JP4032825B2 - Method for producing 3,4-dihydroxybenzonitrile - Google Patents

Method for producing 3,4-dihydroxybenzonitrile Download PDF

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JP4032825B2
JP4032825B2 JP2002148876A JP2002148876A JP4032825B2 JP 4032825 B2 JP4032825 B2 JP 4032825B2 JP 2002148876 A JP2002148876 A JP 2002148876A JP 2002148876 A JP2002148876 A JP 2002148876A JP 4032825 B2 JP4032825 B2 JP 4032825B2
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Prior art keywords
dihydroxybenzonitrile
reaction
dihydroxybenzaldehyde
mass
producing
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JP2002148876A
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JP2003342248A (en
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昌志 白井
敏男 古谷
昌彦 渡部
光正 津川
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宇部興産株式会社
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Description

【0001】
【発明の属する技術分野】
本発明は、3,4-ジヒドロキシベンズアルデヒドから3,4-ジヒドロキシベンゾニトリルを製造する方法に関する。3,4-ジヒドロキシベンゾニトリルは、医薬・農薬等の合成原料、特に抗癌剤として有用なキナゾリン化合物の原料となり得る化合物である。
【0002】
【従来の技術】
従来、3,4-ジヒドロキシベンズアルデヒドから3,4-ジヒドロキシベンゾニトリルを製造する方法としては、例えば、Synthetic Commun.,1998,3765には、3,4-ジヒドロキシベンズアルデヒド、ヒドロキシルアミン塩酸塩、ギ酸/SiO2触媒をメノウ乳鉢で混合し、得られた粉末にマイクロウェーブを照射して、収率70%で3,4-ジヒドロキシベンゾニトリルを得る方法、又、Tetrahedron,55,13265(1999)には、3,4-ジヒドロキシベンズアルデヒド、ヒドロキシルアミン塩酸塩及びN-メチル-2-ピロリジノンを混合し、マイクロウェーブを照射しながら15分間反応させて収率89%で3,4-ジヒドロキシベンゾニトリルを得る方法が開示されている。しかしながら、これらの方法では、工業的に実施が困難なマイクロウェーブを用いなければならないという問題があった。
【0003】
【発明が解決しようとする課題】
本発明の課題は、即ち、上記問題点を解決し、簡便な方法によって、高収率で3,4-ジヒドロキシベンゾニトリルを得る、工業的に好適な3,4-ジヒドロキシベンゾニトリルを製造する方法を提供するものである。
【0004】
【課題を解決するための手段】
本発明の課題は、3,4-ジヒドロキシベンズアルデヒドとヒドロキシルアミン-O-スルホン酸とを反応させることを特徴とする、3,4-ジヒドロキシベンゾニトリルを製造する方法によって解決される。
【0005】
【発明の実施の形態】
本発明の反応によって使用する3,4-ジヒドロキシベンズアルデヒドは、市販品のもので構わないが、バナジウム、クロム、マンガン、鉄、コバルト、ニッケル銅、亜鉛等の重金属の含有量が、好ましくは50質量ppm以下、更に好ましくは20質量ppm以下、特に好ましくは10質量ppm以下のものが使用される。
【0006】
本発明の反応によって使用するヒドロキシルアミン-O-スルホン酸の量は、3,4-ジヒドロキシベンズアルデヒド1molに対して、好ましくは1.0〜2.0mol、更に好ましくは1.05〜1.6mol、特に好ましくは1.1〜1.5molである。
【0007】
本発明の反応は溶媒の存在下又は非存在下において行われ、溶媒を使用する場合には、反応を阻害しないものならば特に限定されず、例えば、水、メタノール、エタノール、イソプロピルアルコール等のアルコール類が挙げられるが、好ましくは水、更に好ましくは蒸留やイオン交換によって精製された水が使用される。なお、これらの溶媒は、単独又は二種以上を混合して使用しても良い。
【0008】
前記溶媒の使用量は、反応液の均一性や攪拌性のよって適宜調節するが、3,4-ジヒドロキシベンズアルデヒド1gに対して、好ましくは2〜20g、更に好ましくは2.5〜15g、特に好ましくは3〜13gである。
【0009】
本発明の反応は、例えば、不活性ガス雰囲気にて、3,4-ジヒドロキシベンズアルデヒド、ヒドロキシルアミン-O-スルホン酸及び溶媒を加えて-10〜30℃で攪拌しながら反応させて3,4-ジヒドロキシベンズアルドキシム-O-スルホン酸を生成させた後、次いで、40〜70℃に加熱して攪拌しながら反応させる等の方法によって行われる。その際の反応圧力は特に制限されない。
【0010】
なお、本発明の反応によって得られる3,4-ジヒドロキシベンゾニトリルは、例えば、反応終了後、抽出、濾過、濃縮、蒸留、再結晶、晶析、カラムクロマトグラフィー等の一般的な方法によって単離・精製される。
【0011】
【実施例】
次に、実施例を挙げて本発明を具体的に説明するが、本発明の範囲はこれらに限定されるものではない。
【0012】
実施例1(3,4-ジヒドロキシベンゾニトリルの合成)
攪拌装置及び温度計を備えた内容積2Lのフラスコに、窒素雰囲気にて、水645mlを加え、次いで、液温を5℃以下に保ちながら、81質量%ヒドロキシルアミン-O-スルホン酸159.0g(1.14mol)をゆるやかに加えた。更に、同温度で、3,4-ジヒドロキシベンズアルデヒド121.0g(0.88mol)をゆるやかに加え、攪拌しながら30分間反応させた。その後、反応液を50℃まで昇温し、攪拌しながら50〜58℃で1時間反応させた。反応終了後、反応液を氷水浴で冷却すると結晶が析出した。次いで、30質量%水酸化ナトリウム水溶液を加えて反応液のpHを2.5に調整し、析出した結晶を濾過した。濾過後、濾液を酢酸エチル1Lで抽出した後、先ほど得られた結晶を酢酸エチル溶液に溶解させた。次いで、酢酸エチル溶液を無水硫酸ナトリウムを加えて乾燥した。濾過後、濾液を減圧下で濃縮すると結晶が析出したので、更に、得られた結晶を減圧下50℃で乾燥させ、白色結晶として3,4-ジヒドロキシベンゾニトリル114.8gを得た(単離収率:97%)。
【0013】
実施例2(3,4-ジヒドロキシベンゾニトリルの合成)
攪拌装置及び温度計を備えた内容積1Lのガラス製セパラブルフラスコに、窒素雰囲気にて、イオン交換水645gを加え、次いで、液温を5℃以下に保ちながら、88.0質量%ヒドロキシルアミン-O-スルホン酸(硫酸含量10.9質量%)72.6g(0.565mol)を攪拌しながらゆるやかに加えた。更に、5〜10℃を保ったまま、3,4-ジヒドロキシベンズアルデヒド(鉄含量2質量ppm以下)60.0g(0.434mol)をゆるやかに加え、攪拌しながら1時間反応させた。その後、反応液を30分間かけて30℃まで昇温して1時間反応させ、更に、反応液を30分間かけて50℃まで昇温して2時間反応させた。反応終了後、反応液の温度を40〜50℃に保ち、攪拌しながら48質量%水酸化ナトリウム水溶液53.8g(0.646mol)を加えて中和した。次いで、反応液を20〜30℃に冷却した後、酢酸エチルで2回抽出した。この酢酸エチル層に24質量%塩化ナトリウム水溶液48gを加えて攪拌し、更に、攪拌しながら8質量%炭酸水素ナトリウム水溶液を加えてpHを2.5に調整して酢酸エチル層を分離した。再び、酢酸エチル層に24質量%塩化ナトリウム水溶液72gを加えて攪拌した後、酢酸エチル層を分離して無水硫酸マグネシウムで乾燥した。濾過後、濾液を減圧下で濃縮すると結晶が析出した。得られた結晶に水440gを加えて50〜60℃に昇温し、活性炭1.2gを加えて攪拌後、50〜60℃を保ったまま濾過した。その後、5℃まで冷却して結晶を析出させた。濾過後、水で洗浄し、結晶を減圧下で乾燥させ、白色結晶として純度99.3質量%の3,4-ジヒドロキシベンゾニトリル50.4gを得た(単離収率:85.4%)。なお、得られた3,4-ジヒドロキシベンゾニトリルの比色分析法によるAPHA値は100であった。
【0014】
比較例1(3,4-ジヒドロキシベンゾ二トリルの合成)
実施例2において、鉄含量が170質量ppmである3,4-ジヒドロキシベンズアルデヒドを用いた以外は、実施例2と同様な方法で反応を行った。その結果、淡黄色結晶として純度90.0質量%の3,4-ジヒドロキシベンゾニトリル43.4gを得た(単離収率:66.6%)。なお、得られた3,4-ジヒドロキシベンゾニトリルの比色分析法によるAPHA値は500以上であった。
【0015】
【発明の効果】
本発明により、簡便な方法によって、高収率で3,4-ジヒドロキシベンゾニトリルを得る、工業的に好適な3,4-ジヒドロキシベンゾニトリルを製造する方法を提供することが出来る。
[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a method for producing 3,4-dihydroxybenzonitrile from 3,4-dihydroxybenzaldehyde. 3,4-Dihydroxybenzonitrile is a compound that can be a raw material for synthetic quinazoline compounds that are useful as synthetic raw materials for pharmaceuticals and agricultural chemicals, particularly as anticancer agents.
[0002]
[Prior art]
Conventional methods for producing 3,4-dihydroxybenzonitrile from 3,4-dihydroxybenzaldehyde include, for example, Synthetic Commun., 1998 , 3765, 3,4-dihydroxybenzaldehyde, hydroxylamine hydrochloride, formic acid / SiO 2 2 The catalyst is mixed in an agate mortar, and the resulting powder is irradiated with microwaves to obtain 3,4-dihydroxybenzonitrile in a yield of 70%, and Tetrahedron, 55, 13265 (1999) 3,4-dihydroxybenzaldehyde, hydroxylamine hydrochloride and N-methyl-2-pyrrolidinone are mixed and reacted for 15 minutes while irradiating with microwaves to obtain 3,4-dihydroxybenzonitrile in 89% yield. It is disclosed. However, these methods have a problem that microwaves that are difficult to implement industrially must be used.
[0003]
[Problems to be solved by the invention]
An object of the present invention is to provide an industrially suitable 3,4-dihydroxybenzonitrile, which solves the above problems and obtains 3,4-dihydroxybenzonitrile in a high yield by a simple method. Is to provide.
[0004]
[Means for Solving the Problems]
The object of the present invention is solved by a method for producing 3,4-dihydroxybenzonitrile, characterized by reacting 3,4-dihydroxybenzaldehyde and hydroxylamine-O-sulfonic acid.
[0005]
DETAILED DESCRIPTION OF THE INVENTION
The 3,4-dihydroxybenzaldehyde used in the reaction of the present invention may be a commercially available product, but the content of heavy metals such as vanadium, chromium, manganese, iron, cobalt, nickel copper, and zinc is preferably 50 masses. Those having ppm or less, more preferably 20 ppm by mass or less, and particularly preferably 10 ppm by mass or less are used.
[0006]
The amount of hydroxylamine-O-sulfonic acid used in the reaction of the present invention is preferably 1.0 to 2.0 mol, more preferably 1.05 to 1.6 mol, particularly preferably 1.1 to 1.5 mol, based on 1 mol of 3,4-dihydroxybenzaldehyde. mol.
[0007]
The reaction of the present invention is carried out in the presence or absence of a solvent, and when a solvent is used, it is not particularly limited as long as it does not inhibit the reaction. For example, water, methanol, ethanol, isopropyl alcohol and other alcohols Preferably, water, more preferably water purified by distillation or ion exchange is used. In addition, you may use these solvents individually or in mixture of 2 or more types.
[0008]
The amount of the solvent used is appropriately adjusted depending on the uniformity and stirring properties of the reaction solution, but is preferably 2 to 20 g, more preferably 2.5 to 15 g, particularly preferably 3 to 1 g of 3,4-dihydroxybenzaldehyde. ~ 13g.
[0009]
The reaction of the present invention is carried out, for example, by adding 3,4-dihydroxybenzaldehyde, hydroxylamine-O-sulfonic acid and a solvent in an inert gas atmosphere and reacting with stirring at −10 to 30 ° C. After producing dihydroxybenzaldoxime-O-sulfonic acid, it is then carried out by a method such as heating to 40 to 70 ° C. and reacting with stirring. The reaction pressure at that time is not particularly limited.
[0010]
The 3,4-dihydroxybenzonitrile obtained by the reaction of the present invention is isolated by a general method such as extraction, filtration, concentration, distillation, recrystallization, crystallization, column chromatography after completion of the reaction. -Purified.
[0011]
【Example】
Next, the present invention will be specifically described with reference to examples, but the scope of the present invention is not limited thereto.
[0012]
Example 1 (Synthesis of 3,4-dihydroxybenzonitrile)
To a 2 L flask equipped with a stirrer and a thermometer, 645 ml of water was added in a nitrogen atmosphere, and then 159.0 g of 81% by weight hydroxylamine-O-sulfonic acid while keeping the liquid temperature at 5 ° C. or lower ( 1.14 mol) was added slowly. Further, 121.0 g (0.88 mol) of 3,4-dihydroxybenzaldehyde was slowly added at the same temperature, and the mixture was reacted for 30 minutes with stirring. Thereafter, the temperature of the reaction solution was raised to 50 ° C. and reacted at 50 to 58 ° C. for 1 hour with stirring. After completion of the reaction, the reaction solution was cooled in an ice water bath to precipitate crystals. Subsequently, 30 mass% sodium hydroxide aqueous solution was added, pH of the reaction liquid was adjusted to 2.5, and the precipitated crystal | crystallization was filtered. After filtration, the filtrate was extracted with 1 L of ethyl acetate, and the crystals obtained earlier were dissolved in the ethyl acetate solution. Subsequently, the ethyl acetate solution was dried by adding anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to precipitate crystals. The obtained crystals were further dried at 50 ° C. under reduced pressure to obtain 114.8 g of 3,4-dihydroxybenzonitrile as white crystals (isolated product). Rate: 97%).
[0013]
Example 2 (Synthesis of 3,4-dihydroxybenzonitrile)
To a 1 L glass separable flask equipped with a stirrer and a thermometer, 645 g of ion-exchanged water was added in a nitrogen atmosphere, and then 88.0% by mass hydroxylamine-O while maintaining the liquid temperature at 5 ° C. or lower. -72.6 g (0.565 mol) of sulfonic acid (sulfuric acid content 10.9 mass%) was slowly added with stirring. Further, while maintaining the temperature at 5 to 10 ° C., 60.0 g (0.434 mol) of 3,4-dihydroxybenzaldehyde (iron content of 2 mass ppm or less) was slowly added and reacted for 1 hour with stirring. Thereafter, the reaction solution was heated to 30 ° C. over 30 minutes and reacted for 1 hour, and further the reaction solution was heated to 50 ° C. over 30 minutes and reacted for 2 hours. After completion of the reaction, the temperature of the reaction solution was kept at 40 to 50 ° C., and neutralized by adding 53.8 g (0.646 mol) of a 48 mass% sodium hydroxide aqueous solution while stirring. Next, the reaction solution was cooled to 20 to 30 ° C. and extracted twice with ethyl acetate. To this ethyl acetate layer, 48 g of a 24% by mass sodium chloride aqueous solution was added and stirred, and further, with stirring, an 8% by mass sodium hydrogen carbonate aqueous solution was added to adjust the pH to 2.5, and the ethyl acetate layer was separated. Again, 72 g of a 24 mass% sodium chloride aqueous solution was added to the ethyl acetate layer and stirred, and then the ethyl acetate layer was separated and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to precipitate crystals. 440 g of water was added to the obtained crystals and the temperature was raised to 50 to 60 ° C., and 1.2 g of activated carbon was added and stirred, followed by filtration while maintaining 50 to 60 ° C. Then, it cooled to 5 degreeC and the crystal | crystallization was deposited. After filtration, it was washed with water, and the crystals were dried under reduced pressure to obtain 50.4 g of 3,4-dihydroxybenzonitrile having a purity of 99.3% by mass as white crystals (isolated yield: 85.4%). The APHA value of the obtained 3,4-dihydroxybenzonitrile by colorimetric analysis was 100.
[0014]
Comparative Example 1 (Synthesis of 3,4-dihydroxybenzonitryl)
In Example 2, the reaction was performed in the same manner as in Example 2, except that 3,4-dihydroxybenzaldehyde having an iron content of 170 mass ppm was used. As a result, 43.4 g of 3,4-dihydroxybenzonitrile having a purity of 90.0% by mass was obtained as light yellow crystals (isolation yield: 66.6%). The APHA value of the obtained 3,4-dihydroxybenzonitrile by colorimetric analysis was 500 or more.
[0015]
【The invention's effect】
INDUSTRIAL APPLICABILITY According to the present invention, an industrially suitable method for producing 3,4-dihydroxybenzonitrile can be provided by which 3,4-dihydroxybenzonitrile is obtained in a high yield by a simple method.

Claims (2)

50 質量 ppm 以下の重金属を含有する3,4-ジヒドロキシベンズアルデヒドとヒドロキシルアミン-O-スルホン酸とを反応させることを特徴とする、3,4-ジヒドロキシベンゾニトリルを製造する方法。A method for producing 3,4-dihydroxybenzonitrile, comprising reacting 3,4-dihydroxybenzaldehyde containing 50 mass ppm or less of heavy metal with hydroxylamine-O-sulfonic acid. 50 質量 ppm 以下の重金属を含有する3,4-ジヒドロキシベンズアルデヒドとヒドロキシルアミン-O-スルホン酸とを-10〜30℃で反応させて3,4-ジヒドロキシベンズアルドキシム-O-スルホン酸を生成させた後、40〜70℃に加熱して反応させることを特徴とする、3,4-ジヒドロキシベンゾニトリルを製造する方法。Reaction of 3,4-dihydroxybenzaldehyde containing 50 mass ppm or less of heavy metal with hydroxylamine-O-sulfonic acid at −10 to 30 ° C. to produce 3,4-dihydroxybenzaldoxime-O-sulfonic acid And then reacting by heating to 40 to 70 ° C., to produce 3,4-dihydroxybenzonitrile.
JP2002148876A 2002-05-23 2002-05-23 Method for producing 3,4-dihydroxybenzonitrile Expired - Fee Related JP4032825B2 (en)

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JP2002148876A JP4032825B2 (en) 2002-05-23 2002-05-23 Method for producing 3,4-dihydroxybenzonitrile
TW92113196A TWI241285B (en) 2002-05-23 2003-05-15 Process for producing 3,4-dihydroxybenzonitrile
CN 03131384 CN1209345C (en) 2002-05-23 2003-05-16 Process for preparing 3,4-dihydroxy-benzene formonitrile

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JP4032825B2 true JP4032825B2 (en) 2008-01-16

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TWI241285B (en) 2005-10-11
CN1209345C (en) 2005-07-06
JP2003342248A (en) 2003-12-03
CN1460675A (en) 2003-12-10

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