WO2023157814A1 - Method for producing phenyl phosphonic acid ester and phenyl phosphonic acid compound - Google Patents

Method for producing phenyl phosphonic acid ester and phenyl phosphonic acid compound Download PDF

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WO2023157814A1
WO2023157814A1 PCT/JP2023/004878 JP2023004878W WO2023157814A1 WO 2023157814 A1 WO2023157814 A1 WO 2023157814A1 JP 2023004878 W JP2023004878 W JP 2023004878W WO 2023157814 A1 WO2023157814 A1 WO 2023157814A1
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producing
phenylphosphonate
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acid
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梨乃 木村
武明 庄子
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日産化学株式会社
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]

Definitions

  • the present invention relates to methods for producing phenylphosphonate esters and phenylphosphonic acid compounds.
  • a method for producing a 4-halophenylphosphonate such as a 4-bromophenylphosphonate
  • a method of reacting a 1,4-dihalogenated benzene and a phosphite triester in the presence of a metal catalyst is conventionally known. It is
  • Non-Patent Document 1 discloses a method of synthesizing diethyl 4-bromophenylphosphonate from 1-bromo-4-iodobenzene and triethyl phosphite in the presence of a Pd catalyst.
  • Non-Patent Document 2 discloses a method for synthesizing diethyl 4-bromophenylphosphonate from 1-bromo-4-iodobenzene and triethyl phosphite under a Cu catalyst.
  • Non-Patent Document 3 discloses a method of synthesizing diethyl 4-bromophenylphosphonate from 1,4-dibromobenzene and triethyl phosphite under Ni catalyst.
  • An object of the present invention is to provide a method for producing a phenylphosphonic acid compound.
  • the present inventors have found that by reacting a dihalogenated aromatic compound with a phosphite triester in the presence of a predetermined metal-supported catalyst, reaction conversion The present inventors have found that the desired phenylphosphonic acid ester can be obtained at a high yield while the yield is improved and the production of by-products is reduced, thus completing the present invention.
  • formula (1) (Wherein, X and Y each represent a different halogen atom.)
  • a dihalogenated aromatic compound represented by formula (2) (In the formula, each R independently represents an alkyl group having 1 to 3 carbon atoms.) and a phosphite triester represented by the formula (3), which comprises a step (A) of reacting in an organic solvent in the presence of a supported catalyst in which a zero-valent metal is supported on a support.
  • the method for producing a phenylphosphonate ester according to any one of 1 to 10, comprising the step (B) of removing the metal component derived from the supported catalyst by washing the reaction solution after the step (A) with an aqueous thiourea solution under acidic conditions. , 12. (C) step of heating the phenylphosphonate obtained by the production method of 11 in an aqueous acid solution to hydrolyze the ester group bonded to the phosphorus atom, and after the step (C), the hydrolysis product
  • a method for producing a phenylphosphonic acid compound comprising the step (D) of crystallizing in an organic solvent, 13.
  • the method for producing a phenylphosphonic acid ester of the present invention has a high reaction conversion rate and produces little by-product, so that the desired product can be obtained in good yield. Further, the obtained phenylphosphonate ester is washed with an aqueous thiourea solution under acidic conditions and then hydrolyzed to obtain a phenylphosphonate compound with reduced metal content.
  • X and Y each represent a different halogen atom, and each R independently represents an alkyl group having 1 to 3 carbon atoms.
  • the halogen atom includes a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
  • X and Y in formula (1) may be different halogen atoms so that a phosphonate ester group is introduced into only one of them.
  • a bromine atom and Y are preferably chlorine, bromine or iodine atoms, and more preferably X is a bromine atom and Y is an iodine atom.
  • compound (1) examples include 1-bromo-4-iodobenzene, 1-chloro-4-iodobenzene, 1-fluoro-4-iodobenzene, 1-chloro-4-bromobenzene, 1-fluoro- Examples thereof include 4-bromobenzene and 1-fluoro-4-chlorobenzene. Among these, 1-bromo-4-iodobenzene is preferable in consideration of reactivity balance and the like.
  • alkyl group having 1 to 3 carbon atoms for R in formula (2) examples include methyl, ethyl, n-propyl, i-propyl groups and the like, preferably an alkyl group having 2 or 3 carbon atoms, and an ethyl group. more preferred.
  • compound (2) examples include trimethyl phosphite, triethyl phosphite, tripropyl phosphite, triisopropyl phosphite, etc. Among these, triethyl phosphite is preferred.
  • the metal used for the zerovalent metal-supported catalyst can be appropriately selected from known metals that exhibit catalytic activity in the above reaction, but elements of Group 10 of the periodic table are preferred, and nickel and palladium are more preferred. Preferably, palladium is even more preferred.
  • the carrier constituting the supported catalyst is not particularly limited, and carbon materials such as activated carbon; metal oxides such as aluminum oxide (alumina), titanium oxide (titania), silica and silica/alumina; silicates such as zeolite Materials: alkaline earth metal salts such as calcium sulfate and barium sulfate.
  • the support used in the present invention is preferably at least one selected from alkaline earth metal salts and metal oxides, more preferably metal oxides, and sulfuric acid, considering the conversion rate of the desired reaction. Barium and aluminum oxide (alumina) are more preferred.
  • Suitable metal-supported catalysts include, but are not limited to, Pd--Al 2 O 3 , Pd--BaSO 4 and the like.
  • organic solvent used in the reaction of step (A) various solvents can be used as long as they do not affect the reaction, for example, pentane, hexane, heptane, octane, aliphatic hydrocarbons such as cyclohexane; Ethers such as ether, diisopropyl ether, dibutyl ether, cyclopentyl methyl ether, tetrahydrofuran, and 1,4-dioxane; Aromatic hydrocarbons such as benzene, toluene, xylene, and mesitylene; Methanol, ethanol, 2-propanol, 2-butanol and the like can be used, and these may be used singly or in combination of two or more. Among these, aromatic hydrocarbons and ethers are preferred, aromatic hydrocarbons are more preferred, and toluene and xylene are even more preferred.
  • step (A) the use ratio of compound (1) and compound (2) is not particularly limited as long as the desired product can be obtained. Taking this into consideration, compound (2) is preferably 1.1 to 2.0 mol, more preferably 1.2 to 1.8 mol, and even more preferably 1.3 to 1.8 mol, per 1 mol of compound (1).
  • the amount of the supported catalyst to be used is also not particularly limited, but from the viewpoint of increasing the reaction conversion rate, the amount of metal is preferably 0.1 to 1.0 mol % relative to compound (1), and 0.1 to 1.0 mol %. 2 to 0.8 mol % is more preferred, and 0.3 to 0.7 mol % is even more preferred.
  • the reaction temperature may be appropriately set, for example, between about 80 and 200.degree. C., preferably between 100 and 150.degree. C., more preferably between 110 and 140.degree.
  • the reaction time can be set to about 0.1 to 24 hours depending on the amount of catalyst used and the reaction temperature, for example, while checking the conversion rate and by-products, preferably 1 to 12 hours, and 2 to 6 hours. time is more preferred.
  • Step (B) After completion of the reaction in step (A), general post-treatments such as filtration and liquid separation are performed, and purification is performed as necessary to obtain the target phenylphosphonate ester.
  • the reaction solution after the step (A) is acidified in order to reduce the metal content of the obtained phenylphosphonate and the phenylphosphonate compound obtained by hydrolyzing it.
  • an acid aqueous solution and an aqueous thiourea solution are added to the above filtrate (organic phase), and the filtrate is washed with the acidic thiourea aqueous solution by stirring, liquid separation, or the like. After that, the organic and aqueous phases are separated.
  • the acid used in the aqueous acid solution is preferably an inorganic acid such as hydrochloric acid or sulfuric acid, more preferably sulfuric acid.
  • the concentration of the acid is not particularly limited, it is preferably about 0.01 to 5% by mass, more preferably 0.05 to 3% by mass, and 0.1 to 2.8% by mass in the acidic thiourea aqueous solution (aqueous phase). is even more preferred.
  • the concentration of thiourea is also not particularly limited, but it is preferably 1 to 10% by mass, more preferably 2 to 7% by mass, and even more preferably 2.5 to 6% by mass in the acidic thiourea aqueous solution (aqueous phase). .
  • the temperature during washing can be about 0 to 80.degree. C., preferably 15 to 70.degree. C., more preferably 20 to 60.degree.
  • the washing with the acidic thiourea aqueous solution may be performed only once or may be performed multiple times. Moreover, you may wash with water after that as needed.
  • the washing treatment in the step (B) can reduce the content of metal components in the phenylphosphonate to, for example, less than 10 ppm.
  • the desired phenylphosphonate can be isolated by ordinary post-treatment such as distilling off the solvent.
  • Step (C) is a step of heating the phenylphosphonate ester obtained above in an aqueous acid solution to hydrolyze the ester group bonded to the phosphorus atom, leading to phenylphosphonic acid. is.
  • the method of mixing the phenylphosphonate with the aqueous acid solution is arbitrary, but the method of adding the phenylphosphonate to the aqueous solution of the acid is preferred, and the method of adding the phenylphosphonate dropwise is more preferred. .
  • the acid organic acids such as p-toluenesulfonic acid and trifluoromethanesulfonic acid; and inorganic acids such as hydrochloric acid and sulfuric acid can be used.
  • Hydrochloric acid and sulfuric acid are preferred from the viewpoint of the conversion rate of the hydrolysis reaction.
  • the amount of the acid to be used is preferably an excess amount, more preferably 5 to 20 equivalents, and even more preferably 8 to 18 equivalents, relative to the phenylphosphonic acid ester, from the viewpoint of allowing the hydrolysis reaction to proceed efficiently.
  • the reaction temperature is not particularly limited, it is preferably 80 to 130°C, more preferably 100 to 130°C.
  • the reaction time is also not particularly limited, but preferably 1 to 48 hours, more preferably 12 to 36 hours.
  • general post-treatments such as liquid separation using an organic solvent, washing, concentration, etc. are performed to remove the acid, and a hydrolysis product (phenylphosphonic acid) can be obtained.
  • this organic solvent the same organic solvent as used in the step (D), which will be described later, can be used.
  • Step (D) is a step of crystallizing the hydrolysis product (phenylphosphonic acid) obtained in step (C) in an organic solvent.
  • the organic solvent is not particularly limited as long as phenylphosphonic acid can be crystallized, but at least one selected from hydrocarbons having 5 to 10 carbon atoms and ketones having 3 to 10 carbon atoms is preferable.
  • hydrocarbons having 5 to 10 carbon atoms include aliphatic or alicyclic hydrocarbons such as n-pentane, n-hexane, cyclohexane, n-heptane, n-octane, n-nonane and n-decane. be done.
  • ketones having 3 to 10 carbon atoms include acetone, 2-butanone, 3-pentanone, 2-pentanone, 4-methyl-2-pentanone, 3-hexanone, 4-heptanone and 2,6-dimethyl-4-heptanone. etc.
  • the amount of the organic solvent used is not particularly limited as long as the phenylphosphonic acid crystallizes, but it is preferably 2 to 150 times by mass, more preferably 5 to 20 times by mass, the phenylphosphonic acid ester used as the raw material. Preferably, 7 to 15 times by mass is more preferable.
  • a specific method of crystallization includes a method of preparing a solution of phenylphosphonic acid in an organic solvent under heating, cooling the solution, and filtering the crystallized phenylphosphonic acid.
  • the heating temperature is preferably 50 to 90°C, more preferably 60 to 80°C.
  • the cooling temperature is preferably 20° C. or lower, more preferably 10° C. or lower, and even more preferably 5° C.
  • a small amount of water or an alcoholic solvent such as ethanol may be added.
  • the amount used is preferably 0.01 to 0.1 times the weight of the phenylphosphonate used as a raw material, and when an alcohol solvent is used, the amount used is phenylphosphonate used as a raw material. It is preferably 0.01 to 0.5 times the weight of the acid ester. Crystallized phenylphosphonic acid can be obtained as crystals by filtering and drying under reduced pressure or the like at room temperature or by heating.
  • the target Pd level in diethyl 4-bromophenylphosphonate is ⁇ 10 ppm. Therefore, the Pd content was evaluated using the APHA value of the organic layer. Since APHA ⁇ 50 for the organic layer corresponds to Pd ⁇ 10 ppm, the target APHA for the organic layer was set to ⁇ 50.
  • Example 1 Synthesis of diethyl 4-bromophenylphosphonate (1) Step A In a 1 L reaction vessel, 99.8 g (0.60 mol) of triethyl phosphite, 150 g of ortho-xylene, 5% by mass of palladium oxide supported on alumina catalyst 2 0.63 g (1.24 mmol, 0.35 mol %) was charged and stirred under a nitrogen atmosphere. After heating the mixture in the reactor to 120-125° C., 100 g (0.35 mol) of iodobromobenzene dissolved in 250 g of ortho-xylene was added dropwise over 5 hours and reacted at 120-125° C. for 3 hours.
  • Step B From the reaction solution containing diethyl 4-bromophenylphosphonate obtained in Step (A), ethyl iodide, a by-product of the reaction, was removed by distillation under reduced pressure.
  • ortho-xylene was added to After that, 50 g of heptane, 50 g of 0.1% aqueous sulfuric acid solution, and 150 g of 5% aqueous thiourea solution were charged and stirred at 50 to 60° C. for 1 hour. After stopping the stirring, the mixture was allowed to stand and separated. The aqueous layer containing metal impurities was discarded, and 50 g of a 0.1% aqueous sulfuric acid solution and 150 g of a 5% thiourea aqueous solution were added to the obtained organic layer, and the same operation was repeated to obtain an organic layer with reduced metals (APHA ⁇ 50 ).
  • Step A Synthesis of diethyl 4-bromophenylphosphonate (Step A) 8.8 g (53.0 mmol) of triethyl phosphite, 10.0 g (35.3 mmol) of iodobromobenzene, 20 g of toluene, and 0.23 g (0.3 mol %) of a 5% by mass palladium oxide supported catalyst on alumina were placed in a 50 mL reaction vessel. was charged, and after purging with nitrogen, the temperature was raised to 120° C. to react. When the reaction conversion rate was confirmed after 6 hours, the conversion rate was 99.5%.
  • Example 4 Synthesis of diethyl 4-bromophenylphosphonate (Step A) A reaction was carried out in the same manner as in Example 3, except that the 5% by mass palladium oxide-supported alumina catalyst was changed to a 5% by mass palladium barium sulfate-supported catalyst. When the reaction conversion rate was confirmed after 3 hours, the conversion rate was 100%.
  • Example 5 Synthesis of diethyl 4-bromophenylphosphonate (Step A) The same procedure as in Example 1 was carried out, except that the amount of catalyst charged was changed from 0.35 mol% to 0.2 mol%, the amount of triethyl phosphite charged was changed from 1.7 equivalents to 2.0 equivalents, and nitrogen was flowed during the reaction. reacted. When the reaction conversion rate was confirmed after 11 hours, the conversion rate was 100%. The nitrogen flow was performed to positively remove ethyl iodide, which is a cause of generation of impurities, out of the system.
  • Example 6 Synthesis of diethyl 4-bromophenylphosphonate The same operation as in Example 1 was performed, except that in step B, the 0.1% sulfuric acid aqueous solution was changed to 0.2% hydrochloric acid. The APHA of the resulting organic layer was ⁇ 50.
  • step B Synthesis of diethyl 4-bromophenylphosphonate
  • step B the same operation as in Example 1 was performed, except that the stirring temperature was changed from 50 to 60°C to 20 to 30°C.
  • the APHA of the resulting organic layer was ⁇ 50.
  • step B instead of washing twice with an aqueous thiourea solution in the presence of sulfuric acid, after washing with 50 g of heptane and 100 g of ion-exchanged water at 45 to 50°C. , 150 g of a 5% aqueous thiourea solution at 20 to 30°C, and further washing with 150 g of a 2.5% aqueous sulfuric acid solution at 20 to 30°C.
  • the APHA of the obtained organic layer was 131.
  • Example 8 Synthesis of 4-bromophenylphosphonic acid (3) Step C In a 500 mL reaction vessel, 125 g of ion-exchanged water and 132.1 g (1.28 mol) of 95% sulfuric acid were charged and stirred. After heating the mixture in the container to 105 to 115° C., 25.0 g (0.085 mol) of diethyl 4-bromophenylphosphonate obtained in Example 1 was added dropwise over 30 minutes. A hydrolysis reaction was carried out at 105-115° C. for 24 hours to obtain a reaction solution containing 4-bromophenylphosphonic acid. When the reaction conversion rate was confirmed, the conversion rate was 100%.
  • Step D The reaction solution obtained in Step (C) was cooled to 60-65°C, charged with 75 g of 4-methyl-2-pentanone, and stirred at 60-65°C for 30 minutes. After stirring was stopped, the same operation was performed on the aqueous layer obtained by standing and separating. The obtained organic layers were mixed and washed with ion-exchanged water (37.5 g ⁇ 3, 60-65° C.). It was confirmed that 75 g of 4-methyl-2-pentanone was removed from the washed organic layer by distillation under reduced pressure, and 4-bromophenylphosphonic acid was precipitated.
  • step C Synthesis of 4-bromophenylphosphonic acid (step C) A 10 mL reaction vessel was charged with 1.8 g of ion-exchanged water, 0.80 g (7.7 mmol) of 95% sulfuric acid, and 0.30 g (1.03 mmol) of diethyl 4-bromophenylphosphonate obtained in Example 1, and stirred. . The mixture in the reaction vessel was heated to an external temperature of 125° C. and reacted for 24 hours. When the reaction conversion rate was confirmed after 24 hours, the conversion rate was 82%.
  • Example 10 Synthesis of 4-bromophenylphosphonic acid (Step C) A reaction was carried out in the same manner as in Example 9, except that 95% sulfuric acid was changed to 35% hydrochloric acid. When the reaction conversion rate was confirmed after 24 hours, the conversion rate was 94%.
  • Example 11 Synthesis of 4-bromophenylphosphonic acid (Step C) A reaction was carried out in the same manner as in Example 9, except that 1.23 g (8.2 mmol) of trifluoromethanesulfonic acid was used instead of 95% sulfuric acid. When the reaction conversion rate was confirmed after 24 hours, the conversion rate was 76%.
  • Example 12 Synthesis of 4-bromophenylphosphonic acid (Step C) A reaction was carried out in the same manner as in Example 9, except that 95% sulfuric acid was changed to 1.56 g (8.2 mmol) of p-toluenesulfonic acid monohydrate. When the reaction conversion rate was confirmed after 24 hours, the conversion rate was 71%.
  • Table 4 shows a summary of Step C in Examples 8 to 12 above.

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Abstract

Provided is a method for producing a phenyl phosphonic acid ester, the method comprising step (A) in which a dihalogenated aromatic compound is reacted with a phosphite triester in an organic solvent in the presence of a supported catalyst in which a zero-valent metal is supported on a carrier, wherein the dihalogenated aromatic compound is represented by formula (1) (in the formula, X and Y represent different halogen atoms), the phosphite triester is represented by formula (2) (in the formula, each R independently represents a C1-3 alkyl group), and the phenyl phosphonic acid ester is represented by formula (3) (in the formula, X and R denote the same as above). The method provides a good reaction conversion rate and produces less by-products.

Description

フェニルホスホン酸エステルおよびフェニルホスホン酸化合物の製造方法Method for producing phenylphosphonic acid ester and phenylphosphonic acid compound
　本発明は、フェニルホスホン酸エステルおよびフェニルホスホン酸化合物の製造方法に関する。 The present invention relates to methods for producing phenylphosphonate esters and phenylphosphonic acid compounds.
　４－ブロモフェニルホスホン酸エステル等の４－ハロフェニルホスホン酸エステルの製造方法として、従来、１，４－ジハロゲン化ベンゼンと亜リン酸トリエステルとを、金属触媒の存在下で反応させる手法が知られている。 As a method for producing a 4-halophenylphosphonate such as a 4-bromophenylphosphonate, a method of reacting a 1,4-dihalogenated benzene and a phosphite triester in the presence of a metal catalyst is conventionally known. It is
　例えば、非特許文献１には、Ｐｄ触媒下、１－ブロモ－４－ヨードベンゼンと、亜リン酸トリエチルとから４－ブロモフェニルホスホン酸ジエチルを合成する手法が開示されている。
　非特許文献２には、Ｃｕ触媒下、１－ブロモ－４－ヨードベンゼンと、亜リン酸トリエチルとから４－ブロモフェニルホスホン酸ジエチルを合成する手法が開示されている。
　非特許文献３には、Ｎｉ触媒下、１，４－ジブロモベンゼンと、亜リン酸トリエチルとから４－ブロモフェニルホスホン酸ジエチルを合成する手法が開示されている。 For example, Non-Patent Document 1 discloses a method of synthesizing diethyl 4-bromophenylphosphonate from 1-bromo-4-iodobenzene and triethyl phosphite in the presence of a Pd catalyst.
Non-Patent Document 2 discloses a method for synthesizing diethyl 4-bromophenylphosphonate from 1-bromo-4-iodobenzene and triethyl phosphite under a Cu catalyst.
Non-Patent Document 3 discloses a method of synthesizing diethyl 4-bromophenylphosphonate from 1,4-dibromobenzene and triethyl phosphite under Ni catalyst.
　しかし、これらの手法では、比較的低温で反応させた場合の反応転化率が低いという問題があるうえ、これを改善するために反応温度を高めた場合、エチルホスホン酸ジエチル等の副生物が生成し、目的物の収率が低下してしまうという問題がある。 However, these methods have the problem that the reaction conversion rate is low when the reaction is carried out at a relatively low temperature, and when the reaction temperature is raised to improve this, by-products such as diethyl ethylphosphonate are produced. However, there is a problem that the yield of the target product is lowered.
　本発明は、上記事情に鑑みてなされたものであり、反応転化率が良好であり、副生物の生成の少ないフェニルホスホン酸エステルの製造方法、およびこの方法により得られたフェニルホスホン酸エステルを原料とするフェニルホスホン酸化合物の製造方法を提供することを目的とする。 The present invention has been made in view of the above circumstances. An object of the present invention is to provide a method for producing a phenylphosphonic acid compound.
　本発明者らは、上記課題を解決するために鋭意検討を重ねた結果、所定の金属担持触媒の存在下で、ジハロゲン化芳香族化合物と亜リン酸トリエステルとを反応させることで、反応転化率が向上するとともに、副生物の生成が少なくなり、目的のフェニルホスホン酸エステルが収率よく得られることを見出し、本発明を完成させた。 As a result of intensive studies to solve the above problems, the present inventors have found that by reacting a dihalogenated aromatic compound with a phosphite triester in the presence of a predetermined metal-supported catalyst, reaction conversion The present inventors have found that the desired phenylphosphonic acid ester can be obtained at a high yield while the yield is improved and the production of by-products is reduced, thus completing the present invention.
　すなわち、本発明は、
１．　式（１）
Figure JPOXMLDOC01-appb-C000004
 （式中、ＸおよびＹは、それぞれ異なるハロゲン原子を表す。）
で表されるジハロゲン化芳香族化合物と、
　式（２）
Figure JPOXMLDOC01-appb-C000005
 （式中、Ｒは、それぞれ独立して炭素数１～３のアルキル基を表す。）
で表される亜リン酸トリエステルとを、有機溶媒中、０価の金属が担体に担持された担持触媒の存在下で反応させる（Ａ）工程を備えることを特徴とする式（３）
Figure JPOXMLDOC01-appb-C000006
 （式中、ＸおよびＲは、前記と同じ意味を表す。）
で表されるフェニルホスホン酸エステルの製造方法、
２．　前記担持触媒が、式（１）で表されるジハロゲン化芳香族化合物に対して、金属量として０．１～１．０ｍｏｌ％用いられる１のフェニルホスホン酸エステルの製造方法、
３．　前記金属が、周期表第１０族元素である１または２のフェニルホスホン酸エステルの製造方法、
４．　前記金属が、パラジウムである３記載のフェニルホスホン酸エステルの製造方法、
５．　前記担体が、アルカリ土類金属塩および金属酸化物から選ばれる少なくとも１種である１～４のいずれかのフェニルホスホン酸エステルの製造方法、
６．　前記担体が、金属酸化物である５のフェニルホスホン酸エステルの製造方法、
７．　前記金属酸化物が、酸化アルミニウムである６のフェニルホスホン酸エステルの製造方法、
８．　前記反応が、１００～１５０℃で行われる１～７のいずれかのフェニルホスホン酸エステルの製造方法、
９．　前記Ｘが、臭素原子であり、前記Ｙが、ヨウ素原子である１～８のいずれかのフェニルホスホン酸エステルの製造方法、
１０．　前記Ｒが、エチル基である１～９のいずれかのフェニルホスホン酸エステルの製造方法、
１１．　前記（Ａ）工程後の反応液を、酸性条件下、チオウレア水溶液で洗浄し、担持触媒由来の金属成分を除去する（Ｂ）工程を備える１～１０のいずれかのフェニルホスホン酸エステルの製造方法、
１２．　１１の製造方法で得られたフェニルホスホン酸エステルを、酸の水溶液中で加熱し、リン原子に結合したエステル基を加水分解する（Ｃ）工程、および
　前記（Ｃ）工程後、加水分解生成物を有機溶媒中で晶析させる（Ｄ）工程を備えるフェニルホスホン酸化合物の製造方法、
１３．　前記酸が、塩酸および硫酸から選ばれる少なくとも１種である１２のフェニルホスホン酸化合物の製造方法、
１４．　前記（Ｄ）工程で用いる有機溶媒が、炭素数５～１０の炭化水素類、炭素数３～１０のケトン類から選ばれる少なくとも１種である１２または１３のフェニルホスホン酸化合物の製造方法
を提供する。 That is, the present invention
1. formula (1)
Figure JPOXMLDOC01-appb-C000004
 (Wherein, X and Y each represent a different halogen atom.)
A dihalogenated aromatic compound represented by
formula (2)
Figure JPOXMLDOC01-appb-C000005
 (In the formula, each R independently represents an alkyl group having 1 to 3 carbon atoms.)
and a phosphite triester represented by the formula (3), which comprises a step (A) of reacting in an organic solvent in the presence of a supported catalyst in which a zero-valent metal is supported on a support.
Figure JPOXMLDOC01-appb-C000006
 (Wherein, X and R have the same meanings as above.)
A method for producing a phenylphosphonate ester represented by
2. The method for producing a phenylphosphonate ester of 1, wherein the supported catalyst is used in a metal amount of 0.1 to 1.0 mol% with respect to the dihalogenated aromatic compound represented by formula (1);
3. A method for producing a phenylphosphonate of 1 or 2, wherein the metal is an element of Group 10 of the periodic table;
4. 3. The method for producing a phenylphosphonate according to 3, wherein the metal is palladium;
5. The method for producing a phenylphosphonate according to any one of 1 to 4, wherein the carrier is at least one selected from alkaline earth metal salts and metal oxides;
6. The method for producing a phenylphosphonate ester of 5, wherein the carrier is a metal oxide;
7. The method for producing a phenylphosphonate ester of 6, wherein the metal oxide is aluminum oxide;
8. The method for producing a phenylphosphonate according to any one of 1 to 7, wherein the reaction is carried out at 100 to 150°C;
9. The method for producing the phenylphosphonate according to any one of 1 to 8, wherein the X is a bromine atom and the Y is an iodine atom;
10. The method for producing the phenylphosphonate according to any one of 1 to 9, wherein R is an ethyl group,
11. The method for producing a phenylphosphonate ester according to any one of 1 to 10, comprising the step (B) of removing the metal component derived from the supported catalyst by washing the reaction solution after the step (A) with an aqueous thiourea solution under acidic conditions. ,
12. (C) step of heating the phenylphosphonate obtained by the production method of 11 in an aqueous acid solution to hydrolyze the ester group bonded to the phosphorus atom, and after the step (C), the hydrolysis product A method for producing a phenylphosphonic acid compound comprising the step (D) of crystallizing in an organic solvent,
13. 12 methods for producing a phenylphosphonic acid compound, wherein the acid is at least one selected from hydrochloric acid and sulfuric acid;
14. Provided is a method for producing a 12 or 13 phenylphosphonic acid compound, wherein the organic solvent used in the step (D) is at least one selected from hydrocarbons having 5 to 10 carbon atoms and ketones having 3 to 10 carbon atoms. do.
　本発明のフェニルホスホン酸エステルの製造方法は、反応転化率が高く、かつ、副生物の生成が少ないため、目的物を収率よく得ることができる。
　また、得られたフェニルホスホン酸エステルを、酸性条件下、チオウレア水溶液で洗浄した後、加水分解することで、金属の低減されたフェニルホスホン酸化合物を得ることができる。 The method for producing a phenylphosphonic acid ester of the present invention has a high reaction conversion rate and produces little by-product, so that the desired product can be obtained in good yield.
Further, the obtained phenylphosphonate ester is washed with an aqueous thiourea solution under acidic conditions and then hydrolyzed to obtain a phenylphosphonate compound with reduced metal content.
　以下、本発明についてさらに詳しく説明する。
［１］（Ａ）工程
　本発明のフェニルホスホン酸エステルの製造方法は、下記スキームで示されるように、式（１）で表されるジハロゲン化芳香族化合物（以下、「化合物（１）」という。）と、式（２）で表される亜リン酸トリエステル（以下、「化合物（２）」という。）とを、有機溶媒中、０価の金属が担体に担持された担持触媒の存在下で反応させる（Ａ）工程を備えることを特徴とする。 The present invention will be described in more detail below.
[1] (A) step In the method for producing a phenylphosphonate ester of the present invention, as shown in the following scheme, a dihalogenated aromatic compound represented by formula (1) (hereinafter referred to as "compound (1)" ) and a phosphite triester represented by formula (2) (hereinafter referred to as “compound (2)”) are mixed in an organic solvent in the presence of a supported catalyst in which a zerovalent metal is supported on a carrier. It is characterized by comprising the step (A) of reacting below.
Figure JPOXMLDOC01-appb-C000007
 （式中、ＸおよびＹは、それぞれ異なるハロゲン原子を表し、Ｒは、それぞれ独立して炭素数１～３のアルキル基を表す。）
Figure JPOXMLDOC01-appb-C000007
 (Wherein, X and Y each represent a different halogen atom, and each R independently represents an alkyl group having 1 to 3 carbon atoms.)
　上記ハロゲン原子としては、フッ素原子、塩素原子、臭素原子、ヨウ素原子が挙げられる。
　式（１）におけるＸおよびＹは、それらの一方のみにホスホン酸エステル基を導入すべく、それぞれ異なるハロゲン原子であればよいが、それらの組み合わせとしては、Ｘが、フッ素原子、塩素原子、または臭素原子、Ｙが、塩素原子、臭素原子またはヨウ素原子が好ましく、Ｘが、臭素原子、Ｙが、ヨウ素原子がより好ましい。 The halogen atom includes a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
X and Y in formula (1) may be different halogen atoms so that a phosphonate ester group is introduced into only one of them. A bromine atom and Y are preferably chlorine, bromine or iodine atoms, and more preferably X is a bromine atom and Y is an iodine atom.
　化合物（１）の具体例としては、１－ブロモ－４－ヨードベンゼン、１－クロロ－４－ヨードベンゼン、１－フルオロ－４－ヨードベンゼン、１－クロロ－４－ブロモベンゼン、１－フルオロ－４－ブロモベンゼン、１－フルオロ－４－クロロベンゼン等が挙げられるが、これらの中でも、反応性のバランス等を考慮すると、１－ブロモ－４－ヨードベンゼンが好ましい。 Specific examples of compound (1) include 1-bromo-4-iodobenzene, 1-chloro-4-iodobenzene, 1-fluoro-4-iodobenzene, 1-chloro-4-bromobenzene, 1-fluoro- Examples thereof include 4-bromobenzene and 1-fluoro-4-chlorobenzene. Among these, 1-bromo-4-iodobenzene is preferable in consideration of reactivity balance and the like.
　式（２）におけるＲの炭素数１～３のアルキル基としては、メチル、エチル、ｎ－プロピル、ｉ－プロピル基等が挙げられるが、炭素数２または３のアルキル基が好ましく、エチル基がより好ましい。 Examples of the alkyl group having 1 to 3 carbon atoms for R in formula (2) include methyl, ethyl, n-propyl, i-propyl groups and the like, preferably an alkyl group having 2 or 3 carbon atoms, and an ethyl group. more preferred.
　化合物（２）の具体例としては、亜リン酸トリメチル、亜リン酸トリエチル、亜リン酸トリプロピル、亜リン酸トリイソプロピル等が挙げられるが、これらの中でも、亜リン酸トリエチルが好ましい。 Specific examples of compound (2) include trimethyl phosphite, triethyl phosphite, tripropyl phosphite, triisopropyl phosphite, etc. Among these, triethyl phosphite is preferred.
　本発明において、０価の金属担持触媒に用いられる金属としては、上記反応に触媒活性を示す公知の金属から適宜選択することができるが、周期表第１０属元素が好ましく、ニッケル、パラジウムがより好ましく、パラジウムがより一層好ましい。 In the present invention, the metal used for the zerovalent metal-supported catalyst can be appropriately selected from known metals that exhibit catalytic activity in the above reaction, but elements of Group 10 of the periodic table are preferred, and nickel and palladium are more preferred. Preferably, palladium is even more preferred.
　担持触媒を構成する担体としては、特に限定されるものではなく、活性炭等の炭素材料；酸化アルミニウム（アルミナ）、酸化チタン（チタニア）、シリカ、シリカ・アルミナ等の金属酸化物：ゼオライト等のシリケート材料；硫酸カルシウム、硫酸バリウム等のアルカリ土類金属塩等が挙げられる。
　これらの中でも、本発明で用いる担体としては、目的とする反応の転化率等を考慮すると、アルカリ土類金属塩および金属酸化物から選ばれる少なくとも１種が好ましく、金属酸化物がより好ましく、硫酸バリウム、酸化アルミニウム（アルミナ）がより一層好ましい。 The carrier constituting the supported catalyst is not particularly limited, and carbon materials such as activated carbon; metal oxides such as aluminum oxide (alumina), titanium oxide (titania), silica and silica/alumina; silicates such as zeolite Materials: alkaline earth metal salts such as calcium sulfate and barium sulfate.
Among these, the support used in the present invention is preferably at least one selected from alkaline earth metal salts and metal oxides, more preferably metal oxides, and sulfuric acid, considering the conversion rate of the desired reaction. Barium and aluminum oxide (alumina) are more preferred.
　好適な金属担持触媒としては、Ｐｄ－Ａｌ2Ｏ3、Ｐｄ－ＢａＳＯ4等が挙げられるが、これらに限定されるものではない。 Suitable metal-supported catalysts include, but are not limited to, Pd--Al 2 O 3 , Pd--BaSO 4 and the like.
　（Ａ）工程の反応に用いられる有機溶媒としては、反応に影響を及ぼさない限りにおいて各種の溶媒類が使用でき、例えば、ペンタン、ヘキサン、ヘプタン、オクタン、シクロヘキサン等の脂肪族炭化水素類；ジエチルエーテル、ジイソプロピルエーテル、ジブチルエーテル、シクロペンチルメチルエーテル、テトラヒドロフラン、１，４－ジオキサン等のエーテル類；ベンゼン、トルエン、キシレン、メシチレン等の芳香族炭化水素類；メタノール、エタノール、２－プロパノール、２－ブタノール等のアルコール類などを用いることができ、これらは１種単独で用いても、２種以上組み合わせて用いてもよい。
　これらの中でも、芳香族炭化水素類、エーテル類が好ましく、芳香族炭化水素類がより好ましく、トルエン、キシレンがより一層好ましい。 As the organic solvent used in the reaction of step (A), various solvents can be used as long as they do not affect the reaction, for example, pentane, hexane, heptane, octane, aliphatic hydrocarbons such as cyclohexane; Ethers such as ether, diisopropyl ether, dibutyl ether, cyclopentyl methyl ether, tetrahydrofuran, and 1,4-dioxane; Aromatic hydrocarbons such as benzene, toluene, xylene, and mesitylene; Methanol, ethanol, 2-propanol, 2-butanol and the like can be used, and these may be used singly or in combination of two or more.
Among these, aromatic hydrocarbons and ethers are preferred, aromatic hydrocarbons are more preferred, and toluene and xylene are even more preferred.
　（Ａ）工程の反応において、化合物（１）と、化合物（２）との使用比率は、目的物が得られる限り特に制限はないが、反応転化率を高めるとともに、過剰反応を抑制することを考慮すると、化合物（１）１ｍｏｌに対し、化合物（２）１．１～２．０ｍｏｌが好ましく、１．２～１．８ｍｏｌがより好ましく、１．３～１．８ｍｏｌがより一層好ましい。 In the reaction of step (A), the use ratio of compound (1) and compound (2) is not particularly limited as long as the desired product can be obtained. Taking this into consideration, compound (2) is preferably 1.1 to 2.0 mol, more preferably 1.2 to 1.8 mol, and even more preferably 1.3 to 1.8 mol, per 1 mol of compound (1).
　また、担持触媒の使用量も特に限定されるものではないが、反応転化率を高めるという点から、化合物（１）に対して、金属量として０．１～１．０ｍｏｌ％が好ましく、０．２～０．８ｍｏｌ％がより好ましく、０．３～０．７ｍｏｌ％がより一層好ましい。 The amount of the supported catalyst to be used is also not particularly limited, but from the viewpoint of increasing the reaction conversion rate, the amount of metal is preferably 0.1 to 1.0 mol % relative to compound (1), and 0.1 to 1.0 mol %. 2 to 0.8 mol % is more preferred, and 0.3 to 0.7 mol % is even more preferred.
　反応温度は、使用する触媒量に応じ、例えば、８０～２００℃程度の間で適宜設定すればよいが、１００～１５０℃が好ましく、１１０～１４０℃がより好ましい。
　反応時間は、使用する触媒量および反応温度に応じ、例えば、転化率や副生物を確認しながら０．１～２４時間程度で設定することができるが、１～１２時間が好ましく、２～６時間がより好ましい。 The reaction temperature may be appropriately set, for example, between about 80 and 200.degree. C., preferably between 100 and 150.degree. C., more preferably between 110 and 140.degree.
The reaction time can be set to about 0.1 to 24 hours depending on the amount of catalyst used and the reaction temperature, for example, while checking the conversion rate and by-products, preferably 1 to 12 hours, and 2 to 6 hours. time is more preferred.
［２］（Ｂ）工程
　（Ａ）工程の反応終了後は、濾過、分液等の一般的な後処理をし、必要に応じて精製することで、目的物であるフェニルホスホン酸エステルを得ることができるが、本発明の製造方法では、得られたフェニルホスホン酸エステルおよびこれを加水分解して得られるフェニルホスホン酸化合物の金属を低減すべく、（Ａ）工程後の反応液を、酸性条件下、チオウレア水溶液で洗浄し、担持触媒由来の金属成分を除去する（Ｂ）工程を備えることが好ましい。
　この工程は、反応後の反応液を濾過して得られた濾液中に溶解している担持触媒由来の金属成分を除去する工程である。 [2] Step (B) After completion of the reaction in step (A), general post-treatments such as filtration and liquid separation are performed, and purification is performed as necessary to obtain the target phenylphosphonate ester. However, in the production method of the present invention, the reaction solution after the step (A) is acidified in order to reduce the metal content of the obtained phenylphosphonate and the phenylphosphonate compound obtained by hydrolyzing it. It is preferable to include the step (B) of removing metal components derived from the supported catalyst by washing with an aqueous thiourea solution under certain conditions.
This step is a step of removing the metal component derived from the supported catalyst dissolved in the filtrate obtained by filtering the reaction solution after the reaction.
　具体的には、上記濾液（有機相）に、酸水溶液およびチオウレア水溶液（併せて「酸性チオウレア水溶液（水相）」という。）を加え、撹拌や分液操作等によって濾液を酸性チオウレア水溶液で洗浄した後、有機相と水相を分離する。
　この場合、酸水溶液に用いられる酸としては、塩酸、硫酸等の無機酸が好ましく、硫酸がより好ましい。酸の濃度に特に制限はないが、酸性チオウレア水溶液（水相）中、０．０１～５質量％程度が好ましく、０．０５～３質量％がより好ましく、０．１～２．８質量％がより一層好ましい。
　また、チオウレアの濃度にも特に制限はないが、酸性チオウレア水溶液（水相）中、１～１０質量％が好ましく、２～７質量％がより好ましく、２．５～６質量％がより一層好ましい。 Specifically, an acid aqueous solution and an aqueous thiourea solution (collectively referred to as an "acidic thiourea aqueous solution (aqueous phase)") are added to the above filtrate (organic phase), and the filtrate is washed with the acidic thiourea aqueous solution by stirring, liquid separation, or the like. After that, the organic and aqueous phases are separated.
In this case, the acid used in the aqueous acid solution is preferably an inorganic acid such as hydrochloric acid or sulfuric acid, more preferably sulfuric acid. Although the concentration of the acid is not particularly limited, it is preferably about 0.01 to 5% by mass, more preferably 0.05 to 3% by mass, and 0.1 to 2.8% by mass in the acidic thiourea aqueous solution (aqueous phase). is even more preferred.
The concentration of thiourea is also not particularly limited, but it is preferably 1 to 10% by mass, more preferably 2 to 7% by mass, and even more preferably 2.5 to 6% by mass in the acidic thiourea aqueous solution (aqueous phase). .
　洗浄時の温度は、０～８０℃程度とすることができるが、金属成分の除去効果をより高めるという点から、１５～７０℃が好ましく、２０～６０℃がより好ましい。
　なお、酸性チオウレア水溶液での洗浄は、１回のみ行っても、複数回行ってもよい。また、その後、必要に応じて水洗浄を行ってもよい。
　（Ｂ）工程での洗浄処理により、フェニルホスホン酸エステル中の金属成分の含有量を、例えば、１０ｐｐｍ未満まで低減することができる。 The temperature during washing can be about 0 to 80.degree. C., preferably 15 to 70.degree. C., more preferably 20 to 60.degree.
The washing with the acidic thiourea aqueous solution may be performed only once or may be performed multiple times. Moreover, you may wash with water after that as needed.
The washing treatment in the step (B) can reduce the content of metal components in the phenylphosphonate to, for example, less than 10 ppm.
　洗浄後は、溶媒を留去等の通常の後処理をして目的のフェニルホスホン酸エステルを単離すればよい。 After washing, the desired phenylphosphonate can be isolated by ordinary post-treatment such as distilling off the solvent.
［３］（Ｃ）工程
　（Ｃ）工程は、上記で得られたフェニルホスホン酸エステルを酸の水溶液中で加熱し、リン原子に結合したエステル基を加水分解し、フェニルホスホン酸へと導く工程である。この場合、フェニルホスホン酸エステルと、酸の水溶液との混合方法は任意であるが、酸の水溶液中に、フェニルホスホン酸エステルを添加する方法が好ましく、フェニルホスホン酸エステルを滴下する方法がより好ましい。 [3] Step (C) Step (C) is a step of heating the phenylphosphonate ester obtained above in an aqueous acid solution to hydrolyze the ester group bonded to the phosphorus atom, leading to phenylphosphonic acid. is. In this case, the method of mixing the phenylphosphonate with the aqueous acid solution is arbitrary, but the method of adding the phenylphosphonate to the aqueous solution of the acid is preferred, and the method of adding the phenylphosphonate dropwise is more preferred. .
　酸としては、パラトルエンスルホン酸、トリフルオロメタンスルホン酸等の有機酸；塩酸、硫酸等の無機酸を用いることができるが、加水分解反応の転化率という点から、塩酸、硫酸が好ましい。
　酸の使用量は、加水分解反応を効率的に進行させるという点から、フェニルホスホン酸エステルに対して過剰量が好ましく、５～２０当量がより好ましく、８～１８当量がより一層好ましい。
　反応温度に特に制限はないが、８０～１３０℃が好ましく、１００～１３０℃がより好ましい。
　反応時間にも特に制限はないが、１～４８時間が好ましく、１２～３６時間がより好ましい。
　反応終了後は、有機溶媒を用いた分液、洗浄、濃縮等の一般的な後処理をして酸を除去し、加水分解生成物（フェニルホスホン酸）を得ることができる。この有機溶媒としては、後述する（Ｄ）工程で用いる有機溶媒と同様のものを用いることができる。なお、分液に使用した有機溶媒を完全に留去しない溶液として、次の（Ｄ）工程に用いてもよい。 As the acid, organic acids such as p-toluenesulfonic acid and trifluoromethanesulfonic acid; and inorganic acids such as hydrochloric acid and sulfuric acid can be used. Hydrochloric acid and sulfuric acid are preferred from the viewpoint of the conversion rate of the hydrolysis reaction.
The amount of the acid to be used is preferably an excess amount, more preferably 5 to 20 equivalents, and even more preferably 8 to 18 equivalents, relative to the phenylphosphonic acid ester, from the viewpoint of allowing the hydrolysis reaction to proceed efficiently.
Although the reaction temperature is not particularly limited, it is preferably 80 to 130°C, more preferably 100 to 130°C.
The reaction time is also not particularly limited, but preferably 1 to 48 hours, more preferably 12 to 36 hours.
After completion of the reaction, general post-treatments such as liquid separation using an organic solvent, washing, concentration, etc. are performed to remove the acid, and a hydrolysis product (phenylphosphonic acid) can be obtained. As this organic solvent, the same organic solvent as used in the step (D), which will be described later, can be used. In addition, you may use for the following (D) process as a solution which does not distill off the organic solvent used for liquid separation completely.
［４］（Ｄ）工程
　（Ｄ）工程は、（Ｃ）工程で得られた加水分解生成物（フェニルホスホン酸）を有機溶媒中で晶析させる工程である。
　有機溶媒としては、フェニルホスホン酸が晶析可能な限り特に制限はないが、炭素数５～１０の炭化水素類、炭素数３～１０のケトン類から選ばれる少なくとも１種が好ましい。
　炭素数５～１０の炭化水素類としては、ｎ－ペンタン、ｎ－ヘキサン、シクロヘキサン、ｎ－ヘプタン、ｎ－オクタン、ｎ－ノナン、ｎ－デカン等の脂肪族または脂環式炭化水素類が挙げられる。これらの中でも、炭素数６～８の脂肪族炭化水素類が好ましく、ｎ－ヘキサン、ｎ－ヘプタンがより好ましい。
　炭素数３～１０のケトン類としては、アセトン、２－ブタノン、３－ペンタノン、２－ペンタノン、４－メチル－２－ペンタノン、３－ヘキサノン、４－ヘプタノン、２，６－ジメチル－４－ヘプタノン等が挙げられる。 [4] Step (D) Step (D) is a step of crystallizing the hydrolysis product (phenylphosphonic acid) obtained in step (C) in an organic solvent.
The organic solvent is not particularly limited as long as phenylphosphonic acid can be crystallized, but at least one selected from hydrocarbons having 5 to 10 carbon atoms and ketones having 3 to 10 carbon atoms is preferable.
Examples of hydrocarbons having 5 to 10 carbon atoms include aliphatic or alicyclic hydrocarbons such as n-pentane, n-hexane, cyclohexane, n-heptane, n-octane, n-nonane and n-decane. be done. Among these, aliphatic hydrocarbons having 6 to 8 carbon atoms are preferred, and n-hexane and n-heptane are more preferred.
Examples of ketones having 3 to 10 carbon atoms include acetone, 2-butanone, 3-pentanone, 2-pentanone, 4-methyl-2-pentanone, 3-hexanone, 4-heptanone and 2,6-dimethyl-4-heptanone. etc.
　有機溶媒の使用量は、フェニルホスホン酸が晶析する範囲であれば特に制限はないが、原料として用いたフェニルホスホン酸エステルに対し、２～１５０質量倍が好ましく、５～２０質量倍がより好ましく、７～１５質量倍がより一層好ましい。
　晶析の具体的な手法としては、加熱下でフェニルホスホン酸の有機溶媒溶液を調製した後、これを冷却後、晶析したフェニルホスホン酸を濾過する手法が挙げられる。
　この場合、加熱温度としては、５０～９０℃が好ましく、６０～８０℃がより好ましい。また、冷却温度としては、２０℃以下が好ましく、１０℃以下がより好ましく、５℃以下がより一層好ましい。
　なお、フェニルホスホン酸の有機溶媒溶液を調製する際に、必要に応じて、水やエタノール等のアルコール溶媒を少量添加してもよい。水を用いる場合、その使用量は、原料として用いたフェニルホスホン酸エステルに対し、０．０１～０．１質量倍が好ましく、アルコール溶媒を用いる場合、その使用量は、原料として用いたフェニルホスホン酸エステルに対し、０．０１～０．５質量倍が好ましい。
　晶析したフェニルホスホン酸は、濾取し、減圧下等で常温または加熱乾燥し、結晶として得ることができる。 The amount of the organic solvent used is not particularly limited as long as the phenylphosphonic acid crystallizes, but it is preferably 2 to 150 times by mass, more preferably 5 to 20 times by mass, the phenylphosphonic acid ester used as the raw material. Preferably, 7 to 15 times by mass is more preferable.
A specific method of crystallization includes a method of preparing a solution of phenylphosphonic acid in an organic solvent under heating, cooling the solution, and filtering the crystallized phenylphosphonic acid.
In this case, the heating temperature is preferably 50 to 90°C, more preferably 60 to 80°C. Also, the cooling temperature is preferably 20° C. or lower, more preferably 10° C. or lower, and even more preferably 5° C. or lower.
When preparing the organic solvent solution of phenylphosphonic acid, if necessary, a small amount of water or an alcoholic solvent such as ethanol may be added. When water is used, the amount used is preferably 0.01 to 0.1 times the weight of the phenylphosphonate used as a raw material, and when an alcohol solvent is used, the amount used is phenylphosphonate used as a raw material. It is preferably 0.01 to 0.5 times the weight of the acid ester.
Crystallized phenylphosphonic acid can be obtained as crystals by filtering and drying under reduced pressure or the like at room temperature or by heating.
　以下、実施例および比較例を挙げて、本発明をより具体的に説明するが、本発明は下記の実施例に限定されるものではない。 The present invention will be described in more detail below with reference to examples and comparative examples, but the present invention is not limited to the following examples.
　実施例で用いた試薬は、以下に示すように市販品を使用した。
オルトキシレン：純正化学（株）製（特級）
ノルマルヘプタン：関東化学（株）製（１級）
エタノール：関東化学（株）製（１級）
４－メチル－２－ペンタノン：純正化学（株）製（特級）
ヨードブロモベンゼン：東京化成工業（株）製
亜リン酸トリエチル：東京化成工業（株）製
５質量％パラジウム酸化アルミナ担持触媒：エボニックジャパン（株）製（品番：ＰＭＣ２１４００４）
９５％硫酸：純正化学（株）製（特級）
チオウレア：関東化学（株）製（特級）
塩化パラジウム：東京化成工業（株）製
５質量％パラジウム硫酸バリウム担持触媒：ジョンソンマッセイ製（品番：Ｔｙｐｅ　２９Ａ）
３５％塩酸：関東化学（株）製（特級）
トリフルオロメタンスルホン酸：東京化成工業（株）製
パラトルエンスルホン酸一水和物：富士フイルム和光純薬（株）製 As the reagents used in the examples, commercially available products were used as shown below.
Ortho-xylene: manufactured by Junsei Chemical Co., Ltd. (special grade)
Normal heptane: manufactured by Kanto Kagaku Co., Ltd. (first grade)
Ethanol: manufactured by Kanto Kagaku Co., Ltd. (first grade)
4-methyl-2-pentanone: manufactured by Junsei Chemical Co., Ltd. (special grade)
Iodobromobenzene: manufactured by Tokyo Chemical Industry Co., Ltd. Triethyl phosphite: manufactured by Tokyo Chemical Industry Co., Ltd. 5 mass% palladium oxide supported on alumina catalyst: manufactured by Evonik Japan Co., Ltd. (product number: PMC214004)
95% sulfuric acid: manufactured by Junsei Chemical Co., Ltd. (special grade)
Thiourea: manufactured by Kanto Kagaku Co., Ltd. (special grade)
Palladium chloride: Tokyo Chemical Industry Co., Ltd. 5 mass% palladium barium sulfate-supported catalyst: Johnson Matthey (product number: Type 29A)
35% hydrochloric acid: manufactured by Kanto Kagaku Co., Ltd. (special grade)
Trifluoromethanesulfonic acid: manufactured by Tokyo Chemical Industry Co., Ltd. Para-toluenesulfonic acid monohydrate: manufactured by FUJIFILM Wako Pure Chemical Industries, Ltd.
　実施例にて採用した分析手法および分析機器は以下のとおりである。
［１］ガスクロマトグラフィー（ＧＣ）
　実施例１～５および比較例１、２では、反応転化率と反応停止後の亜リン酸トリエチルの相対面積百分率(溶媒を除く)を算出するためにＧＣを使用した。
［反応転化率の測定方法］
　下記計算式より算出した。
４－ブロモフェニルホスホン酸ジエチル／（ヨードブロモベンゼン＋４－ブロモフェニルホスホン酸ジエチル）×１００（％）
［ＧＣ条件］
装置：ＧＣ－２０１０（（株）島津製作所製）
カラム：キャピラリーカラムＨＰ－１（３０ｍ×０．３２ｍｍΦ×０．２５μｍ）（アジレント・テクノロジー（株）製）
カラム温度：カラム温度は昇温プログラムを用いて制御した。開始温度５０℃で５分保持した後、１０℃／分で昇温して到達温度２５０℃とした。
インジェクション温度：２５０℃
検出器温度：２５０℃
全流量：６４．２ｍｌ／ｍｉｎ
スプリット比：１／２０
キャリヤーガス：ヘリウム
検出方法：ＦＩＤ法
打ち込み量：２μＬ
保持時間：ヨードブロモベンゼン１３．３分、４－ブロモフェニルホスホン酸ジエチル１９．１分
［２］プロトン核磁気共鳴法（1Ｈ－ＮＭＲ）
装置：ＪＮＭ－ＥＣＰ３００（日本電子（株）製）
測定溶媒：ＣＤＣｌ3またはＤ6－ＤＭＳＯ
［３］ＡＰＨＡ
装置：Ｔｒａｎｓｍｉｓｓｉｏｎ　ｃｏｌｏｒ　ｍｅｔｅｒ　ＴＺ　６０００（日本電色工業（株）製）
　有機層のＡＰＨＡの値と４－ブロモフェニルホスホン酸ジエチル中の残留Ｐｄに直線性があることを確認した（Ｒ2＝０．９９９）。４－ブロモフェニルホスホン酸ジエチル中の目標Ｐｄ量は＜１０ｐｐｍである。そこで、有機層のＡＰＨＡの値を用いてＰｄ含有量を評価した。有機層のＡＰＨＡ＜５０はＰｄ＜１０ｐｐｍに相当するため、有機層の目標ＡＰＨＡを＜５０とした。 The analytical methods and analytical instruments employed in the examples are as follows.
[1] Gas chromatography (GC)
In Examples 1-5 and Comparative Examples 1 and 2, GC was used to calculate the reaction conversion and the relative area percentage of triethyl phosphite after termination of the reaction (excluding the solvent).
[Method for measuring reaction conversion rate]
It was calculated from the following formula.
Diethyl 4-bromophenylphosphonate / (iodobromobenzene + diethyl 4-bromophenylphosphonate) × 100 (%)
[GC conditions]
Apparatus: GC-2010 (manufactured by Shimadzu Corporation)
Column: Capillary column HP-1 (30 m × 0.32 mm Φ × 0.25 μm) (manufactured by Agilent Technologies Inc.)
Column temperature: Column temperature was controlled using a temperature ramp program. After maintaining the starting temperature at 50°C for 5 minutes, the temperature was raised at a rate of 10°C/min to reach a final temperature of 250°C.
Injection temperature: 250°C
Detector temperature: 250°C
Total flow: 64.2ml/min
Split ratio: 1/20
Carrier gas: Helium Detection method: FID method Amount of injection: 2 μL
Retention time: iodobromobenzene 13.3 minutes, diethyl 4-bromophenylphosphonate 19.1 minutes [2] proton nuclear magnetic resonance spectroscopy ( 1 H-NMR)
Apparatus: JNM-ECP300 (manufactured by JEOL Ltd.)
Measurement solvent: CDCl 3 or D 6 -DMSO
[3] APHA
Apparatus: Transmission color meter TZ 6000 (manufactured by Nippon Denshoku Industries Co., Ltd.)
A linearity between the APHA value of the organic layer and the residual Pd in diethyl 4-bromophenylphosphonate was confirmed (R 2 =0.999). The target Pd level in diethyl 4-bromophenylphosphonate is <10 ppm. Therefore, the Pd content was evaluated using the APHA value of the organic layer. Since APHA<50 for the organic layer corresponds to Pd<10 ppm, the target APHA for the organic layer was set to <50.
Figure JPOXMLDOC01-appb-T000008
Figure JPOXMLDOC01-appb-T000008
［４］高速液体クロマトグラフィー（ＨＰＬＣ）
　実施例８～１２では、反応転化率と生成物の相対純度を算出するためにＨＰＬＣを使用した。
［反応転化率の測定方法］
　下記式より算出した。
［｛（４－ブロモフェニルホスホン酸×２）＋中間体｝／｛（４－ブロモフェニルホスホン酸＋中間体＋４－ブロモフェニルホスホン酸ジエチル）｝×２］×１００（％）
［ＨＰＬＣ条件］
装置：１２００シリーズ（アジレント・テクノロジー（株）製）
カラム：Ｉｎｅｒｔｓｉｌ　ＯＤＳ－３　（４．６×１５０ｍｍ、３μｍ）（ＧＬ　ｓｃｉｅｎｃｅｓ製）
オーブン温度：４０．０℃
展開溶媒：ＭｅＯＨ／りん酸緩衝液（ｐＨ＝２．１）＝５０／５０（容積比）から、５分かけて８０／２０へ組成を変え、１０分間保持した。
〔りん酸緩衝液（ｐＨ＝２．１）の調製法〕
　りん酸二水素ナトリウム（ＮａＨ2ＰＯ4・２Ｈ2Ｏ）７．８ｇ（５０ｍｍｏｌ）、８５％りん酸３．４ｍＬ（５０ｍｍｏｌ）に水を加え全量を１Ｌとした。
検出法：ＵＶ２１０ｎｍ
流速：０．７ｍＬ／分
打ち込み量：５μＬ
保持時間：４－ブロモフェニルホスホン酸５．２分、中間体８．１分、４－ブロモフェニルホスホン酸ジエチル９．４分 [4] High performance liquid chromatography (HPLC)
In Examples 8-12, HPLC was used to calculate reaction conversions and relative product purities.
[Method for measuring reaction conversion rate]
It was calculated from the following formula.
[{(4-bromophenylphosphonic acid × 2) + intermediate} / {(4-bromophenylphosphonic acid + intermediate + diethyl 4-bromophenylphosphonate)} × 2] × 100 (%)
[HPLC conditions]
Apparatus: 1200 series (manufactured by Agilent Technologies Inc.)
Column: Inertsil ODS-3 (4.6 × 150 mm, 3 μm) (manufactured by GL sciences)
Oven temperature: 40.0°C
Developing solvent: MeOH/phosphate buffer (pH=2.1)=50/50 (volume ratio) was changed to 80/20 over 5 minutes and held for 10 minutes.
[Method for preparing phosphate buffer (pH = 2.1)]
Water was added to 7.8 g (50 mmol) of sodium dihydrogen phosphate (NaH 2 PO 4 .2H 2 O) and 3.4 mL (50 mmol) of 85% phosphoric acid to bring the total amount to 1 L.
Detection method: UV210nm
Flow rate: 0.7 mL/min Injection amount: 5 μL
Retention times: 4-bromophenylphosphonic acid 5.2 min, intermediate 8.1 min, diethyl 4-bromophenylphosphonate 9.4 min.
［実施例１］４－ブロモフェニルホスホン酸ジエチルの合成
（１）Ａ工程
　１Ｌ反応容器に、亜リン酸トリエチル９９．８ｇ（０．６０ｍｏｌ）、オルトキシレン１５０ｇ、５質量％パラジウム酸化アルミナ担持触媒２．６３ｇ（１．２４ｍｍｏｌ、０．３５ｍｏｌ％）を窒素雰囲気下で仕込み、撹拌した。反応容器内の混合物を１２０～１２５℃まで加熱した後、オルトキシレン２５０ｇに溶解させたヨードブロモベンゼン１００ｇ（０．３５ｍoｌ）を５時間かけて滴下し、１２０～１２５℃で３時間反応させた。その後、３０℃まで冷却して濾過を行い、５％パラジウム酸化アルミナ担持触媒を除去し、４－ブロモフェニルホスホン酸ジエチルを含む反応液を得た。反応転化率を確認したところ、転化率は９９．９％であった。
（２）Ｂ工程
　（Ａ）工程で得られた４－ブロモフェニルホスホン酸ジエチルを含む反応液から、反応で副生するヨウ化エチルを減圧留去により除去した後に、濃縮後溶液重量が４００ｇとなるようオルトキシレンを添加した。その後、ヘプタン５０ｇ、０．１％硫酸水溶液５０ｇ、５％チオウレア水溶液１５０ｇを仕込み、５０～６０℃で１時間撹拌した。撹拌停止後、静置分離した。金属不純物を含む水層は廃棄し、得られた有機層に対して、０．１％硫酸水溶液５０ｇと５％チオウレア水溶液１５０ｇを仕込み同様の操作を繰り返して金属が低減した有機層（ＡＰＨＡ＜５０）を得た。得られた有機層をイオン交換水で洗浄した（２００ｇ×２、２０～３０℃）後、溶媒を減圧留去して、完全濃縮したところ、４－ブロモフェニルホスホン酸ジエチル９８．４ｇ（収率９５％、Ｐｄ＜１０ｐｐｍ）を得た。
1Ｈ－ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ3，δｐｐｍ)：７．６６（４Ｈ，ｍ），４．１１（４Ｈ，ｍ），１．３３（６Ｈ，ｔ） [Example 1] Synthesis of diethyl 4-bromophenylphosphonate (1) Step A In a 1 L reaction vessel, 99.8 g (0.60 mol) of triethyl phosphite, 150 g of ortho-xylene, 5% by mass of palladium oxide supported on alumina catalyst 2 0.63 g (1.24 mmol, 0.35 mol %) was charged and stirred under a nitrogen atmosphere. After heating the mixture in the reactor to 120-125° C., 100 g (0.35 mol) of iodobromobenzene dissolved in 250 g of ortho-xylene was added dropwise over 5 hours and reacted at 120-125° C. for 3 hours. Thereafter, the mixture was cooled to 30° C. and filtered to remove the 5% palladium oxide-alumina-supported catalyst to obtain a reaction liquid containing diethyl 4-bromophenylphosphonate. When the reaction conversion rate was confirmed, the conversion rate was 99.9%.
(2) Step B From the reaction solution containing diethyl 4-bromophenylphosphonate obtained in Step (A), ethyl iodide, a by-product of the reaction, was removed by distillation under reduced pressure. ortho-xylene was added to After that, 50 g of heptane, 50 g of 0.1% aqueous sulfuric acid solution, and 150 g of 5% aqueous thiourea solution were charged and stirred at 50 to 60° C. for 1 hour. After stopping the stirring, the mixture was allowed to stand and separated. The aqueous layer containing metal impurities was discarded, and 50 g of a 0.1% aqueous sulfuric acid solution and 150 g of a 5% thiourea aqueous solution were added to the obtained organic layer, and the same operation was repeated to obtain an organic layer with reduced metals (APHA<50 ). After the obtained organic layer was washed with ion-exchanged water (200 g×2, 20 to 30° C.), the solvent was distilled off under reduced pressure, and when completely concentrated, 98.4 g of diethyl 4-bromophenylphosphonate (yield 95%, Pd<10 ppm).
1 H-NMR (300 MHz, CDCl 3 , δppm): 7.66 (4H, m), 4.11 (4H, m), 1.33 (6H, t)
［実施例２］４－ブロモフェニルホスホン酸ジエチルの合成（Ａ工程）
　５０ｍＬ反応容器に、亜リン酸トリエチル８．８ｇ（５３．０ｍｍｏｌ）、ヨードブロモベンゼン１０．０ｇ（３５．３ｍｍｏｌ）、トルエン２０ｇ、５質量％パラジウム酸化アルミナ担持触媒０．２３ｇ（０．３ｍｏｌ％）を仕込み、窒素置換後、１２０℃まで昇温して反応させた。６時間後に反応転化率を確認したところ、転化率は９９．５％であった。 [Example 2] Synthesis of diethyl 4-bromophenylphosphonate (Step A)
8.8 g (53.0 mmol) of triethyl phosphite, 10.0 g (35.3 mmol) of iodobromobenzene, 20 g of toluene, and 0.23 g (0.3 mol %) of a 5% by mass palladium oxide supported catalyst on alumina were placed in a 50 mL reaction vessel. was charged, and after purging with nitrogen, the temperature was raised to 120° C. to react. When the reaction conversion rate was confirmed after 6 hours, the conversion rate was 99.5%.
［実施例３］４－ブロモフェニルホスホン酸ジエチルの合成（Ａ工程）
　１０ｍＬ反応容器に、亜リン酸トリエチル０．４４ｇ（２．６５ｍｍｏｌ）、ヨードブロモベンゼン０．５０ｇ（１．７７ｍｍｏｌ）、オルトキシレン１．０ｇ、５質量％パラジウム酸化アルミナ担持触媒２５ｍｇ（０．７ｍｏｌ％）を仕込み、窒素置換後、１３０℃まで昇温して反応させた。３時間後に反応転化率を確認したところ、転化率は１００％であった。 [Example 3] Synthesis of diethyl 4-bromophenylphosphonate (Step A)
In a 10 mL reaction vessel, 0.44 g (2.65 mmol) of triethyl phosphite, 0.50 g (1.77 mmol) of iodobromobenzene, 1.0 g of ortho-xylene, 25 mg (0.7 mol % of 5% by mass of palladium oxide-alumina-supported catalyst) were added. ) was charged, and after purging with nitrogen, the temperature was raised to 130° C. to react. When the reaction conversion rate was confirmed after 3 hours, the conversion rate was 100%.
［実施例４］４－ブロモフェニルホスホン酸ジエチルの合成（Ａ工程）
　５質量％パラジウム酸化アルミナ担持触媒を、５質量％パラジウム硫酸バリウム担持触媒へ変更した以外は、実施例３と同様の操作を行って反応させた。３時間後に反応転化率を確認したところ、転化率は１００％であった。 [Example 4] Synthesis of diethyl 4-bromophenylphosphonate (Step A)
A reaction was carried out in the same manner as in Example 3, except that the 5% by mass palladium oxide-supported alumina catalyst was changed to a 5% by mass palladium barium sulfate-supported catalyst. When the reaction conversion rate was confirmed after 3 hours, the conversion rate was 100%.
［実施例５］４－ブロモフェニルホスホン酸ジエチルの合成（Ａ工程）
　触媒仕込み量を０．３５ｍｏｌ％から０．２ｍｏｌ％へ亜リン酸トリエチル仕込み量を１．７当量から２．０当量へ変更し、反応中に窒素フローする以外は実施例１と同様の操作で反応させた。１１時間後に反応転化率を確認したところ、転化率は１００％であった。
　なお、窒素フローは、不純物の生成原因となるヨウ化エチルを系外へ積極的に除去するために行った。 [Example 5] Synthesis of diethyl 4-bromophenylphosphonate (Step A)
The same procedure as in Example 1 was carried out, except that the amount of catalyst charged was changed from 0.35 mol% to 0.2 mol%, the amount of triethyl phosphite charged was changed from 1.7 equivalents to 2.0 equivalents, and nitrogen was flowed during the reaction. reacted. When the reaction conversion rate was confirmed after 11 hours, the conversion rate was 100%.
The nitrogen flow was performed to positively remove ethyl iodide, which is a cause of generation of impurities, out of the system.
［比較例１］４－ブロモフェニルホスホン酸ジエチルの合成（Ａ工程相当）
　３０ｍＬ反応容器に、亜リン酸トリエチル４．４０ｇ（２６．５ｍｍｏｌ）、ヨードブロモベンゼン５．０ｇ（１７．７ｍｍｏｌ）、トルエン１０．０ｇ、塩化パラジウム３１ｍｇ（１．０ｍｏｌ％）を仕込み、窒素置換後、１２０℃まで昇温して反応させた。６時間後に反応転化率を確認したところ、転化率は１０％であった。 [Comparative Example 1] Synthesis of diethyl 4-bromophenylphosphonate (corresponding to step A)
A 30 mL reaction vessel was charged with 4.40 g (26.5 mmol) of triethyl phosphite, 5.0 g (17.7 mmol) of iodobromobenzene, 10.0 g of toluene, and 31 mg (1.0 mol%) of palladium chloride. , and the temperature was raised to 120° C. to react. When the reaction conversion rate was confirmed after 6 hours, the conversion rate was 10%.
［比較例２］４－ブロモフェニルホスホン酸ジエチルの合成（Ａ工程相当）
　反応温度を１２０℃から１３０℃へ、反応溶媒をトルエンからオルトキシレンへ変更した以外は、比較例１と同様の操作で反応させた。６時間後に反応転化率を確認したところ、転化率は８４．３％であった。 [Comparative Example 2] Synthesis of diethyl 4-bromophenylphosphonate (corresponding to step A)
The reaction was carried out in the same manner as in Comparative Example 1, except that the reaction temperature was changed from 120° C. to 130° C. and the reaction solvent was changed from toluene to ortho-xylene. When the reaction conversion rate was confirmed after 6 hours, the conversion rate was 84.3%.
　上記実施例１～５および比較例１，２のＡ工程のまとめを表２に示す。 A summary of the A step of Examples 1 to 5 and Comparative Examples 1 and 2 is shown in Table 2.
Figure JPOXMLDOC01-appb-T000009
Figure JPOXMLDOC01-appb-T000009
［実施例６］４－ブロモフェニルホスホン酸ジエチルの合成
　Ｂ工程において、０．１％硫酸水溶液を０．２％塩酸へ変更した以外は、実施例１と同様の操作を行った。得られた有機層のＡＰＨＡは＜５０であった。 [Example 6] Synthesis of diethyl 4-bromophenylphosphonate The same operation as in Example 1 was performed, except that in step B, the 0.1% sulfuric acid aqueous solution was changed to 0.2% hydrochloric acid. The APHA of the resulting organic layer was <50.
［実施例７］４－ブロモフェニルホスホン酸ジエチルの合成
　Ｂ工程において、撹拌温度を５０～６０℃から２０～３０℃へ変更した以外は、実施例１と同様の操作を行った。得られた有機層のＡＰＨＡは＜５０であった。 [Example 7] Synthesis of diethyl 4-bromophenylphosphonate In step B, the same operation as in Example 1 was performed, except that the stirring temperature was changed from 50 to 60°C to 20 to 30°C. The APHA of the resulting organic layer was <50.
［比較例３］４－ブロモフェニルホスホン酸ジエチルの合成
　Ｂ工程において、硫酸存在下チオウレア水溶液による洗浄を２回行う代わりに、４５～５０℃でヘプタン５０ｇおよびイオン交換水１００ｇによる洗浄を行った後、２０～３０℃で５％チオウレア水溶液１５０ｇによる洗浄を行い、さらに２０～３０℃で２．５％硫酸水溶液１５０ｇによる洗浄を行う以外は、実施例１と同様の操作を行った。得られた有機層のＡＰＨＡは１３１であった。 [Comparative Example 3] Synthesis of diethyl 4-bromophenylphosphonate In step B, instead of washing twice with an aqueous thiourea solution in the presence of sulfuric acid, after washing with 50 g of heptane and 100 g of ion-exchanged water at 45 to 50°C. , 150 g of a 5% aqueous thiourea solution at 20 to 30°C, and further washing with 150 g of a 2.5% aqueous sulfuric acid solution at 20 to 30°C. The APHA of the obtained organic layer was 131.
　上記実施例１，６，７および比較例３のＢ工程のまとめを表３に示す。 A summary of the B step of Examples 1, 6, 7 and Comparative Example 3 is shown in Table 3.
Figure JPOXMLDOC01-appb-T000010
Figure JPOXMLDOC01-appb-T000010
［実施例８］４－ブロモフェニルホスホン酸の合成
（３）Ｃ工程
　５００ｍＬ反応容器に、イオン交換水１２５ｇ、９５％硫酸１３２．１ｇ（１．２８ｍｏｌ）を仕込み、撹拌した。容器内の混合物を１０５～１１５℃まで加熱した後、実施例１で得られた４－ブロモフェニルホスホン酸ジエチル２５．０ｇ（０．０８５ｍｏｌ）を３０分かけて滴下した。１０５～１１５℃で２４時間加水分解反応を実施し、４－ブロモフェニルホスホン酸を含む反応溶液を得た。反応転化率を確認したところ、転化率は１００％であった。
（４）Ｄ工程
　（Ｃ）工程で得られた反応液を６０～６５℃まで冷却し、４－メチル－２－ペンタノン７５ｇを仕込み、６０～６５℃で３０分撹拌した。撹拌停止後、静置分離し、得られた水層に対して、同様の操作を実施した。得られた有機層を混合し、イオン交換水で洗浄した（３７．５ｇ×３、６０～６５℃）。洗浄した有機層から減圧留去により４－メチル－２－ペンタノンを７５ｇ除去し、４－ブロモフェニルホスホン酸が析出することを確認した。留去後溶液にイオン交換水１．５ｇ、エタノール２．５ｇ添加し、反応容器内の混合物を６５～７０℃まで昇温し、均一溶液とした。その後、ヘプタン１５０ｇを内温維持しながら１時間かけて滴下したのちに、０～５℃まで冷却し、４－ブロモフェニルホスホン酸を析出させ、濾過した。得られた湿品を８０℃で減圧乾燥を行い、４－ブロモフェニルホスホン酸の結晶１６．８ｇ（収率８３％、ＨＰＬＣ相対純度９９．５％）を得た。
1Ｈ－ＮＭＲ（３００ＭＨｚ，Ｄ6－ＤＭＳＯ，δｐｐｍ)：７．６３（４Ｈ，ｍ） [Example 8] Synthesis of 4-bromophenylphosphonic acid (3) Step C In a 500 mL reaction vessel, 125 g of ion-exchanged water and 132.1 g (1.28 mol) of 95% sulfuric acid were charged and stirred. After heating the mixture in the container to 105 to 115° C., 25.0 g (0.085 mol) of diethyl 4-bromophenylphosphonate obtained in Example 1 was added dropwise over 30 minutes. A hydrolysis reaction was carried out at 105-115° C. for 24 hours to obtain a reaction solution containing 4-bromophenylphosphonic acid. When the reaction conversion rate was confirmed, the conversion rate was 100%.
(4) Step D The reaction solution obtained in Step (C) was cooled to 60-65°C, charged with 75 g of 4-methyl-2-pentanone, and stirred at 60-65°C for 30 minutes. After stirring was stopped, the same operation was performed on the aqueous layer obtained by standing and separating. The obtained organic layers were mixed and washed with ion-exchanged water (37.5 g×3, 60-65° C.). It was confirmed that 75 g of 4-methyl-2-pentanone was removed from the washed organic layer by distillation under reduced pressure, and 4-bromophenylphosphonic acid was precipitated. After distillation, 1.5 g of ion-exchanged water and 2.5 g of ethanol were added to the solution, and the temperature of the mixture in the reaction vessel was raised to 65-70° C. to obtain a homogeneous solution. Thereafter, 150 g of heptane was added dropwise over 1 hour while maintaining the internal temperature, and then cooled to 0 to 5° C. to precipitate 4-bromophenylphosphonic acid and filtered. The resulting wet product was dried under reduced pressure at 80° C. to obtain 16.8 g of 4-bromophenylphosphonic acid crystals (yield 83%, HPLC relative purity 99.5%).
1 H-NMR (300 MHz, D 6 -DMSO, δppm): 7.63 (4H, m)
［実施例９］４－ブロモフェニルホスホン酸の合成（Ｃ工程）
　１０ｍＬ反応容器に、イオン交換水１．８ｇ、９５％硫酸０．８０ｇ（７．７ｍｍｏｌ）、実施例１で得た４－ブロモフェニルホスホン酸ジエチル０．３０ｇ（１．０３ｍｍｏｌ）を仕込み、撹拌した。反応容器内の混合物を外温１２５℃まで加熱し、２４時間反応させた。２４時間後に反応転化率を確認したところ、転化率は８２％であった。 [Example 9] Synthesis of 4-bromophenylphosphonic acid (step C)
A 10 mL reaction vessel was charged with 1.8 g of ion-exchanged water, 0.80 g (7.7 mmol) of 95% sulfuric acid, and 0.30 g (1.03 mmol) of diethyl 4-bromophenylphosphonate obtained in Example 1, and stirred. . The mixture in the reaction vessel was heated to an external temperature of 125° C. and reacted for 24 hours. When the reaction conversion rate was confirmed after 24 hours, the conversion rate was 82%.
［実施例１０］４－ブロモフェニルホスホン酸の合成（Ｃ工程）
　９５％硫酸を３５％塩酸へ変更した以外は、実施例９と同様の操作で反応を行った。２４時間後に反応転化率を確認したところ、転化率は９４％であった。 [Example 10] Synthesis of 4-bromophenylphosphonic acid (Step C)
A reaction was carried out in the same manner as in Example 9, except that 95% sulfuric acid was changed to 35% hydrochloric acid. When the reaction conversion rate was confirmed after 24 hours, the conversion rate was 94%.
［実施例１１］４－ブロモフェニルホスホン酸の合成（Ｃ工程）
　９５％硫酸をトリフルオロメタンスルホン酸１．２３ｇ（８．２ｍｍｏｌ）へ変更した以外は、実施例９と同様の操作で反応を実施した。２４時間後に反応転化率を確認したところ、転化率は７６％であった。 [Example 11] Synthesis of 4-bromophenylphosphonic acid (Step C)
A reaction was carried out in the same manner as in Example 9, except that 1.23 g (8.2 mmol) of trifluoromethanesulfonic acid was used instead of 95% sulfuric acid. When the reaction conversion rate was confirmed after 24 hours, the conversion rate was 76%.
［実施例１２］４－ブロモフェニルホスホン酸の合成（Ｃ工程）
　９５％硫酸をパラトルエンスルホン酸一水和物１．５６ｇ（８．２ｍｍｏｌ）へ変更した以外は、実施例９と同様の操作で反応を実施した。２４時間後に反応転化率を確認したところ、転化率は７１％であった。 [Example 12] Synthesis of 4-bromophenylphosphonic acid (Step C)
A reaction was carried out in the same manner as in Example 9, except that 95% sulfuric acid was changed to 1.56 g (8.2 mmol) of p-toluenesulfonic acid monohydrate. When the reaction conversion rate was confirmed after 24 hours, the conversion rate was 71%.
　上記実施例８～１２のＣ工程のまとめを表４に示す。 Table 4 shows a summary of Step C in Examples 8 to 12 above.
Figure JPOXMLDOC01-appb-T000011
Figure JPOXMLDOC01-appb-T000011

Claims (14)

  1. 　式（１）
    Figure JPOXMLDOC01-appb-C000001
     （式中、ＸおよびＹは、それぞれ異なるハロゲン原子を表す。）
    で表されるジハロゲン化芳香族化合物と、
    　式（２）
    Figure JPOXMLDOC01-appb-C000002
     （式中、Ｒは、それぞれ独立して炭素数１～３のアルキル基を表す。）
    で表される亜リン酸トリエステルとを、有機溶媒中、０価の金属が担体に担持された担持触媒の存在下で反応させる（Ａ）工程を備えることを特徴とする式（３）
    Figure JPOXMLDOC01-appb-C000003
     （式中、ＸおよびＲは、前記と同じ意味を表す。）
    で表されるフェニルホスホン酸エステルの製造方法。     formula (1)
    Figure JPOXMLDOC01-appb-C000001
     (Wherein, X and Y each represent a different halogen atom.)
    A dihalogenated aromatic compound represented by
    formula (2)
    Figure JPOXMLDOC01-appb-C000002
     (In the formula, each R independently represents an alkyl group having 1 to 3 carbon atoms.)
    and a phosphite triester represented by the formula (3), which comprises a step (A) of reacting in an organic solvent in the presence of a supported catalyst in which a zero-valent metal is supported on a support.
    Figure JPOXMLDOC01-appb-C000003
     (Wherein, X and R have the same meanings as above.)
    A method for producing a phenylphosphonate ester represented by
  2. 　前記担持触媒が、式（１）で表されるジハロゲン化芳香族化合物に対して、金属量として０．１～１．０ｍｏｌ％用いられる請求項１記載のフェニルホスホン酸エステルの製造方法。 The method for producing a phenylphosphonate ester according to claim 1, wherein the supported catalyst is used in an amount of 0.1 to 1.0 mol% as a metal with respect to the dihalogenated aromatic compound represented by formula (1).
  3. 　前記金属が、周期表第１０族元素である請求項１記載のフェニルホスホン酸エステルの製造方法。 The method for producing a phenylphosphonate ester according to claim 1, wherein the metal is an element of Group 10 of the periodic table.
  4. 　前記金属が、パラジウムである請求項３記載のフェニルホスホン酸エステルの製造方法。 The method for producing a phenylphosphonate according to claim 3, wherein the metal is palladium.
  5. 　前記担体が、アルカリ土類金属塩および金属酸化物から選ばれる少なくとも１種である請求項１記載のフェニルホスホン酸エステルの製造方法。 The method for producing a phenylphosphonate according to claim 1, wherein the carrier is at least one selected from alkaline earth metal salts and metal oxides.
  6. 　前記担体が、金属酸化物である請求項５記載のフェニルホスホン酸エステルの製造方法。 The method for producing a phenylphosphonate according to claim 5, wherein the carrier is a metal oxide.
  7. 　前記金属酸化物が、酸化アルミニウムである請求項６記載のフェニルホスホン酸エステルの製造方法。 The method for producing a phenylphosphonate according to claim 6, wherein the metal oxide is aluminum oxide.
  8. 　前記反応が、１００～１５０℃で行われる請求項１記載のフェニルホスホン酸エステルの製造方法。 The method for producing a phenylphosphonate ester according to claim 1, wherein the reaction is carried out at 100 to 150°C.
  9. 　前記Ｘが、臭素原子であり、前記Ｙが、ヨウ素原子である請求項１記載のフェニルホスホン酸エステルの製造方法。 The method for producing a phenylphosphonate according to claim 1, wherein said X is a bromine atom and said Y is an iodine atom.
  10. 　前記Ｒが、エチル基である請求項１記載のフェニルホスホン酸エステルの製造方法。 The method for producing a phenylphosphonate ester according to claim 1, wherein said R is an ethyl group.
  11. 　前記（Ａ）工程後の反応液を、酸性条件下、チオウレア水溶液で洗浄し、担持触媒由来の金属成分を除去する（Ｂ）工程を備える請求項１記載のフェニルホスホン酸エステルの製造方法。 The method for producing a phenylphosphonate ester according to claim 1, comprising the step (B) of washing the reaction solution after the step (A) with an aqueous thiourea solution under acidic conditions to remove metal components derived from the supported catalyst.
  12. 　請求項１１記載の製造方法で得られたフェニルホスホン酸エステルを、酸の水溶液中で加熱し、リン原子に結合したエステル基を加水分解する（Ｃ）工程、および
    　前記（Ｃ）工程後、加水分解生成物を有機溶媒中で晶析させる（Ｄ）工程を備えるフェニルホスホン酸化合物の製造方法。     (C) step of heating the phenylphosphonate obtained by the production method according to claim 11 in an aqueous acid solution to hydrolyze the ester group bonded to the phosphorus atom; A method for producing a phenylphosphonic acid compound, comprising the step (D) of crystallizing a decomposition product in an organic solvent.
  13. 　前記酸が、塩酸および硫酸から選ばれる少なくとも１種である請求項１２記載のフェニルホスホン酸化合物の製造方法。 The method for producing a phenylphosphonic acid compound according to claim 12, wherein the acid is at least one selected from hydrochloric acid and sulfuric acid.
  14. 　前記（Ｄ）工程で用いる有機溶媒が、炭素数５～１０の炭化水素類、炭素数３～１０のケトン類から選ばれる少なくとも１種である請求項１２または１３記載のフェニルホスホン酸化合物の製造方法。 The production of the phenylphosphonic acid compound according to claim 12 or 13, wherein the organic solvent used in step (D) is at least one selected from hydrocarbons having 5 to 10 carbon atoms and ketones having 3 to 10 carbon atoms. Method.
PCT/JP2023/004878 2022-02-17 2023-02-14 Method for producing phenyl phosphonic acid ester and phenyl phosphonic acid compound WO2023157814A1 (en)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3705214A (en) * 1970-04-15 1972-12-05 Stauffer Chemical Co Catalyzed process for producing pentavalent phosphorus derivatives
JPH11193292A (en) * 1997-01-28 1999-07-21 Nissan Chem Ind Ltd Phenylphosphonic acid derivative and its production
JPH11279185A (en) * 1997-12-25 1999-10-12 Nissan Chem Ind Ltd Bis(trifluoromethyl)phenylphosphonic acid compound and its production
WO2004022714A2 (en) * 2002-09-05 2004-03-18 Nanosys, Inc. Organic species that facilitate charge transfer to or from nanostructures
WO2005083131A1 (en) * 2004-02-27 2005-09-09 National Institute Of Advanced Industrial Science And Technology Extractants for palladium and process for separation and recovery of palladium

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3705214A (en) * 1970-04-15 1972-12-05 Stauffer Chemical Co Catalyzed process for producing pentavalent phosphorus derivatives
JPH11193292A (en) * 1997-01-28 1999-07-21 Nissan Chem Ind Ltd Phenylphosphonic acid derivative and its production
JPH11279185A (en) * 1997-12-25 1999-10-12 Nissan Chem Ind Ltd Bis(trifluoromethyl)phenylphosphonic acid compound and its production
WO2004022714A2 (en) * 2002-09-05 2004-03-18 Nanosys, Inc. Organic species that facilitate charge transfer to or from nanostructures
WO2005083131A1 (en) * 2004-02-27 2005-09-09 National Institute Of Advanced Industrial Science And Technology Extractants for palladium and process for separation and recovery of palladium

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