WO2021261393A1 - Method for producing tetrahydrofuran-2-carboxylic acid - Google Patents

Method for producing tetrahydrofuran-2-carboxylic acid Download PDF

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WO2021261393A1
WO2021261393A1 PCT/JP2021/023192 JP2021023192W WO2021261393A1 WO 2021261393 A1 WO2021261393 A1 WO 2021261393A1 JP 2021023192 W JP2021023192 W JP 2021023192W WO 2021261393 A1 WO2021261393 A1 WO 2021261393A1
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carboxylic acid
tetrahydrofuran
furan
producing
reaction
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PCT/JP2021/023192
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French (fr)
Japanese (ja)
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清二 森井
いづみ 西川
悠文 平賀
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東レ・ファインケミカル株式会社
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Priority to CN202180041339.4A priority Critical patent/CN115697982A/en
Priority to JP2021538422A priority patent/JPWO2021261393A1/ja
Publication of WO2021261393A1 publication Critical patent/WO2021261393A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B61/00—Other general methods
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

Definitions

  • the present invention relates to a method for producing a tetrahydrofuran-2-carboxylic acid, which is important as a raw material for pharmaceutical intermediates.
  • Tetrahydrofuran-2-carboxylic acid is known as an industrially useful compound such as pharmaceuticals.
  • a method for producing a tetrahydrofuran-2-carboxylic acid for example, (1) A method for producing a tetrahydrofuran-2-carboxylic acid by a catalytic hydrogenation reaction in water containing furan-2-carboxylic acid in the presence of lane nickel and sodium hydroxide as an additive (see Patent Documents 1 and 2).
  • the method for producing a tetrahydrofuran-2-carboxylic acid by a catalytic hydrogenation reaction in water containing sodium hydroxide as an additive in the presence of Raney nickel from the furan-2-carboxylic acid of (1) above can be easily dried. Uses Raney nickel, which may ignite. Furthermore, the condition of high pressure (80 kg / cm 2 or more) and high temperature (120 ° C or more) is required, and the neutralization step is used for the post-treatment when the product is isolated by using sodium hydroxide as an additive. It has a problem as an industrial manufacturing method because it is necessary and complicated.
  • the furan-2-carboxylic acid of (2) above is subjected to a catalytic hydrogenation reaction in the presence of ruthenium nanoparticles and polyEPG- ⁇ -CD in a mixed solvent of water and ethyl acetate to produce a tetrahydrofuran-2-carboxylic acid.
  • the method is industrially advantageous because it uses special and expensive ruthenium nanoparticles and polyEPG- ⁇ -CD as a catalyst and 90 times by weight of water / ethyl acetate mixed solvent as a solvent. It is not a manufacturing method.
  • a method for producing a tetrahydrofuran-2-carboxylic acid by a catalytic hydrogenation reaction in the presence of palladium or palladium-nickel in which the furan-2-carboxylic acid of the above (3) is supported on ⁇ -Al 2 O 3 is described.
  • the alumina-supported metal catalyst to be used is prepared by the impregnation method, the chloride ion existing in the system and the metal are strongly bonded during the preparation process, and the presence of this chloride ion affects the catalytic hydrogenation reaction.
  • it is not an industrially advantageous manufacturing method because it requires conditions of high pressure (1 MPa or more) and high temperature (150 ° C. or higher).
  • the method for producing 2-methoxycarbonyltetrahydrofuran by catalytic hydrogenation reaction in the presence of the hydrogen storage alloy CaNi 5 in which hydrogen is stored in advance in the above (4) 2-methoxycarbonylfuran is a special and expensive hydrogen storage alloy as a catalyst. Since CaNi 5 is used and high temperature (150 ° C.) conditions are required, there is an industrial problem.
  • An object of the present invention is to provide an industrially suitable method for producing a tetrahydrofuran-2-carboxylic acid, which is important as a raw material for pharmaceuticals.
  • the present inventors have found the present invention as a result of repeated diligent studies in order to solve the above-mentioned problems. That is, in the present invention, in the presence of a palladium carbon catalyst, a base of 0 to 0.5 mol times is added to 1 mol of furan-2-carboxylic acid to obtain furan-2-carboxylic acid in an aqueous solvent.
  • This is a method for producing a tetrahydrofuran-2-carboxylic acid, which produces a tetrahydrofuran-2-carboxylic acid by a catalytic hydrogenation reaction of hydrogen at 100 ° C. or lower.
  • tetrahydrofuran-2-carboxylic acid When tetrahydrofuran-2-carboxylic acid is used as a pharmaceutical raw material, it is strongly required to have high purity. INDUSTRIAL APPLICABILITY According to the present invention, high-purity tetrahydrofuran-2-carboxylic acid can be produced by an industrially suitable method.
  • the catalytic hydrogenation reaction is carried out without using a base such as sodium hydroxide as an additive or by using only a small amount, so that after the reaction is completed.
  • Tetrahydrofuran-2-carboxylic acid can be produced by a simple operation without the need to add a neutralization step to the post-treatment.
  • furan-2-carboxylic acid is added to 1 mol of furan-2-carboxylic acid in an aqueous solvent in the presence of a palladium carbon catalyst, and a base of 0 to 0.5 mol times is added to contact hydrogen. Carry out the chemical reaction.
  • the catalytic hydrogenation reaction is carried out in an aqueous solvent.
  • the water solvent means water or a mixed solvent containing water.
  • various solvents can be used as components other than water.
  • aprotonic polar solvents such as N, N-dimethylformamide and acetonitrile having high solubility of furan-2-carboxylic acid
  • alcohol solvents such as methanol, ethanol and isopropanol
  • ether solvents such as tetrahydrofuran
  • ester solvents such as ethyl acetate.
  • the aqueous solvent is preferably water.
  • the solubility of furan-2-carboxylic acid in water is 12 g with respect to 100 g of water at 40 ° C. and 160 g with respect to 100 g of water at 70 ° C.
  • the catalytic hydrogenation reaction proceeds even if the furan-2-carboxylic acid is not completely dissolved in water.
  • the amount of the aqueous solvent used is preferably 0.5 to 5 times by weight, more preferably 0.5 to 3 times by weight, still more preferably 1 to 2 times by weight, based on the furan-2-carboxylic acid. It is double. The smaller the amount of water used, the easier it is to isolate the reactant tetrahydrofuran-2-carboxylic acid and the higher the productivity.
  • furan-2-carboxylic acid is added in an aqueous solvent in the presence of a palladium carbon catalyst, and a base of 0 to 0.5 mol times is added to 1 mol of furan-2-carboxylic acid.
  • the amount of the base used is preferably 0 to 0.2 mol times, more preferably 0 to 0.1 mol times, with respect to 1 mol of furan-2-carboxylic acid.
  • a base such as sodium hydroxide can be added arbitrarily and may not be added.
  • a base is added more than 0.5 mol times with respect to 1 mol of furan-2-carboxylic acid, the furan-2-carboxylic acid is dissolved in water as a salt, but the catalytic hydrogenation reaction is significantly slowed down.
  • the productivity is lowered.
  • a palladium carbon catalyst is used.
  • a palladium-carbon catalyst in which palladium is supported on carbon is preferable because the surface area of palladium is high and the catalytic activity does not decrease with time.
  • the palladium carbon catalyst may be separated and recovered by precipitating or filtering the palladium carbon catalyst from the reaction solution. In the production method of the present invention, the recovered palladium carbon catalyst is preferably used again.
  • the amount of the palladium carbon catalyst used in the production method of the present invention is preferably 0.0001 to 0.0025 times by weight, more preferably furan, with respect to furan-2-carboxylic acid in terms of metal. It is 0.0002 to 0.00125 times by weight with respect to -2-carboxylic acid, and more preferably 0.0002 to 0.001 times by weight with respect to furan-2-carboxylic acid.
  • 1 MPa is capable of pressurizing reaction using a first-class pressure vessel, which is a relatively simple facility. At the following pressures, the catalytic hydrogenation reaction can be completed in a few hours.
  • a large amount of expensive metal is used, which is economically unfavorable as a manufacturing process.
  • the temperature of the catalytic hydrogenation reaction is 100 ° C. or lower.
  • the reaction temperature is 100 ° C. or lower, the reaction is quick and the purity of the tetrahydrofuran-2-carboxylic acid can be increased.
  • the reaction temperature is preferably 40 to 100 ° C, more preferably 50 to 70 ° C.
  • the hydrogen pressure is preferably 0.8 MPa or less.
  • the reaction time can be shortened, but the reaction heat makes it difficult to control the reaction temperature, and impurities may increase, resulting in a decrease in the purity of the tetrahydrofuran-2-carboxylic acid.
  • the hydrogen pressure is low, the reaction time becomes long, so that the hydrogen pressure is more preferably 0.2 to 0.8 MPa, still more preferably 0.3 to 0.6 MPa.
  • the palladium carbon catalyst used is separated by filtration, and then water is distilled off under reduced pressure to obtain the desired tetrahydrofuran-2-carboxylic acid.
  • a tetrahydrofuran-2-carboxylic acid having a chemical purity of 99.0 area% or more can be produced. Further, in the method for producing a tetrahydrofuran-2-carboxylic acid of the present invention, it is possible to preferably produce a tetrahydrofuran-2-carboxylic acid having a chemical purity of 99.3 area% or more.
  • the chemical purity (area%) of the tetrahydrofuran-2-carboxylic acid can be measured by the gas chromatography (GC) analysis described in the Examples below.
  • Example 1 To a 30 mL SUS pressure resistant reaction vessel equipped with a thermometer and a stirrer, add 1.12 g (0.01 mol) of furan-2-carboxylic acid, and further add 1.68 g of water (1 to furan-2-carboxylic acid). (5.5 times by weight), 0.01 g of 5% palladium carbon (50% WET product) (0.01% by weight with respect to furan-2-carboxylic acid) was added as a catalyst. After the inside of the reaction vessel was replaced with hydrogen, the pressure was increased until the hydrogen pressure reached 0.4 MPa, and then the hydrogen pressure was adjusted to 0.2 to 0.4 MPa until the reaction was completed.
  • 50% WET product 50% WET product
  • the temperature of the reaction vessel was raised in a water bath, and the internal temperature was adjusted to around 60 ° C. It took 6 hours for the absorption of hydrogen to subside.
  • the mixture was aged at a hydrogen pressure of 0.4 MPa and around 60 ° C. for 2 hours. Then, after returning to normal pressure at around 20 ° C. and filtering off the catalyst, the obtained aqueous solution was 1.16 g of tetrahydrofuran-2-carboxylic acid (chemical purity: 99.9 area%, yield: 100 mol). %) Was included.
  • 5% palladium carbon 50% WET product
  • 5% Pd carbon powder (hydrous product) STD type of NE Chemcat Co., Ltd. was used.
  • the quality standard of Pd carbon powder (moisture-containing product) STD type is that the noble metal content (Dry base) is 5.00 ⁇ 0.05% and the water content is 55.00 ⁇ 5.00%.
  • Example 2 To a 3500 L SUS pressure resistant reaction vessel equipped with a thermometer and a stirrer, 500 kg (4.46 kilomol) of furan-2-carboxylic acid was added, and further 500 kg of water (1.0 weight times as much as that of furan-2-carboxylic acid) was added. ), 5 kg of 5% palladium carbon (50% WET product) (0.01 weight times as much as furan-2-carboxylic acid) was added as a catalyst. The pressure in the system was pressurized with hydrogen until the pressure in the system became 0.4 MPa in the reaction vessel substituted with nitrogen, and then the hydrogen pressure was adjusted so as to be around 0.4 MPa until the reaction was completed.
  • Example 2 The same 5% palladium carbon (50% WET product) as in Example 1 was used. After pressurization, the temperature of the reaction vessel was raised in a water bath, and the internal temperature was adjusted to around 60 ° C. It took 6 hours for the absorption of hydrogen to subside. After completion of the reaction, the mixture was aged at a hydrogen pressure of 0.4 MPa and around 60 ° C. for 2 hours. Then, after returning to normal pressure at around 20 ° C. and filtering off the catalyst, the obtained aqueous solution was 511 kg of tetrahydrofuran-2-carboxylic acid (chemical purity: 99.3 area%, yield: 99 mol%). Included.
  • Example 3 The operation was carried out in the same manner as in Example 1 except that 0.04 g of sodium hydroxide (0.1 mol times as much as that of furan-2-carboxylic acid) was added as an additive. After returning to normal pressure at around 20 ° C. and filtering off the catalyst, the obtained aqueous solution was 1.16 g of tetrahydrofuran-2-carboxylic acid (chemical purity: 99.8 area%, yield: 100 mol%). Included.
  • Comparative Example 1 5.6 g of water (5.0 times by weight with respect to furan-2-carboxylic acid), 0.06 g of 5% ruthenium carbon (50% WET product) as a catalyst (0.05 weight with respect to furan-2-carboxylic acid) The operation was carried out in the same manner as in Example 1 except that the reaction time including the aging time was set to 6 hours. The production status of tetrahydrofuran-2-carboxylic acid by changing the reaction conditions was compared and examined. The results are shown in Table 1.
  • Comparative Example 2 5.6 g of water (5.0 times by weight with respect to furan-2-carboxylic acid), 0.06 g of 5% platinum carbon (50% WET product) as a catalyst (0.05 weight with respect to furan-2-carboxylic acid) The operation was carried out in the same manner as in Example 1 except that the reaction time including the aging time was set to 4 hours. The production status of tetrahydrofuran-2-carboxylic acid by changing the reaction conditions was compared and examined. The results are shown in Table 1.
  • Comparative Example 3 Add 5.6 g of water (5.0 times by weight with respect to furan-2-carboxylic acid) and 0.4 g of sodium hydroxide (1.0 mol times with respect to furan-2-carboxylic acid) as an additive. The operation was carried out in the same manner as in Example 1 except that the internal temperature was adjusted to around 100 ° C. and the reaction time including the aging time was set to 27 hours. The production status of tetrahydrofuran-2-carboxylic acid by changing the reaction conditions was compared and examined. The results are shown in Table 1.
  • Comparative Example 4 The operation was carried out in the same manner as in Example 1 except that 5.6 g of water (5.0 times by weight with respect to furan-2-carboxylic acid) was added and the internal temperature was adjusted at around 160 ° C. The production status of tetrahydrofuran-2-carboxylic acid by changing the reaction conditions was compared and examined. The results are shown in Table 1.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Furan Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

Provided is a method suited to industrial production of tetrahydrofuran-2-carboxylic acid, which is important as a pharmaceutical raw material, etc. The method for producing tetrahydrofuran-2-carboxylic acid produces tetrahydrofuran-2-carboxylic acid by adding a 0-0.5-fold molar quantity of a base per 1 mol of furan-2-carboxylic acid in the presence of a palladium-carbon catalyst to subject furan-2-carboxylic acid and hydrogen to a catalytic hydrogenation reaction at 100℃ in an aqueous solvent.

Description

テトラヒドロフラン－２－カルボン酸の製造方法Method for Producing Tetrahydrofuran-2-Carboxylic Acid
　本発明は医薬中間体原料などとして重要なテトラヒドロフラン－２－カルボン酸の製造方法に関するものである。 The present invention relates to a method for producing a tetrahydrofuran-2-carboxylic acid, which is important as a raw material for pharmaceutical intermediates.
　テトラヒドロフラン－２－カルボン酸は、医薬等産業上有用な化合物として知られている。テトラヒドロフラン－２－カルボン酸を製造する方法としては、例えば、
（１）フラン－２－カルボン酸をラネーニッケル存在下、添加物として水酸化ナトリウムを加えた水中で接触水素化反応によってテトラヒドロフラン－２－カルボン酸を製造する方法（特許文献１、２参照）、
（２）フラン－２－カルボン酸をルテニウムナノ粒子とｐｏｌｙＥＰＧ－β－ＣＤの存在下、水と酢酸エチルの混合溶媒中で接触水素化反応によってテトラヒドロフラン－２－カルボン酸を製造する方法（非特許文献１参照）、
（３）フラン－２－カルボン酸をγ－Ａｌ2Ｏ3に担持させたパラジウム、もしくはパラジウム－ニッケル存在下、接触水素化反応によってテトラヒドロフラン－２－カルボン酸を製造する方法（非特許文献２，３参照）などが知られている。 Tetrahydrofuran-2-carboxylic acid is known as an industrially useful compound such as pharmaceuticals. As a method for producing a tetrahydrofuran-2-carboxylic acid, for example,
(1) A method for producing a tetrahydrofuran-2-carboxylic acid by a catalytic hydrogenation reaction in water containing furan-2-carboxylic acid in the presence of lane nickel and sodium hydroxide as an additive (see Patent Documents 1 and 2).
(2) A method for producing a tetrahydrofuran-2-carboxylic acid by catalytic hydrogenation of furan-2-carboxylic acid in the presence of ruthenium nanoparticles and polyEPG-β-CD in a mixed solvent of water and ethyl acetate (non-patent). Reference 1),
(3) A method for producing a tetrahydrofuran-2-carboxylic acid by a catalytic hydrogenation reaction in the presence of palladium or palladium-nickel in which furan-2-carboxylic acid is supported on γ-Al 2 O 3 (Non-Patent Documents 2 and 2). 3) and the like are known.
　また、フラン－２－カルボン酸の類縁体である２－メトキシカルボニルフランを製造する方法としては、例えば、
（４）２－メトキシカルボニルフランを予め水素を貯蔵した水素貯蔵合金ＣａＮｉ5存在下、接触水素化反応によって２－メトキシカルボニルテトラヒドロフランを製造する方法（特許文献３参照）などが知られている。 Further, as a method for producing 2-methoxycarbonylfuran, which is an analog of franc-2-carboxylic acid, for example,
(4) A method for producing 2-methoxycarbonyltetrahydrofuran by a catalytic hydrogenation reaction in the presence of the hydrogen storage alloy CaNi 5 in which hydrogen is stored in advance for 2-methoxycarbonylfuran (see Patent Document 3) is known.
　しかしながら、上記（１）のフラン－２－カルボン酸をラネーニッケル存在下、添加物として水酸化ナトリウムを加えた水中で接触水素化反応によってテトラヒドロフラン－２－カルボン酸を製造する方法は、乾燥すると容易に発火するおそれのあるラネーニッケルを使用している。さらに、高圧（８０ｋｇ／ｃｍ2以上）で高温（１２０℃以上）の条件が必要になる点、添加物として水酸化ナトリウムを併用することで生成物を単離する際の後処理に中和工程が必要となって煩雑になる点などの理由から工業的な製造方法として問題点を有している。 However, the method for producing a tetrahydrofuran-2-carboxylic acid by a catalytic hydrogenation reaction in water containing sodium hydroxide as an additive in the presence of Raney nickel from the furan-2-carboxylic acid of (1) above can be easily dried. Uses Raney nickel, which may ignite. Furthermore, the condition of high pressure (80 kg / cm 2 or more) and high temperature (120 ° C or more) is required, and the neutralization step is used for the post-treatment when the product is isolated by using sodium hydroxide as an additive. It has a problem as an industrial manufacturing method because it is necessary and complicated.
　また、上記（２）のフラン－２－カルボン酸をルテニウムナノ粒子とｐｏｌｙＥＰＧ－β－ＣＤの存在下、水と酢酸エチルの混合溶媒中で接触水素化反応によってテトラヒドロフラン－２－カルボン酸を製造する方法は、触媒として特殊で高価なルテニウムナノ粒子とｐｏｌｙＥＰＧ－β－ＣＤを使用し、溶媒として基質に対して９０重量倍もの水／酢酸エチル混合溶媒を使用しているため、工業的に有利な製造方法ではない。 Further, the furan-2-carboxylic acid of (2) above is subjected to a catalytic hydrogenation reaction in the presence of ruthenium nanoparticles and polyEPG-β-CD in a mixed solvent of water and ethyl acetate to produce a tetrahydrofuran-2-carboxylic acid. The method is industrially advantageous because it uses special and expensive ruthenium nanoparticles and polyEPG-β-CD as a catalyst and 90 times by weight of water / ethyl acetate mixed solvent as a solvent. It is not a manufacturing method.
　さらに、上記（３）のフラン－２－カルボン酸をγ－Ａｌ2Ｏ3に担持させたパラジウム、もしくはパラジウム－ニッケル存在下、接触水素化反応によってテトラヒドロフラン－２－カルボン酸を製造する方法は、使用するアルミナ担持金属触媒を含浸法で調製する際、調製過程で系内に存在する塩化物イオンと金属とが強固に結合し、この塩化物イオンの存在が接触水素化反応に影響を及ぼす点や、高圧（１ＭＰａ以上）で高温（１５０℃以上）の条件が必要になる点から工業的に有利な製造方法ではない。 Further, a method for producing a tetrahydrofuran-2-carboxylic acid by a catalytic hydrogenation reaction in the presence of palladium or palladium-nickel in which the furan-2-carboxylic acid of the above (3) is supported on γ-Al 2 O 3 is described. When the alumina-supported metal catalyst to be used is prepared by the impregnation method, the chloride ion existing in the system and the metal are strongly bonded during the preparation process, and the presence of this chloride ion affects the catalytic hydrogenation reaction. In addition, it is not an industrially advantageous manufacturing method because it requires conditions of high pressure (1 MPa or more) and high temperature (150 ° C. or higher).
　また上記（４）の２－メトキシカルボニルフランを予め水素を貯蔵した水素貯蔵合金ＣａＮｉ5存在下、接触水素化反応によって２－メトキシカルボニルテトラヒドロフランを製造する方法は、触媒として特殊で高価な水素貯蔵合金ＣａＮｉ5を使用し、高温（１５０℃）の条件が必要になるため工業的に問題があった。 Further, the method for producing 2-methoxycarbonyltetrahydrofuran by catalytic hydrogenation reaction in the presence of the hydrogen storage alloy CaNi 5 in which hydrogen is stored in advance in the above (4) 2-methoxycarbonylfuran is a special and expensive hydrogen storage alloy as a catalyst. Since CaNi 5 is used and high temperature (150 ° C.) conditions are required, there is an industrial problem.
米国特許第３３４２８３８号明細書U.S. Pat. No. 3,342,838 日本国特開平０３－１８８０７２号公報Japanese Patent Application Laid-Open No. 03-188072 日本国特開平０６－０５６７０２号公報Japanese Patent Application Laid-Open No. 06-056702
　本発明の目的は、医薬原料などとして重要なテトラヒドロフラン－２－カルボン酸の工業的に適した製造方法を提供することにある。 An object of the present invention is to provide an industrially suitable method for producing a tetrahydrofuran-2-carboxylic acid, which is important as a raw material for pharmaceuticals.
　本発明者等は、前記課題を解決するために鋭意検討を重ねた結果、本発明を見出すに至った。即ち、本発明は、パラジウムカーボン触媒存在下、フラン－２－カルボン酸１モルに対して、０～０．５モル倍の塩基を添加して、水溶媒中で、フラン－２－カルボン酸と水素を、１００℃以下で接触水素化反応により、テトラヒドロフラン－２－カルボン酸を製造するテトラヒドロフラン－２－カルボン酸を製造する方法である。 The present inventors have found the present invention as a result of repeated diligent studies in order to solve the above-mentioned problems. That is, in the present invention, in the presence of a palladium carbon catalyst, a base of 0 to 0.5 mol times is added to 1 mol of furan-2-carboxylic acid to obtain furan-2-carboxylic acid in an aqueous solvent. This is a method for producing a tetrahydrofuran-2-carboxylic acid, which produces a tetrahydrofuran-2-carboxylic acid by a catalytic hydrogenation reaction of hydrogen at 100 ° C. or lower.
　テトラヒドロフラン－２－カルボン酸を医薬原料として用いる場合、高純度を有することが強く求められている。本発明により、高純度なテトラヒドロフラン－２－カルボン酸を工業的に適した方法で製造することが可能である。 When tetrahydrofuran-2-carboxylic acid is used as a pharmaceutical raw material, it is strongly required to have high purity. INDUSTRIAL APPLICABILITY According to the present invention, high-purity tetrahydrofuran-2-carboxylic acid can be produced by an industrially suitable method.
　本発明のテトラヒドロフラン－２－カルボン酸の製造方法では、添加物として水酸化ナトリウムのような塩基を使用せずに、或いはごく少量使用するだけで、接触水素化反応を実施するので、反応終了後の後処理に中和工程を追加する必要がなく、簡便な操作によってテトラヒドロフラン－２－カルボン酸を製造することができる。 In the method for producing a tetrahydrofuran-2-carboxylic acid of the present invention, the catalytic hydrogenation reaction is carried out without using a base such as sodium hydroxide as an additive or by using only a small amount, so that after the reaction is completed. Tetrahydrofuran-2-carboxylic acid can be produced by a simple operation without the need to add a neutralization step to the post-treatment.
　以下、本発明を詳細に説明する。
　本発明は、フラン－２－カルボン酸を水溶媒中で、パラジウムカーボン触媒存在下、フラン－２－カルボン酸１モルに対して、０～０．５モル倍の塩基を添加して、接触水素化反応を実施する。 Hereinafter, the present invention will be described in detail.
In the present invention, furan-2-carboxylic acid is added to 1 mol of furan-2-carboxylic acid in an aqueous solvent in the presence of a palladium carbon catalyst, and a base of 0 to 0.5 mol times is added to contact hydrogen. Carry out the chemical reaction.
　接触水素化反応は水溶媒中で行う。水溶媒とは、水、または、水を含む混合溶媒を意味する。水を含む混合溶媒としては、水以外の成分として各種の溶媒を用いることができる。例えば、フラン－２－カルボン酸の溶解度が高いＮ，Ｎ－ジメチルホルムアミドやアセトニトリルなどの非プロトン性極性溶媒、メタノールやエタノール、イソプロパノールなどのアルコール溶媒、テトラヒドロフランなどのエーテル溶媒、酢酸エチルなどのエステル溶媒などが挙げられる。水溶媒は、好ましくは、水である。フラン－２－カルボン酸の水への溶解度は、４０℃のときに１００ｇの水に対して１２ｇ、７０℃のときに１００ｇの水に対して１６０ｇである。本発明のテトラヒドロフラン－２－カルボン酸の製造方法では、フラン－２－カルボン酸が、水に完全に溶解していなくても接触水素化反応が進行する。水溶媒の使用量は、フラン－２－カルボン酸に対して、好ましくは、０．５～５重量倍、より好ましくは、０．５～３重量倍であり、さらに好ましくは、１～２重量倍である。水の使用量が少ないほど、反応物のテトラヒドロフラン－２－カルボン酸を単離しやすく、生産性が高い。 The catalytic hydrogenation reaction is carried out in an aqueous solvent. The water solvent means water or a mixed solvent containing water. As the mixed solvent containing water, various solvents can be used as components other than water. For example, aprotonic polar solvents such as N, N-dimethylformamide and acetonitrile having high solubility of furan-2-carboxylic acid, alcohol solvents such as methanol, ethanol and isopropanol, ether solvents such as tetrahydrofuran, and ester solvents such as ethyl acetate. And so on. The aqueous solvent is preferably water. The solubility of furan-2-carboxylic acid in water is 12 g with respect to 100 g of water at 40 ° C. and 160 g with respect to 100 g of water at 70 ° C. In the method for producing a tetrahydrofuran-2-carboxylic acid of the present invention, the catalytic hydrogenation reaction proceeds even if the furan-2-carboxylic acid is not completely dissolved in water. The amount of the aqueous solvent used is preferably 0.5 to 5 times by weight, more preferably 0.5 to 3 times by weight, still more preferably 1 to 2 times by weight, based on the furan-2-carboxylic acid. It is double. The smaller the amount of water used, the easier it is to isolate the reactant tetrahydrofuran-2-carboxylic acid and the higher the productivity.
　本発明では、フラン－２－カルボン酸を水溶媒中、パラジウムカーボン触媒存在下、フラン－２－カルボン酸１モルに対して、０～０．５モル倍の塩基を添加する。塩基の使用量は、フラン－２－カルボン酸１モルに対して、好ましくは０～０．２モル倍、より好ましくは０～０．１モル倍である。 In the present invention, furan-2-carboxylic acid is added in an aqueous solvent in the presence of a palladium carbon catalyst, and a base of 0 to 0.5 mol times is added to 1 mol of furan-2-carboxylic acid. The amount of the base used is preferably 0 to 0.2 mol times, more preferably 0 to 0.1 mol times, with respect to 1 mol of furan-2-carboxylic acid.
　水酸化ナトリウムのような塩基は、任意に添加することができ、添加しなくてもよい。フラン－２－カルボン酸1モルに対して、塩基を０．５モル倍より多く添加すると、フラン－２－カルボン酸は塩として水に溶解するが、接触水素化反応が著しく遅くなる。また、反応終了後の後処理において中和工程を追加する必要が生じるため、生産性が低下する。 A base such as sodium hydroxide can be added arbitrarily and may not be added. When a base is added more than 0.5 mol times with respect to 1 mol of furan-2-carboxylic acid, the furan-2-carboxylic acid is dissolved in water as a salt, but the catalytic hydrogenation reaction is significantly slowed down. In addition, since it is necessary to add a neutralization step in the post-treatment after the reaction is completed, the productivity is lowered.
　本発明では、パラジウムカーボン触媒を使用する。パラジウムが炭素に担持されたパラジウムカーボン触媒は、パラジウムの表面積が高く、かつ、経時的な触媒活性の低下が少ないので好ましい。パラジウムカーボン触媒は、反応液からパラジウムカーボン触媒を沈降あるいは濾別することにより、分離・回収を行ってもよい。本発明の製造方法において、回収したパラジウムカーボン触媒は、再度使用することが好ましい。 In the present invention, a palladium carbon catalyst is used. A palladium-carbon catalyst in which palladium is supported on carbon is preferable because the surface area of palladium is high and the catalytic activity does not decrease with time. The palladium carbon catalyst may be separated and recovered by precipitating or filtering the palladium carbon catalyst from the reaction solution. In the production method of the present invention, the recovered palladium carbon catalyst is preferably used again.
　本発明の製造方法で用いられるパラジウムカーボン触媒の使用量が、金属換算で、フラン－２－カルボン酸に対して、０．０００１～０．００２５重量倍であることが好ましく、より好ましくは、フラン－２－カルボン酸に対して、０．０００２～０．００１２５重量倍、さらに好ましくは、フラン－２－カルボン酸に対して、０．０００２～０．００１重量倍である。原料のフラン－２－カルボン酸に対して金属換算で、０．０００１～０．００２５重量倍用いた場合、比較的簡易な設備である第一種圧力容器を使用した加圧反応が可能な１ＭＰａ以下の圧力で、数時間で接触水素化反応を終了することができる。一方、金属換算で、０．００２５重量倍より多い場合には、高価な金属を多量に使用するため、製造プロセスとして経済的に好ましくない。 The amount of the palladium carbon catalyst used in the production method of the present invention is preferably 0.0001 to 0.0025 times by weight, more preferably furan, with respect to furan-2-carboxylic acid in terms of metal. It is 0.0002 to 0.00125 times by weight with respect to -2-carboxylic acid, and more preferably 0.0002 to 0.001 times by weight with respect to furan-2-carboxylic acid. When used 0.0001 to 0.0025 times by weight in terms of metal with respect to the raw material furan-2-carboxylic acid, 1 MPa is capable of pressurizing reaction using a first-class pressure vessel, which is a relatively simple facility. At the following pressures, the catalytic hydrogenation reaction can be completed in a few hours. On the other hand, when it is more than 0.0025 times by weight in terms of metal, a large amount of expensive metal is used, which is economically unfavorable as a manufacturing process.
　本発明では、接触水素化反応の温度は、１００℃以下である。反応温度が１００℃以下である場合、反応が早く、テトラヒドロフラン－２－カルボン酸の純度を高くすることができる。反応の温度は、好ましくは、４０～１００℃であり、さらに好ましくは、５０～７０℃である。 In the present invention, the temperature of the catalytic hydrogenation reaction is 100 ° C. or lower. When the reaction temperature is 100 ° C. or lower, the reaction is quick and the purity of the tetrahydrofuran-2-carboxylic acid can be increased. The reaction temperature is preferably 40 to 100 ° C, more preferably 50 to 70 ° C.
　本発明では、反応容器内を水素で置換してから、接触水素化反応を行うことが、好ましい。水素圧は、０．８ＭＰａ以下が、好ましい。水素圧が高い場合、反応時間を短くすることができるが、反応熱によって反応温度の制御が難しくなり、且つ不純物が増加して、テトラヒドロフラン－２－カルボン酸の純度が低下する場合がある。一方、水素圧が低いと反応時間が長くなるので、水素圧は、より好ましくは、０．２～０．８ＭＰａであり、さらに好ましくは、０．３～０．６ＭＰａである。 In the present invention, it is preferable to replace the inside of the reaction vessel with hydrogen and then carry out the catalytic hydrogenation reaction. The hydrogen pressure is preferably 0.8 MPa or less. When the hydrogen pressure is high, the reaction time can be shortened, but the reaction heat makes it difficult to control the reaction temperature, and impurities may increase, resulting in a decrease in the purity of the tetrahydrofuran-2-carboxylic acid. On the other hand, when the hydrogen pressure is low, the reaction time becomes long, so that the hydrogen pressure is more preferably 0.2 to 0.8 MPa, still more preferably 0.3 to 0.6 MPa.
　接触水素化反応の終了後は、使用したパラジウムカーボン触媒を濾過により分離した後、水を減圧留去することで目的のテトラヒドロフラン－２－カルボン酸を得ることができる。 After completion of the catalytic hydrogenation reaction, the palladium carbon catalyst used is separated by filtration, and then water is distilled off under reduced pressure to obtain the desired tetrahydrofuran-2-carboxylic acid.
　本発明のテトラヒドロフラン－２－カルボン酸の製造方法により、化学純度が９９．０面積％以上のテトラヒドロフラン－２－カルボン酸を製造することができる。さらに、本発明のテトラヒドロフラン－２－カルボン酸の製造方法では、好ましくは、化学純度が９９．３面積％以上のテトラヒドロフラン－２－カルボン酸を製造することができる。テトラヒドロフラン－２－カルボン酸の化学純度（面積％）は、以下の実施例に記載のガスクロマトグラフィー（ＧＣ）分析により測定することができる。 By the method for producing a tetrahydrofuran-2-carboxylic acid of the present invention, a tetrahydrofuran-2-carboxylic acid having a chemical purity of 99.0 area% or more can be produced. Further, in the method for producing a tetrahydrofuran-2-carboxylic acid of the present invention, it is possible to preferably produce a tetrahydrofuran-2-carboxylic acid having a chemical purity of 99.3 area% or more. The chemical purity (area%) of the tetrahydrofuran-2-carboxylic acid can be measured by the gas chromatography (GC) analysis described in the Examples below.
　以下実施例により本発明を説明する。
　実施例、比較例の化学純度（面積％）は以下に示す方法で測定した。
　＜化学純度分析法＞
　ガスクロマトグラフィー（ＧＣ）分析条件
検出器　　　　　ＦＩＤ
カラム　　　　　ＴＣ－ＦＦＡＰ，０．２５ｍｍφ×３０ｍ，０．２５μｍ
　　　　　　　　　（ＧＬ　Ｓｃｉｅｎｃｅ製）
カラム温度　　　８０℃ → （１０℃／ｍｉｎ） → ２２０℃（１０ｍｉｎ）
注入口温度　　　２３０℃
検出器温度　　　２３０℃
全流量　　　　　６９ｍＬ／ｍｉｎ （Ｈｅ　２００ｋＰａ）
スプリット比　　約１／２０
注入量　　　　　０．２μＬ （ｎｅａｔ）　。 The present invention will be described below with reference to examples.
The chemical purity (area%) of Examples and Comparative Examples was measured by the method shown below.
<Chemical purity analysis method>
Gas Chromatography (GC) Analytical Condition Detector FID
Column TC-FFAP, 0.25 mmφ x 30 m, 0.25 μm
(Made by GL Sciences)
Column temperature 80 ° C → (10 ° C / min) → 220 ° C (10 min)
Injection port temperature 230 ℃
Detector temperature 230 ℃
Total flow rate 69mL / min (He 200kPa)
Split ratio about 1/20
Injection volume 0.2 μL (neat).
　実施例１
　温度計、撹拌機の付いた３０ｍＬのＳＵＳ製耐圧反応容器に、フラン－２－カルボン酸１．１２ｇ（０．０１モル）を加え、さらに水１．６８ｇ（フラン－２－カルボン酸に対し１．５重量倍）、触媒として５％パラジウムカーボン（５０％ＷＥＴ品）０．０１ｇ（フラン－２－カルボン酸に対し０．０１重量倍）を加えた。反応容器内を水素で置換してから水素圧として０．４ＭＰａになるまで加圧し、以降反応が終わるまで０．２～０．４ＭＰａになるように水素圧を調整した。加圧後、水浴にて反応容器を昇温し、内温を６０℃付近で調整した。水素の吸収が収まるまで６時間を要した。反応終了後、水素圧０．４ＭＰａ、６０℃付近で２時間熟成した。その後、２０℃付近、常圧に戻してから触媒を濾別した後、得られた水溶液は、１．１６ｇのテトラヒドロフラン－２－カルボン酸（化学純度：９９．９面積％、収率：１００モル％）を含んでいた。 Example 1
To a 30 mL SUS pressure resistant reaction vessel equipped with a thermometer and a stirrer, add 1.12 g (0.01 mol) of furan-2-carboxylic acid, and further add 1.68 g of water (1 to furan-2-carboxylic acid). (5.5 times by weight), 0.01 g of 5% palladium carbon (50% WET product) (0.01% by weight with respect to furan-2-carboxylic acid) was added as a catalyst. After the inside of the reaction vessel was replaced with hydrogen, the pressure was increased until the hydrogen pressure reached 0.4 MPa, and then the hydrogen pressure was adjusted to 0.2 to 0.4 MPa until the reaction was completed. After pressurization, the temperature of the reaction vessel was raised in a water bath, and the internal temperature was adjusted to around 60 ° C. It took 6 hours for the absorption of hydrogen to subside. After completion of the reaction, the mixture was aged at a hydrogen pressure of 0.4 MPa and around 60 ° C. for 2 hours. Then, after returning to normal pressure at around 20 ° C. and filtering off the catalyst, the obtained aqueous solution was 1.16 g of tetrahydrofuran-2-carboxylic acid (chemical purity: 99.9 area%, yield: 100 mol). %) Was included.
　５％パラジウムカーボン（５０％ＷＥＴ品）は、エヌ・イー ケムキャット(株)の５％Ｐｄカーボン粉末(含水品)ＳＴＤタイプを使用した。Ｐｄカーボン粉末(含水品)ＳＴＤタイプの品質規格は、貴金属含有率（Ｄｒｙベース）が、５．００±０．０５％、水分含有率が、５５．００±５．００％である。 For 5% palladium carbon (50% WET product), 5% Pd carbon powder (hydrous product) STD type of NE Chemcat Co., Ltd. was used. The quality standard of Pd carbon powder (moisture-containing product) STD type is that the noble metal content (Dry base) is 5.00 ± 0.05% and the water content is 55.00 ± 5.00%.
　実施例２
　温度計、撹拌機の付いた３５００ＬのＳＵＳ製耐圧反応槽に、フラン－２－カルボン酸５００ｋｇ（４．４６キロモル）を加え、さらに水５００ｋｇ（フラン－２－カルボン酸に対し１．０重量倍）、触媒として５％パラジウムカーボン（５０％ＷＥＴ品）５ｋｇ（フラン－２－カルボン酸に対し０．０１重量倍）を加えた。窒素で置換された反応槽内に系内の圧力が０．４ＭＰａになるまで水素で加圧し、以降反応が終わるまで０．４ＭＰａ付近になるように水素圧を調整した。５％パラジウムカーボン（５０％ＷＥＴ品）は、実施例１と同じものを使用した。加圧後、水浴にて反応容器を昇温し、内温を６０℃付近で調整した。水素の吸収が収まるまで６時間を要した。反応終了後、水素圧０．４ＭＰａ、６０℃付近で２時間熟成した。その後、２０℃付近、常圧に戻してから触媒を濾別した後、得られた水溶液は、５１１ｋｇのテトラヒドロフラン－２－カルボン酸（化学純度：９９．３面積％、収率：９９モル％）を含んでいた。 Example 2
To a 3500 L SUS pressure resistant reaction vessel equipped with a thermometer and a stirrer, 500 kg (4.46 kilomol) of furan-2-carboxylic acid was added, and further 500 kg of water (1.0 weight times as much as that of furan-2-carboxylic acid) was added. ), 5 kg of 5% palladium carbon (50% WET product) (0.01 weight times as much as furan-2-carboxylic acid) was added as a catalyst. The pressure in the system was pressurized with hydrogen until the pressure in the system became 0.4 MPa in the reaction vessel substituted with nitrogen, and then the hydrogen pressure was adjusted so as to be around 0.4 MPa until the reaction was completed. The same 5% palladium carbon (50% WET product) as in Example 1 was used. After pressurization, the temperature of the reaction vessel was raised in a water bath, and the internal temperature was adjusted to around 60 ° C. It took 6 hours for the absorption of hydrogen to subside. After completion of the reaction, the mixture was aged at a hydrogen pressure of 0.4 MPa and around 60 ° C. for 2 hours. Then, after returning to normal pressure at around 20 ° C. and filtering off the catalyst, the obtained aqueous solution was 511 kg of tetrahydrofuran-2-carboxylic acid (chemical purity: 99.3 area%, yield: 99 mol%). Included.
　実施例３
　添加物として水酸化ナトリウム０．０４ｇ（フラン－２－カルボン酸に対して０．１モル倍）を加えた以外は実施例１と同様に操作をおこなった。２０℃付近、常圧に戻してから触媒を濾別した後、得られた水溶液は、１．１６ｇのテトラヒドロフラン－２－カルボン酸（化学純度：９９．８面積％、収率：１００モル％）を含んでいた。 Example 3
The operation was carried out in the same manner as in Example 1 except that 0.04 g of sodium hydroxide (0.1 mol times as much as that of furan-2-carboxylic acid) was added as an additive. After returning to normal pressure at around 20 ° C. and filtering off the catalyst, the obtained aqueous solution was 1.16 g of tetrahydrofuran-2-carboxylic acid (chemical purity: 99.8 area%, yield: 100 mol%). Included.
　比較例１
　水を５．６ｇ（フラン－２－カルボン酸に対して５．０重量倍）、触媒として５％ルテニウムカーボン（５０％ＷＥＴ品）０．０６ｇ（フラン－２－カルボン酸に対し０．０５重量倍）を加え、熟成時間を含めた反応時間を６時間にした以外は実施例１と同様に操作をおこなった。反応条件変更によるテトラヒドロフラン－２－カルボン酸の生成状況を比較検討した。結果を表１に示す。 Comparative Example 1
5.6 g of water (5.0 times by weight with respect to furan-2-carboxylic acid), 0.06 g of 5% ruthenium carbon (50% WET product) as a catalyst (0.05 weight with respect to furan-2-carboxylic acid) The operation was carried out in the same manner as in Example 1 except that the reaction time including the aging time was set to 6 hours. The production status of tetrahydrofuran-2-carboxylic acid by changing the reaction conditions was compared and examined. The results are shown in Table 1.
　比較例２
　水を５．６ｇ（フラン－２－カルボン酸に対して５．０重量倍）、触媒として５％プラチナカーボン（５０％ＷＥＴ品）０．０６ｇ（フラン－２－カルボン酸に対し０．０５重量倍）を加え、熟成時間を含めた反応時間を４時間にした以外は実施例１と同様に操作をおこなった。反応条件変更によるテトラヒドロフラン－２－カルボン酸の生成状況を比較検討した。結果を表１に示す。 Comparative Example 2
5.6 g of water (5.0 times by weight with respect to furan-2-carboxylic acid), 0.06 g of 5% platinum carbon (50% WET product) as a catalyst (0.05 weight with respect to furan-2-carboxylic acid) The operation was carried out in the same manner as in Example 1 except that the reaction time including the aging time was set to 4 hours. The production status of tetrahydrofuran-2-carboxylic acid by changing the reaction conditions was compared and examined. The results are shown in Table 1.
　比較例３
　水を５．６ｇ（フラン－２－カルボン酸に対して５．０重量倍）、添加物として水酸化ナトリウム０．４ｇ（フラン－２－カルボン酸に対して１.０モル倍）を加え、内温を１００℃付近で調整し、熟成時間を含めた反応時間を２７時間にした以外は実施例１と同様に操作をおこなった。反応条件変更によるテトラヒドロフラン－２－カルボン酸の生成状況を比較検討した。結果を表１に示す。 Comparative Example 3
Add 5.6 g of water (5.0 times by weight with respect to furan-2-carboxylic acid) and 0.4 g of sodium hydroxide (1.0 mol times with respect to furan-2-carboxylic acid) as an additive. The operation was carried out in the same manner as in Example 1 except that the internal temperature was adjusted to around 100 ° C. and the reaction time including the aging time was set to 27 hours. The production status of tetrahydrofuran-2-carboxylic acid by changing the reaction conditions was compared and examined. The results are shown in Table 1.
　比較例４
　水を５．６ｇ（フラン－２－カルボン酸に対して５．０重量倍）加え、内温を１６０℃付近で調整した以外は実施例１と同様に操作をおこなった。反応条件変更によるテトラヒドロフラン－２－カルボン酸の生成状況を比較検討した。結果を表１に示す。 Comparative Example 4
The operation was carried out in the same manner as in Example 1 except that 5.6 g of water (5.0 times by weight with respect to furan-2-carboxylic acid) was added and the internal temperature was adjusted at around 160 ° C. The production status of tetrahydrofuran-2-carboxylic acid by changing the reaction conditions was compared and examined. The results are shown in Table 1.
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001

Claims (4)

  1. 　パラジウムカーボン触媒存在下、フラン－２－カルボン酸１モルに対して、０～０．５モル倍の塩基を添加して、水溶媒中で、フラン－２－カルボン酸と水素を、１００℃以下で接触水素化反応により、テトラヒドロフラン－２－カルボン酸を製造するテトラヒドロフラン－２－カルボン酸の製造方法。 In the presence of a palladium carbon catalyst, add 0 to 0.5 mol times of the base to 1 mol of furan-2-carboxylic acid, and add furan-2-carboxylic acid and hydrogen to 100 ° C. or lower in an aqueous solvent. A method for producing a tetrahydrofuran-2-carboxylic acid, which produces a tetrahydrofuran-2-carboxylic acid by a catalytic hydrogenation reaction.
  2. 　水溶媒の使用量が、フラン－２－カルボン酸に対して０．５～３重量倍である請求項１に記載のテトラヒドロフラン－２－カルボン酸の製造方法。 The method for producing a tetrahydrofuran-2-carboxylic acid according to claim 1, wherein the amount of the aqueous solvent used is 0.5 to 3 times by weight the amount of furan-2-carboxylic acid.
  3. 　パラジウムカーボン触媒の使用量が、金属換算で、フラン－２－カルボン酸に対して、０．０００１～０．００２５重量倍である請求項１または２に記載のテトラヒドロフラン－２－カルボン酸の製造方法。 The method for producing a tetrahydrofuran-2-carboxylic acid according to claim 1 or 2, wherein the amount of the palladium carbon catalyst used is 0.0001 to 0.0025 times by weight the amount of furan-2-carboxylic acid in terms of metal. ..
  4. 　化学純度が９９．０面積％以上のテトラヒドロフラン－２－カルボン酸を製造する請求項１～３のいずれかに記載のテトラヒドロフラン－２－カルボン酸の製造方法。 The method for producing a tetrahydrofuran-2-carboxylic acid according to any one of claims 1 to 3, wherein the tetrahydrofuran-2-carboxylic acid having a chemical purity of 99.0 area% or more is produced.
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