Method for producing phosphite / phosphate ester and phosphonylation / phosphorylation agent

Abstract

[Problem] To provide a method for producing a phosphite / phosphate ester with which it is possible to produce a phosphite / phosphate ester efficiently by a small amount of catalyst, and a phosphonylation / phosphorylation agent that can be used in said method. [Solution] A method for producing a phosphite / phosphate ester is provided according to one embodiment of the present invention. This production method comprises a step for preparing a catalyst, an alcohol, and phosphonylation / phosphorylation agent and a step for reacting the alcohol with the phosphonylation / phosphorylation agent in the presence of the catalyst to obtain a phosphite / phosphate ester. When the phosphonylation / phosphorylation agent is a phosphorylation agent, a metal-containing catalyst functioning as a Lewis acid is used as the catalyst. When the phosphonylation / phosphorylation agent is a phosphorylation agent or a phosphonylation agent, an organic catalyst functioning as a base is used as the catalyst.

Description

Method for producing (phosphite) ester and (phosphite) ester

[0001] The present invention relates to a method for producing a phosphite ester and a phosphite agent.

[0002] Phosphite esters and phosphate esters are molecular skeletons commonly found in various physiologically active compounds and functional materials, and are also widely known as important intermediates in the synthesis of nucleic acid drugs. The main conventional synthesis methods for these esters use stoichiometric amounts of activators. This necessitates the consumption and disposal of large amounts of activators, posing problems in terms of efficiency and environmental friendliness (see Patent Documents 1 to 3 and Non-Patent Documents 1 to 3).

[0003] JP 2022-531876 A, Patent No. 7393807, JP 2015-129268 A

[0004] Beaucage, S. L. ; Caruthers, M. H. Deoxynucleoside Phosphoramidites-A New Class of Key Intermediates for Deoxypolynucleotide Synthesis. Tetrahedron Lett. 1981, 22, 1859-1862. Matteucci, M. D. ; Caruthers, M. H. Synthesis of Deoxyoligonucleotides on a Polymer Support. J. Am. Chem. Soc. 1981, 103, 3185-3191. Sergueev, D. S. ; Shaw, B. R. H-Phosphonate Approach for Solid-Phase Synthesis of Oligodeoxyribonucleoside Boranophosphates and Their Characterization. J. Am. Chem. Soc. 1998, 120, 9417-9427.

[0005] In view of the above circumstances, the present invention provides a method for producing a phosphite ester, which can efficiently produce a phosphite ester using a small amount of catalyst, and a phosphite agent that can be used therein.

[0006] According to one aspect of the present invention, there is provided a method for producing a phosphite ester. The method includes the steps of preparing a catalyst, an alcohol, and a phosphite agent, and reacting the alcohol with the phosphite agent in the presence of the catalyst to obtain a phosphite ester. When the phosphite agent is a phosphorylating agent, a metal-containing catalyst functioning as a Lewis acid is used as the catalyst. When the phosphite agent is a phosphorylating agent or a phosphite agent, an organic catalyst functioning as a base is used as the catalyst.

[0007] According to this embodiment, a phosphite ester can be efficiently produced using a small amount of catalyst.

[0008] Hereinafter, embodiments of a method for producing a (phosphite) ester and a (phosphite) ester will be described. Various features shown in the following embodiments can be combined with one another. <First Embodiment> First, the first embodiment will be described. The method for producing a phosphate ester of the first embodiment includes a first step A1 of preparing a catalyst, an alcohol, and a phosphating agent, and a second step A2 of reacting the alcohol with the phosphating agent in the presence of the catalyst to obtain a phosphate ester. Each step will be described in turn below.

[0009] <First Step A1> First, a catalyst, an alcohol, and a phosphating agent are prepared. The alcohol is not particularly limited, but examples thereof include aliphatic saturated alcohols, aliphatic unsaturated alcohols, saturated alicyclic alicyclic alcohols, unsaturated alicyclic alcohols, aromatic alcohols, heterocyclic alcohols, and substituted alcohols obtained by substituting these with a substituent. The alcohol may be a primary alcohol, a secondary alcohol, or a tertiary alcohol.

[0010] Specific examples of aliphatic saturated alcohols include methanol, ethanol, isopropanol, n-butanol, isobutanol, 2-ethylhexanol, lauryl alcohol, ethylene glycol, glycerin, pinacol, etc. Specific examples of aliphatic unsaturated alcohols include methyl vinyl carbinol, oleyl alcohol, allyl alcohol, crotyl alcohol, propargyl alcohol, etc. Specific examples of saturated alicyclic alcohols include cyclopentanol, cyclohexanol, cyclohexanedimethanol, 1,2-cyclohexanediol, etc.

[0011] Specific examples of unsaturated alicyclic alcohols include cholesterol, β-cholestanol, β-sitosterol, bile alcohol, etc. Specific examples of aromatic alcohols include benzyl alcohol, pyridinemethanol, furfuryl alcohol, etc. Specific examples of other alcohols include sugars such as glucose and xylose or derivatives thereof, nucleosides such as adenosine, guanosine, 5-methyluridine, uridine, cytidine, deoxyadenosine, deoxyguanosine, thymidine, deoxyuridine, and deoxycytidine or derivatives thereof, and (poly)alkylene glycols such as polyethylene glycol and polypropylene glycol or derivatives thereof.

[0012] The phosphorylating agent is a compound represented by the following formula (1):

[0013] In formula (1), R １ , R ２ and R ３each independently represents an organic group. By appropriately designing the structure of the organic group, the target phosphate ester can be produced more efficiently. The number of carbon atoms in the organic group is not particularly limited, and is preferably 1 to 30, more preferably 1 to 20, and even more preferably 1 to 10. The type of organic group is not particularly limited, and examples thereof include hydrocarbon groups which may have heteroatoms. Examples of heteroatoms include oxygen atoms, nitrogen atoms, sulfur atoms, and halogen atoms. It is preferable that the organic group does not have a hydroxy group.

[0014] Among these, the organic group is preferably an aliphatic hydrocarbon group which may have a substituent, an aromatic hydrocarbon group which may have a substituent, a heterocyclic group which may have a substituent, or a group which is a combination of two or more of these. The number of carbon atoms in the aliphatic hydrocarbon group is not particularly limited, and is preferably 1 to 30, more preferably 1 to 20, and even more preferably 1 to 10. The aliphatic hydrocarbon group may be linear or branched. The aliphatic hydrocarbon group may have a cyclic structure. The cyclic structure may be a monocyclic structure or a polycyclic structure.

[0015] Examples of the aliphatic hydrocarbon group include alkyl groups, alkenyl groups, alkynyl groups, and groups combining two or more of these (for example, a group represented by alkenyl group-alkylene group-* (* represents a bonding position), a group represented by alkynyl group-alkylene group-* (* represents a bonding position)). The aliphatic hydrocarbon group may contain a fluorine atom. Among these, the aliphatic hydrocarbon group which may contain a fluorine atom is preferably an alkyl group which may contain a fluorine atom. When the aliphatic hydrocarbon group contains a fluorine atom, the number of fluorine atoms is not particularly limited, and is preferably 1 or more and 10 or less, more preferably 1 or more and 5 or less, and even more preferably 3 or more and 5 or less.

[0016] When the aliphatic hydrocarbon group has a fluorine atom, some of the hydrogen atoms of the aliphatic hydrocarbon group may be substituted with fluorine atoms, or all of the hydrogen atoms of the aliphatic hydrocarbon group may be substituted with fluorine atoms. As the aliphatic hydrocarbon group having a fluorine atom, a group represented by the following formula (3) is preferred. Formula (3): R ５ -L ａ - * R ５ represents a perfluoroalkyl group. ａ represents an alkylene group. * represents a bonding position. The number of carbon atoms in the perfluoroalkyl group is not particularly limited, but is preferably 1 to 5, more preferably 1 to 3, and even more preferably 1. The number of carbon atoms in the alkylene group is not particularly limited, but is preferably 1 to 5, more preferably 1 to 3, and even more preferably 1.

[0017] The number of carbon atoms in the aromatic hydrocarbon group is not particularly limited, and is preferably 6 to 18, and more preferably 6 to 12. The aromatic hydrocarbon ring constituting the aromatic hydrocarbon group may have a monocyclic structure or a polycyclic structure. Examples of the aromatic hydrocarbon ring constituting the aromatic hydrocarbon group include a benzene ring, a naphthalene ring, an anthracene ring, a phenanthrene ring, a fluorene ring, a triphenylene ring, a tetracene ring, and a pyrene ring.

[0018] Examples of the heterocyclic group include an aromatic heterocyclic group and an aliphatic heterocyclic group. The number of carbon atoms in the heterocyclic group is not particularly limited, and is preferably 3 to 18, more preferably 3 to 12. Examples of heteroatoms other than carbon atoms constituting the heterocyclic group include oxygen atoms, nitrogen atoms, sulfur atoms, etc. The heterocycle constituting the heterocyclic group may have a monocyclic structure or a polycyclic structure.

[0019] Examples of aromatic heterocycles constituting the aromatic heterocyclic group include a pyridine ring, a pyrrole ring, an imidazole ring, a pyrazole ring, an oxazole ring, a thiazole ring, a triazole ring, a furan ring, a purine ring, a cytosine ring, an adenine ring, a guanine ring, a uracil ring, and a thiophene ring. Examples of aliphatic heterocycles constituting the aliphatic heterocyclic group include an oxolane ring (tetrahydrofuran ring), a pyrrolidine ring, a thiolane ring (tetrahydrothiophene ring), a piperidine ring, an oxane ring (tetrahydropyran ring), a thiane ring (tetrahydrothiopyran ring), a piperazine ring, a morpholine ring, a quinuclidine ring, a pyrrolidine ring, an azetidine ring, an oxetane ring, an aziridine ring, and a dioxane ring.

[0020] Examples of groups combining two or more of the above groups include groups combining an aliphatic hydrocarbon group with an aromatic hydrocarbon group, and groups combining an aliphatic hydrocarbon group with a heterocyclic group. Examples of groups combining an aliphatic hydrocarbon group with an aromatic hydrocarbon group include groups represented by the following formula (4): Formula (4): R ３ -L-* R ３ represents an aromatic hydrocarbon group which may have a substituent. L represents a divalent aliphatic hydrocarbon group. * represents a bonding position. R ３ The preferred embodiments of the aromatic hydrocarbon group represented by the formula (I) are as described above.

[0021] The number of carbon atoms in the divalent aliphatic hydrocarbon group represented by L is not particularly limited, and is preferably 1 to 30, more preferably 1 to 20, and even more preferably 1 to 10. The divalent aliphatic hydrocarbon group may be linear or branched. The aliphatic hydrocarbon group may have a cyclic structure. The cyclic structure may be a monocyclic structure or a polycyclic structure. Examples of the divalent aliphatic hydrocarbon group include an alkylene group, an alkenylene group, and an alkynylene group, and an alkylene group is preferred.

[0022] Examples of the group combining an aliphatic hydrocarbon group and a heterocyclic group include a group represented by the following formula (5): Formula (5): R ４ -L-* R４ represents a heterocyclic group which may have a substituent. L represents a divalent aliphatic hydrocarbon group. * represents a bonding position. R ４ The preferred embodiments of the heterocyclic group represented by the formula (1) are as described above. The definition of L is the same as that of L in the above formula (4).

[0023] The aliphatic hydrocarbon group, the aromatic hydrocarbon group, and the heterocyclic group may each have a substituent. In this case, the number of the substituent is not particularly limited and may be one or more. The type of the substituent is not particularly limited and may be, for example, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, an amino group, an alkoxy group, an aryloxy group, an aromatic heterocyclic oxy group, an acyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, an acyloxy group, an acylamino group, an alkoxycarbonylamino group, an aryloxycarbonylamino group, a sulfonylamino group, a sulfamoyl group, a carbamoyl group, an alkylthio group, an arylthio group, an aromatic heterocyclic thio group, a sulfonyl group, Examples of the protecting group include a sulfinyl group, a ureido group, a phosphoric acid amide group, a mercapto group, a halogen atom (a fluorine atom, a chlorine atom, a bromine atom, an iodine atom), a cyano group, a sulfo group, a carboxy group, a nitro group, a hydroxamic acid group, a sulfino group, a hydrazino group, an imino group, a heterocyclic group (for example, a heteroaryl group), a silyl group, a known protecting group (for example, an amino group protecting group; more specifically, a benzyloxymethyl group (BOM group) or a t-butoxycarbonyl group (Boc group)), and a group combining these. The above-mentioned substituents may be further substituted with a substituent.

[0024] When the aliphatic hydrocarbon group, aromatic hydrocarbon group, or heterocyclic group has a plurality of substituents, the substituents may be bonded to each other to form a ring. For example, the group represented by the following formula (X) corresponds to an embodiment in which two substituents of an oxolane ring are bonded to form a ring. In the following formula (X), * represents a bonding position, and R ｂ represents a hydrogen atom or an organic group. ｂ The definition of the organic group represented by is the same as the definition of the organic group explained here. ｂThe organic group represented by the formula (I) is preferably a heterocyclic group which may have a substituent. The definition of the heterocyclic group is as described above. The type of the substituent which the heterocyclic group may have is not particularly limited, and examples thereof include the groups exemplified above.

[0025] Among these, R ｂ Preferred organic groups represented by the formula (I) include a group derived from a cytosine ring which may have a substituent (for example, a residue formed by removing one hydrogen atom from a cytosine ring which may have a substituent), a group derived from an adenine ring which may have a substituent (for example, a residue formed by removing one hydrogen atom from an adenine ring which may have a substituent), a group derived from a guanine ring which may have a substituent (for example, a residue formed by removing one hydrogen atom from a guanine ring which may have a substituent), or a group derived from a uracil ring which may have a substituent (for example, a residue formed by removing one hydrogen atom from a uracil ring which may have a substituent). Examples of the cytosine ring-derived group, the adenine ring-derived group, the guanine ring-derived group, and the uracil ring-derived group include groups represented by the following formulae (Y1) to (Y4), respectively. In formulae (Y1) to (Y4), R Ｙ１ ~R Ｙ８ each independently represents a hydrogen atom or a substituent. Examples of the substituent include the groups exemplified above. In formulas (Y1) to (Y4), * represents a bonding position.

[0026]

[0027]

[0028] Among these, it is preferable to use a phosphoric acid triester having a substituent containing an oxime structure or a hydroxybenzotriazole structure as the phosphorylating agent. When such a phosphorylating agent is used, the compound derived from the leaving group generated during the reaction with the alcohol is unlikely to adversely affect the catalyst (the metal-containing catalyst functioning as a Lewis acid). Therefore, the activity of the catalyst can be maintained for a long period of time, and the target phosphoric acid ester can be efficiently produced even with a small amount of catalyst.

[0029] The number of carbon atoms in the substituent of the phosphate triester is not particularly limited, and is preferably 1 to 30, more preferably 1 to 20, and even more preferably 1 to 10. The substituent having an oxime structure in the phosphate triester preferably contains a cyano group. In this case, the above-mentioned effects can be further improved. Such a substituent can be introduced (substituted) into the phosphating agent by using, for example, ethyl cyano(hydroxyimino)acetate (also known as oxima), 2-hydroxyiminopropanedinitrile, 2-(hydroxyimino)malonic acid diester, or the like. An alcohol having such an organic group as described above may be used as the alcohol to be reacted with the phosphating agent.

[0030] In the first embodiment, in which the (sub)phosphating agent is a phosphorylating agent, a metal-containing catalyst that functions as a Lewis acid is used as the catalyst. The use of such a metal-containing catalyst that functions as a Lewis acid can satisfactorily activate the phosphorylating agent, which is a pentavalent phosphorus compound that is more stable than trivalent phosphorus. In particular, the use of a metal-containing catalyst that functions as a Lewis acid in combination with the phosphorylating agent designed as described above allows the reaction between the phosphorylating agent and the alcohol to proceed smoothly even with a small amount of catalyst used.

[0031] The metal-containing catalyst preferably contains a compound having a metal atom belonging to Group 2, 4, 12, or 13 of the periodic table and a ligand coordinated to the metal atom. Metal-containing catalysts containing these metal atoms tend to have a higher activation ability for the phosphorylating agent and a higher yield of the target phosphate ester. Examples of metal atoms belonging to Group 2, 4, 12, or 13 of the periodic table include magnesium, calcium, strontium, titanium, zirconium, hafnium, zinc, aluminum, gallium, and indium. Among these, the metal atom is preferably at least one selected from the group consisting of indium, zirconium, and hafnium. Metal-containing catalysts containing these metal atoms have a particularly high activation ability for the phosphorylating agent.

[0032] The ligand may be a monodentate ligand or a polydentate ligand. The type of ligand is not particularly limited, and examples thereof include anionic ligands (negative ions) and neutral ligands. Examples of anionic ligands include sulfonate anions, carboxylate anions, phosphate anions, monoanions having a β-diketone structure, imide anions, halide ions, hydroxide ions, and alkoxy. Examples of neutral ligands include carbonyl, alkene, alkyne, cyclopentadienyl, benzene, cyclooctadiene, and cyclooctatetraene.

[0033] Among these, the ligand is preferably an anionic ligand, and more preferably an oxygen-containing organic ligand. Such a ligand is more preferably at least one selected from the group consisting of a monoanion having a β-diketone structure (β-diketonate-type ligand), a sulfonate anion (particularly, a perfluoroalkylsulfonate-type ligand), and an alkoxy (alkoxy-type ligand). By selecting such a ligand, the activation ability of the phosphorylating agent of the metal-containing catalyst can be further enhanced. Examples of perfluoroalkylsulfonate-type ligands include trifluoromethanesulfonate (OTf) and nonafluorobutanesulfonate (ONf). Examples of alkoxy-type ligands include, for example, a t-butoxy group (O ｔ Bu), a methoxy group (OMe), an ethoxy group (OEt), a phenoxy group (OPh), and the like.

[0034] Examples of the β-diketonate type ligand include ligands represented by the following formula: [wherein, R ａ１ ~R ａ３ each independently represents a hydrogen atom or an organic group.

[0035] R ａ１ ~R ａ３ The definition of the organic group represented by R is the same as the definition of the organic group described above. ａ１ and R ａ３are preferably an aliphatic hydrocarbon group which may have a substituent, more preferably an alkyl group which may have a substituent, and even more preferably an alkyl group having 1 to 4 carbon atoms which may have a substituent. ａ２ is preferably a hydrogen atom. Specific examples of the β-diketonate ligand include acetylacetonate (acac), 2,2,6,6-tetramethyl-3,5-heptanedionate (TMHD), and 1,3-diphenyl-1,3-propanedionate.

[0036] For the above reasons, a suitable metal-containing catalyst is, for example, magnesium (II) acetylacetonate (Mg(acac) ２ ), zinc(II) acetylacetonate (Zn(acac) ２ ), aluminum(III) acetylacetonate (Al(acac) ３ ), gallium(III) acetylacetonate (Ga(acac) ３ ), indium(III) acetylacetonate (In(acac) ３ ), zirconium(IV) acetylacetonate (Zr(acac) ４ ), hafnium(IV) acetylacetonate (Hf(acac) ４ ), zirconium(IV) trifluoromethanesulfonate (Zr(OTf) ４ ), zirconium (IV) t-butoxide (Zr(O ｔ Bu) ４ These metal-containing catalysts may be used alone or in combination of two or more.

[0037] <Second Step A2> Next, the alcohol and the phosphorylating agent are reacted in the presence of a metal-containing catalyst. This results in a phosphoric acid ester. The ratio of the molar amount of the phosphorylating agent to the molar amount of the alcohol (molar amount of the phosphorylating agent used / molar amount of the alcohol used) is not particularly limited, but is preferably 0.1 to 10, more preferably 0.15 to 7.5, and even more preferably 0.2 to 5. The amount of catalyst used is preferably 0.1 to 30 moles, more preferably 0.5 to 25 moles, and even more preferably 1 to 20 moles, relative to 100 moles of the phosphorylating agent. By using the metal-containing catalyst in combination with the phosphorylating agent, the reaction between the alcohol and the phosphorylating agent can proceed smoothly with such a small amount of catalyst used.

[0038] The reaction temperature between the alcohol and the phosphorylating agent is preferably 5°C or higher and 40°C or lower, more preferably 10°C or higher and 35°C or lower, and even more preferably 15°C or higher and 30°C or lower. By using the metal-containing catalyst, the reaction between the alcohol and the phosphorylating agent can proceed smoothly even at a relatively low temperature. The reaction time between the alcohol and the phosphorylating agent is preferably 0.1 hours or higher and 10 hours or lower, more preferably 0.5 hours or higher and 8 hours or lower, and even more preferably 1 hour or higher and 6 hours or lower. By using the metal-containing catalyst, the reaction between the alcohol and the phosphorylating agent can proceed sufficiently in a relatively short time. The reaction atmosphere between the alcohol and the phosphorylating agent is not particularly limited and may be either an air atmosphere or an inert gas atmosphere, but an inert gas atmosphere is particularly preferred. Specific examples of inert gases include nitrogen gas, argon gas, and mixtures thereof.

[0039] The above reaction may be carried out in the presence of a solvent. Such a solvent is not particularly limited, and examples thereof include hydrocarbons, halogenated hydrocarbons, ketones, esters, ethers, and mixtures thereof. Specific examples of the solvent include toluene, tetrahydrofuran, ethyl acetate, benzotrifluoride, dichloromethane, acetonitrile, N,N-dimethylformamide, and mixtures thereof. The phosphate ester produced through the above steps can be separated and purified by, for example, filtration, concentration, distillation, extraction, crystallization, recrystallization, column chromatography, or a combination thereof.

[0040] Next, an example of using the method for producing a phosphate ester according to the first embodiment for nucleotide synthesis will be described with reference to the following reaction scheme. In the reaction scheme, "PhO" represents a substituent derived from phenol.

[0041] This nucleotide synthesis is carried out through three steps. [First Step] The first step is to prepare the phosphorylating agent to be used in the second step. First, 1-hydroxy-6-(trifluoromethane)benzotriazole (CF ３ -HOBt) in a solvent (e.g., tetrahydrofuran: THF) to prepare a solution.

[0042] Next, a reagent for removing hydrogen chloride generated in the first step is added to this solution. A compound (e.g., pyridine) used as an organic catalyst in the second step is preferably selected as this reagent. Then, while cooling the solution, phosphoric acid chloride is added dropwise to obtain a suspension. Next, the suspension is heated to approximately room temperature and thoroughly stirred. The resulting reaction solution is filtered through a filter under an argon gas atmosphere. This yields a solution containing the desired phosphoric acid ester (phosphorylating agent).

[0043] [Second Step] The second step is a step of reacting a phosphorylating agent with an alcohol in the presence of an organic catalyst (an organic catalyst that functions as a base), which is the remainder of the reagent. The first and second steps correspond to the first step A1 of the first embodiment. First, 5'-MMTr-Thy-BOM is dissolved in a solvent (e.g., THF) to prepare a solution. Here, MMTr represents a monomethoxytrityl group, BOM represents a benzyloxymethyl group, and Thy represents thymidine. Next, a solution containing the phosphorylating agent is added to this solution at room temperature and thoroughly stirred. This results in a solution containing the desired phosphate ester (phosphorylating agent).

[0044] By using an organic catalyst that functions as a base in combination with the phosphorylating agent designed as described above, the reaction between the phosphorylating agent and the alcohol can proceed smoothly even with a small amount of catalyst used. The organic catalyst preferably contains a heterocyclic compound containing a nitrogen atom. The use of an organic catalyst containing a heterocyclic compound containing a nitrogen atom makes it easier to increase the reaction rate between the phosphorylating agent and the alcohol. The heterocyclic compound containing a nitrogen atom may or may not be aromatic.

[0045] Specific examples of such heterocyclic compounds include pyridine (Py), as well as N,N-dimethylaminopyridine (DMAP), imidazole (ImH), N-methylimidazole (NMI), 1,4-diazabicyclo[2.2.2]octane (DABCO), diazabicycloundecene (DBU), and N-methylmorpholine (NMM). It is preferable to select a small-molecular-weight compound that is relatively easily available as the heterocyclic compound. From this perspective, the heterocyclic compound is preferably at least one selected from the group consisting of pyridine, N,N-dimethylaminopyridine, imidazole, and N-methylimidazole. Organic catalysts containing such heterocyclic compounds are easily available, and the amount used can be sufficiently reduced.

[0046] The ratio of the molar amount of the phosphorylating agent used to the molar amount of the alcohol used (molar amount of the phosphorylating agent used / molar amount of the alcohol used) is not particularly limited, and is preferably 0.1 to 10, more preferably 0.15 to 7.5, and even more preferably 0.2 to 5. The amount of the catalyst used is preferably 0.1 to 30 mol, more preferably 0.5 to 25 mol, and even more preferably 1 to 20 mol, relative to 100 mol of the phosphorylating agent. By using the organic catalyst in combination with the phosphorylating agent, the reaction between the alcohol and the phosphorylating agent can proceed smoothly with such a small amount of catalyst used.

[0047] The reaction temperature between the alcohol and the phosphorylating agent is preferably 5°C or higher and 40°C or lower, more preferably 10°C or higher and 35°C or lower, and even more preferably 15°C or higher and 30°C or lower. By using the organic catalyst, the reaction between the alcohol and the phosphorylating agent can proceed smoothly even at a relatively low temperature. The reaction time between the alcohol and the phosphorylating agent is preferably 0.1 hours or higher and 10 hours or lower, more preferably 0.5 hours or higher and 8 hours or lower, and even more preferably 1 hour or higher and 6 hours or lower. By using the organic catalyst, the reaction between the alcohol and the phosphorylating agent can proceed sufficiently in a relatively short time. The reaction atmosphere between the alcohol and the phosphorylating agent is not particularly limited and may be either an air atmosphere or an inert gas atmosphere, with an inert gas atmosphere being particularly preferred. Specific examples of inert gases include nitrogen gas, argon gas, and mixtures thereof.

[0048] As described above, the reactions in the first and second steps are preferably carried out in the presence of a solvent. Such solvents are not particularly limited, and examples thereof include hydrocarbons, halogenated hydrocarbons, ketones, esters, ethers, and mixtures thereof. Specific examples of solvents include toluene, tetrahydrofuran, ethyl acetate, benzotrifluoride, dichloromethane, acetonitrile, N,N-dimethylformamide, and mixtures thereof. The phosphorylating agent (phosphate ester) produced through the above steps can be separated and purified by, for example, filtration, concentration, distillation, extraction, crystallization, recrystallization, column chromatography, or a combination thereof.

[0049] [Third Step] The third step is a step of reacting an alcohol with a phosphorylating agent in the presence of a metal-containing catalyst that functions as a Lewis acid, and corresponds to the second step A2 in the first embodiment. The substituent containing a hydroxybenzotriazole structure remaining in the phosphorylating agent is eliminated, and an alcohol is introduced as a substituent. First, a solution is prepared by dissolving the metal-containing catalyst and 3'-TBS-Thy-BOM in a solvent (e.g., THF). Here, TBS represents a t-butyldimethylsilyl group. Next, the solution containing the phosphorylating agent is added to this solution at room temperature and thoroughly stirred. This results in a solution containing the desired phosphate ester.

[0050] The phosphorylating agent of the first embodiment is used to produce a phosphoric acid ester by reaction with an alcohol as described above. This phosphorylating agent is a phosphoric acid triester having a substituent containing an oxime structure or a hydroxybenzotriazole structure. Suitable aspects of the phosphorylating agent are the same as those described above.

[0051] According to the first embodiment described above, the reaction between the alcohol and the phosphorylating agent is carried out in a liquid phase, thereby improving the reaction efficiency compared to solid-phase synthesis using a solid support. Furthermore, the amount of wasted reagent can be reduced, which is economical and reduces the amount of waste, thereby reducing the burden on the environment. Furthermore, a properly designed catalyst has high activity, so that even a small amount can smoothly proceed with the reaction between the alcohol and the phosphorylating agent. Furthermore, the above-mentioned method for producing a phosphoric ester can be a one-pot reaction, which eliminates post-treatment processes and intermediate product purification processes. This allows for a reduction in production time and savings on solvents, thereby improving production efficiency while reducing production costs.

[0052] Second Embodiment Next, a second embodiment will be described. Hereinafter, the second embodiment of the method for producing a (phosphite) ester and the (phosphite) ester production agent will be described, focusing on the differences from the first embodiment, and a description of similar points will be omitted. The method for producing a (phosphite) ester of the second embodiment includes a first step B1 of preparing a catalyst, an alcohol, and a (phosphite) ester production agent, and a second step B2 of reacting the alcohol with the (phosphite) ester production agent in the presence of a catalyst to obtain a (phosphite) ester. Each step will be described below in order.

[0053] First Step B1: First, a catalyst, an alcohol, and a (phosphite) ionizing agent are prepared. Here, the term (phosphorous acid) encompasses phosphoric acid and phosphorous acid, and the same applies to other terms that include (phosphite). The alcohol is the same as that described in the first embodiment.

[0054] The phosphorylating agent is a compound represented by the above formula (1), and the phosphite (phosphonic acid) is a compound represented by the following formula (2).

[0055] In formula (2), R １ , R ２ and R ３ Each independently represents an organic group, but R in formula (1) described in the first embodiment １, R ２ and R ３ By appropriately designing the structure of the organic group, the desired phosphate (or phosphate) ester can be produced more efficiently.

[0056] Among these phosphite (sulfite) agents, it is preferable to use a phosphite diester having an alkoxy group containing a fluorine atom as the phosphite agent, and it is preferable to use a phosphate triester having a substituent containing an oxime structure or a hydroxybenzotriazole structure as described above as the phosphite (sulfite) agent. When these phosphite (sulfite) agents are used, compounds derived from the leaving group generated during the reaction with the alcohol are less likely to adversely affect the catalyst (organic catalyst functioning as a base). Therefore, the activity of the catalyst can be maintained for a long period of time, and the desired phosphite (sulfite) ester can be efficiently produced even with a small amount of catalyst.

[0057] The number of carbon atoms in the fluorine atom-containing alkoxy group of the phosphite diester is not particularly limited, and is preferably 1 to 30, more preferably 1 to 20, and even more preferably 1 to 10. Such an alkoxy group may be linear or branched. Among these, the fluorine atom-containing alkoxy group of the phosphite diester preferably contains a trifluoroethoxy group. Such an alkoxy group is easily eliminated from the phosphite diester and can react quickly with the alcohol. Furthermore, the resulting compound is preferred because it is unlikely to adversely affect the catalyst. An alcohol having such an organic group may be used as the alcohol to be reacted with the (phosphite) phosphate.

[0058] In the second embodiment, in which the (phosphite)ating agent is a phosphating agent or a phosphite, an organic catalyst that functions as a base is used as the catalyst. By using an organic catalyst that functions as a base in combination with the (phosphite)ating agent designed as described above, the reaction between the (phosphite)ating agent and the alcohol can proceed smoothly even with a small amount of catalyst used. The organic catalyst preferably contains a heterocyclic compound containing a nitrogen atom. By using an organic catalyst containing a heterocyclic compound containing a nitrogen atom, the reaction rate between the (phosphite)ating agent and the alcohol can be more easily increased. The heterocyclic compound containing a nitrogen atom may or may not be aromatic.

[0059] Specific examples of such heterocyclic compounds include pyridine (Py), N,N-dimethylaminopyridine (DMAP), imidazole (ImH), N-methylimidazole (NMI), 1,4-diazabicyclo[2.2.2]octane (DABCO), diazabicycloundecene (DBU), and N-methylmorpholine (NMM). It is preferable to select a small-molecular-weight compound that is relatively easily available as the heterocyclic compound. From this perspective, the heterocyclic compound is preferably at least one selected from the group consisting of pyridine, N,N-dimethylaminopyridine, imidazole, and N-methylimidazole. Organic catalysts containing such heterocyclic compounds are easily available, and the amount used can be sufficiently reduced.

[0060] <Second Step B2> Next, the alcohol is reacted with a (phosphite)ating agent in the presence of an organic catalyst. This results in a (phosphite) ester. The ratio of the molar amount of the (phosphite)ating agent to the molar amount of the alcohol (molar amount of (phosphite)ating agent used / molar amount of alcohol used) is not particularly limited, but is preferably 0.1 to 10, more preferably 0.15 to 7.5, and even more preferably 0.2 to 5. The amount of catalyst used is preferably 0.1 to 30 moles, more preferably 0.5 to 25 moles, and even more preferably 1 to 20 moles, relative to 100 moles of the (phosphite)ating agent. By using the organic catalyst in combination with the (phosphite)ating agent, the reaction between the alcohol and the (phosphite)ating agent can proceed smoothly with such a small amount of catalyst used.

[0061] The reaction temperature between the alcohol and the (phosphite)ating agent is preferably 5°C or higher and 40°C or lower, more preferably 10°C or higher and 35°C or lower, and even more preferably 15°C or higher and 30°C or lower. By using the organic catalyst, the reaction between the alcohol and the (phosphite)ating agent can proceed smoothly even at relatively low temperatures. The reaction time between the alcohol and the (phosphite)ating agent is preferably 0.1 hours or higher and 10 hours or lower, more preferably 0.5 hours or higher and 8 hours or lower, and even more preferably 1 hour or higher and 6 hours or lower. By using the organic catalyst, the reaction between the alcohol and the (phosphite)ating agent can proceed sufficiently in a relatively short time. The atmosphere in which the reaction between the alcohol and the (phosphite)ating agent is carried out is not particularly limited and may be either air or an inert gas atmosphere, with an inert gas atmosphere being particularly preferred. Specific examples of inert gases include nitrogen gas, argon gas, and mixtures thereof.

[0062] The above reaction may be carried out in the presence of a solvent similar to that described in the first embodiment. The phosphite ester produced through the above steps can be separated and purified by, for example, filtration, concentration, distillation, extraction, crystallization, recrystallization, column chromatography, or a combination thereof.

[0063] Next, an example of using the method for producing a phosphite ester according to the second embodiment for nucleotide synthesis will be described with reference to the following reaction scheme. In the reaction scheme, "PhO" represents a substituent derived from phenol.

[0064] This nucleotide synthesis is carried out through three steps. [First Step] The first step is a step of preparing (preparing) a phosphorylating agent to be used in the second step, and corresponds to the first step B1 in the second embodiment. This first step is carried out in the same manner as the first step of nucleotide synthesis in the first embodiment described above.

[0065] [Second Step] The second step is a step of reacting a phosphorylating agent with an alcohol in the presence of an organic catalyst, which is the remainder of the reagent, and corresponds to the second step B2 of the second embodiment. This second step is carried out in the same manner as the second step of the nucleotide synthesis of the first embodiment.

[0066] [Third Step] The third step is a step in which an alcohol is reacted with a phosphorylating agent in the presence of a metal-containing catalyst that functions as a Lewis acid. The substituent containing a hydroxybenzotriazole structure remaining in the phosphorylating agent is eliminated, and an alcohol is introduced as a substituent. This third step is carried out in the same manner as the third step of the nucleotide synthesis of the first embodiment described above. This results in a solution containing the target phosphate ester. The use of such a metal-containing catalyst that functions as a Lewis acid can satisfactorily activate the phosphorylating agent, which is a pentavalent phosphorus compound that is more stable than trivalent phosphorus.

[0067] The phosphite (phosphite) agent of the second embodiment is used to produce a phosphite ester by reaction with an alcohol as described above. This phosphite (phosphite) agent is a phosphite diester having a fluorine atom-containing alkoxy group, or a phosphate triester having a substituent containing an oxime structure or a hydroxybenzotriazole structure. Suitable aspects of the phosphite (phosphite) agent are the same as those described above.

[0068] According to the second embodiment described above, the reaction between the alcohol and the (phosphite) ester is carried out in a liquid phase, thereby improving the reaction efficiency compared to solid-phase synthesis using a solid support. Furthermore, the amount of wasted reagent can be reduced, which is economical and reduces the amount of waste, thereby reducing the environmental impact. Furthermore, a properly designed catalyst has high activity, so that even a small amount can smoothly promote the reaction between the alcohol and the (phosphite) ester. Furthermore, the above-mentioned method for producing a (phosphite) ester can be a one-pot reaction, which eliminates post-treatment processes and intermediate product purification processes. This reduces production time and saves on solvents, etc., thereby improving production efficiency while reducing production costs. Furthermore, the method may be provided in the following aspects.

[0069] (1) A method for producing a phosphoric acid ester, comprising the steps of: preparing a catalyst, an alcohol, and a phosphorylating agent; and reacting the alcohol with the phosphorylating agent in the presence of the catalyst to obtain a phosphoric acid ester, wherein a metal-containing catalyst that functions as a Lewis acid is used as the catalyst.

[0070] (2) In the method for producing a phosphoric acid ester according to (1) above, the metal-containing catalyst contains a compound having a metal atom belonging to Group 2, Group 4, Group 12, or Group 13 of the periodic table and a ligand coordinated to the metal atom.

[0071] (3) The method for producing a phosphate ester according to (2) above, wherein the metal atom is at least one selected from the group consisting of indium, zirconium, and hafnium.

[0072] (4) The method for producing a phosphate ester according to (2) or (3) above, wherein the ligand is at least one selected from the group consisting of a β-diketonate ligand, a perfluoroalkylsulfonate ligand, and an alkoxy ligand.

[0073] (5) The method for producing a phosphoric acid ester according to any one of (1) to (4) above, wherein a phosphoric acid triester having a substituent containing an oxime structure or a hydroxybenzotriazole structure is used as the phosphorylating agent.

[0074] (6) The method for producing a phosphoric acid ester according to (5) above, wherein the substituent having an oxime structure of the phosphoric acid triester contains a cyano group.

[0075] (7) The method for producing a phosphoric acid ester according to any one of (1) to (6), wherein the reaction temperature between the alcohol and the phosphorylating agent is 5°C or higher and 40°C or lower.

[0076] (8) The method for producing a phosphoric acid ester according to any one of (1) to (7) above, wherein the reaction time between the alcohol and the phosphorylating agent is 0.1 hours or more and 10 hours or less.

[0077] (9) The method for producing a phosphoric acid ester according to any one of (1) to (8), wherein the amount of the catalyst used is 0.1 mol or more and 30 mol or less per 100 mol of the phosphorylating agent.

[0078] (10) A phosphorylating agent used to produce a phosphoric acid ester by reaction with an alcohol, which is a phosphoric acid triester having a substituent containing an oxime structure or a hydroxybenzotriazole structure.

[0079] (11) A method for producing a (phosphite) ester, comprising the steps of: preparing a catalyst, an alcohol, and a (phosphite) ester; and reacting the alcohol with the (phosphite) ester in the presence of the catalyst to obtain a (phosphite) ester, wherein an organic catalyst that functions as a base is used as the catalyst.

[0080] (12) The method for producing a phosphite ester according to (11) above, wherein the organic catalyst contains a heterocyclic compound containing a nitrogen atom.

[0081] (13) The method for producing a phosphite ester according to (12) above, wherein the heterocyclic compound is at least one selected from the group consisting of pyridine, N,N-dimethylaminopyridine, imidazole, and N-methylimidazole.

[0082] (14) The method for producing a phosphite ester according to any one of (11) to (13) above, wherein a phosphite diester having an alkoxy group containing a fluorine atom, or a phosphate triester having a substituent containing an oxime structure or a hydroxybenzotriazole structure, is used as the phosphite diester.

[0083] (15) The method for producing a phosphite ester according to (14) above, wherein the fluorine atom-containing alkoxy group of the phosphite diester includes a trifluoroethoxy group.

[0084] (16) The method for producing a phosphite ester according to (14) or (15) above, wherein the substituent having an oxime structure of the phosphate triester contains a cyano group.

[0085] (17) In the method for producing a (phosphite) ester according to any one of (11) to (16), the reaction temperature between the alcohol and the (phosphite) reacting agent is 5°C or higher and 40°C or lower.

[0086] (18) The method for producing a (phosphite) ester according to any one of (11) to (17) above, wherein the reaction time between the alcohol and the (phosphite)ating agent is 0.1 hours or more and 10 hours or less.

[0087] (19) The method for producing a (phosphite) ester according to any one of (11) to (18) above, wherein the amount of the catalyst used is 0.1 mol or more and 30 mol or less per 100 mol of the (phosphite) adding agent.

[0088] (20) A phosphite (phosphate) agent used to produce a phosphite ester by reaction with an alcohol, which is a phosphite diester having an alkoxy group containing a fluorine atom, or a phosphate triester having a substituent containing an oxime structure or a hydroxybenzotriazole structure. Of course, the phosphite (phosphate) agent is not limited to this.

[0089] Finally, while various embodiments of the present invention have been described, these are presented by way of example only and are not intended to limit the scope of the invention. The novel embodiments may be embodied in various other forms, and various omissions, substitutions, and modifications may be made without departing from the spirit of the invention. Such embodiments and modifications are intended to be included within the scope and spirit of the invention, as well as within the scope of the inventions and their equivalents as defined in the accompanying claims.

[0090] The present invention will be explained in more detail below by way of examples, but the present invention is not limited to these examples.

[0091] 1. Nucleotide Synthesis Nucleotides were synthesized according to the following reaction scheme.

[0092] [Step 1: Preparation of phosphorylating agent] First, CF4 was placed in a 30 mL two-necked round-bottom flask. ３-HOBt (1.7063 g, 8.4 mmol) was added and the inside of the flask was replaced with argon gas. Next, THF (8.0 mL) was added to the flask to prepare a homogeneous solution, and then pyridine (Py) (866 μL, 8.4 mmol) was added. Then, while the flask was cooled in an ice bath, phosphoric acid chloride (594 μL, 4.0 mmol) was added dropwise to obtain a white suspension. After the flask was warmed to room temperature, the suspension was stirred for 1 hour.

[0093] Next, the resulting solution was transferred using a cannula under an argon gas atmosphere and filtered through a glass filter. This gave the target pale yellow solution containing 10 mol% pyridine. 0.7 mL of the solution was taken out using a syringe and (PhO) ３ Using P═O as an internal standard, ３１ The concentration of the target compound was determined by P-NMR. NMR measurements were performed without deuterated solvent lock, and the target compound appeared at -7.71 ppm when the internal standard was set to -17 ppm. The concentration of the target compound was 0.36 M or more and 0.37 M or less. The solution could be stored in a refrigerator at -20°C under an argon gas atmosphere for up to one week.

[0094] [Step 2: Phosphorylation Reaction with the Remaining Organic Catalyst] First, 5'-MMTr-Thy-BOM (488.7 mg, 0.77 mmol) was placed in a 20 mL two-neck round-bottom flask, and the atmosphere was replaced with argon gas. Next, THF (1.6 mL; adjusted depending on the concentration of the phosphorylating agent so that the reaction solution concentration was 0.2 M) was added to the flask to prepare a homogeneous solution, and then a solution of the phosphorylating agent containing 10 mol% pyridine (0.36 M, 1.94 mL, 0.7 mmol) was added at room temperature.

[0095] The solution was then stirred at room temperature for 1 hour, and 0.7 mL of the resulting solution was taken with a syringe and analyzed using (PhO)3P=O as an internal standard. ３１ The concentration of the target compound was determined by P-NMR. NMR measurements were performed without deuterated solvent lock, and the internal standard was set to -17 ppm. The diastereomeric mixture of the target compound appeared at -7.40 and -7.82 ppm. The concentration of the target compound was approximately 0.16 M.

[0096] [Third Step: Phosphorylation Reaction with a Metal-Containing Catalyst] First, Hf(acac) ４ (5.2 mg, 0.009 mmol) and 3'-TBS-Thy-BOM (188.5 mg, 0.396 mmol) were added, and the atmosphere was replaced with argon gas. Next, THF (1.4 mL; adjusted according to the concentration of the intermediate so that the reaction solution concentration was 0.1 M) was added to the flask to prepare a homogeneous solution, and then the second-stage solution (0.16 M, 2.25 mL, 0.36 mmol) was added at room temperature.

[0097] The solution was then stirred at room temperature for 6 hours, and the resulting solution was added with (PhO) ３ P=O was added as an internal standard ３１ The target compound was identified by P-NMR. NMR measurement was performed without deuterated solvent lock, and the internal standard was set to −17 ppm. The diastereomeric mixture of the target compound appeared at −5.86 and 6.11 ppm (dr=42 / 58).

[0098] The solution was then diluted with dichloromethane (DCM) / saturated aqueous sodium carbonate (sat. Na ２ CO ３　 The resulting organic layer was washed with saturated brine (Brine), and the resulting mixture was washed with NaCl. ２ SO ４ After drying at 500°C, the organic solvent was removed using an evaporator to obtain a crude product. The crude product was then subjected to two silica gel column chromatography runs to isolate the target compound as a white solid (yield: 85%). The first run used a 3:2 mixture of hexane and ethyl acetate, while the second run used a 9:1 mixture of DCM and diethyl ether.

[0099] 2. Investigation of phosphorylation reaction using metal-containing catalysts The phosphorylation reaction was carried out according to the following reaction scheme. In the reaction scheme, "OCy" represents a substituent derived from cyclohexanol.

[0100] (Entry No. A1) First, Mg(acac) ２20 mol% of HCl and 1 equivalent of a phosphoric acid triester having a substituent containing an oxime structure were added, and the atmosphere was purged with argon gas. Next, THF was added to the flask to prepare a homogeneous solution, and then 1.1 equivalents of benzyl alcohol (BnOH) was added at room temperature. The solution was then stirred at room temperature for 6 hours, and the target compound was isolated from the resulting solution in the same manner as above. As a result, the yield of the target compound was 10%.

[0101] (Entry Nos. A2 to A12) A phosphorylation reaction was carried out in the same manner as Entry No. A1, except that the type and amount of metal-containing catalyst used were changed as shown in Table 1. (Entry No. A13) A phosphorylation reaction was carried out in the same manner as Entry No. A1, except that the use of the metal-containing catalyst was omitted. The results are shown in Table 1 below.

[0102]

[0103] The abbreviations in Table 1 are as follows: Mg(acac) ２ : Magnesium(II) acetylacetonate Zn(acac) ２ : Zinc (II) acetylacetonate Al(acac) ３ : Aluminum (III) acetylacetonate Ga(acac) ３ : Gallium (III) acetylacetonate In(acac) ３ : Indium (III) acetylacetonate Zr(acac) ４ : Zirconium (IV) acetylacetonate Hf(acac) ４ : Hafnium (IV) acetylacetonate Zr(OTf) ４ : Zirconium (IV) trifluoromethanesulfonate Zr(O ｔ Bu) ４ : Zirconium (IV) t-butoxide

[0104] In the phosphorylation reaction described above, when no catalyst was used, the yield of the target compound was 5%. In contrast, the use of a metal-containing catalyst improved the yield of the target compound. Zn(acac) ２When using Zr(acac) as a metal-containing catalyst, the yield of the target compound was 12%, but by examining the metal atoms, a catalyst with better catalytic ability was found. ４ or Hf(acac) ４ When the catalyst was used, the target compound was obtained in a yield of 74% even when the catalyst amount was 10 mol %.

[0105] 3. Examination of the structure of the phosphorylating agent in the phosphorylation reaction The phosphorylation reaction was carried out according to the following reaction scheme. In the reaction scheme, "LG" represents a leaving group, "OCy" represents a substituent derived from cyclohexanol, and "OBn" represents a substituent derived from benzyl alcohol.

[0106] (Entry No. B1) First, a two-neck round-bottom flask was charged with either omitting the addition of a metal-containing catalyst or Zr(acac) ４ or Hf(acac) ４ 7.5 mol% of benzophenone and 1 equivalent of a phosphate triester having an oxyma-derived substituent were added, and the atmosphere was replaced with argon gas. Next, THF was added to the flask to prepare a homogeneous solution, and then 1.1 equivalents of benzyl alcohol (BnOH) was added at room temperature. The solution was then stirred at room temperature for 3 hours, and the target compound was isolated from the resulting solution in the same manner as described above.

[0107] (Entry Nos. B2 to B5) Phosphorylation reactions were carried out in the same manner as in Entry No. B1, except that phosphate triesters with different leaving groups were used as phosphorylating agents. The results are shown in Table 2 below.

[0108]

[0109] The abbreviations in Table 2 are as follows: oxyma: oxyma (ethyl cyano(hydroxyimino)acetate) HOBt: 1-hydroxybenzotriazole HOBt Ｃｌ : 1-hydroxy-6-chlorobenzotriazole HOBt ＣＦ３ : 1-hydroxy-6-(trifluoromethyl)benzotriazole Bt: Benzotriazole

[0110] In the above phosphorylation reaction, the effect of differences in the leaving group possessed by the phosphorylating agent was investigated. When a phosphorylating agent having an oxyma-derived substituent as the leaving group was used, the target compound was not obtained at all in the absence of a metal-containing catalyst. In contrast, when Zr(acac) was used as the metal-containing catalyst, ４ The target compound was obtained in 60% yield by using the phosphorylating agent having a leaving group derived from other HOBts. The target compound was also obtained in moderate to good yield.

[0111] 4. Study of phosphorylation reaction using organic catalysts The phosphorylation reaction was carried out according to the following reaction scheme. In the reaction scheme, "PhO" represents a substituent derived from phenol, and "oxim" represents a substituent derived from oxima (ethyl cyano(hydroxyimino)acetate).

[0112] (Entry No. C0) [Phosphorylating Agent Preparation Step] First, 2.1 equivalents of oxime were added to a two-necked round-bottom flask, and the atmosphere was replaced with argon gas. Next, THF was added to the flask to prepare a homogeneous solution, and then 2.7 equivalents of pyridine (Py) was added as a substrate. Then, while cooling the flask in an ice bath, phosphoric acid chloride was added dropwise to obtain a suspension. After warming the flask to room temperature, the suspension was stirred for 1 hour. Next, the obtained solution was transferred using a cannula under an argon gas atmosphere and filtered through a glass filter. This yielded the target solution containing a phosphoric acid triester having a substituent containing an oxime structure.

[0113] [Phosphorylation Reaction Step] First, 1.1 equivalents of cyclohexanol (CyOH) was added to a two-necked round-bottom flask, and the atmosphere was replaced with argon gas. Next, THF was added to the flask to prepare a homogeneous solution, and the solution obtained above was added at room temperature. The solution was then stirred at room temperature for 1 hour, and a predetermined amount of the obtained solution was taken with a syringe and (PhO) ３ Using P═O as an internal standard, ３１ The conversion rate of the target compound was determined by P-NMR, and the result was that the conversion rate to the target compound was 100%.

[0114] (Entry No. C1-1) A phosphorylation reaction was carried out in the same manner as in Entry No. C0, except that the amount of pyridine used in the phosphorylating agent preparation step was changed to 2.0 equivalents. (Entry No. C1-2) A phosphorylation reaction was carried out in the same manner as in Entry No. C1-1, except that 10 mol% of pyridine was added in the phosphorylation reaction step. (Entry No. C1-3) In the phosphorylation reaction step, Zr(acac) ４ A phosphorylation reaction was carried out in the same manner as in Entry No. C1-1, except that 5 mol % of was added.

[0115] (Entry No. C2-1) A phosphorylation reaction was carried out in the same manner as in Entry No. C0, except that 2.3 equivalents of methylmorpholine (NMM) were used instead of 2.7 equivalents of pyridine in the phosphorylating agent preparation step. (Entry No. C2-2) A phosphorylation reaction was carried out in the same manner as in Entry No. C2-1, except that 10 mol% of pyridine was added in the phosphorylation reaction step. (Entry No. C2-3) In the phosphorylation reaction step, Zr(acac) ４ A phosphorylation reaction was carried out in the same manner as in Entry No. C2-1, except that 5 mol % of was added.

[0116] (Entry No. C3-1) A phosphorylation reaction was carried out in the same manner as Entry No. C0, except that 2.3 equivalents of 2,6-lutidine were used instead of 2.7 equivalents of pyridine in the phosphorylating agent preparation step. (Entry No. C3-2) A phosphorylation reaction was carried out in the same manner as Entry No. C3-1, except that the reaction time in the phosphorylation reaction step was changed to 8 hours. (Entry No. C3-3) A phosphorylation reaction was carried out in the same manner as Entry No. C3-1, except that the reaction time in the phosphorylation reaction step was changed to 24 hours. The results are shown in Table 3 below.

[0117]

[0118] In the phosphorylation reaction step, we investigated the effects of different catalyst types and reaction times. In the phosphorylation agent preparation step, two equivalents of the reagent (base) reacted and were removed from the reaction system. First, when 2.7 equivalents of pyridine were used in the phosphorylation agent preparation step, the reaction also proceeded smoothly in the phosphorylation reaction step. On the other hand, when the amount of pyridine used in the phosphorylation agent preparation step was reduced to 2.0 equivalents, the conversion rate in the phosphorylation reaction step decreased to 54%. This data suggests that in Entry No. C0, the pyridine remaining in the phosphorylation agent preparation step catalyzed the reaction in the phosphorylation reaction step. In fact, adding pyridine to a reaction system with a low conversion rate (Sample No. C1-1) improved the conversion rate. Furthermore, the conversion rate in the phosphorylation reaction step varied depending on the type of reagent (base) used in the phosphorylation agent preparation step, and this data also supports the promotion effect of the organic catalyst on the phosphorylation reaction.

[0119] 5. Synthesis of phosphate ester by one-pot reaction Phosphate ester was synthesized according to the following reaction scheme.

[0120] [First Step: Preparation of Phosphorylating Agent] First, HOAt (81.7 mg, 0.60 mmol) was added to a test tube, and the atmosphere was replaced with argon gas. Next, THF (1.5 mL) was added to the flask to prepare a homogeneous solution, and then triethylamine (NEt ３ ) (83.6 μL, 0.60 mmol) was added. Then, while the test tube was cooled in an ice bath, phosphoric acid chloride (48.4 μL, 0.30 mmol) was added dropwise to obtain a white suspension. The suspension was stirred for 0.5 hours.

[0121] [Second stage: Phosphorylation reaction using the remaining organic catalyst] Cyclohexanol (34.4 μL, 0.33 mmol) was added dropwise to the test tube in the first stage, and the suspension was stirred for 1 hour while the test tube was cooled in an ice bath. [Third stage: Phosphorylation reaction using a metal-containing catalyst] The test tube in the second stage was warmed to room temperature, and triethylamine (NEt ３) (12.5 μL, 0.09 mmol) was added. Next, a solution of Zr(acac) (7.3 mg, 0.015 mmol) in THF (0.5 mL) was added. Finally, benzyl alcohol (34.3 μL, 0.33 mmol) was added. The suspension was stirred for 3 h.

[0122] The solution was then diluted with diethyl ether (Et ２ O) / saturated sodium carbonate aqueous solution (sat. Na ２ CO ３　 aq.), and the aqueous layer was separated with Et ２ The resulting organic layer was washed with saturated brine and ２ SO ４ After drying at 500°C, the organic solvent was removed using an evaporator to obtain a crude product. The crude product was then isolated by thin-layer chromatography to obtain the target compound as a colorless liquid (yield: 82%). The developing solvent used was DCM:ethyl acetate = 100:1.

[0123] 6. Study of phosphorylation reaction using organic catalysts The phosphorylation reaction was carried out according to the following reaction scheme. In the reaction scheme, "OCy" represents a substituent derived from cyclohexanol, and "OBn" represents a substituent derived from benzyl alcohol.

[0124] (Entry No. D1) [First Step] First, 5.0 mol% of imidazole (ImH) was added to a two-necked round-bottom flask, and the inside of the flask was replaced with argon gas. Next, toluene (PhMe) was added to the flask to prepare a homogeneous solution, and then 1.1 equivalents of bis(2,2,2-trifluoroethyl) phosphite and 1 equivalent of cyclohexanol were added at room temperature. The solution was then stirred at room temperature for 3 hours.

[0125] [Second Step] First, 5.0 mol% of imidazole (ImH) was added as an organic catalyst to a two-necked round-bottom flask, and the atmosphere was replaced with argon gas. Next, toluene (PhMe) was added to the flask to prepare a uniform solution, and then 1 equivalent of benzyl alcohol (BnOH) and the solution obtained above were added at room temperature. The solution was then stirred for 3 hours at room temperature, and the solvent was distilled off under reduced pressure to obtain a crude product. The obtained crude product was subjected to column chromatography (developing solvent: hexane / acetone = 9 / 1) to isolate the target compound and by-products. As a result, the yield of the target compound was 31%, and PH(O)(OBn) ２ The yield of PH(O)(OCy) was 4%. ２ The yield was 1%.

[0126] (Entry Nos. D2 to D11) Phosphorylation reactions were carried out in the same manner as in Entry No. D1, except that the type and amount of organic catalyst used were changed as shown in Table 2. The results are shown in Table 2 below.

[0127]

[0128] The abbreviations in Table 4 are as follows: ImH: imidazole NMI: N-methylimidazole DMAP: 4-dimethylaminopyridine DABCO: 1,4-diazabicyclo[2.2.2]octane DBU: diazabicycloundecene

[0129] The effect of organic catalysts was investigated in the above two-step phosphite oxidation reaction. When ImH was used as the organic catalyst, the yield of the target compound reached up to 90%. When other Lewis bases, such as NMI, DMAP, and DABCO, were used as the organic catalyst, the yield of the target compound tended to be lower than when ImH was used. When the strong base DBU was used as the organic catalyst, the amount of by-products produced was confirmed to be slightly higher, and the yield of the target compound was approximately 70%.

Claims

1. A method for producing a phosphite ester, comprising the steps of: preparing a catalyst, an alcohol, and a phosphite agent; and reacting the alcohol with the phosphite agent in the presence of the catalyst to obtain a phosphite ester, wherein when the phosphite agent is a phosphorylating agent, a metal-containing catalyst that functions as a Lewis acid is used as the catalyst; and when the phosphite agent is a phosphorylating agent or a phosphite agent, an organic catalyst that functions as a base is used as the catalyst.

2. A method for producing a (phosphite) ester according to claim 1, wherein the metal-containing catalyst comprises a compound having a metal atom belonging to Group 2, 4, 12 or 13 of the periodic table and a ligand coordinated to the metal atom.

3. The method for producing a (phosphite) ester according to claim 2, wherein the metal atom is at least one selected from the group consisting of indium, zirconium, and hafnium.

4. The method for producing a phosphate (or phosphorous) ester according to claim 2 or 3, wherein the ligand is at least one selected from the group consisting of β-diketonate ligands, perfluoroalkylsulfonate ligands, and alkoxy ligands.

5. A method for producing a phosphite ester according to any one of claims 1 to 4, wherein a phosphate triester having a substituent containing an oxime structure or a hydroxybenzotriazole structure is used as the phosphating agent.

6. The method for producing a phosphite ester according to claim 5, wherein the substituent having an oxime structure of the phosphate triester contains a cyano group.

7. The method for producing a phosphite ester according to any one of claims 1 to 6, wherein the organic catalyst comprises a heterocyclic compound containing a nitrogen atom.

8. The method for producing a phosphite ester according to claim 7, wherein the heterocyclic compound is at least one selected from the group consisting of pyridine, N,N-dimethylaminopyridine, imidazole, and N-methylimidazole.

9. A method for producing a phosphite ester according to any one of claims 1 to 8, wherein a phosphite diester having an alkoxy group containing a fluorine atom, or a phosphate triester having a substituent containing an oxime structure or a hydroxybenzotriazole structure, is used as the phosphite diester.

10. The method for producing a phosphite ester according to claim 9, wherein the fluorine atom-containing alkoxy group of the phosphite diester includes a trifluoroethoxy group.

11. The method for producing a (phosphite) ester according to any one of claims 1 to 10, wherein the reaction temperature between the alcohol and the (phosphite) reacting agent is 5°C or higher and 40°C or lower.

12. The method for producing a (phosphite) ester according to any one of claims 1 to 11, wherein the reaction time between the alcohol and the (phosphite)ating agent is 0.1 hours or more and 10 hours or less.

13. A method for producing a (phosphite) ester according to any one of claims 1 to 12, wherein the amount of the catalyst used is 0.1 mol or more and 30 mol or less per 100 mol of the (phosphite) ester.

14. A phosphite (or phosphite) agent used to produce a phosphate ester by reaction with an alcohol, which is a phosphate triester having a substituent containing an oxime structure or a hydroxybenzotriazole structure, or a phosphite diester having an alkoxy group containing a fluorine atom.

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