JP4022316B2 - Method for producing fluorophenols - Google Patents
Method for producing fluorophenols Download PDFInfo
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- JP4022316B2 JP4022316B2 JP17679298A JP17679298A JP4022316B2 JP 4022316 B2 JP4022316 B2 JP 4022316B2 JP 17679298 A JP17679298 A JP 17679298A JP 17679298 A JP17679298 A JP 17679298A JP 4022316 B2 JP4022316 B2 JP 4022316B2
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- fluorophenol
- diazonium salt
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
- C07C39/24—Halogenated derivatives
- C07C39/26—Halogenated derivatives monocyclic monohydroxylic containing halogen bound to ring carbon atoms
- C07C39/27—Halogenated derivatives monocyclic monohydroxylic containing halogen bound to ring carbon atoms all halogen atoms being bound to ring carbon atoms
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- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Description
【0001】
【発明の属する技術分野】
本発明は、医薬、農薬等の重要な中間体となりうるフルオロフェノール類を効率良く製造する方法に関するものである。
【0002】
【従来の技術】
従来、フルオロフェノール類の製造方法としては、1)フルオロアニリンをジアゾ化した後、加水分解する方法〔J.Am.Chem.Soc., 61,165,(1939) 〕、2)アミノアニソールからシーマン反応によりフルオロアニソールを得た後、メトキシ基を加水分解する方法〔日化79,1121(1979)〕、3)クロロフルオロベンゼンをアルカリで加水分解する方法〔J.Fluorine Chem.,50,377(1990) 〕等が知られている。1)の方法は実験室的には手軽にできる利点があるが、収率が低く廃物が多量にできるなど工業的に実用化しうる方法とは言い難い。2)の方法は工程が長く全体の収率が50%以下と低い。また、シーマン反応における熱分解反応は工業的には制御が難しく、発生する三フッ化ホウ素の公害処理等厄介な問題を含んでいる。3)の方法は反応温度が 200〜300 ℃と高く、アルカリによる反応器の腐蝕等工業的には問題がある。
【0003】
【発明が解決しようとする課題】
本発明の目的は、上記課題を解決し、中間体化合物として有用なフルオロフェノール類を効率良く製造できる合成ルートを提供することである。
【0004】
【課題を解決するための手段】
本発明者らはこれまでに上記1)〜3)の方法の問題点を解決すべく鋭意検討し、ポリフルオロアニリン類からフルオロアニソール類を得た後、メトキシ基を加水分解する方法〔Chem.Lett.,1996,23、特開平7-27803 号、特開平8-188545号〕を見出した。この方法は特にメタ位にフルオロ基を有するフェノール類の製造方法として有用な方法である。
本発明者らは、その後も鋭意検討を重ねた結果、上記の方法をさらに改善し、ポリフルオロアニリン類から直接フルオロフェノール類を製造できる方法を見出した。本発明によれば、工程を格段に短縮でき、大過剰のメタノールおよび臭化水素酸等の使用を省くことができる。
即ち本発明は、下記一般式(I)で示されるポリフルオロアニリンをジアゾ化して下記一般式(II)で示されるジアゾニウム塩とし、次いで当該ジアゾニウム塩を加熱攪拌後、次亜リン酸と反応させることを特徴とする下記一般式(III)で示されるフルオロフェノール類の製造方法である。
【0005】
【化2】
【0006】
(これらの式において、n は2,3,4または5の整数であり、X はHSO4,BF4 またはPF6 を表す。)
本発明の要旨は、ポリフルオロアニリンをジアゾ化してジアゾニウム塩とし、次いでこのジアゾニウム塩を加熱攪拌後、次亜リン酸と反応させ、1個のフルオロ基をヒドロキシ基で置換するとともにジアゾニウム塩を還元して、フッ素が1個減少したフルオロフェノール類を直接得るということにある。
【0007】
【発明の実施の形態】
本発明の方法の具体的な実施に関しては、次の実施例で詳細に説明するが、まず反応器に一般式(I)で示されるポリフルオロアニリンを仕込んでジアゾ化し、かくして得られる一般式(II)で示される生成ジアゾニウム塩を含む溶液を所定時間、所定温度で加熱攪拌後、次亜リン酸水溶液と混合し、所定時間、所定温度で反応を行う。反応後、ジクロロメタンを加えて2層に分離し、水性層を除去する。有機層中のフルオロフェノールは、通常の方法、例えば蒸留により容易に分離精製できる。
【0008】
ポリフルオロアニリンのジアゾニウム塩の調製方法は、硫酸溶液中で常法によりジアゾ化するのが好ましい。濃硫酸と亜硝酸ナトリウムとから調製した硫酸水素ニトロシルによりジアゾ化を行ったり、テトラフルオロホウ酸塩やヘキサフルオロリン酸塩を調製して使用してもよい。
【0009】
本発明の脱フルオロ・ヒドロキシ化反応の反応温度は、約0〜100 ℃、好ましくは約30〜70℃である。反応温度が低すぎると反応速度が減少し、高すぎると副反応が生じやすい。脱フルオロ・ヒドロキシ化反応の反応時間は 0.5〜5時間、好ましくは1〜2時間の範囲である。
使用する水(硫酸溶液および亜硝酸ナトリウム溶液中の水)の量はポリフルオロアニリンに対して5〜100 倍モル量、好ましくは10〜50倍モル量の範囲である。
【0010】
また、本発明の脱ジアゾ・水素化反応の反応温度は、約0〜50℃、好ましくは約30〜50℃である。脱ジアゾ・水素化反応の反応時間は、 0.5〜5時間、好ましくは1〜2時間の範囲である。
本発明の脱ジアゾ・水素化反応に使用する次亜リン酸は50%水溶液を用いるのが好ましい。その使用量はポリフルオロアニリンに対して1〜2倍モル量が適当である。
【0011】
本反応の脱ジアゾ・水素化反応では、金属触媒を使用するとより良い結果を与える。金属触媒としては銅または銅(I)塩を用いるのが好ましい。特に好ましいのは、銅である。その使用量はポリフルオロアニリンに対して約 0.005〜0.05倍モル量で十分である。
【0012】
本発明の一般式(I)で示されるポリフルオロアニリンは、複数のフルオロ基を有し、内1個以上のフルオロ基がアミノ基のオルト位あるいはパラ位にあるもので、例えば、2,3,4,5,6 −ペンタフルオロアニリン、2,3,4,5 −テトラフルオロアニリン、2,3,4,6 −テトラフルオロアニリン、2,3,5,6 −テトラフルオロアニリン、2,3,4 −トリフルオロアニリン、2,3,5 −トリフルオロアニリン、2,3,6 −トリフルオロアニリン、2,4,5 −トリフルオロアニリン、2,4,6 −トリフルオロアニリン、2,3 −ジフルオロアニリン、2,4 −ジフルオロアニリン、2,5 −ジフルオロアニリン、2,6 −ジフルオロアニリン、3,4 −ジフルオロアニリンなどが挙げられる。特に好ましくは、2,4 −ジフルオロアニリン、2,6 −ジフルオロアニリン、2,3,4 −トリフルオロアニリン、2,4,6 −トリフルオロアニリンである。また、上記以外にも置換基としてフルオロ基のみに限らず、例えば、クロロ基、ブロモ基、ニトロ基、シアノ基、メチル基等を含んでいてもよい。
【0013】
【実施例】
[3−フルオロフェノールの製造]
実施例1
攪拌器、温度計および冷却・加熱浴を備えた1リットルのポリエチレン製容器に50%硫酸 600g(3.06モル)を仕込み、室温攪拌下、2,4 −ジフルオロアニリン 100g(0.77モル)を滴下し硫酸塩溶液を調製した。この硫酸塩溶液に30%亜硝酸ナトリウム水溶液 196g(0.85モル)を液温が30℃を超えないように冷却しながら滴下しジアゾニウム塩溶液を調製した。このジアゾニウム塩溶液を50℃に加熱し、2時間加熱攪拌した。
攪拌器、温度計および冷却浴を備えた2リットルのポリエチレン製容器に50%次亜リン酸水溶液 200g(1.52モル)を仕込んだ。ここに加熱攪拌を終えたジアゾニウム塩溶液を液温が50℃を超えないように冷却しながら攪拌下滴下した。滴下終了後、さらに1時間室温下攪拌した。ジクロロメタン 500mlで溶媒抽出し、ジクロロメタンを留去後、蒸留して3−フルオロフェノール(ガスクロマトグラフィー純度99.0%)を得た。収量35.6g、収率41%(アニリン基準)であった。
【0014】
実施例2
次亜リン酸との反応において、触媒として銅粉を 0.5g(0.0079モル)添加する以外は実施例1と同様の手順で行った。3−フルオロフェノールの収量46.9g、収率54%(アニリン基準)であった。
【0015】
実施例3
次亜リン酸との反応において、触媒として塩化第一銅を 0.5g(0.0051モル)添加する以外は実施例1と同様の手順で行った。3−フルオロフェノールの収量43.4g、収率50%(アニリン基準)であった。
【0016】
実施例4
原料の2,4 −ジフルオロアニリンを2,6 −ジフルオロアニリンに変えた以外は実施例1と同様の手順で行った。3−フルオロフェノールの収量33.9g、収率39%(アニリン基準)であった。
【0017】
実施例5
次亜リン酸との反応において、触媒として銅粉を 0.5g(0.0079モル)添加する以外は実施例4と同様の手順で行った。3−フルオロフェノールの収量44.3g、収率51%(アニリン基準)であった。
【0018】
[2,3 −ジフルオロフェノールの製造]
実施例6
攪拌器、温度計および冷却・加熱浴を備えた1リットルのポリエチレン製容器に50%硫酸 600g(3.06モル)を仕込み、室温攪拌下、2,3,4 −トリフルオロアニリン 100g(0.68モル)を滴下し硫酸塩溶液を調製した。この硫酸塩溶液に30%亜硝酸ナトリウム水溶液 173g(0.75モル)を液温が30℃を超えないように冷却しながら滴下しジアゾニウム塩溶液を調製した。このジアゾニウム塩溶液を50℃に加熱し、2時間加熱攪拌した。
攪拌器、温度計および冷却浴を備えた2リットルのポリエチレン製容器に50%次亜リン酸水溶液 177g(1.34モル)を仕込んだ。ここに加熱攪拌を終えたジアゾニウム塩溶液を液温が50℃を超えないように冷却しながら攪拌下滴下する。滴下終了後、さらに1時間室温下攪拌した。ジクロロメタン 500mlで溶媒抽出し、ジクロロメタンを留去後、蒸留して2,3 −ジフルオロフェノール(ガスクロマトグラフィー純度99.4%)を得た。収量45.9g、収率52%(アニリン基準)であった。
【0019】
実施例7
次亜リン酸との反応において、触媒として銅粉を0.44g(0.0070モル)添加する以外は実施例6と同様の手順で行った。2,3 −ジフルオロフェノールの収量53.9g、収率61%(アニリン基準)であった。
【0020】
[3,5 −ジフルオロフェノールの製造]
実施例8
原料の2,3,4 −トリフルオロアニリンを2,4,6 −トリフルオロアニリンに変えた以外は実施例6と同様の手順で行った。3,5 −ジフルオロフェノールの収量43.3g、収率49%(アニリン基準)であった。
【0021】
実施例9
次亜リン酸との反応において、触媒として銅粉を0.44g(0.0070モル)添加する以外は実施例8と同様の手順で行った。3,5 −ジフルオロフェノールの収量51.2g、収率58%(アニリン基準)であった。
【0022】
【発明の効果】
本発明の方法によれば、温和な反応条件下、ポリフルオロアニリンからフルオロフェノールを収率50%以上の良好な収率(銅触媒使用時、アニリン基準)で直接製造することができる。既存の方法に比べて、簡易な製造装置を用いて短い製造工程で効率良くフルオロフェノール類を製造することができる。[0001]
BACKGROUND OF THE INVENTION
The present invention pharmaceutical relates to a process for efficiently producing a key intermediate and will be fluorophenol such pesticides and the like.
[0002]
[Prior art]
Conventionally, as a method for producing fluorophenols, 1) a method in which fluoroaniline is diazotized and then hydrolyzed (J. Am. Chem. Soc., 61 , 165, (1939)), 2) from aminoanisole to seaman After obtaining fluoroanisole by reaction, a method of hydrolyzing a methoxy group (Nikka 79 , 1121 (1979)), 3) a method of hydrolyzing chlorofluorobenzene with an alkali [J. Fluorine Chem. , 50, 377 ( 1990)] etc. are known. Although the method 1) has the advantage of being easy in the laboratory, it is difficult to say that the method can be put to practical use industrially because the yield is low and the amount of waste can be increased. The method 2) has a long process and the overall yield is as low as 50% or less. In addition, the thermal decomposition reaction in the Seaman reaction is difficult to control industrially and includes troublesome problems such as pollution treatment of the generated boron trifluoride. The method (3) has a high reaction temperature of 200 to 300 ° C. and has industrial problems such as corrosion of the reactor by alkali.
[0003]
[Problems to be solved by the invention]
An object of the present invention is to solve the above-described problems and provide a synthetic route that can efficiently produce fluorophenols useful as an intermediate compound.
[0004]
[Means for Solving the Problems]
The present inventors have intensively studied to solve the problems of the above methods 1) to 3), and after obtaining fluoroanisoles from polyfluoroanilines, a method of hydrolyzing a methoxy group (Chem. Lett., 1996, 23, JP-A-7-27803, JP-A-8-188545]. This method is particularly useful as a method for producing phenols having a fluoro group at the meta position.
As a result of intensive investigations thereafter, the present inventors have found a method by which the above-described method can be further improved and fluorophenols can be produced directly from polyfluoroanilines. According to the present invention, the process can be remarkably shortened, and the use of a large excess of methanol, hydrobromic acid and the like can be omitted.
That is, in the present invention, the polyfluoroaniline represented by the following general formula (I) is diazotized to form a diazonium salt represented by the following general formula (II), and then the diazonium salt is heated and stirred and then reacted with hypophosphorous acid. This is a method for producing a fluorophenol represented by the following general formula (III).
[0005]
[Chemical 2]
[0006]
(In these formulas, n is an integer of 2, 3, 4 or 5, and X represents HSO 4 , BF 4 or PF 6 )
The gist of the present invention is to diazotize polyfluoroaniline to form a diazonium salt, which is then heated and stirred, and then reacted with hypophosphorous acid to replace one fluoro group with a hydroxy group and reduce the diazonium salt. Thus, it is possible to directly obtain fluorophenols with one fluorine decreased.
[0007]
DETAILED DESCRIPTION OF THE INVENTION
The specific implementation of the method of the present invention will be described in detail in the following examples. First, a polyfluoroaniline represented by the general formula (I) is charged into a reactor and diazotized. A solution containing the produced diazonium salt represented by II) is heated and stirred at a predetermined temperature for a predetermined time, and then mixed with a hypophosphorous acid aqueous solution, and reacted at a predetermined temperature for a predetermined time. After the reaction, dichloromethane is added to separate into two layers, and the aqueous layer is removed. The fluorophenol in the organic layer can be easily separated and purified by ordinary methods such as distillation.
[0008]
The method for preparing the diazonium salt of polyfluoroaniline is preferably diazotized in a sulfuric acid solution by a conventional method. Diazotization may be performed with nitrosyl hydrogen sulfate prepared from concentrated sulfuric acid and sodium nitrite, or tetrafluoroborate or hexafluorophosphate may be prepared and used.
[0009]
The reaction temperature of the defluoro-hydroxylation reaction of the present invention is about 0 to 100 ° C, preferably about 30 to 70 ° C. If the reaction temperature is too low, the reaction rate decreases, and if it is too high, side reactions tend to occur. The reaction time of the defluoro-hydroxylation reaction is 0.5 to 5 hours, preferably 1 to 2 hours.
The amount of water (water in the sulfuric acid solution and sodium nitrite solution) to be used is in the range of 5 to 100 times mol, preferably 10 to 50 times mol, of polyfluoroaniline.
[0010]
The reaction temperature of the dediazo-hydrogenation reaction of the present invention is about 0 to 50 ° C, preferably about 30 to 50 ° C. The reaction time of the dediazo-hydrogenation reaction is in the range of 0.5 to 5 hours, preferably 1 to 2 hours.
The hypophosphorous acid used in the dediazo / hydrogenation reaction of the present invention is preferably a 50% aqueous solution. The amount used is suitably 1 to 2 times the molar amount of polyfluoroaniline.
[0011]
In the dediazo / hydrogenation reaction of this reaction, better results are obtained when a metal catalyst is used. It is preferable to use copper or a copper (I) salt as the metal catalyst. Particularly preferred is copper. The amount used is about 0.005-0.05 times the molar amount of polyfluoroaniline.
[0012]
The polyfluoroaniline represented by the general formula (I) of the present invention has a plurality of fluoro groups, and one or more of the fluoro groups are in the ortho or para position of the amino group. , 4,5,6-pentafluoroaniline, 2,3,4,5-tetrafluoroaniline, 2,3,4,6-tetrafluoroaniline, 2,3,5,6-tetrafluoroaniline, 2,3 , 4-trifluoroaniline, 2,3,5-trifluoroaniline, 2,3,6-trifluoroaniline, 2,4,5-trifluoroaniline, 2,4,6-trifluoroaniline, 2,3 -Difluoroaniline, 2,4-difluoroaniline, 2,5-difluoroaniline, 2,6-difluoroaniline, 3,4-difluoroaniline and the like. Particularly preferred are 2,4-difluoroaniline, 2,6-difluoroaniline, 2,3,4-trifluoroaniline, and 2,4,6-trifluoroaniline. In addition to the above, the substituent is not limited to a fluoro group, and may include, for example, a chloro group, a bromo group, a nitro group, a cyano group, a methyl group, and the like.
[0013]
【Example】
[Production of 3-fluorophenol]
Example 1
A 1 liter polyethylene container equipped with a stirrer, thermometer and cooling / heating bath was charged with 600 g (3.06 mol) of 50% sulfuric acid, and 100 g (0.77 mol) of 2,4-difluoroaniline was added dropwise with stirring at room temperature. A salt solution was prepared. To this sulfate solution, 196 g (0.85 mol) of a 30% aqueous sodium nitrite solution was added dropwise while cooling so that the liquid temperature did not exceed 30 ° C. to prepare a diazonium salt solution. The diazonium salt solution was heated to 50 ° C. and stirred for 2 hours.
A 2-liter polyethylene container equipped with a stirrer, thermometer and cooling bath was charged with 200 g (1.52 mol) of 50% aqueous hypophosphorous acid solution. The diazonium salt solution after heating and stirring was added dropwise with stirring while cooling so that the liquid temperature did not exceed 50 ° C. After completion of dropping, the mixture was further stirred at room temperature for 1 hour. The solvent was extracted with 500 ml of dichloromethane, and the dichloromethane was distilled off, followed by distillation to obtain 3-fluorophenol (gas chromatography purity 99.0%). The yield was 35.6 g and the yield was 41% (aniline basis).
[0014]
Example 2
The reaction with hypophosphorous acid was carried out in the same procedure as in Example 1 except that 0.5 g (0.0079 mol) of copper powder was added as a catalyst. The yield of 3-fluorophenol was 46.9 g, and the yield was 54% (aniline basis).
[0015]
Example 3
The reaction with hypophosphorous acid was carried out in the same procedure as in Example 1 except that 0.5 g (0.0051 mol) of cuprous chloride was added as a catalyst. The yield of 3-fluorophenol was 43.4 g, and the yield was 50% (aniline basis).
[0016]
Example 4
The procedure was the same as in Example 1 except that 2,4-difluoroaniline as a raw material was changed to 2,6-difluoroaniline. The yield of 3-fluorophenol was 33.9 g, and the yield was 39% (aniline basis).
[0017]
Example 5
The reaction with hypophosphorous acid was carried out in the same procedure as in Example 4 except that 0.5 g (0.0079 mol) of copper powder was added as a catalyst. The yield of 3-fluorophenol was 44.3 g, and the yield was 51% (based on aniline).
[0018]
[Production of 2,3-difluorophenol]
Example 6
A 1 liter polyethylene container equipped with a stirrer, thermometer and cooling / heating bath is charged with 600 g (3.06 mol) of 50% sulfuric acid, and 100 g (0.68 mol) of 2,3,4-trifluoroaniline is stirred at room temperature. A sulfate solution was prepared by dropwise addition. To this sulfate solution, 173 g (0.75 mol) of 30% aqueous sodium nitrite solution was added dropwise while cooling so that the liquid temperature did not exceed 30 ° C. to prepare a diazonium salt solution. The diazonium salt solution was heated to 50 ° C. and stirred for 2 hours.
A 2 liter polyethylene container equipped with a stirrer, thermometer and cooling bath was charged with 177 g (1.34 mol) of a 50% aqueous hypophosphorous acid solution. The diazonium salt solution that has been heated and stirred is added dropwise with stirring while cooling so that the liquid temperature does not exceed 50 ° C. After completion of dropping, the mixture was further stirred at room temperature for 1 hour. The solvent was extracted with 500 ml of dichloromethane, and the dichloromethane was distilled off, followed by distillation to obtain 2,3-difluorophenol (gas chromatography purity 99.4%). The yield was 45.9 g and the yield was 52% (aniline basis).
[0019]
Example 7
The reaction with hypophosphorous acid was carried out in the same procedure as in Example 6 except that 0.44 g (0.0070 mol) of copper powder was added as a catalyst. The yield of 2,3-difluorophenol was 53.9 g, and the yield was 61% (aniline basis).
[0020]
[Production of 3,5-difluorophenol]
Example 8
The procedure was the same as in Example 6 except that 2,3,4-trifluoroaniline as a raw material was changed to 2,4,6-trifluoroaniline. The yield of 3,5-difluorophenol was 43.3 g, and the yield was 49% (aniline basis).
[0021]
Example 9
The reaction with hypophosphorous acid was carried out in the same procedure as in Example 8, except that 0.44 g (0.0070 mol) of copper powder was added as a catalyst. The yield of 3,5-difluorophenol was 51.2 g, and the yield was 58% (aniline basis).
[0022]
【The invention's effect】
According to the method of the present invention, fluorophenol can be directly produced from polyfluoroaniline in a favorable yield of 50% or more (based on aniline when using a copper catalyst) under mild reaction conditions. Compared with existing methods, fluorophenols can be efficiently produced in a short production process using a simple production apparatus.
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JP17679298A JP4022316B2 (en) | 1998-06-24 | 1998-06-24 | Method for producing fluorophenols |
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JP17679298A JP4022316B2 (en) | 1998-06-24 | 1998-06-24 | Method for producing fluorophenols |
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JP2000007599A5 JP2000007599A5 (en) | 2005-10-06 |
JP4022316B2 true JP4022316B2 (en) | 2007-12-19 |
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