Method for producing anhydrous cyclic phosphonic acid and method for producing phosphonic acid monoester

Abstract

Provided is a method for producing an anhydrous cyclic phosphonic acid by reacting phosphonic acid (A) with a basic compound (B) and at least one type of halogenating agent (C) selected from thionyl chloride, phosphoryl chloride, and oxalyl chloride. Also provided is a method for producing a phosphonic acid monoester by reacting the anhydrous cyclic phosphonic acid obtained by said production method with an alcohol.

Description

Method for producing cyclic phosphonic anhydride and method for producing phosphonic acid monoesters

[0001] The present invention relates to a method for producing cyclic phosphonic anhydride and a method for producing phosphonic acid monoesters.

[0002] Cyclic phosphonic anhydrides are useful compounds used as condensing agents in peptide synthesis, and in particular, cyclic propylphosphonic anhydride (commonly known as "T3P" or propylphosphonic anhydride), shown below, is used in the formation of amide bonds in pharmaceutical synthesis. Various methods for synthesizing such cyclic phosphonic anhydrides have been investigated. On the other hand, phosphonic acid monoesters are expected to be useful as metal extractants used in wet extraction (solvent extraction). Although various methods for synthesizing phosphonic acid monoesters are known, such as the method using diethyl phosphite, the synthesis process is multi-step and not convenient. In addition, a method of hydrolyzing phosphonic acid diesters is generally known, but this synthesis method involves the elimination of excess alcohol and is not atomically efficient.

[0003] As a method for synthesizing cyclic phosphonic anhydride, for example, Non-Patent Document 1 describes a method for synthesizing T3P by adding water to n-propylphosphonic acid dichloride and then performing vacuum distillation. In this synthesis method, hydrogen chloride is generated and released outside the reaction system. Patent Document 1 describes an improved method from Non-Patent Document 1 that does not generate hydrogen chloride, which is a corrosive and toxic gas. Specifically, Patent Document 1 describes a method in which an alkylphosphonic acid derivative is reacted with acetic anhydride, and at the same time the mixture of acetic acid and acetic anhydride is removed by distillation, and then the resulting oligomeric phosphonic anhydride is subjected to reactive distillation under external temperature of 350°C and pressure of 0.1 mbar to convert it into cyclic trimer phosphonic anhydride.

[0004] Special Publication No. 2006-528140

[0005] Angew. Chem. Int. Ed, Engl. 19(1980), No.2, 133-134

[0006] The method described in Non-Patent Document 1, as also described in Patent Document 1, has the problem of releasing corrosive and highly toxic hydrogen chloride and other substances outside the reaction system. On the other hand, although the method described in Patent Document 1 is said not to generate corrosive gases, it requires distillation operations at each step, and in particular, the reactive distillation during conversion requires high external temperatures of 350°C and vacuum conditions of 0.1 mbar. In recent years, with growing interest in reducing environmental impact and improving productivity, there is a desire for a method of synthesizing cyclic phosphonic anhydride that can synthesize cyclic phosphonic anhydride under mild reaction conditions while suppressing the release of corrosive gases outside the reaction system. However, neither Non-Patent Document 1 nor Patent Document 1 has considered this perspective. Similarly, in the method of producing phosphonic acid monoesters, there is a desire for a method that can be produced with a small number of steps or with a simple process.

[0007] The present invention aims to provide a method for producing cyclic phosphonic anhydride under mild reaction conditions while suppressing the release of corrosive gases outside the reaction system. Furthermore, the present invention aims to provide a method for producing phosphonic acid monoesters through a simple process.

[0008] The inventors of the present invention diligently studied methods for producing cyclic phosphonic anhydride and discovered that by coexisting a basic compound (B) with the reaction system of phosphonic acid (A) and halogenating agent (C), cyclic phosphonic anhydride can be produced from phosphonic acid (A) under mild conditions while suppressing the release of corrosive gases outside the reaction system. They also discovered that phosphonic acid monoesters can be produced by a simple process (operation) of mixing the obtained cyclic phosphonic anhydride with an alcohol and heating it. The present invention was completed after further investigation based on these findings.

[0009] In other words, the above problems were solved by the following means: <1> A method for producing cyclic phosphonic anhydride, comprising reacting phosphonic acid (A) with at least one halogenating agent (C) selected from thionyl chloride, phosphoryl chloride, and oxalyl chloride, and a base compound (B). <2> The method according to <1>, wherein the base compound (B) is an amide compound or amine compound having 4 or more carbon atoms. <3> The method according to <1> or <2>, wherein the above reaction is carried out in a homogeneous system. <4> The method according to <1> or <2>, wherein the above reaction is carried out in a heterogeneous system, and a phase (P) mainly containing cyclic phosphonic anhydride is separated from the reaction mixture to obtain cyclic phosphonic anhydride. <5> The method according to <4>, wherein both phases constituting the reaction mixture are liquid phases, and the two phases are separated by liquid-liquid separation. <6> The method according to any one of <1> to <5>, wherein the phosphonic acid (A) has an organic group having a branched structure. <7> A method for producing a phosphonic acid monoester according to any one of <1> to <6>, wherein the phosphonic acid (A) has an alkyl group having 4 or more carbon atoms. <8> A method for producing a phosphonic acid monoester, comprising reacting a cyclic phosphonic anhydride obtained by the method for producing a phosphonic acid monoester according to any one of <1> to <7> with an alcohol.

[0010] The present invention provides a method for producing cyclic phosphonic anhydride under mild reaction conditions while suppressing the release of corrosive gases outside the reaction system. Furthermore, the present invention provides a method for producing phosphonic acid monoesters through a simple process. The above and other features and advantages of the present invention will become clearer from the following description, with reference to the accompanying drawings as appropriate.

[0011] Figure 1 shows the compound synthesized in Example 1. ３１ This is a P-NMR chart.

[0012] In this invention, when describing the content, physical properties, etc., of components by indicating numerical ranges, if the upper and lower limits of the numerical range are described separately, either upper or lower limit can be appropriately combined to form a specific numerical range. On the other hand, when multiple numerical ranges expressed using "~" are set and described, the upper and lower limits forming the numerical range are not limited to a specific combination of the upper and lower limits described before and after "~" as a specific numerical range, but can be a numerical range formed by appropriately combining the upper and lower limits of each numerical range. In this invention, a numerical range expressed using "~" means a range that includes the values ​​described before and after "~" as the lower and upper limits. In this invention, the indication of a compound (for example, when referred to as a compound) includes not only the compound itself, but also its salts and ions. It also means including derivatives in which parts have been altered, such as by introducing substituents, to the extent that the effects of this invention are not impaired. In the present invention, substituents, linking groups, etc. (hereinafter referred to as substituents, etc.) that are not explicitly stated as substituted or unsubstituted may have appropriate substituents. Therefore, in the present invention, even when simply referred to as a YYY group, this YYY group includes not only an unsubstituted form but also a further substituted form. The same applies to compounds that are not explicitly stated as substituted or unsubstituted. Preferred substituents include, for example, groups selected from substituents GZ described later. In the present invention, when there are multiple substituents, etc. indicated by a specific symbol, or when multiple substituents, etc. are specified simultaneously or alternatively, it means that each substituent, etc. may be the same as or different from one another. Furthermore, even if not specifically stated, when multiple substituents, etc. are adjacent to each other, they may be linked to each other or fused to form a ring.

[0013] [Method for Producing Anhydrous Cyclic Phosphonic Acid] The method for producing an anhydrous cyclic phosphonic acid of the present invention (hereinafter sometimes referred to as "the method for producing an anhydrous cyclic phosphonic acid of the present invention") has a step of reacting a phosphonic acid (A) with at least one halogenating agent (C) selected from thionyl chloride, phosphoryl chloride, and oxalyl chloride and a base compound (B) (hereinafter sometimes referred to as "the reaction step"). This reaction step can also be said to be a step of reacting the phosphonic acid (A) and the halogenating agent (C) in the presence of the base compound (B). In the method for producing an anhydrous cyclic phosphonic acid of the present invention, using the phosphonic acid (A) as a raw material compound, it is considered that an anhydrous cyclic phosphonic acid can be produced by the reaction route shown in the following presumed scheme, that is, halogenating the phosphonic acid (A) with the halogenating agent (C) and then condensing it in the presence of the base compound (B). In the following presumed scheme, R and n are synonymous with R and n in the formula (P) described later.

[0014]

[0015] The method for producing an anhydrous cyclic phosphonic acid of the present invention can suppress the release of corrosive gas outside the reaction system, and moreover, an anhydrous cyclic phosphonic acid can be produced under mild conditions, for example, at a reaction temperature lower than that of Patent Document 1. In the method for producing an anhydrous cyclic phosphonic acid of the present invention, the conversion rate of the phosphonic acid (A) is not particularly limited, but for example, it can be 60% or more, preferably 80% or more, more preferably 85% or more, and still more preferably 90% or more. The conversion rate of the phosphonic acid (A) is calculated as the product of the yield of the anhydrous cyclic phosphonic acid with respect to the amount (mol) of the phosphonic acid (A) used and the purity of the anhydrous cyclic phosphonic acid. The yield of the anhydrous cyclic phosphonic acid can be calculated by the ratio of the measurement result of the solid content corresponding to the anhydrous cyclic phosphonic acid in the reaction mixture (reaction product) to the theoretical yield.

[0016] In the method for producing an anhydrous cyclic phosphonic acid of the present invention, the phosphonic acid (A), the base compound (B), and the halogenating agent (C) may each be used singly or in combination of two or more.

[0017] [Phosphonic Acid (A)] The phosphonic acid (compound) (A) used in the present invention is usually an organic phosphonic acid (organophosphonic acid) having an organic group to which a phosphorus atom is bonded, and examples of organic groups include hydrocarbon groups and heterogeneous groups. The chain structure of this organic group may be a straight chain, a branched chain (a structure having a branched structure), or a cyclic chain, but a branched chain is preferred. The hydrocarbon group is not particularly limited, and examples include saturated or unsaturated aliphatic hydrocarbon groups and aromatic hydrocarbon groups. Specifically, examples of aliphatic hydrocarbon groups include alkyl groups, alkenyl groups, alkynyl groups, etc., with alkyl groups being preferred. In the present invention, alkyl groups include aralkyl groups substituted with aryl groups. The aromatic hydrocarbon group (aryl group) may be a monocyclic structure, a fused ring structure, or a polycyclic structure, but a monocyclic structure is preferred. The heterogeneous group is not particularly limited, and examples include saturated or unsaturated aliphatic heterocyclic groups and aromatic heterocyclic groups (heteroaryl groups), and examples include heterocyclic groups in substituent GZ described later.

[0018] As described above, the chain structure of the aliphatic hydrocarbon group of phosphonic acid (A) may be a straight chain, a branched chain, or a cyclic chain, but a branched chain is more preferred. The number of branches (number of branched carbon atoms) in an aliphatic hydrocarbon group having a branched structure may be one or more, can be 1 to 8, preferably 1 to 6, and more preferably 1 to 4. The number of carbon atoms constituting the aliphatic hydrocarbon group (hereinafter, "number of carbon atoms" is also simply referred to as "number of carbon atoms") is not particularly limited and can be determined as appropriate. For example, the number of carbon atoms in an aliphatic hydrocarbon group may be 1 to 20, preferably 4 or more, more preferably 6 or more, and even more preferably 8 or more. On the other hand, the upper limit of the number of carbon atoms is not particularly limited and can be determined as appropriate, for example, preferably 30 or less, more preferably 24 or less, and even more preferably 20 or less. The number of carbon atoms in an aliphatic hydrocarbon group refers to the total number of carbon atoms constituting the aliphatic hydrocarbon, and if the aliphatic hydrocarbon group has substituents other than the aliphatic hydrocarbon group (e.g., aromatic hydrocarbons), the number of carbon atoms of these substituents is included.

[0019] The number of carbon atoms in the aromatic hydrocarbon group of the phosphonic acid (A) is not particularly limited and can be determined as appropriate. For example, it can be 6 to 26, and preferably 6 to 20.

[0020] As the organic group, a hydrocarbon group is preferred, an aliphatic hydrocarbon group is more preferred, an alkyl group is still more preferred, an alkyl group having a branched structure is particularly preferred, and an alkyl group having a branched structure and having 4 or more carbon atoms is most preferred.

[0021] Examples of the phosphonic acid (A) having the above organic group preferably include alkylphosphonic acid, arylphosphonic acid, heteroarylphosphonic acid, etc. Alkylphosphonic acid is more preferred, alkylphosphonic acid having a branched structure is still more preferred, and alkylphosphonic acid having a branched structure and having 4 or more carbon atoms is particularly preferred. In the present invention, the phosphonic acid (A) includes thiophosphonic acid in which at least one oxygen atom of the phosphonic acid is substituted with a sulfur atom. The phosphonic acid (A) may have a substituent. Examples of the substituent that the phosphonic acid (A) may have include a group selected from the following substituent GZ.

[0022] - Substituent GZ - Alkyl group (preferably an alkyl group having 1 to 20 carbon atoms, e.g., methyl, ethyl, isopropyl, t-butyl, pentyl, heptyl, 1-ethylpentyl, benzyl, 2-ethoxyethyl, 1-carboxymethyl, etc.), alkenyl group (preferably an alkenyl group having 2 to 20 carbon atoms, e.g., vinyl, allyl, oleyl, etc.), alkynyl group (preferably an alkynyl group having 2 to 20 carbon atoms, e.g., ethynyl, butadiinyl, phenylethynyl, etc.), cycloalkyl group (preferably a cycloalkyl group having 3 to 20 carbon atoms, e.g., cyclopropyl, cyclopentyl, cyclohexyl, 4-methylcyclohexyl, etc.). In the present invention, when we refer to alkyl groups, we usually mean cycloalkyl groups. The term "alkyl group" in this invention usually includes an aralkyl group, but this will be explained separately here.), aryl group (preferably an aryl group having 6 to 26 carbon atoms, for example, phenyl, 1-naphthyl, 4-methoxyphenyl, 2-chlorophenyl, 3-methylphenyl, etc.), aralkyl group (preferably an aralkyl group having 7 to 23 carbon atoms, for example, benzyl, phenethyl, etc., although the term "alkyl group" in this invention usually includes an aralkyl group, this will be explained separately here.), heterocyclic group (preferably a heterocyclic group having 2 to 20 carbon atoms, more preferably a 5 or 6-membered heterocyclic ring having at least one oxygen atom, a sulfur atom, or a nitrogen atom. Heterocyclic groups include aromatic heterocyclic groups and aliphatic heterocyclic groups.For example, tetrahydropyran ring group, tetrahydrofuran ring group, 2-pyridyl, 4-pyridyl, 2-imidazolyl, 2-benzimidazolyl, 2-thiazolyl, 2-oxazolyl, pyrrolidone group, etc.), alkoxy group (preferably an alkoxy group having 1 to 20 carbon atoms, for example, methoxy, ethoxy, isopropyloxy, benzyloxy, etc.), aryloxy group (preferably an aryloxy group having 6 to 26 carbon atoms, for example, phenoxy, 1-naphthyloxy, 3-methylphenoxy, 4-methoxyphenoxy, etc.), heterocyclic oxy group (a group in which an -O- group is bonded to the above heterocyclic group), alkoxycarbonyl group (preferably Or, alkoxycarbonyl groups having 2 to 20 carbon atoms, for example, ethoxycarbonyl, 2-ethylhexyloxycarbonyl, dodecyloxycarbonyl, etc.), aryloxycarbonyl groups (preferably aryloxycarbonyl groups having 7 to 26 carbon atoms, for example, phenoxycarbonyl, 1-naphthyloxycarbonyl, 3-methylphenoxycarbonyl, 4-methoxyphenoxycarbonyl, etc.), heterocyclic oxycarbonyl groups (groups in which an -O-CO- group is bonded to the above heterocyclic group), amino groups (preferably amino groups having 0 to 20 carbon atoms, alkylamino groups, arylamino groups, for example, amino(-NH). ２), N,N-dimethylamino, N,N-diethylamino, N-ethylamino, anilino, etc.), sulfamoyl group (preferably a sulfamoyl group having 0 to 20 carbon atoms, for example, N,N-dimethylsulfamoyl, N-phenylsulfamoyl, etc.), acyl group (including alkylcarbonyl group, alkenylcarbonyl group, alkynylcarbonyl group, arylcarbonyl group, heterocyclic carbonyl group, preferably an acyl group having 1 to 20 carbon atoms, for example, acetyl, propionyl, butyryl, octanoyl, hexadecanoyl, acryloyl, methacryloyl, crotonoyl, benzoyl, naphthoyl, nicotinoyl, etc.), acyl Oxy groups (including alkylcarbonyloxy groups, alkenylcarbonyloxy groups, alkynylcarbonyloxy groups, and heterocyclic carbonyloxy groups, preferably acyloxy groups having 1 to 20 carbon atoms, for example, acetyloxy, propionyloxy, butyryloxy, octanoyloxy, hexadecanoyloxy, acryloyloxy, methacryloyloxy, crotonoyloxy, nicotinoyloxy, etc.), allyloxy groups (preferably allyloxy groups having 7 to 23 carbon atoms, for example, benzoyloxy, naphthoyloxy, etc.), carbamoyl groups (preferably carbamoyl groups having 1 to 20 carbon atoms, for example, N,N-dimethylcarbamoyl, N-phenylcarbamoyl, etc.), acylamino group (preferably an acylamino group having 1 to 20 carbon atoms, such as acetylamino, benzoylamino, etc.), alkylthio group (preferably an alkylthio group having 1 to 20 carbon atoms, such as methylthio, ethylthio, isopropylthio, benzylthio, etc.), arylthio group (preferably an arylthio group having 6 to 26 carbon atoms, such as phenylthio, 1-naphthylthio, 3-methylphenylthio, 4-methoxyphenylthio, etc.), heterocyclic thio group (a group in which a -S- group is bonded to the above heterocyclic group), alkylsulfonyl group (preferably an alkylsulfonyl group having 1 to 20 carbon atoms, such as methylsulfonyl, ethylsulfonyl, etc.), arylsulfonyl group (preferably an arylsulfonyl group having 6 to 22 carbon atoms, such as benzenesulfonyl, etc.), alkylsilyl group (preferably an alkylsilyl group having 1 to 20 carbon atoms, such as monomethylsilyl, dimethylsilyl, trimethylsilyl, triethylsilyl, etc.), arylsilyl group (preferably an arylsilyl group having 6 to 42 carbon atoms, such as triphenylsilyl, etc.), alkoxysilyl group (preferably an alkoxysilyl group having 1 to 20 carbon atoms, such as monomethoxysilyl, dimethoxysilyl, trimethoxysilyl, triethoxysilyl, etc.), aryloxysilyl group (preferably an aryloxysilyl group having 6 to 42 carbon atoms, such as triphenyloxysilyl, etc.), phosphoryl group (preferably a phosphate group having 0 to 20 carbon atoms, such as -OP(=O)(R, Ｐ ), ２ ), phosphonyl group (preferably a phosphonyl group having 0 to 20 carbon atoms, such as -P(=O)(R Ｐ ), ２ ), phosphinyl group (preferably a phosphinyl group having 0 to 20 carbon atoms, such as -P(R Ｐ ), ２ ), phosphonic acid group (preferably a phosphonic acid group having 0 to 20 carbon atoms, such as -PO(OR Ｐ ), ２ ), sulfonic group (sulfonic acid group), carboxy group, hydroxy group, sulfanyl group, cyano group, halogen atom (such as fluorine atom, chlorine atom, bromine atom, iodine atom, etc.). R Ｐis a hydrogen atom or a substituent (preferably a group selected from substituent GZ). Furthermore, each of the groups listed as substituent GZ may be further substituted with the above substituent GZ. The alkyl group, alkylene group, alkenyl group, alkenylene group, alkynyl group and / or alkynylene group, etc. may be cyclic or linear, and may be linear or branched.

[0023] Specific examples of phosphonic acid (A) include those used in the examples, but the present invention is not limited to these.

[0024] [Basic Compound (B)] The basic compound (B) used in the present invention is not particularly limited as long as it exhibits basicity as a compound, for example, a compound in which the pKa of the conjugate acid is 0 to 20.0. Preferably, the pKa of the conjugate acid of the basic compound (B) is 0 to 15.0. The pKa can be measured by neutralization titration. By coexisting the basic compound (B) in the reaction system, the acidic components produced as by-products are captured and salts are formed, thereby suppressing the release of corrosive gases from the acidic components outside the reaction system. Furthermore, the basic compound (B) preferably has the property of forming an ionic liquid together with the acidic components produced as by-products, etc., which simplifies the post-treatment of the reaction mixture. The property of forming an ionic liquid is not unique depending on the type, polarity, acidic components, etc. of the basic compound (B), but it is possible to confirm and determine whether or not the basic compound (B) has the property of forming an ionic liquid by mixing it with the acidic components produced as by-products beforehand. From these perspectives, basic compounds (B) can be considered as scavengers for acidic components (especially corrosive gases) and as components that form ionic liquids.

[0025] The base compound (B) is preferably a compound having at least one nitrogen atom in its molecule, and more preferably a compound having one or two nitrogen atoms. The base compound (B) is preferably a liquid at the reaction temperature or 25°C, as described later, as it readily forms an ionic liquid. The base compound (B) is not particularly limited, but examples include amine compounds, amide compounds, urea compounds, imino compounds, urethane compounds, etc., and in terms of the conversion rate of phosphonic acid (A), amine compounds or amide compounds (particularly amide compounds with 4 or more carbon atoms) are preferred.

[0026] The amine compound is not particularly limited, and examples include compounds in which at least one hydrogen atom of ammonia is substituted with a hydrocarbon group, a heterogroup, etc. The amine compound may be a primary amine compound, a secondary amine compound, or a tertiary amine compound, but a secondary amine compound or a tertiary amine compound is preferred, and a tertiary amine compound is preferred because it is easier to create a heterogeneous reaction system.

[0027] The hydrocarbon group of the amine compound is not particularly limited and includes, for example, saturated or unsaturated aliphatic hydrocarbon groups and aromatic hydrocarbon groups. The heterocyclic group is not particularly limited and includes, for example, saturated or unsaturated aliphatic heterocyclic groups and aromatic heterocyclic groups, and for example, the heterocyclic group in the substituent GZ described above. The chain structure of the aliphatic hydrocarbon group may be a straight chain, a branched chain, or a cyclic chain, but a branched chain or a cyclic chain is more preferred. The number of branches (number of branched carbon atoms) in the aliphatic hydrocarbon group having a branched structure can be 1 to 4. The number of carbon atoms in the aliphatic hydrocarbon group is not particularly limited and can be determined as appropriate, for example, it can be 1 to 18, and in terms of reaction rate, it is preferably 1 to 8 and more preferably 1 to 4. If the aliphatic hydrocarbon group has substituents, the number of carbon atoms of these substituents is included in the number of carbon atoms of the substituents. Specifically, examples of aliphatic hydrocarbon groups include alkyl groups, alkenyl groups, alkynyl groups, etc., with alkyl groups being preferred. The aromatic hydrocarbon group may have a monocyclic, fused, or polycyclic structure, but a monocyclic structure is preferred. The number of carbon atoms in the aromatic hydrocarbon group is not particularly limited and can be determined as appropriate; for example, it can be 6 to 20, and preferably 6 to 16.

[0028] In amine compounds, the group that substitutes the hydrogen atom of ammonia (nitrogen substituent) is preferably a hydrocarbon group, more preferably an aliphatic hydrocarbon group, and even more preferably an alkyl group. In secondary and tertiary amine compounds, the combination of multiple nitrogen substituents is not particularly limited and any appropriate combination can be given, with combinations of hydrocarbon groups being preferred, combinations of aliphatic hydrocarbon groups being more preferred, and combinations of alkyl groups being even more preferred. The multiple nitrogen substituents may be the same or different. Examples of nitrogen substituent combinations include those used in the amine compounds in the examples, but the present invention is not limited to these.

[0029] The total number of carbon atoms constituting the amine compound varies depending on the number of carbon atoms in the nitrogen substituent, the number of nitrogen substituents, the presence or absence of substituents, etc., and is not particularly limited, but for example it can be 3 or more, and in terms of the conversion rate of phosphonic acid (A), it is preferably 4 to 16, and more preferably 4 to 12.

[0030] Examples of amine compounds include (mono, di, or tri)alkylamine compounds, (mono, di, or tri)arylamine compounds, and (mono or di)alkyl(di or mono)arylamine compounds, with (mono, di, or tri)alkylamine compounds being preferred and trialkylamine compounds being more preferred. In the present invention, the amine compound may have a ring structure containing a nitrogen atom formed by the bonding of two nitrogen substituents, and this ring structure may contain heteroatoms other than nitrogen, such as oxygen atoms, sulfur atoms, or phosphorus atoms. Examples of amine compounds having a ring structure include N-unsubstituted or N-substituted piperidine, N-unsubstituted or N-substituted piperazine, morpholine, and N-alkylmorpholine.

[0031] The amide compound can be any compound having at least one amide bond, such as R-C(=O)-N(R Ｎ１ ) ２A carboxylic acid amide compound represented by is preferred. Here, R can be a hydrogen atom, a hydrocarbon group, a heterogroup, etc., with a hydrogen atom or a hydrocarbon group being preferred, and a hydrogen atom or an alkyl group being more preferred. The hydrocarbon groups and heterogroups that can be taken as R are the same as the hydrocarbon groups and heterogroups that can be taken as nitrogen substituents of the amine compound. Ｎ１ Examples include hydrogen atoms, hydrocarbon groups, and heterogroups, with hydrogen atoms or hydrocarbon groups being preferred, and alkyl groups being more preferred. Ｎ１ The hydrocarbon groups and heterogeneous groups that can be used as nitrogen substituents in amine compounds are the same as those that can be used as nitrogen substituents in amine compounds. Ｎ１ In both cases, hydrocarbon groups are preferred, and alkyl groups are more preferred. Ｎ１ They may be the same or different. Also, R and two Rs Ｎ１ These may all be the same or different. The total number of carbon atoms constituting the amide compound is not particularly limited, but in terms of the conversion rate of phosphonic acid (A), it is preferably 3 or more, more preferably 4 or more, and even more preferably 4 to 12. Examples of amide compounds include N-unsubstituted, N-monosubstituted or N,N-disubstituted formamides, N-unsubstituted, N-monosubstituted or N,N-disubstituted alkanamides, etc.

[0032] The urea compound can be any compound having at least one urea bond, (R Ｎ２ ) ２ -N-C(=O)-N(R Ｎ２ ) ２ A urea compound represented by is preferred. Here, R Ｎ２ Examples include hydrogen atoms, hydrocarbon groups, and heterogroups, with hydrogen atoms or hydrocarbon groups being preferred, and alkyl groups being more preferred. Ｎ２ The hydrocarbon groups and heterogeneous groups that can be used are the same as the hydrocarbon groups and heterogeneous groups that can be used as nitrogen substituents in amine compounds. (Four R's) Ｎ２ In all cases, hydrocarbon groups are preferred, and alkyl groups are more preferred. (Four R's) Ｎ１These may be the same or different. The total number of carbon atoms constituting the urea compound is not particularly limited, but in terms of the conversion rate of phosphonic acid (A), it is preferably 3 to 17, and more preferably 3 to 13.

[0033] As an imino compound, at least one imino group (-C=NR Ｎ３ Any compound having ) and R-C=NR Ｎ３ An imino compound represented by is preferred. Here, R can be a hydrogen atom, a hydrocarbon group, a heterogroup, etc., with a hydrogen atom or a hydrocarbon group being preferred, and a hydrogen atom or an alkyl group being more preferred. The hydrocarbon groups and heterogroups that can be taken as R are the same as the hydrocarbon groups and heterogroups that can be taken as nitrogen substituents of the amine compound. Ｎ３ Examples include hydrogen atoms, hydrocarbon groups, and heterogroups, with hydrogen atoms or hydrocarbon groups being preferred, and alkyl groups being more preferred. Ｎ３ The hydrocarbon groups and heterogeneous groups that can be used as nitrogen substituents in amine compounds are the same as those that can be used as nitrogen substituents in amine compounds. Ｎ３ These may be the same or different. The total number of carbon atoms constituting the imino compound is not particularly limited, but in terms of the conversion rate of phosphonic acid (A), it is preferably 3 to 17, and more preferably 3 to 13.

[0034] The urethane compound can be any compound having at least one urethane bond, such as R-O-C(=O)-N(R Ｎ４ ) ２ A urethane compound represented by is preferred. Here, R can be a hydrogen atom, a hydrocarbon group, a heterogroup, etc., with a hydrogen atom or a hydrocarbon group being preferred, and a hydrogen atom or an alkyl group being more preferred. The hydrocarbon groups and heterogroups that can be taken as R are the same as the hydrocarbon groups and heterogroups that can be taken as nitrogen substituents of the amine compound. Ｎ４ Examples include hydrogen atoms, hydrocarbon groups, and heterogroups, with hydrogen atoms or hydrocarbon groups being preferred, and alkyl groups being more preferred. Ｎ４ The hydrocarbon groups and heterogeneous groups that can be used as nitrogen substituents in amine compounds are the same as those that can be used as nitrogen substituents in amine compounds. Ｎ４In both cases, hydrocarbon groups are preferred, and alkyl groups are more preferred. Ｎ４ They may be the same or different. Also, R and two Rs Ｎ４ These may all be the same or different. The total number of carbon atoms constituting the urethane compound is not particularly limited, but in terms of the conversion rate of phosphonic acid (A), it is preferably 3 to 17, and more preferably 3 to 13.

[0035] The base compound (B) may have substituents. Examples of substituents that the base compound (B) may have include groups selected from the substituents GZ described above. Specific examples of the base compound (B) include those used in the examples, but the present invention is not limited to these.

[0036] [Halogenating agent (C)] The halogenating agent (C) used in the present invention is at least one selected from thionyl chloride, phosphoryl chloride, and oxalyl chloride, and is preferably one selected from thionyl chloride, phosphoryl chloride, and oxalyl chloride, and is more preferably thionyl chloride in terms of reactivity and ease of handling.

[0037] [Other Components] In the method for producing cyclic phosphonic anhydride of the present invention, components other than phosphonic acid (A), basic compound (B), and halogenating agent (C) (sometimes referred to as "other components") may be present in the reaction system. Examples of other components include solvents and phase separation agents, which will be described later. In the present invention, it is preferable that the other components do not contain water (moisture).

[0038] [Reaction Conditions] In the method for producing cyclic phosphonic anhydride of the present invention, the mixing order (addition order) of phosphonic acid (A), base compound (B), and halogenating agent (C) is not particularly limited, and they can be mixed and reacted all at once. However, it is preferable to mix the halogenating agent (C) with the phosphonic acid (A) to halogenate it (halogenation step), and then mix in the base compound (B) to carry out a condensation reaction (condensation step). By reacting in two stages in this way, the release of corrosive gases outside the reaction system can be effectively suppressed, and mild reaction conditions can be applied. The basic compound (B) and halogenating agent (C) can each be mixed at once, but it is preferable to mix them intermittently, taking into account the temperature rise in the reaction system, etc., in order to suppress runaway reactions and increase reaction efficiency, and it is more preferable to mix them dropwise. The mixing time at this time is not unique, but can be appropriately determined depending on the degree of temperature rise in the reaction system.

[0039] The reaction atmosphere in the method for producing cyclic phosphonic anhydride of the present invention (halogenation step and condensation step) is not particularly limited and can be an atmospheric atmosphere, a dry air atmosphere (e.g., dew point of -20°C or lower), or an inert atmosphere, with an inert atmosphere being preferred. The inert gas used for the inert atmosphere is not particularly limited, but examples include nitrogen gas, helium gas, argon gas, etc.

[0040] The method for producing cyclic phosphonic anhydride of the present invention can be carried out without a solvent, but it is preferable to carry it out in a solvent in terms of reaction efficiency and reaction homogeneity. The solvent is not particularly limited, and various known solvents can be used, but organic solvents are preferred, such as ether solvents, ketone solvents, aromatic hydrocarbon solvents, aliphatic hydrocarbon solvents, nitrile solvents, and ester solvents. As for the solvent, nonpolar dispersion media (hydrophobic solvents) are preferred in terms of reaction efficiency and, if the reaction system is heterogeneous, because they facilitate phase separation. In the present invention, a nonpolar solvent generally refers to a solvent with low affinity for water, but in the present invention, examples include ether solvents, ketone solvents, aromatic hydrocarbon solvents, aliphatic hydrocarbon solvents, and ester solvents. Among these, aromatic hydrocarbon solvents and aliphatic hydrocarbon solvents are preferred. Examples of aromatic hydrocarbon solvents include benzene, toluene, and xylene, and examples of aliphatic hydrocarbon solvents include hexane, heptane, octane, nonane, decane, dodecane, decalin, and paraffin. The solvent used in the method for producing cyclic phosphonic anhydride of the present invention is preferably an anhydrous solvent (dehydrated solvent). Here, the anhydrous solvent is not limited to a solvent with a water content of 0% by mass or a super-dehydrated solvent, but can be any solvent that has been dehydrated to the extent that can be achieved by a general solvent dehydration method, or a solvent that has been dehydrated to the extent that a water-reactive system, as described later, can be achieved. In the present invention, an excess amount of the above-mentioned base compound (B) can also be used as a solvent, but it is preferable to use a solvent that does not contain nitrogen atoms in its molecule. One type of solvent or two or more types can be used. The amount of solvent used is not particularly limited and can be set as appropriate, for example, it can be 50 to 900 parts by mass per 100 parts by mass of phosphonic acid (A), and preferably 80 to 500 parts by mass.

[0041] The present invention's method for producing cyclic phosphonic anhydride is preferably a water-restricted system, particularly in the halogenation step, as it effectively suppresses the release of hydrogen halides outside the reaction system. The water-restricted system in the present invention's method for producing cyclic phosphonic anhydride is any system that can be achieved by using anhydrous reagents or solvents, or by conventional methods such as substitution with an inert gas or bubbling. For example, the amount of water in the reaction system (measured using Karl Fischer titration) is preferably 1000 ppm by mass or less.

[0042] In the present invention's method for producing cyclic phosphonic anhydride, the amount of halogenating agent (C) used is preferably 0.8 to 5.0 moles per mole of phosphonic acid (A), more preferably 1.0 to 4.0 moles, even more preferably 1.0 to 3.0 moles, and particularly preferably 1.0 to 1.5 moles, in terms of the conversion rate of phosphonic acid (A).

[0043] In the present invention's method for producing cyclic phosphonic anhydride, the amount of base compound (B) used is preferably 0.5 to 4.0 moles per mole of phosphonic acid (A), more preferably 0.5 to 3.0 moles, even more preferably 0.5 to 2.0 moles, and particularly preferably 1.0 to 1.5 moles, in terms of the conversion rate of phosphonic acid (A) and, if the reaction system becomes heterogeneous, the amount of base compound (B) used is preferably 0.8 to 5.0 moles per mole of halogenating agent (C), more preferably 0.8 to 3.0 moles, even more preferably 1.0 to 2.0 moles, and particularly preferably 1.0 to 1.5 moles, in terms of effectively suppressing the release of corrosive gases outside the reaction system.

[0044] In the present invention's method for producing cyclic phosphonic acid anhydride, it is preferable to stir or shake the reaction system.

[0045] In the present invention's method for producing cyclic phosphonic anhydride, the reaction system containing phosphonic acid (A), a halogenating agent (C), and a basic compound (B) can be either homogeneous or heterogeneous. When the present invention's method for producing cyclic phosphonic anhydride is carried out in a homogeneous system, the conversion rate of phosphonic acid to cyclic phosphonic anhydride is excellent. On the other hand, when carried out in a heterogeneous system, post-reaction workup (treatment of the reaction mixture) is simpler, while cyclic phosphonic anhydride can be isolated in high purity. In the present invention's method for producing cyclic phosphonic anhydride, the control of whether the reaction system is homogeneous or heterogeneous cannot be uniquely determined, but it can be determined, for example, by the type of phosphonic acid (A), the amount of halogenating agent (C) used, the type or amount of basic compound (B) used, the presence or absence or amount of solvent used, and furthermore, the structure of the basic compound (B). For example, when a base compound (B) containing a nitrogen atom bonded to a hydrogen atom (e.g., a primary or secondary amine compound) is used, the reaction tends to be homogeneous. On the other hand, when a base compound (B) containing a nitrogen atom not bonded to a hydrogen atom (e.g., a tertiary amine compound) is used, the reaction tends to be heterogeneous. Furthermore, depending on the type or amount of halogenating agent (C) and base compound (B) used, if the by-product is an ionic liquid, or if a nonpolar solvent is used, the reaction system tends to be heterogeneous. Also, if the total number of carbon atoms in the basic compound (B) is 16 or more, the reaction tends to be homogeneous, while if it is 15 or less, the reaction tends to be heterogeneous.

[0046] The conditions common to the present invention's method for producing cyclic phosphonic anhydride (halogenation step and condensation step) have been described above. Below, the reaction conditions for each step will be described. <Reaction conditions for the halogenation step> The reaction temperature in the halogenation step can be set to mild conditions, for example, 20 to 100°C. It is preferable to set it to 30 to 90°C, and more preferably to 40 to 80°C, in terms of the conversion rate of phosphonic acid (A) and the conversion rate. The reaction time in the halogenation step is not particularly limited and can be determined as appropriate. For example, it is preferable to set it to 0.5 to 6 hours, and more preferably to 1 to 4 hours, in terms of the conversion rate of phosphonic acid (A). The reaction time in the halogenation step starts from the point when the entire amount of halogenating agent (C) has been mixed with phosphonic acid (A).

[0047] <Reaction conditions for the condensation process> In the condensation process, the temperature of the reaction system at the start of mixing of the base compound (B) (initial temperature) is preferably lower than room temperature (25°C). For example, in terms of the conversion rate of phosphonic acid (A) and the ease of controlling the internal temperature, it is more preferably -80 to 20°C, and even more preferably -20 to 20°C. In the condensation process, the temperature of the reaction system may rise due to the mixing of the base compound (B). However, the temperature inside the reaction system during the mixing of the base compound (B) (mixing temperature) is preferably a mild temperature of 40°C or less. In terms of the conversion rate of phosphonic acid (A), it is more preferably -20 to 30°C, and even more preferably 0 to 30°C. In the condensation process, after the entire amount of base compound (B) has been mixed, mild conditions can be applied to the temperature inside the reaction system (reaction temperature), and for example, it can be in the same range as the mixing temperature described above. The reaction time in the condensation step is not particularly limited and can be determined as appropriate. For example, in terms of the conversion rate of phosphonic acid (A), it is preferably 10 minutes to 8 hours, and more preferably 10 minutes to 2 hours. The reaction time in the condensation step starts from the point when the entire amount of the base compound (B) has been mixed.

[0048] [Post-reaction post-treatment] In the present invention's method for producing cyclic phosphonic anhydride, when phosphonic acid (A), halogenating agent (C), and base compound (B) are reacted as described above, the resulting reaction mixture will be homogeneous or heterogeneous, similar to the reaction system. If the reaction mixture is homogeneous, cyclic phosphonic anhydride can be obtained by removing by-products or reactants other than cyclic phosphonic anhydride from the reaction mixture. Methods for this include distillation and adsorption treatment.

[0049] When the reaction mixture is heterogeneous, the number of phases constituting the reaction mixture is not particularly limited, but is usually two. In the present invention, the phase constituting the reaction mixture that contains the most cyclic phosphonic anhydride is called the "phase mainly containing cyclic phosphonic anhydride (P)". The other phase (W) may contain cyclic phosphonic anhydride if the content is lower than that of phase (P). Both phases may be gas phases, but are usually solid or liquid phases, and being liquid phases is preferable in terms of the conversion rate of phosphonic acid (A) and the ease of post-treatment. In the present invention, phase (P) usually exhibits low polarity, and phase (W) usually exhibits high polarity, and phases (P) and (W) become immiscible with each other and separate over time. Therefore, after the reaction is complete, cyclic phosphonic anhydride can be isolated by separating phase (P) from the reaction mixture, for example, by allowing the reaction mixture to stand. In other words, cyclic phosphonic anhydride can be isolated by separating the reaction mixture into two phases, (P) and (W), by allowing the reaction mixture to stand, and then removing (W). Phase separation can be achieved by liquid-liquid separation using simple operations such as allowing the reaction mixture to stand, provided both phases are liquid phases.

[0050] [Cyctic Phosphodic Anhydride] The cyclic phosphonic anhydride produced by the method for producing cyclic phosphonic anhydride of the present invention is a cyclic dehydration condensate of phosphonic acid (A), as represented by the following formula (P). In formula (P), R represents an organic group, which is the same as the organic group described in phosphonic acid (A) above. n represents an integer from 0 to 100, preferably an integer from 1 to 10, and more preferably an integer from 1 to 5.

[0051] The number of molecules of phosphonic acid (A) constituting cyclic phosphonic anhydride (the number corresponding to (n+2) in formula (P) above) is not particularly limited, and can be, for example, 2 to 102, preferably 2 to 50, more preferably 3 to 12, even more preferably 3 to 10, and particularly preferably 3 to 7. The cyclic phosphonic anhydride produced by the method for producing cyclic phosphonic anhydride of the present invention is usually a mixture of compounds with different n values ​​in formula (P) (in the present invention, this may be referred to as a "cyclic phosphonic anhydride mixture"). The composition of the cyclic phosphonic anhydride mixture is not unique, depending on the types of phosphonic acid (A) and base compound (B), reaction conditions, etc. The method for isolating and purifying cyclic phosphonic anhydride having a specific n from the cyclic phosphonic anhydride mixture is not particularly limited, and can be any ordinary isolation and purification method, such as recrystallization, chromatography, or distillation.

[0052] The reaction mixture in the method for producing cyclic phosphonic anhydride of the present invention contains by-products (reaction residues) in addition to the cyclic phosphonic anhydride. By-products of the halogenation reaction and condensation reaction include acidic components such as hydrogen chloride and sulfur dioxide (sulfurous acid gas), and further include salts consisting of these acidic components and a base compound (B), preferably ionic liquids. These by-products are usually mostly contained in phase (W) or form phase (W). The presence of ionic liquids as by-products makes the reaction system and reaction mixture heterogeneous, which simplifies post-treatment. The conditions for generating ionic liquids as by-products are the same as the control methods for homogeneous or heterogeneous reaction systems described above.

[0053] [Other steps] The present invention's method for producing cyclic phosphonic anhydride may include steps other than the reaction step described above (other steps). Examples of other steps include a step of recovering the basic compound (B), a step of capturing or neutralizing hydrogen chloride leaking from the reaction system to the outside of the reaction system, and so on.

[0054] [[Method for Producing Phosphonic Acid Monoesters of the Present Invention]] The method for producing phosphonic acid monoesters of the present invention (hereinafter sometimes referred to as "the method for producing phosphonic acid monoesters of the present invention") comprises a step of reacting cyclic phosphonic anhydride obtained by the method for producing cyclic phosphonic anhydride of the present invention with an alcohol. Since the method for producing phosphonic acid monoesters of the present invention uses cyclic phosphonic anhydride obtained by the method for producing cyclic phosphonic anhydride of the present invention as a raw material compound, phosphonic acid monoesters can be produced in a simple step of reacting with an alcohol.

[0055] In the phosphonic acid monoester production method of the present invention, the yield of the phosphonic acid monoester is not particularly limited, but for example, in terms of the molar ratio to the amount of phosphonic acid (A) used in the anhydrous cyclic phosphonic acid production method of the present invention, it can be 60% or more, preferably 70% or more, and more preferably 80% or more.

[0056] [Cycnic Anhydride] In the phosphonic acid monoester production method of the present invention, cyclic phosphonic anhydride obtained by the cyclic phosphonic anhydride production method of the present invention is used as the raw material compound. The cyclic phosphonic anhydride used in the phosphonic acid monoester production method of the present invention may be any cyclic phosphonic anhydride obtained by the cyclic phosphonic anhydride production method of the present invention. A cyclic phosphonic anhydride with a specific n, such as T3P, isolated and purified from the cyclic phosphonic anhydride mixture obtained by the cyclic phosphonic anhydride production method of the present invention can be used, or a cyclic phosphonic anhydride mixture obtained by the cyclic phosphonic anhydride production method of the present invention can be used. It is preferable to use a cyclic phosphonic anhydride mixture (especially phase (P)) because it eliminates the need for isolation and purification of the cyclic phosphonic anhydride mixture and allows for a simple reaction with alcohol in succession with the cyclic phosphonic anhydride production method of the present invention, preferably in a single pot. In this invention, "reacting with alcohol in succession with the cyclic phosphonic anhydride production method of the present invention" means reacting with alcohol after the cyclic phosphonic anhydride production method of the present invention (performing the phosphonic acid monoester production method of the present invention). Therefore, other steps may be performed between the method for producing cyclic phosphonic anhydride and the method for producing phosphonic acid monoester of the present invention, and the methods for producing cyclic phosphonic anhydride and the method for producing phosphonic acid monoester of the present invention may be performed consecutively or with a time interval between them.

[0057] [Alcohol] The alcohol (compound) used in the phosphonic acid monoester production method of the present invention includes hydrocarbon alcohol compounds (including phenol compounds), heterogeneous alcohol compounds, etc. The hydrocarbon is not particularly limited and includes, for example, saturated or unsaturated aliphatic hydrocarbons and aromatic hydrocarbons. The saturated or unsaturated aliphatic hydrocarbons and aromatic hydrocarbons are the same as the hydrocarbons that form the saturated or unsaturated aliphatic hydrocarbon group and aromatic hydrocarbon group in the phosphonic acid (A) described above. The heterogeneous compound is not particularly limited and includes, for example, saturated or unsaturated aliphatic heterocycles and aromatic heterocycles, and is the same as the heterocycles that form the saturated or unsaturated aliphatic heterocyclic group and aromatic heterocyclic group in the phosphonic acid (A) described above. The number of hydroxyl groups in one molecule of alcohol is not particularly limited and can be 1 to 3, but 1 is preferred. The alcohol may also be a tertiary alcohol, but in terms of reactivity, etc., it is preferred to be a primary alcohol (including methanol) or a secondary alcohol. As for the alcohol, aliphatic hydrocarbon alcohols are preferred, alkane alcohols (alkyl alcohols) are more preferred, branched alkane alcohols are even more preferred, and branched long-chain alkane alcohols having 6 or more carbon atoms are particularly preferred.

[0058] Alcohols may have substituents, and examples of substituents include groups selected from the substituents GZ described above. When an alcohol has substituents, the carbon number of the alcohol includes the carbon number of the substituent. Specific examples of alcohols include those used in the examples, but the present invention is not limited to these.

[0059] [Other Components] In the phosphonic acid monoester production method of the present invention, components that do not fall under either cyclic phosphonic anhydride or alcohol (sometimes referred to as "other components") can be used. Examples of other components include the solvents, bases, and dehydrating agents mentioned above.

[0060] [Reaction Conditions] In the phosphonic acid monoester production method of the present invention, the amount of alcohol used is determined based on the structural units derived from phosphonic acid (A) that constitute the anhydrous cyclic phosphonic acid used. For example, if the amount of phosphonic acid (A) used in the anhydrous cyclic phosphonic acid production method of the present invention is known, it is preferably 0.4 to 1.5 moles, more preferably 0.5 to 1.2 moles, and even more preferably 0.6 to 1.1 moles per mole of phosphonic acid (A) used in the anhydrous cyclic phosphonic acid production method of the present invention. On the other hand, if the amount of phosphonic acid (A) used in the anhydrous cyclic phosphonic acid production method of the present invention is unknown, the total number of moles of structural units derived from phosphonic acid (A) present in the anhydrous cyclic phosphonic acid obtained by the anhydrous cyclic phosphonic acid production method of the present invention is determined by a conventional method, and the amount used is set to the above amount per mole of these structural units.

[0061] In the present invention's method for producing phosphonic acid monoesters, the mixing order (addition order) of cyclic phosphonic anhydride and alcohol is not particularly limited, and cyclic phosphonic anhydride can be mixed with alcohol, but it is generally preferable to mix the alcohol with cyclic phosphonic anhydride. The cyclic phosphonic anhydride and alcohol may be mixed at once, but it is preferable to mix them intermittently, and more preferably by dropwise addition, in order to suppress runaway reactions and improve reaction efficiency. The mixing time at this time is determined appropriately.

[0062] The reaction temperature of cyclic phosphonic anhydride and alcohol is not particularly limited and can be determined as appropriate. For example, it is preferably 0 to 200°C, more preferably 20 to 150°C, and even more preferably 50 to 130°C. In the phosphonic acid monoester production method of the present invention, it is also a preferred embodiment to set the reaction temperature to be different for the temperature during or between mixing the cyclic phosphonic anhydride and the alcohol (mixing temperature) and the temperature after mixing (post-mixing temperature). In this embodiment, the mixing temperature is set within the above reaction temperature range. For example, it is preferably 0 to 100°C, more preferably 10 to 80°C, and even more preferably 20 to 70°C. On the other hand, the post-mixing temperature is preferably set to a higher temperature than the mixing temperature within the above reaction temperature range. For example, it is preferably 20 to 200°C, even more preferably 50 to 150°C, and particularly preferably 70 to 130°C.

[0063] The reaction time is not particularly limited and can be determined as appropriate, for example, preferably 1 to 72 hours, more preferably 3 to 24 hours. The reaction time starts from the beginning of mixing of the cyclic phosphonic anhydride and the alcohol. In the above preferred embodiment, the reaction time during mixing, from the start of mixing of the cyclic phosphonic anhydride and the alcohol to the start of heating to the post-mixing temperature, is set within the above reaction time range, for example, preferably 10 minutes to 5 hours, more preferably 15 minutes to 4 hours, and even more preferably 30 minutes to 3 hours. On the other hand, the reaction time after mixing, from reaching the post-mixing temperature to the end of the reaction, is set within the above reaction time range, for example, preferably 10 minutes to 72 hours, more preferably 10 minutes to 24 hours, and even more preferably 30 minutes to 6 hours.

[0064] The reaction atmosphere in the phosphonic acid monoester production method of the present invention is not particularly limited and can be an atmospheric atmosphere, a dry air atmosphere (e.g., dew point of -20°C or lower), or an inert atmosphere, with an inert atmosphere being preferred. The inert gas used for the inert atmosphere is not particularly limited, but examples include nitrogen gas, helium gas, argon gas, etc.

[0065] The phosphonic acid monoester production method of the present invention can be carried out without a solvent, but it is preferable to carry it out in a solvent in terms of reaction efficiency, reaction uniformity, etc. The solvent is not particularly limited, and various known solvents can be used, but an organic solvent is preferred. The solvent used in the phosphonic acid monoester production method of the present invention is the same as the organic solvent described above for the solvent used in the cyclic phosphonic anhydride production method of the present invention. In the phosphonic acid monoester production method of the present invention, when a solvent is used separately from cyclic phosphonic anhydride and alcohol, the cyclic phosphonic anhydride obtained in the cyclic phosphonic anhydride production method of the present invention may be used as a solution (for example, phase (P)), or it may be used as an alcohol solution. It is preferable to use the cyclic phosphonic anhydride obtained in the cyclic phosphonic anhydride production method of the present invention as a solution. The amount of solvent used is not particularly limited and can be set as appropriate, for example, it can be 50 to 900 parts by mass per 100 parts by mass of phosphonic acid (A), and is preferably 80 to 500 parts by mass.

[0066] In the phosphonic acid monoester production method of the present invention, it is also preferable to make the reaction system a water-restricted system. The water-restricted system in the phosphonic acid monoester production method of the present invention is any water-restricted system that can be achieved by using anhydrous reagents or anhydrous solvents, or by conventional methods such as substitution with an inert gas or bubbling. For example, it is preferable that the amount of water in the reaction system (a value measured using Karl Fischer titration) be 1000 ppm by mass or less.

[0067] In the present invention's method for producing phosphonic acid monoesters, it is preferable to stir or shake the reaction system.

[0068] In the present invention's method for producing phosphonic acid monoesters, a phosphonic acid monoester is obtained by reacting a cyclic phosphonic anhydride with an alcohol as described above.

[0069] [Other Steps] The present invention's method for producing phosphonic acid monoesters may include steps other than the step of reacting cyclic anhydride with an alcohol (other steps). Examples of other steps include a step of stopping the reaction, and a step of isolating and purifying the phosphonic acid monoester from the reaction product by a conventional isolation and purification method. The step of stopping the reaction is not particularly limited, but usually involves adding an excess amount of water and stirring, and it is also possible to further wash the reaction product with an aqueous solution of acid or base.

[0070] The present invention will be described in more detail below based on examples, but the present invention is not to be construed as being limited thereto. In the following examples, "parts" and "%" representing the composition are by mass unless otherwise specified. In the present invention, "room temperature" means 25°C.

[0071] [Synthesis of (2-ethylhexyl)phosphonic acid] 89 g of diethyl phosphite (manufactured by Tokyo Chemical Industries, Ltd.) and 450 g of tetrahydrofuran (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) were added to a 1 L three-necked round-bottom flask and stirred well. While cooling the three-necked round-bottom flask with ice, 23.2 g of sodium hydride (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) was added and stirred for 20 minutes while remaining on ice. Then the reaction mixture was heated and stirred in a flux state for 30 minutes. Next, while cooling the three-necked round-bottom flask with ice, 70.0 g of 1-bromo-2-ethylhexane (manufactured by Tokyo Chemical Industries, Ltd.) was added dropwise to the resulting reaction mixture over 20 minutes, and then stirred at an internal temperature of 45°C for 24 hours. 300 g of water was added to the resulting reaction mixture, and then the mixture was extracted with toluene. The solvent was removed by distillation under reduced pressure to obtain 107 g of a yellow liquid.

[0072] Next, the obtained yellow liquid and 400 g of dichloromethane (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) were added to a 1 L three-necked round-bottom flask and stirred well. 113 g of bromotrimethylsilane (manufactured by Tokyo Chemical Industries, Ltd.) was then added to the three-necked round-bottom flask and stirred at room temperature for 4 hours. After removing the solvent from the resulting reaction solution under reduced pressure, 530 g of methanol (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) was added and stirred at an internal temperature of 40°C for 3 hours. 200 mL of aqueous sodium hydroxide solution (4 mol / L) was added to the resulting reaction solution, and the aqueous layer was washed twice with toluene. 65 mL of concentrated hydrochloric acid was added to the resulting aqueous solution, and after extraction with toluene, the solvent was removed under reduced pressure to obtain 43.6 g of (2-ethylhexyl)phosphonic acid (yield 62%, 2 steps).

[0073] [Preparation of phosphonic acid (A), basic compound (B), and halogenating agent (C)] The following phosphonic acid (A), basic compound (B), and halogenating agent (C) were prepared. <Phosphonic acid (A)> n-Hexylphosphonic acid: Manufactured by Tokyo Chemical Industries, Ltd. n-Propylphosphonic acid: Manufactured by Tokyo Chemical Industries, Ltd. A-1: ​​Phosphonic acid shown in the following chemical formula, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.

[0074] <Basic Compounds (B)> DIPEA: N,N-diisopropylethylamine, conjugate acid pKa 10.0, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd. BEHA: Bis(2-ethylhexyl)amine, conjugate acid pKa 8.5, manufactured by Tokyo Chemical Industries, Ltd. DMF: N,N-dimethylformamide, conjugate acid pKa 5.7, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd. NMM: N-methylmorpholine, conjugate acid pKa 9.1, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd. TEA: Triethylamine, conjugate acid pKa 9.8, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd. B-1: Urea compound shown in the chemical formula below, conjugate acid pKa 5.5, manufactured by Tokyo Chemical Industries, Ltd. B-2: Amide compound shown in the chemical formula below, conjugate acid pKa 5.6, manufactured by Tokyo Chemical Industries, Ltd. <Halogenating Agents (C)> Thionyl chloride: Manufactured by Fujifilm Wako Pure Chemical Industries, Ltd. Phosphoryl chloride: Manufactured by Fujifilm Wako Pure Chemical Industries, Ltd. Oxalyl chloride: Manufactured by Fujifilm Wako Pure Chemical Industries, Ltd. <Other compounds> Phenyl phosphate: Manufactured by Tokyo Chemical Industries, Ltd.

[0075] In base compound B-1, n-Bu represents an n-butyl group, and in base compound B-2, Me represents a methyl group.

[0076] [Production of Cyclic Phosphodic Anhydride] <Example 1> Under a nitrogen atmosphere, 250 g (1.29 mol) of (2-ethylhexyl)phosphonic acid and 650 g of anhydrous toluene were added to a 2 L three-necked round-bottom flask and the temperature was raised to 50°C. Then, 168 g of thionyl chloride (1.1 times the molar amount relative to (2-ethylhexyl)phosphonic acid) was added dropwise over 20 minutes, and the mixture was stirred at the same temperature for 1 hour. The reaction vessel was cooled with ice, and when the internal temperature was below 5°C, 183 g of diisopropylethylamine (1.1 times the molar amount relative to (2-ethylhexyl)phosphonic acid) was added dropwise over 40 minutes. The internal temperature during the dropwise addition was confirmed to be below 20°C. After stirring for 30 minutes, the reaction mixture was allowed to stand for 10 minutes, at which point the reaction mixture separated into two phases: an upper and a lower layer. Of the two phases separated, 298 g of the lower layer was removed, and the upper layer was collected. Thus, cyclic phosphonic anhydride ((2-ethylhexyl)phosphonic anhydride) of (2-ethylhexyl)phosphonic acid, as shown in the above chemical formula, was produced. The reaction system (homogeneous or heterogeneous) and the form of phase separation in Example 1 are shown in the "Reaction System (Phase Separation)" column of Table 1. The same applies to Examples 2 to 12, Comparative Examples 1 and 2, and Reference Example 1.

[0077] ３１ P-NMR measurements confirmed that the upper layer was a toluene solution (phase (P)) mainly containing (2-ethylhexyl)phosphonic acid anhydride. ３１ The P-NMR chart is shown in Figure 1. Also, ３１ P-NMR confirmed that the purity of the obtained (2-ethylhexyl)phosphonic anhydride was 90%, and further ESI mass spectrometry confirmed that the (2-ethylhexyl)phosphonic anhydride was a mixture of trimers to heptomers of (2-ethylhexyl)phosphonic acid (where n in the above formula (P) is 1 to 5) (trimer: [M + H ＋ ]529, tetramer: [M+H ＋ ]705, pentamer: [M+H ＋ ]899, hexamer: [M+H ＋ ]1058, heptamer: [M+H ＋ ]1252). Note that the purity of (2-ethylhexyl)phosphonic anhydride is ３１ ​In the P-NMR chart, the total integral value of the peak areas of 10-20 ppm originating from (2-ethylhexyl)phosphonic anhydride is "S Ｃ " and the total integral value of the peak area originating from the phosphorus atom "S Ｐ The following formula was used to calculate the purity (%): [S Ｃ / S Ｐ ] × 100 Furthermore, the yield of (2-ethylhexyl)phosphonic acid anhydride was 100% as measured by the solid content of phase (P). The results of calculating the conversion rate (yield × purity) of (2-ethylhexyl)phosphonic acid in Example 1 are shown in the "Conversion Rate" column of Table 1.

[0078] On the other hand, the lower levels, １ H-NMR measurement revealed that the phase (W) mainly contains diisopropylethylamine, and ３１ P-NMR measurements confirmed the absence of phosphorus components. Furthermore, considering the reaction mechanism and the mass of the resulting lower layer, it became clear that the lower layer contained hydrogen chloride and sulfur dioxide in addition to diisopropylethylamine, indicating that the lower layer mainly contained diisopropylethylamine and a mixture of these acidic components. This mixture formed a salt, and since the lower layer was liquid, it was presumed that the mixture was an ionic liquid.

[0079] <Example 2> The reaction was carried out in the same manner as in Example 1, except that the base compound (B) was changed to the compound shown in Table 1. (2-ethylhexyl)phosphonic acid, thionyl chloride, and base compound (B) were reacted. After the reaction was completed, the reaction mixture remained homogeneous without layer separation even when allowed to stand. From the obtained reaction mixture, thionyl chloride and the base compound were removed by distillation under reduced pressure to produce (2-ethylhexyl)phosphonic anhydride (mixture). The conversion rate in Example 2 was calculated in the same manner as in Example 1 and is shown in the "Conversion Rate" column of Table 1.

[0080] <Examples 3-12> In Examples 3-12, the phosphonic acid (A), halogenating agent (C), and basic compound (B) were reacted in the same manner as in Example 1, except that the phosphonic acid (A), basic compound (B), and halogenating agent (C) were changed to the compounds shown in Table 1. After the reaction was complete, the reaction mixture was allowed to stand, and liquid-liquid separation into two layers occurred, as in Example 1. In this way, (2-ethylhexyl)phosphonic anhydride (mixture) was produced. In each example, it was presumed that the lower layer contained an ionic liquid. The conversion rates for Examples 3-12 were calculated in the same manner as in Example 1 and are shown in the "Conversion Rate" column of Table 1.

[0081] <Comparative Example 1> n-propylphosphonic anhydride (T3P) was synthesized in the same manner as in "Example 1" described in Patent Document 1 (Japanese Patent Publication No. 2006-528140). In Comparative Example 1, the final reaction temperature was 280°C. The yield, calculated in the same manner as in Example 1, was 80%. ３１ The purity measured by P-NMR was 100%, and the conversion rate was 80%.

[0082] <Comparative Example 2> In Comparative Example 2, phosphonic acid (A) and halogenating agent (C) were reacted in the same manner as in Example 2, except that the base compound (B) was not used, to produce (2-ethylhexyl)phosphonic anhydride. The conversion rate in Comparative Example 2 was calculated in the same manner as in Example 1 and the results are shown in the "Conversion Rate" column of Table 1.

[0083] <Comparative Example 3> n-propylphosphonic anhydride (T3P) was produced using the same method and scale as in Non-Patent Document 1. n-propylphosphonic dichloride was synthesized by reacting 586 g of n-propylphosphonic acid with 562 g of thionyl chloride at 50°C for 6 hours. The conversion rate for Comparative Example 3 was calculated in the same manner as in Example 1 and is shown in the "Conversion Rate" column of Table 1. Since Comparative Example 3 is a reaction in water, "Reaction System (Phase Separation)" in Table 1 is labeled "Reaction in Water".

[0084] <Comparative Example 4> n-propylphosphonic anhydride (T3P) was produced in the same manner as in Comparative Example 3, except that 610 g of diisopropylethylamine was added as the base compound (B). The conversion rate in Comparative Example 4 was calculated in the same manner as in Example 1 and is shown in the "Conversion Rate" column of Table 1. Since Comparative Example 4 is a reaction in water, "Reaction System (Phase Separation)" in Table 1 is labeled "Reaction in Water".

[0085] <Reference Example 1> In Reference Example 1, phenyl phosphate, halogenating agent (C), and base compound (B) were reacted in the same manner as in Example 1, except that (2-ethylhexyl)phosphonic acid was replaced with phenyl phosphate. After the reaction was complete, the reaction mixture separated into two phases: a liquid phase and a solid phase. Thus, cyclic phosphoric anhydride of phenyl phosphate was produced. Analysis in the same manner as in Example 1 confirmed that the liquid phase mainly contained cyclic phosphoric anhydride of phenyl phosphate, and the solid phase contained an acidic component and base compound (B), and that the solid phase did not form an ionic liquid. The conversion rate in Reference Example 1 was calculated in the same manner as in Example 1 and is shown in the "Conversion Rate" column of Table 1.

[0086] [Evaluation: Amount of hydrogen chloride released outside the reaction system] A 500 mL trap container containing 400 mL of water was prepared, and its mass (W1) was measured. In each example, comparative example, and reference example, the above reaction was carried out with this trap container connected to a round-bottom flask, and the mass of the trap container (W2) was measured again at the end of the reaction. In each example, comparative example, and reference example, the increase in the mass of the trap container before and after the reaction (W2 - W1) was taken as the amount of hydrogen chloride gas released outside the reaction system and was evaluated according to the following criteria. The results are shown in the "Amount of corrosive gas released" column of Table 1. Note that no hydrogen chloride was generated in Comparative Example 1, so "None" is written in that column. - Evaluation Criteria - "A": Release amount is less than 2.0 g, which is very low (Pass) "B": Release amount is 2.0 g or more and less than 5.0 g, which is low (Pass) "C": Release amount is 5.0 g or more and less than 10.0 g, which is moderate (Fail) "D": Release amount is 10.0 g or more, which is high (Fail)

[0087]

[0088] The following can be seen from the results shown in Table 1. Comparative Example 1, which followed "Example 1" of Patent Document 1, required the final reaction temperature to be set to a high temperature of 280°C. Comparative Example 2, which did not use the base compound (B), released a large amount of hydrogen chloride outside the reaction system, and the conversion rate was only 46%. Comparative Example 3 released a large amount of hydrogen chloride outside the reaction system. In Comparative Example 4, the amount of hydrogen chloride released outside the reaction system could be suppressed to some extent by the presence of the base compound (B), but a relatively large amount was still released outside the reaction system. Reference Example 1, which used phenyl phosphate, was not inferior in terms of the amount of hydrogen chloride released and the conversion rate, but the reaction mixture became a solid-liquid phase, making post-treatment difficult, and it was not suitable for one-pot reactions with alcohol. In contrast, Examples 1 to 12, in which phosphonic acid (A) was reacted with a halogenating agent (C) and a base compound (B), were able to effectively suppress the release of corrosive gases outside the reaction system, and anhydrous cyclic phosphonic acid could be produced under mild reaction conditions of 50°C or less.

[0089] [[Method for Producing Phosphonic Acid Monoesters]] <Example A> A mixture of (2-ethylhexyl)phosphonic anhydride was prepared in the same manner as in Example 1, and the lower layer was removed from a 2 L three-necked round-bottom flask. The 2 L three-necked round-bottom flask was heated under a nitrogen atmosphere, and the upper layer remaining in the flask (toluene solution of (2-ethylhexyl)phosphonic anhydride, no operations other than liquid-liquid separation from the lower layer) was raised to 50°C. 125.8 g of 2-ethylhexanol (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., 0.75 times the molar amount relative to (2-ethylhexyl)phosphonic acid) was added over 10 minutes, stirred for 10 minutes, and then the temperature was raised to 110°C. The mixture was stirred at the same temperature for 6 hours to react the (2-ethylhexyl)phosphonic anhydride with 2-ethylhexanol. The resulting reaction mixture was then cooled to 80°C. 300 g of water was added, and the mixture was stirred at the same temperature for 3 hours, then allowed to cool at room temperature. The resulting liquid was allowed to stand to remove the aqueous layer, and 300 g of 1 M potassium carbonate aqueous solution was added and stirred for 30 minutes. After that, the mixture was allowed to stand to remove the phase-separated aqueous layer, and then 500 g of 1 M hydrochloric acid was added and stirred for 30 minutes. After allowing the mixture to stand to remove the phase-separated aqueous layer, 300 g of water was added and stirred for 10 minutes. Next, after allowing the mixture to stand to remove the phase-separated aqueous layer, the solvent was removed by vacuum distillation to obtain 276 g of (2-ethylhexyl)phosphonic acid mono-2-ethylhexyl (70% yield relative to (2-ethylhexyl)phosphonic acid). The obtained compound is a commercially available product (manufactured by Tokyo Chemical Industry Co., Ltd.) １ H-NMR and ３１ The shift and integral values ​​of the P-NMR spectrum, as well as the mass peak observed in mass spectrometry, all matched, leading to the identification of the target product as (2-ethylhexyl)phosphonic acid mono-2-ethylhexyl.

[0090] As shown in Example A, in the method for producing phosphonic acid monoesters, by using cyclic phosphonic anhydride produced by the present invention's method for producing cyclic phosphonic anhydride, the reaction with alcohol proceeded with simple operations, and the target phosphonic acid monoester could be produced. In particular, when an ionic liquid was formed using the present invention's method for producing cyclic phosphonic anhydride, the obtained cyclic phosphonic anhydride (phase (P)) could be used as is, and it could be reacted with alcohol simply in a single pot, continuously with the present invention's method for producing cyclic phosphonic anhydride.

[0091] Although we have described the present invention along with its embodiments, we do not intend to limit our invention in any detail of the description unless specifically designated, and we believe that it should be interpreted broadly without contradicting the spirit and scope of the invention as set forth in the appended claims.

[0092] This application claims priority based on Japanese Patent Application No. 2024-168755, filed in Japan on 27 September 2024, the contents of which are incorporated herein by reference as part of this specification.

Claims

1. A method for producing cyclic phosphonic anhydride, comprising reacting phosphonic acid (A) with at least one halogenating agent (C) selected from thionyl chloride, phosphoryl chloride, and oxalyl chloride, and a base compound (B).

2. The manufacturing method according to claim 1, wherein the base compound (B) is an amide compound or an amine compound having 4 or more carbon atoms.

3. The manufacturing method according to claim 1, wherein the above reaction is carried out in a homogeneous system.

4. The method for producing the cyclic phosphonic anhydride according to claim 1, wherein the reaction is carried out in a heterogeneous system, and the phase (P) mainly containing the cyclic phosphonic anhydride is separated from the reaction mixture to obtain the cyclic phosphonic anhydride.

5. The manufacturing method according to claim 4, wherein both phases constituting the reaction mixture are liquid phases, and the two phases are separated by liquid-liquid separation.

6. The method for producing the product according to claim 1, wherein the phosphonic acid (A) has an organic group having a branched structure.

7. The method for producing the product according to claim 1, wherein the phosphonic acid (A) has an alkyl group having 4 or more carbon atoms.

8. A method for producing a phosphonic acid monoester, comprising reacting a cyclic phosphonic acid obtained by the production method described in any one of claims 1 to 7 with an alcohol.

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