JP4183813B2 - Process for producing benzamide oximes - Google Patents
Process for producing benzamide oximes Download PDFInfo
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- JP4183813B2 JP4183813B2 JP34144798A JP34144798A JP4183813B2 JP 4183813 B2 JP4183813 B2 JP 4183813B2 JP 34144798 A JP34144798 A JP 34144798A JP 34144798 A JP34144798 A JP 34144798A JP 4183813 B2 JP4183813 B2 JP 4183813B2
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Description
【0001】
【産業上の利用分野】
本発明は、農医薬中間体として有用な式(II)
【0002】
【化6】
【0003】
(式中、Xは、ハロゲン原子、C1-5アルキル基、C1-3アルコキシ基、C1-3アルキルチオ基、水酸基、メルカプト基、アミノ基、ニトロ基又はC1-5ハロアルキル基を、nは、0又は1から5の整数を示す。)で表されるベンズアミドオキシムを安定した高収率で得る製造法に関する。本発明の製造法により製造される化合物のうち、特に2,3−ジフルオロ−6−トリフルオロメチルベンズアミドオキシムは農園芸用殺菌剤の中間体として有用である。
【0004】
【従来の技術】
アミドオキシム類は一般にニトリル類とヒドロキシルアミン類を反応させることにより合成されることが知られている(Houben-Weyl Methoden der Organischen Chemie Band VIII Sauerstoff ver Bindungen III p.692) 。
【0005】
式(II)で表されるベンズアミドオキシムに含まれる2,3−ジフルオロ−6−トリフルオロメチルベンズアミドオキシムについても、2,3−ジフルオロ−6−トリフルオロメチルベンゾニトリルに炭酸ナトリウム等の存在下、ヒドロキシルアミン塩酸塩を作用させることにより製造できることが報告されている(WO96/19442)。
【0006】
しかしながら、従来の技術では溶媒中に鉄などの微量金属イオンを含む場合、また反応容器として褐色ガラス製やSUS製のものを使用する場合等ではいずれも目的とするアミドオキシム化合物の収率が顕著に低下し、副生物として式(III)
【0007】
【化7】
【0008】
で表されるベンズアミドが多く生成してしまう。
【0009】
【発明が解決しようとする課題】
本発明は、式(I)で表されるベンゾニトリルとヒドロキシルアミンとから式(II)で表されるベンズアミドオキシムを安定した高収率で製造することを目的とする。
【0010】
【課題を解決するための手段】
本発明は、式(I)で表されるベンゾニトリルとヒドロキシルアミンをキレート剤の存在下で反応させることを特徴とする式(II)で表されるベンズアミドオキシムの製造法である。本発明を反応式で示すと以下のとおりである。
【0011】
【化8】
【0012】
【発明の実施の形態】
本発明の製造法が適用できる化合物の代表例を表1に示す。
【0013】
【表1】
【0014】
本反応は溶媒中、キレート剤の存在下、ベンゾニトリル(I)に、ヒドロキシルアミン(HA)を作用させて行う。HAの使用量は好ましくは(I):HA=1:1.5〜3である。また、HAの供給形態についてはHA塩酸塩等を塩基存在下に使用してもよいが、好ましくはフリーのHAである。
【0015】
本発明の溶媒については反応に不活性な溶媒が好ましく、例えばアセトニトリルのような溶媒は好ましくない。
【0016】
その中で極性が高くキレート剤を溶解させ得る溶媒が好ましく、例えばメタノール−水の混合溶媒が挙げられる。より好ましくはメタノールに対し水を過剰に使用する。
【0017】
本発明のキレート剤とは、主に鉄イオンと錯体を形成しやすいキレート剤であり、好ましくは式(IV)で表される8−ヒドロキシキノリンや式(V)で表されるo−フェナントロリンが挙げられる。
【0018】
【化9】
【0019】
【化10】
【0020】
キレート剤の量的割合は、ベンゾニトリル(I)に対して、触媒量でよいが、より好ましくは(I)に対して0.1〜1mol%である。
【0021】
反応終了後は通常の後処理を行うことにより目的物を得ることができる。
【0022】
次に実施例を挙げ本発明をさらに詳しく説明するが、本発明はこれにより何ら限定されるものでない。
【0023】
【実施例】
実施例1(含鉄イオン溶媒中の反応)
無色透明ガラス製反応容器にてあらかじめ50%ヒドロキシルアミン水溶液9.91g(150mmol)、o−フェナントロリン99mg(0.50mmol)、および故意に塩化第一鉄86μg(0.00068mmol)を溶解させたメタノール−蒸留水(体積比1:2)150mlの混合溶媒中へ、2,3−ジフルオロ−6−トリフルオロメチルベンゾニトリル(I'')10.36g(50.0mmol)を添加し、反応液を60℃で6時間熟成した後、室温に戻した。反応液はHPLC[カラム;Inertsil ODS-3 4.6 mm φ×250mm(GL Sciences Inc.)、移動相;CH3CN-H2O-10% H3PO4 500:500:10(v/v/v)、流量;1.0ml/min 、検出波長;225nm 、実施例2以降も同条件]上、(I'')(tR 16.0min)の消失を示し、2,3−ジフルオロ−6−トリフルオロメチルベンズアミドオキシム(II')の主生成(収率76.9%、tR 3.6min)を、また2,3−ジフルオロ−6−トリフルオロメチルベンズアミド(III')の副生(収率8.4%、tR 4.8min)をそれぞれ示した。
【0024】
実施例2(SUS製反応容器中の反応)
SUS製反応容器にてあらかじめ50%ヒドロキシルアミン水溶液99.09g(1.50mol)およびo−フェナントロリン198mg(1.00mmol)を溶解させたメタノール−水(体積比1:2、水としては水道水を使用)1.5Lの混合溶媒中へ、2,3−ジフルオロ−6−トリフルオロメチルベンゾニトリル(I'')103.56g(500mmol)を添加し、反応液を60℃で7時間熟成した後、室温に戻した。反応液はHPLC上(I'')の消失を示し、2,3−ジフルオロ−6−トリフルオロメチルベンズアミドオキシム(II')の主生成(収率78.9%)を、また2,3−ジフルオロ−6−トリフルオロメチルベンズアミド(III')の副生(収率9.0%)をそれぞれ示した。
【0025】
比較例1(含鉄イオン溶媒中の反応)
無色透明ガラス製反応容器にてあらかじめ50%ヒドロキシルアミン水溶液9.91g(150mmol)、および故意に塩化第一鉄86μg(0.00068mmol)を溶解させたメタノール−蒸留水(体積比1:2)150mlの混合溶媒中へ、2,3−ジフルオロ−6−トリフルオロメチルベンゾニトリル(I'')10.36g(50.0mmol)を添加し、反応液を60℃で6時間熟成した後、室温に戻した。反応液はHPLC上(I'')の消失を示し、2,3−ジフルオロ−6−トリフルオロメチルベンズアミドオキシム(II')の主生成(収率62.4%)を、また2,3−ジフルオロ−6−トリフルオロメチルベンズアミド(III')の顕著な副生(収率22.8%)をそれぞれ示した。
【0026】
比較例2(SUS製反応容器中の反応)
SUS製反応容器にてあらかじめ50%ヒドロキシルアミン水溶液99.09g(1.50mol)を溶解させたメタノール−水(体積比1:2、水としては実施例2と同一の水道水を使用)1.5Lの混合溶媒中へ、2,3−ジフルオロ−6−トリフルオロメチルベンゾニトリル(I'')103.56g(500mmol)を添加し、反応液を60℃で7時間熟成した後、室温に戻した。反応液はHPLC上(I'')の消失を示し、2,3−ジフルオロ−6−トリフルオロメチルベンズアミドオキシム(II')の主生成(収率63.2%)を、また2,3−ジフルオロ−6−トリフルオロメチルベンズアミド(III')の顕著な副生(収率16.6%)をそれぞれ示した。
【0027】
以下に2,3−ジフルオロ−6−トリフルオロメチルベンゾニトリル(I'')の反応を例に、反応条件の違いによるキレート剤の効果について比較も含め表2に示した。
【0028】
【表2】
【0029】
【発明の効果】
以上説明したように、本発明の方法によれば、ベンゾニトリルとヒドロキシルアミンとからベンズアミドオキシム類を安定した高収率にて得ることができる。すなわち、キレート剤を添加することにより本反応における鉄などの微量金属イオンの混入、溶出等による収率低下の変動要因を除去し、また本反応に使用する反応容器の材質上の制約を広げ得る効果があり、本発明の製造法は工業的に優れた製造法である。[0001]
[Industrial application fields]
The present invention provides a compound of formula (II) useful as an agricultural pharmaceutical intermediate.
[0002]
[Chemical 6]
[0003]
(Wherein X represents a halogen atom, a C 1-5 alkyl group, a C 1-3 alkoxy group, a C 1-3 alkylthio group, a hydroxyl group, a mercapto group, an amino group, a nitro group, or a C 1-5 haloalkyl group, n represents 0 or an integer of 1 to 5). This relates to a production method for obtaining a benzamide oxime represented by Of the compounds produced by the production method of the present invention, 2,3-difluoro-6-trifluoromethylbenzamide oxime is particularly useful as an intermediate for agricultural and horticultural fungicides.
[0004]
[Prior art]
Amidooximes are generally known to be synthesized by reacting nitriles with hydroxylamines (Houben-Weyl Methoden der Organischen Chemie Band VIII Sauerstoff ver Bindungen III p.692).
[0005]
As for 2,3-difluoro-6-trifluoromethylbenzamide oxime contained in the benzamide oxime represented by the formula (II), 2,3-difluoro-6-trifluoromethylbenzonitrile in the presence of sodium carbonate or the like, It has been reported that it can be produced by the action of hydroxylamine hydrochloride (WO 96/19442).
[0006]
However, in the conventional technique, the yield of the target amide oxime compound is remarkable when a trace metal ion such as iron is contained in the solvent or when a reaction vessel made of brown glass or SUS is used. As a by-product of formula (III)
[0007]
[Chemical 7]
[0008]
A large amount of benzamide represented by
[0009]
[Problems to be solved by the invention]
An object of the present invention is to produce a benzamide oxime represented by the formula (II) from a benzonitrile represented by the formula (I) and hydroxylamine in a stable and high yield.
[0010]
[Means for Solving the Problems]
The present invention is a process for producing a benzamide oxime represented by formula (II), which comprises reacting benzonitrile represented by formula (I) with hydroxylamine in the presence of a chelating agent. The present invention is represented by the following reaction formula.
[0011]
[Chemical 8]
[0012]
DETAILED DESCRIPTION OF THE INVENTION
Table 1 shows typical examples of compounds to which the production method of the present invention can be applied.
[0013]
[Table 1]
[0014]
This reaction is performed by allowing hydroxylamine (HA) to act on benzonitrile (I) in the presence of a chelating agent in a solvent. The amount of HA used is preferably (I): HA = 1: 1.5-3. Moreover, although HA hydrochloride etc. may be used in base presence about the supply form of HA, Preferably it is free HA.
[0015]
As the solvent of the present invention, a solvent inert to the reaction is preferable, and a solvent such as acetonitrile is not preferable.
[0016]
Among them, a solvent having high polarity and capable of dissolving the chelating agent is preferable. For example, a mixed solvent of methanol and water can be mentioned. More preferably, water is used in excess of methanol.
[0017]
The chelating agent of the present invention is a chelating agent that easily forms a complex mainly with iron ions, and preferably 8-hydroxyquinoline represented by the formula (IV) or o-phenanthroline represented by the formula (V). Can be mentioned.
[0018]
[Chemical 9]
[0019]
Embedded image
[0020]
The quantitative ratio of the chelating agent may be a catalytic amount with respect to benzonitrile (I), but is more preferably 0.1 to 1 mol% with respect to (I).
[0021]
After completion of the reaction, the desired product can be obtained by carrying out ordinary post-treatment.
[0022]
EXAMPLES Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto.
[0023]
【Example】
Example 1 (Reaction in an iron-containing ion solvent)
Methanol in which 9.91 g (150 mmol) of 50% aqueous hydroxylamine solution, 99 mg (0.50 mmol) of o-phenanthroline, and 86 μg (0.00068 mmol) of ferrous chloride were intentionally dissolved in a colorless transparent glass reaction vessel in advance 10.36 g (50.0 mmol) of 2,3-difluoro-6-trifluoromethylbenzonitrile (I ″) was added to 150 ml of a mixed solvent of distilled water (volume ratio 1: 2), and the reaction solution was added to 60 ml. After aging at 6 ° C. for 6 hours, the temperature was returned to room temperature. The reaction solution was HPLC [column; Inertsil ODS-3 4.6 mm φ × 250 mm (GL Sciences Inc.), mobile phase: CH3CN-H2O-10% H3PO4 500: 500: 10 (v / v / v), flow rate: 1.0 ml / min, detection wavelength: 225 nm, the same as in Example 2 and above], and the disappearance of (I ″) (tR 16.0 min) was observed, indicating that 2,3-difluoro-6-trifluoromethylbenzamide oxime (II ′ ) Main product (yield 76.9%, tR 3.6 min) and 2,3-difluoro-6-trifluoromethylbenzamide (III ′) byproduct (yield 8.4%, tR 4. 8 min).
[0024]
Example 2 (Reaction in a SUS reaction vessel)
Methanol-water (volume ratio 1: 2, with tap water as water) in which 99.09 g (1.50 mol) of 50% aqueous hydroxylamine solution and 198 mg (1.00 mmol) of o-phenanthroline were previously dissolved in a SUS reaction vessel. Use) 103.56 g (500 mmol) of 2,3-difluoro-6-trifluoromethylbenzonitrile (I ″) was added to 1.5 L of a mixed solvent, and the reaction solution was aged at 60 ° C. for 7 hours. , Returned to room temperature. The reaction solution showed disappearance of (I ″) on HPLC, and the main production of 2,3-difluoro-6-trifluoromethylbenzamide oxime (II ′) (yield 78.9%) A by-product (yield: 9.0%) of difluoro-6-trifluoromethylbenzamide (III ′) was shown.
[0025]
Comparative Example 1 (Reaction in an iron-containing ion solvent)
150 ml of methanol-distilled water (volume ratio 1: 2) in which 9.91 g (150 mmol) of 50% hydroxylamine aqueous solution and 86 μg (0.00068 mmol) of ferrous chloride were intentionally dissolved in a colorless transparent glass reaction vessel. 2,3-difluoro-6-trifluoromethylbenzonitrile (I ″) (10.36 g, 50.0 mmol) was added to the mixed solvent, and the reaction solution was aged at 60 ° C. for 6 hours, and then brought to room temperature. Returned. The reaction solution showed disappearance of (I ″) on HPLC, and the main production of 2,3-difluoro-6-trifluoromethylbenzamide oxime (II ′) (yield 62.4%) Remarkable by-products (yield 22.8%) of difluoro-6-trifluoromethylbenzamide (III ′) were respectively shown.
[0026]
Comparative Example 2 (reaction in a SUS reaction vessel)
1. Methanol-water in which 99.09 g (1.50 mol) of 50% aqueous hydroxylamine solution was previously dissolved in a SUS reaction vessel (volume ratio 1: 2, the same tap water as in Example 2 was used as water). To the 5 L mixed solvent, 103.56 g (500 mmol) of 2,3-difluoro-6-trifluoromethylbenzonitrile (I ″) was added, the reaction solution was aged at 60 ° C. for 7 hours, and then returned to room temperature. It was. The reaction solution showed disappearance of (I ″) on HPLC, and the main production of 2,3-difluoro-6-trifluoromethylbenzamide oxime (II ′) (yield 63.2%) Remarkable by-products (yield 16.6%) of difluoro-6-trifluoromethylbenzamide (III ′) were respectively shown.
[0027]
The reaction of 2,3-difluoro-6-trifluoromethylbenzonitrile (I ″) is taken as an example below, and the effect of the chelating agent due to the difference in reaction conditions is shown in Table 2 including comparison.
[0028]
[Table 2]
[0029]
【The invention's effect】
As described above, according to the method of the present invention, benzamide oximes can be obtained in a stable and high yield from benzonitrile and hydroxylamine. In other words, by adding a chelating agent, it is possible to remove the factors that cause a decrease in yield due to the mixing and elution of trace metal ions such as iron in this reaction, and to expand the restrictions on the material of the reaction vessel used in this reaction. There is an effect, and the manufacturing method of the present invention is an industrially excellent manufacturing method.
Claims (3)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
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JP34144798A JP4183813B2 (en) | 1998-01-08 | 1998-12-01 | Process for producing benzamide oximes |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP10-13257 | 1998-01-08 | ||
JP1325798 | 1998-01-08 | ||
JP34144798A JP4183813B2 (en) | 1998-01-08 | 1998-12-01 | Process for producing benzamide oximes |
Publications (2)
Publication Number | Publication Date |
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JPH11255733A JPH11255733A (en) | 1999-09-21 |
JP4183813B2 true JP4183813B2 (en) | 2008-11-19 |
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JP34144798A Expired - Lifetime JP4183813B2 (en) | 1998-01-08 | 1998-12-01 | Process for producing benzamide oximes |
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- 1998-12-01 JP JP34144798A patent/JP4183813B2/en not_active Expired - Lifetime
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