JPH0327555B2 - - Google Patents

Description

[Detailed description of the invention]

[Industrial Application Field] The present invention relates to a novel phosphoric acid ester, and more particularly to a fluorine-containing phosphoric acid ester having surface activity, self-assembly properties, and polymerizability. [Problems to be solved by the prior art and the invention] A cell is the smallest unit of a living organism, and is covered by a cell membrane. This cell membrane has various functions such as cell partition and compartment formation, cell movement, substance transport, and information transmission, and is the source of life activities. On the other hand, in the field of polymer chemistry, research has been actively conducted in recent years to create artificial polymer membranes that have the functions possessed by cell membranes and to apply them to a wide range of fields such as engineering, medicine, and pharmacy. There is. For example, research is being conducted on polymer separation membranes with mass transport functions, and artificial polymer membranes are widely used in the engineering field as ion exchange membranes, dialysis membranes, ultrafiltration membranes,
Widely used industrially, such as reverse osmosis membranes and gas separation membranes. In addition, in the field of medicine, research is actively being conducted on solute-permeable blood purification membranes found in artificial kidneys and gas-permeable blood purification membranes found in heart-lung machines. Research has also been conducted on microcapsules with a compartmental protection function, and artificial polymer membranes have been applied to microencapsulation of liquids, such as fragrances, and copy paper with microencapsulation of ink. Furthermore, research is being conducted on applications of microcapsules that also have a permeability function, such as sustained release drug formulation systems, microencapsulation of enzymes, and artificial red blood cells. Furthermore, it has become clear that the cell membrane is a bimolecular structure of phospholipids, and bilayer membrane vesicles (liposomes) similar to cell membranes are made using natural phospholipids (natural liposomes). It is used as a model material to elucidate various phenomena in biological membranes. Biological membranes are oriented in an orderly manner due to the physical properties of phospholipid molecules, which are unique to amphiphilic compounds with hydrophobic and hydrophilic properties (self-organization), and form a bilayer membrane structure. is forming. Therefore, conventional artificial polymer membranes have a completely different structure from biological membranes. However, in recent years, not only natural phospholipids but also synthetic compounds have been discovered that have self-assembly properties and can form bilayer membrane structures, and it has become possible to create artificial liposomes using synthetic compounds. Furthermore, research into polymer liposomes, which stabilize the membrane by polymerizing this bilayer membrane structure, has become active, and compounds with polymerizable groups in the hydrophobic or hydrophilic groups used as monomers are being actively researched. For example, a compound represented by the following formula () has been synthesized by Regan et al.
American Chemical Society (J.
Amer.Chem.Soc.), 105 , 2975 (1983)]. The forms of natural, artificial, and polymeric liposomes obtained in this way can be considered as a type of microcapsule, and are expected to be applied in engineering, medicine, etc. in the future. Therefore, when considering the monomer used as a material for membranes, it is important to note that the monomer has not only chemical properties but also physical properties such as surfactant ability and self-organizing ability, and that it is suitable for future pharmaceuticals and medical applications. When considering application to molecules, etc.
A substance with good compatibility with living organisms is desired. Phospholipids have exactly these desirable functions such as surface activity, self-assembly, and biocompatibility, and compounds in which polymerizable groups are introduced into phospholipids are attracting increasing attention. [Problems to be solved by the invention] However, phospholipids are difficult to obtain with high purity and are expensive, so there are limits to their application, and they cannot be easily produced industrially. , has surface activity, self-assembly property, and polymerizability,
It has been desired to develop a phosphate ester monomer that is also highly safe for the human body. [Means for Solving the Problems] Under these circumstances, the inventor has conducted extensive research and has developed the following general formula (). (In the formula, R' is a hydrogen atom or a methyl group, R is a straight or branched alkyl group having 1 to 36 carbon atoms,
M represents a hydrogen atom, an alkali metal, ammonium, or a salt of an alkylamine or an alkanolamine). (Special Application No. 60-57025). The present inventor conducted further research and found that a novel fluorine-containing phosphoric acid ester in which a fluorine-containing alkyl group was introduced into R in the above formula () has excellent surfactant ability, self-assembly ability, and polymerizability. However, they have discovered that it can be synthesized with high purity and high yield by simple operations from inexpensive and easily available raw materials, and have completed the present invention. That is, the present invention is based on the following general formula () (R' in the formula is a hydrogen atom or a methyl group, Rf is a linear or branched fluoroalkyl group having 1 to 36 carbon atoms in which at least one hydrogen atom is substituted with a fluorine atom, M is hydrogen (indicates that it is a salt of an alkali metal, ammonium, alkylamine or alkanolamine). The fluorine-containing phosphorus residual ester represented by the formula () of the present invention can be obtained by adding methacrylic acid represented by the formula () to a monoalkali metal salt of a monofluoroalkyl phosphoric acid represented by the formula (), for example, according to the following reaction formula. A fluorine-containing phosphate ester (Ia) is produced by reacting glycidyl or glycidyl acrylate,
It can be easily produced by acidification if necessary and further neutralization with a base. (In the formula, M' represents an alkali metal, and Rf and R' are the same as above.) In the fluorine-containing phosphate ester represented by the formula (), a linear chain having 1 to 36 carbon atoms represented by Rf Or as a branched fluoroalkyl group in which at least one hydrogen atom is substituted with a fluorine atom, tridecafluorooctyl, heptadecafluorododecyl, heneicosafluorododecyl,
Pentacosafluorotetradecyl, nonacosafluorohexadecyl, tritriacontafluorooctadecyl, 2-pentafluoroethylpentafluorohexyl, 2-tridecafluorohexyltridecafluorodecyl, 2-heptadecafluorooctylheptadecafluorododecyl, 2 -heneicosafluorodecylheneicosafluorotetradecyl, 2-pentacosafluorododecylpentacosafluorohexadecyl, 2-nonacosafluorotetradecylnonacosafluorooctadecyl group, among others, surfactant ability, Those having 8 to 36 carbon atoms are preferred from the viewpoint of self-assembly ability.
Particularly preferred examples include tridecafluorooctyl, heptadecafluorodecyl, heneicosafluorododecyl, and 2-tridecafluorohexyltridecafluorodecyl groups. The group represented by R' is preferably a methyl group. In the above reaction formula, the monofluoroalkyl phosphate represented by the formula () is produced by reacting a phosphorylating agent such as phosphorus pentoxide, phosphorus oxychloride, or polyphosphoric acid with the corresponding organic hydroxy compound having a fluorine-containing alkyl group. It can be obtained by obtaining monofluoroalkyl phosphoric acid and then neutralizing it, and it may be obtained by any of these methods, but it can be used in the production of the fluorine-containing phosphate ester () of the present invention. Preferably, the monofluoroalkyl phosphate () is of high purity. If the purity of the monofluoroalkyl phosphate is low and it is contaminated with many by-product impurities, the following damage will occur. In other words, when phosphorus pentoxide or phosphorus oxychloride is used as a phosphorylating agent, if difluoroalkyl phosphate is a by-product, the surfactant ability and self-assembly ability of monofluoroalkyl phosphate will decrease or disappear. Furthermore, in the subsequent reaction with an epoxy compound, the purity of the target compound is reduced, and purification to obtain a highly pure target compound becomes difficult. In addition, orthophosphoric acid, which is produced as a by-product when polyphosphoric acid is used as a phosphorylating agent, also reduces the yield of the desired reaction in the reaction with the epoxy compound.
In addition to reducing the purity of the target compound,
Purification to obtain a highly pure target compound becomes difficult. Therefore, it is preferable to use a monofluoroalkyl phosphate () with a purity of 90% by weight or more. In the above reaction, glycidyl methacrylate or glycidyl acrylate () is preferably reacted in an amount of 1 to 10 moles, particularly 3 to 5 moles, per mole of the monoalkali metal salt of monofluoroalkyl phosphoric acid (). If this reaction is carried out without converting the monofluoroalkyl phosphoric acid into a monoalkali metal salt, not only the desired compound but also phosphoric acid triester in which 1 mole of the compound represented by the formula () has reacted will be produced as a by-product. Moreover, at the end of the reaction, since the system is acidic, the ester bonds are susceptible to hydrolysis, which reduces the yield of the target compound, which is undesirable. Therefore, when carrying out this reaction, it is necessary to use monofluoroalkyl phosphoric acid in the form of a monoalkali metal salt. The solvent used in the reaction is an inert polar solvent such as water, methyl alcohol, ethyl alcohol, etc., and water is particularly preferred. The reaction temperature is preferably 30 to 100°C, particularly 50 to 90°C. Furthermore, polymerization inhibitors or polymerization inhibitors may be added during the reaction, such as hydroquinone monomethyl ether, hydroquinone, 2,
It is preferable to add 2'-methylenebis(4-ethyl-6-t-butylphenol) or the like in an amount of 50 to 10,000 ppm based on glycidyl (meth)acrylate. In the reaction solution thus obtained, in addition to the target compound, the fluorine-containing phosphate ester (), the unreacted compound represented by the formula () or the epoxy moiety of the compound represented by the formula () is hydrolyzed. Contains glyceryl methacrylate. Depending on the purpose of use, the reaction product may be used as it is, but it may be further purified to obtain a highly pure product. For example, sodium heptadecafluorodecyl 2 _- hydroxy-3 _- methacryloyloxypropyl phosphate [in the compound of formula (), R'= _CH3 , Rf= _C2H4C8F17 , _M =
In the case of Na, hereinafter referred to as compound ()], after reacting glycidyl methacrylate with an aqueous solution of sodium heptadecafluorodecyl phosphate,
By adding acetone to the reaction solution and cooling it, the produced sodium heptadecafluorodecyl 2-hydroxy-3-methacryloyloxypropyl phosphate was precipitated and separated from the acetone-soluble glycidyl methacrylate hydrolyzate. A target product with good purity can be obtained. Regarding the acid form of heptadecafluorodecyl 2-hydroxy-3-methacryloyloxypropyl phosphate [R'=CH ₃ , Rf=C ₂ H ₄ C ₈ F ₁₇ , M=H in the compound of formula ()], see above. It can be obtained by making the aqueous solution of Na salt obtained in the above manner acidic with an acid such as hydrochloric acid and extracting with a solvent such as ethyl ether. In the present invention, a small amount of the compound represented by the following formula () may be produced depending on the reaction conditions. (Rf, R' and M in the formula are the same as above.) [Function] The fact that the compound () of the present invention is an excellent surfactant can be seen from the fact that the surface tension of its aqueous solution decreases. As shown in Table 1, it is particularly superior to the compound of general formula () for which the present inventor previously applied for a patent.

〔Effect of the invention〕

The fluorine-containing phosphate ester of the present invention has surfactant ability, self-assembly ability, and polymerizability, is highly safe for the human body, and can be produced industrially with great advantage. Therefore, it can be widely used in fields such as engineering and medicine. [Example] Next, the present invention will be explained with reference to Examples. Example 1 95.5 g of 97% pure heptadecafluorodecyl phosphoric acid (0.19 mol, but the AV1 of this sample
(Number of mg of KOH required to neutralize 1 g of sample of this phosphoric acid monoester to the first equivalent point, the same applies below) = 108.9, AV2 = (Number of mg of KOH required to neutralize 1 g of sample of this phosphoric acid monoester to the second equivalent point) necessary to neutralize up to
The number of mg of KOH (the same applies hereafter) was 217.0), and 185 ml of a 1N aqueous sodium hydroxide solution was added and stirred, and the temperature was raised to 70°C to make it homogeneous. At this time, the brewing value of the reaction system (necessary to neutralize 1 g of sample)
The number of mg of KOH (hereinafter the same) was 36.8.
Next, while keeping the reaction system at 70°C, 104.5 g (0.74 mol) of glycidyl methacrylate was gradually added and stirred at this temperature for 9 hours. At this time, the acid value of the reaction system became almost 0, and the reaction was completed. I know what you did. Furthermore, when the sample at this time was analyzed by HPLC (high performance liquid chromatography, the same applies hereinafter), a peak of unreacted glycidyl methacrylate was observed. After further stirring and reaction for a total of 20 hours, glycidyl methacrylate was completely hydrolyzed and disappeared, and peaks of glyceryl methacrylate and the target compound, in which the epoxy moiety of glycidyl methacrylate was hydrolyzed, were observed. Next, cool the reaction solution to room temperature, add 200 g of acetone, and -5
When cooled to ℃, heptadecafluorodecyl 2-
92 g (yield 70%) of sodium hydroxy-3-methacryloyloxypropyl phosphate was obtained. ¹ H _NMR : δ2.0ppm (s, 3H _{, H2} = C- _CH3 ) δ2.6ppm (tt, 2H, _-P -OCH2CH2F2-) δ3.5-4.5ppm (m, 7H,

【formula】) δ5.6ppm (broad s, 1H,

【formula】) δ6.1ppm (broad s, 1H,

[Formula]) ¹³ C NMR (Standard sample: Si(CH ₃ ) ₄ ) Elemental analysis δ (ppm): a18.5, i33.4, h58.7, e66.5, g67.6,
f69.9, b126.5, c137.6, d168.9

[Table] As a result of HPLC analysis, the purity was 98-99%. Test Example 1 Heptadecafluorodecyl obtained in Example 1 2
- Add K ₂ S ₂ O ₈ as a polymerization initiator to an approximately 10% aqueous solution of sodium hydroxy-3-methacryloyloxypropyl phosphate [compound ()] as a counter compound ()
When 1% of the polymer was added and heated at 60 to 70°C for 4 to 5 hours, a colorless and transparent high viscosity aqueous solution was produced.Furthermore, when this polymer was placed on a slide glass and left to stand, a colorless and transparent film-like substance was obtained. Moreover, this high viscosity aqueous solution had anisotropic properties and had an organized liquid crystal structure. Example 2 20 g of 2-tridecafluorohexyltridecafluorodecyl phosphoric acid (0.025 mol, however, AV1 = 70.1, AV2 = 139.8 of this sample) with a purity of 92% was added to 1
Disperse in 24.8 ml of normal sodium hydroxide aqueous solution (the acid value of the reaction system at this time was 31.1), gradually add 14.2 g (0.10 mol) of glycidyl methacrylate at 70°C, and stir at this temperature for 30 hours. did. It can be seen that the acid value of the reaction system at this time was approximately 0, and the reaction rate of monoalkyl phosphoric acid was 100%. reaction solution
When analyzed by HPLC, peaks of a hydrolyzate of glycidyl methacrylate and a new product were observed. The product was separated by HPLC and the solvent was distilled off under reduced pressure to obtain 2-tridecafluorohexyltridecafluorodecyl 2-hydroxy-3-methacryloyloxypropyl sodium phosphate.
21.5g (yield 89%) was obtained. elemental analysis

[Table] As a result of HPLC analysis, the purity was 98-99%.

Claims (1)

[Claims] 1 General formula () (R' in the formula is a hydrogen atom or a methyl group, Rf is a linear or branched fluoroalkyl group having 1 to 36 carbon atoms in which at least one hydrogen atom is substituted with a fluorine atom, M is hydrogen A fluorine-containing phosphate ester represented by (indicates that it is a salt of an alkali metal, ammonium, alkylamine or alkanolamine).