JPH07101967A - Ammonium phosphate derivative and its production - Google Patents

Abstract

PURPOSE:To simply and efficiently obtain a new ammonium phosphate derivative having a structure similar to the polar group of a phospholipid, and having as an azo polymerization initiator, etc., by reacting a specific azo compound with a specific phosphorane compound. CONSTITUTION:A compound of formula I [R<1>, R<2> are 1-4C alkyl; R<3> is 1-6C alkyl; m is 1-6)], concretely, 2-[(2-ethoxyphosphate ethyl)dimethylammonio]ethyl=4,4'-azobis(4-cyanovaleate), etc., is obtained by reacting an azo compound of formula II with a phosphorane compound of formula III. An organic solvent such as acetonitrile is preferably used for the reaction.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel and useful ammonium phosphate derivative and a method for producing the same, more specifically, it has a structure similar to the polar group of phospholipids at the terminal and can be used as an azo polymerization initiator. It relates to an ammonium phosphate derivative and a method for producing the same.

[0002]

BACKGROUND OF THE INVENTION Phospholipids are widely present in the living world and are one of the main constituents of biological membranes. It has a close relationship with various metabolic processes of the living body and is deeply involved in fat transportation and absorption, blood coagulation, etc., and plays an important role in maintaining the living body.

When such phospholipids are used for medical materials such as catheters, artificial organs and blood circuits, as well as contact lenses, cosmetics, biosensors or diagnostic agents, they have a function similar to that of biological membranes, that is, antithrombotic properties. And may exhibit inhibition of protein attachment. In recent years, many monomers and polymers having polar groups of phospholipids have been developed as such attempts and are used for the above applications.

For example, 2 which is a phosphorylcholine derivative
A method for producing-(methacryloyloxy) ethyl-2 '-(trimethylammonium) ethyl phosphate and a phospholipid-like monomer having various polymer groups has been proposed (JP-A-54-63025, JP-A-60-18409).
No. 3). However, it is very difficult to industrially mass-produce such monomers having polar groups of phospholipids and to prepare monomers having different polymerization groups depending on the polymerization method and purpose of use.

By the way, in general, the polymerization initiator determines the polymerization rate, the molecular weight, and other polymer characteristics during radical polymerization. Further, the structure of the polymerization initiator is located at the end of the polymer, so that it is possible to impart special polymer characteristics. In particular, when the polymerization initiator having a polar group of phospholipid is located at the polymer terminal, it becomes possible to impart physiological functions such as antithrombotic property and protein adhesion prevention. Further, when such a polymerization initiator is used, it is considered that various monomers can be polymerized and the above problems can be solved. However, an ammonium phosphate derivative having such a polar group of phospholipid is not known.

[0006]

The object of the present invention is to provide a novel and useful ammonium phosphate derivative having a structure similar to the polar group of phospholipids and which can be used as a polymerization initiator when polymerizing various monomers. , And its manufacturing method.

[0007]

The present invention provides the following ammonium phosphate derivative and a method for producing the same. (1) General formula (1)

[Chemical 6] (In the formula, R ¹ and R ² represent an alkyl group having 1 to 4 carbon atoms, and R ¹ and R ² may be the same or different. R ³
Represents an alkyl group having 1 to 6 carbon atoms. m represents an integer of 1 to 6. ) An ammonium phosphate derivative represented by: (2) In the general formula (1), R ¹ and R ² are each CH.
₃ , R ³ is CH ₂ CH ₃ and m is 2.

[Chemical 7] The ammonium phosphate derivative according to claim 1, which is represented by: (3) General formula (3)

[Chemical 8] (In the formula, R ¹ and R ² represent an alkyl group having 1 to 4 carbon atoms, R ¹ and R ² may be the same or different, and m represents an integer of 1 to 6.) Compound and general formula (4)

[Chemical 9] (In the formula, R ³ represents an alkyl group having 1 to 6 carbon atoms.) A method for producing an ammonium phosphate derivative represented by the above general formula (1), which comprises reacting with a phosphorane compound represented by the formula.

Examples of the alkyl group represented by R ¹ or R ² in the general formula (1) include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group and s.
ec-butyl group, tert-butyl group, etc. having 1 to 1 carbon atoms
4 is an alkyl group. Examples of the alkyl group represented by R ³ include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, s
Examples thereof include alkyl groups having 1 to 6 carbon atoms such as ec-butyl group, tert-butyl group, n-pentyl group, tert-pentyl group and n-hexyl group.

Typical examples of the ammonium phosphate derivative represented by the general formula (1) include the compounds represented by the above formula (2), and the following compounds are also included in the compounds represented by the general formula (1). .

[Chemical 10]

[0010]

[Chemical 11]

Such an ammonium phosphate derivative can be produced by reacting the azo compound represented by the general formula (3) with the phosphorane compound represented by the general formula (4). This reaction formula is shown below. In the formula, R ¹ , R ² , R ³ and m are the same as above.

[Chemical 12]

Specific examples of the azo compound represented by the general formula (3) include the followings. N, N'-dimethylammonioethyl = 4
4'-azobis (4-cyanovalerate), N, N'-
Dimethylammoniopropyl = 4,4'-azobis (4
-Cyanovalerate), N, N'-dimethylammoniobutyl = 4,4'-azobis (4-cyanovalerate), N, N'-dimethylammoniopentyl = 4,
4'-azobis (4-cyanovalerate), N, N'-
Dimethylammoniohexyl = 4,4'-azobis (4
-Cyanovalerate), N, N'-diethylammonioethyl = 4,4'-azobis (4-cyanovalerate), N, N'-diethylammoniopropyl = 4,
4'-azobis (4-cyanovalerate), N, N'-
Dipropylethylammoniobutyl = 4,4′-azobis (4-cyanovalerate), N, N′-ethylmethylammoniohexyl = 4,4′-azobis (4-cyanovalerate), N, N ′ -Ethylpropylammonioethyl = 4,4'-azobis (4-cyanovalerate)

Specific examples of the phosphorane compound represented by the general formula (4) include the following. 2-ethoxy-2-oxo-1,3,2
-Λ5-dioxaphosphorane, 2-methoxy-2-oxo-1,3,2-λ5-dioxaphosphorane, 2-propyloxy-2-oxo-1,3,2-λ5-dioxaphosphorane , 2-butyloxy-2-oxo-1,3,
2-λ5-dioxaphosphorane, 2-pentyloxy-
2-oxo-1,3,2-λ5-dioxaphosphorane,
2-hexyloxy-2-oxo-1,3,2-λ5-
Dioxaphosphorane

The reaction between the azo compound represented by the general formula (3) and the phosphorane compound represented by the general formula (4) is
It is preferable to rapidly add the solution of the phosphorane compound dissolved in a suitable organic solvent to the solution of the azo compound dissolved in a suitable organic solvent to carry out the reaction. In addition, in order to avoid mixing of water into the reaction system, it is preferable to appropriately perform dehydration distillation.

As the organic solvent, an organic solvent in which the azo compound and the phosphorane compound are dissolved and the formed reaction product is deposited can be used. For example, tetrahydrofuran,
Acetonitrile, acetone, chloroform, methylene chloride, benzene and the like can be used.

The reaction proceeds even at room temperature, but the higher the temperature, the faster the reaction. However, if the reaction temperature exceeds 60 ° C, the decomposition is promoted, so 60 ° C or less, preferably room temperature to 40 ° C, is desirable. The reaction time is 30 minutes to 72 hours, preferably 6 to 36 hours, and the reaction pressure is 0.
-20 kgf / cm ² , preferably 0-5 kgf / cm ²
Is desirable.

The reaction molar ratio of the azo compound represented by the general formula (3) as a starting material and the phosphorane compound represented by the general formula (4) is 1: 1.6 to 1:10, preferably 1: 2 to 2. It is desirable to set it to 1: 6. When the amount of the phosphorane compound is less than this range, the reaction rate is lowered, and even when the amount of the phosphorane compound is more than this range, the reaction rate cannot be improved.

As the reaction proceeds, the desired ammonium phosphate derivative is deposited. After completion of the reaction, the precipitated product is filtered and then washed with the organic solvent used in the reaction to isolate the ammonium phosphate derivative.

Next, a method for producing the azo compound represented by the general formula (3) and the phosphorane compound represented by the general formula (4) as starting materials will be described. The azo compound represented by the general formula (3) includes, for example, 4,4′azobis (4-cyanovaleric acid) and phosphorus pentachloride in a ratio of 1: 1.
A molar ratio of 6 to 1:10, preferably 1: 2 to 1: 6,
The reaction is carried out in an organic solvent such as benzene to obtain 4,4′-azobis (4-cyanovaleric acid chloride) (Makromomo
l. Chem. , 103, 301, (1967)) and then the 4,4'-azobis (4-cyanovaleric acid chloride) and an aminoalcohol compound represented by the following general formula (5): 1: 1.6 to 1 : 10, preferably 1: 2
It can be produced by a method such as reacting in an organic solvent such as benzene at a molar ratio of ˜1: 6.

[Chemical 13] (In the formula, R ¹ and R ² represent an alkyl group having 1 to 4 carbon atoms, R ¹ and R ² may be the same or different, and m represents an integer of 1 to 6.)

Specific examples of the aminoalcohol compound represented by the above general formula (5) include the following. 2- (N, N'-dimethylamino) ethanol, 3- (N, N'-dimethylamino)
-1-Propanol, 4- (N, N'-dimethylamino) -1-butanol, 5- (N, N'-dimethylamino) -1-pentanol, 6- (N, N'-dimethylamino)- 1-hexanol, 2- (N, N'-diethylamino) ethanol, 3- (N, N'-diethylamino) -1-propanol, 4- (N, N'-dipropylamino) -1-butanol, 6- (N-ethyl-N'-
Methylamino) -1-hexanol, 2- (N-ethyl-N′-propylamino) ethanol

The above reaction formula is shown below. In addition, R ¹ , R ² and m in the formula have the same meanings as described above. Et represents an ethyl group.

[Chemical 14]

The phosphorane compound represented by the general formula (4) is, for example, phosphorus trichloride and ethylene glycol,
2-chloro-1,3,2-λ5-dioxaphosphonate is reacted in an organic solvent such as ethylene chloride at a molar ratio of 1: 0.8 to 1: 5, preferably 1: 1 to 1: 3. The orchid was obtained and then oxidized to 2-chloro-2-oxo-1,3,2-λ5
-Dioxaphospholane was obtained (J. Am. Chem. So
c. 72, 5491, (1950), Chem. In
d. (London), 1962, 1828 (196
2)), then this 2-chloro-2-oxo-1,3,2
-[Lambda] 5-dioxaphosphorane and an alcohol compound represented by the following general formula (6) at an organic ratio such as tetrahydrofuran at a molar ratio of 1: 0.8 to 1: 5, preferably 1: 1 to 1: 3. It can be produced by a method such as reacting in a solvent.

[Chemical 15] (In the formula, R ³ represents an alkyl group having 1 to 6 carbon atoms.)

Specific examples of the alcohol compound represented by the above general formula (6) include methanol, ethanol, 1-propanol, 1-butanol, 1-pentanol and 1-hexanol.

The above reaction formula is shown below. In the formula, R ³
Indicates the same as above.

[Chemical 16]

The ammonium phosphate derivative of the present invention can be used as a polymerization initiator, particularly as a radical polymerization initiator. That is, since the ammonium phosphate derivative of the present invention is an azo compound, it can be used as an azo polymerization initiator.

As the polymerizable monomer using the ammonium phosphate derivative of the present invention as a polymerization initiator, ethylene, propylene, vinyl chloride, acrylonitrile, vinyl acetate, methyl acrylate, methyl methacrylate, acrylic acid, methacrylic acid, Examples thereof include monomers having a radically polymerizable polymerizable unsaturated bond such as styrene, acrylamide, N-vinylpyrrolidone, maleic anhydride and derivatives thereof.

As the polymerization solvent, water, methanol, ethanol, dimethylformamide, dimethylsulfoxide or the like can be used, and as the polymerization method, emulsion polymerization, suspension polymerization, solution polymerization or the like can be selected according to the monomer. It is possible. The polymerization reaction ratio of the polymerization initiator is monomer:
The molar ratio of ammonium phosphate derivative is 100:
0.01-100: 20, preferably 100: 0.5-
100: 5 is desirable, and the polymerization temperature is 30 ° C.
It is desirable to set the temperature to 100 ° C, preferably 50 ° C to 80 ° C.

By polymerizing in this manner, a polymer in which the structure of the polymerization initiator is located at the terminal of the molecule is obtained regardless of the kind of the monomer. Since such a polymer has a structure similar to the polar group of the phospholipid derived from the polymerization initiator located at the terminal, it is possible to use such a polymer for medical materials such as catheters, artificial organs, blood circuits, or contact lenses. In the case of producing cosmetics, biosensors, diagnostic agents, etc., the obtained medical materials are provided with antithrombotic properties or physiological functions such as protein adhesion prevention.

[0029]

Industrial Applicability According to the present invention, a novel and useful ammonium phosphate derivative having a structure similar to the polar group of phospholipids and which can be used as a polymerization initiator when polymerizing with various monomers is obtained. When such an ammonium phosphate derivative is used as a polymerization initiator, a polymer having a structure similar to the polar group of the phospholipid at the terminal of the molecule is obtained regardless of the type of monomer to be polymerized. By manufacturing medical materials from
Physiological functions such as antithrombogenicity or prevention of protein adhesion can be imparted to medical materials.

According to the production method of the present invention, the ammonium phosphate derivative as described above can be produced simply and efficiently.

[0031]

EXAMPLES Next, examples of the present invention will be described. Reference Example 1 [Synthesis of N, N'-dimethylammonioethyl = 4,4'-azobis (4-cyanovalerate)] An azo compound which is one of the starting materials for producing the ammonium phosphate derivative of the present invention Was manufactured as follows. 4,
4'-azobis (4-cyanovaleric acid) (manufactured by Wako Pure Chemical Industries, Ltd .: trade name V-501) 15.0 g (53.5 m)
M) was suspended in 150 ml of benzene in the form of a slurry in ice-cooling, and 30 g (144.1 mM) of phosphorus pentachloride was added to
The mixture was reacted with stirring for a minute. The reaction was then continued at room temperature until everything dissolved. After filtration, the solution was concentrated under vacuum, immersed in a mixed solution of ether-hexane (1: 3) to remove phosphorus oxychloride, further dissolved in methylene chloride, and precipitated with hexane to obtain 4,4'-azobis (4 -Cyanovaleric acid chloride) was obtained.

Then, 4,4'-azobis (4-cyanovaleric acid chloride) 10 was added in a 300 ml three-necked flask equipped with a mechanical stirrer, a drying tube and a dropping funnel.
g (32 mM) and triethylamine 4.14 g (7
0 mM) in 200 ml of tetrahydrofuran,
Dimethylaminoethanol 7.13 g (80 mM at 0 ° C
The mixture was added dropwise with stirring over 2 hours at 0 ° C. and further reacted at 0 ° C. for 5 hours. Triethylamine hydrochloride was filtered off, precipitated in 20 times hexane and recrystallized from hexane-acetone (7: 3) to give N, N'-dimethylammonioethyl = 4,4'-azobis (4-cyanovarie). rate)
Was obtained (yield 62%).

The results of IR and NMR analysis of this compound are as follows. IR (cm ^-1 ): 2740, 2780, 2810 (-N
_{(CH 3) 2), 2260} (-CN), 1735 (-CO
O-) ¹ H-NMR (CDCl ₃ ): δ (ppm) 1.79 (s, 6H, CH ₃ ), 2.38 (s, 12)
_{H, N (CH 3) 2} ), 2.54-2.75 (m, 12
_{H, CH 2), 4.22-4.38 (} t, 4H, COO
CH ₂ )

Reference Example 2 [Synthesis of 2-ethoxy-2-oxo-1,3,2-λ5-dioxaphospholane] A phosphorane compound which is the other starting material for producing the ammonium phosphate derivative of the present invention. Was manufactured as follows. 15.0 g (97.8 mM) phosphorus trichloride in a 50 ml three-necked flask equipped with a magnetic stirrer, a reflux tube and a dropping funnel.
And methylene chloride (20 ml) are added, and ethylene glycol (6.28 g, 101.2 mM) is stirred at room temperature for 2 hours.
It dripped over time. Furthermore, after reacting for 1 hour at room temperature, methylene chloride was removed under reduced pressure, and after distillation, 2-chloro-1,3,2-dioxaphosphorane was obtained (13 mm
Hg / 42-43 ° C).

Then, in a 50 ml three-necked flask equipped with a magnetic stirrer, a reflux tube and an oxygen bubbler, 7.10 g (56.1 mM) of 2-chloro-1,3,2-λ5-dioxaphospholane was added to benzene. Oxidation was carried out for 8 to 12 hours by dissolving in 15 ml and bubbling oxygen at 10 ml per minute while stirring at room temperature. Benzene was removed under reduced pressure and distillation was performed to obtain 2-chloro-2-oxo-1,3,2-λ5-dioxaphospholane (2 mmHg / 91-92 ° C, yield 65%).

Tetrahydrofuran in which 4.15 g (90 mM) of absolute ethanol was dissolved was placed in a three-necked flask equipped with a magnetic stirrer, a nitrogen gas blowing tube and a dropping funnel, and 4.27 g (30
mM) 2-chloro-2-oxo-1,3,2-λ5-
Dioxaphospholane was slowly added dropwise, and the reaction was continued until the hydrogen chloride gas completely disappeared. After the reaction was completed, ethanol and tetrahydrofuran were removed under reduced pressure,
2-Ethoxy-2-oxo-1,3,2-λ5-dioxaphosphorane was obtained (yield 86%).

The results of IR and NMR analysis of this compound are as follows. IR (cm ^-1 ): 1300, 1240, 1160, 10
^{_{80 (-POCH 2) 1 H-}} NMR (CDCl 3): δ (ppm) 1.25-1.48 (t, 3H, CH 3) 3.79-4.03 (q, 2H, CH 2), 4.09-
4.28 (t, 4H, OCH ₂ CH ₂ O)

Example 1 [Synthesis of 2-[(2-ethoxyphosphate ethyl) dimethylammonio] ethyl = 4,4'-azobis (4-cyanovalerate)] Obtained in Reference Example 1 in a 200 ml pressure resistant bottle. N, N′-dimethylammonioethyl = 4,4′-azobis (4-cyanovalerate) 4.23 g (10 mM) and 100 ml
Of tetrahydrofuran was added, and a solution of 3.0 g (20 mM) of 2-ethoxy-2-oxo-1,3,2-λ5-dioxaphospholane obtained in Reference Example 2 in 10 ml of tetrahydrofuran was immediately added. . After reacting with stirring at room temperature for 24 hours, the formed precipitate was filtered, washed twice with tetrahydrofuran, and 2-[(2-ethoxyphosphate ethyl) dimethylammonio] ethyl = 4.
4'-azobis (4-cyanovalerate) [compound represented by the formula (2)] was obtained (yield 74%).

The results of NMR analysis of the obtained compound are as follows. ¹ H-NMR (D ₂ O): δ (ppm) 1.26-1.44 (t, 6H, CH ₃ ), 1.76
(S, 6H, CCH ₃ ), 2.56 (s, 8H, C
H ₂ ), 2.92 (s, 12H, N ⁺ (CH ₃ ) ₂ ), 3.
_{47-3.79 (t, 8H, NCH 2} ), 3.85-
_{4.28 (m, 8H, POCH 2} ), 4.31-4.4
6 (t, 4H, COOCH ₂ )

Test Example 1 (Emulsion Polymerization of Styrene) 2-[(2-ethoxyphosphate ethyl) dimethyl obtained in Example 1 was placed in a 500 ml separate flask equipped with a mechanical stirrer, a reflux tube and a nitrogen gas blowing tube. Emulsion polymerization of styrene was carried out as follows using ammonio] ethyl = 4,4'-azobis (4-cyanovalerate) as a polymerization initiator in the absence of an emulsifier. 240 mM styrene dispersed in 250 ml of water was stirred at 70 ° C. for 1 hour at 350 rpm in a nitrogen gas atmosphere, and 1.2 to 12 mM of the aqueous azo polymerization initiator solution obtained in Example 1 was added, followed by addition of 5 Polymerization was carried out for a time.

After completion of the polymerization, the polystyrene microspheres produced were filtered with a glass filter (17G2),
Coarse particles and coagulated polymer were removed. The filtrate containing polystyrene microspheres was precipitated by centrifugation, and the supernatant was discarded and then dispersed in water. This operation is repeated three times, and the ion exchange resin (PK-212, PA31
2: manufactured by Mitsubishi Kasei Co., Ltd.). Coarse particles and coagulated polymer were separately dried and weighed as aggregates. Table 1 shows the yield, degree of polymerization, diameter, and X-ray photoelectron spectroscopy (XPS) analysis results of the obtained polystyrene microspheres.

[0042]

[Table 1]

Test Example 2 (Bovine Serum Albumin Adsorption Test) An adsorption test of BSA (bovine serum albumin) on the polystyrene microspheres obtained in Test Example 1 was conducted as follows. A polystyrene microsphere prepared by using potassium persulfate as a polymerization initiator under the same conditions was used as a control. pH 5.6, ionic strength 0.01
Surface area of polystyrene microspheres in BSA aqueous solution of any concentration which was adjusted to (NaCl) is 5.5 m ^2/1
It was dispersed so as to be 00 ml. The mixture was left at 25 ° C. for 2 hours, and after the adsorption reached equilibrium, it was centrifuged and the supernatant was collected. The BSA concentration in the supernatant was determined by the micro burette method (protein quantification method, biochemistry experimental method, 7 Academic Publishing Center).
The amount of decrease in the BSA concentration was calculated as the amount of adsorption per area of polystyrene microspheres. The results are shown in Fig. 1.

As can be seen from the results of FIG. 1, BSA of polystyrene microspheres using the compound obtained in Example 1 as a polymerization initiator was compared with polystyrene microspheres prepared using potassium persulfate as a polymerization initiator.
The adsorption amount was significantly lower.

[Brief description of drawings]

FIG. 1 is a graph showing the results of Test Example 2.

Claims (3)

[Claims] 1. A compound represented by the general formula (1): (In the formula, R ¹ and R ² represent an alkyl group having 1 to 4 carbon atoms, and R ¹ and R ² may be the same or different. R ³
Represents an alkyl group having 1 to 6 carbon atoms. m represents an integer of 1 to 6. ) An ammonium phosphate derivative represented by: 2. A formula represented by the general formula (1), wherein R ¹ and R ² are each CH ₃ , R ³ is CH ₂ CH ₃ , and m is 2. The ammonium phosphate derivative according to claim 1, which is represented by: 3. A compound represented by the general formula (3): (In the formula, R ¹ and R ² represent an alkyl group having 1 to 4 carbon atoms, R ¹ and R ² may be the same or different, and m represents an integer of 1 to 6.) The compound and the compound represented by the general formula (4): (In the formula, R ³ represents an alkyl group having 1 to 6 carbon atoms), which is reacted with a phosphorane compound represented by the general formula (1): (In the formula, R ¹ and R ² represent an alkyl group having 1 to 4 carbon atoms, and R ¹ and R ² may be the same or different. R ³
Represents an alkyl group having 1 to 6 carbon atoms. m represents an integer of 1 to 6. The manufacturing method of the ammonium phosphate derivative represented by these.