JP5067752B2 - Method for producing phosphate ester - Google Patents

Description

  The present invention relates to a method for producing a phosphate ester by reacting phosphoric acid with an alcohol. More specifically, the present invention relates to a method for efficiently producing a phosphate ester by reacting phosphoric acid with an alcohol in the presence of a specific solvent and catalyst.

  Phosphate esters are useful compounds as intermediate raw materials for pharmaceuticals, agricultural chemicals, etc., surfactants, etc., and development of an efficient production method is desired. As its production method, the method of directly dehydrating and condensing phosphoric acid and alcohol is considered to be the most efficient, but the direct synthesis method known so far is extremely low because the reactivity of these compounds is very low. It is limited and has many problems. Known methods for direct dehydration condensation include heating to reflux in N, N-dimethylformamide (DMF) in the presence of an excess amount of tributylamine (Non-patent Document 1), in a solvent that also contains DMF, etc. A method of reacting in the presence of a molar amount of tributylamine and a catalytic amount of N-alkylimidazole or N, N-dialkylaminopyridine (Non-Patent Document 2), and further reacting in the presence of a rhenium peroxide catalyst and dibutylamine. There are only a few known methods (Non-Patent Document 3). In the first two methods, there is a problem in that an organic base must be used in an equimolar amount or more in order to compensate for the low reactivity. In the third method, an expensive metal catalyst is used. The problem is that there is a risk of metal contamination in the product. As a method for producing a phosphate ester from phosphoric acid and alcohol using a catalytic amount of an inexpensive base catalyst, as a comparative example of the method of reacting in the presence of a rhenium peroxide catalyst and dibutylamine in Non-patent Document 3, Although a method of reacting in the presence of an amount of dibutylamine has been disclosed, the yield of phosphate ester is low and not satisfactory. That is, a method for efficiently producing a phosphate ester from phosphoric acid and alcohol using a catalytic amount of an inexpensive catalyst has not yet been found.

As a method other than the direct dehydration condensation method of phosphoric acid and alcohol, for example, phosphoric acid and alcohol in the presence of a dehydration condensation agent such as 2,4,6-triisopropylphenylsulfonyl chloride and N, N′-dicyclohexylcarbodiimide And a method of reacting alcohol with phosphorus chloride as a phosphoric acid source. However, the former has the disadvantage that it is necessary to use an equimolar amount or more of an expensive dehydrating condensing agent, and the latter has a disadvantage that a more expensive phosphorus compound must be used as a raw material.
Chemical & Pharmaceutical Bulletin, 1966, 14, 1061 Organic Letters, 2005, Vol. 7, p. 1999 Kazuaki Ishihara et al., “The Oxorhenium (VII) —Catalyzed Direct Condensation of Phosphoric Acid with an Alcohol”, Angende Chemie Int.

  The subject of this invention is providing the method which can manufacture phosphate ester simply and efficiently from phosphoric acid and alcohol.

As a result of continual studies to solve the above problems, the present inventors have found that when a solvent containing a specific amide compound or urea compound is reacted with phosphoric acid and an alcohol in the presence of a specific base catalyst, the amount of the catalyst is reduced. The inventors have found that a phosphate ester can be produced very efficiently by using a base, and have completed the present invention.

That is, the method for producing a phosphate ester of the present invention is a method for producing a phosphate ester by reacting phosphoric acid and alcohol in a solvent,
The amide compound represented by the general formula (1) or the urea compound represented by the general formula (2) per 20% by volume of the solvent is 20% by volume or more,
In the presence of at least one catalyst selected from the group consisting of tertiary amines, N-alkylimidazoles, N-arylimidazoles, and phosphazene compounds;
It is characterized by reacting phosphoric acid and alcohol.

(In the formula, R ¹ represents a hydrocarbon group having 1 to 10 carbon atoms. R ² and R ³ each independently represents a hydrogen atom or a hydrocarbon group having 1 to 20 carbon atoms, and further R ¹ and R ^2. Or R ¹ and R ³ may be bonded to each other to form a ring structure.)

(Wherein R ⁴ , R ⁵ , R ⁶ and R ⁷ each independently represents a hydrocarbon group having 1 to 10 carbon atoms, and further, two hydrocarbon groups on different nitrogen atoms are bonded to each other to form a ring structure) May be formed.)
In the reaction, it is preferable to carry out the reaction while removing water in the reaction system from the reaction system.

It is preferred that the phosphoric acid is orthophosphoric acid.
It is preferable to use a solvent containing 20% by volume or more of N-methyl-2-pyrrolidone.

The amount of catalyst used is preferably 50 mol% or less with respect to phosphoric acid.
The catalyst is preferably a phosphazenium compound represented by the general formula (3).

(In the formula, n is an integer of 1 to 8 and represents the number of phosphazenium cations, and Z ⁿ⁻ is an anion derived by elimination of n protons from the inorganic acid or active hydrogen compound. , B, c and d are each independently a positive integer of 3 or less or 0, but all are not simultaneously 0. R ⁸ is each independently a hydrocarbon group having 1 to 10 carbon atoms and the same nitrogen Two R ⁸ on the atom may be bonded to each other to form a ring structure.)
More preferably, the catalyst is tetrakis [tris (dimethylamino) phosphoranylideneamino] phosphonium hydroxide.

  The phosphoric acid ester produced by reacting phosphoric acid and alcohol is preferably a phosphoric acid monoester.

  According to the present invention, by using a catalytic amount of a base, a phosphoric acid ester can be efficiently produced by directly dehydrating and condensing phosphoric acid and alcohol under mild reaction conditions.

Hereinafter, the present invention will be described in detail.
The method for producing a phosphate ester according to the present invention is a method for producing a phosphate ester by reacting phosphoric acid and an alcohol in a solvent, and the amide represented by the general formula (1) per 100 vol% of the solvent. At least one catalyst selected from the group consisting of a tertiary amine, an N-alkylimidazole, an N-arylimidazole, and a phosphazene compound, wherein the compound or the urea compound represented by the general formula (2) is 20% by volume or more It is characterized by reacting phosphoric acid and alcohol in the presence of.

(In the formula, R ¹ represents a hydrocarbon group having 1 to 10 carbon atoms. R ² and R ³ each independently represents a hydrogen atom or a hydrocarbon group having 1 to 20 carbon atoms, and further R ¹ and R ^2. Or R ¹ and R ³ may be bonded to each other to form a ring structure.)

(Wherein R ⁴ , R ⁵ , R ⁶ and R ⁷ each independently represents a hydrocarbon group having 1 to 10 carbon atoms, and further, two hydrocarbon groups on different nitrogen atoms are bonded to each other to form a ring structure) May be formed.)
Specific examples of phosphoric acid as a raw material in the method for producing a phosphate ester of the present invention include orthophosphoric acid (H ₃ PO ₄ ), for example, linear forms such as pyrophosphoric acid, triphosphoric acid, and tetraphosphoric acid. Mention may be made of polyphosphoric acids, for example cyclic polyphosphoric acids such as metaphosphoric acid. Of these phosphoric acids, use of orthophosphoric acid is preferable because a phosphoric acid ester can be produced efficiently.

  The alcohol that is the other raw material in the method for producing a phosphate ester of the present invention is not particularly limited, and examples thereof include aliphatic saturated alcohols, aliphatic unsaturated alcohols, alicyclic alcohols, aromatic alcohols, and heterocyclic alcohols. Alcohol or the like can be used. Further, substituted alcohols in which a part of each alcohol is substituted with another group can also be used.

  There is no restriction | limiting in the series of alcohol, Any of primary alcohol, secondary alcohol, or tertiary alcohol may be sufficient. Further, the alkyl group or the substituted alkyl group may be a chain or a ring. The alcohol used in the present invention may contain multiple bonds, alicyclic rings, aromatic rings, heterocyclic rings, halogen atoms and the like in the molecule. Specific examples of such alcohols include linear or branched aliphatic saturated alcohols having 1 to 50 carbon atoms such as methanol, isopropanol, 2-ethylhexanol, lauryl alcohol, eicosyl alcohol, farnesol, ethylene glycol, and glycerin. A linear or branched aliphatic unsaturated alcohol having 2 to 50 carbon atoms, such as crotyl alcohol, propargyl alcohol, methyl vinyl carbinol, oleyl alcohol, such as cyclopentanol, cyclohexanol, or cholesterol, Saturated alicyclic or unsaturated alicyclic alcohols having 3 to 100 carbon atoms such as sterols such as stanol, for example, aromatic alcohols having 7 to 50 carbon atoms such as benzyl alcohol and cinnamyl alcohol, such as gluco Sucrose, ribose, xylose and the like saccharides and derivatives thereof such as uridine, 2 ′, 3′-O-isopropylideneuridine, 2 ′, 3′-O-isopropylidene adenosine, 2 ′, 3 ′ -O-isopropylidene cytidine, nucleic acids having 5 to 100 carbon atoms such as 2 ', 3'-O-isopropylideneguanosine and derivatives thereof, such as carbon such as 2-methoxyethanol, polyethylene glycol, polypropylene glycol, lauryl alcohol ethoxylate (Poly) alkylene glycols having a number of 2 to 1000, for example, an oxygen atom such as furfuryl alcohol, 2- (octylthio) -ethanol, p-nitrobenzyl alcohol, triethanolamine, ethylene chlorohydrin, diethylene glycol monododecyl ether, C1-C50 alcohol which has a substituted alkyl group containing a sulfur atom, a nitrogen atom, or a halogen atom etc. are mentioned. All of these alcohols can be suitably used as the raw material of the present invention, but among these alcohols, the use of primary alcohols or secondary alcohols is preferred, and the use of primary alcohols is more preferred.

  The solvent used in the present invention contains 20% by volume or more of an amide compound represented by the following general formula (1) or a urea compound represented by the following general formula (2) per 100% by volume of the solvent.

(In the formula, R ¹ represents a hydrocarbon group having 1 to 10 carbon atoms. R ² and R ³ each independently represents a hydrogen atom or a hydrocarbon group having 1 to 20 carbon atoms, and further R ¹ and R ^2. Or R ¹ and R ³ may be bonded to each other to form a ring structure.)

(Wherein R ⁴ , R ⁵ , R ⁶ and R ⁷ each independently represents a hydrocarbon group having 1 to 10 carbon atoms, and further, two hydrocarbon groups on different nitrogen atoms are bonded to each other to form a ring structure) May be formed.)
In the general formula (1), R ¹ represents a hydrocarbon group having 1 to 10 carbon atoms. More specifically, as such R ¹ , for example, an alkyl group having 1 to 10 carbon atoms such as a methyl group, an ethyl group, a 2-butyl group, an n-pentyl group, and a 2-ethylhexyl group, such as a cyclohexyl group, etc. A cycloalkyl group having 3 to 10 carbon atoms, such as a alkenyl group having 2 to 10 carbon atoms such as a vinyl group or a propenyl group, a cycloalkenyl group having 3 to 10 carbon atoms such as a cyclohexenyl group, such as a phenyl group or a naphthyl group. And a substituted or unsubstituted aryl group having 6 to 10 carbon atoms such as an ethylphenyl group. Among these hydrocarbon groups, an alkyl group having 1 to 10 carbon atoms is preferable, and a methyl group or an ethyl group is more preferable.

Moreover, in General formula (1), R < ² > and R < ³ > represents a hydrogen atom or a C1-C20 hydrocarbon group each independently. The hydrocarbon group is preferably a hydrocarbon group having 1 to 10 carbon atoms, and specific examples thereof include the same groups as the hydrocarbon groups mentioned as specific examples of R ¹ .

R ² and R ³ are preferably a hydrogen atom or an alkyl group having 1 to 10 carbon atoms.
Furthermore, in the general formula (1), R ¹ and R ² , or R ¹ and R ³ may be bonded to each other to form a ring structure. Specifically, as the group in this case, for example, an alkylene group having 2 to 10 carbon atoms such as an ethylene group, trimethylene group or pentamethylene group, for example, a cycloalkylene group having 3 to 10 carbon atoms such as a cyclohexylene group, for example, Examples include C2-C10 alkenylene groups such as vinylene groups, C3-C10 cycloalkenylene groups such as cyclohexenylene groups, C8-C10 aralkylene groups such as phenylethylene groups, and the like. Among these groups, an alkylene group having 2 to 10 carbon atoms is preferable.

  More specifically, examples of the amide compound represented by the general formula (1) include chain amide compounds such as acetamide, N-methylacetamide, N, N-dimethylacetamide, and N-methylpropionamide, such as 2-pyrrolidone. And cyclic amide compounds such as N-methyl-2-pyrrolidone. Of these amide compounds, use of N-methylacetamide and N-methyl-2-pyrrolidone is preferable, and use of N-methyl-2-pyrrolidone is more preferable.

In General formula (2), R < ⁴ >, R < ⁵ >, R < ⁶ > and R < ⁷ > represent a C1-C10 hydrocarbon group each independently. Specific examples of R ⁴ , R ⁵ , R ⁶ and R ⁷ include the same groups as the hydrocarbon groups mentioned as specific examples of R ¹ . Of these groups, an alkyl group having 1 to 10 carbon atoms is preferable.

In the general formula (2), two hydrocarbon groups on different nitrogen atoms may be bonded to each other to form a ring structure. Specific examples of the group in this case include the same groups as those exemplified as specific examples in the case where R ¹ and R ² , or R ¹ and R ³ are bonded to each other to form a ring structure. it can. Among these groups, an alkylene group having 2 to 10 carbon atoms is preferable.

  More specifically, examples of the urea compound represented by the general formula (2) include chain urea compounds such as N, N, N ′, N′-tetramethylurea, such as N, N′-dimethylethyleneurea, Examples include cyclic urea compounds such as N, N′-dimethylpropyleneurea. Of these urea compounds, the use of N, N'-dimethylethyleneurea and N, N'-dimethylpropyleneurea is preferred.

  In the present invention, it is most preferable that N-methyl-2-pyrrolidone is 20% by volume or more per 100% by volume of the solvent. N-methyl-2-pyrrolidone is preferable because it is excellent in solubility of phosphoric acid and the reaction between phosphoric acid and alcohol proceeds rapidly, so that a phosphoric acid ester can be produced efficiently. N-methyl-2-pyrrolidone is preferable because it can be easily distilled off under reduced pressure after the reaction.

  In the present invention, it is effective to use a solvent in which the amide compound represented by the general formula (1) or the urea compound represented by the general formula (2) is 20% by volume or more per 100 volume% of the solvent. A phosphate ester is produced. A solvent in which the amide compound represented by the general formula (1) or the urea compound represented by the general formula (2) is 40 to 100% by volume is more preferable.

  In the present invention, any solvent other than the amide compound represented by the general formula (1) or the urea compound represented by the general formula (2) may be any solvent as long as the reaction of the present invention is not inhibited. Specifically, aliphatic saturated hydrocarbon compounds having 6 to 20 carbon atoms such as octane and undecane, for example, unsubstituted or substituted aromatic hydrocarbon compounds having 6 to 20 carbon atoms such as toluene, xylene and ethylbenzene Examples thereof include halogenated aromatic hydrocarbon compounds having 6 to 20 carbon atoms such as chlorobenzene and o-dichlorobenzene, and nitrile compounds having 2 to 20 carbon atoms such as propionitrile, butyronitrile and benzonitrile. Of these solvents, the use of unsubstituted or substituted aromatic hydrocarbon compounds, halogenated aromatic hydrocarbon compounds and nitrile compounds is preferred. Although the usage-amount of these additional solvents changes with kinds of solvent, it is the range of 0-80 volume% per 100 volume% of solvents used for reaction, Preferably it is the range of 0-60 volume%.

The catalyst used in the present invention is at least one catalyst selected from the group consisting of tertiary amines, N-alkylimidazoles, N-arylimidazoles, and phosphazene compounds.
Specific examples of the tertiary amine include linear or branched tertiary alkyl amines such as triisopropylamine and tri-n-butylamine, and tertiary aromatics such as triphenylamine and N, N-dimethylaniline. Amines such as N-methylpyrrolidine, 1,8-diazabicyclo [5.4.0] undec-7-ene, cyclic tertiary amines such as triethylenediamine, pyridine group-containing tertiary amines such as 4-dimethylaminopyridine, etc. Is mentioned.

Examples of N-alkylimidazole include N-methylimidazole (1-methyl-1
N-alkylimidazoles such as H-imidazole), N-butylimidazole (1-butyl-1H-imidazole), and 1,2-dimethylimidazole (1,2-dimethyl-1H-imidazole).

  Examples of the N-arylimidazole include N-arylimidazoles such as N-phenylimidazole (1-phenyl-1H-imidazole) and N-2,4,6-trimethylphenylimidazole.

  Examples of the phosphazene compound include a phosphazenium compound represented by the following general formula (3) and a phosphazene base represented by the following general formula (4).

(In the formula, n is an integer of 1 to 8 and represents the number of phosphazenium cations, and Z ⁿ⁻ is an anion derived by elimination of n protons from the inorganic acid or active hydrogen compound. , B, c and d are each independently a positive integer of 3 or less or 0, but all are not simultaneously 0. R ⁸ is each independently a hydrocarbon group having 1 to 10 carbon atoms and the same nitrogen Two R ⁸ on the atom may be bonded to each other to form a ring structure.)

(In the formula, e, f and g are each independently a positive integer of 3 or less or 0. R ⁹ is each independently a hydrocarbon group having 1 to 10 carbon atoms, R ⁹ may be bonded to each other to form a ring structure.)
In general formula (3), n with represents the number of phosphazenium cations, represents the number of protons released from an inorganic acid or an active hydrogen compound leads to Z ^n-. n is an integer of 1 to 8, preferably an integer of 1 to 3. When the active hydrogen compound that leads Zn ⁿ has a plurality of active hydrogens, all of these active hydrogens may be eliminated and led to the anion, or only some of them may be detached and led to the anion. is there.

In the general formula (3), Z ⁿ⁻ represents an n-valent anion derived from n protons desorbed from an inorganic acid or an active hydrogen compound.
Among the compounds leading to Z ^n-, specifically as inorganic acids, for example hydrogen fluoride, hydrogen chloride, hydrogen halides, phosphoric acids, such as hydrobromic, sulfuric, perchloric acid, hexafluoro phosphoric acid, tetra Examples thereof include fluoroboric acid, hydrogen cyanide, and thiocyanic acid.

Among the compounds leading to Z ^n-, examples of the active hydrogen compound, limited as long as it is a compound capable of providing desorbed by anion proton is not, for example, compounds in which active hydrogen atom bonded to a carbon atom, an oxygen atom A compound in which an active hydrogen atom is bonded to a nitrogen atom, a compound in which an active hydrogen atom is bonded to a nitrogen atom, a compound in which an active hydrogen atom is bonded to a sulfur atom, and the like.

Among the active hydrogen compound leading to Z ^n-, as the compound bound active hydrogen atom on a carbon atom, an electron-withdrawing group, such as having at least one such as cyano group and a nitro group to a carbon atom to a hydrogen atom And a compound having a hydrogen atom directly bonded to an alkenyl group or alkynyl group. More specifically, a compound having a cyano group such as acetonitrile or butyronitrile, for example, an alkoxycarbonyl such as methyl acetate or isopropyl acetate. A compound having a nitro group such as 1-nitropropane and 1-nitrobutane, a compound having an alkenyl group such as 1,2,3,4,5-pentamethylcyclopentadiene, such as acetylene, 2- Compounds having an alkynyl group such as butyne, such as dimethyl malonate What malonates and the like.

Among the active hydrogen compound leading to Z ^n-, as the compound active hydrogen atom on an oxygen atom is bonded, specifically, to including water, such as methanol, isopropanol, benzyl alcohol, alcohols such as ethylene glycol Saccharides such as glucose and sorbitol or derivatives thereof, such as carboxylic acids such as acetic acid, propionic acid, benzoic acid and malonic acid, such as carbamic acids such as N, N-diethylcarbamic acid and N-carboxypyrrolidone, Phenolic compounds such as phenol and 2-naphthol.

Among the active hydrogen compound leading to Z ^n-, as the compound is an active hydrogen atom on the nitrogen atom is bonded, specifically, to the beginning of ammonia, such as methylamine, ethylamine, benzylamine, dimethylamine, methyl Primary or secondary amines such as ethylamine, diphenylamine and ethylenediamine, for example, saturated cyclic secondary amines such as pyrrolidine and piperidine, for example, unsubstituted 2 to 20 carbon atoms such as acetamido and N-methylpropionamide or N -Monosubstituted acid amides and the like.

Among the active hydrogen compound leading to Z ^n-, as the compound active hydrogen atoms on the sulfur atom is bonded, specifically, to the beginning of the hydrogen sulfide, for example methanethiol, decane thiol, 1,2-ethane Examples include thiols such as dithiol, thiophenols such as thiophenol and o-thiocresol.

Among these compounds that lead to Z ^n- , an active hydrogen compound in which an active hydrogen atom is bonded to an inorganic acid or an oxygen atom is preferable, phosphoric acid, water, or alcohols are more preferable, and water is further preferable.

  In the general formula (3), a, b, c and d are each independently a positive integer of 3 or less or 0, but all are not 0 at the same time. Preferably, each is independently a positive integer of 2 or less or 0. More preferably, a, b, c and d are all 2 or 1 at the same time, and more preferably all are 1 at the same time.

In the general formula (3), each R ⁸ is independently a hydrocarbon group having 1 to 10 carbon atoms,
In some cases, two R ⁸ on the same nitrogen atom may be bonded to each other to form a ring structure.
Specific examples of R ⁸ include the same groups as the hydrocarbon groups mentioned as specific examples of R ¹ . Among these groups, an alkyl group having 1 to 10 carbon atoms is preferable, and a methyl group is more preferable.

In the general formula (3), two R ⁸ on the same nitrogen atom may be bonded to each other to form a ring structure. Specific examples of the group in this case include the same groups as those exemplified as specific examples in the case where R ¹ and R ² , or R ¹ and R ³ are bonded to each other to form a ring structure. it can. Among these groups, an alkylene group having 2 to 10 carbon atoms is preferable, and a tetramethylene group and a pentamethylene group are more preferable.

Specific examples of the phosphazenium compound represented by the general formula (3) include tetrakis [tris (dimethylamino) phosphoranylideneamino] phosphonium hydroxide (general formula (3
) In which R ⁸ = methyl group, a = b = c = d = 1, n = 1, Z ⁿ⁻ = OH ⁻ ) (the following general formula (5)), for example, Japanese Patent No. 3497054 Examples include phosphazenium compounds synthesized in the examples.

  In the general formula (4), e, f and g are each independently a positive integer of 3 or less or 0. Preferably, e, f and g are not all 0 at the same time, but are each a positive integer of 2 or less or 0. More preferably, e, f and g are all 2 or 1 at the same time, and more preferably all are 1 at the same time.

In the general formula (4), each R ⁹ is independently a hydrocarbon group having 1 to 10 carbon atoms,
In some cases, two R ⁹ on the same nitrogen atom may be bonded to each other to form a ring structure. Moreover,
All R ⁹ in the phosphonium salt may be the same or different.

Specific examples of R ⁹ include the same groups as the hydrocarbon groups mentioned as specific examples of R ¹ . Among these groups, an alkyl group having 1 to 10 carbon atoms is preferable, and a methyl group is more preferable.
In the general formula (4), two hydrocarbon groups on different nitrogen atoms may be bonded to each other to form a ring structure. Specific examples of the group in this case include the same groups as those exemplified as specific examples in the case where R ¹ and R ² , or R ¹ and R ³ are bonded to each other to form a ring structure. it can. Among these groups, an alkylene group having 2 to 10 carbon atoms is preferable, and a tetramethylene group and a pentamethylene group are more preferable.

Specific examples of the phosphazene base represented by the general formula (4), for example t- butyl imino-tris (dimethylamino) phosphorane (R ⁹ is a methyl group -NR ⁹ ₂ group in the general formula (4), = NR R ^{9 in 9} groups is a t-butyl group, e = f = g = 0), 1-t-butyl-4,4,4-tris (dimethylamino) -2,2-bis [tris (dimethylamino) phosphorous two isopropylidene amino] -2λ ^5, 4λ ⁵ - catena di phosphazene (formula (in 4) R ⁹ is a methyl group -NR ⁹ ₂ group, = R ⁹ is t- butyl group in NR ⁹ group, e Phosphazene bases listed in Scheme 1 of Journal of Organic Chemistry, 2003, Vol. 68, page 9989, and the like.

The catalyst used in the present invention may take the form of an immobilized catalyst that is chemically or physically supported on a carrier such as polystyrene gel.
Of these catalysts, cyclic tertiary amines, pyridine group-containing tertiary amines, N-alkylimidazoles, and phosphazene compounds are preferable, phosphazenium compounds represented by the general formula (3) are more preferable, and tetrakis [tris (dimethylamino). Phosphoranilideneamino] phosphonium hydroxide (the following general formula (5)) is more preferable.

The amount of the catalyst of the present invention used is 100 mol% or less with respect to phosphoric acid, preferably 50 mol% or less with respect to phosphoric acid, and more preferably 30 mol% or less.
In the present invention, it is preferable to carry out the reaction while removing water brought into the reaction system and water generated during the reaction out of the reaction system. There are no particular restrictions on the method of removing the reaction system outside, but a method of removing only water by distillation, a method of adding an azeotropic mixture with water and removing it as an azeotrope, and a dehydrating agent layer such as molecular sieves. For example, a method of removing by passing can be used.

  The reaction temperature is usually in the range of 0 to 250 ° C, preferably in the range of 50 to 200 ° C, more preferably in the range of 100 to 150 ° C. The reaction time is usually 50 hours or less, preferably 0.1 to 30 hours, more preferably 0.5 to 20 hours. The reaction pressure can be any of normal pressure, increased pressure, and reduced pressure. In addition, any of the batch, semi-batch and continuous flow types can be used.

  The structure of the phosphate ester produced by the method of the present invention is not particularly limited, and monophosphate esters such as phosphate monoester, phosphate diester, phosphate triester, pyrophosphate monoester, pyrophosphate diester, triphosphate Polyphosphate esters such as acid monoesters can be obtained efficiently. The hydrocarbon group portion of the resulting phosphate ester corresponds to the structure of the alcohol used.

Further, the phosphoric acid portion of the obtained phosphoric acid ester does not need to correspond to the structure of the phosphoric acid used, and for example, pyrophosphoric acid ester can be produced using orthophosphoric acid.
Especially, this invention is suitable as a manufacturing method of phosphoric acid monoester which manufactures phosphoric acid monoester as a main product by reaction of orthophosphoric acid and alcohol.

  The phosphate ester produced by the method for producing phosphate ester of the present invention can be isolated and purified by conventional purification such as distillation, recrystallization, column purification and the like.

EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples, but the present invention is not limited thereto.
[Example 1]
In a 20 mL flask, 1-octadecanol (2.0 mmol), orthophosphoric acid (2.0 mmol), tri-n-butylamine (0.2 mmol), 5 mL of N-methyl-2-pyrrolidone and 5 mL of o-xylene were used as solvents. Prepared.

Pellet molecular sieves 4A (about 3 mL) was placed in a Soxhlet extractor, which was attached to a reaction flask, and a condenser tube was attached thereon.
The reaction solution was heated with a 180 ° C. oil bath with stirring and heated to reflux for 10 hours, and then cooled to room temperature.

When the obtained reaction mixture was analyzed by ¹ H-NMR and ³¹ P-NMR, monooctadecyl phosphate was produced in a yield of 43% (based on 1-octadecanol).
The results are shown in Table 1.

[Examples 2 to 5]
In Example 1, a reaction was performed in the same manner as in Example 1 except that the catalyst (0.2 mmol) described in Table 1 was used instead of tri-n-butylamine, and analysis was performed by ¹ H-NMR.

The results are shown in Table 1.
[Comparative Example 1]
In Example 1, except that tri-n-butylamine was not used, the reaction was conducted in the same manner as in Example 1 and analyzed by ¹ H-NMR.

The results are shown in Table 1.
In the absence of catalyst, the yield of monooctadecyl phosphate was very low.
[Comparative Example 2]
The reaction was conducted in the same manner as in Example 1 except that di-n-butylamine (0.4 mmol) was used instead of tri-n-butylamine (0.2 mmol) in Example 1 and the reaction time was changed to 12 hours. The analysis was performed by ¹ H-NMR.

When a secondary amine was used as the catalyst, the yield of monooctadecyl phosphate was as low as 39% despite the increase in the amount of catalyst and the reaction time.
[Comparative Example 3]
In Example 1, 4-phenyl-1-butanol (2.0 mmol) was used instead of 1-octadecanol, and the amount of tri-n-butylamine used was 2.0 mmol, instead of N-methyl-2-pyrrolidone. The reaction was conducted in the same manner as in Example 1 except that 5 mL of N, N-dimethylformamide was used and the heating and refluxing time was changed to 6 hours, and the analysis was conducted by ¹ H-NMR.

When N, N-dimethylformaldehyde was used as a solvent, the yield of mono -4-phenylbutyl phosphate was as low as 20% despite the increased amount of amine used.
[Example 6]
In Example 5, reaction and analysis were performed in the same manner as in Example 5 except that the amount of orthophosphoric acid used was changed to 3.0 mmol.

  Monooctadecyl phosphate, dioctadecyl phosphate, monooctadecyl pyrophosphate and dioctadecyl pyrophosphate were produced, and the total phosphate ester yield was 92% (based on 1-octadecanol). The monooctadecyl phosphate content in the total phosphate ester was 97%.

[Example 7]
In Example 5, the reaction and analysis were performed in the same manner as in Example 5 except that the amount of orthophosphoric acid used was changed to 4.0 mmol.

Monooctadecyl phosphate, dioctadecyl phosphate, monooctadecyl pyrophosphate and dioctadecyl pyrophosphate were produced, and the total phosphate ester yield was 87% (based on 1-octadecanol). In addition, the monooctadecyl phosphate content in the total phosphate ester is 92%
Met.

[Examples 8 to 10]
The reaction and analysis were performed in the same manner as in Example 6 except that the alcohol (2.0 mmol) shown in Table 2 was used instead of 1-octadecanol in Example 6.

The reaction results are shown in Table 2. Regardless of the type of alcohol, phosphoric acid monoester was obtained in high yield.
[Example 11]
The reaction was carried out in the same manner as in Example 7 except that the alcohol (2.0 mmol) shown in Table 2 was used instead of 1-octadecanol in Example 7.

Analysis of the reaction mixture was performed using high performance liquid chromatography. The analysis conditions are as follows.
Column: Nomura Chemical Develosil ODS-5
Mobile phase: 0.02M ammonium acetate aqueous solution-methanol (3: 1 volume ratio)
Flow rate: 0.75 mL / min
Detection: UV detector (254 nm)
Retention time of phosphoric acid monoester: 6.2 min
The reaction results are shown in Table 2. Regardless of the type of alcohol, phosphoric acid monoester was obtained in high yield.

[Example 12]
1-octadecanol (0.5 mmol), orthophosphoric acid (4.0 mmol), tetrakis [tris (dimethylamino) phosphoranylideneamino] phosphonium hydroxide (0.2 mmol) in a 20 mL flask, N-methyl- 2-pyrrolidone 5 mL and butyronitrile 5 mL were charged.

Pellet molecular sieves 4A (about 3 mL) was placed in a Soxhlet extractor, which was attached to a reaction flask, and a condenser tube was attached thereon.
While stirring the reaction solution with an oil bath at 180 ° C. and heating to reflux for 2 hours, 0.5 mmol of 1-octadecanol was added. Each time the mixture was further refluxed for 2 hours, 0.5 mmol of 1-octadecanol was added twice (a total of 2.0 mmol of 1-octadecanol was used) and the mixture was heated to reflux for a total of 10 hours. The liquid was cooled to room temperature.

The obtained reaction mixture was analyzed by ¹ H-NMR and ³¹ P-NMR. Monooctadecyl phosphate, dioctadecyl phosphate, monooctadecyl pyrophosphate and dioctadecyl pyrophosphate were produced, and the combined yield of the phosphate ester was 94% (based on 1-octadecanol). The monooctadecyl phosphate content in the total phosphate ester was 85%.

[Examples 13 to 16]
The reaction was carried out in the same manner as in Example 12 except that the alcohols (total 2.0 mmol) shown in Table 3 were used instead of 1-octadecanol in Example 12, and the mixture was cooled to room temperature.

  Then, the reaction solvent was distilled off under reduced pressure and purified with an anion exchange resin (DOWEX1x2-200, formate anion type, 20 mL, eluent: ammonium formate aqueous solution). Table 3 shows the isolated yield (based on alcohol) of the phosphoric acid monoester.

The results are shown in Table 3.
Regardless of the type of alcohol, phosphoric acid monoester was obtained in high yield.
[Example 17]
The reaction and analysis were all performed in the same manner as in Example 6, except that N-methylacetamide (5 mL) was used instead of N-methyl-2-pyrrolidone (5 mL) as a solvent in Example 6.

The phosphate ester yield was 82% (based on 1-octadecanol). The monooctadecyl phosphate content in the total phosphate ester was 74%.
[Example 18]
The reaction and analysis were all carried out in the same manner as in Example 6, except that N, N′-dimethylethyleneurea (5 mL) was used instead of N-methyl-2-pyrrolidone (5 mL) as the solvent in Example 6.

  The phosphate ester yield was 93% (based on 1-octadecanol). The monooctadecyl phosphate content in the total phosphate ester was 78%.

  By the method for producing a phosphate ester of the present invention, a phosphate ester useful as an intermediate raw material for pharmaceuticals and agricultural chemicals, a surfactant or the like can be efficiently produced.

Claims (8)

A method for producing a phosphate ester by reacting phosphoric acid and alcohol in a solvent,
The amide compound represented by the general formula (1) or the urea compound represented by the general formula (2) per 20% by volume of the solvent is 20% by volume or more,
In the presence of the catalyst phosphazene compound ,
A method for producing a phosphate ester, characterized by reacting phosphoric acid and alcohol.

(In the formula, R ¹ represents a hydrocarbon group having 1 to 10 carbon atoms. R ² and R ³ each independently represents a hydrogen atom or a hydrocarbon group having 1 to 20 carbon atoms, and further R ¹ and R ^2. Or R ¹ and R ³ may be bonded to each other to form a ring structure.)

(Wherein R ⁴ , R ⁵ , R ⁶ and R ⁷ each independently represents a hydrocarbon group having 1 to 10 carbon atoms, and further, two hydrocarbon groups on different nitrogen atoms are bonded to each other to form a ring structure) May be formed.)   The method for producing a phosphate ester according to claim 1, wherein the reaction is carried out while removing water in the reaction system from the reaction system.   The method for producing a phosphate ester according to claim 1 or 2, wherein the phosphoric acid is orthophosphoric acid.   The method for producing a phosphate ester according to any one of claims 1 to 3, wherein a solvent containing 20% by volume or more of N-methyl-2-pyrrolidone is used.   The method for producing a phosphate ester according to any one of claims 1 to 4, wherein the amount of the catalyst used is 50 mol% or less based on phosphoric acid. The method for producing a phosphate ester according to any one of claims 1 to 5, wherein the catalyst is a phosphazenium compound represented by the general formula (3).

(In the formula, n is an integer of 1 to 8 and represents the number of phosphazenium cations, and Z ⁿ⁻ is an anion derived by elimination of n protons from the inorganic acid or active hydrogen compound. , B, c and d are each independently a positive integer of 3 or less or 0, but all are not simultaneously 0. R ⁸ is each independently a hydrocarbon group having 1 to 10 carbon atoms and the same nitrogen Two R ⁸ on the atom may be bonded to each other to form a ring structure.)   The method for producing a phosphate ester according to any one of claims 1 to 6, wherein the catalyst is tetrakis [tris (dimethylamino) phosphoranylideneamino] phosphonium hydroxide.   The manufacturing method according to any one of claims 1 to 7, wherein the phosphoric acid ester produced by reacting phosphoric acid and alcohol is a phosphoric acid monoester.