Process for producing asymmetric phosphoric acid triester, process for producing symmetric phosphoric acid triester, process for producing phosphoric acid ester, and process for producing organic phosphorus compound

Abstract

A method for producing an asymmetric phosphoric acid triester using a flow system reaction apparatus, the method comprising: a step (A1) in which phosphorus trichloride or phosphorus tribromide is reacted with a first hydroxyl compound; a step (B1) in which a compound obtained in the step (A1) is reacted with a second hydroxyl compound; a step (C1) in which a compound obtained in the step (B1) is reacted with a third hydroxyl compound; and a step (D1) in which a compound obtained in the step (C1) is oxidized, wherein the reaction temperature in the step (A1) and the step (B1) is -80°C or higher, and the flow rate of the phosphorus trichloride or the phosphorus tribromide, the first hydroxyl compound, and the second hydroxyl compound flowing in the flow path in the step (A1) and the step (B1) is 0.01 mL / min or higher.

Description

Technical Field

[0001] This invention relates to methods for manufacturing asymmetric triphosphates, methods for manufacturing symmetric triphosphates, methods for manufacturing phosphate esters, and methods for manufacturing organophosphorus compounds. This application claims priority based on Japan Patent Application No. 2021-033869, filed on March 3, 2021, the contents of which are incorporated herein by reference. Background Technology

[0002] Triphosphates have a structure formed by the condensation of phosphoric acid and hydroxyl compounds. Among these triphosphates, there are symmetrical and asymmetrical triphosphates. The symmetrical triphosphates are formed by the condensation of two identical hydroxyl compounds with one different hydroxyl compound, while the asymmetrical triphosphates are formed by the condensation of three different hydroxyl compounds.

[0003] Symmetric and asymmetric phosphate triesters are used in various fields such as plasticizers, flame retardants, and pesticides. Furthermore, asymmetric phosphate triesters are also used as prodrugs for nucleic acids (ProTide) and as intermediates in DNA chemical synthesis.

[0004] One method for producing asymmetric triphosphates is the phosphoramidite method. In this method, tetrazolium is typically used as a promoter, and the triphosphate is obtained through the condensation reaction of phosphoramidite and alcohol. The triphosphate is then oxidized to triphosphate by I2, tert-butyl hydroperoxide, etc.

[0005] In addition, Patent Document 1 discloses a method for manufacturing an asymmetric phosphate triester, characterized in that, in a nonpolar solvent, in the presence of a tertiary amine, at a temperature of about 10°C or below, phosphorus oxychloride is added to phenol under stirring to cause it to react, and then a monovalent alkanol is added to cause it to react, wherein the phenol is in a molar amount of about 1.8 to 2.2 times that of the phosphorus oxychloride used, is substituted or unsubstituted with a halogen or a lower alkyl group, and the alkanol is in a molar amount of about 1 time that of the phosphorus oxychloride used, and may contain a halogen or an ether bond. Existing technical documents Patent documents

[0006] [Patent Document 1] Japanese Patent Application Publication No. 52-113949 Summary of the Invention The technical problem that the invention aims to solve

[0007] However, in the manufacturing methods of both asymmetric and symmetric triphosphates, there is a need for a method that can produce the target triphosphate at a lower cost and with a higher yield. In addition, there is a need for manufacturing methods that can produce the target monophosphate and diphosphate esters at a lower cost and with a higher yield, as other phosphate esters. In addition, there is a need for a method to manufacture organophosphorus compounds that can be produced at a lower cost and in a higher yield.

[0008] The present invention was made in view of the above circumstances, and its object is to provide a method for manufacturing a phosphate ester that can produce the target phosphate ester at a lower cost and with a higher yield. Furthermore, the present invention was made in view of the above circumstances, and its object is to provide a method for manufacturing an organophosphorus compound that can produce the target organophosphorus compound at a lower cost and in a higher yield. Technical means to solve technical problems

[0009] To address the aforementioned problems, the present invention employs the following configuration. That is, the first aspect of the present invention is: a method for manufacturing an asymmetric triphosphate, which is a method for synthesizing an asymmetric triphosphate using a flow-through reaction apparatus, wherein the method for manufacturing the asymmetric triphosphate comprises: a step (A1), wherein phosphorus trichloride or phosphorus tribromide is reacted with a first hydroxyl compound represented by the following general formula (H-1) to synthesize compound P1 represented by the following general formula (P-1); and a step (B1), wherein compound P1 is reacted with a second hydroxyl compound represented by the following general formula (H-2) to synthesize compound P2 represented by the following general formula (P-2). P2; step (C1), wherein step (C1) reacts compound P2 with a third hydroxyl compound represented by general formula (H-3) to synthesize compound P3 represented by general formula (P-3); and step (D1), wherein step (D1) oxidizes compound P3 to synthesize an asymmetric phosphate triester, wherein the reaction temperature in steps (A1) and (B1) is above -80°C, and the flow rates of phosphorus trichloride or phosphorus tribromide, the first hydroxyl compound, and the second hydroxyl compound flowing in the flow path in steps (A1) and (B1) are above 0.01 mL / min.

[0010] [Chemistry 1] [In the formula, R] 1 ~R 3 Each is an independent organic group. However, R 1 ~R 3 These are all different organic groups. X is a bromine or chlorine atom.

[0011] In the method for manufacturing asymmetric triphosphates according to the first aspect of the present invention, the reaction temperature in steps (A1) and (B1) can be above 0°C.

[0012] In the method for manufacturing asymmetric triphosphate according to the first aspect of the present invention, in steps (A1) and (B1), the flow rate of the phosphorus trichloride or phosphorus tribromide, the first hydroxyl compound and the second hydroxyl compound flowing in the flow path can be 1 mL / min or more.

[0013] In the method for manufacturing the asymmetric phosphate triester according to the first aspect of the present invention, a step (N1) in which the compound P1 is reacted with a base may be provided between the step (A1) and the step (B1).

[0014] In the method for manufacturing the asymmetric triphosphate 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 manufacturing the asymmetric triphosphate according to the first aspect of the present invention, the base may be a compound represented by the following general formula (I-1).

[0016] [Chemistry 2] [In the formula, RI 1 and RI 2 It is a hydrogen atom or a hydrocarbon group.

[0017] In the method for manufacturing the asymmetric triphosphate according to the first aspect of the present invention, in step (A1), phosphorus trichloride or phosphorus tribromide is reacted with R... 1 Equivalent ratio of OH in the reaction system (phosphorus trichloride or phosphorus tribromide:R) 1 OH) can be 0.1:1 to 10:1.

[0018] In the method for manufacturing asymmetric triphosphates according to the first aspect of the present invention, the reaction temperature in steps (A1) and (B1) can be above 20°C and below 40°C.

[0019] In the method for manufacturing asymmetric triphosphate according to the first aspect of the present invention, in steps (A1) and (B1), the flow rates of the phosphorus trichloride or phosphorus tribromide, the first hydroxyl compound, and the second hydroxyl compound flowing in the flow path can be 1 mL / min or more and 5 mL / min or less.

[0020] In the method for manufacturing asymmetric triphosphates according to the first aspect of the present invention, in step (A1), the flow rate of phosphorus trichloride or phosphorus tribromide is related to R. 1 The flow rate of OH can be different.

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

[0022] In the method for manufacturing the asymmetric triphosphate according to the first aspect of the present invention, in step (A1), R 1 The flow rate of OH can be 0.3 to 0.9 times that of phosphorus trichloride or phosphorus tribromide.

[0023] The second aspect of the present invention is: a method for manufacturing a symmetrical triphosphate, which is a method for synthesizing a symmetrical triphosphate using a flow-through reaction apparatus, wherein the method for manufacturing the symmetrical triphosphate comprises: a step (A2), wherein phosphorus trichloride or phosphorus tribromide is reacted with a first hydroxyl compound represented by the following general formula (H-1) to synthesize a compound P1 represented by the following general formula (P-1); and a step (B2), wherein compound P1 is reacted with the following general formula (H-2). The reaction of the second hydroxyl compound shown below is used to synthesize compound P4 represented by the following general formula (P-4); and step (D2) is used to oxidize compound P4 to synthesize a symmetrical phosphate triester, wherein the reaction temperature in steps (A2) and (B2) is above -80°C, and the flow rate of phosphorus trichloride or phosphorus tribromide, the first hydroxyl compound, and the second hydroxyl compound flowing in the flow path in steps (A2) and (B2) is above 0.01 mL / min.

[0024] [Chemistry 3] [In the formula, R] 1 and R 2 These are different organic groups. X is a bromine or chlorine atom.

[0025] In the method for manufacturing symmetrical triphosphates according to the second aspect of the present invention, the reaction temperature in steps (A2) and (B2) can be above 0°C.

[0026] In the method for manufacturing symmetrical triphosphates according to the second aspect of the present invention, in steps (A2) and (B2), the flow rates of the phosphorus trichloride or phosphorus tribromide, the first hydroxyl compound, and the second hydroxyl compound flowing in the flow path can be 1 mL / min or more.

[0027] A third aspect of the present invention is: a method for manufacturing a phosphate ester, wherein the method for manufacturing a phosphate ester is a method for synthesizing a phosphate ester using a flow-through reaction apparatus, wherein the method for manufacturing the phosphate ester comprises: step (A11), wherein step (A11) involves reacting phosphorus trichloride or phosphorus tribromide with a first hydroxyl compound represented by the following general formula (H1-1) to synthesize compound P11 represented by the following general formula (P1-1); step (B11), wherein step (B11) involves reacting compound P11 with a second hydroxyl compound represented by the following general formula (H1-2) to synthesize compound P12 represented by the following general formula (P1-2); step (C11)... The process (C11) involves reacting compound P12 with a third hydroxyl compound represented by the following general formula (H1-3) to synthesize compound P13 represented by the following general formula (P1-3); and the process (D11) involves oxidizing compound P13 to synthesize a phosphate ester, wherein the reaction temperature in processes (A11) and (B11) is above -80°C, and the flow rate of phosphorus trichloride or phosphorus tribromide, the first hydroxyl compound, and the second hydroxyl compound flowing in the flow path in processes (A11) and (B11) is above 0.01 mL / min.

[0028] [Chemistry 4] [In the formula, R] 11 ~R 13 Each can be independently a hydrogen atom or an organic group. However, R 11 ~R 13 In this context, at least one is an organic group, and at least one is a hydrogen atom. X is a bromine or chlorine atom.

[0029] The fourth aspect of the present invention is: a method for manufacturing an organophosphorus compound, wherein the method uses a flow-through reaction apparatus to synthesize the organophosphorus compound, the method comprising: step (A01), wherein phosphorus trichloride or phosphorus tribromide is reacted with a first hydroxyl compound represented by the following general formula (H0-1) to synthesize compound PO1 represented by the following general formula (PO-1); and step (B01), wherein compound PO1 is reacted with a second hydroxyl compound represented by the following general formula (H0-2) to synthesize the following... The compound PO2 represented by general formula (PO-2); and step (CO1), wherein step (CO1) reacts the compound PO2 with a third hydroxyl compound represented by general formula (HO-3) to synthesize compound PO3 represented by general formula (PO-3), wherein the reaction temperature in steps (A01) and (B01) is above -80°C, and the flow rates of the phosphorus trichloride or phosphorus tribromide, the first hydroxyl compound, and the second hydroxyl compound flowing in the flow path in steps (A01) and (B01) are above 0.01 mL / min.

[0030] [Chemistry 5] [R 01 ~R 03 Each can be independently a hydrogen atom or an organic group. However, R 01 ~R 03 In R, at least one is an organic group. 01 ~R 03 If all groups are organic, not all of the organic groups are the same. X is a bromine atom or a chlorine atom.

[0031] The fifth aspect of the present invention is: a method for manufacturing an organophosphorus compound, wherein the method uses a flow-through reaction apparatus to synthesize the organophosphorus compound, the method comprising: a step (AZ1) in which phosphorus trichloride or phosphorus tribromide is reacted with a first compound to synthesize a compound PZ1 represented by the general formula (PZ-1), wherein the first compound is any one of a hydroxyl compound, an amine compound, or a thiol compound; and a step (BZ1) in which the compound PZ1 is reacted with a second compound to synthesize a compound PZ2 represented by the general formula (PZ-2), wherein the first compound is... The second compound is any one of a hydroxyl compound, an amine compound, or a thiol compound; and step (CZ1) involves reacting compound PZ2 with the third compound to synthesize compound PZ3 represented by the following general formula (PZ-3), wherein the third compound is any one of a hydroxyl compound, an amine compound, or a thiol compound, wherein the reaction temperature in steps (AZ1) and (BZ1) is above -80°C, and the flow rate of phosphorus trichloride or phosphorus tribromide, the first compound, and the second compound flowing in the flow path in steps (AZ1) and (BZ1) is above 0.01 mL / min.

[0032] [Chemistry 6] [In the formula, Z] 1 ~Z 3 Each of these can be independently represented by a hydrogen atom, a group that has removed one hydrogen atom from a hydroxyl compound, a group that has removed one hydrogen atom from an amine compound, or a group that has removed one hydrogen atom from a thiol compound. However, Z 1 ~Z 3 Not all are the same. X is either a bromine atom or a chlorine atom. The effects of the invention

[0033] According to the manufacturing method of the present invention, the target phosphate ester can be manufactured at a lower cost and with a higher yield. Furthermore, according to the manufacturing method of the present invention, the target organophosphorus compound can be manufactured at a lower cost and with a higher yield. Attached Figure Description

[0034] [ Figure 1 [A schematic diagram of the method for manufacturing the asymmetric triphosphate in this embodiment.] [ Figure 2 [A schematic diagram of the method for manufacturing symmetrical triphosphates according to this embodiment.] [ Figure 3 [A schematic diagram of the method for manufacturing symmetrical triphosphates in the embodiment.] [ Figure 4 [A schematic diagram of the method for manufacturing symmetrical triphosphates in the embodiment.] [ Figure 5 [A schematic diagram of the method for manufacturing asymmetric triphosphates in the embodiment.] [ Figure 6 [A schematic diagram of the method for manufacturing asymmetric triphosphates in the embodiment.] Detailed Implementation

[0035] [summary] In the manufacturing methods of asymmetric and symmetric triphosphates, there is a need for a method that can produce the target triphosphate at a lower cost and with a higher yield. However, for example, the phosphoramidite method, as an existing manufacturing method, has high selectivity, but it also has problems such as the need to use expensive reagents, a lot of waste, a large number of steps, and the need to use explosive tetrazolium. In addition, the method for manufacturing asymmetric triphosphates described in Patent Document 1 has problems such as requiring a long reaction time and difficulty in producing the target triphosphates with high yields depending on the type of hydroxyl compound used.

[0036] In order to solve the above problems, the inventors have conducted in-depth research on the manufacturing method of phosphate esters. The results showed that when a first reaction is carried out, in which phosphorus trichloride or phosphorus tribromide reacts with the first hydroxyl compound, and then a second reaction is carried out, in which the compound obtained in the first reaction reacts with the second hydroxyl compound, a side reaction occurs before the second reaction, whereby the compound obtained in the first reaction reacts again with the first hydroxyl compound used in the first reaction, if the reaction rate of the first reaction is higher than the stirring rate. Therefore, the inventors conducted research on using a flow-through reaction apparatus and discovered that by appropriately controlling the reaction temperature and flow rate and improving the stirring efficiency, the target phosphate ester can be produced at a lower cost and with a higher yield, thus completing the present invention.

[0037] <Flow-through system reaction apparatus> The method for manufacturing the asymmetric triphosphate according to the first aspect of the present invention, the method for manufacturing the symmetric triphosphate according to the second aspect, the method for manufacturing the phosphate ester according to the third aspect, and the method for manufacturing the organophosphorus compound according to the fourth aspect are manufacturing methods using a flow-through reaction apparatus. A flow-through reaction apparatus carries out chemical reactions in a continuous flow rather than a batch process. Flow-through reaction apparatuses are typically tubular and made of non-reactive materials. These non-reactive materials are known in the prior art and depend on the properties of the raw materials or reactants. The mixing method is diffusion. The residence time of the raw material in the mixer is calculated by the mixer volume and the flow rate through it (residence time = mixer volume / flow rate). For example, to achieve a relatively long residence time, the raw material can be pumped more slowly or a larger mixer can be used.

[0038] Because of the very large surface area per unit volume, the mixer in a flow-through reaction device can achieve precise temperature control and maximize the efficiency of interfacial reactions. Furthermore, flow-through reactors are fluid systems, which shorten residence time, allowing product molecules to be rapidly released outside the reactor and reducing the likelihood of secondary reactions. Therefore, flow-through reactors can effectively suppress the formation of unwanted byproducts.

[0039] As for mixers, examples include T-shaped mixers and V-shaped mixers. From the perspective of improving mixing efficiency, V-shaped mixers are preferred.

[0040] (Method for manufacturing asymmetric triphosphates according to the first aspect of the present invention) The following is for reference Figure 1 The method of the flow-through reaction apparatus described in this embodiment and the method of manufacturing asymmetric triphosphate using the apparatus will be explained. Figure 1 This is a schematic diagram showing the schematic configuration of a flow-through reaction apparatus 1. The flow-through reaction apparatus 1 includes: a tank 11 containing a first liquid, a tank 12 containing a second liquid, a tank 13 containing a third liquid, a tank 14 containing a fourth liquid, and a tank 15 containing a fifth liquid.

[0041] For example, the first liquid contains the first hydroxyl compound (hereinafter also referred to as "R"). 1 The second liquid contains phosphorus trichloride or phosphorus tribromide, the third liquid contains a nucleophilic base, and the fourth liquid contains a second hydroxyl compound (hereinafter also referred to as "R"). 2 The fifth liquid contains the third hydroxyl compound (hereinafter also referred to as "R"). 3 OH”).

[0042] The flow-through reaction apparatus 1 includes flow paths f1, f2, f3, f4, f5, f6, and f7 for conveying fluid. The inner diameter of the flow paths and the mixer can be, for example, 0.1 mm to 1 mm, 0.1 mm to 0.8 mm, or 0.2 mm to 0.6 mm. Alternatively, the inner diameter of the flow paths and the mixer can be 1 mm to several centimeters. Cans 11, 12, 13, 14, and 15, as well as flow paths f1, f2, f3, f4, f5, f6, and f7, are formed, for example, of plastics, elastomers, resins, glass materials, metals, ceramics, etc.

[0043] Tank 11 is connected to pump 21. Through the operation of pump 21, the first liquid contained in tank 11 moves within flow path f1 and flows into mixer 31. Tank 12 is connected to pump 22. Through the operation of pump 22, the second liquid contained in tank 12 moves within flow path f2 and flows into mixer 31. Then, the first liquid and the second liquid are mixed by mixer 31 to become a first mixture, which is then conveyed to flow path f5. During this mixing process, the R contained in the first liquid... 1 OH reacts with phosphorus trichloride or phosphorus tribromide contained in the second liquid to yield one chlorine atom of phosphorus trichloride or one bromine atom of phosphorus tribromide, which is then converted by R. 1 O-substituted compound P1 (step A1 of the method for manufacturing asymmetric triphosphate). The first mixture containing the obtained compound P1 moves in flow path f5 and flows into mixer 32.

[0044] Tank 13 is connected to pump 23. Through the operation of pump 23, the third liquid contained in tank 13 moves within flow path f3 and flows into mixer 32. Then, the third liquid and the first mixture are mixed to form a second mixture, which is conveyed to flow path f6. During this mixing process, compound P1 obtained in step A1 reacts with the nucleophilic base contained in the third liquid to obtain a compound in which the two chlorine atoms (or the two bromine atoms) of compound P1 are each replaced by a group that has removed one hydrogen atom from the nucleophilic base (hereinafter also referred to as "compound N1"). The second mixture containing the obtained compound N1 moves within flow path f6 and flows into mixer 33.

[0045] Tank 14 is connected to pump 24. Through the operation of pump 24, the fourth liquid contained in tank 14 moves within flow path f4 and flows into mixer 33. Then, the fourth liquid and the second mixture are mixed to form a third mixture, which is then conveyed to flow path f7. During this mixing process, compound N1 reacts with R contained in the fourth liquid. 2 The reaction with OH yields compound N2 (hereinafter also referred to as "compound N2"), which is the product of compound N1 with the removal of one hydrogen atom from one nucleophilic base by the R group. 2 O-substituted compounds. The third mixture containing the obtained compound N2 moves within flow path f7 and flows into tank 15.

[0046] Tank 15 contains R 3The fifth liquid containing OH, and the third mixture containing compound N2, flowed into it. Thus, compound N2 and R... 3 The OH reaction synthesizes compound P3, which is stored in tank 15 (step C1 of the method for manufacturing asymmetric triphosphate). Then, by oxidizing compound P3, the asymmetric triphosphate is synthesized and stored in tank 15 (step D1 of the method for manufacturing asymmetric triphosphate).

[0047] According to the flow-through reaction apparatus 1 described in this embodiment, the heat exchange area per volume of the reaction solution can be increased. Furthermore, the reaction time can be controlled by the flow rate and the length of the flow path. Therefore, the reaction solution can be strictly controlled, resulting in minimizing undesirable side reactions and improving the yield of the target substance.

[0048] Compounds P1 and P2 are highly reactive and readily react with R. 1 Side reactions of OH reacting again, and the reaction of compound P2 with R 2 The side reaction of OH reacts again, making reaction control important. According to the flow-through reaction apparatus 1 described in this embodiment, since the synthesized compounds P1 and P2 can be rapidly released from the mixer, side reactions can be suppressed, and the target triphosphate can be produced in high yield.

[0049] Regarding the flow-through system reaction apparatus 1, an example is shown of mixing liquids using a mixer. However, since the mixing of liquids can be achieved simply by connecting the flow paths to each other, the flow-through system reaction apparatus of this embodiment does not necessarily need to include a mixer.

[0050] <First Implementation> The method for manufacturing an asymmetric triphosphate according to the first embodiment is a method for synthesizing an asymmetric triphosphate using a flow-through reaction apparatus, wherein the method comprises: step (A1) (hereinafter referred to as "step (A1)"), wherein step (A1) reacts phosphorus trichloride or phosphorus tribromide with a first hydroxyl compound to synthesize compound P1; step (B1) (hereinafter referred to as "step (B1)"), wherein step (B1) reacts compound P1 with a second hydroxyl compound to synthesize compound P2; step (C1) (hereinafter referred to as "step (C1)"), wherein step (C1) reacts compound P2 with a third hydroxyl compound to synthesize compound P3; and step (D1) (hereinafter referred to as "step (D1)"), wherein step (D1) oxidizes compound P3 to synthesize the asymmetric triphosphate.

[0051] Process (A1) Step (A1) involves reacting phosphorus trichloride or phosphorus tribromide with the first hydroxyl compound (R) represented by the following general formula (H-1). 1 The process of synthesizing compound P1, represented by the general formula (P-1), by reacting OH) with OH.

[0052] [Chemistry 7] [In the formula, R] 1 [This is an organic group. X is a bromine or chlorine atom.]

[0053] In the above general formulas (H-1) and (P-1), R 1 It is an organic group. Examples of such organic groups include hydrocarbon groups, and the hydroxyl group may have substituents. The hydrocarbon group can be straight-chain, branched, or cyclic. In the case of a cyclic hydrocarbon group, it can be an aliphatic hydrocarbon group or an aromatic hydrocarbon group. In addition, it can be a polycyclic group or a monocyclic group. There are no particular limitations on the substituents used; examples include alkoxy groups, halogen atoms, haloalkyl groups, carboxyl groups, cyano groups, and amino groups. In addition, a portion of the carbon atom of the hydrocarbon group can be replaced by a substituent containing a heteroatom. Examples of such substituents containing heteroatoms include -O-, -C(=O)-O-, -S-, -S(=O)2-, and -S(=O)2-O-.

[0054] As R 1 More specifically, it is preferable to remove one hydroxyl group from the first hydroxyl compound described later.

[0055] [First hydroxy compound (R)] 1 OH)] 1st hydroxyl compound (R) 1 (OH) Any compound having one or more hydroxyl groups is acceptable; there are no particular limitations, and well-known compounds can be used. R 1 OH can have substituents other than hydroxyl groups.

[0056] As R 1 Specifically, examples of OH include monohydric alcohols, polyalkylene glycol monoethers, polyalkylene glycol monoesters, polyhydric alcohols, sugars, glycerol fatty acid esters, ethanolamides, and nucleosides.

[0057] Monohydric alcohols As monohydric alcohols, more specifically, monohydric aliphatic alcohols and monohydric aromatic alcohols can be cited.

[0058] Aliphatic alcohols Monohydric aliphatic alcohols are compounds that have one hydroxyl group on a straight-chain, branched-chain, or cyclic aliphatic hydrocarbon group. As a monohydric aliphatic alcohol, aliphatic alcohols with 1 to 20 carbon atoms are preferred, aliphatic alcohols with 1 to 10 carbon atoms are more preferred, and aliphatic alcohols with 1 to 7 carbon atoms are even more preferred. Specifically, examples include methanol, ethanol, 1-propanol, 2-propanol, 1-butanol (n-butanol), 2-methylpropanol (isobutanol), 2-butanol (sec-butanol), 2-methyl-2-propanol (tert-butanol), 1-pentanol (n-pentanol), 2-pentanol (sec-pentanol), 3-pentanol, 2-methyl-1-butanol, 3-methyl-1-butanol (isopentanol), 2-methyl-2-butanol (tert-pentanol), 3-methyl-2-butanol, 2,2-dimethyl-1-propanol (neopentanol), and tert-butyl glycolate. Saturated aliphatic alcohols such as tert-butyl glycolate, 2-[[tert-butyl(dimethyl)silyl]oxy]ethanol, 2-methoxy-ethane-1-ol (ethylene glycol monomethyl ether), tert-butyl (2-hydroxyethyl)carbamate, and 2-cyanoethanol; and unsaturated 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.

[0059] Monomeric aromatic alcohols Aromatic alcohols are compounds having one hydroxyl group and one or more aromatic rings. There are no particular limitations on whether the aromatic ring is a cyclic conjugated system with 4n+2 π electrons; it can be monocyclic or polycyclic. As a monovalent aromatic alcohol, aromatic alcohols with 6 to 30 carbon atoms are preferred, and aromatic alcohols with 6 to 15 carbon atoms are more preferred. Specifically, examples include phenol, cresol, ethylphenol, tert-butylphenol, hexylphenol, octylphenol, nonylphenol, decylphenol, undecylphenol, dodecylphenol, tridecylphenol, tetradecylphenol, phenylphenol, benzylphenol, styrylated phenol, p-cumylphenol, 2-phenylethanol (phenylethanol, フェネチルアルコール), 2-indole (2-ヒドロキシインダン) (2-indole), etc.

[0060] Polyalkylene glycol monoether Examples of polyalkylene glycol monoethers include compounds obtained by adding alkylene oxides to the aforementioned monohydric alcohols, such as ethylene oxide, propylene oxide, butane oxide, and long-chain α-olefin oxides. Specifically, examples 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 monooilyl ether, polyoxyethylene / polyoxypropylene monooilyl ether, polyoxyethylene monococoyl alkyl ether, polyoxyethylene / polyoxypropylene monococoyl alkyl ether, polyoxyethylene monopalmityl ether, polyoxyethylene / polyoxypropylene monopalmityl ether, polyoxyethylene monotallow alkyl ether, and polyoxyethylene / polyoxypropylene monotallow alkyl ether.

[0061] · Polyalkylene glycol monoester Examples of polyalkylene glycol monoesters include compounds obtained by adding alkylene oxides to fatty acids and compounds obtained by esterifying polyalkylene glycols with fatty acids. Specifically, examples include polyethylene glycol monolaurate, polyethylene glycol / polypropylene glycol monolaurate, polyethylene glycol monomyristate, polyethylene glycol / polypropylene glycol monomyristate, polyethylene glycol monopalmitate, polyethylene glycol / polypropylene glycol monopalmitate, polyethylene glycol monostearate, polyethylene glycol / polypropylene glycol monostearate, polyethylene glycol monooleate, polyethylene glycol / polypropylene glycol monooleate, polyethylene glycol monococonut oil fatty acid ester, polyethylene glycol / polypropylene glycol monococonut oil fatty acid ester, polyethylene glycol monopalmitoyl fatty acid ester, polyethylene glycol / polypropylene glycol monopalmitoyl fatty acid ester, polyethylene glycol monotallow fatty acid ester, and polyethylene glycol / polypropylene glycol monotallow fatty acid ester.

[0062] Polyols Polyols are compounds that have two or more hydroxyl groups. Specifically, examples include 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, and 3-methyl-1,6-hexanediol. Diols, 1,6-Heptanediol, 2-Methyl-1,7-Heptanediol, 3-Methyl-1,7-Heptanediol, 4-Methyl-1,7-Heptanediol, 1,7-Octandiol, 2-Methyl-1,8-Octandiol, 3-Methyl-1,8-Octandiol, 4-Methyl-1,8-Octandiol, 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, Neopentanediol Diols such as 2,2-diethylpropanediol and 2-butyl-2-ethylpropanediol; glycerol, trioxyisobutane, 1,2,3-butanetriol, 1,2,3-pentanetriol, 2-methyl-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, pentamethylglycerol, pentaglycerol, 1,2,4-butanetriol, 1,2,4-pentanetriol, trimethyl... Triols such as hydroxymethyl ethane and trimethylolpropane; tetraols such as pentaerythritol, erythritol, 1,2,3,4-pentanetetrol, 2,3,4,5-hexanetetrol, 1,2,4,5-pentanetetrol, 1,3,4,5-hexanetetrol, diglycerol, and sorbitol; pentaneols such as ribitol, arabinitol, xylitol, and triglycerides; hexaols such as dipentaerythritol, sorbitol, mannitol, idotitol, inositol, euonymustol, tarose, and allose; or derivatives of these polyols in which some or all of the hydrogen atoms are replaced by other substituents. Taking inositol as an example, inositol has nine stereoisomers: cis-inositol, epi-inositol, allo-inositol, myo-inositol, muco-inositol, neo-inositol, chiro-inositol (which exists in D and L forms), and scyllo-inositol. The same applies to other compounds; one isomer can be used, or two or more isomers can be used in combination.

[0063] ·sugar Sugars can be either monosaccharides or oligosaccharides. Here, monosaccharides refer to sugars that are no longer hydrolyzed and are compounds that form polysaccharides. Monosaccharides can also be considered the smallest unit of carbohydrates. Oligosaccharides are oligomers of sugars linked together by glycosidic bonds.

[0064] Monosaccharides As monosaccharides, examples include glucose, fructose, galactose, ribose, xylose, mannitol, sorbitol, xylitol, erythritol, pentaerythritol, etc.

[0065] Oligosaccharides Specifically, examples of oligosaccharides include disaccharides such as sucrose, lactose, maltose, isomaltose, trehalose, cellobiose, and maltitol; trisaccharides such as raffinose, maltodextrin, and maltodextrin; tetrasaccharides such as stachyose; hexasaccharides such as α-cyclodextrin; heptasaccharides such as β-cyclodextrin; and octasaccharides such as γ-cyclodextrin.

[0066] Other sugars In addition, as a sugar, it can also be other sugars, such as heptose, deoxy sugar, amino sugar, sulfose, seleno sugar, aldonic acid, uronic acid, sugar acid, ascorbic acid, ketouronic acid, dehydrated sugar, unsaturated sugar, sugar ester, sugar ether, glycoside, etc., or it can be a substance obtained by hydrolyzing polysaccharides such as starch, glycogen, and cellulose.

[0067] · Glycerol fatty acid esters Glycerol fatty acid esters are compounds formed by the ester bond between fatty acids and one or two of the three hydroxyl groups present in glycerol. Specifically, examples include glyceryl monolaurate, glyceryl monomyristate, glyceryl monopalmitate, glyceryl monostearate, glyceryl monooleate, glyceryl monococoa oil fatty acid ester, glyceryl monopalmitate fatty acid ester, and glyceryl monotallow fatty acid ester.

[0068] ·ethanolamide Examples of ethanolamides include fatty acid amides of monoethanolamine or diethanolamine, and compounds obtained by further addition of the fatty acid amide with epoxides. Specifically, examples include 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, oleic acid monoethanolamide, and oleic acid monoethanolamide. Amines, oleic acid diethanolamide, oleic acid monoethanolamide ethylene oxide adduct, oleic acid diethanolamide ethylene oxide adduct, coconut oil fatty acid monoethanolamide, coconut oil fatty acid diethanolamide, coconut oil fatty acid monoethanolamide ethylene oxide adduct, coconut oil 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, tallow fatty acid monoethanolamide, tallow fatty acid diethanolamide, tallow fatty acid monoethanolamide ethylene oxide adduct, tallow fatty acid diethanolamide ethylene oxide adduct, etc.

[0069] Nucleosides Nucleosides are compounds formed by the combination of a base and a sugar. Examples of such bases include purine bases such as adenine and guanine; pyrimidine bases such as thymine, cytosine, and uracil; nicotinamide; and dimethylisocoridine. Specifically, examples include adenosine, guanosine, 5-methyluridine, uridine, cytidine, deoxyadenosine, deoxyguanosine, thymidine, deoxyuridine, and deoxycytidine. Additionally, examples include nucleoside derivatives of these compounds where some or all of the hydrogen atoms or hydroxyl groups are substituted with other substituents (e.g., 5-(3-benzoyl-5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-(hydroxymethyl)tetrahydrofuran-3-ylbenzoate, or 3-benzoyl-1-[4-hydroxy-5-(tert-butyldimethylsiloxymethyl)tetrahydrofuran-2-yl)-5-methylpyrimidin-2,4(1H,3H)-dione), etc.

[0070] R 1 OH can be any substance other than the above-mentioned monohydric alcohols, polyalkylene glycol monoethers, polyalkylene glycol monoesters, polyhydric alcohols, sugars, glycerol fatty acid esters, alcoholamides, and nucleosides. For example, it can be hydroxy amino acids such as threonine and serine, or derivatives of such amino acids (e.g., [[(9H-fluorenyl)methoxy]carbonyl]serine methyl ester); hydroxy acids such as glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, and ricinoleic acid.

[0071] As R 1OH, among the above substances, is preferably a monohydric alcohol, an amino acid (including amino acid derivatives), or a nucleoside (including nucleoside derivatives). The preferred monohydric alcohol is an aliphatic alcohol with 1 to 20 carbon atoms or an aromatic alcohol with 6 to 30 carbon atoms, and more preferably an aliphatic alcohol with 1 to 7 carbon atoms or an aromatic alcohol with 6 to 15 carbon atoms.

[0072] More specifically, as R 1 The monohydric alcohol in OH is preferably ethanol, 1-butanol, 2-methylpropanol, 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 glycolate, 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, and tridecylphenol. Alkylphenol, tetradecylphenol, phenylphenol, benzylphenol, styrylated phenol, p-cumylphenol, 2-phenylethanol or 2-indanol, more preferably ethanol, 1-butanol (n-butanol), 2-methylpropanol (isobutanol), 2-butanol (sec-butanol), 2-methyl-2-propanol (tert-butanol), tert-butyl glycolate (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-indanol (2-indanol), 2-methoxy-ethane-1-ol, propargyl alcohol, (2-hydroxyethyl)carbamate tert-butyl ester, 2-cyanoethanol.

[0073] As R 1 The amino acid (including amino acid derivatives) in OH is preferably [[(9H-fluorenyl)methoxy]carbonyl]serine methyl ester.

[0074] As R 1 The nucleoside (including nucleoside derivatives) in OH is preferably 5-(3-benzoyl-5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-(hydroxymethyl)tetrahydrofuran-3-ylbenzoate, or 3-benzoyl-1-[4-hydroxy-5-(tert-butyldimethylsiloxymethyl)tetrahydrofuran-2-yl]-5-methylpyrimidin-2,4(1H,3H)-dione.

[0075] In process (A1), regarding phosphorus trichloride or phosphorus tribromide and R 1 The usage of each OH group, taking into account R 1The type of OH can be adjusted appropriately according to the target reaction. Phosphorus trichloride or phosphorus tribromide and R 1 The stoichiometric ratio of OH in the reaction system (phosphorus trichloride or phosphorus tribromide:R) 1 The ratio of OH can be 0.1:1 to 10:1, 0.2:1 to 5:1, or 0.5:1 to 3:1. In step (A1) of the method for manufacturing asymmetric triphosphates according to this embodiment, even when relative to R... 1 Compound P1 can also be synthesized in high yield when OH is present in a relatively small amount of phosphorus trichloride or phosphorus tribromide at a near-equivalent amount.

[0076] The lower limit of the reaction temperature of process (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. In addition, there is no particular limit to the upper limit of the reaction temperature of process (A1), but it is preferably 80°C or less, more preferably 60°C or less, and even more preferably 40°C or less.

[0077] If the lower limit of the reaction temperature in step (A1) is -80°C or higher, the stirring efficiency is improved, which can further suppress side reactions. Furthermore, if the lower limit of the reaction temperature in step (A1) is higher than the aforementioned preferred lower limit, the stirring efficiency is further improved, which can further suppress side reactions and further increase the yield of compound P1. If the upper limit of the reaction temperature in process (A1) is below the above-mentioned preferred upper limit, the reaction temperature of phosphorus trichloride or phosphorus tribromide with R can be appropriately controlled. 1 The reaction rate of OH can further suppress side reactions.

[0078] For example, the reaction temperature of process (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 in the flow path is 0.01 mL / min or more, preferably 0.1 mL / min or more, and more preferably 1 mL / min or more. In addition, in process (A1), there is no particular limit to the upper limit of the flow rate of phosphorus trichloride or phosphorus tribromide flowing in the flow path. For example, it can be less than 10 mL / min, less than 8 mL / min, or less than 5 mL / min.

[0080] In step (A1), if the lower limit of the flow rate of phosphorus trichloride or phosphorus tribromide flowing in the flow path is 0.01 mL / min or higher, the stirring efficiency is improved, which can further suppress side reactions. Furthermore, if the lower limit of the flow rate of phosphorus trichloride or phosphorus tribromide flowing in the flow path in step (A1) is 0.01 mL / min or higher than the aforementioned preferred lower limit, the stirring efficiency is further improved, which can further suppress side reactions and further improve the yield of compound P1. Furthermore, in process (A1), if the upper limit of the flow rate of phosphorus trichloride or phosphorus tribromide flowing in the flow path is below the aforementioned preferred upper limit, the flow rate of phosphorus trichloride or phosphorus tribromide and R can be appropriately controlled. 1 The reaction rate of OH can further suppress side reactions.

[0081] For example, in step (A1), the flow rate of phosphorus trichloride or phosphorus tribromide flowing in 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 process (A1), R flows within the flow path. 1 The lower limit of the OH flow rate is 0.01 mL / min or more, preferably 0.1 mL / min or more, more preferably 1 mL / min or more, and even more preferably 2 mL / min or more. Additionally, in process (A1), R flows within the flow path. 1 There is no specific upper limit to the flow rate of OH; for example, it can be below 10 mL / min, below 8 mL / min, or below 5 mL / min.

[0083] In process (A1), if R flows within the flow path 1 If the lower limit of the OH flow rate is above 0.01 mL / min, the stirring efficiency will be improved, which can further suppress side reactions. Additionally, in process (A1), if R flows within the flow path... 1 If the lower limit of the OH flow rate is above the aforementioned preferred lower limit, the stirring efficiency will be further improved, side reactions can be further suppressed, and the yield of compound P1 can be further improved. Additionally, in process (A1), if R flows within the flow path... 1 If the upper limit of the OH flow rate is below the aforementioned preferred upper limit, the flow rate of phosphorus trichloride or phosphorus tribromide and R can be appropriately controlled. 1 The reaction rate of OH can further suppress side reactions.

[0084] For example, in process (A1), R flows within the flow path. 1The flow rate of OH 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, even more preferably 1 mL / min or more and 5 mL / min or less, and particularly preferably 2 mL / min or more and 5 mL / min or less.

[0085] In process (A1), the flow rate of phosphorus trichloride or phosphorus tribromide is related to R. 1 The flow rate of OH can be different or the same, but it is preferred to be different. Specifically, relative to the flow rate of any one of the two flow rates, the flow rate of the remaining flow rate is preferably 0.1 to 1.0 times, more preferably 0.3 to 0.9 times.

[0086] For example, the flow rate of phosphorus trichloride or phosphorus tribromide is above 1 mL / min and below 5 mL / min, R 1 The flow rate of OH can be 0.3 to 0.9 times that of phosphorus trichloride or phosphorus tribromide; the flow rate of phosphorus trichloride or phosphorus tribromide should be above 2 mL / min and below 5 mL / min. 1 The flow rate of OH can be 0.3 to 0.9 times that of phosphorus trichloride or phosphorus tribromide. Conversely, R 1 The flow rate of OH is above 1 mL / min and below 5 mL / min, and the flow rate of phosphorus trichloride or phosphorus tribromide can be within this range. 1 0.3 to 0.9 times the flow rate of OH; R 1 The flow rate of OH is above 2 mL / min and below 5 mL / min, and the flow rate of phosphorus trichloride or phosphorus tribromide can be within this range. 1 The flow rate of OH is 0.3 to 0.9 times that of OH.

[0087] In process (A1), phosphorus trichloride or phosphorus tribromide is reacted with R in the mixer of the flow-through reaction apparatus. 1 There is no particular limitation on the reaction time of OH reaction; for example, it can be 0.01 seconds to 1 minute, 1 second to 30 seconds, or 1 second to 20 seconds.

[0088] In step (A1), the synthesized compound P1 is formed by the removal of one chlorine atom from phosphorus trichloride or one bromine atom from phosphorus tribromide, from R. 1 A compound in which the hydroxyl group of OH is replaced by a group that has one hydrogen atom removed. For example, compound P1 can be a compound in which one chlorine atom of phosphorus trichloride or one bromine atom of phosphorus tribromide is replaced by a group that removes one hydrogen atom from the hydroxyl group of the aforementioned monohydric alcohol, polyalkylene glycol monoether, polyalkylene glycol monoester, polyhydric alcohol, sugar, glycerol fatty acid ester, ethanolamide, or nucleoside.

[0089] Process (B1) Step (B1) involves reacting the above compound P1 with the second hydroxyl compound (R). 2 The process of synthesizing compound P2, represented by the general formula (P-2), by reacting OH) with OH.

[0090] [Chemistry 8] [In the formula, R] 1 and R 2 These are different organic groups. X is a bromine or chlorine atom.

[0091] In the above general formulas (H-2) and (P-2), R 2 As an organic group, examples of groups related to R mentioned above can be given. 1 Same group. However, R 1 and R 2 They are different organic groups.

[0092] As R 2 OH, examples of R mentioned above can be cited. 1 The same substance as OH, but R 2 OH and R 1 OH is not the same compound.

[0093] The lower limit of the reaction temperature in process (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. In addition, there is no particular limit to the upper limit of the reaction temperature of process (B1), but it is preferably 80°C or less, more preferably 60°C or less, and even more preferably 40°C or less.

[0094] If the lower limit of the reaction temperature in step (B1) is -80°C or higher, the stirring efficiency is improved, which can further suppress side reactions. Furthermore, if the lower limit of the reaction temperature in step (B1) is higher than the aforementioned preferred lower limit, the stirring efficiency is further improved, which can further suppress side reactions and further increase the yield of compound P2. If the upper limit of the reaction temperature in step (B1) is below the above-mentioned preferred upper limit, the reaction temperature of compound P1 and R can be appropriately controlled. 2 The reaction rate of OH can further suppress side reactions.

[0095] For example, the reaction temperature of 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 process (B1), R flows within the flow path. 2 The lower limit of the OH flow rate is 0.01 mL / min or more, preferably 0.1 mL / min or more, more preferably 1 mL / min or more, and even more preferably 2 mL / min or more. Additionally, in process (B1), R flows within the flow path. 2 There is no specific upper limit to the flow rate of OH; for example, it can be below 10 mL / min, below 8 mL / min, or below 5 mL / min.

[0097] In process (B1), if R flows within the flow path 2 If the lower limit of the OH flow rate is above 0.01 mL / min, the stirring efficiency will be improved, which can further suppress side reactions. Additionally, in process (B1), if R flows within the flow path... 2 If the lower limit of the OH flow rate is above the aforementioned preferred lower limit, the stirring efficiency will be further improved, side reactions can be further suppressed, and the yield of compound P2 can be further improved. Additionally, in process (B1), if R flows within the flow path... 2 If the upper limit of the OH flow rate is below the aforementioned preferred upper limit, the flow rate of compound P1 and R can be appropriately controlled. 2 The reaction rate of OH can further suppress side reactions.

[0098] For example, in process (B1), R flows within the flow path. 2 The flow rate of OH 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, even more preferably 1 mL / min or more and 5 mL / min or less, and particularly preferably 2 mL / min or more and 5 mL / min or less.

[0099] In step (B1), compounds P1 and R are reacted in the mixer of the flow-through reaction apparatus. 2 There is no particular limitation on the reaction time of the OH reaction. For example, it can be from 0.01 seconds to 1 minute, from 1 second to 30 seconds, or from 1 second to 20 seconds.

[0100] In step (B1), compound P2 is synthesized by removing one chlorine atom (or one bromine atom) of compound P1 from R. 2 A compound in which the hydroxyl group of OH is substituted with a group that removes one hydrogen atom. Alternatively, compound P2 can also be described as a compound in which one chlorine atom of phosphorus trichloride (or one bromine atom of phosphorus tribromide) is removed from R. 1 The hydroxyl group of OH is substituted with a group that removes one hydrogen atom, and the other chlorine atom (or another bromine atom) is removed from R.2 A compound in which the hydroxyl group of OH is replaced by 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 replaced by a group (HG1), and another chlorine atom of phosphorus trichloride or another bromine atom of phosphorus tribromide is replaced by a group (HG2), wherein said group (HG1) is a group that removes one hydrogen atom from the hydroxyl group of the aforementioned monohydric alcohol, polyalkylene glycol monoether, polyalkylene glycol monoester, polyhydric alcohol, sugar, glycerol fatty acid ester, glycolamide, or nucleoside, and said group (HG2) is a group that removes one hydrogen atom from the hydroxyl group of the aforementioned monohydric alcohol, polyalkylene glycol monoether, polyalkylene glycol monoester, polyhydric alcohol, sugar, glycerol fatty acid ester, glycolamide, or nucleoside (however, HG1 and HG2 are different substituents).

[0101] Process (C1) Step (C1) involves reacting the above compound P2 with the third hydroxyl compound (R). 3 The process of synthesizing compound P3, represented by the general formula (P-3), by reacting OH) with OH.

[0102] [Chemistry 9] [In the formula, R] 1 ~R 3 Each is an independent organic group. However, R 1 ~R 3 These are all different organic groups. X is a bromine or chlorine atom.

[0103] In the above general formulas (H-3) and (P-3), R 3 As an organic group, examples of groups related to R mentioned above can be given. 1 Same group. However, R 1 ~R 3 They are all different organic groups.

[0104] As R 3 OH, examples of R mentioned above can be cited. 1 The same substance as OH. However, R 3 OH and R 2 OH and R 1 OH is not the same compound.

[0105] As described above, process (C1) can, for example, convert R... 3 OH is stored in a container, and compound P3 is synthesized by allowing the above compound P2 to flow into the container.

[0106] The reaction temperature of step (C1) is not particularly limited, but 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] In step (C1), compound P3 is synthesized by removing one chlorine atom (or one bromine atom) from compound P2 from R. 3 A compound in which the hydroxyl group of OH is replaced by a group that has 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 replaced by a group (HG1), and another chlorine atom of phosphorus trichloride or another bromine atom of phosphorus tribromide is replaced by a group (HG2), and the remaining chlorine atom of phosphorus trichloride or the remaining bromine atom of phosphorus tribromide is replaced by a group (HG3), wherein said group (HG1) is derived from the above-mentioned monohydric alcohol, polyalkylene glycol monoether, polyalkylene glycol monoester, polyol, sugar, glycerol fatty acid ester, glycolamide, or The group (HG2) is a group that removes one hydrogen atom from the hydroxyl group of the aforementioned monohydric alcohol, polyalkylene glycol monoether, polyalkylene glycol monoester, polyol, sugar, glycerol fatty acid ester, glycolamide, or nucleoside. The group (HG3) is a group that removes one hydrogen atom from the hydroxyl group of the aforementioned monohydric alcohol, polyalkylene glycol monoether, polyalkylene glycol monoester, polyol, sugar, glycerol fatty acid ester, glycolamide, or nucleoside (however, HG1, HG2, and HG3 are different substituents).

[0108] Process (D1) Step (D1) is the process of oxidizing the above compound P3 to synthesize an asymmetric phosphate triester.

[0109] [Chemistry 10] [In the formula, R] 1 ~R 3 Each is an independent organic group. However, R 1 ~R 3 These are all different organic groups.

[0110] There are no particular limitations on the method of oxidizing compound P3 to obtain an asymmetric phosphate triester. For example, compound P3 can be oxidized by reacting it with a specific oxidizing agent. The oxidizing agent is not particularly limited, but examples include: m-chloroperbenzoic acid (mCPBA), sodium hypochlorite pentahydrate, trichloroisocyanuric acid, tert-butyl hypochlorite, N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, iodine and other halogen-containing oxidizing agents; aqueous solution of hydrogen peroxide (peracidified hydrogen water); tert-butyl hydrogen peroxide, etc.

[0111] The reactions in steps (A1) to (D1) can also be carried out in the presence of a solvent. The solvent is not particularly limited, but a solvent that does not hinder the reaction of the compounds is preferred, and solvents with high solubility for the reactants used in the reaction and for the compounds produced during the reaction are also preferred. Examples include dichloromethane (DCM), tetrahydrofuran (THF), diethyl ether (Et2O), 1,4-dioxane, acetonitrile (MeCN), chloroform, and N,N-dimethylformamide (DMF).

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

[0113] The asymmetric triphosphates obtained through the above process (D1) also include asymmetric trithiophosphates. For example, an asymmetric trithiophosphate can be obtained through the reaction shown below.

[0114] [Chemistry 11] [In the formula, R] 1 ~R 3 Each is an independent organic group. However, R 1 ~R 3 These are all different organic groups.

[0115] There is no particular limitation on the method of oxidizing compound P3 to obtain asymmetric trithiophosphate. For example, compound P3 can be oxidized by reacting it with a specific oxidizing agent. There are no particular limitations on the oxidizing agent; for example, hydrogenated xanthanin can be cited.

[0116] The method for manufacturing asymmetric triphosphates according to the first embodiment described above is a method for manufacturing asymmetric triphosphates, characterized by using a flow-through reaction apparatus, maintaining the reaction temperature in steps (A1) and (B1) at -80°C or higher, and maintaining the flow rates of phosphorus trichloride or phosphorus tribromide, the first hydroxyl compound, and the second hydroxyl compound flowing in the flow path at 0.01 mL / min or higher. By appropriately controlling the reaction temperature and flow rate, stirring efficiency can be improved and side reactions can be suppressed. Therefore, according to the method for manufacturing asymmetric triphosphates according to the first embodiment, the target triphosphate can be manufactured at a lower cost and with a higher yield.

[0117] In the method for manufacturing asymmetric triphosphates according to the first embodiment described above, the preferred flow rate varies depending on the inner diameter of the mixer in the flow-through reaction apparatus. For example, the preferred range of flow rates for the aforementioned phosphorus trichloride or phosphorus tribromide, the first hydroxyl compound, and the second hydroxyl compound is particularly preferred when the inner diameter of the mixer is 0.25 mm. For example, in a flow-through reaction apparatus, the inner diameter of the mixer is N times (making the cross-sectional area N). 2 In the case of (times), the preferred values ​​for the above-mentioned flow rates are respectively N 2 times.

[0118] More specifically, when the inner diameter of the mixer in the flow-through reaction apparatus is 0.25 mm, the flow rate of each compound 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, even more preferably 1 mL / min or more and 5 mL / min or less, and particularly preferably 2 mL / min or more and 5 mL / min or less.

[0119] When the inner diameter of the mixer in the flow-through reaction apparatus is 1 mm, it is preferable to set the above value to 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] Furthermore, in the method for manufacturing the asymmetric triphosphate in the first embodiment described above, it can be said that when the inner diameter of the mixer in the flow-through reaction apparatus is set to ID, the flow rate of each compound is preferably the aforementioned preferred flow rate multiplied by (ID / 0.25). 2 The value of . That is, in the method for manufacturing asymmetric triphosphates according to the first embodiment described above, when the inner diameter of the mixer in the flow-through reaction apparatus is set to ID, the flow rate of each compound is preferably 0.01 × (ID / 0.25). 2 The flow rate is above mL / min and 10 × (ID / 0.25) 2 Below mL / min, more preferably 0.1×(ID / 0.25) 2 The flow rate is above mL / min and 8×(ID / 0.25) 2 Below mL / min, more preferably 1×(ID / 0.25) 2 ≥ mL / min and 5×(ID / 0.25) 2 Below mL / min, particularly preferably 2×(ID / 0.25) 2 ≥ mL / min and 5×(ID / 0.25) 2 Below mL / min.

[0121] <Second Implementation Method> The method for manufacturing an asymmetric triphosphate according to the second embodiment is a method for synthesizing an asymmetric triphosphate using a flow-through reaction apparatus. The method comprises: step (A1), in which phosphorus trichloride or phosphorus tribromide is reacted with a first hydroxyl compound to synthesize compound P1; step (N1), in which compound P1 is reacted with a base to synthesize compound N1; step (BN1), in which compound N1 is reacted with a second hydroxyl compound to synthesize compound N2; step (CN1), in which compound N2 is reacted with a third hydroxyl compound to synthesize compound P3; and step (D1), in which compound P3 is oxidized to synthesize the asymmetric triphosphate.

[0122] The steps (A1) and (D1) in the method for manufacturing the asymmetric triphosphate of the second embodiment are the same as the steps (A1) and (D1) in the method for manufacturing the asymmetric triphosphate of the first embodiment described above.

[0123] Process (N1) Step (N1) is the process of reacting compound P1 with a base (nucleophilic base) to synthesize compound N1, which is represented by the following general formula (N-1).

[0124] [Chemistry 12] [In the formula, R] 1 It is an organic group. B 1This is a group that removes one hydrogen atom from a base. X is a bromine or chlorine atom.

[0125] As long as it is a nucleophilic base, there are no particular limitations. Specifically, the base is preferably selected from 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 (4-methylimidazole)), and 1,4-diazabicyclo[2,2,2]octane, more preferably imidazole or imidazole derivatives, and even more preferably compounds represented by the following general formula (I-1).

[0126] [Chemistry 13] [In the formula, RI 1 and RI 2 It is a hydrogen atom or a hydrocarbon group.

[0127] RI in the above general formula (I-1) 1 and RI 2 The hydrocarbon group in it can be an aliphatic hydrocarbon group or an aromatic hydrocarbon group (aryl). The aliphatic hydrocarbon group can be straight-chain, branched, or cyclic. If cyclic, it can be monocyclic or polycyclic. The number of carbon atoms in the aliphatic hydrocarbon group can be 1–20 or 1–15. The aliphatic hydrocarbon group can be a saturated aliphatic hydrocarbon group (alkyl) or an unsaturated aliphatic hydrocarbon group, preferably an alkyl group. The alkyl group can have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 5 carbon atoms.

[0128] Examples of linear or branched alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 3,3-dimethylpentyl, 3-ethylpentyl, 2,2,3-trimethylbutyl, n-octyl, isooctyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecanyl, octadecyl, nonadecanyl, eicosyl, etc.

[0129] The lower limit of the reaction temperature of process (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. In addition, there is no particular limit to the upper limit of the reaction temperature of process (N1), but it is preferably 80°C or less, more preferably 60°C or less, and even more preferably 40°C or less.

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

[0131] For example, the reaction temperature of process (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 process (N1), the lower limit of the flow rate of the alkali flowing in the flow path is 0.01 mL / min or more, preferably 0.1 mL / min or more, and more preferably 1 mL / min or more. In addition, in process (N1), there is no particular limit to the upper limit of the flow rate of the alkali flowing in the flow path. For example, it can be less than 10 mL / min, less than 8 mL / min, or less than 5 mL / min.

[0133] In step (N1), if the flow rate of the alkali flowing in the flow path 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 process (N1), the flow rate of the alkali flowing in the flow path can 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 process (N1), the reaction time for compound P1 and base to react in the mixer of the flow system reaction apparatus is not particularly limited, for example, it can be 0.01 seconds to 1 minute, 1 second to 30 seconds, or 1 second to 20 seconds.

[0136] In process (N1), the synthesized compound N1 is formed by the removal of one chlorine atom from phosphorus trichloride or one bromine atom from phosphorus tribromide, from R. 1 A compound in which the hydroxyl group of OH is substituted with a group that removes one hydrogen atom, and the remaining two chlorine atoms or the remaining two bromine atoms are substituted with a group that removes one hydrogen atom 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 replaced by a group that removes one hydrogen atom from the hydroxyl group of the aforementioned monohydric alcohol, polyalkylene glycol monoether, polyalkylene glycol monoester, polyhydric alcohol, sugar, glycerol 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 each replaced by a group that removes one hydrogen atom from pyridine, pyridine derivatives, imidazole, imidazole derivatives, or 1,4-diazabicyclo[2,2,2]octane.

[0137] Process (BN1) Step (BN1) is the process of reacting compound N1 with a second hydroxyl compound to synthesize compound N2, which is represented by the following general formula (N-2).

[0138] [Chemistry 14] [In the formula, R] 1 and R 2 These are different organic groups. B 1 It is a group formed by removing one hydrogen atom from a base.

[0139] In step (BN1), except that compound P1 is compound N1, it is the same as step (B1) in the method for manufacturing asymmetric triphosphate of the first embodiment described above.

[0140] In process (BN1), compound N2 is synthesized from a group of compound N1 that has had one hydrogen atom removed from the base and is obtained from R. 2 A compound in which the hydroxyl group of OH is replaced by a group that has 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 replaced by a group (HG1), and another chlorine atom of phosphorus trichloride or another bromine atom of phosphorus tribromide is replaced by a group (HG2) (however, HG1 and HG2 are different substituents), and the remaining chlorine atom of phosphorus trichloride or the remaining bromine atom of phosphorus tribromide is derived from pyridine, pyridine derivatives, imidazole, imidazole derivatives, or 1,4-diazabicyclo[2,2, 2] A compound substituted with a group having one hydrogen atom removed from octane, wherein the group (HG1) is a group having one hydrogen atom removed from the hydroxyl group of the aforementioned monohydric alcohol, polyalkylene glycol monoether, polyalkylene glycol monoester, polyhydric alcohol, sugar, glycerol fatty acid ester, alcoholamide, or nucleoside, and the group (HG2) is a group having one hydrogen atom removed from the hydroxyl group of the aforementioned monohydric alcohol, polyalkylene glycol monoether, polyalkylene glycol monoester, polyhydric alcohol, sugar, glycerol fatty acid ester, alcoholamide, or nucleoside.

[0141] Process (CN1) Step (CN1) is the process of reacting compound N2 with the third hydroxyl compound to synthesize compound P3.

[0142] [Chemistry 15] [In the formula, R] 1 ~R 3 Each is an independent organic group. However, R 1 ~R 3 They are all different organic groups. B 1 It is a group formed by removing one hydrogen atom from a base.

[0143] In step (CN1), except that compound P2 is compound N2, it is the same as step (C1) in the method for manufacturing asymmetric triphosphate of the first embodiment described above.

[0144] The reactions in steps (A1), (N1), (BN1), and (CN1) can also be carried out in the presence of a solvent. This solvent is not particularly limited, but a solvent that does not hinder the reaction of the compounds is preferred, and a solvent with high solubility for the starting materials used in the reaction is also preferred. Examples 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) can also be carried out in the presence of a non-nucleophilic base. This non-nucleophilic base is not particularly limited, as long as it can capture the HCl produced during the reaction. Examples include N,N-diisopropylethylamine (DIEA), triethylamine, diazabicycloundecene, 2,6-dimethylpyridine, N-methylmorpholine, N-ethylmorpholine, N-benzyldimethylamine, and tributylamine.

[0146] The method for manufacturing the asymmetric triphosphate in the second embodiment described above further includes a step (N1) in addition to each step of the method for manufacturing the asymmetric triphosphate in the first embodiment. By replacing the two chlorine atoms (or the two bromine atoms) of compound P1 with groups that have had one hydrogen atom removed from the base, reactivity can be appropriately suppressed. Therefore, the method for manufacturing asymmetric triphosphates according to the second embodiment can produce the target triphosphates with higher yields.

[0147] Regarding the method for manufacturing the asymmetric triphosphate in the second embodiment, the preferred relationship between the flow rate and the inner diameter of the mixer in the flow system reaction apparatus is the same as that in the method for manufacturing the asymmetric triphosphate in the first embodiment described above. That is, when the inner diameter of the mixer in the flow-through reaction apparatus is set to ID, the preferred flow rate of each compound is preferably multiplied by (ID / 0.25) the aforementioned preferred flow rate. 2 The value of .

[0148] (Method for manufacturing symmetrical triphosphates according to the second aspect of the present invention) The following is for reference Figure 2 The method of the flow-through reaction apparatus described in this embodiment and the method of manufacturing symmetrical triphosphate using the apparatus will be explained. Figure 2 This is a schematic diagram showing the schematic configuration of a flow-through reaction apparatus 100. The flow-through reaction apparatus 100 includes: a tank 110 for containing a first liquid, a tank 120 for containing a second liquid, a tank 130 for containing a third liquid, and a tank 140 for containing a mixture of the third liquid and a fourth liquid.

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

[0150] The flow-through reaction apparatus 100 includes flow paths f10, f20, f30, f40, and f50 for conveying fluid. The inner diameter of the flow paths and the mixer can be, for example, 0.1 mm to 1 mm, 0.1 mm to 0.8 mm, or 0.2 mm to 0.6 mm. Alternatively, the inner diameter of the flow paths and the mixer can be 1 mm to several centimeters. Cans 110, 120, 130, and 140, as well as flow paths f10, f20, f30, f40, and f50, are formed, for example, of plastics, elastomers, resins, glass materials, metals, ceramics, etc.

[0151] Tank 110 is connected to pump 210. Through the operation of pump 210, the first liquid contained in tank 110 moves within flow path f10 and flows into mixer 310. Tank 120 is connected to pump 220. Through the operation of pump 220, the second liquid contained in tank 120 moves within flow path f20 and flows into mixer 310. Then, the first liquid and the second liquid are mixed by mixer 310 to become a first mixture, which is then conveyed to flow path f50. During this mixing process, R contained in the first liquid... 1 OH reacts with phosphorus trichloride or phosphorus tribromide contained in the second liquid to yield one chlorine atom of phosphorus trichloride or one bromine atom of phosphorus tribromide, which is then reacted with R. 1O-substituted compound P1 (step A2 of the method for manufacturing symmetric triphosphate). The first mixture containing the obtained compound P1 moves within flow path f40 and flows into mixer 320.

[0152] Tank 130 is connected to pump 230. Through the operation of pump 230, the third liquid contained in tank 130 moves within flow path f30 and flows into mixer 320. Then, the third liquid and the first mixture are mixed to form a second mixture, which is then conveyed to flow path f50. During this mixing process, compound P1 obtained in step A2 reacts with R contained in the third liquid. 2 The OH reaction yields compound P1, in which two chlorine atoms (or two bromine atoms) are reacted with R. 2 O-substituted compound P4 (step B2 of the method for manufacturing symmetrical triphosphate). The obtained compound P4 moves within flow path f50 and is stored in tank 140. Then, by oxidizing compound P4, a symmetrical triphosphate is synthesized, and the symmetrical triphosphate is stored in tank 140 (step D2 of the method for manufacturing symmetrical triphosphate).

[0153] Compound P1 is highly reactive and readily reacts with R. 1 The side reaction of OH reacts again, making reaction control important. According to the flow-through reaction apparatus 100 described in this embodiment, the synthesized compound P1 can be rapidly released from the mixer, thereby suppressing side reactions and producing the target triphosphate in high yield.

[0154] The flow-through reaction apparatus 100 illustrates a method of mixing liquids using a mixer. However, since the mixing of liquids can be achieved simply by connecting the flow paths to each other, the flow-through reaction apparatus of this embodiment does not necessarily need to include a mixer.

[0155] <Third Implementation Method> The method for manufacturing symmetrical triphosphates according to the third embodiment is a method for synthesizing symmetrical triphosphates using a flow-through reaction apparatus. The method includes a step (A2) (hereinafter referred to as "step (A2)") in which phosphorus trichloride or phosphorus tribromide reacts with a first hydroxyl compound (R... 1 The reaction of OH) to synthesize compound P1; step (B2) (hereinafter referred to as "step (B2)"), wherein compound P1 is reacted with a second hydroxyl compound (R) to synthesize compound P1; step (B2) further involves reacting compound P1 with a second hydroxyl compound (R) to synthesize compound P1. 2 The process involves a reaction of OH to synthesize compound P4; and a step (D2) (hereinafter referred to as "step (D2)"), which oxidizes compound P4 to synthesize a symmetrical phosphate triester.

[0156] [Chemistry 16] [In the formula, R] 1 and R 2 These are different organic groups. X is a bromine or chlorine atom.

[0157] The reaction temperature in steps (A2) and (B2) is above -80°C, and the flow rate of phosphorus trichloride or phosphorus tribromide, the first hydroxyl compound, and the second hydroxyl compound in the flow path in steps (A2) and (B2) is above 0.01 mL / min. Furthermore, the preferred ranges for the reaction temperature and flow rate are the same as those described in steps (A1) and (B1) of the method for manufacturing the asymmetric triphosphate in the first embodiment described above. Furthermore, step (D2) is the same as step (D1) described in the method for manufacturing asymmetric triphosphates in the first embodiment described above.

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

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

[0160] The method for manufacturing a symmetrical triphosphate according to the third embodiment described above is characterized by using a flow-through reaction apparatus, maintaining the reaction temperature in steps (A2) and (B2) at -80°C or higher, and maintaining the flow rates of phosphorus trichloride or phosphorus tribromide, the first hydroxyl compound, and the second hydroxyl compound flowing in the flow path at 0.01 mL / min or higher. By appropriately controlling the reaction temperature and flow rate, stirring efficiency can be improved and side reactions can be suppressed. Therefore, according to the method for manufacturing symmetrical triphosphates according to the third embodiment, the target triphosphate can be manufactured at a lower cost and with a higher yield.

[0161] Regarding the method for manufacturing the symmetrical triphosphate in the third embodiment, the preferred relationship between the flow rate and the inner diameter of the mixer in the flow system reaction apparatus is the same as that in the method for manufacturing the asymmetrical triphosphate in the first embodiment described above. That is, when the inner diameter of the mixer in the flow-through reaction apparatus is set to ID, the preferred flow rate of each compound is preferably multiplied by (ID / 0.25) the aforementioned preferred flow rate. 2 The value of .

[0162] (Method for manufacturing phosphate esters according to the third aspect of the present invention) The method for manufacturing phosphate esters according to the third aspect of the present invention is a method for synthesizing phosphate esters using a flow-through reaction apparatus, wherein the method comprises: step (A11) (hereinafter referred to as "step (A11)"), wherein step (A11) involves reacting phosphorus trichloride or phosphorus tribromide with a first hydroxyl compound represented by the following general formula (H1-1) to synthesize compound P11 represented by the following general formula (P1-1); and step (B11) (hereinafter referred to as "step (B11)"), wherein step (B11) involves reacting compound P11 with a first hydroxyl compound represented by the following general formula (H1-1) to synthesize compound P11. 11 reacts with the second hydroxyl compound represented by the following general formula (H1-2) to synthesize compound P12 represented by the following general formula (P1-2); step (C11) (hereinafter referred to as "step (C11)"), said step (C11) reacts compound P12 with the third hydroxyl compound represented by the following general formula (H1-3) to synthesize compound P13 represented by the following general formula (P1-3); and step (D11) (hereinafter referred to as "step (D11)"), said step (D11) oxidizes compound P13 to synthesize a phosphate ester. Unlike the manufacturing methods described above, in the manufacturing method of the phosphate ester according to the third aspect of the present invention, at least one of the first to third hydroxyl compounds is water, therefore the manufacturing method of the phosphate ester is specifically a manufacturing method of monophosphate or diephosphate.

[0163] [Chemistry 17] [R 11 ~R 13 Each can be independently a hydrogen atom or an organic group. However, R 11 ~R 13 In this context, at least one is an organic group, and at least one is a hydrogen atom. X is a bromine or chlorine atom.

[0164] An example of the reaction formula when the method for producing the phosphate ester is the method for producing a phosphate monoester is shown below. In the following reaction formula, compound P12, which is represented by the general formula (P1-2) when the second hydroxyl compound is water, is labeled as compound P12-1, and compound P13, which is represented by the general formula (P1-3) when the third hydroxyl compound is also water, is labeled as compound P13-1.

[0165] [Chemistry 18]

[0166] An example of the reaction formula when the method for producing the phosphate ester is the method for producing a phosphate diester is shown below. In the following reaction formula, compound P13, which is represented by the general formula (P1-3) when only the third hydroxyl compound is water, is designated as compound P13-2.

[0167] [Chemistry 19]

[0168] Regarding the first hydroxyl compound, the second hydroxyl compound, and the third hydroxyl compound in the method for manufacturing the phosphate ester according to the third aspect of the present invention, examples can be cited that are similar to the above-described R. 1 OH, R 2 OH and R 3 OH is an example of the same substance as the hydroxyl compound shown, as well as water.

[0169] The reaction temperature in steps (A11) and (B11) is above -80°C, and the flow rate of phosphorus trichloride or phosphorus tribromide, the first hydroxyl compound, and the second hydroxyl compound flowing in the flow path in steps (A11) and (B11) is above 0.01 mL / min. Furthermore, the preferred ranges for the reaction temperature and flow rate are the same as those described in steps (A1) and (B1) of the method for manufacturing the asymmetric triphosphate in the first embodiment described above. Furthermore, the process (D11) is the same as the process (D1) described in the method for manufacturing asymmetric triphosphates in the first embodiment described above.

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

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

[0172] The method for manufacturing phosphate esters described above in the third aspect of the present invention is a method for manufacturing monophosphate or diphosphate esters. The method is characterized by using a flow-through reaction apparatus, maintaining the reaction temperature in steps (A11) and (B11) at -80°C or higher, and maintaining the flow rates of phosphorus trichloride or phosphorus tribromide, the first hydroxyl compound, and the second hydroxyl compound flowing within the flow path at 0.01 mL / min or higher. By appropriately controlling the reaction temperature and flow rate, stirring efficiency can be improved and side reactions suppressed. Therefore, according to the method for manufacturing phosphate esters according to the third aspect of the present invention, the target monophosphate or phosphate diester can be manufactured at a lower cost and with a higher yield.

[0173] Regarding the method for manufacturing phosphate esters according to the third aspect of the present invention, the preferred relationship between the flow rate and the inner diameter of the mixer in the flow system reaction apparatus is the same as that in the method for manufacturing asymmetric triphosphate esters according to the first embodiment described above. That is, when the inner diameter of the mixer in the flow-through reaction apparatus is set to ID, the preferred flow rate of each compound is preferably multiplied by (ID / 0.25) the aforementioned preferred flow rate. 2 The value of .

[0174] (Method for manufacturing organophosphorus compounds according to the fourth aspect of the present invention) The method for manufacturing an organophosphorus compound according to the fourth aspect of the present invention is a method for manufacturing an organophosphorus compound that uses a flow-through reaction apparatus to synthesize the organophosphorus compound. The method comprises: step (A01), in which phosphorus trichloride or phosphorus tribromide is reacted with a first hydroxyl compound represented by the following general formula (HO-1) to synthesize compound PO1 represented by the following general formula (PO-1); and step (B01), in which compound PO1 is reacted with a second hydroxyl compound represented by the following general formula (HO-2). The reaction of a hydroxyl compound to synthesize compound PO2 as shown in general formula (PO-2); and step (C01) in which compound PO2 is reacted with a third hydroxyl compound to synthesize compound PO3 as shown in general formula (PO-3), wherein the reaction temperature in steps (A01) and (B01) is above -80°C, and the flow rates of phosphorus trichloride or phosphorus tribromide, the first hydroxyl compound, and the second hydroxyl compound flowing in the flow path in steps (A01) and (B01) are above 0.01 mL / min.

[0175] [Chem.20] [R 01 ~R 03 Each can be independently a hydrogen atom or an organic group. However, R 01 ~R 03 In R, at least one is an organic group. 01 ~R 03 If all groups are organic, not all of the organic groups are the same. X is a bromine atom or a chlorine atom.

[0176] More specifically, the method for manufacturing the organophosphorus compound according to the fourth aspect of the present invention is a method for manufacturing an intermediate in the method for manufacturing the asymmetric phosphate triester according to the first aspect of the present invention, the method for manufacturing the symmetric phosphate triester according to the second aspect of the present invention, and the method for manufacturing the phosphate ester according to the third aspect of the present invention. That is, the above-mentioned compound PO3 includes all of the above-mentioned compounds P3, P4, and P13. This organophosphorus compound also includes tautomers. For example, as tautomers of the above-mentioned compound P13, examples of tautomers of compounds P13-1 and P13-2 can be given, specifically examples of compounds P13-1-1 and P13-2-1.

[0177] [Chemistry 21]

[0178] Specifically, examples of the first hydroxyl compound, the second hydroxyl compound, and the third hydroxyl compound in the method for manufacturing the organophosphorus compound according to the fourth aspect of the present invention can be given as R. 1 OH, R 2 OH and R 3 The hydroxyl compounds exemplified by OH are the same compounds as water.

[0179] The reaction temperature in process (A01) and process (B01) is above -80℃, and the flow rate of phosphorus trichloride or phosphorus tribromide, the first hydroxyl compound and the second hydroxyl compound flowing in the flow path in process (A01) and process (B01) is above 0.01mL / min. Furthermore, the preferred ranges for the reaction temperature and flow rate are the same as those described in steps (A1) and (B1) of the method for manufacturing the asymmetric triphosphate in the first embodiment described above.

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

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

[0182] The method for manufacturing organophosphorus compounds according to the fourth aspect of the present invention described above is a method for manufacturing organophosphorus compounds (intermediates) for producing monophosphate, diephosphate, or triphosphate esters. The method is characterized by using a flow-through reaction apparatus, maintaining the reaction temperature in steps (A01) and (B01) at -80°C or higher, and maintaining the flow rate of phosphorus trichloride or phosphorus tribromide, the first hydroxyl compound, and the second hydroxyl compound flowing in the flow path at 0.01 mL / min or higher. By appropriately controlling the reaction temperature and flow rate, stirring efficiency can be improved and side reactions suppressed. Therefore, according to the method for manufacturing organophosphorus compounds according to the fourth aspect of the present invention, organophosphorus compounds (intermediates) can be manufactured at a lower cost and in higher yield, said organophosphorus compounds (intermediates) being used to manufacture phosphate monoesters, phosphate diesters or phosphate triesters as targets.

[0183] Regarding the method for manufacturing organophosphorus compounds according to the fourth aspect of the present invention, the preferred relationship between the flow rate and the inner diameter of the mixer in the flow system reaction apparatus is the same as that in the method for manufacturing asymmetric triphosphates according to the first embodiment described above. That is, when the inner diameter of the mixer in the flow-through reaction apparatus is set to ID, the preferred flow rate of each compound is preferably multiplied by (ID / 0.25) the aforementioned preferred flow rate. 2 The value of .

[0184] (Method for manufacturing organophosphorus compounds according to the fifth aspect of the present invention) The fifth aspect of the present invention describes a method for manufacturing an organophosphorus compound, which is a method for synthesizing an organophosphorus compound using a flow-through reaction apparatus. The method comprises: a step (AZ1) in which phosphorus trichloride or phosphorus tribromide is reacted with a first compound to synthesize a compound PZ1 represented by the general formula (PZ-1), wherein the first compound is any one of a hydroxyl compound, an amine compound, or a thiol compound; and a step (BZ1) in which compound PZ1 is reacted with a second compound to synthesize a compound PZ represented by the general formula (PZ-2). 2, wherein the second compound is any one of a hydroxyl compound, an amine compound, or a thiol compound; and step (CZ1), wherein step (CZ1) reacts compound PZ2 with the third compound to synthesize compound PZ3 represented by the following general formula (PZ-3), wherein the third compound is any one of a hydroxyl compound, an amine compound, or a thiol compound, wherein the reaction temperature in steps (AZ1) and (BZ1) is above -80°C, and the flow rate of phosphorus trichloride or phosphorus tribromide, the first compound, and the second compound flowing in the flow path in steps (AZ1) and (BZ1) is above 0.01 mL / min.

[0185] [Chemistry 22] [In the formula, Z] 1 ~Z 3 Each of these can be independently represented by a hydrogen atom, a group that has removed one hydrogen atom from a hydroxyl compound, a group that has removed one hydrogen atom from an amine compound, or a group that has removed one hydrogen atom from a thiol compound. However, Z 1 ~Z3 Not all are the same. X is either a bromine atom or a chlorine atom.

[0186] The reaction temperature in process (AZ1) and process (BZ1) is above -80°C, and the flow rate of phosphorus trichloride or phosphorus tribromide, compound 1 and compound 2 flowing in the flow path in process (AZ1) and process (BZ1) is above 0.01 mL / min. Furthermore, the preferred ranges for the reaction temperature and flow rate are the same as those described in steps (A1) and (B1) of the method for manufacturing the asymmetric triphosphate in the first embodiment described above.

[0187] The reactions in steps (AZ1) and (BZ1) can also be carried out in the presence of a solvent. This solvent is not particularly limited, but a solvent that does not hinder the reaction of the compounds is preferred, and a solvent with high solubility of the starting materials used in the reaction is also preferred. Examples include dichloromethane (DCM), tetrahydrofuran (THF), diethyl ether (Et2O), 1,4-dioxane, acetonitrile (MeCN), chloroform, and N,N-dimethylformamide (DMF).

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

[0189] <Compound 1 to Compound 3> Compounds 1 through 3 are different hydroxyl compounds, amine compounds, or thiols.

[0190] Hydroxy compounds Examples of hydroxyl compounds among compounds 1 through 3 that are related to the aforementioned R 1 OH, R 2 OH and R 3 The hydroxyl compounds exemplified by OH are the same compounds as water.

[0191] <Amine compounds> Examples of amine compounds among compounds 1 to 3 include aliphatic amines, mixed amines, aromatic amines, heterocyclic amines, nitrogen-containing compounds with carboxyl groups, nitrogen-containing compounds with sulfonyl groups, nitrogen-containing compounds with hydroxyl groups, amide derivatives, and imide derivatives.

[0192] Examples of aliphatic amines include primary aliphatic amines and secondary aliphatic amines. As aliphatic primary amines, examples include methylamine, ethylamine, n-propylamine, isopropylamine, n-butylamine, isobutylamine, sec-butylamine, tert-butylamine, pentylamine, tert-pentylamine, cyclopentylamine, hexylamine, cyclohexylamine, heptylamine, octylamine, nonylamine, decylamine, dodecylamine, hexadecylamine, methylenediamine, ethylenediamine, and tetraethylenepentamine.

[0193] As aliphatic secondary amines, examples include dimethylamine, diethylamine, di-n-propylamine, diisopropylamine, di-n-butylamine, diisobutylamine, di-sec-butylamine, dipentylamine, dicyclopentylamine, dihexylamine, dicyclohexylamine, diheptylamine, dioctylamine, dinonylamine, didecylamine, di(dodecyl)amine, di(hexadecyl)amine, N,N-dimethylmethylenediamine, N,N-dimethylethylenediamine, and N,N-dimethyltetraethylenepentamine.

[0194] Examples of mixed amines include benzylamine, phenylethylamine, and benzyldimethylamine.

[0195] As aromatic amines and heterocyclic amines, specifically, 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, 3,5-dinitroaniline), diphenyl(p-tolyl)amine, phenylenediamine, naphthylamine, diaminonaphthalene, pyrrole derivatives (e.g., pyrrole, 1-methylpyrrole, 2,4-dimethylpyrrole, 2,5-dimethylpyrrole, etc.), imidazole derivatives, etc. Biological derivatives (e.g., imidazole, 4-methylimidazolium, 4-methyl-2-phenylimidazolium, etc.), pyrazole derivatives, pyrrololine derivatives (e.g., 2-pyrrololine, 3-pyrrololine, etc.), pyrrolidine derivatives (e.g., 2-methyl-pyrrolidine), imidazoline derivatives, imidazoline derivatives, pyrazoleline derivatives, pyrazoleidine derivatives, piperidine derivatives, piperazine derivatives, morpholine derivatives, indole derivatives, isoindole derivatives, 1H-indazole derivatives, dihydroindole derivatives, purine derivatives, carbazole derivatives, adenine derivatives, adenosine derivatives, guanine derivatives, guanosine derivatives, uracil derivatives, uridine derivatives, etc.

[0196] Examples of nitrogen-containing compounds with carboxyl groups include aminobenzoic acid, indolecarboxylic acid, and amino acid derivatives (such as 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] Examples of nitrogen-containing compounds with hydroxyl groups include carbamophenol, 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] As amide derivatives, examples include formamide, N-methylformamide, acetamide, N-methylacetamide, propionamide, benzamide, etc. Examples of imide derivatives include phthalimide, succinimide, and maleimide.

[0199] <Thiols> Examples of thiols among compounds 1 through 3 include aliphatic thiols, aromatic thiols, aliphatic polythiols, thiocarboxylic acid esters, thiocarboxylic acids, and thioethers.

[0200] As aliphatic thiols, specific examples include methyl thiols, ethyl thiols, 1-propyl thiols (n-propyl thiols), isopropyl thiols, 1-butyl thiols (n-butyl thiols), isobutyl thiols, tert-butyl thiols, 1-pentyl thiols, isopentyl thiols, 2-pentyl thiols, 3-pentyl thiols, 1-hexyl thiols, cyclohexyl thiols, 4-methyl-2-pentyl thiols, 1- Heptylthiol (n-heptylthiol), 2-heptylthiol, 1-octylthiol (n-octylthiol), isooctylthiol, 2-ethylhexylthiol, 2,4,4-trimethyl-2-pentylthiol (tert-octylthiol), 1-nonylthiol (n-nonylthiol), tert-nonylthiol (tert-nonylchool, tert-nonylmelcaptan), isononylthiol, 1-decyl 1-Undecylthiol, 1-Dodecylthiol, Tert-Dodecylthiol, Tridecylthiol, Tetradecylthiol, 1-Pentyldecylthiol, 1-Hexyldecylthiol, 1-Heptyldecylthiol, 1-Octyldecylthiol, Nonadecanylthiol, Eicosylthiol, Triacontylthiol Thiols, including tetraalkylthiols, pentaalkylthiols, hexaalkylthiols, heptanealkylthiols, octaalkylthiols, nonadecylthiols, cycloalkylthiols, 1-myristylthiols, hexadecylthiols, 1-stearylthiols, isostearylthiols, 2-octyldecylthiols, 2-octyldodecylthiols, 2-hexyldecylthiols, dodecylthiols, etc.

[0201] As aromatic thiols, specific examples include benzenethiol, benzylthiol, xylenethiol, 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, 1,2-bis(2-mercaptoethoxy)benzene, 1,3-bis(2-mercaptoethoxy)benzene, 1,4-bis(2-mercaptoethoxy)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-mercaptoethoxy)benzene, 1,2,4-Tris(2-mercaptoethoxy)benzene, 1,3,5-Tris(2-mercaptoethoxy)benzene, 1,2,3,4-Tetramercaptobenzene, 1,2,3,5-Tetramercaptobenzene, 1,2,4,5-Tetramercaptobenzene, 1,2,3,4-Tetra(mercaptomethyl)benzene, 1,2,3,5-Tetra( Mercaptomethyl)benzene, 1,2,4,5-tetra(mercaptomethyl)benzene, 1,2,3,4-tetra(2-mercaptoethyl)benzene, 1,2,3,5-tetra(2-mercaptoethyl)benzene, 1,2,4,5-tetra(2-mercaptoethyl)benzene, 1,2,3,4-tetra(2-mercaptoethoxy)benzene, 1,2,4,5-tetra(2-mercaptoethoxy)benzene, 2,2'-dimercaptobiphenyl, 4,4'-thiobis-benzyl, 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-Anthracenedimethylthiol, 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, 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-tetra(2-mercaptoethylthio)benzene, 1,2,4,5-Tetra(2-mercaptoethylthio)benzene, benzyl thiol, m-toluenethiol, p-toluenethiol, 2-naphthyl thiol, 2-pyridine thiol, 2-mercaptobenzimidazole, 2-mercaptobenzothiazole, etc.

[0202] Examples of aliphatic polythiols include: methyl dithiol, 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-1,5-pentanedithiol, 2-methyl-1,8-octanedithiol, 1,4-cyclohexanedithiol, 1,4-bis(mercaptomethyl)cyclohexane, 1,1-cyclohexanedithiol, 1,2-cyclohexanedithiol, bicyclo[2,2,1]hept-exo-cis-2,3-dithiol, 1,1-bis(mercaptomethyl)cyclohexane, 1,1-cyclohexanedithiol, 1,2-cyclohexanedithiol, bicyclo[2,2,1]hept-exo-cis-2,3-dithiol, and 1,1-bis(mercaptomethyl)cyclohexane. Dithiols such as cyclohexane (2-mercaptoethyl) ether, ethylene glycol bis(2-mercaptoacetate), and ethylene glycol bis(3-mercaptopropionate); trithiols 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 thiols with four or more SH groups such as pentaerythritol tetra(2-mercaptoacetate), pentaerythritol tetra(3-mercaptopropionate), pentaerythritol tetra(3-mercaptobutyrate), and dipentaerythritol hexa-3-mercaptopropionate.

[0203] Examples of 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), and trimethylolethane tris(3-mercaptobutyric acid). (Ester), trimethylolpropane tris(3-mercaptopropionate), trimethylolpropane tris(3-mercaptobutyrate), pentaerythritol tetra(3-mercaptopropionate), pentaerythritol tetra(3-mercaptobutyrate), dipentaerythritol hexa(3-mercaptopropionate), dipentaerythritol hexa(3-mercaptobutyrate), tris[2-(3-mercaptopropionyloxy)ethyl]isocyanurate, tris[2-(3-mercaptobutyryloxy)ethyl]isocyanurate, etc.

[0204] Other thiol compounds include mercaptoacetic acid, 3-mercaptopropionic acid, 2-mercaptopropionic acid, 3-mercaptobutyric acid, mercaptohexanoic acid, mercaptooctanoic acid, mercaptostearic acid, thioglycolic acid, and other thiocarboxylic acids; thioethers such as di(mercaptoethyl) ether; thioalcohol 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 equations (PZ-1) to (PZ-3), Z 1 ~Z 3 Each of the following is independently a hydrogen atom: a group that has removed one hydrogen atom from the aforementioned hydroxyl compound, a group that has removed one hydrogen atom from the aforementioned amine compound, or a group that has removed one hydrogen atom from the aforementioned thiol compound. However, Z 1 ~Z 3 Not all are the same.

[0206] The method for manufacturing an organophosphorus compound according to the fifth aspect of the present invention described above is a method for manufacturing an organophosphorus compound, characterized in that the manufacturing method uses a flow-through reaction apparatus, the reaction temperature in the above-described 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 in the flow path 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 manufacturing organophosphorus compounds according to the fifth aspect of the present invention, the target organophosphorus compound can be manufactured at a lower cost and in a higher yield.

[0207] Regarding the method for manufacturing the organophosphorus compound according to the fifth aspect of the present invention, the preferred relationship between the flow rate and the inner diameter of the mixer in the flow system reaction apparatus is the same as that in the method for manufacturing the asymmetric triphosphate of the first embodiment described above. That is, when the inner diameter of the mixer in the flow-through reaction apparatus is set to ID, the preferred flow rate of each compound is preferably multiplied by (ID / 0.25) the aforementioned preferred flow rate. 2 The value of . Example

[0208] The invention will then be described in more detail with reference to the embodiments shown, but the invention is not limited to the following embodiments.

[0209] [Synthesis of Symmetrical Triphosphates 1] (Examples 1-8, Comparative Example 1) Schematic diagrams of the methods for manufacturing symmetrical triphosphates in Examples 1 to 8 are shown below. Figure 3 . [raw material] 2-Indanol was used as R. 1 OH. Using ethanol as R 2 OH.

[0210] Examples 1 through 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 (inner diameter 0.25 mm) as described in Table 1 is used.

[0211] The solutions before the reaction were prepared in three different ways. Solution 1 was prepared by mixing 2-indanol, DIEA, and dichloromethane (DCM). The second solution was prepared by mixing phosphorus trichloride and dichloromethane (DCM). The third solution was prepared by mixing ethanol and dichloromethane (DCM). Regarding their respective equivalent ratios, it is 1.0 relative to 2-indanol, 3.0 relative to DIEA, 1.0 relative to phosphorus trichloride, and 10 relative to ethanol.

[0212] To synthesize the symmetrical phosphate triester, solutions 1 and 2 were first mixed in a T-type or V-type mixer as shown in Table 1 and reacted for 10 seconds at the reaction temperature shown in Table 1, thereby obtaining compound 3a. Then, the reaction solution containing compound 3a was immediately mixed with solution 3 using a new T-type mixer and reacted for 5 seconds at the reaction temperature shown in Table 1, thereby obtaining compound 4a. Compound 4a was then stored while being stirred at room temperature (25°C) for 10 minutes. Then, compound 4a was reacted with m-chloroperbenzoic acid (mCPBA) at room temperature (25°C) for 1 hour to oxidize compound 4a, thereby giving the main product 5a. Additionally, byproduct 5b was also obtained from a side reaction. The solutions were dispensed using a syringe pump. The flow rates of the first and third solutions are shown in Table 1, and the flow rate of the second solution was the flow rate shown in Table 1 × 0.6.

[0213] Comparative Example 1 Following the same order as above, the first solution, the second solution, the third solution, and mCPBA were added dropwise to a test tube stirred by a magnetic stirrer to obtain the main product 5a and the byproduct 5b in batches.

[0214] The reactions used to synthesize symmetrical phosphate triesters by the manufacturing methods of Examples 1 to 8 and Comparative Example 1 are shown below.

[0215] [Chemistry 23]

[0216] [Analytical Method] The main product 5a and byproduct 5b were identified by NMR spectroscopy. Additionally, the yields were measured using HPLC-UV. The NMR spectral data are shown below, and the yields of the main product 5a and byproduct 5b are shown in Table 1.

[0217] Main product 5a: Colorless oily substance;

[0218] Byproduct 5b: Colorless oily substance;

[0219] [Table 1]

[0220] As shown in Table 1, when symmetrical phosphate triesters are manufactured by the manufacturing method of the examples, the yield of the main product 5a is higher than that of the manufacturing method of the comparative examples.

[0221] [Synthesis of Symmetrical Triphosphates 2] (Examples 9 to 14) Schematic diagrams of the methods for producing symmetrical phosphate triesters in Examples 9 to 14 are shown below. Figure 4 . [raw material] 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 glycolate (Example 14) were used as R 1 OH. 2-Indanol (Examples 9-14) was used as R. 2 OH.

[0222] As a flow-through reaction apparatus, a flow-through reaction apparatus consisting of PTFE tubing (inner diameter 0.80 mm, outer diameter 1.59 mm) and a T-type mixer and a V-type mixer (both with an inner diameter of 0.25 mm) is used.

[0223] The solutions before the reaction were prepared in three different ways. R above 1 The first solution is prepared by mixing any one of the OH groups, DIEA, and DCM. The second solution was prepared by mixing phosphorus trichloride and DCM. The third solution was prepared by mixing 2-indanol and DCM. Regarding their respective equivalence ratios, relative to R 1 OH is 1.0, DIEA is 3.0, phosphorus trichloride is 1.0, and 2-indanol is 2.5.

[0224] To synthesize the symmetrical phosphate triester, solutions 1 and 2 were first mixed in a V-type mixer and reacted at 20°C for 10 seconds to obtain compound 3. Then, the reaction solution containing compound 3 was immediately mixed with solution 3 using a new T-type 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 it, thereby obtaining main products 5c to 5h. The solutions were dispensed using a syringe pump. The flow rates for solutions 1 and 3 were 2.0 mL / min, and the flow rate for solution 2 was 1.2 mL / min.

[0225] The main products 5c to 5h were identified by NMR spectroscopy. Additionally, the yields were measured using HPLC-UV. The NMR spectral data, structure, and yield of the main product 5c to 5h are shown below. The relationship between the methods for producing the symmetrical phosphate triesters in Examples 9 to 14 and the obtained main products is as follows. Example 9: Main product 5c, Example 10: Main product 5d, Example 11: Main product 5e, Example 12: Main product 5f, Example 13: Main product 5g, Example 14: Main product 5h.

[0226] [Chemistry 24]

[0227] 5c: Purification method for n-butyl bis(2-inden-2-yl) phosphate: Column chromatography (hexane:ethyl acetate = 3:2) Colorless oily substance;

[0228] 5d: Purification method for sec-butylbis(2-inden-2-yl)phosphate: Column chromatography (hexane:ethyl acetate = 3:2) Colorless oily substance;

[0229] 5e: tert-butyl bis(inden-2-yl) phosphate Purification method: Column chromatography (hexane:ethyl acetate = 3:2) Colorless oily substance;

[0230] 5f: Bis(inden-2-yl)2-propen-1-yl-phosphate Purification methods: column chromatography (hexane:ethyl acetate = 3:2) and gel permeation chromatography. Colorless oily substance;

[0231] 5g: 3-[[tert-butyl(dimethyl)silyl]oxy]propane-1-yl bis(inden-2-yl)phosphate. Purification method: column chromatography (hexane:diethyl ether = 1:4). Colorless oily substance;

[0232] 5h: tert-Butyl glycolatyl bis(indan-2-yl)phosphate Purification method: Column chromatography (hexane:diethyl ether = 1:4) Colorless oily substance;

[0233] As described above, when symmetrical phosphate triesters are manufactured using the manufacturing method of the examples, main products 5c to 5h can be obtained in high yields.

[0234] [Synthesis of Asymmetric Triphosphates 1] (Examples 15-25, Comparative Example 2) Schematic diagrams of the methods for producing asymmetric triphosphates in Examples 15 to 25 are shown below. Figure 5 . Figure 5 As an example, N,N-diisopropylethylamine (DIEA) is shown as a base. Additionally, the term "base" in a compound refers to a group that has one hydrogen atom removed from a nucleophilic base. [raw material] 2-Indanol was used as R in Examples 15 to 25. 1 OH, using 2-phenylethanol (phenylethanol) as R 2 OH, using ethanol as R 3 OH. Use N,N-diisopropylethylamine (i-Pr2NEt), 2,6-dimethylpyridine (lutidine), N-methylmorpholine (NMM), N-ethylmorpholine (N-ethylmorpholine), N-benzyldimethylamine (Me2NBn), or tributylamine (n-Bu3N) as the base (non-nucleophilic base). Pyridine, imidazole, N-methylimidazole (NMI), 4-methylimidazole (4-methylimidazole), or 4-dimethylaminopyridine (DMAP) are used as nucleophilic bases.

[0235] Examples 15 to 25 As a flow-through reaction apparatus, a flow-through reaction apparatus consisting of PTFE tubing (inner diameter 0.80 mm, outer diameter 1.59 mm) and a T-type mixer and a V-type mixer (both with an inner diameter of 0.25 mm) is used.

[0236] The solutions before the reaction were prepared in four different ways. Solution 1 was prepared by mixing 2-indanol, the base shown in Table 2, and dichloromethane. The second solution was prepared by mixing phosphorus trichloride and DCM. The third solution was prepared by mixing the nucleophilic bases shown in Table 2 with DCM. The fourth solution was prepared by mixing 2-phenylethanol and DCM. Regarding the respective equivalent ratios, the ratios are as follows: 1.0 for 2-indanol, 3.0 for the base, 1.0 for phosphorus trichloride (0.5 for Examples 23-28), 2.0 for the nucleophilic base, 1.0 for 2-phenylethanol, and 10 for ethanol. The concentration Y[M] in Table 2 is the molar concentration of phosphorus trichloride.

[0237] To synthesize the asymmetric phosphate triester, solutions 1 and 2 were first mixed in a V-type mixer and reacted at 20°C for 10 seconds to obtain compound 3a. Then, immediately using a new T-type mixer, the reaction solution containing compound 3a was mixed with solution 3 and reacted at 20°C for 10 seconds to obtain compound 6a. Next, immediately using a new T-type mixer, the reaction solution containing compound 6a was mixed with solution 4 and reacted at 20°C for 5 seconds to obtain compound 7a. Then, the reaction solution containing compound 7a was transferred to a beaker containing ethanol and reacted at room temperature (25°C) for 10 minutes to obtain compound 7ab. Then, compound 7ab was reacted with mCPBA at room temperature (25°C) for 10 minutes to oxidize compound 7ab, thereby obtaining the main product 8a. Additionally, byproducts 8b and 8c were obtained through side reactions. The solutions were dispensed using a syringe pump. The flow rates for solutions 1 and 4 were 2.0 mL / min, and the flow rates for solutions 2 and 3 were 1.2 mL / min.

[0238] Comparative Example 2 Following the same order as above, the first solution, the second solution, the third solution, the fourth solution, ethanol, and mCPBA were added dropwise to a test tube stirred by a magnetic stirrer to obtain the main product 8a, byproduct 8b, and byproduct 8c in batches.

[0239] The reactions used to synthesize asymmetric triphosphates by the manufacturing methods of Examples 15 to 25 and Comparative Example 2 are shown below.

[0240] [Chemistry 25]

[0241] [Analytical Method] The main product 8a, byproduct 8b, and byproduct 8c were identified by NMR spectroscopy. Additionally, the yields were measured using HPLC-UV. The NMR spectral data are shown below, and the yields of main product 8a, byproduct 8b, and byproduct 8c are shown in Tables 2 and 3.

[0242] Main product 8a: Purification method: Preparative TLC (toluene:EtOAc = 4:1)

[0243] Byproduct 8b: Purification method: Preparative TLC (toluene:EtOAc = 4:1)

[0244] Byproduct 8c: Purification method: Preparative TLC (toluene:EtOAc = 4:1)

[0245] [Table 2]

[0246] [Table 3]

[0247] As shown in Tables 2 and 3, when the asymmetric phosphate triester was manufactured by the manufacturing method of the examples, the yield of the main product 8a was higher than that of the manufacturing method of the comparative examples.

[0248] [Synthesis of Asymmetric Triphosphates 2] (Examples 26 to 33) Schematic diagrams of the methods for manufacturing asymmetric triphosphates in Examples 26 to 33 are shown below. Figure 6 . [raw material] 2-Indanol was used as R in Example 26. 1 OH, using ethanol as R 2 OH, using phenol as R 3 OH. 1-Butanol was used as R in Example 27. 1 OH, using 2-indanol as R 2 OH, using phenol as R 3 OH. 2-Butanol was used as R in Example 28. 1 OH, using 2-indanol as R 2 OH, using phenol as R 3 OH. 2-Indanol was used as R in Example 29. 1 OH, using allyl alcohol as R 2 OH, using 2-methoxy-ethane-1-ol as R 3 OH. 2-Indanol was used as R in Example 30. 1 OH, using propargyl alcohol as R 2 OH, using 2-methoxy-ethane-1-ol as R 3 OH. 2-Indanol was used as R in Example 31. 1 OH, using tert-butyl (2-hydroxyethyl)carbamate as R 2 OH, using ethanol as R 3 OH. 2-Indanol was used as R in Example 32. 1 OH, using [[(9H-fluorenyl)methoxy]carbonyl]serine methyl ester as R 2 OH, using ethanol as R 3 OH. 3-benzoyl-1-[4-hydroxy-5-(tert-butyldimethylsiloxymethyl)tetrahydrofuran-2-yl]-5-methylpyrimidin-2,4(1H,3H)-dione was used as R in Example 33. 1 OH, using 5-(3-benzoyl-5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-(hydroxymethyl)tetrahydrofuran-3-ylbenzoate as R 2 OH, using 2-cyanoethanol as R 3 OH.

[0249] As a flow-through reaction apparatus, a flow-through reaction apparatus consisting of PTFE tubing (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) is used.

[0250] The solutions before the reaction were prepared in four different ways. R above 1 The first solution is prepared by mixing any of the OH groups, DIEA, and DCM. The second solution was prepared by mixing phosphorus trichloride and DCM. Imidazole and DCM were mixed to prepare solution 3. R above 2 To prepare the fourth solution, mix any of the OH groups with DCM. Regarding their respective equivalence ratios, relative to R 1 OH is 1.0, DIEA is 3.0, phosphorus trichloride is 1.0, R 2 OH is 1.0, imidazole is 2.0, R 3 The OH value is 4.0, and the mCPBA value (described later) is 1.4.

[0251] To synthesize the asymmetric triphosphate, solutions 1 and 2 were first mixed in a V-type mixer and reacted at 20°C for 10 seconds to obtain compound 1x. Then, immediately using a new T-type mixer, the reaction solution containing compound 1x was mixed with solution 3 and reacted at 20°C for 10 seconds to obtain compound 2x. Then, immediately using a new T-type mixer, the reaction solution containing compound 2x was mixed with solution 4 and reacted at 20°C for 30 seconds to obtain compound 3x. Finally, the reaction solution containing compound 3x was allowed to flow into a storage container containing R... 3 The OH group was reacted in a beaker at room temperature (25°C) for 10 minutes to obtain compound 4x. Then, compound 4x was reacted with mCPBA at room temperature (25°C) for 10 minutes to oxidize compound 4x, thereby obtaining main products 1y to 8y. The solutions were dispensed using a syringe pump. The flow rates for solutions 2 and 4 were 2.0 mL / min, and the flow rates for solutions 1 and 3 were 1.2 mL / min.

[0252] The reactions used to synthesize asymmetric phosphate triesters by the manufacturing methods of Examples 26 to 33 are shown below.

[0253] [Chemistry 26]

[0254] The main product was identified by NMR spectroscopy from 1 μL to 8 μL. Additionally, the yield was measured using HPLC-UV. The NMR spectral data, as well as the structures and yields of the main products 1y to 8y, are shown below. The relationship between the methods for producing 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] [Chemistry 27]

[0256] 1y: Ethylinden-2-ylphenyl phosphate Purification method: Column chromatography (hexane:EtOAc = 2:1) Colorless oily substance;

[0257] 2y: n-Butylinden-2-ylphenyl phosphate Purification method: Column chromatography (hexane:EtOAc = 2:1) Colorless oily substance;

[0258] 3y: sec-butylindene-2-ylphenyl phosphate Purification method: Column chromatography (hexane:EtOAc = 2:1) Colorless oily substance;

[0259] Purification method for 4y: indene-2-yl-2-methoxyethane-1-yl-2-propen-1-yl phosphate: preparative TLC (hexane:EtOAc = 2:3)

[0260] 5y: Purification method for inden-2-yl-2-methoxyethane-1-yl-2-propyn-1-yl phosphate: Column chromatography (hexane:EtOAc = 2:3) Colorless oily substance;

[0261] 6y: 2-(N-(tert-Butoxycarbonyl)-amino)-ethane-1-ylethylinden-1-yl phosphate Purification method: Column chromatography (hexane:EtOAc = 2:3) Colorless oily substance;

[0262] 7y: Ethyl 2-(N-(9-fluorenylmethoxycarbonyl)-amino)-3-methoxycarbonylethane-1-ylinden-1-yl phosphate Purification method: Column chromatography (hexane:EtOAc = 2:3) Colorless oily substance;

[0263] 8y: N3-Bz-5'-O-TBS-thymidine-3'-yl-2-cyanoethane-1-ylN3-Bz-3'-O-Bz-thymidine-5'-yl phosphate Purification method: Column chromatography (hexane:EtOAc = 1:4) Colorless oily substance;

[0264] As described above, when asymmetric phosphate triesters are manufactured using the manufacturing method of the examples, main products 1y to 8y can be obtained in high yields.

[0265] [Synthesis of Organophosphorus Compounds 1] (Example 34) [raw material] 2-Indanol was used as R. 1 OH. Using 2-butanol as R 2 OH. Use saturated saline solution as R. 3 OH.

[0266] As a flow-through reaction apparatus, a flow-through reaction apparatus consisting of PTFE tubing (inner diameter 0.80 mm, outer diameter 1.59 mm) and a T-type mixer and a V-type mixer (both with an inner diameter of 0.25 mm) is used.

[0267] The solutions before the reaction were prepared in four different ways. Solution 1 was prepared by mixing 2-indanol, DIEA, and DCM. The second solution was prepared by mixing phosphorus trichloride and DCM. Imidazole and DCM were mixed to prepare solution 3. The fourth solution was prepared by mixing 2-butanol and DCM. Regarding their respective equivalent ratios, they are 1.0 relative to 2-indanol, 3.0 relative to DIEA, 1.0 relative to phosphorus trichloride, 2.0 relative to imidazole, and 1.0 relative to 2-butanol.

[0268] To synthesize the organophosphorus compound, solutions 1 and 2 were first mixed in a V-type mixer and reacted at 20°C for 10 seconds to obtain compound 1p. Then, immediately using a new T-type mixer, the reaction solution containing compound 1p was mixed with solution 3 and reacted at 20°C for 10 seconds to obtain compound 2p. Next, immediately using a new T-type mixer, the reaction solution containing compound 2p was mixed with solution 4 and reacted at 20°C for 30 seconds to obtain compound 3p. Finally, the reaction solution containing compound 3p was transferred into a beaker containing 1 mL of saturated brine and reacted at room temperature (25°C) for 10 minutes to obtain organophosphorus compound 4p. The solutions were dispensed using a syringe pump. The flow rates for solutions 1 and 4 were 2.0 mL / min, and the flow rates for solutions 2 and 3 were 1.2 mL / min.

[0269] The reactions used to synthesize organophosphorus compounds by the manufacturing method of Example 34 are shown below. In addition, the 4p of organophosphorus compounds was identified by NMR determination. The structure, yield, and NMR spectral data of organophosphorus compound 4p are shown below.

[0270] [Chemistry 28]

[0271] Organophosphorus compounds 4p: Purification method: Preparative TLC (hexane:EtOAc = 3:2) (A mixture of diastereomers) [ (a mixture of diastereomers)

[0272] As described above, when an organophosphorus compound is manufactured using the manufacturing method of the examples, organophosphorus compound 4p can be obtained in high yield.

[0273] [Synthesis of Symmetrical Triphosphates 3] (Examples 35-40) In addition to R 1 OH and R 2 Except for the raw materials described below, symmetrical triphosphates are produced by the same method as in [Synthesis of Symmetrical Triphosphates 1].

[0274] In Example 35, n-butanol was used as R. 1 OH, using 2-phenylethanol (phenylethanol) as R 2 OH. In Example 36, 2-butanol was used as R. 1 OH, using 2-phenylethanol (phenylethanol) as R 2 OH. In Example 37, tert-butanol was used as R. 1 OH, using 2-phenylethanol (phenylethanol) as R 2 OH. In Example 38, 2-phenylethanol (phenylethanol) was used as R. 1 OH, using n-butanol as R 2 OH. In Example 39, 2-phenylethanol (phenylethanol) was used as R. 1 OH, using 2-butanol as R 2 OH. In Example 40, 2-phenylethanol (phenylethanol) was used as R. 1 OH, using phenol as R 2 OH.

[0275] The main products 5i to 5n were identified by NMR spectroscopy. The yields were measured using HPLC-UV. The NMR spectral data, precision mass determination data, and the structures and yields of main products 5i to 5n are shown below. The relationship between the methods for producing the symmetrical triphosphates in Examples 35 to 40 and the obtained main products is as follows. Example 35: Main product 5i, Example 36: Main product 5j, Example 37: Main product 5k, Example 38: Main product 5l, Example 39: Main product 5m, Example 40: Main product 5n.

[0276] [Chemistry 29]

[0277] Main product 5i: Butyl diphenylethyl phosphate Purification method: Preparative TLC (toluene:EtOAc = 4:1) Colorless oily substance;

[0278] Main product 5j: Diphenylethyl 1-methylpropyl phosphate Purification method: Preparative TLC (hexane:EtOAc = 3:1) Colorless oily substance;

[0279] Main product 5k: 1,1-Dimethylethyl diphenylethyl phosphate Purification method: GPC Colorless oily substance;

[0280] Main product 5l: Dibutylphenylethyl phosphate. Purification method: Preparative TLC (toluene:EtOAc = 4:1) and GPC. Colorless oily substance;

[0281] Main product 5m (a mixture of diastereomers): di-1-methylpropylphenethyl phosphate Purification method: Preparative TLC (toluene:EtOAc = 4:1) Colorless oily substance;

[0282] Main product 5n: diphenylphenylethyl phosphate Purification method: Preparative TLC (hexane:EtOAc = 4:1)

[0283] [Synthesis of Asymmetric Triphosphates 3] (Examples 41 to 45) In addition to R 1 OH, R 2 OH and R 3 Except for the raw materials described below, asymmetric triphosphates are produced by the same method as in [Synthesis of Asymmetric Triphosphates 2].

[0284] (Example 46) In addition to R 1 OH, R 2 OH and R 3 The asymmetric triphosphate (asymmetric trithiophosphate) is prepared by changing the OH to the following raw materials and changing the reagent used for oxidation from mCPBA to hydrogenated xanthanin, in the same manner as in [Synthesis of Asymmetric Triphosphate 2].

[0285] In Example 41, 2-indanol was used as R. 1 OH, using 2-phenylethanol (phenylethanol) as R 2 OH, using ethanol as R 3 OH. In Example 42, 2-indanol was used as R. 1 OH, using menthol as R 2 OH, using ethanol as R 3 OH. In Example 43, 2-indanol was used as R. 1 OH, using 2,2-dimethyl-1,3-dioxolane-4-methanol as R 2 OH, using phenol as R 3 OH. In Example 44, 2-indanol was used as R. 1 OH, using 2-methyl-2,3,4-tris-O-benzyl-α-D-glucopyranoside as R 2 OH, using phenol as R 3 OH. In Example 45, 2-indanol was used as R. 1 OH, using 1-O,2-O-dipalmitoyl-D-glycerol as R 2 OH, using ethanol as R 3 OH. In Example 46, 2-indanol was used as R. 1 OH, using 2-butanol as R 2 OH, using phenol as R 3 OH.

[0286] The main product was identified by NMR spectroscopy from 9 μL to 14 μL. Additionally, the yield was measured using HPLC-UV. The NMR spectral data, precision mass determination data, and the structure and yield of the main product 9y to the main product 14y are shown below. The relationship between the methods for producing asymmetric phosphate triesters in Examples 41 to 46 and the obtained main products is as follows. Example 41: Main product 9y, Example 42: Main product 10y, Example 43: Main product 11y, Example 44: Main product 12y, Example 45: Main product 13y, Example 46: Main product 14y.

[0287] [Chemistry 30]

[0288] Main product 9y: Ethyl-2-indenylphenylethyl phosphate Purification method: Preparative TLC (toluene:EtOAc = 4:1) Colorless oily substance;

[0289] Main product 10y (a mixture of diastereomers): Ethyl 2-indenyl(-)-p-menthane-3-yl phosphate Purification method: Preparative TLC (hexane:EtOAc = 4:1) Colorless oily substance;

[0290] Main product 11y (a mixture of diastereomers): 2,2-dimethyl-1,3-dioxolane-4-methyl-2-indenylphenyl phosphate Purification method: Preparative TLC (hexane:EtOAc = 3:2) Colorless oily substance;

[0291] Main product 12y (a mixture of diastereomers): 2-indenylmethyl-2,3,4-tri-O-Bz-α-D-glucopyranoside-6-ylphenyl phosphate Purification method: Preparative TLC (hexane:EtOAc = 3:2) Colorless oily substance;

[0292] Main product 13y (a mixture of diastereomers): 1,2-O-dipalmitoyl-glycerol-3-ylethyl-2-indenyl phosphate Purification method: Preparative TLC (hexane:EtOAc = 7:3) Colorless oily substance;

[0293] Main product 14y: O-(sec-n-butyl)O-(2,3-dihydro-1H-inden-2-yl)O-phenyl thiophosphate Purification method: Preparative TLC (hexane:EtOAc = 4:1) Colorless oily substance;

[0294] The preferred embodiments of the present invention have been described above, but the present invention is not limited to these embodiments. Additions, omissions, substitutions, and other modifications to the structure may be made without departing from the spirit of the invention. The present invention is not limited by the foregoing description, but only by the scope of the appended claims. Symbol Explanation

[0295] 1. 100··· Flow-through reaction apparatus; 11, 12, 13, 14, 15, 110, 120, 130, 140··· Tanks; 21, 22, 23, 24, 210, 220, 230·· Pumps; 31, 32, 33, 310, 320·· Mixers; f1, f2, f3, f4, f5, f6, f7, f10, f20, f30, f40, f50… Flow paths.

Claims

1. A method for manufacturing an asymmetric triphosphate, comprising using a flow-through reaction apparatus to synthesize the asymmetric triphosphate, wherein, The method for manufacturing the asymmetric triphosphate has the following characteristics: Step (A1) involves reacting phosphorus trichloride or phosphorus tribromide with the first hydroxyl compound represented by the following general formula (H-1) to synthesize compound P1 represented by the following general formula (P-1); Step (B1) involves reacting compound P1 with a second hydroxyl compound represented by the following general formula (H-2) to synthesize compound P2 represented by the following general formula (P-2); Step (C1), wherein compound P2 is reacted with a third hydroxyl compound represented by general formula (H-3) to synthesize compound P3 represented by general formula (P-3); and Step (D1), wherein the compound P3 is oxidized to synthesize an asymmetric phosphate triester, in, The reaction temperature in processes (A1) and (B1) is above -80°C. In steps (A1) and (B1), the flow rates of the phosphorus trichloride or phosphorus tribromide, the first hydroxyl compound, and the second hydroxyl compound flowing within the flow path are 0.01 mL / min or higher. R 1 ~R 3 Each of the following groups is independently formed by removing one hydroxyl group from the following compounds: aliphatic monohydric alcohols having 1 to 20 carbon atoms, aromatic monohydric alcohols having 6 to 30 carbon atoms, [[(9H-fluorenyl)methoxy]carbonyl]serine methyl ester, 5-(3-benzoyl-5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-(hydroxymethyl)tetrahydrofuran-3-ylbenzoate, or 3-benzoyl-1-[4-hydroxy-5-(tert-butyldimethylsiloxymethyl)tetrahydrofuran-2-yl]-5-methylpyrimidin-2,4(1H,3H)-dione; however, R 1 ~R 3 They are all different; X is a bromine atom or a chlorine atom.

2. The method for manufacturing asymmetric triphosphates according to claim 1, wherein, The reaction temperature in process (A1) and process (B1) is above 0°C.

3. The method for manufacturing the asymmetric triphosphate according to claim 1 or 2, wherein, In steps (A1) and (B1), the flow rate of the phosphorus trichloride or phosphorus tribromide, the first hydroxyl compound, and the second hydroxyl compound flowing in the flow path is 1 mL / min or more.

4. The method for manufacturing the asymmetric triphosphate according to claim 1 or 2, wherein, Between the steps (A1) and (B1), there is a step (N1) in which the compound P1 reacts with a base.

5. The method for manufacturing the asymmetric triphosphate according to claim 4, wherein, The base is selected from one or more bases in the group consisting of pyridine, 4-dimethylaminopyridine, imidazole, N-methylimidazolium, 4-methylimidazolium and 1,4-diazabicyclo[2,2,2]octane.

6. The method for manufacturing the asymmetric triphosphate according to claim 4, wherein, The base is a compound represented by the following general formula (I-1). In the formula, RI 1 and RI 2 It is a hydrogen atom or a hydrocarbon group.

7. The method for producing the asymmetric triphosphate according to claim 1 or 2, wherein, The reaction temperature in process (A1) and process (B1) is above 20°C and below 40°C.

8. The method for producing the asymmetric triphosphate according to claim 1 or 2, wherein, In steps (A1) and (B1), the flow rates of the phosphorus trichloride or phosphorus tribromide, the first hydroxyl compound, and the second hydroxyl compound flowing in the flow path are 1 mL / min or more and 5 mL / min or less.

9. The method for producing the asymmetric triphosphate according to claim 1 or 2, wherein, In step (A1), the flow rate of phosphorus trichloride or phosphorus tribromide is different from the flow rate of the first hydroxyl compound.

10. The method for manufacturing the asymmetric triphosphate according to claim 9, wherein, In step (A1), the flow rate of phosphorus trichloride or phosphorus tribromide is 0.3 to 0.9 times that of the flow rate of the first hydroxyl compound.

11. The method for manufacturing the asymmetric triphosphate according to claim 9, wherein, In step (A1), the flow rate of the first hydroxy compound is 0.3 to 0.9 times that of phosphorus trichloride or phosphorus tribromide.

12. A method for manufacturing a symmetrical triphosphate, comprising using a flow-through reaction apparatus to synthesize the symmetrical triphosphate, wherein... The method for manufacturing the symmetrical triphosphate has the following characteristics: Step (A2) involves reacting phosphorus trichloride or phosphorus tribromide with the first hydroxyl compound represented by the following general formula (H-1) to synthesize compound P1 represented by the following general formula (P-1); Step (B2), wherein compound P1 is reacted with a second hydroxyl compound represented by general formula (H-2) to synthesize compound P4 represented by general formula (P-4); and Step (D2), wherein the compound P4 is oxidized to synthesize a symmetrical phosphate triester, in, The reaction temperature in processes (A2) and (B2) is above -80°C. In steps (A2) and (B2), the flow rates of the phosphorus trichloride or phosphorus tribromide, the first hydroxyl compound, and the second hydroxyl compound flowing within the flow path are 0.01 mL / min or higher. In the formula, R 1 and R 2 The groups that remove one hydroxyl group from the following compounds are respectively: aliphatic monohydric alcohols with 1 to 20 carbon atoms, aromatic monohydric alcohols with 6 to 30 carbon atoms, [[(9H-fluorenyl)methoxy]carbonyl]serine methyl ester, 5-(3-benzoyl-5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-(hydroxymethyl)tetrahydrofuran-3-ylbenzoate, or 3-benzoyl-1-[4-hydroxy-5-(tert-butyldimethylsiloxymethyl)tetrahydrofuran-2-yl]-5-methylpyrimidin-2,4(1H,3H)-dione; however, R 1 and R 2 They are all different; X is a bromine atom or a chlorine atom.

13. The method for manufacturing the symmetrical phosphate triester according to claim 12, wherein, The reaction temperature in process (A2) and process (B2) is above 0°C.

14. The method for producing the symmetrical phosphate triester according to claim 12 or 13, wherein, In steps (A2) and (B2), the flow rate of the phosphorus trichloride or phosphorus tribromide, the first hydroxyl compound, and the second hydroxyl compound flowing in the flow path is 1 mL / min or more.

15. A method for manufacturing a phosphate ester, wherein the method uses a flow-through reaction apparatus to synthesize the phosphate ester, wherein... The method for manufacturing the phosphate ester includes: Step (A11) involves reacting phosphorus trichloride or phosphorus tribromide with the first hydroxyl compound represented by the following general formula (H1-1) to synthesize compound P11 represented by the following general formula (P1-1); Step (B11) involves reacting compound P11 with a second hydroxyl compound represented by the following general formula (H1-2) to synthesize compound P12 represented by the following general formula (P1-2); Step (C11), wherein compound P12 is reacted with a third hydroxyl compound represented by general formula (H1-3) to synthesize compound P13 represented by general formula (P1-3); and Step (D11), wherein the compound P13 is oxidized to synthesize a phosphate ester, in, The reaction temperature in processes (A11) and (B11) is above -80°C. In steps (A11) and (B11), the flow rates of the phosphorus trichloride or phosphorus tribromide, the first hydroxyl compound, and the second hydroxyl compound flowing within the flow path are 0.01 mL / min or higher. In the formula, R 11 ~R 13 Each group is independently a hydrogen atom or a group formed by removing one hydroxyl group from the following compounds: aliphatic monohydric alcohols having 1 to 20 carbon atoms, aromatic monohydric alcohols having 6 to 30 carbon atoms, [[(9H-fluorenyl)methoxy]carbonyl]serine methyl ester, 5-(3-benzoyl-5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-(hydroxymethyl)tetrahydrofuran-3-ylbenzoate, or 3-benzoyl-1-[4-hydroxy-5-(tert-butyldimethylsiloxymethyl)tetrahydrofuran-2-yl]-5-methylpyrimidin-2,4(1H,3H)-dione; however, R 11 ~R 13 In this compound, at least one of the following groups is a group from which one hydroxyl group has been removed: an aliphatic monohydric alcohol having 1 to 20 carbon atoms, an aromatic monohydric alcohol having 6 to 30 carbon atoms, [[(9H-fluorenyl)methoxy]carbonyl]serine methyl ester, 5-(3-benzoyl-5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-(hydroxymethyl)tetrahydrofuran-3-ylbenzoate, or 3-benzoyl-1-[4-hydroxy-5-(tert-butyldimethylsiloxymethyl)tetrahydrofuran-2-yl]-5-methylpyrimidin-2,4(1H,3H)-dione, wherein at least one is a hydrogen atom; X is a bromine atom or a chlorine atom.

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