above).
The substituted ethanolamine is silylated to form O-silylation 2
-A substituted aminoethanol, which is then reacted with acryloyl halide and then hydrolyzed with an acid to remove the silyl group.

This method proceeds according to the following reaction formula.

Embedded image (X in the formula is a halogen atom, and R has the same meaning as described above.)

In this method, the N-substituted ethanolamine used as a starting material can be obtained by reacting a known compound such as 2-aminoethanol with an alkyl halide, aryl halide or aralkyl halide.

Next, in order to protect the hydroxyl group of the N-substituted ethanolamine with a silyl group, the N-substituted ethanolamine is reacted with halogen trimethylsilane in the presence of a base to form an O-silylated compound.
-Substituted aminoethanol.

Next, the O-silylated 2-substituted aminoethanol is reacted with acryloyl halide in the presence of a catalyst such as triethylamine, and the reaction mixture is filtered to remove ammonium salt as a by-product, and the pressure in the filtrate is reduced. And recovering the silylated product by distillation. Next, the silylated product thus obtained is hydrolyzed with an acid to remove the silyl group, whereby the N-formula represented by the general formula (I) is obtained.
-(2-hydroxyethyl) -N-substituted acrylamide is obtained.

In the production of the N-substituted ethanolamine, the alkyl halide to be reacted with 2-aminoethanol is a linear or branched alkane chloride, bromide or iodide. Something like
For example, methyl chloride, ethyl chloride, propyl chloride, isopropyl chloride, butyl chloride, isobutyl chloride, pentyl chloride, hexyl chloride, heptyl chloride, octyl chloride, (2-ethylhexyl) chloride, decyl chloride, dodecyl chloride,
Mention may be made of palmityl chloride and the corresponding bromides, iodides.

The aryl halide and aralkyl halide are phenyl chloride and benzyl chloride which may have a substituent on the benzene nucleus, and corresponding bromides and iodides. Examples of the nuclear substituent include lower alkyl. Groups, halogen atoms, nitrile groups, nitro groups and the like.

The reaction of these alkyl halides, aryl halides or aralkyl halides with 2-aminoethanol is carried out by using alcohols, dialkylformamides,
In an inert solvent such as ethers, both are dissolved in approximately equimolar amounts, and the mixture is heated under reflux for about 15 to 20 hours. The solvent is distilled off from the reaction mixture, and the residue is extracted with an aqueous alkaline solution such as aqueous caustic soda to separate the N-substituted ethanolamine. The N-substituted ethanolamines thus obtained are usually high-boiling oily substances.

Next, as the halogen trimethylsilane used for protecting the hydroxyl group of N-substituted ethanolamine, chlorotrimethylsilane is preferable, but bromotrimethylsilane, iodotrimethylsilane and the like can also be used. The reaction between the N-substituted ethanolamine and the halogenotrimethylsilane is performed in an inert solvent such as tetrahydrofuran, dimethylformamide, and diethylacetamide in the presence of a base. Examples of the base include triethylamine, dimethylethylamine,
Tertiary amines such as dimethylpropylamine and tripropylamine are preferred.

The 2-hydroxyaminoethanol silylated in this manner is then reacted with acryloyl halide.
Acryloyl chloride and acryloyl bromide are preferred. This reaction can be carried out in an inert solvent such as benzene, in the presence of a base such as triethylamine, at a temperature of 0 to 5C. Hydrochloric acid is preferred as the acid for removing the silyl group from the silylated product thus obtained, but other acids such as sulfuric acid can also be used.

The compounds thus obtained include:
For example, N- (2-hydroxyethyl) -N-ethylacrylamide, N- (2-hydroxyethyl) -N-propylacrylamide, N- (2-hydroxyethyl)-
N-butylacrylamide, N- (2-hydroxyethyl) -N-hexylacrylamide, N- (2-hydroxyethyl) -N-octylacrylamide, N- (2
-Hydroxyethyl) -N-phenylacrylamide,
N- (2-hydroxyethyl) -N-benzylacrylamide and the like can be mentioned.

These compounds can be purified, if necessary, by distillation, chromatography and the like.

The N- (2-hydroxyethyl)-of the present invention
The N-substituted acrylamide can be polymerized with a radical polymerization initiator, for example, azobisisobutyronitrile, benzoyl peroxide or the like, to obtain a polymer having excellent antithrombotic properties and cell proliferation.

[0020]

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

Example 1 2-aminoethanol 6 in 1000 ml of ethanol
1 g and 123 g of propyl bromide were dissolved and heated under reflux for 16 hours.

Then, ethanol was distilled off from the reaction mixture, and the residue was mixed with 500 ml of a 30% aqueous solution of caustic soda.
Was added and shaken, and the separated upper layer was separated and distilled.

Thus, the boiling point is 80 ° C./6 mmHg
Of 2-propylaminoethanol was obtained. Next, the 2-propylaminoethanol thus obtained was dissolved in 500 ml of tetrahydrofuran, and 2 g of triethylamine was added thereto.
After adding 0 g and reacting at 20 ° C. for 5 hours, the solvent and unreacted chlorotrimethylsilane were distilled off to obtain O-silylated 2-propylaminoethanol.

This O-silylated 2-propylaminoethanol was dissolved in 300 ml of benzene, and 95 g of triethylamine and 91 g of acryloyl chloride were added.
After stirring at 10 ° C. for 10 hours, the resulting precipitate of triethylammonium chloride is removed by filtration, and the filtrate is distilled under reduced pressure. To the residue was added 2N-hydrochloric acid (30 ml), and the mixture was stirred at room temperature for 5 hours, allowed to stand, separated from the separated oil layer, and distilled three times under reduced pressure.

Thus, N- (2-hydroxyethyl) -N-propylacrylamide (70 g, yield 80%) was obtained as a fraction at 110 ° C./4 mmHg. Its d was 1.0346.

Example 2 Octyl bromide 1 in place of propyl bromide in Example 1
Exactly the same process as above except that 93 g was used,
74 g of N- (2-hydroxyethyl) -N-octylacrylamide having a temperature of 4 ° C./4 mmHg and d = 0.8755 was obtained (yield: 80%).

Example 3 The procedure of Example 1 was repeated, except that 171 g of benzyl bromide was used instead of propyl bromide.
57 g of N- (2-hydroxyethyl) -N-benzylacrylamide having a temperature of 4 ° C./4 mmHg and d = 1.0090 was obtained (yield: 80%).

Reference Example 100 g of N- (2-hydroxyethyl) -N-octylacrylamide obtained in Example 2 was dissolved in 500 ml of dimethylformamide, and azobisisobutyronitrile was used as a polymerization initiator at 8.26 × 10 6. -3 mol / liter and polymerized at 65 ° C. for 2 hours in a nitrogen stream.

Next, the polymerization product was poured into cold water, the formed white precipitate was collected by filtration, dried, dissolved again in dimethylformamide, poured into water, reprecipitated, filtered, and filtered with water. And methanol, and dried.

Thus, poly [N- (2-hydroxyethyl) -N-octylacrylamide] was obtained at a conversion of 70%.

This has an intrinsic viscosity [η] of 0.704 d.
l / g and the glass transition temperature was 46.6 ° C.

When a blood coagulation test was performed on this product, a remarkable coagulation delay effect was exhibited.

[0033]

The N- (2-hydroxyethyl) of the present invention
-N-substituted acrylamide is a novel compound and is easily polymerized in the presence of a radical polymerization initiator, and becomes a polymer having excellent antithrombotic and cell proliferating properties. Can be.

Claims (2)

(57) [Claims] 1. A compound of the general formula (Wherein R is an alkyl or aralkyl group ) N- (2-hydroxyethyl) -N-substituted acrylamide. 2. An N-substituted ethanolamine represented by the general formula R-NHCH ₂ CH ₂ OH (where R is an alkyl or aralkyl group ) is silylated to form an O-silylated 2-substituted aminoethanol. Which is then reacted with acryloyl halide, and then the silyl group is eliminated by hydrolysis with an acid. (Wherein R has the same meaning as described above)
A method for producing (2-hydroxyethyl) -N-substituted acrylamide.