Method for producing phosphoric acid ester compound

Abstract

This method for producing a phosphoric acid ester compound comprises introducing a solution (i) containing an alcohol compound and a solution (ii) containing a phosphorylating agent into different flow channels, causing each solution to flow through each flow channel, and merging the solution (i) and the solution (ii) to react the alcohol compound with the phosphorylating agent while the merged solution (M1) is flowing downstream.

Description

Method for producing phosphate ester compounds

[0001] The present invention relates to a method for producing a phosphoric acid ester compound.

[0002] Phosphate ester compounds are known as various functional materials, and are also highly compatible with bones and teeth. For example, adhesives that bond dental materials to teeth contain phosphate ester compounds with polymerizable groups.

[0003] Phosphate compounds can be obtained by reacting a phosphorylating agent with an alcohol compound. This reaction is generally carried out in a batch system, and tends to be a complicated and lengthy reaction, requiring the alcohol compound to be added in portions to a solution of the phosphorylating agent over several hours to mitigate the heat generated by the reaction between the phosphorylating agent and the alcohol compound, and the heat generated by the subsequent hydrolysis reaction, and the hydrolysis reaction to be carried out under mild conditions. For example, an example of a batch system synthesis reaction for 10-methacryloyloxydecyl phosphate monoester (MDP) as a phosphoric acid ester compound will be described. In this reaction, first, phosphorus oxychloride (POCl ), a phosphorylating agent, is added. ３ A mixed solution of the raw material alcohols 10-hydroxydecyl methacrylate (MDME) and triethylamine (TEA) is added in portions to a solution of 10-hydroxydecyl methacrylate (MDME) at below freezing point over several hours to obtain a dichlorophosphate monoester. Water is then added, and TEA is added in portions at low temperature over several hours to induce a hydrolysis reaction, converting the -Cl in the dichlorophosphate monoester to -OH. This method requires complicated procedures to suppress heat generation, resulting in a long reaction time. Furthermore, a certain amount of by-products, such as a dimer formed by condensation of phosphate groups, is produced, limiting the improvement of the purity and yield of the target phosphate ester compound.

[0004] In the synthesis of phosphoric acid monoester compounds, a technique for specifically producing a monoester while suppressing the production of a diester is known. For example, Patent Document 1 describes a method for producing a phosphoric acid ester monomer, which is characterized by reacting a hydroxyalkyl (meth)acrylate having a specific structure with polyphosphoric acid in the presence of N,N'-dimethylformamide. The technique described in Patent Document 1 is said to be able to suppress an increase in viscosity and gelation of the reaction system, and to produce a high-purity phosphoric acid monoester monomer in high yield with reduced phosphoric acid diester and unreacted phosphorylating agent.

[0005] Japanese Patent Application Laid-Open No. 2018-27927

[0006] In the above batch-type reaction using phosphorus oxychloride as the phosphorylating agent, there is a problem that a certain amount of dimers resulting from condensation of phosphate groups are produced, as described above. The reason for this is thought to be that the hydrolysis rate of the dichlorophosphate monoester is slowed by adding TEA in portions over several hours at a low temperature, creating a state in which the dichlorophosphate monoester or monochlorophosphate monoester coexists with the completely hydrolyzed phosphate monoester, resulting in a condensation reaction between -Cl and -OH.

[0007] The present invention provides a method for producing a phosphate ester compound, which produces a phosphate ester compound through a step of reacting an alcohol compound with a phosphating agent, and an object of the present invention is to provide a method for producing a phosphate ester compound, which enables the production of a target phosphate ester compound with higher purity and higher efficiency.

[0008] The above problems of the present invention are solved by the following means: [1] A method for producing a phosphate ester compound, comprising introducing a solution (i) containing an alcohol compound and a solution (ii) containing a phosphorylating agent into different channels, allowing each solution to flow through each channel, and combining the solutions (i) and (ii) so that the combined liquid (M1) reacts the alcohol compound and the phosphorylating agent as it flows downstream. [2] The method for producing a phosphate ester compound according to [1], comprising mixing a solution (iii) containing a non-nucleophilic base with the combined liquid (M1), and producing a phosphate monoester compound or a phosphate diester compound through a step of causing a hydrolysis reaction in the mixed liquid (M2) in the presence of water. [3] The method for producing a phosphate ester compound according to [2], comprising combining the solution (iii) flowing through a channel with the combined liquid (M1), and producing a phosphate monoester compound or a phosphate diester compound through a step of causing a hydrolysis reaction in the presence of water as the combined liquid (M2) flows downstream. [4] A method for producing a phosphate ester compound according to [2] or [3], wherein the temperature of the hydrolysis reaction is controlled to be within the range of 0°C to 80°C. [5] A method for producing a phosphate ester compound according to any one of [2] to [4], wherein the solution (iii) contains water. [6] A method for producing a phosphate ester compound according to any one of [1] to [5], wherein the solution (i) contains a non-nucleophilic base. [7] A method for producing a phosphate ester compound according to any one of [1] to [6], wherein the temperature of the combined liquid (M1) is controlled to be within the range of -50°C to 50°C to react the alcohol compound with the phosphorylating agent. [8] A method for producing a phosphate ester compound according to any one of [1] to [7], wherein the alcohol compound is a monohydric alcohol compound. [9] A method for producing a phosphate ester compound according to [8], wherein the monohydric alcohol compound has a polymerizable group that undergoes addition polymerization.

[10] A method for producing a phosphate ester compound according to any one of [1] to [9], wherein the phosphate ester compound is a (meth)acryloyloxyalkyl phosphate monoester compound.

[11] The method for producing a phosphate ester compound according to any one of [1] to

[10] , wherein the phosphating agent is a pentavalent phosphorus compound.

[12] The method for producing a phosphoric acid ester compound according to any one of [1] to

[11] , wherein the phosphorylating agent is a phosphorus oxyhalide.

[0009] In the present invention, a numerical range expressed using "to" means a range that includes the numerical values ​​written before and after "to" as the lower and upper limits. In the present invention, groups that are not specified as substituted or unsubstituted include those that have any substituent within the range that does not impair the intended effect. For example, an "alkyl group" is meant to include both substituted and unsubstituted alkyl groups.

[0010] The present invention provides a method for producing phosphate ester compounds, which involves reacting an alcohol compound with a phosphorylating agent to obtain a phosphate ester compound. This method makes it possible to obtain the target phosphate ester compound with higher purity and greater efficiency.

[0011] Fig. 1 is an explanatory diagram showing one embodiment of the manufacturing method of the present invention. Fig. 2 is an explanatory diagram showing another embodiment of the manufacturing method of the present invention. Fig. 3 is an explanatory diagram showing yet another embodiment of the manufacturing method of the present invention. Fig. 4 is an explanatory diagram showing yet another embodiment of the manufacturing method of the present invention. Fig. 5 is an explanatory diagram showing yet another embodiment of the manufacturing method of the present invention.

[0012] [Method for Producing Phosphate Ester Compound] The method for producing a phosphate ester compound of the present invention (hereinafter referred to as the "production method of the present invention") comprises flowing a solution (i) containing an alcohol compound and a solution (ii) containing a phosphorylating agent through different flow paths, joining these flowing liquids, and reacting the alcohol compound with the phosphorylating agent while this combined liquid (M1) flows downstream. That is, a primary feature of the production method of the present invention is that the reaction between the alcohol compound and the phosphorylating agent is carried out in a flow reaction system.

[0013] In the present invention, the term "phosphate ester compound" includes salt forms of phosphate monoester compounds and phosphate diester compounds. In the production method of the present invention, when the phosphating agent is a pentavalent phosphorus compound (a compound in which phosphorus is in a pentavalent state) and the target compound is a phosphate triester compound, the phosphating agent reacts with the alcohol compound in the combined liquid (M1) to produce a phosphate triester compound, and the reaction liquid is removed to obtain the target phosphate triester compound in the reaction liquid. This reaction can be classified into the following three types (a-1) to (a-3). Note that, hereinafter, the "reactive group" of the phosphating agent refers to a group that reacts with a hydroxy group of an alcohol compound (R—OH, R: organic group) to produce a "P—O—R" bond (phosphate ester bond or phosphite ester bond). For example, when the phosphating agent is phosphorus oxychloride (POCl ３ In the case of ), the three "-Cl" groups are reactive groups. Also, the phosphorylating agent is phosphorus trichloride (PCL ３ In this case, the three "-Cl" groups are reactive groups.

[0014] (a-1) When the phosphorylating agent has three reactive groups, one molecule of the alcohol compound reacts with each of these three reactive groups in the reaction in the merged liquid (M1), producing the target phosphate triester compound.

[0015] (a-2) When the phosphorylating agent has two reactive groups (when the phosphorylating agent is already in the form of a phosphoric acid monoester), one molecule of the alcohol compound reacts with each of the two reactive groups in the combined liquid (M1), producing the target phosphoric acid triester compound.

[0016] (a-3) When the phosphorylating agent has one reactive group (when the phosphorylating agent is already in the form of a phosphoric acid diester), one molecule of an alcohol compound reacts with the reactive group in the combined liquid (M1), producing the target phosphoric acid triester compound.

[0017] In the production method of the present invention, when the phosphorylating agent is a trivalent phosphorus compound (a compound in which phosphorus is trivalent) and the target compound is a phosphate triester compound, the phosphorylating agent reacts with the alcohol compound in the combined liquid (M1) to produce a phosphite triester compound, and the target phosphate triester compound can be obtained by subjecting this phosphite triester compound to an oxidation treatment (oxidation reaction). This series of reactions can be classified into the following three types (b-1) to (b-3).

[0018] (b-1) When the phosphorylating agent has three reactive groups, one molecule of the alcohol compound reacts with each of the three reactive groups in the reaction in the combined liquid (M1) to produce a phosphite triester compound. By subjecting this phosphite triester compound to oxidation treatment, the target phosphate triester compound is produced.

[0019] (b-2) When the phosphorylating agent has two reactive groups (when the phosphorylating agent is already in the form of a phosphorous acid monoester), one molecule of the alcohol compound reacts with each of the two reactive groups in the combined liquid (M1), producing a phosphorous acid triester compound. By subjecting this phosphorous acid triester compound to an oxidation treatment, the target phosphorous acid triester compound is produced.

[0020] (b-3) When the phosphorylating agent has one reactive group (when the phosphorylating agent is already in the form of a phosphite diester), one molecule of the alcohol compound reacts with the reactive group in the combined liquid (M1) to produce a phosphite triester compound. By subjecting this phosphite triester compound to an oxidation treatment, the target phosphate triester compound is produced.

[0021] The structure of the phosphate triester compound obtainable by the production method of the present invention is not particularly limited. Preferred specific examples of this phosphate triester compound are shown below, but the present invention is not limited to these specific examples. Me represents methyl, and Et represents ethyl.

[0022]

[0023] In the production method of the present invention, when the phosphorylating agent is a pentavalent phosphorus compound and the target compound is a phosphoric acid monoester compound, a phosphorylating agent having three reactive groups is typically used. In this case, a reaction in the combined liquid (M1) causes one of the three reactive groups of the phosphorylating agent to react with one molecule of the alcohol compound to produce a monoesterified compound (phosphorylating agent monoester compound). This phosphorylating agent monoester compound is subjected to a hydrolysis reaction in the presence of water, converting the remaining two reactive groups of the phosphorylating agent to hydroxy groups, thereby obtaining the target phosphoric acid monoester compound. When the phosphorylating agent is a trivalent phosphorus compound, a phosphorous acid monoester compound is obtained by the reaction in the combined liquid (M1) and subsequent hydrolysis treatment, and the target phosphoric acid monoester compound can be obtained by subjecting this phosphorous acid monoester compound to an oxidation treatment.

[0024] The structure of the phosphoric acid monoester compound obtainable by the production method of the present invention is not particularly limited. Preferred specific examples of this phosphoric acid monoester compound are shown below, but the present invention is not limited to these specific examples. In the specific examples below, the number of repeating units (oxyethylene units) shown in parentheses (the number at the bottom right of the parentheses) is a median value, and the number of repeating units in the specific examples below is not limited to the number at the bottom right of the parentheses.

[0025]

[0026] In the production method of the present invention, when the phosphorylating agent is a pentavalent phosphorus compound and the target compound is a phosphoric acid diester compound, a phosphorylating agent having three reactive groups can be used. In this case, the reaction in the combined liquid (M1) causes two of the three reactive groups of the phosphorylating agent to react with one molecule of the alcohol compound, thereby producing a diesterified compound (phosphorylating agent diester compound). By subjecting this phosphorylating agent diester compound to a hydrolysis reaction in the presence of water, the remaining reactive group of the phosphorylating agent is converted to a hydroxy group, thereby producing the target phosphoric acid diester compound. Furthermore, when the phosphorylating agent is a pentavalent phosphorus compound having two reactive groups (when the phosphorylating agent is already in a monoester form), the reaction in the combined liquid (M1) causes one molecule of the alcohol compound to react with one of the two reactive groups, thereby producing a diesterified compound (phosphorylating agent diester compound). This phosphorylating agent diester compound is subjected to a hydrolysis reaction in the presence of water to convert one remaining reactive group of the phosphorylating agent into a hydroxy group, thereby obtaining the target phosphoric acid diester compound. When the phosphorylating agent is a trivalent phosphorus compound, a phosphorous acid diester compound is obtained by the reaction in the combined liquid (M1) and the subsequent hydrolysis treatment, and the target phosphoric acid diester compound can be obtained by subjecting this phosphorous acid diester compound to an oxidation treatment.

[0027] The structure of the phosphoric acid diester compound obtainable by the production method of the present invention is not particularly limited. Preferred specific examples of this phosphoric acid diester compound are shown below, but the present invention is not limited to these specific examples. In the specific examples below, the number of repeating units (oxyethylene units) shown in parentheses (the number at the bottom right of the parentheses) is a median value, and the number of repeating units in the specific examples below is not limited to the number at the bottom right of the parentheses.

[0028]

[0029] As described above, when the phosphorylating agent used is a trivalent phosphorus compound, it is necessary to oxidize the phosphite ester compound after the esterification reaction to convert it to a phosphate ester compound. On the other hand, when the phosphorylating agent used is a pentavalent phosphorus compound, this oxidation treatment is unnecessary. Therefore, from the viewpoint of work efficiency, it is preferable that the phosphorylating agent be a pentavalent phosphorus compound.

[0030] The raw materials, reagents, etc. that can be used in the production method of the present invention will now be described.

[0031] <Solution (i)> (Alcohol compound) The above alcohol compound may be a monohydric alcohol (a compound having one hydroxyl group in one molecule) or a polyhydric alcohol (a compound having multiple hydroxyl groups in one molecule). From the viewpoint of suppressing side reactions, monohydric or dihydric alcohols are preferred, and monohydric alcohols are more preferred. The hydroxyl group of the above alcohol compound reacts with the reactive group of the above phosphorylating agent to form a phosphate ester bond (when the phosphorylating agent is a pentahydric phosphorus compound) or a phosphite ester bond (when the phosphorylating agent is a trihydric phosphorus compound).

[0032] The above alcohol compound may be an aliphatic primary alcohol, an aliphatic secondary alcohol, or an aliphatic tertiary alcohol, with an aliphatic primary alcohol being preferred. The above alcohol compound may have a group containing a heteroatom, such as an ester bond or a carbonyl group, in its molecule. Furthermore, the above alcohol compound may be a phenol compound. In other words, in this invention, "alcohol compound" is synonymous with "hydroxy compound" and includes compounds having a phenolic hydroxyl group.

[0033] The above alcohol compound preferably has an alkylene group having 1 to 30 carbon atoms, more preferably an alkylene group having 2 to 25 carbon atoms, even more preferably an alkylene group having 2 to 20 carbon atoms, and particularly preferably an alkylene group having 2 to 15 carbon atoms. Furthermore, the number of carbon atoms is also preferably 4 to 20, and also preferably 6 to 15. This alkylene group may be linear or branched, with linearity being more preferable.

[0034] The above alcohol compounds may have reactive groups other than hydroxyl groups. In particular, it is preferable that they have polymerizable groups that undergo addition polymerization. Polymerizable groups that undergo addition polymerization include groups having carbon-carbon unsaturated bonds, and groups having ethylenically unsaturated bonds are preferred. Examples include (meth)acryloyl groups, (meth)acrylamide groups, styryl groups, vinyl groups, allyl groups, etc. As an example, considering use as an adhesive in the dental field, the (meth)acryloyl group is particularly preferred based on its track record. In the present invention, the (meth)acryloyl group means either an acryloyl group or a methacryloyl group. The same applies to the (meth)acrylamide group.

[0035] The molecular weight of the above alcohol compound is preferably 50 to 2000, more preferably 100 to 1000, and even more preferably 200 to 1000. Alternatively, this molecular weight may be 50 to 800, 100 to 600, or 150 to 500.

[0036] Suitable examples of the above alcohol compounds include 10-hydroxydecyl (meth)acrylate, hydroxyethyl (meth)acrylate, 3-phenylpropanol, 2-(2-methoxyethoxy)ethanol, 1-undecanol, isopropanol, etc., but the present invention is not limited to forms using these.

[0037] The content of the alcohol compound in solution (i) is not particularly limited. For example, it can be 5 to 70% by mass, more preferably 5 to 60% by mass, and even more preferably 10 to 50% by mass.

[0038] (Solvent) The solvent constituting solution (i) can be any non-alcohol compound without particular limitation. From the viewpoint of reactivity and liquid transferability, this solvent preferably contains an aromatic hydrocarbon solvent, and more preferably is an aromatic hydrocarbon solvent. Examples of aromatic hydrocarbon solvents include toluene, xylene, mesitylene, anisole, dimethoxybenzene, chlorobenzene, etc. If a solvent other than an aromatic hydrocarbon solvent is included, examples include hexane, heptane, tetrahydrofuran, diethyl ether, diisopropyl ether, tert-butyl methyl ether, ethyl acetate, acetonitrile, acetone, methyl ethyl ketone, dichloromethane, chloroform, etc.

[0039] <Solution (ii)> (Phosphorylating Agent) Examples of the phosphorylating agent include pentavalent phosphorus compounds and trivalent phosphorus compounds.

[0040] As a phosphorylating agent which is a pentavalent phosphorus compound, phosphorus oxyhalide (PO(Hal) ３ Examples include phosphorus oxyhalogenates (Hal: halogen atom), polyphosphate, and phosphorus pentoxide. The halogen atom of phosphorus oxyhalogenates is preferably a chlorine atom, a bromine atom, or an iodine atom, with a chlorine atom being more preferred. Also, phosphorus phosphate esters of phosphorus oxyhalogenates (PO(Hal) ２ (OR), PO (Hal) (OR) ２ , R (organic group) can also be used as a phosphorylating agent, which is a pentavalent phosphorus compound. Since these already have one or two phosphate ester bonds in their molecules, the resulting phosphate ester compounds are diesters or triesters.

[0041] As a phosphorylating agent, which is a trivalent phosphorus compound, phosphorus trihalide (P(Hal) ３, Hal: halogen atom), dialkyl phosphorochloridite (the alkyl group preferably has 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms), monoalkyl phosphorodichloridite (the alkyl group preferably has 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms). The halogen atom of the phosphorus trihalide is preferably a chlorine atom, bromine atom, or iodine atom, more preferably a chlorine atom. Dialkyl phosphorochloridite can be used to produce a triester, and monoalkyl phosphorodichloridite can be used to produce a diester or triester.

[0042] In the production method of the present invention, it is preferable to use a pentavalent phosphorus compound as the phosphating agent, not only from the viewpoint of the above-mentioned operational efficiency (oxidation treatment is not required) but also because the raw material is easy to handle. The phosphating agent used in the production method of the present invention is preferably a phosphorus oxyhalide, and particularly preferably phosphorus oxychloride.

[0043] The content of the phosphating agent in the solution (ii) is appropriately set in consideration of the ratio of the amount of the phosphating agent to the amount of the alcohol compound in the combined liquid (M1). For example, the content of the phosphating agent in the solution (ii) can be 5 to 60 mass%, more preferably 5 to 50 mass%, and even more preferably 5 to 40 mass%.

[0044] (Solvent) The solvent constituting solution (ii) can be any non-alcoholic solvent without any particular limitations. From the viewpoint of reactivity and liquid transportability, this solvent preferably contains an aromatic hydrocarbon solvent, and more preferably is an aromatic hydrocarbon solvent. Examples of aromatic hydrocarbon solvents include toluene, mesitylene, anisole, dimethoxybenzene, and chlorobenzene. In addition, when a solvent other than an aromatic hydrocarbon solvent is contained, examples thereof include hexane, heptane, tetrahydrofuran, diethyl ether, diisopropyl ether, tert-butyl methyl ether, ethyl acetate, acetonitrile, acetone, methyl ethyl ketone, dichloromethane, and chloroform.

[0045] In the manufacturing method of the present invention, the molar ratio of the alcohol compound to the phosphorylating agent in the combined liquid (M1) is approximately determined by the stoichiometric ratio. For example, if the molar amount of the alcohol compound is 1.0, and the molar amount of the phosphorylating agent is set to about 1.0 (for example, 0.7 to 1.4, preferably 0.8 to 1.3, more preferably 0.9 to 1.2), a phosphate ester compound or phosphite ester compound can be obtained in which the alcohol compound and the phosphorylating agent react in a molar ratio of approximately 1:1. Furthermore, if it is desired to react one molecule of the alcohol compound with each of the two reactive groups of the phosphorylating agent, the molar amount of the phosphorylating agent should be set to about 0.5 (for example, 0.3 to 0.7, preferably 0.4 to 0.6) relative to the molar amount of the alcohol compound (1.0). This reactivity can also be adjusted to a certain extent by the amount of catalyst (non-nucleophilic base, etc.) used. For example, if a non-nucleophilic base is included in the combined solution (M1) at a high concentration, even if the molar ratio of the alcohol compound and the phosphorylating agent is approximately 1:1, the proportion of the diester compound tends to increase in addition to the monoester compound. Therefore, when a non-nucleophilic base is included in solution (i) and combined with solution (ii) to produce the combined solution (M1), from the viewpoint of both reaction efficiency and suppression of by-products, it is preferable, more preferable, 1.8 or less, even more preferable, 1.6 or less, even more preferable, 1.4 or less, and even more preferable, 1.3 or less, for every 1.0 molar amount of the alcohol compound in the combined solution (M1) (in the combined solution (M1) immediately after combination). The molar amount of this non-nucleophilic base is usually 0.2 or more, preferably 0.4 or more, even more preferable, and even more preferable, 0.8 or more. In the combined liquid (M1) (in the combined liquid (M1) immediately after confluence), the preferred range for the molar amount of a non-nucleophilic base relative to 1.0 molar amount of an alcohol compound is 0.2 to 2.0, more preferably 0.4 to 1.8, even more preferably 0.6 to 1.6, even more preferably 0.8 to 1.4, and even more preferably 0.8 to 1.3.

[0046] In the production method of the present invention, the target phosphate ester compound is preferably a phosphate monoester compound or a phosphate diester compound. In this case, the phosphate monoester compound or the phosphate diester compound produced by the reaction of the alcohol compound and the phosphate agent in the combined liquid (M1) is hydrolyzed as described above to convert the reactive group to a hydroxy group. In the production method of the present invention, when the target phosphate ester compound is a phosphate monoester compound or a phosphate diester compound, it is preferable to subject the combined liquid (M1) to the following step in order to more efficiently proceed with the hydrolysis reaction.

[0047] The process involves mixing a solution containing a non-nucleophilic base (iii) with the above-mentioned combined solution (M1), and then inducing a hydrolysis reaction in the presence of water within this mixture (M2) (this process will hereafter be referred to as process (X)).

[0048] Water for the hydrolysis reaction may be contained in solution (iii), or may be supplied to the combined liquid (M2) separately from solution (iii). Alternatively, the combined liquid (M1) may be mixed with water, and then solution (iii) may be mixed with the resulting mixture. This type of configuration is also included in step (X) in the present invention. When water is supplied to the combined liquid (M2) separately from solution (iii), solution (iii) may or may not contain water. When water is supplied to the combined liquid (M2) separately from solution (iii), water may be supplied alone, or may be supplied as a mixture of a non-nucleophilic base and water.

[0049] If the phosphating agent is a trivalent phosphorus compound, the hydrolysis reaction is followed by an oxidation treatment to convert the phosphite compound into a phosphate compound. Therefore, in the present invention, the phrase "through a step in which a hydrolysis reaction occurs" (through step (X)) is intended to encompass embodiments in which other treatments such as an oxidation treatment are carried out after the hydrolysis reaction.

[0050] <Solution (iii)> (Non-nucleophilic base) A tertiary amine is preferred as the non-nucleophilic base. The tertiary amine used as the non-nucleophilic base is not particularly limited, and examples include triethylamine, diisopropylethylamine, methylmorpholine, and diazabicycloundecene.

[0051] (Solvent) The solution (iii) usually contains a solvent. Examples of the solvent that can be used include ether solvents, alcohol solvents, ester solvents, amide solvents, nitrile solvents, ketone solvents, and halogenated solvents. Specific preferred examples of the solvent include tetrahydrofuran, methanol, ethyl acetate, dimethylformamide, acetonitrile, cyclopentanone, and dichloromethane, but the present invention is not limited to the use of these solvents.

[0052] In step (X), the molar amount of non-nucleophilic base in the mixture (M2) is preferably 2.0 to 30.0, more preferably 2.0 to 20.0, even more preferably 3.0 to 18.0, even more preferably 4.0 to 16.0, even more preferably 5.0 to 14.0, even more preferably 6.0 to 14.0, even more preferably 7.0 to 14.0, even more preferably 8.0 to 14.0, and even more preferably 9.0 to 13.0, when the total molar amount of phosphorylating agent or phosphorylating agent ester in the mixture (M2) is set to 1.0, from the viewpoint of promoting the hydrolysis reaction more quickly. Furthermore, in step (X), when the hydrolysis reaction is carried out in the mixed solution (M2) in the presence of water, the molar amount of water in the mixed solution (M2) is preferably 10.0 to 250.0, more preferably 20.0 to 230.0, more preferably 30.0 to 200.0, even more preferably 35.0 to 180.0, even more preferably 40.0 to 160.0, even more preferably 50.0 to 140.0, even more preferably 60.0 to 120.0, and even more preferably 70.0 to 100.0, with the total molar amount of phosphorylating agent or phosphorylating agent ester in the mixed solution (M2) being 1.0. Furthermore, when obtaining a phosphate monoester compound, the molar amount of water in the mixed solution (M2) is preferably 50.0 to 120.0, 55.0 to 100.0, 57.0 to 95.0, 60.0 to 90.0, or 60.0 to 85.0, when the total molar amount of phosphorylating agent or phosphorylating agent ester in the mixed solution (M2) is set to 1.0.

[0053] Step (X) may be carried out in a flow reaction system or a batch reaction system. When step (X) is carried out in a flow reaction system, it can be specified as follows.

[0054] A process in which the solution (iii) containing a non-nucleophilic base flowing through the flow path is combined with the combined liquid (M1), and a hydrolysis reaction occurs in the presence of water as the combined liquid (m2) flows downstream.

[0055] The mixed solution (M2) in the above step (X) and the combined solution (m2) are the same; however, the mixed solution (M2) is intended for both a flow reaction system and a batch reaction system, whereas the combined solution (m2) is intended for only a flow reaction system. Therefore, for convenience, the expressions "M2" and "m2" are used interchangeably.

[0056] In an embodiment where the manufacturing method of the present invention includes step (X), phosphorus oxychloride (POCl) is used as the phosphorylating agent. ３ ) and assuming that the target compound is a phosphoric acid monoester compound, the following description will be given with reference to the drawings. The following embodiment is merely an example, and the present invention is not limited to the following embodiment except as defined in the present invention.

[0057] <Embodiment 1> Figure 1 is an explanatory diagram for explaining embodiment 1. When solution (i) and solution (ii) flowing through different flow paths are joined, the alcohol compound and the phosphorylating agent react while the combined liquid (M1) flows downstream (the reaction occurs in the "phosphorylation" zone in Figure 1). Next, the combined liquid (M1) and solution (iii) are joined, and while the combined liquid (m2) (mixed liquid M2) flows downstream, water is further joined, and a hydrolysis reaction occurs downstream to produce the target phosphoric acid monoester compound. In embodiment 1, solution (iii) does not contain water. It is also preferable to further subject the liquid containing the phosphoric acid monoester compound obtained by the flow reaction shown in Figure 1 to a batch-type stirring treatment to further thoroughly carry out hydrolysis.

[0058] 2 is an explanatory diagram for explaining embodiment 2. This embodiment differs from embodiment 1 in that the combined liquid (M1) and solution (iii) are mixed batchwise. That is, the combined liquid (M1) is added dropwise to a container containing solution (iii) and mixed with solution (iii), and then water is added thereto for hydrolysis to produce the target phosphoric acid monoester compound.

[0059] <Embodiment 3> Figure 3 is an explanatory diagram for explaining embodiment 3. Instead of the confluence of water in embodiment 1, a mixed solution of water and a non-nucleophilic base is confluenced. This makes it possible to cause hydrolysis to occur more efficiently. It is also preferable to further subject the solution containing the phosphoric acid monoester compound obtained by the flow reaction shown in Figure 3 to a batch-type stirring treatment to further thoroughly cause hydrolysis.

[0060] <Embodiment 4> Fig. 4 is an explanatory diagram for illustrating embodiment 4. While water is supplied separately from solution (iii) in embodiment 1, water is contained in solution (iii) in embodiment 4. It is also preferable to further subject the solution containing the phosphoric acid monoester compound obtained by the flow reaction shown in Fig. 4 to a batch-type stirring treatment to further thoroughly carry out hydrolysis.

[0061] <Embodiment 5> Fig. 5 is an explanatory diagram for explaining embodiment 5. In embodiment 2, water is supplied separately from solution (iii), but in embodiment 5, water is contained in solution (iii).

[0062] In the above-described embodiments 1 to 5, a reaction system can be constructed in which the target compound is a phosphoric acid diester compound by appropriately changing the quantitative ratio of the alcohol compound to the phosphorylating agent in the combined liquid (M1) based on a stoichiometric ratio depending on the purpose, or by using a monoester as the phosphorylating agent. Furthermore, in embodiments 1 to 5, a reaction system can be constructed in which a trivalent phosphorus compound is used as the phosphorylating agent by incorporating an oxidation treatment step after the hydrolysis reaction. In this way, various reaction systems can be constructed depending on the purpose within the range specified in the present invention.

[0063] In the production method of the present invention, the temperature of the confluent liquid (M1) is preferably controlled within a range of −50° C. to 50° C., more preferably −40° C. to 40° C., and even more preferably −30° C. to 30° C. The temperature of the confluent liquid (M1) may be varied within the above range. The reaction time (flow time in the flow channel) between the alcohol compound and the phosphorylating agent in the confluent liquid (M1) can be 5 seconds to 10 minutes, and more preferably 10 seconds to 5 minutes.

[0064] The temperature of the hydrolysis reaction in step (X) is preferably controlled within a range of 0°C to 80°C, more preferably 0°C to 70°C, and even more preferably 0°C to 60°C. This temperature may be 0°C to 50°C, 0°C to 40°C, 0°C to 30°C, 0°C to 25°C, or 0°C to 22°C. The temperature of the hydrolysis reaction may be varied within the above range. The time for the hydrolysis reaction may be 1 second to 30 minutes, and more preferably 5 seconds to 10 minutes.

[0065] After the hydrolysis reaction, a step of stirring the solution (post-stirring step) may be performed. The stirring method is not particularly limited, and known methods can be used. The stirring time is preferably within 24 hours, more preferably within 12 hours, even more preferably within 6 hours, and particularly preferably within 2 hours. In one embodiment of the production method of the present invention, the hydrolysis reaction can be carried out quickly by instantaneously mixing water in the presence of a high concentration of a non-nucleophilic base. In particular, when the hydrolysis reaction is carried out by a flow reaction, it is possible to rapidly proceed with hydrolysis and heat removal, and it is possible to more effectively suppress the production of the by-product dimer. In consideration of the ease of handling of the phosphating agent, the simplification of the reaction, the efficiency of the hydrolysis reaction, and the accuracy of reaction control based on the stoichiometric ratio, the production method of the present invention is particularly preferably production method (Z) specified as follows.

[0066] Production method (Z): A method for producing a phosphoric acid monoester compound, comprising: introducing a solution (i-1) containing an alcohol compound and a non-nucleophilic base and a solution (ii-1) containing a phosphorylating agent, which is a pentavalent phosphorus compound, into different flow paths; allowing each solution to flow through each flow path; joining the solution (i-1) with the solution (ii-1); reacting the alcohol compound with the phosphorylating agent while the combined liquid (M1-1) flows downstream; joining the combined liquid (M1-1) with a solution (iii) containing a non-nucleophilic base flowing through another flow path; and generating a phosphoric acid monoester compound by hydrolysis in the presence of water in the combined liquid (M2-1).

[0067] In production method (Z), the molar amount of the non-nucleophilic base in solution (i-1) is preferably 0.2 to 2.0, more preferably 0.4 to 1.8, even more preferably 0.6 to 1.6, still more preferably 0.8 to 1.4, and even more preferably 0.8 to 1.3, relative to 1.0 molar amount of the alcohol compound.

[0068] In production method (Z), the quantitative ratio of the alcohol compound to the phosphorylating agent in the combined liquid (M1-1) is approximately determined by a stoichiometric ratio. For example, when the molar amount of the alcohol compound is 1.0, by adjusting the molar amount of the phosphorylating agent to about 1.0 (e.g., 0.7 to 1.4, preferably 0.8 to 1.3, more preferably 0.9 to 1.2), a phosphate compound or a phosphite compound can be obtained in which the alcohol compound and the phosphorylating agent have reacted in a ratio of approximately 1:1.

[0069] In the manufacturing method (Z), when the total molar amount of unreacted phosphorylating agent or phosphorylating agent ester formed by the reaction of the phosphorylating agent with an alcohol compound in the combined liquid (M2-1) (in the combined liquid (M2-1) immediately after confluence) is set to 1.0, the molar amount of non-nucleophilic base is preferably 2.0 to 30.0, more preferably 2.0 to 20.0, even more preferably 3.0 to 18.0, even more preferably 4.0 to 16.0, even more preferably 5.0 to 14.0, even more preferably 6.0 to 14.0, even more preferably 7.0 to 14.0, even more preferably 8.0 to 14.0, and even more preferably 9.0 to 13.0. In this way, by having a relatively large amount of nucleophilic base in the combined liquid (M2-1), the hydrolysis reaction can proceed rapidly under the advantage of rapid heat removal, which is a benefit of the flow reaction, and the formation of dimers, which are by-products, can be effectively suppressed.

[0070] In the manufacturing method (Z), the amount of water used to induce hydrolysis in the combined liquid (M2-1) is preferably 10.0 to 250.0, more preferably 20.0 to 230.0, more preferably 30.0 to 200.0, even more preferably 35.0 to 180.0, even more preferably 40.0 to 160.0, even more preferably 50.0 to 140.0, even more preferably 60.0 to 120.0, and even more preferably 70.0 to 100.0, when the total amount of unreacted phosphorylating agent or phosphorylating agent ester in the combined liquid (M2-1) is set to 1.0, from the viewpoint of promoting the hydrolysis reaction more quickly.

[0071] The preferred reaction temperature in the production method (Z) is as described above.

[0072] In the manufacturing method (Z), the type of target phosphate monoester compound is not particularly limited. For example, (meth)acryloyloxyalkyl phosphate monoester compounds (preferably with 1 to 30 carbon atoms in the alkyl group, more preferably 2 to 25, even more preferably 4 to 20, and even more preferably 6 to 15 carbon atoms) are available. Among these, 10-(meth)acryloyloxydecyl phosphate monoester is suitable as an adhesive component in the dental field.

[0073] The flow reaction system applied to the manufacturing method of the present invention can be appropriately selected in terms of the size, shape, and material of its flow channels, confluence sections, etc., depending on the purpose. The concept of performing chemical reactions in a flow reaction system is well known, and a flow reaction system applicable to the manufacturing method of the present invention can be constructed by appropriately referring to existing flow reaction systems. In the manufacturing method of the present invention, the flow reaction may be carried out while irradiating with ultrasound. Ultrasonic irradiation can prevent by-products from adhering to the flow channels.

[0074] In the manufacturing method of the present invention, when the target product is a phosphate monoester compound or a phosphate diester compound, after the reaction is complete, if the reaction solution is basic, the phosphate monoester compound or phosphate diester compound will be present in the aqueous layer. In this case, after washing with an organic solvent, the aqueous layer can be made acidic, and then extracted with an organic solvent. By concentrating this extract, the target phosphate monoester compound or phosphate diester compound can be obtained at a desired concentration. The organic solvent used for the washing or extraction is an organic solvent that is immiscible with water, such as an ester solvent, a ketone solvent, or an ether solvent, and preferably an ether solvent. Furthermore, in the manufacturing method of the present invention, when the target product is a phosphate triester compound, after the reaction is complete, the phosphate triester compound is usually present in the organic layer. Therefore, after washing the organic layer, the target phosphate triester compound can be obtained at a desired concentration by concentrating it.

[0075] The applications of the phosphate ester compounds obtained by the production method of the present invention are not particularly limited, and they can be used in a wide range of fields, for example, as adhesive components in the dental field, as well as detergents, fiber treatment agents, emulsifiers, preservatives, dispersants, adsorbents, liquid ion exchangers, and raw materials for pharmaceuticals.

[0076] The present invention will be described in more detail based on examples, but the present invention is not limited to these examples other than those specified herein.

[0077] [Preparation of 10-hydroxydecyl methacrylate (MDME)] 1.2 L of toluene was placed in a 3 L three-neck flask and heated to 70-80°C. 784.3 g of 1,10-decanediol, 4.3 g of p-toluenesulfonic acid monohydrate, 0.83 g of 2,2'-methylenebis(4-ethyl-6-tert-butylphenol), and 38.7 g of methacrylic acid were added. The flask was reduced in pressure to 500-600 mmHg, and the mixture was stirred at 110°C while removing water. After stirring for 5 hours, the mixture was cooled to below 50°C, 600 mL of heptane was added, and the precipitated 1,10-decanediol was removed by vacuum filtration. 0.42 g of 2,2'-methylenebis(4-ethyl-6-tert-butylphenol) was added to the filtrate, which was then washed twice with 4% aqueous sodium bicarbonate and once with 10% saline. Anhydrous sodium sulfate was added to the obtained organic layer to dry it, and the dried organic layer was concentrated to obtain 231 g of a toluene solution of MDME (MDME content: 86% by mass, yield: 85%).

[0078] [Preparation of Solution (i)] 22.0 g of the MDME-toluene solution prepared above, 9.5 g of triethylamine (TEA) and 44.1 g of toluene were mixed at room temperature (25° C.) to prepare solution (i).

[0079] [Preparation of Solution (ii)] 17.0 g of phosphorus oxychloride and 61.2 g of toluene were mixed at room temperature (25°C) to prepare solution (ii).

[0080] [Preparation of Solution (iii)] 133.0 g of TEA, 182.3 g of water, and 75.0 g of tetrahydrofuran were mixed at 5°C to prepare a solution (iii).

[0081] [Example 1] Preparation of phosphate monoester compounds Using the solutions (i) to (iii) prepared above, 10-methacryloyloxydecyl phosphate monoester (MDP) was prepared as follows using the flow reaction system shown in Figure 4. The temperature of the "phosphorylation" zone in Figure 4 was set to -10°C, and the temperature of the "hydrolysis" zone was set to 5°C. Perfluoroalkoxyalkane (PFA) tubing with an outer diameter of 1 / 8 inch and an inner diameter of 1.58 mm was used for each channel in the flow reaction system. Swagelok Union Tee (SS-200-3) was used at the junction of the channels.

[0082] Solution (i) was introduced into the flow channel at a flow rate of 2.2 mL / min using a syringe pump. Solution (ii) was also introduced into the flow channel at a flow rate of 1.7 mL / min using a syringe pump. The two solutions were combined, and the combined solution (M1) was circulated through the downstream reaction channel, producing phosphorodichloridate (monoester of the phosphorylating agent) in the combined solution (reaction in the "phosphorylation" zone). The combined solution (M1) flowed through the reaction channel for 90 seconds. Solution (iii) was introduced using a plunger pump at a flow rate of 8.8 mL / min, combining solution (iii) and the combined solution (M1). The combined solution (M2 (M2)) was circulated through the downstream reaction channel, allowing the hydrolysis reaction to proceed (reaction in the "hydrolysis" zone). The combined solution (M2) flowed through the reaction channel for 33 seconds. MDP was thus produced in the combined liquid (m2). The combined liquid (m2) was sampled from the outlet of the reaction channel over a period of 16 minutes. The sampled combined liquid (m2) was separated, and the aqueous layer was washed with diethyl ether three times. After this, diethyl ether (20 mL) was added, and concentrated hydrochloric acid was added to adjust the pH to 1.0, and the target MDP was extracted into the organic layer. The organic layer was washed twice with 1N hydrochloric acid and three times with water, and then dried with sodium sulfate. The dried organic layer was concentrated to obtain MDP (yield 8.2 g, 80% yield, 96% HPLC purity). The by-product, a dimer of phosphate monoester, was suppressed to 2% (area % in HPLC analysis), and phosphate diester and phosphate triester were not detected. Furthermore, during this flow reaction, no flow obstructions, such as blockages, occurred within each channel or at the confluence. Here, "HPLC purity" refers to the ratio of the peak area of ​​the target substance (MDP in this example) to the total peak area detected using the following high performance liquid chromatography (HPLC) apparatus under the following operating conditions:HPLC apparatus: Prominence series (Shimadzu Corporation) Detector: UV / VIS absorption detector SPD-20A, 220 nm Column: YMC-Triart C8, S-5 μm, 12 nm, 4.6 mmφ×250 mm Column oven: 40°C Mobile phase A: water, 0.1% by mass phosphoric acid Mobile phase B: methanol, 0.1% by mass phosphoric acid Mobile phase concentration gradient: 0.01 min (60% by volume of B), 15.00 min (100% by volume of B), 20.00 min (100% by volume of B), 25.00 min (10% by volume of B), 25.01 min (60% by volume of B), 30.00 min (60% by volume of B).

[0083] [Examples 2 to 7] Preparation of phosphoric acid monoester compounds. The same procedure as in Example 1 was repeated except that the reaction raw materials and conditions were changed as shown in the table below to obtain phosphoric acid monoester compounds corresponding to the alcohol compounds used.

[0084] [Example 8] Preparation of phosphoric acid diester compounds

[0123] The same procedure as in Example 1 was repeated, except that the reaction raw materials and conditions were changed as shown in the table below, to obtain phosphoric acid diester compounds corresponding to the alcohol compounds used.

[0085] Example 9 Preparation of Phosphate Triester Compounds Phosphate triester compounds corresponding to the alcohol compounds (2-hydroxyethyl methacrylate and ethanol) used were obtained in the same manner as in Example 1, except that the reaction raw materials and conditions in Example 1 were changed as shown in the table below. Note that in Example 9, hydrolysis was not required, and ethanol (EtOH) was used instead of water in solution (iii) to obtain the phosphate triester compounds.

[0086] [Example 10] Preparation of a Phosphate Triester Compound A phosphate triester compound corresponding to the alcohol compound and phosphating agent used was obtained in the same manner as in Example 1, except that the reaction raw materials and conditions were changed as shown in the table below. Note that, since hydrolysis was not necessary in Example 10, ethanol was used instead of water in solution (iii). Furthermore, since the phosphating agent used in Example 10 was a trivalent phosphorus compound, after the flow reaction, the phosphite triester was converted to a phosphate triester by oxidation treatment in which it was reacted with metachloroperbenzoic acid (mCPBA) at 25°C for 1 hour.

[0087] [Example 11] Production of Phosphate Monoester Compounds A phosphate monoester compound corresponding to the alcohol compound used was obtained in the same manner as in Example 1, except that the temperature of the "phosphorylation" zone was changed to -50°C.

[0088] [Example 12] Production of a phosphate monoester compound A phosphate monoester compound corresponding to the alcohol compound used was obtained in the same manner as in Example 1, except that the temperature of the "phosphorylation" zone was changed to 50°C.

[0089] [Example 13] Production of a phosphate monoester compound A phosphate monoester compound corresponding to the alcohol compound used was obtained in the same manner as in Example 1, except that the temperature of the "hydrolysis" zone was changed to 0°C.

[0090] Example 14 Production of Phosphoric Acid Monoester Compound A phosphoric acid monoester compound corresponding to the alcohol compound used was obtained in the same manner as in Example 1, except that the "hydrolysis" zone was run at 5°C for 33 seconds, then the downstream zone was run at 80°C for 33 seconds, and the downstream zone was run at 5°C for 33 seconds.

[0091] Example 15 Production of Phosphoric Acid Monoester Compound A phosphoric acid monoester compound corresponding to the alcohol compound used was obtained in the same manner as in Example 1, except that the "hydrolysis" zone was run at 5°C for 33 seconds, then the downstream zone was run at 50°C for 33 seconds, and the downstream zone was run at 5°C for another 33 seconds.

[0092] [Example 16] Production of a phosphate monoester compound In the same manner as in Example 1, a phosphate monoester compound corresponding to the alcohol compound used was obtained, except that the "hydrolysis" zone was run at 5°C for 33 seconds, the downstream section was run at 20°C for 33 seconds, and the downstream section was run at 5°C for 33 seconds.

[0093] [Example 17] Production of a phosphate monoester compound In the same manner as in Example 1, a phosphate monoester compound corresponding to the alcohol compound used was obtained, except that the "hydrolysis" zone was run at 5°C for 33 seconds, the downstream section was run at 20°C for 120 seconds, and the downstream section was run at 5°C for 33 seconds.

[0094] [Example 18] Production of a phosphate monoester compound In the same manner as in Example 1, a phosphate monoester compound corresponding to the alcohol compound used was obtained, except that the "hydrolysis" zone was run at 5°C for 33 seconds, the downstream section was run at 20°C for 300 seconds, and the downstream section was run at 5°C for 33 seconds.

[0095] Comparative Example 1: Preparation of a phosphoric acid monoester compound by batch reaction. 5.5 g (0.036 mol) of phosphorus oxychloride was dissolved in 10 mL of diethyl ether and placed in a three-neck flask and cooled to -40°C. 8.5 g of the MDME-toluene solution prepared above (0.030 mol as MDME) and 3.7 g (0.036 mol) of triethylamine were dissolved in 12 mL of diethyl ether and added dropwise to the phosphorus oxychloride solution. After the addition was complete, the mixture was stirred at -30°C for 3 hours and then heated to 0°C. Next, 30 g of water was placed in the dropping funnel and added dropwise with continued stirring. 7.29 g (0.072 mol) of triethylamine was dissolved in 10 mL of diethyl ether and added dropwise. After the addition was complete, the mixture was stirred at 0°C for 10 hours. The precipitated triethylamine salt was then filtered off using a glass filter, and the filtrate was repeatedly washed with water, after which anhydrous sodium sulfate was added, followed by dehydration and drying. 20 mg of 4-methoxyphenol (MEHQ) was added, and then diethyl ether was distilled off under reduced pressure at 40°C to obtain a liquid residue. This liquid residue was repeatedly washed with hexane, and the hexane was further distilled off under reduced pressure to obtain MDP (yield 7.3 g, yield 76%, HPLC purity 78%). The by-product dimer of phosphate monoester was 22%, and phosphate diester and phosphate triester were not detected.

[0096] The above results are summarized in the table below.

[0097]

[0098]

[0099] Example 19 Production of a Phosphoric Acid Monoester Compound A phosphoric acid monoester compound was obtained in the same manner as in Example 1, except that the "hydrolysis" zone was run at 5°C for 33 seconds, then the downstream zone was run at 20°C for 60 seconds, and the downstream zone was run at 5°C for a further 33 seconds, and the resulting reaction solution was stirred in a flask at 20°C for 2 hours. The HPLC purity of the phosphoric acid monoester compound was the same as in Example 1.

[0100] Example 20 Production of Phosphoric Acid Monoester Compound A phosphoric acid monoester compound was obtained in the same manner as in Example 1, except that the "hydrolysis" zone was run at 5°C for 33 seconds, then the downstream zone was run at 20°C for 60 seconds, and the downstream zone was run at 5°C for a further 33 seconds, and the resulting reaction solution was stirred in a flask at 20°C for 6 hours. The HPLC purity of the phosphoric acid monoester compound was the same as in Example 1.

[0101] As shown in the above table, it can be seen that the production method of the present invention enables the production of the target phosphate ester compound with higher purity and higher efficiency without producing the by-product dimer or while further suppressing the production of the dimer.

[0102] [Preparation of Solution (i)] 100.0 g of polyoxyethylene (12) tridecyl ether, 22.21 g of TEA, 32.5 g of tetrahydrofuran, and 162.7 g of toluene were mixed at room temperature (25°C) to prepare a solution (i).

[0103] [Preparation of Solution (ii)] 30.0 g of phosphorus oxychloride and 70.0 g of toluene were mixed at room temperature (25°C) to prepare solution (ii).

[0104] [Preparation of Solution (iii)] 266.1 g of TEA, 364.5 g of water, and 150.0 g of tetrahydrofuran were mixed at 5°C to prepare solution (iii).

[0105] Example 21 Production of Phosphoric Acid Monoester Compound Using the solutions (i) to (iii) prepared above, phosphoric acid monoesters were prepared as follows using the flow reaction system shown in Figure 4. The temperature of the "phosphorylation" zone shown in Figure 4 was 20°C, and the temperature of the "hydrolysis" zone was 5°C. Each flow path in the flow reaction system used a perfluoroalkoxyalkane (PFA) tube with an outer diameter of 1 / 8 inch and an inner diameter of 1.58 mm. A union tee (SS-200-3) manufactured by Swagelok was used at the junction of the flow paths.

[0106] Solution (i) was introduced into the flow channel at a flow rate of 9.0 mL / min using a syringe pump. Solution (ii) was introduced into the flow channel at a flow rate of 2.8 mL / min using a syringe pump. The two solutions were combined, and the combined solution (M1) was circulated through the downstream reaction channel, producing phosphorodichloridate (monoester of the phosphorylating agent) in the combined solution (reaction in the "phosphorylation" zone). The combined solution (M1) flowed through the reaction channel for 200 seconds. Solution (iii) was introduced using a plunger pump at a flow rate of 15.3 mL / min, resulting in the combined solution (M1), and the combined solution (M2 (M2)) was circulated through the downstream reaction channel, allowing the hydrolysis reaction to proceed (reaction in the "hydrolysis" zone). The combined liquid (m2) was allowed to flow through the reaction channel (5°C) for 37 seconds, and then further flowed downstream at 20°C for 60 seconds. The combined liquid (m2) was then sampled at the outlet of the reaction channel over 20 minutes. The sampled liquid was then stirred at 20°C for 15 minutes in a 1-L three-neck flask, producing a phosphoric acid monoester compound in the combined liquid (m2). The sampled combined liquid (m2) was separated, and the aqueous layer was washed with methyl ethyl ketone three times. Then, methyl ethyl ketone (200 mL) was added, and concentrated hydrochloric acid was added to adjust the pH to 1.0, and the target phosphoric acid monoester was extracted into the organic layer. The organic layer was washed three times with 10% aqueous sodium chloride, and then sodium sulfate was added and dried. The dried organic layer was concentrated to obtain a phosphoric acid ester (yield: 46 g, 83%, ３１ P-NMR purity: 100%). By-products such as dimers of phosphate monoester, phosphate diester, and phosphate triester were not detected. Furthermore, in this flow reaction, no flow obstructions such as blockages occurred in the individual flow paths or at the junctions. ３１ The "P-NMR purity" is the proportion of the target substance (phosphate monoester in this example) in the total peak integrated value detected using an NMR apparatus (400 MHz, manufactured by Bruker).

[0107] Examples 22 to 28 Production of Phosphoric Acid Monoester Compounds Phosphoric acid monoester compounds corresponding to the alcohol compounds used were obtained in the same manner as in Example 21, except that the reaction raw materials and conditions in Example 21 were changed as shown in the table below.

[0108] [Example 29] Preparation of phosphoric acid diester compounds

[0123] The same procedure as in Example 21 was repeated, except that the reaction raw materials and conditions were changed as shown in the table below, to obtain phosphoric acid diester compounds corresponding to the alcohol compounds used.

[0109] The above results are summarized in the table below. In the table below, *1, *2 and "ND" are as explained in the table above.

[0110]

[0111] As shown in Table 2 above, it can be seen that the production method of the present invention enables the production of the target phosphate ester compound with higher purity and higher efficiency without producing by-products or while further suppressing the production of dimers.

[0112] While the present invention has been described in connection with embodiments thereof, we do not intend to limit our invention to any of the details of the description unless otherwise specified, and believe that the claims should be construed broadly without departing from the spirit and scope of the invention as set forth in the appended claims.

[0113] This application claims priority based on Japanese Patent Application No. 2024-155043, filed on September 9, 2024, the contents of which are incorporated herein by reference as part of the present specification.

Claims

1. A method for producing a phosphoric acid ester compound, comprising introducing a solution (i) containing an alcohol compound and a solution (ii) containing a phosphorylating agent into different flow paths, allowing each solution to flow through each flow path, and then merging the solutions (i) and (ii), thereby reacting the alcohol compound with the phosphorylating agent while the combined liquid (M1) flows downstream.

2. The method for producing a phosphoric acid ester compound according to claim 1, comprising the steps of mixing a solution (iii) containing a non-nucleophilic base with the combined liquid (M1) and causing a hydrolysis reaction in the presence of water in the mixed liquid (M2), thereby producing a phosphoric acid monoester compound or a phosphoric acid diester compound.

3. A method for producing a phosphoric acid ester compound according to claim 2, wherein the solution (iii) flowing through a flow path and the combined liquid (M1) are combined, and the combined liquid (m2) undergoes a hydrolysis reaction in the presence of water while flowing downstream, thereby producing the phosphoric acid monoester compound or the phosphoric acid diester compound.

4. The method for producing a phosphoric acid ester compound according to claim 3, wherein the temperature of the hydrolysis reaction is controlled within the range of 0°C or higher and 80°C or lower.

5. The method for producing a phosphoric acid ester compound according to claim 3, wherein the solution (iii) contains water.

6. The method for producing a phosphate ester compound according to claim 3, wherein the solution (i) contains a non-nucleophilic base.

7. The method for producing a phosphoric ester compound according to claim 6, wherein the temperature of the combined liquid (M1) is controlled within a range of -50°C or higher and 50°C or lower to react the alcohol compound with the phosphorylating agent.

8. The method for producing a phosphoric acid ester compound according to claim 7, wherein the alcohol compound is a monohydric alcohol compound.

9. The method for producing a phosphoric acid ester compound according to claim 8, wherein the monohydric alcohol compound has a polymerizable group that undergoes addition polymerization.

10. The method for producing a phosphoric acid ester compound according to claim 9, wherein the phosphoric acid ester compound is a (meth)acryloyloxyalkyl phosphoric acid monoester compound.

11. The method for producing a phosphoric acid ester compound according to any one of claims 1 to 10, wherein the phosphorylating agent is a pentavalent phosphorus compound.

12. The method for producing a phosphate ester compound according to claim 11, wherein the phosphating agent is a phosphorus oxyhalide.

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