JP6925604B2 - Monofluorophosphate ester salt, its production method and fluorine ion-releasing composition - Google Patents

Description

The present invention relates to a monofluorophosphate ester salt having excellent sustained release of fluorine ions, a method for producing the same, and a fluorine ion-releasing composition.

Examples of the fluorine-releasing compound capable of releasing fluorine ions include those contained in an oral composition and a dental composition.

Examples of the fluorine releasing compound for use in the oral composition, for _{example, SnF 2, NaF, Na 2} PO 3 F (MFP: sodium monofluorophosphate) (see Patent Document 1) which include. These fluorine-releasing compounds are known to be compounded for the purpose of preventing dental caries, which is one of oral diseases.

Examples of the fluorine-releasing compound used in the dental composition include the dental composition having fluorine ion-releasing property and X-ray contrast property disclosed in Patent Document 2 below, and Patent Document 3 below. Included are disclosed fluoroion-releasing substances. These fluorine-releasing compounds are used in composite resins and glass ionomer cements as so-called fillings for the purpose of repairing defects such as teeth.

However, it is difficult for conventional fluorine-releasing compounds to continuously release a constant amount of fluorine ions, and it is desired to improve the property of releasing a significant amount of the fluorine ions in a constant amount for a long period of time, so-called sustained release. It is rare.

Japanese Unexamined Patent Publication No. 2003-128530 Japanese Unexamined Patent Publication No. 2004-67597 Japanese Unexamined Patent Publication No. 2003-81731

The present invention has been made in view of the above problems, and an object of the present invention is a monofluorophosphate ester salt capable of continuously releasing fluorine ions in a significant release amount, a method for producing the same, and fluorine ion release property. The purpose is to provide the composition.

As a result of studies to solve the above-mentioned conventional problems, the inventors of the present application develop a function in which a monofluorophosphate ester salt continuously releases a constant amount of fluorine ions by a reaction mediated by a specific enzyme. We have found that it is possible to complete the present invention.

That is, the monofluorophosphate ester salt according to the present invention is characterized by being represented by the following chemical formula (1) in order to solve the above-mentioned problems.

（但し、前記Ｍ^ｎ＋は、水素イオン、アルカリ金属イオン、アルカリ土類金属イオン、遷移金属イオン、希土類元素イオン、亜鉛イオン、アルミニウムイオン、ガリウムイオン、インジウムイオン、ゲルマニウムイオン、スズイオン、鉛イオン及びオニウムイオンからなる群より選ばれる何れか１種を表す。前記Ｒ^１は、炭素数が１〜２０の炭化水素基、又は炭素数が１〜２０の範囲であって、ハロゲン原子、ヘテロ原子若しくは不飽和結合の少なくとも何れか１つを有する炭化水素基を表す。前記ｎは価数を表す。）

(However, the ^{Mn +} is hydrogen ion, alkali metal ion, alkaline earth metal ion, transition metal ion, rare earth element ion, zinc ion, aluminum ion, gallium ion, indium ion, germanium ion, tin ion, lead ion and onium. Represents any one selected from the group consisting of ions. The R ¹ is a hydrocarbon group having 1 to 20 carbon atoms, or a halogen atom, a hetero atom or a non-hydrogen atom having a carbon number in the range of 1 to 20. Represents a hydrocarbon group having at least one of the saturated bonds. The n represents a valence.)

In the above configuration, the alkali metal ion is preferably any one selected from the group consisting of lithium ion, sodium ion, potassium ion, rubidium ion and cesium ion.

Further, in the above configuration, it is preferable that the alkaline earth metal ion is any one selected from the group consisting of magnesium ion, calcium ion, strontium ion and barium ion.

Further, in the above configuration, the transition metal ion is selected from the group consisting of manganese ion, cobalt ion, nickel ion, chromium ion, copper ion, silver ion, molybdenum ion, tungsten ion and vanadium ion. It is preferably one kind.

In the above configuration, the rare earth element ions are scandium ion, ytterbium ion, lanthanum ion, cerium ion, praseodymium ion, neodymium ion, promethium ion, samarium ion, europium ion, gadolinium ion, terbium ion, and dysprosium. It is preferably any one selected from the group consisting of ions, formium ions, elbium ions, thulium ions, ytterbium ions and lutetium ions.

Further, in the above configuration, the onium ion is an ammonium ion, a primary ammonium ion, a secondary ammonium ion, a tertiary ammonium ion, a quaternary ammonium ion, a quaternary phosphonium ion and a sulfonium ion. It is preferable that it is any one selected from the group consisting of.

In the method for producing a monofluorophosphate ester salt according to the present invention, in order to solve the above-mentioned problems, the monohalophosphate diester represented by the following chemical formula (2) is fluorinated and represented by the following chemical formula (3). The step of producing the monofluorophosphate diester, the monofluorophosphate diester, and M ^{n +} X ² n (where M ^{n +} is an alkali metal ion, an alkaline earth metal ion, a transition metal ion, a rare earth element ion, Represents any one selected from the group consisting of zinc ion, aluminum ion, gallium ion, indium ion, germanium ion, tin ion, lead ion and onium ion. The X ² represents any one of F, Cl, Br or I. It represents a halogen atom. The n represents a valence), which comprises a step of producing a monofluorophosphate ester salt represented by the following chemical formula (1).

（但し、前記Ｒ^１及びＲ^２は相互に独立して、炭素数が１〜２０の炭化水素基、又は炭素数が１〜２０の範囲であって、ハロゲン原子、ヘテロ原子若しくは不飽和結合の少なくとも何れか１つを有する炭化水素基を表す。Ｘ^１はＦ以外のハロゲン原子を表す。）

(However, R ¹ and R ² are independent of each other and have a hydrocarbon group having 1 to 20 carbon atoms or a range of 1 to 20 carbon atoms and have a halogen atom, a hetero atom or an unsaturated bond. Represents a hydrocarbon group having at least one. X ¹ represents a halogen atom other than F.)

（前記Ｒ^１及びＲ^２は相互に独立して、炭素数が１〜２０の炭化水素基、又は炭素数が１〜２０の範囲であり、ハロゲン原子、ヘテロ原子若しくは不飽和結合の少なくとも何れか１つを有する炭化水素基を表す。）

(The R ¹ and R ² are independent of each other and have a hydrocarbon group having 1 to 20 carbon atoms or a range of 1 to 20 carbon atoms and are at least one of a halogen atom, a hetero atom or an unsaturated bond. Represents a hydrocarbon group having one.)

（但し、前記Ｍ^ｎ＋は水素、アルカリ金属イオン、アルカリ土類金属イオン、遷移金属イオン、希土類元素イオン、亜鉛イオン、アルミニウムイオン、ガリウムイオン、インジウムイオン、ゲルマニウムイオン、スズイオン、鉛イオン及びオニウムイオンからなる群より選ばれる何れか１種を表す。前記Ｒ^１は、炭素数が１〜２０の炭化水素基、又は炭素数が１〜２０の範囲であって、ハロゲン原子、ヘテロ原子若しくは不飽和結合の少なくとも何れか１つを有する炭化水素基を表す。前記ｎは価数を表す。）

(However, the ^{Mn +} is derived from hydrogen, alkali metal ion, alkaline earth metal ion, transition metal ion, rare earth element ion, zinc ion, aluminum ion, gallium ion, indium ion, germanium ion, tin ion, lead ion and onium ion. R ¹ represents a hydrocarbon group having 1 to 20 carbon atoms or a halogen atom, a hetero atom or an unsaturated bond having a carbon number in the range of 1 to 20. Represents a hydrocarbon group having at least one of. The n represents a valence.)

The fluorine ion-releasing composition according to the present invention is characterized by containing a monofluorophosphate ester salt in order to solve the above-mentioned problems.

The oral composition according to the present invention is characterized by containing a monofluorophosphate ester salt in order to solve the above-mentioned problems.

The dental composition according to the present invention is characterized by containing a monofluorophosphate ester salt in order to solve the above-mentioned problems.

According to the present invention, the monofluorophosphate ester salt represented by the chemical formula (1) can release fluorine ions by a reaction mediated by a specific enzyme, for example, phosphatase. Further, according to the monofluorophosphate ester salt having the above constitution, the release of fluorine ions can be continuously carried out in a constant amount, and the monofluorophosphate ester salt has a continuous release property such as excellent sustained release property.

Furthermore, the fluorine ion-releasing composition of the present invention can continuously release the fluorine ion by a reaction mediated by a specific enzyme such as the phosphatase by containing the monofluorophosphate ester salt. It is possible to release fluorine ions efficiently in a certain amount, and has continuous release properties such as excellent sustained release properties.

(Monofluorophosphate ester salt)
First, the monofluorophosphate ester salt according to the present embodiment will be described below.
The monofluorophosphate ester salt of the present embodiment is represented by the following chemical formula (1) and has a sustained release property of fluorine ions. The monofluorophosphate ester salt exhibits a function of releasing fluorine ions by a reaction mediated by a specific enzyme, specifically, phosphatase. In addition, fluorine ions are continuously released for a long period of time, and since they are released in a constant amount, they have sustained release properties such as excellent sustained release properties.

Here, the sustained release of fluorine ions is the release of fluorine ions from a monofluorophosphate ester salt, and is a conventional fluorine ion-releasing compound (for example, SnF ₂ , NaF, Na ₂ PO ₃ F, etc.). Means a release that occurs over a long period of time during which a significant amount of release can be obtained. The sustained release of fluorine ions is preferably a release that occurs over a period of at least 4 hours or more, at least 8 hours or more, or at least 24 hours.

In addition, the sustained release of fluorine ions has a relatively constant or variable release rate. Furthermore, the sustained release of fluorine ions can be a continuous release. The continuity and amount of release of fluorine ions can be controlled by the type and amount of the phosphatase and the mode of use.

Further, the sustained release property of fluorine ions means that the amount of fluorine ions continuously released from the monofluorophosphate ester salt is constant (constant amount). For example, it means that a more uniform amount of fluorine ion released can be obtained as compared with a conventional fluorine ion releasing compound (for example, SnF ₂ , NaF, Na ₂ PO _{3 F, etc.).}

Uniform release (sustained release) of fluorine ions at a constant concentration can be evaluated by S (%) defined by the following formula. For example, when S (%) is a value close to 50%, it means that the release of fluorine ions is a constant amount even after a lapse of a certain period of time, which means that it is excellent in sustained release. There is.
S (%) = (A _1- A ₀ ) / (A _2- A ₀ ) x 100 (In the formula, A ₀ represents the fluorine ion concentration at 0 hours, and A ₁ is _{fluorine after t 1} hour has passed. It represents the ion concentration, and A ₂ represents the fluorine ion concentration after t ₂ hours have passed. However, 2t ₁ = t ₂ ).

Examples of the phosphatase include alkaline phosphatase, acid phosphatase, glucose-1-phosphatase, protein phosphatase and the like. Of these, acid phosphatase is preferred in this embodiment.

In the chemical formula (1), M ^{n +} is hydrogen ion, alkali metal ion, alkaline earth metal ion, transition metal ion, rare earth element ion, zinc ion, aluminum ion, gallium ion, indium ion, germanium ion, tin ion, lead. Represents any one selected from the group consisting of ions and onium ions.

The alkali metal ion is not particularly limited, and examples thereof include lithium ion, sodium ion, potassium ion, rubidium ion, and cesium ion. Among these alkali metal ions, potassium ion can impart a pain-relieving effect on dentin hypersensitivity to a monofluorophosphate ester salt.

Examples of the alkaline earth metal ion include magnesium ion, calcium ion, strontium ion, barium ion and the like.

The transition metal ion is not particularly limited, and examples thereof include manganese ion, cobalt ion, nickel ion, chromium ion, copper ion, silver ion, molybdenum ion, tungsten ion, vanadium ion and the like. Of these transition metal ions, copper ions and silver ions can further impart antibacterial activity to the monofluorophosphate ester salt. This antibacterial activity is against periodontal disease bacteria such as P. gingivalis and F. nucleatum, and caries bacteria such as S. mutans and S. sobrinus. It is valid.

The rare earth element ion is not particularly limited, and for example, scandium ion, ytterbium ion, lanthanum ion, cerium ion, praseodymium ion, neodymium ion, promethium ion, samarium ion, europium ion, gadolinium ion, terbium ion, dysprosium ion, and formium. Examples thereof include ions, elbium ions, thulium ions, ytterbium ions, and lutetium ions.

Examples of metal ion species other than the above include zinc ion, aluminum ion, gallium ion, indium ion, germanium ion, tin ion, lead ion and the like. Among these metal ions, tin ion can further impart antibacterial activity to the monofluorophosphate ester salt. The targets for which this antibacterial activity is effective are the above-mentioned periodontal disease bacteria and dental caries bacteria.

The onium ion is not particularly limited, and ammonium ion (NH ⁴⁺ ), primary ammonium ion, secondary ammonium ion, tertiary ammonium ion, quaternary ammonium ion, quaternary phosphonium ion, sulfonium ion and the like. Can be mentioned. The onium ion can further impart antibacterial activity to the monofluorophosphate ester salt. The targets for which this antibacterial activity is effective are the above-mentioned periodontal disease bacteria and dental caries bacteria.

The primary ammonium ion is not particularly limited, and examples thereof include methylammonium ion, ethylammonium ion, propylammonium ion, and isopropylammonium ion.

The secondary ammonium ion is not particularly limited, and for example, dimethylammonium ion, diethylammonium ion, dipropylammonium ion, dibutylammonium ion, ethylmethylammonium ion, methylpropylammonium ion, methylbutylammonium ion, propylbutylammonium. Ions, diisopropylammonium ions and the like can be mentioned.

The tertiary ammonium ion is not particularly limited, and for example, trimethylammonium ion, triethylammonium ion, tripropylammonium ammonium ion, tributylammonium ion, ethyldimethylammonium ion, diethylmethylammonium ion, triisopropylammonium ion, dimethylisopropyl. Ammonium ion, diethylisopropylammonium ion, dimethylpropylammonium ion, butyldimethylammonium ion, 1-methylpyrrolidinium ion, 1-ethylpyrrolidinium ion, 1-propylpyrrolidinium ion, 1-butylpropylpyrrolidinium ion, 1-methyl Imidazolium ion, 1-ethyl imidazolium ion, 1-propyl imidazolium ion, 1-butyl imidazolium ion, pyrazolium ion, 1-methylpyrazolium ion, 1-ethylpyrazolium ion, 1-propylpyrazolium ion, Examples thereof include 1-butylpyrazolium ion and pyridinium ion.

The quaternary ammonium forming the quaternary ammonium ion is not particularly limited, and examples thereof include aliphatic quaternary ammoniums, imidazoliums, pyridiniums, pyrazoliums, and pyridadiniums.

Further, the aliphatic quaternary ammoniums are not particularly limited, and for example, tetraethylammonium, tetrapropylammonium, tetraisopropylammonium, trimethylethylammonium, dimethyldiethylammonium, methyltriethylammonium, trimethylpropylammonium, trimethylisopropylammonium, tetra. Butylammonium, trimethylbutylammonium, trimethylpentylammonium, trimethylhexylammonium, 1-ethyl-1-methyl-pyrrolidinium, 1-butyl-1-methylpyrrolidinium, 1-ethyl-1-methyl-piperidinium, 1-butyl- Examples thereof include 1-methylpiperidinium, octyltrimethylammonium, hexadecyltrimethylammonium, hexadecyl (2-hydroxyethyl) dimethylammonium, and allylhexadecyldimethylammonium.

The imidazoliums are not particularly limited, and for example, 1,3 dimethyl-imidazolium, 1-ethyl-3-methylimidazolium, 1-n-propyl-3-methylimidazolium, 1-n-butyl-3. -Methylimidazolium, 1-n-hexyl-3-methylimidazolium and the like can be mentioned.

The pyridiniums are not particularly limited, and examples thereof include 1-methylpyridinium, 1-ethylpyridinium, 1-n-propylpyridinium, 1-hexylpyridinium, and cetylpyridinium.

The pyrazols are not particularly limited, and for example, 1,2-dimethylpyrazolium, 1-methyl-2-ethylpyrazolium, 1-propyl-2-methylpyrazolium, 1-methyl-2-butyl. Pyrazolium, 1-Methylpyrazolium, 3-Methylpyrazolium, 4-Methylpyrazolium, 4-Iodopyrazolium, 4-Bromopyrazolium, 4-Iodo 3-Methylpyrazolium, 4 −Bromo-3-methylpyrazolium, 3-trifluoromethylpyrazolium can be mentioned.

The pyridadiniums are not particularly limited, and for example, 1-methylpyridazinium, 1-ethylpyridazinium, 1-propylpyridazinium, 1-butylpyridazinium, 3-methylpyridazinium. Nium, 4-methylpyridazinium, 3-methoxypyridazinium, 3,6-dichloropyridazinium, 3,6-diclo-4-methylpyridazinium, 3-chloro-6-methylpyry Examples thereof include dadinium and 3-chloro-6-methoxypyridazinium.

The quaternary phosphonium forming the quaternary phosphonium ion is not particularly limited, and examples thereof include benzyltriphenylphosphonium, tetraethylphosphonium, and tetraphenylphosphonium.

The sulfonium forming the sulfonium ion is not particularly limited, and examples thereof include trimethylsulfonium, triphenylsulfonium, and triethylsulfonium.

^{Among those listed as examples of Mn +} , from the viewpoint of availability, lithium, sodium ion, potassium, magnesium, calcium, tin, tetraalkylammonium ion, alkylimidazolium ion, alkylpyrrolidinium ion, alkylpyridinium ion Is preferable.

In the chemical formula (1), the R ¹ is a hydrocarbon group or a hydrocarbon group having at least one of a halogen atom, a hetero atom or an unsaturated bond (hereinafter, “hydrocarbon group having a halogen atom or the like””. ). The hydrocarbon group has 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms. The hydrocarbon group having a halogen atom or the like has 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, and more preferably 1 to 4 carbon atoms. The number of unsaturated bonds is preferably in the range of 1 to 10, more preferably in the range of 1 to 5, and particularly preferably in the range of 1 to 3.

The hydrocarbon group having a hydrocarbon group or a halogen atom is not particularly limited, and for example, a methyl group, an ethyl group, a propyl group, a butyl group, an isopropyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group and the like. Cyclic alkyl groups such as chain alkyl groups, cyclopentyl groups, cyclohexyl groups, 2-iodoethyl groups, 2-bromoethyl groups, 2-chloroethyl groups, 2-fluoroethyl groups, 1,2-diiodoethyl groups, 1,2-dibromoethyl groups Group, 1,2-dichloroethyl group, 1,2-difluoroethyl group, 2,2-diiodoethyl group, 2,2-dibromoethyl group, 2,2-dichloroethyl group, 2,2-difluoroethyl group, 2 , 2,2-Tribromoethyl group, 2,2,2-trichloroethyl group, 2,2,2-trifluoroethyl group, hexafluoro-2-propyl group and other chain halogen-containing alkyl groups, 2-iodo Chains such as cyclic halogen-containing alkyl groups such as cyclohexyl group, 2-bromocyclohexyl group, 2-chlorocyclohexyl group and 2-fluorocyclohexyl group, 2-propenyl group, isopropenyl group, 2-butenyl group and 3-butenyl group. Cyclic alkenyl groups such as alkenyl group, 2-cyclopentenyl group, 2-cyclohexenyl group, 3-cyclohexenyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group, 1-pentynyl group , 2-Pentynyl group, 3-Pentynyl group, 4-Pentynyl group and other chain alkynyl groups, phenyl group, 3-methoxyphenyl group, 4-methoxyphenyl group, 3,5-dimethoxyphenyl group, 4-phenoxyphenyl group Etc., phenyl group, 2-iodophenyl group, 2-bromophenyl group, 2-chlorophenyl group, 2-fluorophenyl group, 3-iodophenyl group, 3-bromophenyl group, 3-chlorophenyl group, 3-fluorophenyl group , 4-Iodophenyl group, 4-bromophenyl group, 4-chlorophenyl group, 4-fluorophenyl group, 3,5-diiodophenyl group, 3,5-dibromophenyl group, 3,5-dichlorophenyl group, 3, Examples thereof include a halogen-containing phenyl group such as a 5-difluorophenyl group, a naphthyl group such as a 1-naphthyl group, a 2-naphthyl group and a 3-amino-2-naphthyl group.

The halogen atom means an atom of fluorine, chlorine, bromine or iodine. A hydrocarbon group having a halogen atom means that a part or all of hydrogen in the hydrocarbon group may be substituted with any of these halogen atoms. Further, the hetero atom means an atom such as oxygen, nitrogen or sulfur. A hydrocarbon group having a heteroatom means that a part or all of hydrogen and carbon in the hydrocarbon group may be substituted with any of these heteroatoms.

Specific examples of the hydrocarbon group having a hetero atom include a 2-methoxyethyl group, a 2- (2-methoxyethoxy) ethyl group, and a 2- (2- (2-methoxyethoxy) ethoxy) ethyl group. , 2- (2- (2- (2-methoxyethoxy) ethoxy) ethoxy) ethyl group, 2-ethoxyethyl and the like.

In the chemical formula (1), the n represents a valence. For example, when M is a monovalent cation, n = 1, when it is a divalent cation, n = 2, and when it is a trivalent cation, n = 3.

Specific examples of the monofluorophosphate ester salt represented by the chemical formula (1) include methyl sodium monofluorophosphate, ethyl sodium monofluorophosphate, propyl sodium monofluorophosphate, and monofluorophosphate (2). , 2,2-Trichloroethyl) sodium phosphate, monofluorophosphate (2,2,2-trichloroethyl) sodium, monofluorophosphate (1,1,1,3,3,3-hexachloroisopropyl) sodium, Sodium monofluorophosphate (2,2,2-trifluoroethyl), sodium monofluorophosphate (1,1,1,3,3,3-hexafluoroisopropyl), monofluorophosphate (2-methoxyethyl) Sodium, monofluorophosphate (2- (2-methoxyethoxy) ethyl) sodium, monofluorophosphate (2- (2- (2-methoxyethoxy) ethoxy) ethyl) sodium, monofluorophosphate (2- (2) -(2- (2-methoxyethoxy) ethoxy) ethoxy) ethyl) sodium, 1-ethyl-3-methylimidazolium monofluorophosphate methyl, 1-ethyl-3-methylimidazolium monofluorophosphate ethyl, 1- Ethyl-3-methylimidazolium monofluorophosphate (2,2,2-trichloroethyl), 1-ethyl-3-methylimidazolium monofluorophosphate (2,2,2-trichloroethyl), 1-ethyl- 3-Methylimidazolium monofluorophosphate (1,1,1,3,3,3-hexachloroisopropyl), 1-ethyl-3-methylimidazolium monofluorophosphate (2,2,2-trifluoroethyl) , 1-Ethyl-3-methylimidazolium monofluorophosphate (2,2,2-trifluoroethyl), 1-ethyl-3-methylimidazolium monofluorophosphate (2,2,2-trifluoroethyl) , 1-Ethyl-3-methylimidazolium monofluorophosphate (1,1,1,3,3,3-hexafluoroisopropyl), 1-ethyl-3-methylimidazolium monofluorophosphate (2-methoxyethyl) ), 1-Ethyl-3-methylimidazolium monofluorophosphate (2- (2-methoxyethoxy) ethyl), 1-ethyl-3-methylimidazolium monofluorophosphate (2- (2- (2-methoxy) ethyl) Ethoxy) ethoxy) ethyl), 1-ethyl-3-methylimidazolium monofluorophosphate (2- (2- (2- (2) − Methoxyethoxy) ethoxy) ethoxy) ethyl), methyl triethylmethylammonium monofluorophosphate, ethyl triethylmethylammonium monofluorophosphate, propyl triethylmethylammonium monofluorophosphate, triethylmethylammonium monofluorophosphate (2,2) 2-Trichloroethyl), triethylmethylammonium monofluorophosphate (2,2,2-trichloroethyl), triethylmethylammonium monofluorophosphate (1,1,1,3,3,3-hexachloroisopropyl), triethylmethyl Ammonium monofluorophosphate (2,2,2-trifluoroethyl), triethylmethylammonium monofluorophosphate (2,2,2-trifluoroethyl), triethylmethylammonium monofluorophosphate (2,2,2- Trifluoroethyl), triethylmethylammonium monofluorophosphate (1,1,1,3,3,3-hexafluoroisopropyl), triethylmethylammonium monofluorophosphate (2-methoxyethyl), triethylmethylammonium monofluorophosphate Acid (2- (2-methoxyethoxy) ethyl), triethylmethylammonium monofluorophosphate (2- (2- (2-methoxyethoxy) ethoxy) ethyl), triethylmethylammonium monofluorophosphate (2- (2- (2-)2- (2- (2-methoxyethoxy) ethoxy) ethoxy) ethyl), methyl lithium monofluorophosphate, ethyl lithium monofluorophosphate, butyl lithium monofluorophosphate, lithium (2-ethoxyethyl) monofluorophosphate, mono Ethyl potassium fluorophosphate, ethyl magnesium monofluorophosphate, ethyl calcium monofluorophosphate, silver ethyl monofluorophosphate, ethyl copper monofluorophosphate, isopropyllithium monofluorophosphate, monofluorophosphate (2,2) 2-Trichloroethyl) lithium phosphate, monofluorophosphate (2,2,2-trichloroethyl) lithium, monofluorophosphate (1,1,1,3,3,3-hexachloroisopropyl) lithium, monofluorophosphorus Lithium acid (2,2,2-trifluoroethyl), lithium monofluorophosphate (1,1,1,3,3,3-hexafluoroisopropyl) lithium, lithium monofluorophosphate (2-methoxyethyl), mono Fluorophosphate (2- (2-methoxyethoxy) ) Ethyl) lithium, monofluorophosphate (2- (2- (2-methoxyethoxy) ethoxy) ethyl) lithium, monofluorophosphate (2- (2- (2- (2-methoxyethoxy) ethoxy) ethoxy) Ethyl) Lithium, 1-ethylpyridinium monofluorophosphate ethyl, 1-hexylpyridinium monofluorophosphate ethyl, cetylpyridinium monofluorophosphate ethyl, octyltrimethylammonium monofluorophosphate ethyl, hexadecyltrimethylammonium monofluorophosphate ethyl , Hexadecyl (2-hydroxyethyl) dimethylammonium monofluorophosphate ethyl, allylhexadecyldimethylammonium monofluorophosphate ethyl and the like.

(Manufacturing method of monofluorophosphate ester salt)
Next, a method for producing a monofluorophosphate ester salt according to the present embodiment will be described below.

In the method for producing a monofluorophosphate ester salt of the present embodiment, the monofluorophosphate diester is fluorinated to produce a monofluorophosphate diester, and the monofluorophosphate diester is reacted with a halide. , At least including step B for producing a monofluorophosphate ester salt.

The monohalophosphodiester used as a raw material in the step A is represented by the following chemical formula (2).

In the above formula (2), wherein R ¹ is the same as R ¹ in Formula (1), it is as previously described. ^{Further, the R 2} in the chemical formula (2) is the same as ^{the R 1} in the chemical formula (1). Therefore, the R ² is selected from the functional group group listed in the description of the ^{R 1.} However, R ¹ and R ² may be of the same type or may be different from each other. The X ¹ represents a halogen atom other than the fluorine atom F.

Fluorination by the fluorination treatment of the monohalophosphate diester can be performed, for example, by contacting potassium fluoride or the like as a fluorinating agent in an organic solvent. As a result, a reaction as shown by the following chemical reaction formula (4) occurs, and a monofluorophosphate diester can be produced.

The reaction start temperature when the monohalophosphate diester and the fluorinating agent start the reaction under a non-aqueous solvent (in an organic solvent) is not particularly limited as long as the reaction proceeds, and is appropriately set according to the reaction species. do it. Usually, it is in the range of 0 ° C. to 200 ° C., preferably 20 to 150 ° C., and more preferably 40 ° C. to 120 ° C. from the viewpoint of reactivity. By setting the reaction start temperature to 0 ° C. or higher, it is possible to prevent the reaction rate from being significantly attenuated. Further, by setting the reaction start temperature to 200 ° C. or lower, energy loss due to the use of excess energy can be suppressed. The method for adjusting the reaction start temperature is not particularly limited, and when the reaction vessel is cooled and controlled so as to be within the temperature range, the reaction vessel containing the monohalophosphate diester and the fluorinating agent is ice-cooled or the like. Can be done by Further, when the reaction start temperature is controlled by heating so as to be within the above temperature range, it can be performed by using an oil bath or the like set to an arbitrary temperature.

An aprotic solvent is preferable as the solvent used when the monohalophosphate diester and the fluorinating agent are reacted under a non-aqueous solvent. By using an aprotic solvent, it is possible to prevent the inhibition of the fluorination reaction. When a protic solvent is used, the monohalophosphodiester and the protic solvent may cause a halogen exchange reaction. Further, when such a nucleophilic fluorination reaction is carried out, the hydrogen element in the protonic solvent and the fluorine anion of the fluorinating agent significantly reduce the fluorination ability due to the influence of hydrogen bonds. Moreover, monohalophosphodiester can also be used as a solvent.

The aprotic solvent is not particularly limited, and examples thereof include nitriles, esters, ketones, ethers, halogenated hydrocarbons, and the like.

The nitriles are not particularly limited, and examples thereof include acetonitrile, propionitrile, and the like. The esters are not particularly limited, and examples thereof include dimethyl carbonate, diethyl carbonate, ethyl methyl carbonate, ethylene carbonate, propylene carbonate, ethyl acetate, methyl acetate, butyl acetate and the like. The ketones are not particularly limited, and examples thereof include acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone and the like. The ethers are not particularly limited, and examples thereof include diethyl ether, tetrahydrofuran, ethylene glycol and the like. The halogenated hydrocarbon is not particularly limited, and examples thereof include dichloromethane, chloroform and the like. Further examples of other aprotic solvents include nitromethane, nitroethane, dimethylformamide and the like. These aprotic solvents can be used alone or in combination of two or more.

The fluorinating agent used in the reaction between the monohalophosphate diester and the fluorinating agent is not particularly limited, and examples thereof include alkali metal fluoride, alkaline earth metal fluoride, and onium fluorolide.

The alkali metal fluoride is not particularly limited, and examples thereof include lithium fluoride, sodium fluoride, potassium fluoride, rubidium fluoride, and cesium fluoride. The alkaline earth metal fluoride is not particularly limited, and examples thereof include beryllium fluoride, magnesium fluoride, calcium fluoride, strontium fluoride, and barium fluoride. The onium fluorolide is not particularly limited, and examples thereof include triethylamine trifluoride, triethylamine pentafluoride, bilysin fluoride, and tetrabutylammonium fluoride. These fluorinating agents may be used alone or in combination of two or more.

The step B is a step of producing a monofluorophosphate ester salt represented by the chemical formula (1) by reacting the monofluorophosphate diester with the halide.

The halide has a chemical formula of M ^{n +} X ² n (the M ^{n +} is an alkali metal ion, an alkaline earth metal ion, a transition metal ion, a rare earth element ion, a zinc ion, an aluminum ion, a gallium ion, an indium ion, a germanium ion, etc. It represents any one selected from the group consisting of tin ion, lead ion and indium ion. The X ² represents a halogen atom of any one of F, Cl, Br or I. The n represents a valence). It is represented by.

Here, since the M ^{n +} in the halide has already been described, detailed description thereof will be omitted. Further, the n in the halide represents a valence as in the case of the general formula (1).

The reaction between the monofluorophosphate diester and the halide in step B is as represented by the following chemical reaction formulas (5) and (6).

That is, the halogen of the halide ^{nucleophilically attacks R 2} of the monofluorophosphate, whereby the monofluorophosphate anion containing ^{R 1} is eliminated, and the alkyl halide represented by ^{R 2} X ^{2 is released.} Generate. Furthermore, it is speculated that the desorbed monofluorophosphate anion forms a salt with the counter cation of the halide to form a monofluorophosphate ester salt.

Here, when the halide is reacted with the monofluorophosphate diester, two leaving groups represented by the following chemical formulas can be generated.

（前記Ｒ^１は、炭素数が１〜２０の炭化水素基、又は炭素数が１〜２０の範囲であり、ハロゲン原子、ヘテロ原子若しくは不飽和結合の少なくとも何れか１つを有する炭化水素基を表す。）

（前記Ｒ^２は、炭素数が１〜２０の炭化水素基、又は炭素数が１〜２０の範囲であり、ハロゲン原子、ヘテロ原子若しくは不飽和結合の少なくとも何れか１つを有する炭化水素基を表す。）

(Wherein R ¹ is in the range of the hydrocarbon group having 1 to 20 carbon atoms, or 1 to 20 carbons, a halogen atom, a hydrocarbon group having at least one of hetero atoms or unsaturated bonds show.)

(Wherein R ² is in the range of the hydrocarbon group having 1 to 20 carbon atoms, or 1 to 20 carbons, a halogen atom, a hydrocarbon group having at least one of hetero atoms or unsaturated bonds show.)

Then, when the halide is reacted with a monofluorophosphate diester to produce a monofluorophosphate ester salt, when R ¹ and R ² are different, the monofluorophosphate anion represented by the chemical formula (7) is produced. The desorption ability of the above is required to be higher than the desorption ability of the monofluorophosphate anion represented by the chemical formula (8). Thereby, the monofluorophosphate ester salt of the present embodiment containing ^{R 1 can be obtained.}

The leaving ability of the monofluorophosphate anion, which is a leaving group and is represented by the chemical formula (7) or (8), is roughly estimated from, for example, the pKa value of each proton compound. Specifically, the pKa value of the monofluorophosphate anion represented by the chemical formula (7), that is, the monofluorophosphate anion is the monofluorophosphate anion represented by the chemical formula (8). It is preferable that it is smaller than the proton form of. The pKa value can be estimated from, for example, the Bordwell pKa Table and the like. Alternatively, it can be presumed that a leaving group containing an electron attracting group has a high leaving ability.

When the halide and the monofluorophosphate diester are reacted under another non-aqueous solvent to produce a monofluorophosphate ester salt, the amount of the halide and the monofluorophosphate diester used as long as the desired compound can be obtained. Is not particularly limited. Usually, the amount of monofluorophosphate diester is 0.5 to 5 equivalents, preferably 0.9 to 4 equivalents, and more preferably 0.95 to 3.3 equivalents, relative to 1 equivalent of the halide. be. By using 0.5 equivalent or more of the monofluorophosphate diester, it is possible to prevent the reactivity between the halide and the monofluorophosphate diester from deteriorating, and to prevent unreacted hydroxide from remaining. It can be suppressed. As a result, it is possible to suppress a decrease in the purity of the monofluorophosphate ester salt. If the amount of the monofluorophosphate diester used is larger than 5 equal amounts, it requires more production time and energy to distill off the monofluorophosphate diester, which may be industrially disadvantageous.

The reaction start temperature when the halide and the monofluorophosphate diester start the reaction under another non-aqueous solvent is not particularly limited as long as the reaction proceeds, and may be appropriately set according to the reaction species. good. Usually, it is in the range of 0 ° C. to 200 ° C., preferably 20 to 150 ° C., and more preferably 40 ° C. to 120 ° C. from the viewpoint of reactivity. By setting the reaction start temperature to 0 ° C. or higher, it is possible to prevent the reaction rate from being significantly attenuated. Further, by setting the reaction start temperature to 200 ° C. or lower, energy loss due to the use of excess energy can be suppressed. The method for adjusting the reaction start temperature is not particularly limited, and when the reaction vessel is cooled and controlled so as to be within the temperature range, the reaction vessel containing the halide and the monofluorophosphate diester is ice-cooled or the like. It can be done by. Further, when the reaction start temperature is controlled by heating so as to be within the above temperature range, it can be performed by using an oil bath or the like set to an arbitrary temperature.

The reaction time when the halide and the monofluorophosphate diester are reacted under another non-aqueous solvent is not particularly limited, and may be appropriately set according to the reaction species. Usually, it is in the range of 30 minutes to 20 hours, preferably 30 minutes to 15 hours, more preferably 30 minutes to 10 hours from the viewpoint of industrial production.

In the reaction between the halide and the monofluorophosphate diester, the monofluorophosphate diester can be used as the reaction solvent in addition to the other non-aqueous solvent. In this case, the reaction start temperature at which the halide and the monofluorophosphate diester start the reaction is not particularly limited as long as the reaction proceeds, and may be appropriately set according to the reaction species. Usually, it is in the range of 0 ° C. to 200 ° C., preferably 20 ° C. to 150 ° C., and more preferably 40 ° C. to 120 ° C. from the viewpoint of reactivity. Further, the reaction time is not particularly limited, and may be appropriately set according to the reaction species. Usually, it is in the range of 30 minutes to 20 hours, preferably 30 minutes to 15 hours, more preferably 30 minutes to 10 hours from the viewpoint of industrial production.

The other non-aqueous solvent (organic solvent) is not particularly limited as long as it does not cause a problem of reacting with other reactants or products. Specific examples thereof include alcohols, nitriles, esters, ketones, ethers, halogenated hydrocarbons and the like. These can be used alone or in combination of two or more.

The alcohols are not particularly limited, and for example, methanol, ethanol, propanol, butanol, isopropyl alcohol, pentanol, hexanol, heptanol, octanol, 2-iodoethanol, 2-bromoethanol, 2-chloroethanol, 2- Fluoroethanol, 1,2-diiodoethanol, 1,2-dibromoethanol, 1,2-dichloroethanol, 1,2-difluoroethanol, 2,2-diiodoethanol, 2,2-dibromoethanol, 2,2 -Dichloroethanol, 2,2-difluoroethanol, 2,2,2-tribromoethanol, 2,2,2-trichloroethanol, 2,2,2-trifluoroethanol, 1,1,1,3,3 Examples thereof include 3-hexafluoro-2-propanol. These can be used alone or in combination of two or more.

The nitriles are not particularly limited, and examples thereof include acetonitrile, propionitril, and the like. These can be used alone or in combination of two or more.

The esters are not particularly limited, and examples thereof include dimethyl carbonate, diethyl carbonate, ethyl methyl carbonate, ethylene carbonate, propylene carbonate, ethyl acetate, methyl acetate, butyl acetate and the like. These can be used alone or in combination of two or more.

The ketones are not particularly limited, and examples thereof include acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone and the like. These can be used alone or in combination of two or more.

The ethers are not particularly limited, and examples thereof include diethyl ether, tetrahydrofuran, dimethoxyethane and the like. These can be used alone or in combination of two or more.

The halogenated hydrocarbon is not particularly limited, and examples thereof include dichloromethane, chloroform and the like. These can be used alone or in combination of two or more.

Further, as another example of the other non-aqueous solvent (organic solvent), nitromethane, nitroethane, dimethylformamide and the like can be mentioned.

The amount of the other non-aqueous solvent (organic solvent) used is preferably 1-fold or more, more preferably 1-fold to 200-fold, and 1-fold to 100 times the amount of the monofluorophosphate diester. Double the amount is more preferable, and 1 to 50 times the amount is particularly preferable. By increasing the amount of the organic solvent used to 1 times or more, it is possible to prevent the reactivity between the phosphoric acid triester and the hydroxide from deteriorating, and to suppress the decrease in the yield of the phosphoric acid diester salt and its purity. be able to. The upper limit of the amount of the organic solvent used is not particularly limited, but if an organic solvent is used excessively with respect to the monofluorophosphate diester, more energy than necessary is required to distill off the organic solvent, which is industrially disadvantageous. May be. Therefore, it is preferable to appropriately set the upper limit of the amount of the organic solvent used according to the reaction species.

When an organic solvent is used as the reaction solvent, the order of adding the halide and the monofluorophosphate diester is not particularly limited. When a monofluorophosphate diester is used as the reaction solvent, the order of addition of the halide and the monofluorophosphate diester is not particularly limited.

The monofluorophosphate ester salt obtained by the method of the present embodiment is monofluorophosphate having a desired different type of cation by performing cation exchange using solubility or cation exchange using an ion exchange resin or the like. Acid ester salts can also be produced.

Further, a monofluorophosphate ester can also be produced by reacting the monofluorophosphate ester salt obtained by the method of the present embodiment with an allenius acid such as sulfuric acid or hydrochloric acid. A monofluorophosphate can also be obtained by performing proton exchange using an ion exchange resin. Further, a monofluorophosphate ester salt can be produced by reacting the monofluorophosphate obtained by these methods with a halide or a hydroxide.

In the present embodiment, the step of purifying the monofluorophosphate ester salt may be performed immediately after the step of producing the monofluorophosphate ester salt. Further, even immediately after the step of producing a monofluorophosphate ester salt having another kind of cation, purification can be performed by performing cation exchange with the monofluorophosphate ester salt. Further, purification can be performed immediately after the monofluorophosphate ester is reacted with the halide to produce a monofluorophosphate ester salt. The purification method is not particularly limited, and for example, a method by operations such as distillation and drying, or a method using an adsorbent such as activated carbon or an ion exchange resin can be adopted. By performing these purifications, the purity of the monofluorophosphate ester salt can be increased.

(Fluorine ion-releasing composition)
The monofluorophosphate ester salt of the present embodiment is used as an additive for imparting sustained release of fluorine ions in, for example, a fluorine ion-releasing composition such as an oral composition or a dental composition. Can be done. In this case, the monofluorophosphate ester salt as the fluorine-releasing compound has a structure containing at least one type, and two or more types can be used in combination.

The monofluorophosphate ester salt of the present embodiment has, for example, a specific enzyme such as phosphatase without controlling the release rate of fluorine ions by coating the particle surface with a specific substance such as polysiloxane. By the reaction mediated by, a significant amount of fluorine ions can be continuously released over a long period of time. As a result, it is possible to obtain an oral composition or a dental composition that imparts high caries resistance to the dentin for a long period of time.

Examples of the oral composition include a dentifrice composition for preventing dental caries. Examples of the dental composition include dental coating agents, dental fillers such as dental composite resins and glass ionomer cements, dental adhesives, and dental cements.

In addition, in the toothpaste composition, in addition, fluorine ions such as sodium fluoride, tin fluoride, potassium fluoride, sodium monofluorophosphate, sodium fluorosilate, ammonium fluorosilate, amine fluoride, ammonium fluoride and the like are used. It is also possible to add a component as a supply source and use it in combination with the monofluorophosphate ester salt of the present embodiment. In this case, the amount of these components added can be appropriately set as needed.

The amount of the monofluorophosphate ester added is preferably 50 ppm to 10000 ppm, more preferably 50 ppm to 5000 ppm, more preferably 50 ppm to 5000 ppm, based on the intramolecular fluorine, based on the total amount of the fluorine ion-releasing composition. It is 100 ppm to 2000 ppm. By setting the addition amount to 50 ppm or more, the amount of fluorine ions released can be maintained. On the other hand, by setting the addition amount to 10,000 ppm or less, when applied to an additive for an oral composition, fluorosis due to excessive intake of fluorine can be suppressed, and the additive for a dental composition can be used. When applied, it is possible to prevent deterioration of handleability as a dental material.

Hereinafter, preferred embodiments of the present invention will be described in detail exemplarily. However, the materials, blending amounts, and the like described in this example do not limit the scope of the present invention to those alone unless otherwise specified.

(Precursor synthesis of monofluorophosphate ester salt)
<Synthesis of diethyl monofluorophosphate>
33.7 g of potassium fluoride and 150 g of acetonitrile were placed in a 300 mL eggplant flask containing a stir bar, and 50.3 g of diethyl chlorophosphate (manufactured by Tokyo Chemical Industry Co., Ltd.) was further added. Subsequently, the mixture was heated under reflux at 100 ° C. for 7 hours under a nitrogen stream. Then, the solution in the eggplant flask was allowed to cool to room temperature, and excess potassium fluoride and precipitated potassium chloride were removed by suction filtration. The solvent in the filtrate obtained by the evaporator was distilled off to obtain 42 g of diethyl monofluorophosphate, which is a pale yellow transparent liquid, as the target monofluorophosphate ester salt.

When diethyl chlorophosphate, which is a raw material, was anion-analyzed by ion chromatography <Metrome Co., Ltd., model number: IC-850>, two peaks of chloride ion and diethyl phosphate anion were detected. In addition, when the obtained pale yellow transparent liquid was also subjected to anion analysis, two peaks of fluoride ion and diethyl phosphate anion were detected, and the peak of chloride ion disappeared cleanly. As a result, it was confirmed that diethyl monofluorophosphate was produced. Further, when the obtained pale yellow transparent liquid was subjected to positive ion analysis by LC / MS (manufactured by Waters), a mass peak was observed at m / z = 157.1. This was almost the same as the molecular weight of diethyl monofluorophosphate, and it was confirmed that the obtained pale yellow transparent liquid was diethyl monofluorophosphate.

<Synthesis of ethyl monofluorophosphate>
13.7 g of the lithium ethylfluorophosphate and 50 g of diethyl ether were put into a 50 mL eggplant flask containing a stirrer. Subsequently, 4.0 g of sulfuric acid was added little by little while stirring the solution in the eggplant flask. Then, the mixture was stirred at room temperature for 1 hour. Further, vacuum filtration was performed to separate the white precipitate and the filtrate. Subsequently, the solvent in the filtrate was distilled off under reduced pressure to obtain 9.6 g of ethyl monofluorophosphate, which is a colorless and transparent liquid.

When the obtained colorless and transparent liquid was subjected to anion analysis by ion chromatography <Metrome Co., Ltd., model number: IC-850>, one peak was detected in the same detection time as the lithium ethylfluorophosphate. Also, no sulfate ion was detected. As a result, it was confirmed that the obtained colorless and transparent liquid was ethyl monofluorophosphate.

(Example 1)
<Synthesis of ethyl sodium monofluorophosphate>
To a 50 mL eggplant flask containing a stirrer, 1.9 g of sodium iodide and 10 g of acetonitrile were placed, and 2.0 g of the above-mentioned diethyl monofluorophosphate was further added. Then, while stirring the solution in the eggplant flask, the mixture was heated under reflux at 120 ° C. for 3 hours under a nitrogen stream. Further, the solution in the eggplant flask was allowed to cool to room temperature, and the precipitate in the solution was filtered off by vacuum filtration. Then, the precipitate was dried at 130 ° C. under a nitrogen stream to obtain 1.5 g of a white solid.

<Analysis>
When the obtained white solid was subjected to anion analysis by ion chromatography <Metrohm Co., Ltd., model number: IC-850>, one new peak was detected. As a result, it was confirmed that a new anion was generated. Further, when cation analysis was performed by ion chromatography <manufactured by Dionex, model number: ICS-1500>, a peak of sodium ion was detected. Further, when the obtained white solid was subjected to negative ion analysis by LC / MS (manufactured by Waters), a mass peak was observed at m / z = 126.9. This was almost the same as the molecular weight of the ethyl anion monofluorophosphate, and it was confirmed that the obtained white solid was ethyl sodium monofluorophosphate.

(Example 2)
<Synthesis of ethyllithium monofluorophosphate>
1.1 g of lithium chloride and 20.0 g of the above-mentioned diethyl monofluorophosphate were added to a 100 mL eggplant flask containing a stir bar. Then, while stirring the solution in the eggplant flask, heating and refluxing was performed at 120 ° C. under a nitrogen stream for 1.5 hours. Further, the solution in the eggplant flask was allowed to cool to room temperature, and the precipitate in the solution was filtered off by vacuum filtration. Then, the precipitate was dried at 130 ° C. under a nitrogen stream to obtain 3.0 g of a white solid.

<Analysis>
When the obtained white solid was subjected to anion analysis by ion chromatography <Metrohm Co., Ltd., model number: IC-850>, one new peak was detected. As a result, it was confirmed that a new anion was generated. Further, when cation analysis was performed by ion chromatography <manufactured by Dionex Co., Ltd., model number: ICS-1500>, a peak of lithium ions was detected. Further, when the obtained white solid was subjected to negative ion analysis by LC / MS (manufactured by Waters), a mass peak was observed at m / z = 126.9. This was almost the same as the molecular weight of the ethyl anion monofluorophosphate, and it was confirmed that the obtained white solid was ethyl sodium monofluorophosphate.

(Example 3)
<Synthesis of ethyl potassium monofluorophosphate>
2.1 g of potassium iodide and 20 g of acetonitrile were put into a 50 mL eggplant flask containing a stir bar, and then 3.0 g of the diethyl monofluorophosphate was put into the flask. Then, while stirring the solution in the eggplant flask, the mixture was heated under reflux at 140 ° C. to 150 ° C. for 13 hours under a nitrogen stream. Further, the solution in the eggplant flask was allowed to cool to room temperature, and the precipitate in the solution was filtered off by vacuum filtration. Then, the precipitate was dried at 130 ° C. under a nitrogen stream to obtain 2.0 g of a white solid.

<Analysis>
When the obtained white solid was anion-analyzed by ion chromatography <Metrohm, model number: IC-850>, one new peak was detected in the same detection time as the above-mentioned ethyllithium monofluorophosphate. Was done. As a result, it was confirmed that the produced novel anion was ethylfluorophosphate anion and the obtained white solid was ethyl potassium monofluorophosphate.

(Example 4)
<Synthesis of ethyl magnesium monofluorophosphate>
0.6 g of magnesium chloride anhydrous and 5 g of acetonitrile were put into a 50 mL eggplant flask containing a stirrer, and then 2.0 g of the above-mentioned diethyl monofluorophosphate was put into the flask. Then, while stirring the solution in the eggplant flask, the mixture was heated under reflux at 140 ° C. to 150 ° C. for 7 hours under a nitrogen stream. Further, the solution in the eggplant flask was allowed to cool to room temperature and then filtered under reduced pressure to separate unreacted magnesium chloride and filtrate. Subsequently, the solvent in the filtrate was distilled off under reduced pressure to obtain 1.7 g of a white solid.

<Analysis>
When the obtained white solid was anion-analyzed by ion chromatography <Metrohm, model number: IC-850>, one new peak was detected in the same detection time as the above-mentioned ethyllithium monofluorophosphate. Was done. As a result, it was confirmed that the generated novel anion was ethyl monofluorophosphate anion and the obtained white solid was ethyl magnesium monofluorophosphate.

(Example 5)
<Synthesis of ethyl calcium monofluorophosphate>
0.7 g of anhydrous calcium chloride and 10 g of acetonitrile were put into a 50 mL eggplant flask containing a stir bar, and then 2.0 g of diethyl monofluorophosphate was put into the flask. Then, while stirring the solution in the eggplant flask, the mixture was heated under reflux at 140 ° C. to 150 ° C. for 14 hours under a nitrogen stream. Further, the solution in the eggplant flask was allowed to cool to room temperature and then filtered under reduced pressure to separate unreacted calcium chloride and filtrate. Subsequently, the solvent in the filtrate was distilled off under reduced pressure to obtain 0.6 g of a white solid.

<Analysis>
When the obtained white solid was anion-analyzed by ion chromatography <Metrome Co., Ltd., model number: IC-850>, one new peak was detected in the same detection time as the lithium ethylfluorophosphate. rice field. As a result, it was confirmed that the produced novel anion was ethyl monofluorophosphate anion and the obtained white solid was ethyl calcium monofluorophosphate.

(Example 6)
<Synthesis of silver monofluorophosphate>
1.1 g of silver carbonate (I) and 10 g of water were put into a 50 mL eggplant flask containing a stir bar. Subsequently, 1.0 g of the ethyl monofluorophosphate was added little by little while stirring the solution in the eggplant flask. Then, the mixture was stirred at room temperature for 2 hours. Further, the precipitate and the filtrate were separated by vacuum filtration of the solution in the eggplant flask. Subsequently, the solvent in the filtrate was distilled off under reduced pressure to obtain 1.6 g of a white solid.

<Analysis>
When the obtained white solid was anion-analyzed by ion chromatography <Metrohm, model number: IC-850>, one peak was detected in the same detection time as the above-mentioned ethyllithium monofluorophosphate. .. In addition, when silver ions were quantified using the Forhardt method, which is one of the precipitation titrations (standard solution for volumetric analysis: 0.1 M ammonium thiocyanate solution, indicator: ammonium iron (III) sulfate, titration temperature: room temperature). , 43% by mass. This measured value was close to the theoretical value (46% by mass) of the silver ion content in ethyl silver monofluorophosphate, and it was confirmed that the obtained white solid was ethyl silver monofluorophosphate.

(Example 7)
<Synthesis of ethyl copper monofluorophosphate>
0.4 g of copper (II) hydroxide and 5 g of acetonitrile were put into a 50 mL eggplant flask containing a stir bar. Subsequently, 1.0 g of the ethyl monofluorophosphate was added little by little while stirring the solution in the eggplant flask. Then, the solution in the eggplant flask was stirred at room temperature for 1 hour. Further, the precipitate and the filtrate were separated by vacuum filtration of the solution in the eggplant flask. Subsequently, the solvent in the filtrate was distilled off under reduced pressure to obtain 1.2 g of a blue-green solid.

<Analysis>
When the obtained blue-green solid was anion-analyzed by ion chromatography <Metrohm, model number: IC-850>, one peak was detected in the same detection time as the above-mentioned ethyllithium monofluorophosphate. Was done. Further, when copper ions were quantified using the iodine titration method, which is one of the precipitation titrations (standard solution for volumetric analysis: 0.1 M sodium thiosulfate solution, titration temperature: room temperature), it was 20% by mass. .. This measured value was almost in agreement with the theoretical value (20% by mass) of the copper ion content in copper ethylfluorophosphate, and it was confirmed that the obtained blue-green solid was copper ethylfluorophosphate.

(Example 8)
<Synthesis of 1-Ethyl-3-methylimidazolium monofluorophosphate ethyl>
1.1 g of 1-ethyl-3-methylimidazolium chloride was charged into a 50 mL eggplant flask containing a stir bar, and then 1.0 g of the above-mentioned diethyl monofluorophosphate was charged. Then, the solution in the eggplant flask was heated at 110 ° C. to 120 ° C. for 3 hours with stirring to obtain 1.4 g of a yellow transparent oily liquid.

<Analysis>
When the obtained yellow transparent oily liquid was subjected to anion analysis by ion chromatography <Metrohm Co., Ltd., model number: IC-850>, one new peak was detected. As a result, it was confirmed that a new anion was generated. Further, when the obtained yellow transparent oily liquid was subjected to negative ion analysis by LC / MS (manufactured by Waters), a mass peak was observed at m / z = 126.9. Further, when the positive ion analysis was performed in the same manner, a mass peak was observed at m / z = 111.1. This is almost the same as the molecular weight of each of the anion and cation of 1-ethyl-3-methylimidazolium monofluorophosphate, and the obtained yellow transparent oily liquid is 1-ethyl-3-methylimidazolium mono. It was confirmed that it was ethyl fluorophosphate.

(Example 9)
<Synthesis of 1-ethylpyridinium monofluorophosphate ethyl>
1.8 g of 1-ethylpyridinium bromide and 10 g of acetonitrile were put into a 50 mL eggplant flask containing a stir bar, and then 1.5 g of the diethyl monofluorophosphate was put into the flask. Then, while stirring the solution in the eggplant flask, the mixture was heated under reflux at 140 ° C. to 150 ° C. for 15 hours under a nitrogen stream. After allowing the solution in the eggplant flask to cool to room temperature, the solvent in the solution was distilled off under reduced pressure, washed with hexane, and vacuum dried at room temperature to obtain 1.2 g of a colorless and transparent oily liquid. ..

<Analysis>
When the obtained colorless and transparent oily liquid was anion-analyzed by ion chromatography <Metrome Co., Ltd., model number: IC-850>, a new peak was found in the same detection time as the lithium ethylfluorophosphate. One was detected. As a result, it was confirmed that the novel anion produced was an ethyl monofluorophosphate anion, and the obtained colorless and transparent oily liquid was ethyl 1-ethylpyridinium monofluorophosphate.

(Example 10)
<Synthesis of 1-hexylpyridinium monofluorophosphate ethyl>
4.2 g of 1-hexylpyridinium bromide and 20 g of acetonitrile were put into a 50 mL eggplant flask containing a stir bar, and then 5.4 g of the diethyl monofluorophosphate was put into the flask. Then, while stirring the solution in the eggplant flask, the mixture was heated under reflux at 110 ° C. to 120 ° C. for 15 hours under a nitrogen stream. After allowing the solution in the eggplant flask to cool to room temperature, the solvent in the solution was distilled off under reduced pressure, washed with hexane, and vacuum dried at room temperature to obtain 4.9 g of a colorless and transparent oily liquid. ..

<Analysis>
When the obtained colorless and transparent oily liquid was subjected to anion analysis by ion chromatography <Metrohm Co., Ltd., model number: IC-850>, one new peak was detected. As a result, it was confirmed that a new anion was generated. Further, when the obtained colorless and transparent oily liquid was subjected to negative ion analysis by LC / MS (manufactured by Waters), a mass peak was observed at m / z = 127.0. Further, when the positive ion analysis was performed in the same manner, a mass peak was observed at m / z = 164.1. This was almost the same as the molecular weights of the anions and cations of ethyl 1-hexylpyridinium monofluorophosphate, and it was confirmed that the obtained colorless and transparent oily liquid was ethyl 1-hexylpyridinium monofluorophosphate. ..

(Example 11)
<Synthesis of cetylpyridinium monofluorophosphate ethyl>
In a 50 mL eggplant flask containing a stirrer, 4.4 g of cetylpyridinium chloride anhydrous and 20 g of acetonitrile were charged, and then 2.7 g of the above-mentioned diethyl monofluorophosphate was charged. Then, while stirring the solution in the eggplant flask, the mixture was heated under reflux at 140 ° C. to 150 ° C. for 7 hours under a nitrogen stream. Further, the solution in the eggplant flask was cooled to −10 ° C., and the precipitate in the solution was filtered off by vacuum filtration to obtain 3.2 g of a white solid.

<Analysis>
When the obtained white solid was anion-analyzed by ion chromatography <Metrohm, model number: IC-850>, one new peak was detected in the same detection time as the above-mentioned ethyllithium monofluorophosphate. Was done. As a result, it was confirmed that the generated novel anion was ethyl monofluorophosphate anion and the obtained white solid was ethyl cetylpyridinium monofluorophosphate.

(Example 12)
<Synthesis of ethyl octyltrimethylammonium monofluorophosphate>
4.4 g of octyltrimethylammonium bromide and 20 g of acetonitrile were put into a 50 mL eggplant flask containing a stir bar, and then 5.4 g of the diethyl monofluorophosphate was put into the flask. Then, while stirring the solution in the eggplant flask, the mixture was heated under reflux at 110 ° C. to 120 ° C. for 15 hours under a nitrogen stream. After allowing the solution in the eggplant flask to cool to room temperature, the solvent in the solution was distilled off under reduced pressure, washed with hexane, and vacuum dried at room temperature to obtain 4.2 g of a colorless and transparent oily liquid. ..

<Analysis>
When the obtained colorless and transparent oily liquid was subjected to anion analysis by ion chromatography <Metrohm Co., Ltd., model number: IC-850>, one new peak was detected. As a result, it was confirmed that a new anion was generated. Further, when the obtained colorless and transparent oily liquid was subjected to negative ion analysis by LC / MS (manufactured by Waters), a mass peak was observed at m / z = 127.0. Further, when the positive ion analysis was performed in the same manner, a mass peak was observed at m / z = 172.3. This was almost the same as the molecular weights of the anion and the cation of ethyl octyltrimethylammonium monofluorophosphate, and it was confirmed that the obtained colorless and transparent oily liquid was ethyl octyltrimethylammonium monofluorophosphate.

(Example 13)
<Synthesis of ethyl hexadecyltrimethylammonium monofluorophosphate>
4.5 g of hexadecyltrimethylammonium bromide and 20 g of acetonitrile were put into a 50 mL eggplant flask containing a stir bar, and then 3.9 g of diethyl monofluorophosphate was put into the flask. Then, while stirring the solution in the eggplant flask, the mixture was heated under reflux at 110 ° C. to 120 ° C. for 15 hours under a nitrogen stream. After allowing the solution in the eggplant flask to cool to room temperature, the solvent in the solution was distilled off under reduced pressure to obtain a white solid. The solid was recrystallized from acetone, collected by suction filtration, and vacuum dried at room temperature to obtain 2.9 g of a white solid.

<Analysis>
When the obtained white solid was subjected to anion analysis by ion chromatography <Metrohm Co., Ltd., model number: IC-850>, one new peak was detected. As a result, it was confirmed that a new anion was generated. Further, when the obtained white solid was subjected to negative ion analysis by LC / MS (manufactured by Waters), a mass peak was observed at m / z = 127.0. Further, when the positive ion analysis was performed in the same manner, a mass peak was observed at m / z = 284.6. This was almost the same as the molecular weights of the anion and cation of ethyl hexadecyltrimethylammonium monofluorophosphate, and it was confirmed that the obtained colorless and transparent oily liquid was ethyl hexadecyltrimethylammonium ethyl fluorophosphate. ..

(Example 14)
<Synthesis of hexadecyl (2-hydroxyethyl) dimethylammonium bromide>
In a 50 mL eggplant flask containing a stirrer, 3.5 g of hexadecyldimethylamine and 20 g of acetonitrile were charged, followed by 1.6 g of 2-bromoethanol. Then, while stirring the solution in the eggplant flask, the mixture was heated under reflux at 100 ° C. for 3 hours under a nitrogen stream. After allowing the solution in the eggplant flask to cool to room temperature, the solvent in the solution was distilled off under reduced pressure to obtain a white solid. After recrystallization from acetone, the solvent was decanted, and then vacuum dried at room temperature to obtain 4.8 g of hexadecyl (2-hydroxyethyl) dimethylammonium bromide as a white solid.

<Synthesis of hexadecyl (2-hydroxyethyl) dimethylammonium monofluorophosphate ethyl>
3.8 g of the hexadecyl (2-hydroxyethyl) dimethylammonium bromide and 20 g of acetonitrile were charged into a 50 mL eggplant flask containing a stirrer, and then 3.0 g of the diethyl monofluorophosphate was charged. Then, while stirring the solution in the eggplant flask, the mixture was heated under reflux at 110 ° C. to 120 ° C. for 3 hours under a nitrogen stream. After allowing the solution in the eggplant flask to cool to room temperature, the solvent in the solution was distilled off under reduced pressure to obtain a white solid. After recrystallization from acetone, the solvent was decanted, and then vacuum dried at room temperature to obtain 2.8 g of a white solid.

When the obtained white solid was subjected to anion analysis by ion chromatography <Metrohm Co., Ltd., model number: IC-850>, one new peak was detected. As a result, it was confirmed that a new anion was generated. Further, when the obtained white solid was subjected to negative ion analysis by LC / MS (manufactured by Waters), a mass peak was observed at m / z = 127.0. Further, when the positive ion analysis was performed in the same manner, a mass peak was observed at m / z = 314.6. This is almost the same as the molecular weight of each of the anion and cation of hexadecyl (2-hydroxyethyl) dimethylammonium ethylfluorophosphate, and the obtained colorless and transparent oily liquid is hexadecyl (2-hydroxyethyl) dimethylammonium mono. It was confirmed that it was ethyl fluorophosphate.

(Example 15)
<Synthesis of allyl hexadecyl dimethyl ammonium bromide>
3.5 g of hexadecyldimethylamine and 20 g of acetonitrile were put into a 50 mL eggplant flask containing a stir bar, and then 1.6 g of allyl bromide was put into the flask. Then, while stirring the solution in the eggplant flask, the mixture was heated under reflux at 60 ° C. for 3 hours under a nitrogen stream. After allowing the solution in the eggplant flask to cool to room temperature, the solvent in the solution was distilled off under reduced pressure to obtain a white solid. After recrystallization from acetone, the solvent was decanted, and then vacuum dried at room temperature to obtain 4.4 g of allylhexadecyldimethylammonium bromide as a white solid.

<Synthesis of allyl hexadecyl dimethyl ammonium monofluorophosphate ethyl>
3.8 g of the allylhexadecyldimethylammonium bromide and 20 g of acetonitrile were charged into a 50 mL eggplant flask containing a stirrer, and then 3.0 g of the diethyl monofluorophosphate was charged. Then, while stirring the solution in the eggplant flask, the mixture was heated under reflux at 110 ° C. to 120 ° C. for 3 hours under a nitrogen stream. Further, the solution in the eggplant flask was allowed to cool to room temperature, and then the solvent in the solution was distilled off under reduced pressure to obtain a colorless and transparent oily liquid. The mixture was recrystallized from acetone under cooling at −20 ° C., the solvent was decanted, and then vacuum dried at room temperature to obtain 1.7 g of a white solid.

When the obtained white solid was subjected to anion analysis by ion chromatography <Metrohm Co., Ltd., model number: IC-850>, one new peak was detected. As a result, it was confirmed that a new anion was generated. Further, when the obtained white solid was subjected to negative ion analysis by LC / MS (manufactured by Waters), a mass peak was observed at m / z = 127.0. Further, when the positive ion analysis was performed in the same manner, a mass peak was observed at m / z = 310.6. As a result, the molecular weights of the anions and cations of ethyl allylhexadecyldimethylammonium monofluorophosphate are almost the same, and the obtained colorless and transparent oily liquid is ethyl allylhexadecyldimethylammonium monofluorophosphate. confirmed.

(Example 16)

<Synthesis of dimethyl fluorophosphate>
3.9 g of potassium fluoride and 20 g of acetonitrile were put into a 100 mL eggplant flask containing a stir bar, and then 6.5 g of dimethyl chlorophosphate was put into the flask. Then, while stirring the solution in the eggplant flask, the mixture was heated under reflux at 80 ° C. to 100 ° C. for 2 hours under a nitrogen stream. Further, the solution in the eggplant flask was allowed to cool to room temperature and then filtered under reduced pressure to separate the white solid and the filtrate. As a result, an acetonitrile solution of dimethyl fluorophosphate, which is a slightly yellow transparent liquid, was obtained.

<Synthesis of methyllithium monofluorophosphate>
1.0 g of lithium chloride anhydrous was put into a 50 mL eggplant flask containing a stir bar, and then the acetonitrile solution of dimethyl fluorophosphate was put into it. Then, while stirring the solution in the eggplant flask, the mixture was heated under reflux at 110 ° C. to 120 ° C. for 4 hours under a nitrogen stream. Further, the solution in the eggplant flask was allowed to cool to room temperature, and then the solvent in the solution was distilled off at 40 ° C. under reduced pressure to obtain 2.1 g of a white solid.

When the obtained white solid was subjected to anion analysis by ion chromatography <Metrohm Co., Ltd., model number: IC-850>, one new peak was detected. As a result, it was confirmed that a new anion was generated. Further, when the obtained white solid was subjected to negative ion analysis by LC / MS (manufactured by Waters), a mass peak was observed at m / z = 112.9. This was almost the same as the molecular weight of methyl anion monofluorophosphate, and it was confirmed that the obtained white solid was methyllithium monofluorophosphate.

(Example 17)
<Synthesis of diisopropylfluorophosphate>
5.2 g of potassium fluoride and 20 g of acetonitrile were put into a 100 mL eggplant flask containing a stir bar, and then 12.0 g of diisopropyl chlorophosphate was put into the flask. Then, while stirring the solution in the eggplant flask, the mixture was heated under reflux at 80 ° C. to 100 ° C. for 2 hours under a nitrogen stream. Further, the solution in the eggplant flask was allowed to cool to room temperature and then filtered under reduced pressure to separate the white solid and the filtrate. Subsequently, the solvent in the filtrate was distilled off at 40 ° C. under reduced pressure to obtain 10.0 g of diisopropyl fluorophosphate, which is a slightly yellow transparent liquid.

<Synthesis of isopropyllithium monofluorophosphate>
1.2 g of lithium bromide anhydrous and 20 g of acetonitrile were put into a 100 mL eggplant flask containing a stir bar, and then 5.0 g of the diisopropyl fluorophosphate was put into the flask. Then, while stirring the solution in the eggplant flask, the mixture was heated under reflux at 110 ° C. to 120 ° C. for 5 hours under a nitrogen stream. Further, the solution in the eggplant flask was allowed to cool to room temperature, and the precipitate in the solution was filtered off by vacuum filtration. Then, the precipitate was dried at 130 ° C. under a nitrogen stream to obtain 1.6 g of a white solid.

When the obtained white solid was subjected to anion analysis by ion chromatography <Metrohm Co., Ltd., model number: IC-850>, one new peak was detected. As a result, it was confirmed that a new anion was generated. Further, when the obtained white solid was subjected to negative ion analysis by LC / MS (manufactured by Waters), a mass peak was observed at m / z = 140.9. This was almost the same as the molecular weight of the isopropyl anion monofluorophosphate, and it was confirmed that the obtained white solid was isopropyllithium monofluorophosphate.

(Example 18)
<Synthesis of dibutyl phthalate>
4.4 g of potassium fluoride and 20 g of acetonitrile were put into a 100 mL eggplant flask containing a stir bar, and then 11.5 g of dibutyl chlorophosphate was put into the flask. Then, while stirring the solution in the eggplant flask, the mixture was heated under reflux at 80 ° C. to 100 ° C. for 2 hours under a nitrogen stream. Further, the solution in the eggplant flask was allowed to cool to room temperature and then filtered under reduced pressure to separate the white solid and the filtrate. Subsequently, the solvent in the filtrate was distilled off at 40 ° C. under reduced pressure to obtain 6.8 g of dibutyl fluorophosphate, which is a slightly yellow transparent liquid.

<Synthesis of butyllithium monofluorophosphate>
1.0 g of lithium bromide anhydrous and 20 g of acetonitrile were put into a 100 mL eggplant flask containing a stirrer, and then 5.0 g of the dibutyl fluorophosphate was put into the flask. Then, while stirring the solution in the eggplant flask, the mixture was heated under reflux at 110 ° C. to 120 ° C. for 3 hours under a nitrogen stream. Further, the solution in the eggplant flask was allowed to cool to room temperature, and the precipitate in the solution was filtered off by vacuum filtration. Then, the precipitate was dried at 130 ° C. under a nitrogen stream to obtain 1.6 g of a white solid.

When the obtained white solid was subjected to anion analysis by ion chromatography <Metrohm Co., Ltd., model number: IC-850>, one new peak was detected. As a result, it was confirmed that a new anion was generated. Further, when the obtained white solid was subjected to negative ion analysis by LC / MS (manufactured by Waters), a mass peak was observed at m / z = 155.0. This was almost the same as the molecular weight of the butyl anion monofluorophosphate, and it was confirmed that the obtained white solid was butyllithium monofluorophosphate.

(Example 19)
<Synthesis of bis (2-ethoxyethyl) fluorophosphate>
1.5 g of potassium fluoride and 16 g of acetonitrile were put into a 50 mL eggplant flask containing a stir bar, and then 4.6 g of the bis (2-ethoxyethyl) chlorophosphate was put into the flask. Then, while stirring the solution in the eggplant flask, heating was performed at 50 ° C. to 60 ° C. for 2 hours under a nitrogen stream. Further, silica gel was added to the solution and stirred, and the solvent in the solution was distilled off at 40 ° C. under reduced pressure to obtain a white solid mixture containing the desired product. A small amount of silica gel was loaded in a column tube equipped with a glass filter, the obtained white solid mixture was charged, and extraction (flash column) was performed with ethyl acetate. The solvent was distilled off at 40 ° C. under reduced pressure to obtain 1.5 g of bis (2-ethoxyethyl) fluorophosphate, which is a colorless and transparent liquid.

<Synthesis of lithium monofluorophosphate (2-ethoxyethyl)>
0.2 g of lithium bromide anhydrous and 10 g of acetonitrile were put into a 50 mL eggplant flask containing a stir bar, and then 1.0 g of the bis (2-ethoxyethyl) fluorophosphate was put into the flask. Then, while stirring the solution in the eggplant flask, heating was performed at 50 ° C. to 60 ° C. for 4.5 hours under a nitrogen stream. Further, the solution in the eggplant flask was allowed to cool to room temperature, and the precipitate in the solution was filtered off by vacuum filtration. Then, the precipitate was dried at 130 ° C. under a nitrogen stream to obtain 0.4 g of a white solid.

When the obtained white solid was subjected to anion analysis by ion chromatography <Metrohm Co., Ltd., model number: IC-850>, one new peak was detected. As a result, it was confirmed that a new anion was generated. Further, when the obtained white solid was subjected to negative ion analysis by LC / MS (manufactured by Waters), a mass peak was observed at m / z = 170.9. This was almost the same as the molecular weight of the monofluorophosphate (2-ethoxyethyl) anion, and it was confirmed that the obtained white solid was monofluorophosphate (ethoxyethyl) lithium.

(Comparative Example 1)
In this comparative example, sodium fluoride ((manufactured by Stella Chemifa Co., Ltd.)) was used as a compound that imparts fluorine-releasing property.

(Comparative Example 2)
In this comparative example, sodium monofluorophosphate (manufactured by Strem Chemicals Co., Ltd.) was used as a compound that imparts fluorine-releasing property.

(Evaluation of sustained release of fluorine ions)
A sample aqueous solution was prepared using the monofluorophosphate ester salts obtained in Examples 1 to 19, sodium fluoride of Comparative Example 1, and sodium monofluorophosphate of Comparative Example 2, respectively. The abundance of all fluorine atoms in each sample aqueous solution was 1000 ppm. In addition, a 0.1% acid phosphatase phosphate buffer was prepared using acid phosphatase (3.3 U / mg) and 0.1 M phosphate buffer (pH 7) <manufactured by Wako Pure Chemical Industries, Ltd.>.

Subsequently, 4.7 g of the sample aqueous solution and 0.3 g of 0.1% acid phosphatase phosphate buffer were placed in a 20 mL vial to prepare an evaluation sample. A vial containing the evaluation sample was placed in a constant temperature bath at 37 ° C. and heated for 8 hours.

Then, ion chromatography <Metrohm Co., Ltd., model number: IC-850> at regular intervals perform a quantitative analysis of fluoride ions in the evaluation sample in, after a fluorine ion concentration after 8 hours A _{8, 4} hours the fluoride ion concentration of fluorine ion concentration in the case of a _{4, 0} hours and a _0, according to the following equation to calculate the S (%). The results are shown in Table 1 below.
S (%) = (A _4- A ₀ ) / (A _8- A ₀ ) x 100

Regarding the release property and sustained release property of fluorine ions, it can be said that the closer the value of S is to 50%, the more the fluorine ions are uniformly released over 8 hours, and the sustained release property is high. Then, as shown in Table 1 below, S (%) showed a value of about 50% for each Example, and it was confirmed that the sustained release property of fluorine ions was excellent. On the other hand, Comparative Examples 1 and 2 were 99% and 68%, respectively, and it was confirmed that after 8 hours, the amount of fluorine ions released was small and the sustained release property was inferior. ..

Claims (16)

Represented by the following chemical formula (1), and the reaction by oral composition containing monofluorophosphate ester salts that have a sustained release fluoride ions or dental composition with a phosphatase.

(However, the M ^{n +} is hydrogen ion, alkali metal ion (excluding sodium ion) , alkaline earth metal ion, transition metal ion, rare earth element ion, zinc ion, aluminum ion, gallium ion, indium ion, germanium ions, tin ions, represents any one selected from the group consisting of lead ions and onium ions. the R ¹ is a hydrocarbon group having 1 to 20 carbon atoms, a range of 1 to 20 carbon atoms , the halogen atom youth properly hydrocarbon group having at least one of unsaturated bond include 2-methoxyethyl group, 2- (2-methoxyethoxy) ethyl group, 2- (2- (2-methoxyethoxy) ethoxy ) Ethyl group, 2- (2- (2- (2-methoxyethoxy) ethoxy) ethoxy) ethyl group, or 2-ethoxyethyl group . The n represents a valence.) The oral composition or dental composition according to claim 1, wherein the alkali metal ion is any one selected from the group consisting of lithium ion, potassium ion, rubidium ion and cesium ion. The oral composition or dental composition according to claim 1 or 2, wherein the alkaline earth metal ion is any one selected from the group consisting of magnesium ion, calcium ion, strontium ion and barium ion. Claims 1 to 3 wherein the transition metal ion is any one selected from the group consisting of manganese ion, cobalt ion, nickel ion, chromium ion, copper ion, silver ion, molybdenum ion, tungsten ion and vanadium ion. The oral composition or dental composition according to any one of the following items. The rare earth element ions are scandium ion, ytterbium ion, lanthanum ion, cerium ion, praseodymium ion, neodymium ion, promethium ion, samarium ion, uropium ion, gadolinium ion, terbium ion, dysprosium ion, formium ion, erbium ion, thulium ion. The oral composition or dental composition according to any one of claims 1 to 4, which is any one selected from the group consisting of ytterbium ion and lutetium ion. One of the onium ions selected from the group consisting of ammonium ion, primary ammonium ion, secondary ammonium ion, tertiary ammonium ion, quaternary ammonium ion, quaternary phosphonium ion and sulfonium ion. The oral composition or dental composition according to any one of claims 1 to 5. An oral composition containing a monofluorophosphate ester salt represented by the following chemical formula (4) and having a sustained release property of fluorine ions by reaction with phosphatase.

(However, the above R ¹ Is a hydrocarbon group having 1 to 20 carbon atoms, a hydrocarbon group having 1 to 20 carbon atoms and having at least one of a halogen atom or an unsaturated bond, a 2-methoxyethyl group, and 2 -(2-methoxyethoxy) ethyl group, 2- (2- (2-methoxyethoxy) ethoxy) ethyl group, 2- (2- (2- (2-methoxyethoxy) ethoxy) ethoxy) ethyl group, or 2- Represents any of the ethoxyethyl groups. ) A step of fluorinating the monohalophosphodiester represented by the following chemical formula (2) to produce a monofluorophosphate diester represented by the following chemical formula (3).
The monofluorophosphate diester and M ^{n +} X ² n (M ^{n +} is an alkali metal ion, an alkaline earth metal ion, a transition metal ion, a rare earth element ion, a zinc ion, an aluminum ion, a gallium ion, an indium ion, and a germanium. It represents any one selected from the group consisting of an ion, a tin ion, a lead ion and an onium ion. The X ² represents a halogen atom of any one of F, Cl, Br or I. The n represents a valence. ), A method for producing a monofluorophosphate ester salt, which comprises a step of producing a monofluorophosphate ester salt represented by the following chemical formula (1).

(Provided that R ¹ and R ² independently of one another, a hydrocarbon group having 1 to 20 carbon atoms, a range of 1 to 20 carbon atoms, a halogen atom young properly are all at least unsaturated bond Hydrocarbon group having one , 2-methoxyethyl group, 2- (2-methoxyethoxy) ethyl group, 2- (2- (2-methoxyethoxy) ethoxy) ethyl group, 2- (2- (2- (2-) (2-methoxyethoxy) ethoxy) ethoxy) represents either an ethyl group or a 2-ethoxyethyl group. ^{X 1} represents a halogen atom other than F.)

(Independently R ¹ and R ² are mutually hydrocarbon group having 1 to 20 carbon atoms in the range of 1 to 20 carbon atoms, a halogen atom young properly is at least one of the unsaturated bonds Hydrocarbon group having , 2-methoxyethyl group, 2- (2-methoxyethoxy) ethyl group, 2- (2- (2-methoxyethoxy) ethoxy) ethyl group, 2- (2- (2- (2-) Represents either a methoxyethoxy) ethoxy) ethoxy) ethyl group or a 2-ethoxyethyl group .)

(However, the ^{Mn +} is derived from hydrogen, alkali metal ion, alkaline earth metal ion, transition metal ion, rare earth element ion, zinc ion, aluminum ion, gallium ion, indium ion, germanium ion, tin ion, lead ion and onium ion. . the R ¹ representing any one selected from the group consisting of a hydrocarbon group having 1 to 20 carbon atoms, a range of 1 to 20 carbon atoms, a halogen atom young properly at least unsaturated bond A hydrocarbon group having any one, a 2-methoxyethyl group, a 2- (2-methoxyethoxy) ethyl group, a 2- (2- (2-methoxyethoxy) ethoxy) ethyl group, a 2- (2- (2) Represents either a-(2-methoxyethoxy) ethoxy) ethoxy) ethyl group or a 2-ethoxyethyl group . The n represents a valence.) The production of the monofluorophosphate ester salt according to claim 8 , wherein the fluorination treatment in the step of producing the monofluorophosphate diester is carried out by contacting the monohalophosphate diester with a fluorinating agent in a non-aqueous solvent. Method. The method for producing a monofluorophosphate ester salt according to claim 9 , wherein an alkali metal fluoride, an alkaline earth metal fluoride, or an onium fluorolide is used as the fluorinating agent. The method for producing a monofluorophosphate ester salt according to claim 9 or 10 , wherein the reaction start temperature of the fluorination treatment is in the range of 0 ° C. to 200 ° C. Any one of claims 9 to 11 using any one of the aprotonic solvents selected from the group consisting of nitriles, esters, ketones, ethers and halogenated hydrocarbons as the non-aqueous solvent. The method for producing a monofluorophosphate ester salt according to. In the step of producing the monofluorophosphate ester salt, the monofluorophosphate diester in the range of 0.5 equivalent to 5 equivalent is added to ^{1 equivalent of the M n +} X ^{2 n in another non-aqueous solvent.} The method for producing a monofluorophosphate ester salt according to any one of claims 9 to 12 , which is carried out by reacting. The reaction of the in the step of generating the mono-fluoro phosphate salt and monofluorophosphate diester and the M ^{n + X} 2 ⁿ is any one of claims 9 to 13 for performing the monofluorophosphate diester as a reaction solvent The method for producing a monofluorophosphate ester salt according to the section. ^{The reaction between the monofluorophosphate diester and the M n +} X ² n in the step of producing the monofluorophosphate ester salt is carried out in another non-aqueous solvent.
The method according to any one of claims 9 to 13 , wherein any one selected from the group consisting of alcohols, nitriles, esters, ketones, ethers and halogenated hydrocarbons is used as the other non-aqueous solvent. The method for producing a monofluorophosphate ester salt according to the above method. The 14 or 15 according to claim 14 or 15, wherein the reaction start temperature of the monofluorophosphate diester and the M ^{n +} X ² n is in the range of 0 ° C. to 200 ° C., and the reaction time is in the range of 30 minutes to 20 hours. Method for producing monofluorophosphate ester salt.