Method for producing asymmetric phosphate triester, method for producing symmetric phosphate triester, method for producing phosphate ester, and method for producing organic phosphorus compound

Abstract

This method for producing an asymmetric phosphoric acid triester comprises: step (A1) for reacting phosphorus trichloride or phosphorus tribromide with a first hydroxy compound by using a flow system reactor; step (B1) for reacting the compound obtained in step (A1) with a second hydroxy compound; step (C1) for reacting the compound obtained in step (B1) with a third hydroxy compound; and step (D1) for oxidizing the compound obtained in step (C1), wherein the reaction temperatures in step (A1) and step (B1) are each at least -80ºC, and the flow rates of the phosphorus trichloride or phosphorus tribromide, first hydroxy compound, and second hydroxy compound, which flow through the inside of a flow path in step (A1) and step (B1), are each at least 0.01 mL / min.

Description

[Technical field]

[0001] The present invention relates to a method for producing an asymmetric phosphate triester, a method for producing a symmetric phosphate triester, a method for producing a phosphate ester, and a method for producing an organophosphorus compound. This application claims priority based on Japanese Patent Application No. 2021-033869, filed in Japan on March 3, 2021, the contents of which are incorporated herein by reference. [Background technology]

[0002] A phosphate triester has a structure in which phosphoric acid and a hydroxy compound are condensed. Among the phosphate triesters, there are symmetric phosphate triesters in which two identical hydroxy compounds are condensed with one different hydroxy compound, and asymmetric phosphate triesters in which three different hydroxy compounds are condensed.

[0003] Symmetric and asymmetric phosphate triesters are used in various fields such as plasticizers, flame retardants, and insecticides, etc. Asymmetric phosphate triesters are also used in protides, which are prodrugs of nucleic acids, and intermediates in the chemical synthesis of DNA.

[0004] An example of a method for producing an asymmetric phosphate triester is the phosphoramidite method, which generally involves a condensation reaction between a phosphoramidite and an alcohol using tetrazole as an accelerator to obtain a phosphite triester, which is then oxidized with I2, tert-butyl hydroperoxide, or the like to convert it into a phosphate triester.

[0005] Patent Document 1 discloses a method for producing an asymmetric phosphate triester, which comprises adding phosphorus oxychloride to about 1.8 to 2.2 times by molar amount, relative to the phosphorus oxychloride used, of halogen- or lower alkyl-substituted or unsubstituted phenol under stirring at a temperature of about 10° C. or lower in a nonpolar solvent in the presence of a tertiary amine, to react the phenol, and then adding and reacting a monovalent alkanol which may contain a halogen or an ether bond in an amount of about 1 time or more by molar amount, relative to the phosphorus oxychloride used. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] Japanese Patent Application Publication No. 52-113949 Summary of the Invention [Problem to be solved by the invention]

[0007] In the process for producing an asymmetric phosphate triester and a symmetric phosphate triester, there is a demand for a process for producing a phosphate triester that is capable of producing a target phosphate triester at a lower cost and in a higher yield. In addition, for other phosphoric acid esters, namely, phosphoric acid monoesters and phosphoric acid diesters, there is a demand for a production method that can produce the target phosphoric acid monoesters and phosphoric acid diesters at a lower cost and in a higher yield. Furthermore, there is a demand for a production method for organophosphorus compounds that is capable of producing the target organophosphorus compounds at a lower cost and in a higher yield.

[0008] The present invention has been made in consideration of the above circumstances, and an object of the present invention is to provide a method for producing a phosphate ester, which can produce a target phosphate ester at a lower cost and in a high yield. The present invention has been made in view of the above circumstances, and has an object to provide a method for producing an organophosphorus compound, which can produce a target organophosphorus compound at a lower cost and in a high yield. [Means for solving the problem]

[0009] In order to solve the above problems, the present invention employs the following configuration. That is, a first aspect of the present invention is a method for producing an asymmetric phosphate triester using a flow-through reactor, the method including: a step (A1) of reacting phosphorus trichloride or phosphorus tribromide with a first hydroxy compound represented by the following general formula (H-1) to synthesize a compound P1 represented by the following general formula (P-1); a step (B1) of reacting the compound P1 with a second hydroxy compound represented by the following general formula (H-2) to synthesize a compound P2 represented by the following general formula (P-2); and a step (B2) of reacting the compound P2 with a second hydroxy compound represented by the following general formula (H-3): and a step (D1) of oxidizing the compound P3 to synthesize an asymmetric phosphate triester, wherein the reaction temperature in the steps (A1) and (B1) is -80°C or higher, and the flow rates of the phosphorus trichloride or phosphorus tribromide, the first hydroxy compound, and the second hydroxy compound flowing through a flow path in the steps (A1) and (B1) are 0.01 mL / min or higher.

[0010] [ka] [In the formula, R 1 ~R 3 are each independently an organic group. 1 ~R 3 are different organic groups. X is a bromine atom or a chlorine atom.

[0011] In the method for producing an asymmetric phosphate triester according to the first aspect of the present invention, the reaction temperature in the steps (A1) and (B1) may be 0° C. or higher.

[0012] In the method for producing an asymmetric phosphate triester related to the first aspect of the present invention, in the steps (A1) and (B1), the flow rates of the phosphorus trichloride or phosphorus tribromide, the first hydroxy compound, and the second hydroxy compound flowing through a flow channel may be 1 mL / min or more.

[0013] The method for producing an asymmetric phosphate triester according to the first aspect of the present invention may include a step (N1) of reacting the compound P1 with a base between the step (A1) and the step (B1).

[0014] In the method for producing an asymmetric phosphate triester according to the first aspect of the present invention, the base may be one or more bases selected from the group consisting of pyridine, pyridine derivatives, imidazole, imidazole derivatives, and 1,4-diazabicyclo[2,2,2]octane.

[0015] In the method for producing an asymmetric phosphate triester according to the first aspect of the present invention, the base may be a compound represented by the following general formula (I-1).

[0016] [ka] [Wherein, RI 1 and R.I. 2 is a hydrogen atom or a hydrocarbon group.

[0017] In the method for producing an asymmetric phosphate triester according to the first aspect of the present invention, 1 The equivalent ratio of phosphorus trichloride or phosphorus tribromide in the reaction system (R 1 OH) may be 0.1:1 to 10:1.

[0018] In the method for producing an asymmetric phosphate triester according to the first aspect of the present invention, the reaction temperature in the steps (A1) and (B1) may be 20°C or higher and 40°C or lower.

[0019] In the method for producing an asymmetric phosphate triester according to the first aspect of the present invention, the flow rates of the phosphorus trichloride or phosphorus tribromide, the first hydroxy compound, and the second hydroxy compound flowing through a flow channel in the steps (A1) and (B1) may be 1 mL / min or more and 5 mL / min or less.

[0020] In the method for producing an asymmetric phosphate triester according to the first aspect of the present invention, the flow rate of phosphorus trichloride or phosphorus tribromide in the step (A1) and R 1 The flow rate of OH may be different.

[0021] In the method for producing an asymmetric phosphate triester according to the first aspect of the present invention, the flow rate of phosphorus trichloride or phosphorus tribromide in the step (A1) is R 1 The flow rate may be 0.3 to 0.9 times the flow rate of OH.

[0022] In the method for producing an asymmetric phosphate triester according to the first aspect of the present invention, 1 The flow rate of OH may be 0.3 to 0.9 times the flow rate of phosphorus trichloride or phosphorus tribromide.

[0023] A second aspect of the present invention is a method for producing a symmetric phosphate triester using a flow-through reactor, the method comprising: a step (A2) of reacting phosphorus trichloride or phosphorus tribromide with a first hydroxy compound represented by the following general formula (H-1) to synthesize a compound P1 represented by the following general formula (P-1); a step (B2) of reacting the compound P1 with a second hydroxy compound represented by the following general formula (H-2) to synthesize a compound P4 represented by the following general formula (P-4); and a step (D2) of oxidizing the compound P4 to synthesize a symmetric phosphate triester, wherein the reaction temperature in the steps (A2) and (B2) is −80° C. or higher, and the flow rates of the phosphorus trichloride or phosphorus tribromide, the first hydroxy compound, and the second hydroxy compound flowing through a flow path in the steps (A2) and (B2) are 0.01 mL / min or higher.

[0024] [ka] [In the formula, R 1 and R 2 are different organic groups. X is a bromine atom or a chlorine atom.

[0025] In the method for producing a symmetric phosphate triester according to the second aspect of the present invention, the reaction temperature in the steps (A2) and (B2) may be 0° C. or higher.

[0026] In the method for producing a symmetric phosphate triester according to the second aspect of the present invention, in the steps (A2) and (B2), the flow rates of phosphorus trichloride or phosphorus tribromide, the first hydroxy compound, and the second hydroxy compound flowing through the flow channel may be 1 mL / min or more.

[0027] A third aspect of the present invention is a method for producing a phosphate ester using a flow-through reactor, the method comprising the steps of: a step (A11) of reacting phosphorus trichloride or phosphorus tribromide with a first hydroxy compound represented by the following general formula (H1-1) to synthesize a compound P11 represented by the following general formula (P1-1); a step (B11) of reacting the compound P11 with a second hydroxy compound represented by the following general formula (H1-2) to synthesize a compound P12 represented by the following general formula (P1-2); and a step (B12) of reacting the compound P12 with a second hydroxy compound represented by the following general formula (H1-3) to synthesize a compound P13 represented by the following general formula (H1-4). and a step (D11) of oxidizing the compound P13 to synthesize a phosphate ester, wherein the reaction temperature in the steps (A11) and (B11) is -80°C or higher, and the flow rates of the phosphorus trichloride or phosphorus tribromide, the first hydroxy compound, and the second hydroxy compound flowing through a flow path in the steps (A11) and (B11) are 0.01 mL / min or higher.

[0028] [ka] [R 11 ~R 13 are each independently a hydrogen atom or an organic group. 11 ~R 13 At least one of the groups is an organic group and at least one of the groups is a hydrogen atom. X is a bromine atom or a chlorine atom.

[0029] A fourth aspect of the present invention relates to a method for producing an organic phosphorus compound, which uses a flow-through reaction apparatus to synthesize an organic phosphorus compound, and includes a step (A01) of reacting phosphorus trichloride or phosphorus tribromide with a first hydroxy compound represented by the following general formula (H0-1) to synthesize a compound P01 represented by the following general formula (P0-1), and a step (B01) of reacting the compound P01 with a second hydroxy compound represented by the following general formula (H0-2) to synthesize a compound P02 represented by the following general formula (P0-2). and a step (C01) of reacting the compound P02 with a tertiary hydroxy compound represented by the following general formula (H0-3) to synthesize a compound P03 represented by the following general formula (P0-3), wherein the reaction temperature in the steps (A01) and (B01) is -80°C or higher, and the flow rates of the phosphorus trichloride or phosphorus tribromide, the first hydroxy compound, and the second hydroxy compound flowing through a flow path in the steps (A01) and (B01) are 0.01 mL / min or higher.

[0030] [ka] [R 01 ~R 03 are each independently a hydrogen atom or an organic group. 01 ~R 03 At least one of R is an organic group. 01 ~R 03 When all of are organic groups, the organic groups are not all the same. X is a bromine atom or a chlorine atom.

[0031] A method for producing an organic phosphorus compound according to a fifth aspect of the present invention is a method for producing an organic phosphorus compound using a flow-through reaction apparatus, the method comprising the steps of: (AZ1) reacting phosphorus trichloride or phosphorus tribromide with a first compound which is any one of a hydroxy compound, an amine compound, or a thiol compound to synthesize a compound PZ1 represented by the following general formula (PZ-1); and (AZ2) reacting the compound PZ1 with a second compound which is any one of a hydroxy compound, an amine compound, or a thiol compound to synthesize a compound PZ2 represented by the following general formula (PZ-2). and a step (CZ1) of reacting the compound PX2 with a third compound which is any one of a hydroxy compound, an amine compound, or a thiol compound to synthesize a compound PZ3 represented by the following general formula (PZ-3), wherein the reaction temperature in the steps (AZ1) and (BZ1) is -80°C or higher, and the flow rates of the phosphorus trichloride or phosphorus tribromide, the first compound, and the second compound flowing through a flow path in the steps (AZ1) and (BZ1) are 0.01 mL / min or higher.

[0032] [ka] [In the formula, Z 1 ~Z 3 are each independently a hydrogen atom, a group in which one hydrogen atom has been removed from a hydroxy compound, a group in which one hydrogen atom has been removed from an amine compound, or a group in which one hydrogen atom has been removed from a thiol compound. 1 ~Z 3 cannot all be the same. X is a bromine atom or a chlorine atom. Effect of the Invention

[0033] According to the production method of the present invention, the target phosphate ester can be produced at a lower cost and in a higher yield. Furthermore, according to the production method of the present invention, the target organophosphorus compound can be produced at a lower cost and in a higher yield. [Brief description of the drawings]

[0034] [Figure 1] FIG. 1 is a schematic diagram of a method for producing an asymmetric phosphate triester according to the present embodiment. [Diagram 2] FIG. 1 is a schematic diagram of a method for producing a symmetric phosphate triester according to the present embodiment. [Diagram 3] FIG. 1 is a schematic diagram of a method for producing a symmetric phosphate triester in an embodiment. [Figure 4] FIG. 1 is a schematic diagram of a method for producing a symmetric phosphate triester in an embodiment. [Diagram 5] FIG. 1 is a schematic diagram of a method for producing an asymmetric phosphate triester in an embodiment. [Figure 6] FIG. 1 is a schematic diagram of a method for producing an asymmetric phosphate triester in an embodiment. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0035] [overview] In the process for producing an asymmetric phosphate triester and a symmetric phosphate triester, there is a demand for a process for producing a phosphate triester that is capable of producing a target phosphate triester at a lower cost and in a higher yield. However, for example, the phosphoramidite method, which is a conventional production method, has problems such as the need to use expensive reagents, a large amount of waste, a large number of steps, and the need to use explosive tetrazole, although it has high selectivity. In addition, the method for producing an asymmetric phosphate triester described in Patent Document 1 has problems such as the need for a long reaction time and the difficulty of producing the target phosphate triester in high yield depending on the type of hydroxy compound used.

[0036] Means for Solving the Problems In order to solve the above problems, the present inventors have conducted extensive research into a method for producing a phosphoric ester. As a result, it was found that when a first reaction is carried out in which phosphorus trichloride or phosphorus tribromide is reacted with a first hydroxy compound, and then a second reaction is carried out in which the compound obtained in the first reaction is reacted with a second hydroxy compound, if the reaction rate of the first reaction is higher than the stirring speed, a side reaction occurs in which the compound obtained in the first reaction reacts again with the first hydroxy compound used in the first reaction before the second reaction is carried out. Therefore, the present inventors conducted studies using a flow-type reactor and found that the target phosphate ester can be produced at higher yield and at lower cost by appropriately controlling the reaction temperature and flow rate and improving the stirring efficiency, thereby completing the present invention.

[0037] <Flow-through reactor> The method for producing an asymmetric phosphate triester according to the first aspect of the present invention, the method for producing a symmetric phosphate triester according to the second aspect, the method for producing a phosphate ester according to the third aspect, and the method for producing an organophosphorus compound according to the fourth aspect are production methods using a flow-type reactor. Flow reactors carry out chemical reactions in a continuous flow rather than batchwise fashion. Flow-through reactors are usually tubular and made of non-reactive materials, which are known in the art and depend on the properties of the feedstocks or reactants. The mixing method is a diffusion method. The residence time of the ingredients in a mixer is calculated by the mixer volume and the flow rate through it (residence time = mixer volume / flow rate). For example, a longer residence time can be achieved by pumping the ingredients slower or by using a mixer with a larger volume.

[0038] The mixer of a flow-type reactor has a very large surface area per unit volume, making it possible to precisely control the temperature and to make the interface reaction more efficient. In addition, since the flow reactor is a flow system and the residence time can be shortened, the product molecules are quickly released outside the reactor, and the possibility of secondary reactions can be reduced. Therefore, the flow reactor can effectively suppress the generation of unwanted by-products.

[0039] Examples of the mixer include a T-shaped mixer and a V-shaped mixer, with a V-shaped mixer being preferred from the viewpoint of improving the mixing efficiency.

[0040] (Production method of asymmetric phosphate triester according to the first aspect of the present invention) Hereinafter, the configuration of a flow-type reactor according to this embodiment and a method for producing an asymmetric phosphate triester using the same will be described with reference to FIG. 1 is a schematic diagram showing a general configuration of a flow-through reactor 1. The flow-through reactor 1 includes a tank 11 for containing a first liquid, a tank 12 for containing a second liquid, a tank 13 for containing a third liquid, a tank 14 for containing a fourth liquid, and a tank 15 for containing a fifth liquid.

[0041] For example, the first liquid may contain a first hydroxy compound (hereinafter, referred to as "R 1 The first liquid contains phosphorus trichloride or phosphorus tribromide, the third liquid contains a nucleophilic base, and the fourth liquid contains a secondary hydroxy compound (hereinafter referred to as "R 2 The fifth liquid contains tertiary hydroxy compounds (hereafter referred to as "R 3 (also called "OH").

[0042] The flow reactor 1 includes flow paths f1, f2, f3, f4, f5, f6, and f7 for transporting a fluid. The inner diameters of the flow paths and mixers may be, for example, 0.1 to 1 mm, 0.1 to 0.8 mm, or 0.2 to 0.6 mm. The inner diameters of the flow paths and mixers may be 1 mm to several cm. The tanks 11, 12, 13, 14, and 15 and the flow paths f1, f2, f3, f4, f5, f6, and f7 are formed of, for example, a resin such as plastic or elastomer, a glass material, a metal, or a ceramic.

[0043] The tank 11 is connected to a pump 21, and when the pump 21 is operated, the first liquid contained in the tank 11 moves through a flow path f1 and flows into the mixer 31. The tank 12 is connected to a pump 22, and when the pump 22 is operated, the second liquid contained in the tank 12 moves through a flow path f2 and flows into the mixer 31. Next, the first liquid and the second liquid are mixed by the mixer 31 to become a first mixed liquid, which is sent to the flow path f5. During this mixing process, R contained in the first liquid is 1 OH reacts with phosphorus trichloride or phosphorus tribromide contained in the second liquid, and one chlorine atom of phosphorus trichloride or one bromine atom of phosphorus tribromide is converted to R 1 A compound P1 substituted with an O-group is obtained (step A1 of the method for producing an asymmetric phosphate triester). The first mixture containing the obtained compound P1 moves through a flow path f5 and flows into a mixer 32.

[0044] The tank 13 is connected to a pump 23, and by operating the pump 23, the third liquid contained in the tank 13 moves through the flow path f3 and flows into the mixer 32. Next, the third liquid and the first mixed liquid are mixed to become a second mixed liquid, which is sent to the flow path f6. In the process of this mixing, the compound P1 obtained in the step A1 reacts with a nucleophilic base contained in the third liquid, and a compound (hereinafter also referred to as "compound N1") is obtained in which two chlorine atoms of the compound P1 (or two bromine atoms of the compound P1) are replaced by groups obtained by removing one hydrogen atom from the nucleophilic base. The obtained second mixed liquid containing the compound N1 moves through the flow path f6 and flows into the mixer 33.

[0045] The tank 14 is connected to a pump 24, and by the operation of the pump 24, the fourth liquid contained in the tank 14 moves through a flow path f4 and flows into the mixer 33. Next, the fourth liquid and the second mixed liquid are mixed to become a third mixed liquid, which is sent to a flow path f7. During this mixing process, the compound N1 and the R 2 OH reacts with the nucleophilic base of compound N1, and the group obtained by removing one hydrogen atom from the base becomes R 2A compound N2 substituted with an O- group (hereinafter also referred to as "compound N2") is obtained. The obtained third mixture containing compound N2 moves through flow path f7 and flows into tank 15.

[0046] Tank 15 has R 3 The fifth liquid containing OH is stored, and the third mixed liquid containing compound N2 flows into it. 3 OH reacts with the compound P3 to synthesize the compound P3, which is then stored in the tank 15 (step C1 of the method for producing an asymmetric phosphate triester). Next, the compound P3 is oxidized to synthesize the asymmetric phosphate triester, which is then stored in the tank 15 (step D1 of the method for producing an asymmetric phosphate triester).

[0047] According to the flow-through reactor 1 of this embodiment, the area for heat exchange per volume of the reaction solution can be increased. In addition, the reaction time can be controlled by the flow rate and the length of the flow path. This allows for strict control of the reaction solution, and as a result, the progression of undesired side reactions can be minimized, and the yield of the target product can be improved.

[0048] Compound P1 and compound P2 are highly reactive. 1 A side reaction in which P2 reacts with R 2 Since a side reaction in which OH reacts again easily occurs, it is important to control the reaction. According to the flow-through reactor 1 of this embodiment, the synthesized compounds P1 and P2 can be quickly released from the mixer, thereby suppressing side reactions and producing the target phosphate triester with high yield.

[0049] Although the flow-through reactor 1 has been described as an example in which liquids are mixed by a mixer, the flow-through reactor of this embodiment does not necessarily need to be equipped with a mixer, since liquid mixing can be achieved simply by connecting flow paths to each other.

[0050] <First embodiment> The method for producing an asymmetric phosphate triester of the first embodiment is a method for producing an asymmetric phosphate triester using a flow-through reaction apparatus, and includes a step (A1) (hereinafter referred to as "step (A1)") of reacting phosphorus trichloride or phosphorus tribromide with a first hydroxy compound to synthesize compound P1, a step (B1) (hereinafter referred to as "step (B1)") of reacting compound P1 with a second hydroxy compound to synthesize compound P2, a step (C1) (hereinafter referred to as "step (C1)") of reacting compound P2 with a third hydroxy compound to synthesize compound P3, and a step (D1) (hereinafter referred to as "step (D1)") of oxidizing compound P3 to synthesize an asymmetric phosphate triester.

[0051] ≪Process (A1)≫ In step (A1), phosphorus trichloride or phosphorus tribromide and a first hydroxy compound (R 1 This is a process for synthesizing compound P1 represented by the following general formula (P-1) by reacting with aryloxyalkyleneoxy group (OH).

[0052] [ka] [In the formula, R 1 is an organic group. X is a bromine atom or a chlorine atom.

[0053] In the above general formulas (H-1) and (P-1), R 1 is an organic group. The organic group includes a hydrocarbon group which may have a substituent. The hydrocarbon group may be linear, branched, or cyclic. If the hydrocarbon group is cyclic, it may be an aliphatic or aromatic hydrocarbon group, or a polycyclic or monocyclic group. The substituent is not particularly limited, and examples thereof include an alkoxy group, a halogen atom, a halogenated alkyl group, a carboxy group, a cyano group, and an amino group. In addition, some of the carbon atoms of the hydrocarbon group may be substituted with a substituent containing a heteroatom, such as -O-, -C(=O)-O-, -S-, -S(=O)2-, -S(=O)2-O-, etc.

[0054] R 1 More specifically, it is preferably a group in which one hydroxy group has been removed from a primary hydroxy compound described below.

[0055] [Primary hydroxy compound (R 1 OH)] Primary hydroxy compound (R 1 R is not particularly limited as long as it is a compound having one or more hydroxy groups, and any known compound can be used. 1 The OH may have a substituent other than a hydroxy group.

[0056] R 1 Specific examples of OH include monool, polyalkylene glycol monoether, polyalkylene glycol monoester, polyol, sugar, glycerin fatty acid ester, ethanolamide, and nucleoside.

[0057] Monoall More specifically, the monool includes a monohydric aliphatic alcohol and a monohydric aromatic alcohol.

[0058] Fatty alcohols A monohydric aliphatic alcohol is a compound having one hydroxy group in a linear, branched, or cyclic aliphatic hydrocarbon group. As the monohydric aliphatic alcohol, for example, an aliphatic alcohol having 1 to 20 carbon atoms is preferable, an aliphatic alcohol having 1 to 10 carbon atoms is more preferable, and an aliphatic alcohol having 1 to 7 carbon atoms is even more preferable. Specifically, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol (n-butanol), 2-methylpropyl alcohol (isobutanol), 2-butanol (sec-butanol), 2-methyl-2-propanol (tert-butanol), 1-pentanol (n-amyl alcohol), 2-pentanol (sec-amyl alcohol), 3-pentanol, 2-methyl-1-butanol, 3-methyl-1-butanol (isoamyl alcohol), 2-methyl-2-butanol (tert-amyl alcohol), 3-methyl-2-butanol, 2,2-dimethyl-1-propanol saturated aliphatic alcohols such as 2-propen-1-ol (allyl alcohol), 3-buten-1-ol, 4-penten-1-ol, 5-hexen-1-ol, 6-hepten-1-ol, and propargyl alcohol; and the like.

[0059] Monohydric aromatic alcohols A monohydric aromatic alcohol is a compound having one hydroxyl group and one or more aromatic rings. The aromatic rings are not particularly limited as long as they are cyclic conjugated systems having 4n+2 π electrons, and may be monocyclic or polycyclic. As the monohydric aromatic alcohol, for example, an aromatic alcohol having 6 to 30 carbon atoms is preferable, and an aromatic alcohol having 6 to 15 carbon atoms is more preferable. Specific examples include phenol, cresol, ethylphenol, tert-butylphenol, hexylphenol, octylphenol, nonylphenol, decylphenol, undecylphenol, dodecylphenol, tridecylphenol, tetradecylphenol, phenylphenol, benzylphenol, styrenated phenol, p-cumylphenol, 2-phenylethanol (phenethyl alcohol), and 2-hydroxyindan (2-indanol).

[0060] Polyalkylene glycol monoether Examples of the polyalkylene glycol monoether include compounds in which an alkylene oxide such as ethylene oxide, propylene oxide, butylene oxide, or long-chain α-olefin oxide is added to the above-mentioned monool. Specific examples thereof include polyoxyethylene monooctyl ether, polyoxyethylene / polyoxypropylene monooctyl ether, polyoxyethylene monodecyl ether, polyoxyethylene / polyoxypropylene monodecyl ether, polyoxyethylene monolauryl ether, polyoxyethylene / polyoxypropylene monolauryl ether, polyoxyethylene monomyristyl ether, polyoxyethylene / polyoxypropylene monomyristyl ether, polyoxyethylene monopalmityl ether, polyoxyethylene / polyoxypropylene monopalmityl ether, polyoxyethylene monostearyl ether, polyoxyethylene / polyoxypropylene monostearyl ether, polyoxyethylene monooleyl ether, polyoxyethylene / polyoxypropylene monooleyl ether, polyoxyethylene monococo alkyl ether, polyoxyethylene / polyoxypropylene monococo alkyl ether, polyoxyethylene monopalm alkyl ether, polyoxyethylene / polyoxypropylene monopalm alkyl ether, polyoxyethylene monobeef tallow alkyl ether, and polyoxyethylene / polyoxypropylene monobeef tallow alkyl ether.

[0061] Polyalkylene glycol monoester Examples of polyalkylene glycol monoesters include compounds in which an alkylene oxide is added to a fatty acid, and compounds in which a polyalkylene glycol and a fatty acid are subjected to an esterification reaction. Specific examples include polyethylene glycol monolaurate, polyethylene / polypropylene glycol monolaurate, polyethylene glycol myristate, polyethylene / polypropylene glycol monomyristate, polyethylene glycol palmitate, polyethylene / polypropylene glycol monopalmitate, polyethylene glycol monostearate, polyethylene / polypropylene glycol monostearate, polyethylene glycol monooleate, polyethylene / polypropylene glycol monooleate, polyethylene glycol monococonut fatty acid ester, polyethylene / polypropylene glycol monococonut fatty acid ester, polyethylene glycol monopalm fatty acid ester, polyethylene / polypropylene glycol monopalm fatty acid ester laurate, polyethylene glycol monobeef tallow fatty acid ester, and polyethylene / polypropylene glycol monobeef tallow fatty acid ester.

[0062] Polyol A polyol is a compound that has two or more hydroxy groups. Specifically, ethylene glycol, propylene glycol, 1,3-propanediol, 1,4-butanediol, 1,5-pentanediol, 1,6-hexanediol, 1,7-heptanediol, 1,8-octanediol, 1,9-nonanediol, 1,10-decanediol, 1,2-propanediol, 2-methyl-1,3-propanediol, 1,3-butanediol, 2-methyl-1,4-butanediol, 1,4-pentanediol, 2-methyl-1,5-pentanediol, 3-Methyl-1,5-pentanediol, 1,5-hexanediol, 2-methyl-1,6-hexanediol, 3-methyl-1,6-hexanediol, 1,6-heptanediol, 2-methyl-1,7-heptanediol, 3-methyl-1,7-heptanediol, 4-methyl-1,7-heptanediol, 1,7-octanediol, 2-methyl-1,8-octanediol, 3-methyl-1,8-octanediol, 4-methyl-1,8-octanediol, 1,8-nonanediol, 2 -Methyl-1,9-nonanediol, 3-methyl-1,9-nonanediol, 4-methyl-1,9-nonanediol, 5-methyl-1,9-nonanediol, 2-ethyl-1,3-hexanediol, 2,4-diethyl-1,5-pentanediol, neopentyl glycol, 2,2-diethylpropanediol, 2-butyl 2-ethylpropanediol and other dihydric alcohols; glycerin, trioxyisobutane, 1,2,3-butanetriol, 1,2,3-pentanetriol, 2-methyl - Trihydric alcohols such as 1,2,3-propanetriol, 2-methyl-2,3,4-butanetriol, 2-ethyl-1,2,3-butanetriol, 2,3,4-pentanetriol, 2,3,4-hexanetriol, 4-propyl-3,4,5-heptanetriol, 2,4-dimethyl-2,3,4-pentanetriol, pentamethylglycerin, pentaglycerin, 1,2,4-butanetriol, 1,2,4-pentanetriol, trimethylolethane, and trimethylolpropane;Examples of the polyol include tetrahydric alcohols such as pentaerythritol, erythritol, 1,2,3,4-pentane tetrol, 2,3,4,5-hexane tetrol, 1,2,4,5-pentane tetrol, 1,3,4,5-hexane tetrol, diglycerin, and sorbitan; pentahydric alcohols such as adonitol, arabitol, xylitol, and triglycerin; hexahydric alcohols such as dipentaerythritol, sorbitol, mannitol, iditol, inositol, dulcitol, talose, and allose; and derivatives of the polyols in which some or all of the hydrogen atoms of these compounds have been substituted with other substituents. Taking inositol as an example, there are nine stereoisomers of inositol: cis-inositol, epi-inositol, allo-inositol, myo-inositol, muco-inositol, neo-inositol, chiro-inositol (D- and L-forms exist), and scyllo-inositol. Similarly, for other compounds, only one type of isomer may be used, or two or more types of isomers may be used in combination.

[0063] ·sugar The sugar may be a monosaccharide or an oligosaccharide. Here, a monosaccharide means a sugar that is not hydrolyzed any further, and is a compound that serves as a building block in forming a polysaccharide. A monosaccharide can also be said to be the smallest unit of sugars. An oligosaccharide is a sugar oligomer in which multiple monosaccharides are linked together by glycosidic bonds.

[0064] · · Monosaccharide Specific examples of monosaccharides include glucose (grape sugar), fructose (fruit sugar), galactose, ribose, xylose, mannitol, sorbitol, xylitol, erythritol, and pentaerythritol.

[0065] Oligosaccharides Specific examples of oligosaccharides include disaccharides such as sucrose (cane sugar), lactose (milk sugar), maltose (malt sugar), isomaltose, trehalose, cellobiose, and maltitol; trisaccharides such as raffinose, melezitose, and maltotriose; tetrasaccharides such as stachyose; hexasaccharides such as α-cyclodextrin; heptasaccharides such as β-cyclodextrin; and octasaccharides such as γ-cyclodextrin.

[0066] Other sugars The sugar may also be other sugars such as heptose, deoxy sugar, amino sugar, thio sugar, seleno sugar, aldonic acid, uronic acid, sugar acid, ascorbic acid, ketoaldonic acid, anhydro sugar, unsaturated sugar, sugar ester, sugar ether, glycoside, etc., or may be a hydrolyzed product of polysaccharides such as starch, glycogen, cellulose, etc.

[0067] Glycerol fatty acid ester Glycerol fatty acid esters are compounds in which fatty acids are ester-bonded to one or two of the three hydroxyl groups of glycerol. Specific examples include glycerin monolaurate, glycerin monomyristate, glycerin monopalmitate, glycerin monostearate, glycerin monooleate, glycerin monococonut fatty acid ester, glycerin monopalm fatty acid ester, and glycerin monobeef tallow fatty acid ester.

[0068] Ethanolamide Examples of the ethanol amide include fatty acid amides of monoethanolamine or diethanolamine, and compounds in which an alkylene oxide is further added to the fatty acid amides. Specifically, lauric acid monoethanolamide, lauric acid diethanolamide, lauric acid monoethanolamide ethylene oxide adduct, lauric acid diethanolamide ethylene oxide adduct, myristic acid monoethanolamide, myristic acid diethanolamide, myristic acid monoethanolamide ethylene oxide adduct, myristic acid diethanolamide ethylene oxide adduct, palmitic acid monoethanolamide, palmitic acid diethanolamide, palmitic acid monoethanolamide ethylene oxide adduct, palmitic acid diethanolamide ethylene oxide adduct, stearic acid monoethanolamide, stearic acid diethanolamide, stearic acid monoethanolamide ethylene oxide adduct, stearic acid diethanolamide ethylene oxide adduct adducts, oleic acid monoethanolamide, oleic acid diethanolamide, oleic acid monoethanolamide ethylene oxide adduct, oleic acid diethanolamide ethylene oxide adduct, coconut fatty acid monoethanolamide, coconut fatty acid diethanolamide, coconut fatty acid monoethanolamide ethylene oxide adduct, coconut fatty acid diethanolamide ethylene oxide adduct, palm fatty acid monoethanolamide, palm fatty acid diethanolamide, palm fatty acid monoethanolamide ethylene oxide adduct, palm fatty acid diethanolamide ethylene oxide adduct, beef tallow fatty acid monoethanolamide, beef tallow fatty acid diethanolamide, beef tallow fatty acid monoethanolamide ethylene oxide adduct, beef tallow fatty acid diethanolamide ethylene oxide adduct, and the like.

[0069] Nucleosides Nucleosides are compounds in which a base is bound to a sugar. Examples of the base include purine bases such as adenine and guanine, pyrimidine bases such as thymine, cytosine and uracil, nicotinamide, and dimethylisoalloxazine. Specific examples include adenosine, guanosine, 5-methyluridine, uridine, cytidine, deoxyadenosine, deoxyguanosine, deoxyguanosine, thymidine, deoxyuridine, deoxycytidine, etc. In addition, nucleoside derivatives in which some or all of the hydrogen atoms or hydroxyl groups of these compounds are substituted with other substituents (for example, 5-(3-benzoyl-5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-(hydroxymethyl)tetrahydrofuran-3-yl benzoate or 3-benzoyl-1-[4-hydroxy-5-(tert-butyldimethylsilyloxymethyl)tetrahydrofuran-2-yl)-5-methylpyrimidine-2,4(1H,3H)-dione) and the like can be mentioned.

[0070] R 1 OH may be other than the above-mentioned monol, polyalkylene glycol monoether, polyalkylene glycol monoester, polyol, sugar, glycerol fatty acid ester, ethanolamide, and nucleoside, and may be, for example, a hydroxyamino acid such as threonine or serine, or a derivative of such an amino acid (for example, methyl[[(9H-fluorenyl)methoxy]carbonyl]serinate); or a hydroxy acid such as glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, or ricinoleic acid.

[0071] R 1 Among the above, OH is preferably a monol, an amino acid (including an amino acid derivative), or a nucleoside (including a nucleoside derivative). The monol is preferably an aliphatic alcohol having 1 to 20 carbon atoms or an aromatic alcohol having 6 to 30 carbon atoms, and more preferably an aliphatic alcohol having 1 to 7 carbon atoms or an aromatic alcohol having 6 to 15 carbon atoms.

[0072] More specifically, R 1Examples of monools in OH include ethanol, 1-butanol, 2-methylpropyl alcohol, 2-butanol, 2-methyl-2-propanol, 1-pentanol, 2-pentanol, 3-pentanol, 2-methyl-1-butanol, 3-methyl-1-butanol, 2-methyl-2-butanol, 3-methyl-2-butanol, 2,2-dimethyl-1-propanol, tert-butyl hydroxyacetate, 2-[[tert-butyl(dimethyl)silyl]oxy]ethanol, 2-propen-1-ol, 3-buten-1-ol, 4-penten-1-ol, 5-hexen-1-ol, 6-hepten-1-ol, phenol, cresol, ethylphenol, tert-butylphenol, hexylphenol, octylphenol, nonylphenol, decylphenol, undecylphenol, dodecylphenol, tridecylphenol, tetradecylphenol, phenylphenol, Preferred are ethanol, 1-butanol (n-butanol), 2-methylpropyl alcohol (isobutanol), 2-butanol (sec-butanol), 2-methyl-2-propanol (tert-butanol), tert-butyl hydroxyacetate (tert-butyl glycolate), 2-[[tert-butyl(dimethyl)silyl]oxy]ethanol, 2-propen-1-ol (allyl alcohol), 3-buten-1-ol, 4-penten-1-ol, phenol, 2-phenylethanol (phenethyl alcohol), 2-hydroxyindane (2-indanol), 2-methoxy-ethan-1-ol, propargyl alcohol, tert-butyl(2-hydroxyethyl)carbamate, and 2-cyanoethanol.

[0073] R 1 As the amino acid (including amino acid derivatives) at OH, methyl [[(9H-fluorenyl)methoxy]carbonyl]serinate is preferred.

[0074] R 1As the nucleoside (including a derivative of a nucleoside) in OH, 5-(3-benzoyl-5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-(hydroxymethyl)tetrahydrofuran-3-yl benzoate or 3-benzoyl-1-[4-hydroxy-5-(tert-butyldimethylsilyloxymethyl)tetrahydrofuran-2-yl]-5-methylpyrimidine-2,4(1H,3H)-dione is preferred.

[0075] In step (A1), phosphorus trichloride or phosphorus tribromide and R 1 The amount of each OH used is R 1 Taking into consideration the type of OH, the amount may be appropriately adjusted according to the target reaction. Phosphorus trichloride or phosphorus tribromide and R 1 The equivalent ratio of phosphorus trichloride or phosphorus tribromide to OH in the reaction system (R 1 OH) may be 0.1:1 to 10:1, may be 0.2:1 to 5:1, or may be 0.5:1 to 3:1. According to the step (A1) in the method for producing an asymmetric phosphate triester of the present embodiment, R 1 Even when a relatively small amount of phosphorus trichloride or phosphorus tribromide, which is nearly an equivalent amount, is reacted with OH, the compound P1 can be synthesized in a high yield.

[0076] The lower limit of the reaction temperature in step (A1) is -80°C or higher, preferably -10°C or higher, more preferably 0°C or higher, even more preferably 10°C or higher, and particularly preferably 20°C or higher. The upper limit of the reaction temperature in step (A1) is not particularly limited, and is, for example, preferably 80° C. or lower, more preferably 60° C. or lower, and further preferably 40° C. or lower.

[0077] If the lower limit of the reaction temperature in step (A1) is -80°C or higher, the stirring efficiency is improved and side reactions can be further suppressed. Also, if the lower limit of the reaction temperature in step (A1) is equal to or higher than the above-mentioned preferable lower limit, the stirring efficiency is further improved, side reactions can be further suppressed, and the yield of compound P1 can be further improved. When the upper limit of the reaction temperature in step (A1) is equal to or lower than the above-mentioned preferable upper limit, phosphorus trichloride or phosphorus tribromide and R 1 The reaction rate with OH can be appropriately controlled, and side reactions can be further suppressed.

[0078] For example, the reaction temperature in step (A1) is preferably -80°C or higher and 80°C or lower, more preferably -10°C or higher and 80°C or lower, even more preferably 0°C or higher and 60°C or lower, particularly preferably 10°C or higher and 40°C or lower, and most preferably 20°C or higher and 40°C or lower.

[0079] In step (A1), the lower limit of the flow rate of phosphorus trichloride or phosphorus tribromide flowing through the flow channel is 0.01 mL / min or more, preferably 0.1 mL / min or more, and more preferably 1 mL / min or more. In step (A1), the upper limit of the flow rate of phosphorus trichloride or phosphorus tribromide flowing through the flow path is not particularly limited, and may be, for example, 10 mL / min or less, 8 mL / min or less, or 5 mL / min or less.

[0080] In step (A1), if the lower limit of the flow rate of phosphorus trichloride or phosphorus tribromide flowing through the flow channel is 0.01 mL / min or more, the stirring efficiency is improved and side reactions can be further suppressed. In addition, in step (A1), if the lower limit of the flow rate of phosphorus trichloride or phosphorus tribromide flowing through the flow channel is the above-mentioned preferred lower limit or more, the stirring efficiency is further improved, side reactions can be further suppressed, and the yield of compound P1 can be further improved. In step (A1), if the upper limit of the flow rate of phosphorus trichloride or phosphorus tribromide flowing through the flow path is equal to or lower than the above-mentioned preferable upper limit, phosphorus trichloride or phosphorus tribromide and R1 The reaction rate with OH can be appropriately controlled, and side reactions can be further suppressed.

[0081] For example, in step (A1), the flow rate of phosphorus trichloride or phosphorus tribromide flowing through the flow path is preferably 0.01 mL / min or more and 10 mL / min or less, more preferably 0.1 mL / min or more and 8 mL / min or less, and even more preferably 1 mL / min or more and 5 mL / min or less.

[0082] In step (A1), R flowing in the flow path 1 The lower limit of the flow rate of OH is 0.01 mL / min or more, preferably 0.1 mL / min or more, more preferably 1 mL / min or more, and further preferably 2 mL / min or more. In step (A1), R flowing in the flow path 1 The upper limit of the flow rate of OH is not particularly limited, and may be, for example, 10 mL / min or less, 8 mL / min or less, or 5 mL / min or less.

[0083] In step (A1), R flowing in the flow path 1 If the lower limit of the flow rate of OH is 0.01 mL / min or more, the stirring efficiency is improved and side reactions can be further suppressed. 1 When the lower limit of the flow rate of OH is equal to or greater than the above-mentioned preferable lower limit, the stirring efficiency is further improved, side reactions can be further suppressed, and the yield of compound P1 can be further improved. In step (A1), R flowing in the flow path 1 If the upper limit of the flow rate of OH is equal to or lower than the above-mentioned preferred upper limit, phosphorus trichloride or phosphorus tribromide and R 1 The reaction rate with OH can be appropriately controlled, and side reactions can be further suppressed.

[0084] For example, in step (A1), R flowing in the flow path 1The flow rate of OH is preferably from 0.01 mL / min to 10 mL / min, more preferably from 0.1 mL / min to 8 mL / min, even more preferably from 1 mL / min to 5 mL / min, and particularly preferably from 2 mL / min to 5 mL / min.

[0085] In step (A1), the flow rate of phosphorus trichloride or phosphorus tribromide and R 1 The flow rate of OH may be different or the same, but it is preferable that they are different. Specifically, the flow rate of one of the two is preferably 0.1 to 1.0 times, and more preferably 0.3 to 0.9 times, the flow rate of the other.

[0086] For example, the flow rate of phosphorus trichloride or phosphorus tribromide is 1 mL / min or more and 5 mL / min or less, and R 1 The flow rate of OH may be 0.3 to 0.9 times the flow rate of the phosphorus trichloride or phosphorus tribromide, the flow rate of phosphorus trichloride or phosphorus tribromide is 2 mL / min or more and 5 mL / min or less, and R 1 The flow rate of OH may be 0.3 to 0.9 times the flow rate of the phosphorus trichloride or phosphorus tribromide. Conversely, R 1 The flow rate of OH is 1 mL / min or more and 5 mL / min or less, and the flow rate of phosphorus trichloride or phosphorus tribromide is 1 The flow rate of R may be 0.3 to 0.9 times that of OH. 1 The flow rate of OH is 2 mL / min or more and 5 mL / min or less, and the flow rate of phosphorus trichloride or phosphorus tribromide is 1 The flow rate may be 0.3 to 0.9 times the flow rate of OH.

[0087] In step (A1), phosphorus trichloride or phosphorus tribromide and R are mixed in a mixer of a flow-through reactor. 1 The reaction time for reacting OH is not particularly limited and is, for example, 0.01 seconds to 1 minute, may be 1 to 30 seconds, or may be 1 to 20 seconds.

[0088] The compound P1 synthesized in step (A1) is a compound in which one chlorine atom of phosphorus trichloride or one bromine atom of phosphorus tribromide is R 1 It is a compound in which a hydroxyl group (OH) has been substituted with a group that has had one hydrogen atom removed. For example, compound P1 is a compound in which one chlorine atom of phosphorus trichloride or one bromine atom of phosphorus tribromide is substituted with a group in which one hydrogen atom has been removed from the hydroxyl group of the above-mentioned monol, polyalkylene glycol monoether, polyalkylene glycol monoester, polyol, sugar, glycerin fatty acid ester, ethanolamide, or nucleoside.

[0089] ≪Process (B1)≫ Step (B1) comprises reacting the above-mentioned compound P1 and a second hydroxy compound (R 2 This is a process for synthesizing compound P2 represented by the following general formula (P-2) by reacting with aryloxyalkylenesilane (R-OH).

[0090] [ka] [In the formula, R 1 and R 2 are different organic groups. X is a bromine atom or a chlorine atom.

[0091] In the above general formulas (H-2) and (P-2), R 2 is an organic group, and is defined as R 1 The same groups as those shown in the above are exemplified, except that R 1 and R 2 are different organic groups.

[0092] R 2 As OH, the above-mentioned R 1 The same as OH, but R 2 OH is R 1 OH is not the same compound.

[0093] The lower limit of the reaction temperature in step (B1) is -80°C or higher, preferably -10°C or higher, more preferably 0°C or higher, even more preferably 10°C or higher, and particularly preferably 20°C or higher. The upper limit of the reaction temperature in step (B1) is not particularly limited, and is, for example, preferably 80° C. or lower, more preferably 60° C. or lower, and further preferably 40° C. or lower.

[0094] If the lower limit of the reaction temperature in step (B1) is -80°C or higher, the stirring efficiency is improved and side reactions can be further suppressed. Also, if the lower limit of the reaction temperature in step (B1) is equal to or higher than the above-mentioned preferable lower limit, the stirring efficiency is further improved, side reactions can be further suppressed, and the yield of compound P2 can be further improved. When the upper limit of the reaction temperature in step (B1) is equal to or lower than the above-mentioned preferable upper limit, the compound P1 and R 2 The reaction rate with OH can be appropriately controlled, and side reactions can be further suppressed.

[0095] For example, the reaction temperature in step (B1) is preferably -80°C or higher and 80°C or lower, more preferably -10°C or higher and 80°C or lower, even more preferably 0°C or higher and 60°C or lower, particularly preferably 10°C or higher and 40°C or lower, and most preferably 20°C or higher and 40°C or lower.

[0096] In step (B1), R flowing in the flow path 2 The lower limit of the flow rate of OH is 0.01 mL / min or more, preferably 0.1 mL / min or more, more preferably 1 mL / min or more, and further preferably 2 mL / min or more. In step (B1), R flowing in the flow path 2 The upper limit of the flow rate of OH is not particularly limited, and may be, for example, 10 mL / min or less, 8 mL / min or less, or 5 mL / min or less.

[0097] In step (B1), R flowing in the flow path 2If the lower limit of the flow rate of OH is 0.01 mL / min or more, the stirring efficiency is improved and side reactions can be further suppressed. 2 When the lower limit of the flow rate of OH is equal to or greater than the above-mentioned preferable lower limit, the stirring efficiency is further improved, side reactions can be further suppressed, and the yield of compound P2 can be further improved. In step (B1), R flowing in the flow path 2 If the upper limit of the flow rate of OH is equal to or lower than the above preferred upper limit, the compounds P1 and R 2 The reaction rate with OH can be appropriately controlled, and side reactions can be further suppressed.

[0098] For example, in step (B1), R flowing in the flow path 2 The flow rate of OH is preferably from 0.01 mL / min to 10 mL / min, more preferably from 0.1 mL / min to 8 mL / min, even more preferably from 1 mL / min to 5 mL / min, and particularly preferably from 2 mL / min to 5 mL / min.

[0099] In step (B1), compounds P1 and R are mixed in a mixer of a flow reactor. 2 The reaction time for reacting OH is not particularly limited and is, for example, 0.01 seconds to 1 minute, may be 1 to 30 seconds, or may be 1 to 20 seconds.

[0100] The compound P2 synthesized in step (B1) is a compound in which one chlorine atom of the compound P1 (or one bromine atom of the compound P1) is R 2 Compound P2 is a compound in which one chlorine atom of phosphorus trichloride (or one bromine atom of phosphorus tribromide) is replaced by a group in which one hydrogen atom has been removed from the hydroxyl group of OH. 1 A hydroxy group of OH is substituted with one hydrogen atom removed, and another chlorine atom (or another bromine atom) is replaced by R 2 It can also be said to be a compound in which a hydroxyl group (OH) has been substituted with a group that has one hydrogen atom removed. For example, compound P2 is a compound in which one chlorine atom of phosphorus trichloride or one bromine atom of phosphorus tribromide is substituted with a group (HG1) in which one hydrogen atom has been removed from a hydroxy group of the above-mentioned monol, polyalkylene glycol monoether, polyalkylene glycol monoester, polyol, sugar, glycerin fatty acid ester, ethanolamide, or nucleoside, and another chlorine atom of phosphorus trichloride or another bromine atom of phosphorus tribromide is substituted with a group (HG2) in which one hydrogen atom has been removed from a hydroxy group of the above-mentioned monol, polyalkylene glycol monoether, polyalkylene glycol monoester, polyol, sugar, glycerin fatty acid ester, ethanolamide, or nucleoside (wherein HG1 and HG2 are different substituents).

[0101] ≪Process (C1)≫ Step (C1) is a step of reacting the above-mentioned compound P2 and a tertiary hydroxy compound (R 3 This is a process for synthesizing compound P3 represented by the following general formula (P-3) by reacting with aryloxyalkylenesilane (R-OH).

[0102] [ka] [In the formula, R 1 ~R 3 are each independently an organic group. 1 ~R 3 are different organic groups. X is a bromine atom or a chlorine atom.

[0103] In the above general formulas (H-3) and (P-3), R 3 is an organic group, and is defined as R 1 The same groups as those shown in the above are exemplified, except that R 1 ~R 3 are all different organic groups.

[0104] R 3 As OH, the above-mentioned R 1 The same as OH, but R 3 OH is R 2 OH and R1 OH is not the same compound.

[0105] Step (C1) can be carried out as described above, for example by reacting R 3 Compound P3 can be synthesized by storing OH in a tank and flowing the above-mentioned compound P2 into the tank.

[0106] The reaction temperature in step (C1) is not particularly limited, and is preferably -80°C or higher and 80°C or lower, more preferably -10°C or higher and 80°C or lower, even more preferably 0°C or higher and 60°C or lower, particularly preferably 10°C or higher and 40°C or lower, and most preferably 20°C or higher and 40°C or lower.

[0107] The compound P3 synthesized in step (C1) is a compound in which one chlorine atom of the compound P2 (or one bromine atom of the compound P2) is R 3 It is a compound in which a hydroxyl group (OH) has been substituted with a group that has had one hydrogen atom removed. For example, compound P3 is a compound in which one chlorine atom of phosphorus trichloride or one bromine atom of phosphorus tribromide is substituted with a group (HG1) in which one hydrogen atom has been removed from a hydroxy group of the above-mentioned monool, polyalkylene glycol monoether, polyalkylene glycol monoester, polyol, sugar, glycerin fatty acid ester, ethanolamide, or nucleoside, and another chlorine atom of phosphorus trichloride or another bromine atom of phosphorus tribromide is substituted with a group (HG1) in which one hydrogen atom has been removed from a hydroxy group of the above-mentioned monool, polyalkylene glycol monoether, polyalkylene glycol monoester, polyol, sugar, glycerin fatty acid ester, ethanolamide, or nucleoside. a compound in which one hydrogen atom has been removed from the hydroxy group of a serine fatty acid ester, ethanolamide, or nucleoside and one remaining chlorine atom of phosphorus trichloride or one remaining bromine atom of phosphorus tribromide is substituted with a group (HG3) in which one hydrogen atom has been removed from the hydroxy group of the above-mentioned monol, polyalkylene glycol monoether, polyalkylene glycol monoester, polyol, sugar, glycerin fatty acid ester, ethanolamide, or nucleoside (wherein HG1, HG2, and HG3 are different substituents).

[0108] ≪Process (D1)≫ Step (D1) is a step of synthesizing an asymmetric phosphate triester by oxidizing the compound P3.

[0109] [ka] [In the formula, R 1 ~R 3 are each independently an organic group. 1 ~R 3 are different organic groups.

[0110] The method for oxidizing compound P3 to obtain an asymmetric phosphate triester compound is not particularly limited. For example, compound P3 can be oxidized by reacting compound P3 with a specific oxidizing agent. The oxidizing agent is not particularly limited, but examples thereof include halogen-containing oxidizing agents such as metachloroperbenzoic acid (mCPBA), sodium hypochlorite pentahydrate, trichloroisocyanuric acid, tertiary butyl hypochlorite, N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, and iodine; aqueous hydrogen peroxide; and tert-butyl hydroperoxide.

[0111] The reaction in step (A1) to step (D1) may be carried out in the presence of a solvent. The solvent is not particularly limited, but is preferably one that does not interfere with the reaction of the compounds and is preferably one that has high solubility for the raw materials used in the reaction and the compounds generated during the reaction. Examples of the solvent include dichloromethane (DCM), tetrahydrofuran (THF), diethyl ether (Et2O), 1,4-dioxane, acetonitrile (MeCN), chloroform, and N,N-dimethylformamide (DMF).

[0112] The reaction in step (A1) to step (D1) may be carried out in the presence of a non-nucleophilic base. The non-nucleophilic base is not particularly limited as long as it can capture HCl generated during the reaction. Examples of the non-nucleophilic base include N,N-diisopropylethylamine (DIEA), triethylamine, diazabicycloundecene, 2,6-lutidine, N-methylmorpholine, N-ethylmorpholine, N-benzyldimethylamine, and tributylamine.

[0113] The asymmetric phosphate triester obtained in the step (D1) also includes an asymmetric thiophosphate triester. For example, an asymmetric thiophosphate triester can be obtained by the reaction shown below.

[0114] [ka] [In the formula, R 1 ~R 3 are each independently an organic group. 1 ~R 3 are different organic groups.

[0115] The method for oxidizing compound P3 to obtain an asymmetric thiophosphate triester compound is not particularly limited. For example, compound P3 can be oxidized by reacting compound P3 with a specific oxidizing agent. The oxidizing agent is not particularly limited, but examples thereof include xanthan hydride.

[0116] The method for producing an asymmetric phosphate triester according to the first embodiment described above is a method for producing an asymmetric phosphate triester, which uses a flow-through reactor, and is characterized in that the reaction temperature in the above-mentioned steps (A1) and (B1) is -80°C or higher, and the flow rates of phosphorus trichloride or phosphorus tribromide, the first hydroxy compound, and the second hydroxy compound flowing through the flow paths are 0.01 mL / min or higher. By appropriately controlling the reaction temperature and flow rates, the stirring efficiency can be improved and side reactions can be suppressed. Therefore, according to the method for producing an asymmetric phosphate triester of the first embodiment, the target phosphate triester can be produced at a lower cost and in a higher yield.

[0117] In the above-mentioned method for producing an asymmetric phosphate triester of the first embodiment, the preferred flow rate changes depending on the inner diameter of the mixer in the flow reactor. For example, the above-mentioned preferred ranges of flow rates of phosphorus trichloride or phosphorus tribromide, the first hydroxy compound, and the second hydroxy compound are particularly preferred ranges when the inner diameter of the mixer is 0.25 mm. For example, the inner diameter of the mixer in a flow reactor is multiplied by N (cross-sectional area is N 2 multiplied by N 2 It is preferable to double

[0118] More specifically, when the inner diameter of the mixer of the flow reaction apparatus is 0.25 mm, the flow rate of each compound is preferably 0.01 mL / min to 10 mL / min, more preferably 0.1 mL / min to 8 mL / min, even more preferably 1 mL / min to 5 mL / min, and particularly preferably 2 mL / min to 5 mL / min.

[0119] If the inner diameter of the mixer in the flow reactor is 1 mm, the above value 4 2 Specifically, the flow rate of each compound is preferably 0.16 mL / min or more and 160 mL / min or less, more preferably 1.6 mL / min or more and 128 mL / min or less, even more preferably 16 mL / min or more and 80 mL / min or less, and particularly preferably 32 mL / min or more and 80 mL / min or less.

[0120] In the above-described first embodiment of the method for producing an asymmetric phosphate triester, when the inner diameter of the mixer of the flow-through reactor is ID, the flow rate of each compound is preferably (ID / 0.25) times the above-described preferable flow rate. 2 It can also be said that a value multiplied by is preferable. That is, in the above-mentioned first embodiment of the method for producing an asymmetric phosphate triester, when the inner diameter of the mixer of the flow-through reactor is ID, the flow rate of each compound is 0.01 × (ID / 0.25) 2 mL / min or more 10× (ID / 0.25) 2 mL / min or less, and 0.1 × (ID / 0.25) 2 mL / min or more 8× (ID / 0.25) 2 mL / min or less is more preferable, and 1×(ID / 0.25) 2 mL / min or more 5× (ID / 0.25) 2 It is more preferable that the ID is 2×(ID / 0.25) or less. 2 mL / min or more 5× (ID / 0.25) 2 It is particularly preferable that the flow rate is equal to or less than mL / min.

[0121] <Second embodiment> The method for producing an asymmetric phosphate triester of the second embodiment is a method for producing an asymmetric phosphate triester using a flow-through reaction apparatus, and includes a step (A1) of reacting phosphorus trichloride or phosphorus tribromide with a first hydroxy compound to synthesize compound P1, a step (N1) of reacting compound P1 with a base to synthesize compound N1, a step (BN1) of reacting compound N1 with a second hydroxy compound to synthesize compound N2, a step (CN1) of reacting compound N2 with a third hydroxy compound to synthesize compound P3, and a step (D1) of oxidizing compound P3 to synthesize an asymmetric phosphate triester.

[0122] Steps (A1) and (D1) in the method for producing an asymmetric phosphate triester of the second embodiment are the same as steps (A1) and (D1) in the method for producing an asymmetric phosphate triester of the above-mentioned first embodiment.

[0123] ≪Process (N1)≫ Step (N1) is a step of synthesizing compound N1 represented by the following general formula (N-1) by reacting compound P1 with a base (nucleophilic base).

[0124] [ka] [In the formula, R 1 is an organic group. 1 is a group in which one hydrogen atom has been removed from a base. X is a bromine atom or a chlorine atom.

[0125] The base is not particularly limited as long as it is a nucleophilic base. Specifically, the base is preferably one or more bases selected from the group consisting of pyridine, pyridine derivatives (e.g., 4-dimethylaminopyridine (DMAP)), imidazole, imidazole derivatives (e.g., N-methylimidazole (NMI), 4-methylimidazole), and 1,4-diazabicyclo[2,2,2]octane, more preferably imidazole or an imidazole derivative, and even more preferably a compound represented by the following general formula (I-1).

[0126] [ka] [Wherein, RI 1 and R.I. 2 is a hydrogen atom or a hydrocarbon group.

[0127] RI in the above general formula (I-1) 1 and R.I. 2 The hydrocarbon group in may be an aliphatic hydrocarbon group or an aromatic hydrocarbon group (aryl group). The aliphatic hydrocarbon group may be linear, branched, or cyclic. If cyclic, it may be monocyclic or polycyclic. The aliphatic hydrocarbon group may have 1 to 20 or 1 to 15 carbon atoms. The aliphatic hydrocarbon group may be a saturated aliphatic hydrocarbon group (alkyl group) or an unsaturated aliphatic hydrocarbon group, with an alkyl group being preferred. The alkyl group may have 1 to 20, 1 to 10, or 1 to 5 carbon atoms.

[0128] Specific examples of the linear or branched alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, an isopentyl group, a neopentyl group, a tert-pentyl group, a 1-methylbutyl group, an n-hexyl group, a 2-methylpentyl group, a 3-methylpentyl group, a 2,2-dimethylbutyl group, a 2,3-dimethylbutyl group, an n-heptyl group, a 2-methylhexyl group, Examples of such alkyl groups include aryl, arylhexyl ...

[0129] The lower limit of the reaction temperature in step (N1) is preferably -80°C or higher, more preferably -10°C or higher, even more preferably 0°C or higher, particularly preferably 10°C or higher, and most preferably 20°C or higher. The upper limit of the reaction temperature in step (N1) is not particularly limited, and is, for example, preferably 80° C. or lower, more preferably 60° C. or lower, and further preferably 40° C. or lower.

[0130] When the reaction temperature in the step (N1) is within the above-mentioned preferred range, the reaction proceeds smoothly, and the yield of the compound N1 can be further improved.

[0131] For example, the reaction temperature in step (N1) is preferably -80°C or higher and 80°C or lower, more preferably -10°C or higher and 80°C or lower, even more preferably 0°C or higher and 60°C or lower, particularly preferably 10°C or higher and 40°C or lower, and most preferably 20°C or higher and 40°C or lower.

[0132] In the step (N1), the lower limit of the flow rate of the base flowing through the flow channel is 0.01 mL / min or more, preferably 0.1 mL / min or more, and more preferably 1 mL / min or more. In step (N1), the upper limit of the flow rate of the base flowing through the flow channel is not particularly limited, and may be, for example, 10 mL / min or less, 8 mL / min or less, or 5 mL / min or less.

[0133] In the step (N1), if the flow rate of the base flowing through the flow channel is within the above-mentioned preferred range, the reaction proceeds smoothly and the yield of compound N1 can be further improved.

[0134] For example, in step (N1), the flow rate of the base flowing through the flow channel may be 0.01 mL / min or more and 10 mL / min or less, 0.1 mL / min or more and 8 mL / min or less, or 1 mL / min or more and 5 mL / min or less.

[0135] In the step (N1), the reaction time for reacting the compound P1 with the base in the mixer of the flow reaction apparatus is not particularly limited, and is, for example, 0.01 seconds to 1 minute, may be 1 to 30 seconds, or may be 1 to 20 seconds.

[0136] The compound N1 synthesized in step (N1) is a compound in which one chlorine atom of phosphorus trichloride or one bromine atom of phosphorus tribromide is R 1 It is a compound in which one hydrogen atom is removed from the hydroxyl group of OH and the remaining two chlorine atoms or the remaining two bromine atoms are each replaced by a group in which one hydrogen atom is removed from a base. For example, compound N1 is a compound in which one chlorine atom of phosphorus trichloride (or one bromine atom of phosphorus tribromide) is substituted with a group in which one hydrogen atom has been removed from a hydroxy group of the above-mentioned monol, polyalkylene glycol monoether, polyalkylene glycol monoester, polyol, sugar, glycerin fatty acid ester, ethanolamide, or nucleoside, and the remaining two chlorine atoms of phosphorus trichloride (or the remaining two bromine atoms of phosphorus tribromide) are substituted with a group in which one hydrogen atom has been removed from pyridine, a pyridine derivative, imidazole, an imidazole derivative, or 1,4-diazabicyclo[2,2,2]octane.

[0137] ≪Process (BN1)≫ The step (BN1) is a step of synthesizing a compound N2 represented by the following general formula (N-2) by reacting a compound N1 with a second hydroxy compound.

[0138] [ka] [In the formula, R 1 and R 2 are different organic groups. 1 is a base with one hydrogen atom removed.

[0139] Step (BN1) is the same as step (B1) in the method for producing an asymmetric phosphate triester of the first embodiment described above, except that compound P1 is compound N1.

[0140] Compound N2 synthesized in step (BN1) is a compound in which a group obtained by removing one hydrogen atom from one base of compound N1 is R 2 It is a compound in which a hydroxyl group (OH) has been substituted with a group that has had one hydrogen atom removed. For example, compound N2 is a compound in which one chlorine atom of phosphorus trichloride or one bromine atom of phosphorus tribromide is substituted with a group (HG1) in which one hydrogen atom has been removed from a hydroxy group of the above-mentioned monool, polyalkylene glycol monoether, polyalkylene glycol monoester, polyol, sugar, glycerin fatty acid ester, ethanolamide, or nucleoside, and another chlorine atom of phosphorus trichloride or another bromine atom of phosphorus tribromide is substituted with a group (HG1) in which one hydrogen atom has been removed from a hydroxy group of the above-mentioned monool, polyalkylene glycol monoether, polyalkylene glycol monoester, polyol, sugar, glycerin fatty acid ester, ethanolamide, or nucleoside. a compound in which one hydrogen atom has been removed from the hydroxyl group of a nucleoside, a polyol, a sugar, a glycerol fatty acid ester, an ethanolamide, or a nucleoside, and one remaining chlorine atom of phosphorus trichloride or one remaining bromine atom of phosphorus tribromide is replaced with a group in which one hydrogen atom has been removed from pyridine, a pyridine derivative, imidazole, an imidazole derivative, or 1,4-diazabicyclo[2,2,2]octane (wherein HG1 and HG2 are different substituents).

[0141] ≪Process (CN1)≫ Step (CN1) is a step of synthesizing compound P3 by reacting compound N2 with a tertiary hydroxy compound.

[0142] [ka] [In the formula, R 1 ~R 3 are each independently an organic group. 1 ~R 3 are all different organic groups. 1 is a base with one hydrogen atom removed.

[0143] Step (CN1) is the same as step (C1) in the method for producing an asymmetric phosphate triester of the above-mentioned first embodiment, except that compound P2 is compound N2.

[0144] The reactions in step (A1), step (N1), step (BN1), and step (CN1) may be carried out in the presence of a solvent. The solvent is not particularly limited, but is preferably one that does not interfere with the reaction of the compounds and is preferably one that has high solubility for the raw materials used in the reaction. Examples of the solvent include dichloromethane (DCM), tetrahydrofuran (THF), diethyl ether (Et2O), 1,4-dioxane, acetonitrile (MeCN), chloroform, and N,N-dimethylformamide (DMF).

[0145] The reactions in steps (A1), (N1), (BN1), and (CN1) may be carried out in the presence of a non-nucleophilic base. The non-nucleophilic base is not particularly limited as long as it can capture HCl generated during the reaction. Examples of the non-nucleophilic base include N,N-diisopropylethylamine (DIEA), triethylamine, diazabicycloundecene, 2,6-lutidine, N-methylmorpholine, N-ethylmorpholine, N-benzyldimethylamine, and tributylamine.

[0146] The method for producing an asymmetric phosphate triester according to the second embodiment described above further includes step (N1) in addition to the steps of the method for producing an asymmetric phosphate triester according to the first embodiment. Reactivity can be appropriately suppressed by substituting two chlorine atoms in compound P1 (or two bromine atoms in compound P1) with a group obtained by removing one hydrogen atom from a base. Therefore, according to the method for producing an asymmetric phosphate triester of the second embodiment, the target phosphate triester can be produced in a higher yield.

[0147] In the method for producing an asymmetric phosphate triester of the second embodiment, the preferable relationship between the flow rate and the inner diameter of the mixer of the flow reactor is the same as in the method for producing an asymmetric phosphate triester of the first embodiment described above. That is, when the inner diameter of the mixer of the flow-through reactor is ID, the flow rate of each compound is the above-mentioned preferable flow rate (ID / 0.25). 2 A value multiplied by is preferred.

[0148] (Method for producing a symmetric phosphate triester according to the second aspect of the present invention) Hereinafter, the configuration of the flow-type reactor according to this embodiment and the method for producing a symmetric phosphate triester using the same will be described with reference to FIG. 2 is a schematic diagram showing a general configuration of a flow-through reactor 100. The flow-through reactor 100 includes a tank 110 for accommodating a first liquid, a tank 120 for accommodating a second liquid, a tank 130 for accommodating a third liquid, and a tank 140 for accommodating a mixture of the third liquid and the fourth liquid.

[0149] For example, the first liquid may contain a first hydroxy compound (R 1 The first liquid contains phosphorus trichloride or phosphorus tribromide, and the third liquid contains a second hydroxy compound (R 2 Contains OH).

[0150] The flow-through reactor 100 includes flow paths f10, f20, f30, f40, and f50 for transporting fluids. The inner diameters of the flow paths and mixers may be, for example, 0.1 to 1 mm, 0.1 to 0.8 mm, or 0.2 to 0.6 mm. The inner diameters of the flow paths and mixers may be 1 mm to several cm. The tanks 110, 120, 130, and 140 and the flow paths f10, f20, f30, f40, and f50 are formed of, for example, a resin such as plastic or elastomer, a glass material, a metal, or a ceramic.

[0151] The tank 110 is connected to a pump 210, and when the pump 210 is operated, the first liquid contained in the tank 110 moves through a flow path f10 and flows into the mixer 310. The tank 120 is connected to a pump 220, and when the pump 220 is operated, the second liquid contained in the tank 120 moves through a flow path f20 and flows into the mixer 310. Next, the first liquid and the second liquid are mixed by the mixer 310 to become a first mixed liquid, which is sent to the flow path f50. During this mixing process, R contained in the first liquid is 1OH reacts with phosphorus trichloride or phosphorus tribromide contained in the second liquid, and one chlorine atom of phosphorus trichloride or one bromine atom of phosphorus tribromide is converted to R 1 A compound P1 substituted with an O-group is obtained (step A2 of the method for producing a symmetric phosphate triester). The first mixture containing the obtained compound P1 moves through a flow path f40 and flows into a mixer 320.

[0152] The tank 130 is connected to a pump 230, and by the operation of the pump 230, the third liquid contained in the tank 130 moves through the flow path f30 and flows into the mixer 320. Next, the third liquid and the first mixed liquid are mixed to become a second mixed liquid, which is sent to the flow path f50. During this mixing process, the compound P1 obtained in the step A2 and the R 2 OH reacts with the two chlorine atoms of compound P1 (or the two bromine atoms of compound P1), and each 2 A compound P4 substituted with an O-group is obtained (step B2 of the method for producing a symmetric phosphate triester). The obtained compound P4 moves through a flow path f50 and is stored in a tank 140. Next, a symmetric phosphate triester is synthesized by oxidizing the compound P4, and the symmetric phosphate triester is stored in the tank 140 (step D2 of the method for producing a symmetric phosphate triester).

[0153] Compound P1 is highly reactive, and the reaction between compound P1 and R 1 Since a side reaction in which OH reacts again easily occurs, it is important to control the reaction. According to the flow-through reactor 100 of this embodiment, the synthesized compound P1 can be quickly released from the mixer, thereby suppressing side reactions and producing the target phosphate triester with high yield.

[0154] Although the flow-through reactor 100 has been described as an example in which liquids are mixed by a mixer, the flow-through reactor of this embodiment does not necessarily need to be equipped with a mixer, since liquid mixing can be achieved simply by connecting flow paths to each other.

[0155] <Third embodiment> The method for producing a symmetric phosphate triester according to the third embodiment is a method for producing a symmetric phosphate triester by using a flow-through reactor to synthesize the symmetric phosphate triester, and the method comprises the steps of: 1 a step (A2) of synthesizing a compound P1 by reacting a second hydroxy compound (R 2 The method includes a step (B2) (hereinafter referred to as "step (B2)") of reacting P4 with aryloxyethyl ether (OH) to synthesize compound P4, and a step (D2) (hereinafter referred to as "step (D2)") of oxidizing compound P4 to synthesize a symmetric phosphate triester.

[0156] [ka] [In the formula, R 1 and R 2 are different organic groups. X is a bromine atom or a chlorine atom.

[0157] The reaction temperature in steps (A2) and (B2) is -80°C or higher, and in steps (A2) and (B2), the flow rates of phosphorus trichloride or phosphorus tribromide, the first hydroxy compound, and the second hydroxy compound flowing through the flow channel are 0.01 mL / min or higher. Moreover, the preferred ranges of the reaction temperature and flow rate are the same as those described in step (A1) and step (B1) in the method for producing an asymmetric phosphate triester of the first embodiment described above. Moreover, step (D2) is also the same as that described in step (D1) in the method for producing an asymmetric phosphate triester of the first embodiment.

[0158] The reaction in steps (A2) and (B2) may be carried out in the presence of a solvent. The solvent is not particularly limited, but is preferably one that does not interfere with the reaction of the compounds and has high solubility for the raw materials used in the reaction. Examples of the solvent include dichloromethane (DCM), tetrahydrofuran (THF), diethyl ether (Et2O), 1,4-dioxane, acetonitrile (MeCN), chloroform, and N,N-dimethylformamide (DMF).

[0159] The reaction in steps (A2) and (B2) may be carried out in the presence of a non-nucleophilic base. The non-nucleophilic base is not particularly limited as long as it can capture HCl generated during the reaction. Examples of the non-nucleophilic base include N,N-diisopropylethylamine (DIEA), triethylamine, diazabicycloundecene, 2,6-lutidine, N-methylmorpholine, N-ethylmorpholine, N-benzyldimethylamine, and tributylamine.

[0160] The method for producing an asymmetric phosphate triester according to the third embodiment described above is a method for producing a symmetric phosphate triester, which uses a flow-through reactor, and is characterized in that the reaction temperature in the above-mentioned steps (A2) and (B2) is -80°C or higher, and the flow rates of phosphorus trichloride or phosphorus tribromide, the first hydroxy compound, and the second hydroxy compound flowing through the flow paths are 0.01 mL / min or higher. By appropriately controlling the reaction temperature and flow rates, the stirring efficiency can be improved and side reactions can be suppressed. Therefore, according to the method for producing a symmetric phosphate triester of the third embodiment, the target phosphate triester can be produced at a lower cost and in a higher yield.

[0161] In the method for producing an asymmetric phosphate triester of the third embodiment, the preferable relationship between the flow rate and the inner diameter of the mixer of the flow reactor is the same as in the method for producing an asymmetric phosphate triester of the first embodiment described above. That is, when the inner diameter of the mixer of the flow-through reactor is ID, the flow rate of each compound is the above-mentioned preferable flow rate (ID / 0.25). 2 A value multiplied by is preferred.

[0162] (Method for Producing Phosphate Ester According to the Third Aspect of the Present Invention) The method for producing a phosphoric ester according to a third aspect of the present invention is a method for producing a phosphoric ester by using a flow-through reaction apparatus, and includes a step (A11) (hereinafter referred to as "step (A11)") of reacting phosphorus trichloride or phosphorus tribromide with a first hydroxy compound represented by the following general formula (H1-1) to synthesize a compound P11 represented by the following general formula (P1-1), and a step (A12) of reacting the compound P11 with a second hydroxy compound represented by the following general formula (H1-2) to synthesize a compound P12 represented by the following general formula (P1-3). The method includes a step (B11) (hereinafter referred to as "step (B11)") of synthesizing a compound P12 represented by the following general formula (P1-2), a step (C11) (hereinafter referred to as "step (C11)") of reacting the compound P12 with a tertiary hydroxy compound represented by the following general formula (H1-3) to synthesize a compound P13 represented by the following general formula (P1-3), and a step (D11) (hereinafter referred to as "step (D11)") of oxidizing the compound P13 to synthesize a phosphate ester. Unlike the production methods of the above-mentioned aspects, in the production method of a phosphoric acid ester according to the third aspect of the present invention, at least one of the primary to tertiary hydroxy compounds is water, and therefore the production method of the phosphoric acid ester is specifically a production method of a phosphoric acid monoester or a phosphoric acid diester.

[0163] [ka] [R 11 ~R 13 are each independently a hydrogen atom or an organic group. 11 ~R 13 At least one of the groups is an organic group and at least one of the groups is a hydrogen atom. X is a bromine atom or a chlorine atom.

[0164] An example of a reaction scheme for the production method of the phosphoric acid ester in the case where the method is a production method of a phosphoric acid monoester is shown below. In the reaction scheme below, compound P12 represented by general formula (P1-2) in which the second hydroxy compound is water is represented as compound P12-1, and compound P13 represented by general formula (P1-3) in which the third hydroxy compound is also water is represented as compound P13-1.

[0165] [ka]

[0166] An example of the reaction scheme when the method for producing the phosphoric acid ester is a method for producing a phosphoric acid diester is shown below. In the following reaction scheme, compound P13 represented by general formula (P1-3) in which only the tertiary hydroxy compound is water is represented as compound P13-2.

[0167] [ka]

[0168] In the method for producing a phosphoric acid ester according to the third aspect of the present invention, the first hydroxy compound, the second hydroxy compound, and the third hydroxy compound are each selected from the group consisting of the above-mentioned R 1 O.H., R. 2 OH and R 3 Examples include the same hydroxy compounds as exemplified by OH, and water.

[0169] The reaction temperature in steps (A11) and (B11) is -80°C or higher, and in steps (A11) and (B11), the flow rates of phosphorus trichloride or phosphorus tribromide, the first hydroxy compound, and the second hydroxy compound flowing through the flow path are 0.01 mL / min or higher. Moreover, the preferred ranges of the reaction temperature and flow rate are the same as those described in step (A1) and step (B1) in the method for producing an asymmetric phosphate triester of the first embodiment described above. Moreover, step (D11) is also the same as that described in step (D1) in the method for producing an asymmetric phosphate triester of the first embodiment.

[0170] The reaction in steps (A11) and (B11) may be carried out in the presence of a solvent. The solvent is not particularly limited, but is preferably one that does not interfere with the reaction of the compounds and has high solubility for the raw materials used in the reaction. Examples of the solvent include dichloromethane (DCM), tetrahydrofuran (THF), diethyl ether (Et2O), 1,4-dioxane, acetonitrile (MeCN), chloroform, and N,N-dimethylformamide (DMF).

[0171] The reaction in steps (A11) and (B11) may be carried out in the presence of a non-nucleophilic base. The non-nucleophilic base is not particularly limited as long as it can capture HCl generated during the reaction. Examples of the non-nucleophilic base include N,N-diisopropylethylamine (DIEA), triethylamine, diazabicycloundecene, 2,6-lutidine, N-methylmorpholine, N-ethylmorpholine, N-benzyldimethylamine, and tributylamine.

[0172] The above-described method for producing a phosphoric acid ester according to the third aspect of the present invention is a method for producing a phosphoric acid monoester or a phosphoric acid diester, which uses a flow-through reactor, and is characterized in that the reaction temperature in the above-described steps (A11) and (B11) is -80°C or higher, and the flow rates of phosphorus trichloride or phosphorus tribromide, the first hydroxy compound, and the second hydroxy compound flowing through the flow paths are 0.01 mL / min or higher. By appropriately controlling the reaction temperature and flow rate, the stirring efficiency can be improved and side reactions can be suppressed. Therefore, according to the method for producing a phosphoric ester according to the third aspect of the present invention, the target phosphoric monoester or phosphoric diester can be produced at a lower cost and in a higher yield.

[0173] In the method for producing a phosphate ester according to the third aspect of the present invention, the preferable relationship between the flow rate and the inner diameter of the mixer of the flow reactor is the same as in the method for producing an asymmetric phosphate triester according to the first embodiment described above. That is, when the inner diameter of the mixer of the flow-through reactor is ID, the flow rate of each compound is the above-mentioned preferable flow rate (ID / 0.25). 2 A value multiplied by is preferred.

[0174] (Method for Producing an Organophosphorus Compound According to the Fourth Aspect of the Present Invention) A fourth aspect of the present invention relates to a method for producing an organic phosphorus compound, which uses a flow-through reaction apparatus to synthesize an organic phosphorus compound, and includes a step (A01) of reacting phosphorus trichloride or phosphorus tribromide with a first hydroxy compound represented by the following general formula (H0-1) to synthesize a compound P01 represented by the following general formula (P0-1), and a step (A02) of reacting the compound P01 with a second hydroxy compound represented by the following general formula (H0-2) to synthesize a compound P02 represented by the following general formula (P0-2). and a step (C01) of reacting the compound P02 with a third hydroxy compound to synthesize a compound P03 represented by the following general formula (P0-3), wherein the reaction temperature in the steps (A01) and (B01) is -80°C or higher, and the flow rates of the phosphorus trichloride or phosphorus tribromide, the first hydroxy compound, and the second hydroxy compound flowing through a flow path in the steps (A01) and (B01) are 0.01 mL / min or higher.

[0175] [ka] [R 01 ~R 03 are each independently a hydrogen atom or an organic group. 01 ~R 03 At least one of R is an organic group. 01 ~R 03 When all of are organic groups, the organic groups are not all the same. X is a bromine atom or a chlorine atom.

[0176] The method for producing an organic phosphorus compound according to the fourth aspect of the present invention is more specifically a method for producing an intermediate in the method for producing an asymmetric phosphate triester according to the first aspect of the present invention, the method for producing a symmetric phosphate triester according to the second aspect, and the method for producing a phosphate ester according to the third aspect of the present invention. That is, the compound P03 is a compound containing all of the above-mentioned compounds P3, P4, and P13. The organophosphorus compounds also include tautomers. For example, tautomers of the above-mentioned compound P13 include tautomers of the above-mentioned compounds P13-1 and P13-2, specifically, the following compounds P13-1-1 and P13-2-1.

[0177] [ka]

[0178] Specifically, the first hydroxy compound, the second hydroxy compound, and the third hydroxy compound in the method for producing an organic phosphorus compound according to the fourth aspect of the present invention are the above-mentioned R 1 O.H., R. 2 OH and R 3 Examples include the same hydroxy compounds as those exemplified for OH, and water.

[0179] The reaction temperature in steps (A01) and (B01) is -80°C or higher, and in steps (A01) and (B01), the flow rates of phosphorus trichloride or phosphorus tribromide, the first hydroxy compound, and the second hydroxy compound flowing through the flow channel are 0.01 mL / min or higher. Moreover, the preferred ranges of the reaction temperature and flow rate are the same as those described in step (A1) and step (B1) in the method for producing an asymmetric phosphate triester of the first embodiment described above.

[0180] The reaction in steps (A01) and (B01) may be carried out in the presence of a solvent. The solvent is not particularly limited, but is preferably one that does not interfere with the reaction of the compounds and has high solubility for the raw materials used in the reaction. Examples of the solvent include dichloromethane (DCM), tetrahydrofuran (THF), diethyl ether (Et2O), 1,4-dioxane, acetonitrile (MeCN), chloroform, and N,N-dimethylformamide (DMF).

[0181] The reaction in steps (A01) and (B01) may be carried out in the presence of a non-nucleophilic base. The non-nucleophilic base is not particularly limited as long as it can capture HCl generated during the reaction. Examples of the non-nucleophilic base include N,N-diisopropylethylamine (DIEA), triethylamine, diazabicycloundecene, 2,6-lutidine, N-methylmorpholine, N-ethylmorpholine, N-benzyldimethylamine, and tributylamine.

[0182] The method for producing an organic phosphorus compound according to the fourth aspect of the present invention described above is a method for producing an organic phosphorus compound (intermediate) used for producing a phosphorus monoester, a phosphorus diester, or a phosphorus triester, characterized in that a flow-through reactor is used, the reaction temperature in the above-mentioned steps (A01) and (B01) is set to -80°C or higher, and the flow rates of phosphorus trichloride or phosphorus tribromide, a first hydroxy compound, and a second hydroxy compound flowing through the flow path are set to 0.01 mL / min or higher. By appropriately controlling the reaction temperature and flow rate, the stirring efficiency can be improved and side reactions can be suppressed. Therefore, according to the organophosphorus compound according to the fourth aspect of the present invention, it is possible to produce an organophosphorus compound (intermediate) used for producing a target phosphoric acid monoester, phosphoric acid diester, or phosphoric acid triester at a lower cost and in a higher yield.

[0183] In the method for producing an organic phosphorus compound according to the fourth aspect of the present invention, the preferable relationship between the flow rate and the inner diameter of the mixer of the flow reactor is the same as in the method for producing an asymmetric phosphate triester according to the first embodiment described above. That is, when the inner diameter of the mixer of the flow-through reactor is ID, the flow rate of each compound is the above-mentioned preferable flow rate (ID / 0.25). 2 A value multiplied by is preferred.

[0184] (Method for Producing an Organophosphorus Compound According to a Fifth Aspect of the Present Invention) A method for producing an organic phosphorus compound according to a fifth aspect of the present invention is a method for producing an organic phosphorus compound using a flow-through reaction apparatus, the method comprising the steps of: (AZ1) reacting phosphorus trichloride or phosphorus tribromide with a first compound which is any one of a hydroxy compound, an amine compound, or a thiol compound to synthesize a compound PZ1 represented by the following general formula (PZ-1); and (AZ2) reacting the compound PZ1 with a second compound which is any one of a hydroxy compound, an amine compound, or a thiol compound to synthesize a compound PZ2 represented by the following general formula (PZ-2). and a step (CZ1) of reacting the compound PX2 with a third compound which is any one of a hydroxy compound, an amine compound, or a thiol compound to synthesize a compound PZ3 represented by the following general formula (PZ-3), wherein the reaction temperature in the steps (AZ1) and (BZ1) is -80°C or higher, and the flow rates of the phosphorus trichloride or phosphorus tribromide, the first compound, and the second compound flowing through a flow path in the steps (AZ1) and (BZ1) are 0.01 mL / min or higher.

[0185] [ka] [In the formula, Z 1 ~Z 3 are each independently a hydrogen atom, a group in which one hydrogen atom has been removed from a hydroxy compound, a group in which one hydrogen atom has been removed from an amine compound, or a group in which one hydrogen atom has been removed from a thiol compound. 1 ~Z 3 cannot all be the same. X is a bromine atom or a chlorine atom.

[0186] The reaction temperature in steps (AZ1) and (BZ1) is -80°C or higher, and in steps (AZ1) and (BZ1), the flow rates of phosphorus trichloride or phosphorus tribromide, the first compound, and the second compound flowing through the flow channel are 0.01 mL / min or higher. Moreover, the preferred ranges of the reaction temperature and flow rate are the same as those described in step (A1) and step (B1) in the method for producing an asymmetric phosphate triester of the first embodiment described above.

[0187] The reaction in steps (AZ1) and (BZ1) may be carried out in the presence of a solvent. The solvent is not particularly limited, but is preferably one that does not interfere with the reaction of the compounds and is preferably one that has high solubility for the raw materials used in the reaction. Examples of the solvent include dichloromethane (DCM), tetrahydrofuran (THF), diethyl ether (Et2O), 1,4-dioxane, acetonitrile (MeCN), chloroform, and N,N-dimethylformamide (DMF).

[0188] The reaction in steps (AZ1) and (BZ1) may be carried out in the presence of a non-nucleophilic base. The non-nucleophilic base is not particularly limited as long as it can capture HCl generated during the reaction. Examples of the non-nucleophilic base include N,N-diisopropylethylamine (DIEA), triethylamine, diazabicycloundecene, 2,6-lutidine, N-methylmorpholine, N-ethylmorpholine, N-benzyldimethylamine, and tributylamine.

[0189] <1st to 3rd compounds> The first to third compounds are different from each other and are hydroxy compounds, amine compounds, or thiol compounds.

[0190] <Hydroxy compounds> The hydroxy compound in the first to third compounds is the above-mentioned R 1 O.H., R. 2 OH and R 3 Examples include the same hydroxy compounds as those exemplified for OH, and water.

[0191] <Amine compounds> Examples of the amine compound among the first to third compounds include aliphatic amines, mixed amines, aromatic amines, heterocyclic amines, nitrogen-containing compounds having a carboxy group, nitrogen-containing compounds having a sulfonyl group, nitrogen-containing compounds having a hydroxyl group, amide derivatives, and imide derivatives.

[0192] The aliphatic amine includes aliphatic primary amines and aliphatic secondary amines. Specific examples of the aliphatic primary amine include methylamine, ethylamine, n-propylamine, isopropylamine, n-butylamine, isobutylamine, sec-butylamine, tert-butylamine, pentylamine, tert-amylamine, cyclopentylamine, hexylamine, cyclohexylamine, heptylamine, octylamine, nonylamine, decylamine, dodecylamine, cetylamine, methylenediamine, ethylenediamine, and tetraethylenepentamine.

[0193] Specific examples of the aliphatic secondary amine include dimethylamine, diethylamine, di-n-propylamine, diisopropylamine, di-n-butylamine, diisobutylamine, di-sec-butylamine, dipentylamine, dicyclopentylamine, dihexylamine, dicyclohexylamine, diheptylamine, dioctylamine, dinonylamine, didecylamine, didodecylamine, dicetylamine, N,N-dimethylmethylenediamine, N,N-dimethylethylenediamine, and N,N-dimethyltetraethylenepentamine.

[0194] Specific examples of the mixed amine include benzylamine, phenethylamine, and benzyldimethylamine.

[0195] Specific examples of aromatic amines and heterocyclic amines include aniline derivatives (e.g., aniline, N-methylaniline, N-ethylaniline, N-propylaniline, 2-methylaniline, 3-methylaniline, 4-methylaniline, ethylaniline, propylaniline, trimethylaniline, 2-nitroaniline, 3-nitroaniline, 4-nitroaniline, 2,4-dinitroaniline, 2,6-dinitroaniline, and 3,5-dinitroaniline), diphenyl(p-tolyl)amine, phenylenediamine, naphthylamine, diaminonaphthalene, pyrrole derivatives (e.g., pyrrole, 1-methylpyrrole, 2,4-dimethylpyrrole, and 2,5-dimethylpyrrole), isopropylamine, ... Examples of the derivatives include midazole derivatives (e.g., imidazole, 4-methylimidazole, 4-methyl-2-phenylimidazole, etc.), pyrazole derivatives, pyrroline derivatives (e.g., 2-pyrroline, 3-pyrroline, etc.), pyrrolidine derivatives (e.g., 2-methyl-pyrrolidine), imidazoline derivatives, imidazolidine derivatives, pyrazoline derivatives, pyrazolidine derivatives, piperidine derivatives, piperazine derivatives, morpholine derivatives, indole derivatives, isoindole derivatives, 1H-indazole derivatives, indoline derivatives, purine derivatives, carbazole derivatives, adenine derivatives, adenosine derivatives, guanine derivatives, guanosine derivatives, uracil derivatives, and uridine derivatives.

[0196] Specific examples of nitrogen-containing compounds having a carboxy group include aminobenzoic acid, indole carboxylic acid, and amino acid derivatives (e.g., nicotinic acid, alanine, arginine, aspartic acid, glutamic acid, glycine, histidine, isoleucine, glycylleucine, leucine, methionine, phenylalanine, threonine, lysine, 3-aminopyrazine-2-carboxylic acid, and methoxyalanine).

[0197] Specific examples of nitrogen-containing compounds having a hydroxyl group include aminocresol, 3-indole methanol hydrate, monoethanolamine, diethanolamine, 2,2'-iminodiethanol, 2-aminoethanol, 3-amino-1-propanol, 4-amino-1-butanol, 1-(2-hydroxyethyl)piperazine, 1-[2-(2-hydroxyethoxy)ethyl]piperazine, and piperidineethanol.

[0198] Specific examples of the amide derivative include formamide, N-methylformamide, acetamide, N-methylacetamide, propionamide, and benzamide. Specific examples of the imide derivative include phthalimide, succinimide, and maleimide.

[0199] <Thiol compounds> Examples of the thiol compound among the first to third compounds include an aliphatic thiol compound, an aromatic thiol compound, an aliphatic polythiol compound, a mercaptocarboxylic acid ester compound, a mercaptocarboxylic acid, and a mercaptoether.

[0200] Specific examples of the aliphatic thiol compound include methyl thiol, ethyl thiol, 1-propyl thiol (n-propyl mercaptan), isopropyl thiol, 1-butyl thiol (n-butyl mercaptan), isobutyl thiol, tert-butyl thiol, 1-pentyl thiol, isopentyl thiol, 2-pentyl thiol, 3-pentyl thiol, 1-hexyl thiol, cyclohexyl thiol, 4-methyl-2-pentyl thiol, 1-heptyl thiol (n-heptyl mercaptan), 2-heptyl thiol, 1-octyl thiol (n-octyl mercaptan), isooctyl thiol, 2-ethylhexyl thiol, 2,4,4-trimethyl-2-pentyl thiol (tert-octyl mercaptan), 1-nonyl thiol (n-nonyl mercaptan), tert-nonyl thiol (tert-nonyl mercaptan), mercaptan), isononyl thiol, 1-decyl thiol, 1-undecyl thiol, 1-dodecyl thiol, tert-dodecyl thiol (tert-dodecyl mercaptan), tridecyl thiol, tetradecyl thiol, 1-pentyldecyl thiol, 1-hexyldecyl thiol, 1-heptyldecyl thiol, 1-octyldecyl thiol, nonadecyl thiol, eicosane thiol, triacontane thiol, tetracontane thiol, pentacontane thiol, hexacontane thiol, heptacontane thiol, octacontane thiol, nonacontane thiol, hexane thiol, 1-myristyl thiol, cetyl thiol, 1-stearyl thiol, isostearyl thiol, 2-octyldecyl thiol, 2-octyldodecyl thiol, 2-hexyldecyl thiol, behenyl thiol, and the like.

[0201] Specific examples of aromatic thiol compounds include benzenethiol, phenylmethanethiol, xylylenethiol, 1,2-dimercaptobenzene, 1,3-dimercaptobenzene, 1,4-dimercaptobenzene, 1,2-bis(mercaptomethyl)benzene, 1,3-bis(mercaptomethyl)benzene, 1,4-bis(mercaptomethyl)benzene, 1,2-bis(2-mercaptoethyl)benzene, 1,3-bis(2-mercaptoethyl)benzene, 1,4-bis(2-mercaptoethyl)benzene, and 1,2-bis(2-mercaptoethyleneoxy). Benzene, 1,3-bis(2-mercaptoethyleneoxy)benzene, 1,4-bis(2-mercaptoethyleneoxy)benzene, 1,2,3-trimercaptobenzene, 1,2,4-trimercaptobenzene, 1,3,5-trimercaptobenzene, 1,2,3-tris(mercaptomethyl)benzene, 1,2,4-tris(mercaptomethyl)benzene, 1,3,5-tris(mercaptomethyl)benzene, 1,2,3-tris(2-mercaptoethyl)benzene, 1,2,4-tris(2-mercaptoethyl)benzene, 1,3,5-tris(2- mercaptoethyl)benzene, 1,2,3-tris(2-mercaptoethyleneoxy)benzene, 1,2,4-tris(2-mercaptoethyleneoxy)benzene, 1,3,5-tris(2-mercaptoethyleneoxy)benzene, 1,2,3,4-tetramercaptobenzene, 1,2,3,5-tetramercaptobenzene, 1,2,4,5-tetramercaptobenzene, 1,2,3,4-tetrakis(mercaptomethyl)benzene, 1,2,3,5-tetrakis(mercaptomethyl)benzene, 1,2,4,5-tetrakis(mercaptomethyl)benzene 1,2,3,4-tetrakis(2-mercaptoethyl)benzene, 1,2,3,5-tetrakis(2-mercaptoethyl)benzene, 1,2,4,5-tetrakis(2-mercaptoethyl)benzene, 1,2,3,4-tetrakis(2-mercaptoethyleneoxy)benzene, 1,2,3,5-tetrakis(2-mercaptoethyleneoxy)benzene, 1,2,4,5-tetrakis(2-mercaptoethyleneoxy)benzene, 2,2'-dimercaptobiphenyl, 4,4'-thiobis-benzenethiol, 4,4'-dimercaptobiphenyl, 4,4'-Dimercaptobibenzyl, 2,5-toluenedithiol, 3,4-toluenedithiol, 1,4-naphthalenedithiol, 1,5-naphthalenedithiol, 2,6-naphthalenedithiol, 2,7-naphthalenedithiol, 2,4-dimethylbenzene-1,3-dithiol, 4,5-dimethylbenzene-1,3-dithiol, 9,10-anthracenedimethanethiol, 1,3-bis(2-mercaptoethylthio)benzene, 1,4-bis(2-mercaptoethylthio)benzene, 1,2-bis(2-mercaptoethylthiomethyl)benzene, 1,3-bis(2-mercaptoethylthiomethyl)benzene, 1,4-bis(2-mercaptoethylthiomethyl)benzene, triethylthiomethyl)benzene, 1,2,3-tris(2-mercaptoethylthio)benzene, 1,2,4-tris(2-mercaptoethylthio)benzene, 1,3,5-tris(2-mercaptoethylthio)benzene, 1,2,3,4-tetrakis(2-mercaptoethylthio)benzene, 1,2,3,5-tetrakis(2-mercaptoethylthio)benzene, 1,2,4,5-tetrakis(2-mercaptoethylthio)benzene, benzylthiol, m-toluenethiol, p-toluenethiol, 2-naphthalenethiol, 2-pyridylthiol, 2-mercaptobenzimidazole, 2-mercaptobenzothiazole, and the like.

[0202] Examples of the aliphatic polythiol compounds include methanedithiol, 1,2-ethanedithiol, 1,2-propanedithiol, 1,3-propanedithiol, 1,4-butanedithiol, 1,6-hexanedithiol, 1,7-heptanedithiol, 1,8-octanedithiol, 1,9-nonanedithiol, 1,10-decanedithiol, 1,12-dodecanedithiol, 2,2-dimethyl-1,3-propanedithiol, 3-methyl-1,4-dimethyl-2,5-dimethyl-1,5-dimethyl-1,6-dimethyl-1,7-dimethyl-1,8-dimethyl-1,9-dimethyl-2 ... 1,5-pentanedithiol, 2-methyl-1,8-octanedithiol, 1,4-cyclohexanedithiol, 1,4-bis(mercaptomethyl)cyclohexane, 1,1-cyclohexanedithiol, 1,2-cyclohexanedithiol, bicyclo[2,2,1]hepta-exo-cis-2,3-dithiol, 1,1-bis(mercaptomethyl)cyclohexane, bis(2-mercaptoethyl)ether, ethylene glycol Examples of the thiol compounds include dithiol compounds such as glycol bis(2-mercaptoacetate) and ethylene glycol bis(3-mercaptopropionate); trithiol compounds such as 1,1,1-tris(mercaptomethyl)ethane, 2-ethyl-2-mercaptomethyl-1,3-propanedithiol, 1,2,3-propanetrithiol, trimethylolpropane tris(2-mercaptoacetate), trimethylolpropane tris(3-mercaptopropionate), and tris((mercaptopropionyloxy)-ethyl)isocyanurate; and thiol compounds having four or more SH groups such as pentaerythritol tetrakis(2-mercaptoacetate), pentaerythritol tetrakis(3-mercaptopropionate), pentaerythritol tetrakis(3-mercaptobutanate), and dipentaerythritol hexa-3-mercaptopropionate.

[0203] Mercaptocarboxylic acid ester compounds include methyl mercaptoacetate, methyl 3-mercaptopropionate, 4-methoxybutyl 3-mercaptopropionate, 2-ethylhexyl 3-mercaptopropionate, n-octyl 3-mercaptopropionate, stearyl 3-mercaptopropionate, 1,4-bis(3-mercaptopropionyloxy)butane, 1,4-bis(3-mercaptobutyryloxy)butane, trimethylolethane tris(3-mercaptopropionate), trimethylolethane tris(3-mercaptobutyrate), trimethylolpropionate, ... Examples of the isocyanurate include pantos(3-mercaptopropionate), trimethylolpropane tris(3-mercaptobutyrate), pentaerythritol tetrakis(3-mercaptopropionate), pentaerythritol tetrakis(3-mercaptobutyrate), dipentaerythritol hexakis(3-mercaptopropionate), dipentaerythritol hexakis(3-mercaptobutyrate), tris[2-(3-mercaptopropionyloxy)ethyl]isocyanurate, and tris[2-(3-mercaptobutyryloxy)ethyl]isocyanurate.

[0204] Other thiol compounds include mercaptocarboxylic acids such as mercaptoacetic acid, 3-mercaptopropionic acid, 2-mercaptopropionic acid, 3-mercaptobutyric acid, mercaptohexanoic acid, mercaptooctanoic acid, mercaptostearic acid, and thioglycolic acid; mercaptoethers such as di(mercaptoethyl)ether; mercaptoalcohol compounds such as 2-mercaptoethanol and 4-mercapto-1-butanol; and silane-containing thiol compounds such as (γ-mercaptopropyl)trimethoxysilane and (γ-mercaptopropyl)triethoxysilane.

[0205] In the above formulas (PZ-1) to (PZ-3), Z 1 ~Z 3 are each independently a hydrogen atom, a group obtained by removing one hydrogen atom from the above-mentioned hydroxy compound, a group obtained by removing one hydrogen atom from the above-mentioned amine compound, or a group obtained by removing one hydrogen atom from the above-mentioned thiol compound. 1~Z 3 will never all be the same.

[0206] The method for producing an organic phosphorus compound according to the fifth aspect of the present invention described above is a method for producing an organic phosphorus compound, which uses a flow-through reactor, and is characterized in that the reaction temperature in the above-mentioned steps (AZ1) and (BZ1) is -80°C or higher, and the flow rates of phosphorus trichloride or phosphorus tribromide, the first compound, and the second compound flowing through the flow paths are 0.01 mL / min or higher. By appropriately controlling the reaction temperature and flow rates, the stirring efficiency can be improved and side reactions can be suppressed. Therefore, according to the organophosphorus compound according to the fifth aspect of the present invention, the target organophosphorus compound can be produced at a lower cost and in a higher yield.

[0207] In the method for producing an organic phosphorus compound according to the fifth aspect of the present invention, the preferable relationship between the flow rate and the inner diameter of the mixer of the flow reactor is the same as in the method for producing an asymmetric phosphate triester according to the first embodiment described above. That is, when the inner diameter of the mixer of the flow-through reactor is ID, the flow rate of each compound is the above-mentioned preferable flow rate (ID / 0.25). 2 A value multiplied by is preferred. EXAMPLES

[0208] The present invention will now be described in more detail with reference to examples, but the present invention is not limited to the following examples.

[0209] [Synthesis of symmetrical phosphate triesters 1] (Examples 1 to 8, Comparative Example 1) A schematic diagram of the process for producing the symmetric phosphate triester of Examples 1 to 8 is shown in FIG. [Raw materials] R 1 2-hydroxyindan was used as OH. 2 Ethanol was used as OH.

[0210] <Examples 1 to 8> As a flow-through reaction apparatus, a flow-through reaction apparatus consisting of a PTFE tube (inner diameter 0.80 mm, outer diameter 1.59 mm) and a T-shaped or V-shaped mixer (both inner diameter 0.25 mm) shown in Table 1 was used.

[0211] The pre-reaction solution was prepared in three portions. A first solution was prepared by mixing 2-hydroxyindan, DIEA and dichloromethane (DCM). A second solution was prepared by mixing phosphorus trichloride and dichloromethane (DCM). A third solution was prepared by mixing ethanol and dichloromethane (DCM). The equivalent ratio of each was 1.0 of 2-hydroxyindan, 3.0 of DIEA, 1.0 of phosphorus trichloride, and 10 of ethanol.

[0212] In order to synthesize a symmetrical phosphate triester, the first solution and the second solution were first mixed in a T-shaped or V-shaped mixer shown in Table 1, and reacted for 10 seconds at the reaction temperature shown in Table 1 to obtain compound 3a. Then, the reaction solution containing compound 3a was immediately mixed with the third solution using a new T-shaped mixer, and reacted for 5 seconds at the reaction temperature shown in Table 1 to obtain compound 4a. Compound 4a was then stored while being stirred at room temperature (25°C) for 10 minutes. Compound 4a was then reacted with metachloroperbenzoic acid (mCPBA) at room temperature (25°C) for 1 hour to oxidize compound 4a, thereby obtaining main product 5a. In addition, by-product 5b was also obtained by a side reaction. The various solutions were discharged using a syringe pump. The flow rates of the first and third solutions were as shown in Table 1, and the flow rate of the second solution was set to the flow rate shown in Table 1 x 0.6.

[0213] Comparative Example 1 Using the same procedure as above, the first solution, the second solution, the third solution, and mCPBA were each added dropwise to a test tube stirred with a magnetic stirrer, to obtain the main product 5a and the by-product 5b in a batchwise manner.

[0214] Each reaction for synthesizing a symmetric phosphate triester by the production methods of Examples 1 to 8 and Comparative Example 1 is shown below.

[0215] [ka]

[0216] [Analysis method] The main product 5a and the by-product 5b were identified by NMR measurement, and the yield was measured by HPLC-UV. The NMR spectrum data is shown below, and the yields of the main product 5a and the by-product 5b are shown in Table 1.

[0217] Main product 5a: Colorless oil;IR(neat):2980,1653,1541,1457,1260,1165,1026,799,744 1 H NMR (400MHz, CDCl3): δ=7.24-7.17(m,4H),5.25-5.22(m,1H),4.13-4.06(m,4H),3. 29(dd,J=6.1,16.6Hz,2H),3.17(dd,J=3.6,16.6Hz,2H),1.33(td,J=0.6,7.0Hz,6H)

[0218] By-product 5b: Colorless oil;IR(neat):2957,1653,1541,1458,1260,1008,740,669 1 H NMR (400MHz, CDCl3): δ=7.23-7.16(m,8H),5.24-5.20(m,2H),4.11-4.04(m,2H), 3.26(dd,J=6.1,16.7Hz,4H),3.15(dd,J=3.6,16.7Hz,4H),1.31(t,J=7.1Hz,3H)

[0219] [Table 1]

[0220] As shown in Table 1, when the symmetric phosphate triester was produced by the production method of the Example, the yield of the main product 5a was higher than that by the production method of the Comparative Example.

[0221] [Synthesis of symmetrical phosphate triesters 2] (Examples 9 to 14) A schematic diagram of the production process of the symmetric phosphate triester of Examples 9 to 14 is shown in FIG. [Raw materials] R 1 As OH, 1-butanol (Example 9), 2-butanol (Example 10), tert-butanol (Example 11), allyl alcohol (Example 12), 2-[[tert-butyl(dimethyl)silyl]oxy]ethanol (Example 13), and tert-butyl hydroxyacetate (Example 14) were used. R 2 As OH, 2-hydroxyindan was used (Examples 9 to 14).

[0222] The flow-through reactor used was a flow-through reactor consisting of a PTFE tube (inner diameter 0.80 mm, outer diameter 1.59 mm), a T-shaped mixer, and a V-shaped mixer (both with an inner diameter of 0.25 mm).

[0223] The pre-reaction solution was prepared in three portions. The first solution was prepared by the method described above. 1 It was prepared by mixing one of the above OH with DIEA and DCM. A second solution was prepared by mixing phosphorus trichloride and DCM. A third solution was prepared by mixing 2-hydroxyindan and DCM. The ratio of each equivalent is R 1 Relative to OH 1.0, DIEA was 3.0, phosphorus trichloride was 1.0, and 2-hydroxyindan was 2.5.

[0224] To synthesize a symmetric phosphate triester, the first solution and the second solution were first mixed in a V-shaped mixer and reacted at 20°C for 10 seconds to obtain compound 3. Then, the reaction solution containing compound 3 was immediately mixed with the third solution using a new T-shaped mixer and reacted at 20°C for 5 seconds to obtain compound 4. Compound 4 was then stored while being stirred at room temperature (25°C) for 10 minutes. Compound 4 was then reacted with mCPBA at room temperature (25°C) for 10 minutes to oxidize compound 4, thereby obtaining main products 5c to 5h, respectively. The various solutions were pumped using a syringe pump. The flow rates of the first and third solutions were 2.0 mL / min, respectively, and the flow rate of the second solution was 1.2 mL / min.

[0225] The main products 5c to 5h were identified by NMR measurement, and the yields were measured by HPLC-UV. The NMR spectrum data, and the structures and yields of the main products 5c to 5h are shown below. The relationship between the production methods of symmetric phosphate triesters in Examples 9 to 14 and the main products obtained is as follows. Example 9: Major Product 5c, Example 10: Major Product 5d, Example 11: Major Product 5e, Example 12: Major Product 5f, Example 13: Major Product 5g, Example 14: Major Product 5h.

[0226] [ka]

[0227] 5c:n-Butylbis(indan-2-yl)phosphate Purification method:columnchromatography(Hexane:Ethylacetate=3:2) Colorless oil;IR(neat):2956,1460,1273,1004,740 1H NMR(400MHz,CDCl3):δ=7.27-7.17(m,8H),5.24-5.20(m,2H),4,03-3.98(m,2H),3.29-3.23(m,4H),3.15(dd,J=3.2,16.9Hz,4H),1.66-1.62(m,2H),1.42-1.36(m,2H),0.91(t,J=7.3Hz,3H)

[0228] 5d:s-Butylbis(indan-2-yl)phosphate Purification method:column chromatography(Hexane:Ethylacetate=3:2) Colorless oil;IR(neat):2968,1460,1261,994,740 1 H NMR(400MHz,CDCl3):δ=7.18-7.09(m,8H),5.15-5.13(m,2H),4.39-4.33(m,1H),3.21-3.15(m,4H),3.10-3.06(m,4H),1.63-1.49(m,2H),1.22(d,J=6.4Hz,3H),0.85(t,J=7.2Hz,3H)

[0229] 5e:t-Butyl bis(indan-2-yl) phosphate Purification method:column chromatography(Hexane:Ethylacetate=3:2) Colorless oil;IR(neat):2977,1460,1276,994,739 1 H NMR(400MHz,CDCl3):δ=7.26-7.16(m,8H),5.20-5.17(m,2H),3.28-3.13(m,8H),1.48(s,9H)

[0230] 5f:Bis(indan-2-yl) 2-propen-1-yl phosphate Purification method:column chromatography(Hexane:Ethylacetate=3:2)and Gel Permeation Chromatography Colorless oil;IR(neat):2954,1459,1277,988,930,739 1 H NMR(400MHz,CDCl3):δ=7.23-7.15(m,8H),5.97-5.87(m,1H),5.37-5.32(m,1H),5.27-5.20(m,3H),4.52-4.48(m,2H),3.28-3.21(m,4H),3.15(dd,J=4.1,16.5Hz)

[0231] 5g:3-[[tert-Butyl(dimethyl)silyl]oxy]propan-1-yl bis(indan-2-yl) phosphate Purification method:column chromatography(Hexane:Diethylether=1:4) Colorless oil;IR(neat):2954,1467,1259,1011,837,741 1 H NMR(400MHz,CDCl3):δ=7.23-7.16(m,8H),5.25-5.19(m,2H),4.11(q,J=6,5Hz),3.69(t,J=6.0Hz),3.26(dd,J=6.1,16.7Hz),3.15(dd,J=3.6,16.7Hz),1.85(q,J=6.1Hz),0.88(s,9H),0.03(s,6H)

[0232] 5h:tert-Butyl glycolatyl bis(indan-2-yl) phosphate Purification method:column chromatography(Hexane:Diethylether=1:4) Colorless oil;IR(neat):2927,1755,1460,1367,1278,1163,1106,1005,741 1 H NMR (400MHz, CDCl3): δ=7.23-7.16(m,8H),5.33-5.27(m,2H),4.43(d,J=10.3Hz,2H),3.27(dd,J=6.0,16.8Hz,2H),3.20-3.15(m,4H),1.48(s,9H)

[0233] As described above, when the symmetric phosphate triesters were produced by the production methods of the Examples, the main products 5c to 5h could be obtained in high yields.

[0234] [Synthesis of asymmetric phosphate triesters 1] (Examples 15 to 25, Comparative Example 2) A schematic diagram of the method for producing an asymmetric phosphate triester in Examples 15 to 25 is shown in Figure 5. In Figure 5, an example is shown in which N,N-diisopropylethylamine (DIEA) is used as a base. In addition, the "base" in the compound represents a group in which one hydrogen atom has been removed from a nucleophilic base. [Raw materials] R in Examples 15 to 25 1 OH is 2-hydroxyindan, R 2 OH is 2-phenylethanol (phenethyl alcohol), R 3 Ethanol was used as OH. As the base (non-nucleophilic base), N,N-diisopropylethylamine (i-Pr2NEt), 2,6-lutidine, N-methylmorpholine (NMM), N-ethylmorpholine, N-benzyldimethylamine (Me2NBn), or tributylamine (n-Bu3N) was used. As the nucleophilic base, pyridine, imidazole, N-methylimidazole (NMI), 4-methylimidazole, or 4-dimethylaminopyridine (DMAP) was used.

[0235] <Examples 15 to 25> The flow-through reactor used was a flow-through reactor consisting of a PTFE tube (inner diameter 0.80 mm, outer diameter 1.59 mm), a T-shaped mixer, and a V-shaped mixer (both with an inner diameter of 0.25 mm).

[0236] The pre-reaction solution was prepared in four portions. A first solution was prepared by mixing 2-hydroxyindan, a base shown in Table 2, and dichloromethane. A second solution was prepared by mixing phosphorus trichloride and DCM. A third solution was prepared by mixing a nucleophilic base shown in Table 2 with DCM. A fourth solution was prepared by mixing 2-phenylethanol and DCM. The ratio of the respective equivalents was 1.0 of 2-hydroxyindan, 3.0 of base, 1.0 of phosphorus trichloride (0.5 in Examples 23 to 28), 2.0 of nucleophilic base, 1.0 of 2-phenylethanol, and 10 of ethanol. The concentration Y [M] in Table 2 is the molar concentration of phosphorus trichloride.

[0237] In order to synthesize an asymmetric phosphate triester, the first solution and the second solution were first mixed in a V-shaped mixer and reacted at 20° C. for 10 seconds to obtain compound 3a. Then, the reaction solution containing compound 3a was immediately mixed with the third solution using a new T-shaped mixer and reacted at 20° C. for 10 seconds to obtain compound 6a. Then, the reaction solution containing compound 6a was immediately mixed with the fourth solution using a new T-shaped mixer and reacted at 20° C. for 5 seconds to obtain compound 7a. Then, the reaction solution containing compound 7a was poured into a beaker in which ethanol was stored and reacted at room temperature (25° C.) for 10 minutes to obtain compound 7ab. Then, compound 7ab was reacted with mCPBA for 10 minutes at room temperature (25° C.) to oxidize compound 7ab to obtain main product 8a. In addition, by-products 8b and 8c were obtained by side reactions. The various solutions were pumped using a syringe pump, with the first and fourth solutions flowing at a rate of 2.0 mL / min, and the second and third solutions flowing at a rate of 1.2 mL / min.

[0238] Comparative Example 2 Using the same procedure as above, the first solution, the second solution, the third solution, the fourth solution, ethanol and mCPBA were each added dropwise to a test tube stirred with a magnetic stirrer, thereby obtaining the main product 8a and by-products 8b and 8c in a batchwise manner.

[0239] Each reaction for synthesizing a symmetric phosphate triester by the production methods of Examples 15 to 25 and Comparative Example 2 is shown below.

[0240] [ka]

[0241] [Analysis method] The main product 8a and the by-products 8b and 8c were identified by NMR measurement, and the yield was measured by HPLC-UV. The NMR spectrum data is shown below, and the yields of the main product 8a, the by-products 8b and 8c are shown in Tables 2 and 3.

[0242] Main Spawn 8a: Purification method:preparative TLC(Toluene:EtOAc=4:1) 1 H NMR (400MHz, CDCl3): δ=7.31-7.16(m,9H),5.16-5.11(m,1H),4.22(q,J=7.0Hz,2H) ,4.01(t,7.3Hz,2H),3.25-3.06(m,4H),2.98(t,J=7.0Hz,2H),1.27(t,J=7.1Hz,3H) 31 P NMR (162MHz,CDCl3):δ=-1.17

[0243] Byproduct 8b: Purification method:preparative TLC(Toluene:EtOAc=4:1) 1 H NMR (400MHz, CDCl3): δ=7.31-7.15(m,13H),5.15-5.11(m,2H),4.20(q,J=6.9Hz,2H),3.22-3.04(m,8H),2.98-2.91(m,2H) 31 P NMR (162MHz,CDCl3):δ=-1.88

[0244] Byproduct 8c: Purification method:preparative TLC(Toluene:EtOAc=4:1) 1 H NMR (400MHz, CDCl3): δ=7.30-7.15(m,14H),5.08-5.03(m,1H),4.17-4.10(m,4H),3.18-3.01(m,4H),2.92(t,J=7.1Hz,4H) 31 P NMR (162MHz,CDCl3):δ=-1.37

[0245]

Table 2

[0246] [Table 3]

[0247] As shown in Tables 2 and 3, when the asymmetric phosphate triester was produced by the production method of the Example, the yield of the main product 8a was higher than that by the production method of the Comparative Example.

[0248] [Synthesis of asymmetric phosphate triester 2] (Examples 26 to 33) A schematic diagram of the production process of the asymmetric phosphate triester of Examples 26 to 33 is shown in FIG. [Raw materials] R of Example 26 1 OH is 2-hydroxyindan, R 2 OH is ethanol, R 3 As the OH group, phenol was used. R of Example 27 1 OH is 1-butanol, R 2 OH is 2-hydroxyindan, R 3 As the OH group, phenol was used. R of Example 28 1 OH is 2-butanol, R 2 OH is 2-hydroxyindan, R 3 As the OH group, phenol was used. R of Example 29 1 OH is 2-hydroxyindan, R 2 OH is allyl alcohol, R 3 As OH, 2-methoxy-ethan-1-ol was used. R of Example 30 1 OH is 2-hydroxyindan, R 2 OH is propargyl alcohol, R 3 As OH, 2-methoxy-ethan-1-ol was used. R of Example 31 1OH is 2-hydroxyindan, R 2 OH is tert-butyl (2-hydroxyethyl) carbamate, R 3 Ethanol was used as OH. R of Example 32 1 OH is 2-hydroxyindan, R 2 OH is methyl [[(9H-fluorenyl)methoxy]carbonyl]serinate, R 3 Ethanol was used as OH. R of Example 33 1 OH is 3-benzoyl-1-[4-hydroxy-5-(tert-butyldimethylsilyloxymethyl)tetrahydrofuran-2-yl]-5-methylpyrimidine-2,4(1H,3H)-dione, R 2 OH is 5-(3-benzoyl-5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-(hydroxymethyl)tetrahydrofuran-3-yl benzoate, 3 As OH, 2-cyanoethanol was used.

[0249] The flow-through reactor used was composed of a PTFE tube (inner diameter 0.80 mm, outer diameter 1.59 mm) and V-shaped and T-shaped mixers (both with an inner diameter of 0.25 mm).

[0250] The pre-reaction solution was prepared in four portions. The first solution was prepared by the method described above. 1 It was prepared by mixing one of the above OH with DIEA and DCM. A second solution was prepared by mixing phosphorus trichloride and DCM. A third solution was prepared by mixing imidazole and DCM. The fourth solution was prepared by the method described above. 2 It was prepared by mixing one of the above OH with DCM. The ratio of each equivalent is R 1 For OH 1.0, DIEA 3.0, phosphorus trichloride 1.0, R 2 OH is 1.0, imidazole is 2.0, R3 OH was set to 4.0, and mCPBA, described below, was set to 1.4.

[0251] To synthesize an asymmetric phosphate triester, first, the first solution and the second solution were mixed in a V-shaped mixer and reacted at 20° C. for 10 seconds to obtain compound 1x. Then, the reaction solution containing compound 1x was immediately mixed with the third solution using a new T-shaped mixer and reacted at 20° C. for 10 seconds to obtain compound 2x. Then, the reaction solution containing compound 2x was immediately mixed with the fourth solution using a new T-shaped mixer and reacted at 20° C. for 30 seconds to obtain compound 3x. Then, the reaction solution containing compound 3x was immediately mixed with the fourth solution using a new T-shaped mixer and reacted at 20° C. for 30 seconds to obtain compound 3x. 3 Compound 4x was obtained by flowing the mixture into a beaker containing OH and reacting it at room temperature (25° C.) for 10 minutes. Compound 4x was then reacted with mCPBA at room temperature (25° C.) for 10 minutes to oxidize compound 4x, thereby obtaining main products 1y to 8y, respectively. The various solutions were pumped using a syringe pump, with the second and fourth solutions flowing at a rate of 2.0 mL / min, and the first and third solutions flowing at a rate of 1.2 mL / min.

[0252] Each reaction for synthesizing an asymmetric phosphate triester according to the production methods of Examples 26 to 33 is shown below.

[0253] [ka]

[0254] The main products 1y to 8y were identified by NMR measurement, and the yields were measured by HPLC-UV. The NMR spectrum data, and the structures and yields of the main products 1y to 8y are shown below. The relationship between the production methods of asymmetric phosphate triesters in Examples 26 to 33 and the main products obtained is as follows. Example 26: main product 1y, Example 27: main product 2y, Example 28: main product 3y, Example 29: main product 4y, Example 30: main product 5y, Example 31: main product 6y, Example 32: main product 7y, Example 33: main product 8y.

[0255]

change

[0256] 1y:Ethyl indan-2-yl phenyl phosphate Purification method:column chromatography(Hexane:EtOAc=2:1) Colorless oil;IR(neat):2981,1592,1490,1279,1210,1164,1009,942,742,689 1 H NMR (400MHz, CDCl3): δ=7.34-7.15(m,9H),5.38-5.32(m,1H),4.24-4.15(m,2H),3.34-3.09(m,4H),1.33(dt,J=1.1,7.1Hz,3H) 13 C NMR (125MHz, CDCl3): δ=150.84,150.78,139.83,139.80,129.8,127.0,125.1,12 4.77,124.75,120.21,120.17,80.15,80.11,64.81,64.76,40.91,40.87,40.79, 40.75,16.2(d,J=6.8Hz) 31 P NMR (162MHz,CDCl3):δ=-6.97

[0257] 2y:n-Butyl indan-2-yl phenyl phosphate Purification method:column chromatography (Hexane:EtOAc=2:1) Colorless oil;IR(neat):2960,1592,1490,1281,1211,1009,943,742,689 1 H NMR(400MHz,CDCl3):δ=7.34-7.15(m,9H),5.36-5.33(m,1H),4.15-4.09(m,2H),3.34-3.09(m,4H),1.67-1.61(m,2H),1.40-1.35(m,2H),0.90(t,J=7.9Hz,3H) 13 C NMR(100MHz,CDCl3):δ=150.9(d,J=7.1Hz),139.8(d,J=2.9Hz),129.8,127.0,125.1,124.8(d,J=1.8Hz),120.2(d,J=5.0Hz),80.1(d,J=6.0Hz),68.4(d,J=6.5Hz),40.9(dd,J=7.4,18.1Hz),32.3(d,J=6.9Hz),18.7,13.6 31 P NMR(162MHz,CDCl3):δ=-6.82

[0258] 3y:s-Butyl indan-2-yl phenyl phosphate Purification method:column chromatography(Hexane:EtOAc=2:1) Colorless oil;IR(neat):2973,1592,1490,1278,1211,997,940,741,689 1 H NMR(400MHz,CDCl3):δ=7.33-7.13(m,9H),5.35-5.32(m,1H),4.59-4.50(m,1H),3.29-3.09(m,4H),1.70-1.58(m,2H),1.34(d,J=6.2Hz,3H),1.27(d,J=6.2Hz,3H),0.93(t,J=7.5Hz,3H),0.88(t,J=7.5Hz,3H) 13C NMR(125MHz,CDCl3):δ=151.0(dd,J=3.3,10.5Hz),139.9(m),129.7,127.0,125.0,124.7(d,J=2.9Hz),120.2(t,J=4.8Hz),79.9(dd,J=2.5,6.2Hz),78.6(d,J=6.6Hz),40.9(d,J=5.4Hz),40.7(dd,J=2.4,8.1Hz),30.4(dd,J=6.2,10.6Hz),21.1(dd,J=3.5,16.5Hz),9.5(d,J=15.9Hz),0.1 31 P NMR(162MHz,CDCl3):δ=-7.52,-7.63

[0259] 4y:Indan-2-yl 2-methoxyethan-1-yl 2-propen-1-yl phosphate Purification method:preparative TLC(Hexane:EtOAc=2:3) 1 H NMR(400MHz,CDCl3):δ=7.24-7.17(m,4H),5.98-5.89(m,1H),5.36(ddd,J=1.4,3.0,17.2Hz,1H),5.30-5.23(m,2H),4.53(t,J=6.4Hz,2H),4.20-4.12(m,2H),3.62-3.58(t,J=4.8Hz,2H),3.38(s,3H),3.31-3.14(m,4H)

[0260] 5y:Indan-2-yl 2-methoxyethan-1-yl 2-propyn-1-yl phosphate Purification method:column chromatography(Hexane:EtOAc=2:3) Colorless oil;IR(neat):3217,2924,1457,1275,1033,843,747 1H NMR(400MHz,CDCl3):δ=7.24-7.17(m,4H),5.33-5.26(m,1H),4.67(dd,J=2.3,10.1Hz,2H),4.21-4.17(m,2H),3.60(t,J=4.6Hz,2H),3.38(s,3H),3.30(dd,J=6.0,16.9Hz,2H),3.21(dd,J=3.4,16.7Hz,2H),2.55(t,J=2.3Hz,1H)

[0261] 6y:2-(N-(tert-Butoxycarbonyl)-amino)-ethan-1-yl ethyl indan-1-yl phosphate Purification method: column chromatography(Hexane:EtOAc=2:3) Colorless oil;IR(neat):3310,2976,1714,1508,1457,1268,1171,1027,741 1 H NMR(400MHz,CDCl3):δ=7.25-7.18(m,4H),5.27-5.23(m,1H),5.02(s,1H),4.15-4.04(m,4H),3.39,(d,J=5.0Hz,2H),3.29(dd,J=16.5,6.0Hz,2H),3.17(dd,J=16.7,3.4Hz,2H),1.44(s,9H),1.34(t,J=6.4Hz,3H)

[0262] 7y:Ethyl 2-(N-(9-fluorenylmethyloxycarbonyl)-amino)-3-methoxycarbonylethan-1-yl indan-1-yl phosphate Purification method:column chromatography (Hexane:EtOAc=2:3) Colorless oil;IR(neat):3279,2953,1723,1541,1449,1261,1213,1026,741 1H NMR(400MHz,CDCl3):δ=7.77-7.73(m,2H),7.62-7.57(m,2H),7.41-7.16(m,8H),5.96-5.93(m,1H),5.27-5.21(m,1H),4.60-4.58(m,1H),4.49-4.40(m,2H),4.36-4.28(m,2H),4.26-4.18(m,1H),4.13-4.02(m,2H),3.82-3.69(m,3H),3.31-3.23(m,2H),3.21-3.13(m,2H),1.36-1.26(m,3H)

[0263] 8y:N3-Bz-5’-O-TBS-thymidine-3’-yl 2-cyanoethan-1-yl N3-Bz-3’-O-Bz-thymidine-5’-yl phosphate Purification method: column chromatography(Hexane:EtOAc=1:4) Colorless oil;IR(neat):2954,1749,1703,1662,1448,1270,1101,1011,835,762 1 H NMR (400 MHz, CDCl3):δ=7.99(d,J=8.0Hz,2H),7.95-7.92(m,4H),7.66-7.57(m,3H),7.52-7.42(m,8H),6.42(dd,J=5.6,8.0Hz,1H),6.38(dd,J=4.0,9.2Hz,1H),5.53(brd,J=6.9Hz,1H),5.11(brt,J=5.5Hz,1H),4.52-4.40(m,2H),4.37(brs,1H),4.32(brs,1H),4.31(t,J=6.0Hz,3H),3.95(brs,2H),2.79(t,J=6.0Hz,2H),2.69-2.60(m,2H),2.46-2.38(m,1H),2.30-2.22(m,1H),2.00(s,3H),1.97(s,3H),0.95(s,9H),0.16(s,3H),0.15(s,3H)

[0264] As described above, when asymmetric phosphate triesters were produced by the production methods of the Examples, the main products 1y to 8y could be obtained in high yields.

[0265] [Synthesis of organophosphorus compounds 1] (Example 34) [Raw materials] R 1 2-hydroxyindan was used as OH. 2 2-butanol was used as OH. 3 Saturated saline was used as the OH.

[0266] The flow-through reactor used was a flow-through reactor consisting of a PTFE tube (inner diameter 0.80 mm, outer diameter 1.59 mm), a T-shaped mixer, and a V-shaped mixer (both with an inner diameter of 0.25 mm).

[0267] The pre-reaction solution was prepared in four portions. A first solution was prepared by mixing 2-hydroxyindan, DIEA and DCM. A second solution was prepared by mixing phosphorus trichloride and DCM. A third solution was prepared by mixing imidazole and DCM. A fourth solution was prepared by mixing 2-butanol and DCM. The equivalent ratio of each was 1.0 of 2-hydroxyindan, 3.0 of DIEA, 1.0 of phosphorus trichloride, 2.0 of imidazole, and 1.0 of 2-butanol.

[0268] In order to synthesize an organic phosphorus compound, first, the first solution and the second solution were mixed in a V-shaped mixer and reacted at 20°C for 10 seconds to obtain compound 1p. Then, the reaction solution containing compound 1p was immediately mixed with the third solution using a new T-shaped mixer and reacted at 20°C for 10 seconds to obtain compound 2p. Then, the reaction solution containing compound 2p was immediately mixed with the fourth solution using a new T-shaped mixer and reacted at 20°C for 30 seconds to obtain compound 3p. Then, the reaction solution containing compound 3p was poured into a beaker containing 1 mL of saturated saline and reacted at room temperature (25°C) for 10 minutes to obtain organic phosphorus compound 4p. The various solutions were pumped using a syringe pump, with the first and fourth solutions flowing at a rate of 2.0 mL / min, and the second and third solutions flowing at a rate of 1.2 mL / min.

[0269] Each reaction for synthesizing an organophosphorus compound according to the production method of Example 34 is shown below. In addition, the organophosphorus compound 4p was identified by NMR measurement. The structure, yield, and NMR spectrum data of organophosphorus compound 4p are also shown below.

[0270] [ka]

[0271] Organophosphorus compounds 4p: Purification method:preparative TLC(Hexane:EtOAc=3:2) 1H NMR (400MHz, CDCl3): δ=7.25-7.18(m,4H),6.88(d,J=692Hz,1H),5.35-5.30(m,1H),4.54(tq,J=6.0,6.4Hz,1H),3.30(dd,J=6.2 ,16.7Hz,2H),3.17(dd,J=3.4,16.7Hz,2H),1.72-1.59(m,2H),1.34(dd,J=6.4,6.9Hz,3H),0.95(t,J=7.3Hz,3H)(diastereomer mixture) 31 P NMR (162MHz, CDCl3): δ = 6.16, 6.51 (diastereomeric mixture)

[0272] As described above, when an organophosphorus compound was produced by the production method of the Example, the organophosphorus compound 4p could be obtained in high yield.

[0273] [Synthesis of symmetrical phosphate triesters 3] (Examples 35 to 40) R 1 OH and R 2 A symmetric phosphate triester was produced in the same manner as in [Synthesis of Symmetric Phosphate Triester 1], except that OH was changed to the following raw material.

[0274] In Example 35, R 1 n-Butanol was used as OH, and R 2 As OH, 2-phenylethanol (phenethyl alcohol) was used. In Example 36, R 1 OH is 2-butanol, R 2 As OH, 2-phenylethanol (phenethyl alcohol) was used. In Example 37, R 1 OH is tert-butanol, R 2 As OH, 2-phenylethanol (phenethyl alcohol) was used. In Example 38, R 1 2-phenylethanol (phenethyl alcohol) was used as OH, and R 2As OH, n-butanol was used. In Example 39, R 1 2-phenylethanol (phenethyl alcohol) was used as OH, and R 2 As OH, 2-butanol was used. In Example 40, R 1 2-phenylethanol (phenethyl alcohol) was used as OH, and R 2 Phenol was used as the OH group.

[0275] The main products 5i to 5n were identified by NMR measurement, and the yields were measured by HPLC-UV. The NMR spectrum data, accurate mass measurement data, structures and yields of the main products 5i to 5n are shown below. The relationship between the production methods of symmetric phosphate triesters in Examples 35 to 40 and the main products obtained is as follows. Example 35: major product 5i, Example 36: major product 5j, Example 37: major product 5k, Example 38: major product 5l, Example 39: major product 5m, Example 40: major product 5n.

[0276] [ka]

[0277] Main product 5i: Butyl diphenethyl phosphate Purification method:preparative TLC(Toluene:EtOAc=4:1) Colorless oil;IR(neat):2959,1271,1019,746cm -1 11H NMR (400 MHz, CDCl3): δ = 7.31 - 7.26 (m, 4H), 7.23 - 7.18 (m, 6H), 4.19 - 4.11 (m, 4H), 3.87 (td, J = 6.8, 6.8 Hz, 2H), 2.94 (t, J = 7.2 Hz, 4H), 1.56 (tt, J = 6.8, 7.6 Hz, 2H), 1.53 (qt, J = 7.2, 7.6 Hz, 2H), 0.90 (t, J = 7.2 Hz, 3H) 13 13C NMR (125 MHz, CDCl3): δ = 137.2, 129.0, 128.5, 126.6, 67.8 (d, J = 5.7 Hz), 67.5 (d, J = 6.6 Hz), 36.7 (d, J = 6.6 Hz), 32.2 (d, J = 6.7 Hz), 18.6, 13.5 31 31P NMR (162 MHz, CDCl3): δ = -0.59 HRMS (ESI): calcd for 20 C 27 H + 4O4P+Na]

[0278] Main product 5j: Diphenethyl 1 - methylpropyl phosphate Purification method: preparative TLC (Hexane:EtOAc = 3:1) Colorless oil; IR (neat): 2969, 1269, 1006, 746 cm -1 1 1H NMR (400 MHz, CDCl3): δ = 7.30 - 7.26 (m, 4H), 7.23 - 7.18 (m, 6H), 4.32 (dtq, J = 6.4, 6.4, 6.4 Hz, 1H), 4.17 - 4.11 (m, 4H), 2.94 (t, J = 7.2 Hz, 4H), 1.65 - 1.46 (m, 2H), 1.23 (d, J = 6.4 Hz, 3H), 0.88 (t, J = 7.4 Hz, 3H) 13C NMR(125MHz,CDCl3):δ=137.2,129.0,128.4,126.6,77.4,67.7(d,J=5.7Hz),36.7(d,J=7.6Hz),30.2(d,J=5.7Hz),20.9(d,J=3.8Hz),9.4 31 P NMR(162MHz,CDCl3):δ=-1.34 HRMS (ESI): calcd for [C 20 H 27 O4P+Na] + 385.1539,found 385.1539

[0279] ingredient 5k:1,1-Dimethylethyl diphenethyl phosphate Purification method:GPC Colorless oil;IR(neat):2975,1271,1006,748 1 H NMR(400MHz,CDCl3):δ=7.30-7.26(m,4H),7.23-7.15(m,6H),4.14-4.06(m,4H),2.93(t,J=7.0Hz,4H),1.41(s,9H); 13 C NMR(125MHz,CDCl3):δ=137.4,129.0,128.4,126.6,82.9(d,J=6.7Hz),67.5(d,J=5.8Hz),36.7(d,J=7.6Hz),29.7(d,J=4.8Hz); 31 P NMR(162MHz,CDCl3):δ=-5.09 HRMS(ESI): calcd for [C 20 H 27 O4P+Na] + 385.1539,found 385.1539

[0280] Formula 5l:Dibutyl phenethyl phosphate Purification method:preparative TLC(Toluene:EtOAc=4:1)andGPC Colorless oil;IR(neat):2959,1272,1022,745cm -1 1 H NMR (400MHz, CDCl3): δ=7.32-7.27(m,2H),7.24-7.18(m,3H),4.23(dt,J=7.1,7.1Hz,2H),3.96(dt,J=6.7,6.7Hz,2H),3.95 (dt,J=6.9,6.9Hz,2H),3.00(t,J=6.8Hz,2H),1.61(tt,J=6.8,7.2Hz,4H),1.37(tq,J=7.2,7.4Hz,4H),0.92(t,J=7.4Hz,6H) 13 C NMR (125MHz, CDCl3): δ=137.2,129.0,128.5,126.6,67.8(d,J=5.7Hz),67.4(d,J=5.7Hz),36.8(d,J=7.7Hz),32.2(d,J=6.7Hz),18.6,13.5 31 P NMR (162MHz,CDCl3):δ=-0.29 HRMS(ESI):calcd for [C 16 H 27 O4P+Na] + 337.1539, found 337.1540

[0281] Main product 5m (ジアステレオ mixture): Di-1-methylpropyl phenethyl phosphate Purification method:preparative TLC(Toluene:EtOAc=4:1) Colorless oil;IR(neat):2971,1266,1002,745cm -1 11H NMR (400 MHz, CDCl3): δ = 7.31 - 7.26 (m, 2H), 7.24 - 7.18 (m, 3H), 4.37 (dtq, J = 5.8, 5.9, 6.4 Hz, 1H), 4.36 (dtq, J = 5.8, 5.9, 6.4 Hz, 1H), 4.24 - 4.17 (m, 2H), 2.99 (t, J = 7.2 Hz, 2H), 1.70 - 1.49 (m, 4H), 1.28 (d, J = 6.4 Hz, 3H), 1.26 (d, J = 6.4 Hz, 3H), 0.92 (t, J = 7.8 Hz, 3H), 0.90 (t, J = 7.8 Hz, 3H) 13 13C NMR (125 MHz, CDCl3): δ = 137.7, 128.9, 128.3, 126.4, 76.2 (d, J = 5.7 Hz), 67.1 (d, J = 6.6 Hz), 35.9 (d, J = 7.6 Hz), 29.6 (d, J = 7.6 Hz), 20.7, 9.2 31 31P NMR (162 MHz, CDCl3): δ = -1.71 HRMS (ESI): calcd for 16 H 27 O4P+Na] + 337.1539, found 337.1540

[0282] Main product 5n: Diphenylphenethylphosphate Purification method: preparative TLC (Hexane:EtOAc = 4:1 1 1H NMR (400 MHz, CDCl3): δ = 7.36 - 7.22 (m, 7H), 7.19 - 7.08 (m, 8H), 4.44 (td, J = 6.8, 7.6 Hz, 2H), 3.01 (t, J = 6.8 Hz, 2H) 13 13C NMR (125 MHz, CDCl3): δ = 150.5 (d, J = 7.6 Hz), 136.6, 129.7, 129.0, 128.6, 126.8, 125.3, 120.0 (d, J = 4.8 Hz), 69.4 (d, J = 6.7 Hz), 36.6 (d, J = 7.6 Hz) 31 31P NMR (162 MHz, CDCl3): δ = -11.41 HRMS(ESI):calcd for [C 20 H 19 O4P+Na] + 377.0913,found377.0914

[0283] [Synthesis of asymmetric phosphate triesters 3] (Examples 41 to 45) R 1 O.H., R. 2 OH and R 3 Asymmetric phosphate triesters were produced in the same manner as in [Synthesis of asymmetric phosphate triesters 2], except that OH was changed to the following raw material:

[0284] (Example 46) R 1 O.H., R. 2 OH and R 3 Asymmetric phosphate triester (asymmetric thiophosphate triester) was produced in the same manner as in [Synthesis of asymmetric phosphate triester 2], except that OH was changed to the following raw material and the reagent used for oxidation was changed from mCPBA to xanthan hydride.

[0285] In Example 41, R 1 OH is 2-hydroxyindan, R 2 2-phenylethanol (phenethyl alcohol) was used as OH, and R 3 Ethanol was used as OH. In Example 42, R 1 OH is 2-hydroxyindan, R 2 Menthol is used as OH, and R 3 Ethanol was used as OH. In Example 43, R 1 OH is 2-hydroxyindan, R 2 OH is 2,2-dimethyl-1,3-dioxolane-4-methanol, R 3 Phenol was used as the OH group. In Example 44, R 1OH is 2-hydroxyindan, R 2 OH is 2-methyl-2,3,4-tri-O-benzyl-α-D-glucopyranoside, and R 3 Phenol was used as the OH group. In Example 45, R 1 OH is 2-hydroxyindan, R 2 1-O,2-O-dipalmitoyl-D-glycerol was used as OH, and R 3 Ethanol was used as OH. In Example 46, R 1 OH is 2-hydroxyindan, R 2 OH is 2-butanol, R 3 Phenol was used as the OH group.

[0286] The main products 9y to 14y were identified by NMR measurement, and the yields were measured by HPLC-UV. The NMR spectrum data, accurate mass measurement data, structures and yields of the main products 9y to 14y are shown below. The relationship between the production methods of asymmetric phosphate triesters in Examples 41 to 46 and the main products obtained is as follows. Example 41: major product 9y, Example 42: major product 10y, Example 43: major product 11y, Example 44: major product 12y, Example 45: major product 13y, Example 46: major product 14y.

[0287] [ka]

[0288] Main product 9y: Ethyl 2-indanyl phenethyl phosphate Purification method:preparative TLC(Toluene:EtOAc=4:1) Colorless oil; IR (neat): 2959, 1276, 1015, 745 cm -1 1 H NMR (400MHz, CDCl3): δ=7.31-7.27(m,2H),7.24-7.16(m,7H),5.14(ttd,J=3.6,6.0,6.0Hz,1H),4.22(td,J=7.2,7.2 Hz,2H),4.05-3.97(m,2H),3.25-3.16(m,2H),3.14-3.06(m,2H),2.98(t,J=7.2Hz,2H),1.27(dt,J=0.8Hz,7.2Hz,3H) 13 C NMR (125MHz, CDCl3): δ=139.8,137.2,129.0,128.5,126.8,126.6,124.6,79.0(d,J=5.7Hz),67.9(d,J =5.8Hz),63.7(d,J=5.7Hz),40.7(d,J=4.8Hz),40.6(d,J=4.7Hz),36.7(d,J=7.6Hz),16.1(d,J=6.7Hz) 31 P NMR (162MHz,CDCl3):δ=-1.125 HRMS(ESI):calcd for[C 19 H 23 O4P+Na] + 369.1226, found 369.1228

[0289] Main product 10y (ジアステレオ mixture): Ethyl 2-indanyl (-)-p-menthane-3-yl phosphate Purification method:preparative TLC(Hexane:EtOAc=4:1) Colorlessoil;IR(neat):2956,1266,1007,743cm -1 1H NMR (400MHz, CDCl3): δ=7.24-7.22(m,2H),7.19-7.16(m,2H),5.26-5.18(m,1H),4.20-4.12(m,1H),4.11-4.03(m,2H ),3.28(dd,J=6.4,16.4Hz,2H),3.20-3.14(m,2H),2.21(brd,J=12.4Hz,1H),2.16-2.08(m,1H),1.66(brs,1H),1.64( brs,1H),1.47-1.38(m,1H),1.37-1.29(m,1H),1.32(t,J=7.2Hz,3H),1.12(ddd,J=2.8,11.2,12.0Hz,1H),1.05-0.9 5(m,1H),0.90(d,J=6.4Hz,6H),0.89(d,J=7.2Hz,6H),0.86-0.82(m,1H),0.79(d,J=6.8Hz,3H),0.75(d,J=7.2Hz,3H) 13 C NMR (125MHz, CDCl3): δ=140.0,126.8,124.6,79.3(d,J=6.7Hz),79.2(d,J=6.7Hz),7 8.8(d,J=5.7Hz),78.7(d,J=7.7Hz),63.5(d,J=4.8Hz),63.4(d,J=5.7Hz),48.4(d,J= 6.7Hz),42.5,40.8(d,J=5.7Hz),40.7(d,J=4.8Hz),34.0,31.5,25.5(d,J=4.8Hz),2 2.8(d,J=3.8Hz),21.9,20.9,16.2(d,J=5.7Hz),16.1(d,J=6.7Hz),15.6(d,J=3.8Hz) 31 P NMR (162MHz, CDCl3): δ=-1.55,-1.63 HRMS(ESI):calcd for[C 21 H 33 O4P+Na] + 403.2009, found 403.2008

[0290] Main product 11y (ジアステレオ mixture): 2,2-Dimethyl-1,3-dioxolane-4-methyl 2-indanyl phenyl phosphate Purification method: preparative TLC(Hexane:EtOAc=3:2) Colorlesssoil;IR(neat):2925.1281.1212.1015.947.749cm -1 1 H NMR(400MHz,CDCl3):δ=7.35-7.31(m,2H),7.25-7.16(m,7H),5.37(ddt,J =3.0,3.2,6.0Hz,1H),5.36(ddt,J=3.0,3.2,6.0Hz,1H),4.29(dq,J=2.8.6 .0Hz,1H),4.18-4.05(m,2H),4.02(dd,J=6.4,8.8Hz,2H),3.79(ddd,J=2.8 ,6.0,8.8Hz,2H),3.34-3.10(m,4H),1.40(s,3H),1.39(s,3H),1.34(s,3H) 13 C NMR(125MHz,CDCl3):δ=150.5(d,J=6.7Hz),139.6,129.7,126.9,125.2,124.6,120.0(d,J=4.7Hz),109.9,80.4 (d,J=5.7Hz), 73.9,73.8,68.0(d,J=6.7Hz),67.9(d,J=5.7Hz),40.7(d,J=4.8Hz),40.6(d,J=5.7Hz),26.7,25.2 31 P NMR(162MHz,CDCl3):δ=-6.39,-6.44 HRMS(ESI):calcd for[C 21 H 25 O6P+Na] + 427.1281, found

[0291] Compound 12y(dilute solvent):2-Indanyl methyl-2,3,4-tri-O-Bz-α-D-glucopyranoside-6-yl phenyl phosphate Purification method: preparative TLC(Hexane:EtOAc=3:2) Colorlessoil;IR(neat):2956,1730,1601,1491,1279,1210,1025,950,757,688cm -1 1 H NMR(400MHz,CDCl3):δ=7.97(d,J=6.8Hz,2H),7.92(d,J=7.6Hz,2H),7.85(d,J=7.6Hz,2H),7.51(t,J=7.4Hz,2H),7.44-7.34(m,5H),7.32-7.25(m,4H),7.23-7.13(m,7H),6.14(dd,J=9.4,9.4Hz,1H),6.12(dd,J=9.4,9.4Hz,1H),5.52(dd,J=9.2,9.2Hz,1H),5.51(dd,J=9.2,9.2Hz,1H),5.38-5.34(m,1H),5.26-5.14(m,2H),4.34-4.24(m,3H),3.41(s,3H),3.38(s,3H),3.31-3.10(m,4H) 13 C NMR(125MHz,CDCl3):δ=165.8,165.7,165.2,139.6,133.5,133.4,133.1,129.92,129.87,129.7,128.45,128.42,128.3,126.9,125.1(d,J=4.8Hz),124.6,120.11(d,J=4.7Hz),120.06(d,J=4.8Hz),96.9(d,J=1.9Hz),80.44(d,J=5.8Hz),80.38(d,J=6.6Hz),71.9(d,J=4.8Hz),70.3,69.1,69.0,68.4(d,J=3.8Hz),68.3(d,J=3.8Hz),66.6(d,J=5.7Hz),66.5(d,J=5.8Hz),55.6(d,J=2.9Hz),40.7(d,J=4.7Hz) 31 P NMR(162MHz,CDCl3):δ=-6.46,-6.51 HRMS(ESI):calcd for[C 43 H 39 O 12 P+Na] + 801.2071, found 801.2071

[0292] Main product 13y (ジアステレオ mixture): 1,2-O-Dipalmitoyl-glycerol-3-yl ethyl 2-indanyl phosphate Purification method: preparative TLC(Hexane:EtOAc=7:3) Colorlessoil;IR(neat):2924,2853,1744,1276,1035,742cm -1 1 H NMR (400MHz, CDCl3): δ=7.24-7.22(m,2H),7.20-7.17(m,2H),5.25-5.22(m,2H),4.32(dd,J=4.0,12.0Hz,1H),4.18-4.08(m,4H),3.29(dd,J=6.0,1 6.6Hz,2H),3.16(dd,J=3.4,16.6Hz,2H),2.31(t,J=7.6Hz,2H),2.30(t,J =7.6Hz,2H),1.62-1.56(m,4H),1.35-1.25(m,51H),0.88(t,J=6.9Hz,6H) 13 C NMR (125MHz, CDCl3): δ=173.2,172.8,139.7,126.9,124.6,79.4(d,J=5.7Hz),69.4(d,J=7.6Hz),65.1(d,J=5.8Hz),64.1(d,J=4. 7Hz),61.7,40.7(d,J=4.7Hz),34.1,34.0,31.9,29.7,29.6,29.4,29.35,29.27,29.11,29.07,24.8,22.7,16.1(d,J=6.7Hz),14.1 31 P NMR (162MHz,CDCl3):δ=-1.13 HRMS(ESI):calcd for[C 46 H 81 O8P+Na] + 815.5561, found 815.5561

[0293] Main product 14y: O-(sec-Butyl) O-(2,3-dihydro-1H-inden-2-yl) O-phenyl phosphorothioate Purification method: preparative TLC (Hexane:EtOAc = 4:1) Colorless oil; IR (neat): 2873, 1593, 1489, 1207, 995, 931, 784, 742, 689 cm -1 1 1H NMR (400 MHz, CDCl3): δ = 7.31 (dd, J = 8.0 8.0 Hz, 2H), 7.23 - 7.15 (m, 7H), 5.42 (ttd, J = 3.2, 6.4, 9.5 Hz, 1H), 4.67 (tqd, J = 2.4, 6.1, 6.2 Hz, 1H), 4.65 (tqd, J = 2.4, 6.1, 6.2 Hz, 1H), 3.34 - 3.22, (m, 2H), 3.22 - 3.09 (m, 2H), 1.68 (dq, J = 6.8, 7.2 Hz, 2H), 1.34 (d, J = 6.2 Hz, 3H), 1.29 (d, J = 6.2 Hz, 3H), 0.94 (t, J = 7.4 Hz, 3H), 0.90 (t, J = 7.4 Hz, 3H) 13 13C NMR (125 MHz, CDCl3): δ = 150.8 (d, J = 7.6 Hz), 139.87, 139.85, 129.4, 126.8, 125.1, 124.62, 124.58, 121.14 (d, J = 4.7 Hz), 121.11 (d, J = 4.8 Hz), 80.38 (d, J = 5.7 Hz), 80.37 (d, J = 5.7 Hz), 79.22 (d, J = 6.7 Hz), 79.15 (d, J = 6.6 Hz), 40.5 (d, J = 5.7 Hz) 40.43 (d, J = 5.7 Hz), 40.41 (d, J = 5.7 Hz), 30.12 (d, J = 6.7 Hz), 30.05 (d, J = 7.6 Hz), 20.8 (d, J = 3.8 Hz), 20.7 (d, J = 3.8 Hz), 9.5, 9.4 31 31P NMR (162 MHz, CDCl3): δ = 62.3, 62.1 HRMS (ESI): calcd for [C 19 H 23 O3PS+Na]+ 385.0998, found 385.0998

[0294] Although the preferred embodiments of the present invention have been described above, the present invention is not limited to these embodiments. Addition, omission, substitution, and other modifications of the configuration are possible without departing from the spirit of the present invention. The present invention is not limited by the above description, but is limited only by the scope of the attached claims. [Explanation of symbols]

[0295] 1, 100···Flow system reactor, 11, 12, 13, 14, 15, 110, 120, 130, 140,···Tank, 21, 22, 23, 24, 210, 220, 230···Pump, 31, 32, 33, 310, 320···Mixer, f1, f2, f3, f4, f5, f6, f7, f10, f20, f30, f40, f50···Flow path

Claims

1. A method for producing an asymmetric phosphate triester by synthesizing an asymmetric phosphate triester using a flow-through reactor, comprising the steps of: A step (A1) of reacting phosphorus trichloride or phosphorus tribromide flowing through a first flow path and a first hydroxy compound represented by the following general formula (H-1) flowing through a second flow path in a first mixer to synthesize a compound P1 represented by the following general formula (P-1); a step (B1) of reacting the compound P1 discharged from the first mixer and flowing through a third flow path and a second hydroxy compound represented by the following general formula (H-2) flowing through a fourth flow path in a second mixer to synthesize a compound P2 represented by the following general formula (P-2); a step (C1) of reacting the compound P2 discharged from the second mixer and flowing through a fifth flow path and a third hydroxy compound represented by the following general formula (H-3) flowing through a sixth flow path in a third mixer to synthesize a compound P3 represented by the following general formula (P-3); and a step (D1) of oxidizing the compound P3 to synthesize an asymmetric phosphate triester, The reaction temperature in the steps (A1) and (B1) is −80° C. or higher; In the steps (A1) and (B1), the flow rates of the phosphorus trichloride or phosphorus tribromide, the first hydroxy compound, and the second hydroxy compound flowing through the flow paths are 0.01 mL / min or more. 【Chemistry 1】 [R １ ~R ３ are each independently an organic group. １ ~R ３ are all different organic groups. X is a bromine atom or a chlorine atom.

2. The method for producing an asymmetric phosphate triester according to claim 1, wherein the reaction temperature in the steps (A1) and (B1) is 0°C or higher.

3. 3. The method for producing an asymmetric phosphate triester according to claim 1 or 2, wherein in the steps (A1) and (B1), the flow rates of the phosphorus trichloride or phosphorus tribromide, the first hydroxy compound, and the second hydroxy compound flowing through the flow channels are 1 mL / min or more.

4. The method for producing an asymmetric phosphate triester according to any one of claims 1 to 3, further comprising, between the step (A1) and the step (B1), a step (N1) of reacting, in a fourth mixer, the compound P1 discharged from the first mixer and flowing through the third flow path with a base flowing through a seventh flow path.

5. The method for producing an asymmetric phosphate triester according to claim 4, wherein the base is one or more bases selected from the group consisting of pyridine, pyridine derivatives, imidazole, imidazole derivatives, and 1,4-diazabicyclo[2,2,2]octane.

6. The method for producing an asymmetric phosphate triester according to claim 4, wherein the base is a compound represented by the following general formula (I-1): 【Chemistry 2】 [Wherein, RI １ and R.I. ２ is a hydrogen atom or a hydrocarbon group.

7. In the step (A1), phosphorus trichloride or phosphorus tribromide and R １ The equivalent ratio of phosphorus trichloride or phosphorus tribromide to OH in the reaction system (R １ The method for producing an asymmetric phosphate triester according to any one of claims 1 to 6, wherein the ratio of the aryl group to the aryl group is from 0.1:1 to 10:

1.

8. The method for producing an asymmetric phosphate triester according to any one of claims 1 to 7, wherein the reaction temperature in the steps (A1) and (B1) is 20°C or higher and 40°C or lower.

9. The method for producing an asymmetric phosphate triester according to any one of claims 1 to 8, wherein in the steps (A1) and (B1), the flow rates of the phosphorus trichloride or phosphorus tribromide, the first hydroxy compound, and the second hydroxy compound flowing through the flow channels are 1 mL / min or more and 5 mL / min or less.

10. In the step (A1), the flow rate of phosphorus trichloride or phosphorus tribromide and R １ The method for producing an asymmetric phosphate triester according to any one of claims 1 to 9, wherein the flow rate of the OH is different from the flow rate of the OH.

11. In the step (A1), the flow rate of phosphorus trichloride or phosphorus tribromide is R １ The method for producing an asymmetric phosphate triester according to claim 10, wherein the flow rate of the OH is 0.3 to 0.9 times the flow rate of the OH.

12. In the step (A1), R １ The method for producing an asymmetric phosphate triester according to claim 10, wherein the flow rate of OH is 0.3 to 0.9 times the flow rate of phosphorus trichloride or phosphorus tribromide.

13. A method for producing a symmetric phosphate triester by synthesizing a symmetric phosphate triester using a flow-through reactor, comprising the steps of: A step (A2) of reacting phosphorus trichloride or phosphorus tribromide flowing through a first flow path and a first hydroxy compound represented by the following general formula (H-1) flowing through a second flow path in a first mixer to synthesize a compound P1 represented by the following general formula (P-1); a step (B2) of reacting the compound P1 discharged from the first mixer and flowing through a third flow path and a second hydroxy compound represented by the following general formula (H-2) flowing through a fourth flow path in a second mixer to synthesize a compound P4 represented by the following general formula (P-4); and a step (D2) of oxidizing the compound P4 to synthesize a symmetric phosphate triester, The reaction temperature in steps (A2) and (B2) is −80° C. or higher; In the steps (A2) and (B2), the flow rates of the phosphorus trichloride or phosphorus tribromide, the first hydroxy compound, and the second hydroxy compound flowing through the flow paths are 0.01 mL / min or more. 【Chemistry 3】 [In the formula, R １ and R ２ are different organic groups. X is a bromine atom or a chlorine atom.

14. The method for producing a symmetric phosphate triester according to claim 13, wherein the reaction temperature in steps (A2) and (B2) is 0° C. or higher.

15. 15. The method for producing a symmetric phosphate triester according to claim 13 or 14, wherein in the steps (A2) and (B2), the flow rates of the phosphorus trichloride or phosphorus tribromide, the first hydroxy compound, and the second hydroxy compound flowing through the flow paths are 1 mL / min or more.

16. A method for producing a phosphate ester by using a flow-through reactor, comprising the steps of: A step (A11) of reacting phosphorus trichloride or phosphorus tribromide flowing through a first flow path and a first hydroxy compound represented by the following general formula (H1-1) flowing through a second flow path in a first mixer to synthesize a compound P11 represented by the following general formula (P1-1); a step (B11) of reacting the compound P11 discharged from the first mixer and flowing through a third flow path with a second hydroxy compound represented by the following general formula (H1-2) flowing through a fourth flow path in a second mixer to synthesize a compound P12 represented by the following general formula (P1-2); a step (C11) of reacting the compound P12 discharged from the second mixer and flowing through a fifth flow path with a third hydroxy compound represented by the following general formula (H1-3) flowing through a sixth flow path in a third mixer to synthesize a compound P13 represented by the following general formula (P1-3); and a step (D11) of oxidizing the compound P13 to synthesize a phosphate ester, The reaction temperature in steps (A11) and (B11) is −80° C. or higher; In the steps (A11) and (B11), the flow rates of the phosphorus trichloride or phosphorus tribromide, the first hydroxy compound, and the second hydroxy compound flowing through the flow paths are 0.01 mL / min or more. 【Chemistry 4】 [In the formula, R １１ ~R １３ are each independently a hydrogen atom or an organic group. １１ ~R １３ At least one of the groups is an organic group and at least one of the groups is a hydrogen atom. X is a bromine atom or a chlorine atom.

17. A method for producing an organophosphorus compound by synthesizing the organophosphorus compound using a flow-through reactor, comprising the steps of: A step (A01) of reacting phosphorus trichloride or phosphorus tribromide flowing through a first flow path and a first hydroxy compound represented by the following general formula (H0-1) flowing through a second flow path in a first mixer to synthesize a compound P01 represented by the following general formula (P0-1); a step (B01) of reacting the compound P01 discharged from the first mixer and flowing through a third flow path and a second hydroxy compound represented by the following general formula (H0-2) flowing through a fourth flow path in a second mixer to synthesize a compound P02 represented by the following general formula (P0-2); and a step (C01) of reacting, in a third mixer, the compound P02 discharged from the second mixer and flowing through a fifth flow path, and a third hydroxy compound represented by the following general formula (H0-3) flowing through a sixth flow path, to synthesize a compound P03 represented by the following general formula (P0-3), The reaction temperature in steps (A01) and (B01) is −80° C. or higher; a flow rate of the phosphorus trichloride or phosphorus tribromide, the first hydroxy compound, and the second hydroxy compound flowing through a flow path of 0.01 mL / min or more in the steps (A01) and (B01). 【Chemistry 5】 [In the formula, R ０１ ~R ０３ are each independently a hydrogen atom or an organic group. ０１ ~R ０３ At least one of R is an organic group. １ ~R ３ When all of are organic groups, the organic groups are not all the same. X is a bromine atom or a chlorine atom.

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