JP2008001597A - Method for producing 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole - Google Patents
Method for producing 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole Download PDFInfo
- Publication number
- JP2008001597A JP2008001597A JP2004293715A JP2004293715A JP2008001597A JP 2008001597 A JP2008001597 A JP 2008001597A JP 2004293715 A JP2004293715 A JP 2004293715A JP 2004293715 A JP2004293715 A JP 2004293715A JP 2008001597 A JP2008001597 A JP 2008001597A
- Authority
- JP
- Japan
- Prior art keywords
- dihydroisoxazole
- dimethyl
- bromo
- reaction
- mol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- OMKAMTCDOWAJAA-UHFFFAOYSA-N CC(C)(C1)ON=C1Br Chemical compound CC(C)(C1)ON=C1Br OMKAMTCDOWAJAA-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/04—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
Description
本発明は、医薬及び農薬の製造中間体として有用な３−ブロモ−５，５−ジメチル−４，５−ジヒドロイソオキサゾールの製造方法及び３−ブロモ−５，５−ジメチル−４，５−ジヒドロイソオキサゾールに関するものである。 The present invention relates to a process for producing 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole useful as an intermediate for producing pharmaceuticals and agricultural chemicals, and 3-bromo-5,5-dimethyl-4,5-dihydro. It relates to isoxazole.
本発明によって得られる３−ブロモ−５，５−ジメチル−４，５−ジヒドロイソオキサゾールは医薬及び農薬の製造中間体として有用である。 3-Bromo-5,5-dimethyl-4,5-dihydroisoxazole obtained by the present invention is useful as an intermediate for producing pharmaceuticals and agricultural chemicals.
３−ブロモ−５，５−ジメチル−４，５−ジヒドロイソオキサゾールの合成方法としては、塩基存在下、ジハロゲノホルムオキシムに２−メチルプロペンを反応させる方法が知られている（特許文献１参照）。 As a method for synthesizing 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole, a method of reacting 2-methylpropene with dihalogenoform oxime in the presence of a base is known (see Patent Document 1). ).
しかしながら、該公報においてはジクロロホルムオキシムからの３−クロロ−５，５−ジメチル−４，５−ジヒドロイソオキサゾールの製造に関しては参考例に具体的な記載はあるものの、３−ブロモ−５，５−ジメチル−４，５−ジヒドロイソオキサゾールに関しては具体的な記載がない。また、該公報によれば、ジクロロホルムオキシムからは４０％程度の低収率でしか目的物が得られていない。 However, in this publication, although there is a specific description in the Reference Example regarding the production of 3-chloro-5,5-dimethyl-4,5-dihydroisoxazole from dichlorochloroform oxime, 3-bromo-5,5 There is no specific description regarding -dimethyl-4,5-dihydroisoxazole. Further, according to the publication, the target product is obtained from dichlorochloroform oxime only at a low yield of about 40%.
また、ジハロゲノホルムオキシム化合物群は、びらん性化合物としての毒性が知られており、なかでもジクロロホルムオキシムはホスゲンオキシム（通称名：ＣＸ）と呼ばれ、その毒性も良く知られている。このジクロロホルムオキシムは、類似の化合物群（ジハロゲノホルムオキシム化合物群）の中でも特に毒性が強く、室温でも症状の発現に十分な蒸気圧を持つことも知られている。従って、取り扱いには細心の注意が必要であり、特に大量に製造することは困難であり、従って、特許文献１に記載の、ジクロロホルムオキシムを用いる３−クロロ−５，５−ジメチル−４，５−ジヒドロイソオキサゾールの製造方法は、工業的製法として適当とはいえない。 In addition, the dihalogenoform oxime compound group is known to be toxic as an erodible compound. Among them, dichloroform oxime is called phosgene oxime (common name: CX), and its toxicity is well known. Dichloroform oxime is particularly toxic among similar compound groups (dihalogenoform oxime compound group), and is known to have a vapor pressure sufficient to develop symptoms even at room temperature. Therefore, it must be handled with great care, and it is particularly difficult to produce in large quantities. Therefore, as disclosed in Patent Document 1, 3-chloro-5,5-dimethyl-4, The production method of 5-dihydroisoxazole is not suitable as an industrial production method.
一方、ジブロモホルムオキシムは、室温で固体の化合物であって蒸気圧も低いため、取り扱いはジクロロホルムオキシムに対してはるかに容易である。 On the other hand, since dibromoform oxime is a compound that is solid at room temperature and has a low vapor pressure, it is much easier to handle than dichloroform oxime.
上記の従来の技術の持つ欠点を解決した、３−ブロモ−５，５−ジメチル−４，５−ジヒドロイソオキサゾールを簡便且つ安全に、収率良く製造する方法が望まれていた。 There has been a demand for a method for producing 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole in a simple and safe manner with a high yield, which has solved the above-described drawbacks of the conventional techniques.
上記のような状況に鑑み、本発明者が３−ブロモ−５，５−ジメチル−４，５−ジヒドロイソオキサゾールを製造する方法について鋭意研究を重ねた結果、ジハロゲノオキシム化合物として、取り扱いの容易な、後記する式（１）で表されるジブロモホルムオキシムを特に選択し、これを、塩基存在下、２−メチルプロペンと反応させることにより、式（２）で表される３−ブロモ−５，５−ジメチル−４，５−ジヒドロイソオキサゾールを短時間で高収率に生成させることができることを見出し、この知見に基づき本発明を完成するに至った。 In view of the situation as described above, the present inventors have conducted extensive research on a method for producing 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole, and as a result, the dihalogenooxime compound is easy to handle. In particular, dibromoform oxime represented by the formula (1) described later is specifically selected and reacted with 2-methylpropene in the presence of a base to give 3-bromo-5 represented by the formula (2). , 5-dimethyl-4,5-dihydroisoxazole can be produced in a high yield in a short time, and the present invention has been completed based on this finding.
本発明方法により、式（２）で表される３−ブロモ−５，５−ジメチル−４，５−ジヒドロイソオキサゾールが短時間で収率良く製造される。原料の取り扱いも簡単で、作業安全性もジクロロホルムオキシムを用いる場合よりもはるかに向上しており、工業的製造方法としてきわめて有用である。 By the method of the present invention, 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole represented by the formula (2) is produced in a high yield in a short time. The handling of the raw material is simple and the work safety is much improved as compared with the case of using dichlorochloroform oxime, which is extremely useful as an industrial production method.
以下、本発明について詳細に説明する。 Hereinafter, the present invention will be described in detail.
本発明は、下記〔１〕〜〔２〕項に記載の発明を提供する事により前記課題を解決したものである。 This invention solves the said subject by providing the invention as described in the following [1]-[2].
〔１〕式（１） [1] Formula (1)
で表されるジブロモホルムオキシムに、塩基存在下、２−メチルプロペンを反応させることを特徴とする、式（２） Wherein 2-methylpropene is reacted with dibromoform oxime represented by formula (2) in the presence of a base.
で表される３−ブロモ−５，５−ジメチル−４，５−ジヒドロイソオキサゾールの製造方法。 The manufacturing method of 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole represented by these.
〔２〕３−ブロモ−５，５−ジメチル−４，５−ジヒドロイソオキサゾール。 [2] 3-Bromo-5,5-dimethyl-4,5-dihydroisoxazole.
以下、本発明について詳細に説明する。 Hereinafter, the present invention will be described in detail.
本発明は、ＣＸよりはるかに取り扱いが容易で安全な、式（１）で表されるジブロモホルムオキシムを、塩基存在下、２−メチルプロペンと反応させて、式（２）で表される３−ブロモ−５，５−ジメチル−４，５−ジヒドロイソオキサゾールを高収率で製造する方法及び該３−ブロモ−５，５−ジメチル−４，５−ジヒドロイソオキサゾールに関するものである。 In the present invention, the dibromoform oxime represented by the formula (1), which is much easier to handle and safer than CX, is reacted with 2-methylpropene in the presence of a base to produce 3 represented by the formula (2). The present invention relates to a method for producing bromo-5,5-dimethyl-4,5-dihydroisoxazole in a high yield and the 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole.
まず、本発明において原料として使用する式（１）で表されるジブロモホルムオキシムについて説明する。 First, the dibromoform oxime represented by Formula (1) used as a raw material in this invention is demonstrated.
式（１）で表されるジブロモホルムオキシムは公知化合物であり、種々の合成方法が知られている。 Dibromoform oxime represented by the formula (1) is a known compound, and various synthetic methods are known.
例えば、グリオキシル酸とヒドロキシルアミンからヒドロキシイミノ酢酸を合成し、これに臭素を反応させることでジブロモホルムオキシムが白色結晶として７８％の収率で得られることが、テトラへドロン レターズ（Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔｅｒｓ），第３３巻，２２号，３１１３頁（１９９２）に報告されている。 For example, by synthesizing hydroxyiminoacetic acid from glyoxylic acid and hydroxylamine and reacting with bromine, dibromoformoxime can be obtained as white crystals in a yield of 78%. Tetrahedron Letters, 33, No. 22, p. 3113 (1992).
例えば前述の方法で得られたジブロモホルムオキシムは、白色結晶として単離することができるが、本発明方法の反応においては、ヒドロキシイミノ酢酸に臭素を反応させた反応液からジブロモホルムオキシムを有機溶媒で抽出するだけで、これをそのまま（すなわち抽出溶液のまま）次工程に使用することも可能である。抽出溶媒は、そのまま３−ブロモ−５，５−ジメチル−４，５−ジヒドロイソオキサゾールの反応溶媒として使用できる。 For example, the dibromoform oxime obtained by the above-mentioned method can be isolated as a white crystal. In the reaction of the method of the present invention, dibromoform oxime is converted into an organic solvent from a reaction solution obtained by reacting hydroxyiminoacetic acid with bromine. It is also possible to use it in the next step as it is (ie, as an extraction solution) simply by extracting with (1). The extraction solvent can be used as a reaction solvent for 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole as it is.
ここで用いうる抽出溶媒としては、水と分液するものであれば特に限定されることはなく、例えば、トルエン、キシレン、クロロベンゼン等の芳香族炭化水素類；例えば、ジクロロメタン、クロロホルム等のハロゲン化脂肪族炭化水素類；例えば、酢酸メチル、酢酸エチル、酢酸ブチル等の酢酸エステルに代表される脂肪酸エステル類；例えば、ジエチルエーテル、ジイソプロピルエーテル、ジオキサン等のエ−テル系溶媒類；例えば、ペンタン、ｎ−ヘキサン等の脂肪族炭化水素類等が挙げられる。抽出効率の観点からジエチルエーテル、ジイソプロピルエーテル、ジオキサン等のエーテル系溶媒類や酢酸メチル、酢酸エチル等の酢酸エステルに代表される脂肪酸エステル類を用いるのが好ましい。 The extraction solvent that can be used here is not particularly limited as long as it can be separated from water, for example, aromatic hydrocarbons such as toluene, xylene, and chlorobenzene; for example, halogenated compounds such as dichloromethane and chloroform. Aliphatic hydrocarbons; for example, fatty acid esters represented by acetate such as methyl acetate, ethyl acetate, and butyl acetate; ether solvents such as diethyl ether, diisopropyl ether, and dioxane; Examples thereof include aliphatic hydrocarbons such as n-hexane. From the viewpoint of extraction efficiency, it is preferable to use ether solvents such as diethyl ether, diisopropyl ether and dioxane, and fatty acid esters typified by acetate such as methyl acetate and ethyl acetate.
次に、式（１）で表されるジブロモホルムオキシムと２−メチルプロペンを反応させて、式（２）で表される３−ブロモ−５，５−ジメチル−４，５−ジヒドロイソオキサゾールを製造する方法について説明する。 Next, dibromoform oxime represented by the formula (1) is reacted with 2-methylpropene to give 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole represented by the formula (2). A manufacturing method will be described.
当反応に用いる塩基としては、例えば、水酸化ナトリウム（ＮａＯＨ）、水酸化カリウム（ＫＯＨ）、水酸化リチウム（ＬｉＯＨ）等のアルカリ金属水酸化物；例えば、水酸化バリウム、水酸化マグネシウム、水酸化カルシウム等のアルカリ土類金属水酸化物；例えば、炭酸ナトリウム（Ｎａ２ＣＯ３）、炭酸カリウム（Ｋ２ＣＯ３）、炭酸水素ナトリウム（ＮａＨＣＯ３）、炭酸水素カリウム等のアルカリ金属炭酸塩；例えば、酸化バリウム、酸化マグネシウム及び酸化カルシウム等のアルカリ土類金属酸化物などを包含する無機塩基；ならびに、ナトリウムメトキシド、ナトリウムエトキシド、カリウムメトキシド、カリウムエトキシド、ｔ−ブトキシカリウム等の金属アルコキシド；トリエチルアミン、１，８−ジアザビシクロ[５．４．０]ウンデカ−７−エン（ＤＢＵ）等を包含する有機塩基を例示できるが、無機塩基を用いて行うのが高収率であり好ましく、特に、水酸化ナトリウム等のアルカリ金属水酸化物や、炭酸カリウム等のアルカリ金属炭酸塩を用いて行うのが良い。 Examples of the base used in this reaction include alkali metal hydroxides such as sodium hydroxide (NaOH), potassium hydroxide (KOH), and lithium hydroxide (LiOH); for example, barium hydroxide, magnesium hydroxide, hydroxide Alkaline earth metal hydroxides such as calcium; for example, alkali metal carbonates such as sodium carbonate (Na 2 CO 3 ), potassium carbonate (K 2 CO 3 ), sodium bicarbonate (NaHCO 3 ), potassium bicarbonate; Inorganic bases including alkaline earth metal oxides such as barium oxide, magnesium oxide and calcium oxide; and metal alkoxides such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide and t-butoxypotassium Triethylamine, 1,8-diazabicyclo [5.4.0] Organic bases including undec-7-ene (DBU) and the like can be exemplified, but the use of an inorganic base is preferable because of high yield, and in particular, an alkali metal such as sodium hydroxide. It is preferable to use a hydroxide or an alkali metal carbonate such as potassium carbonate.
塩基の使用量は、反応が充分に進行する量であれば何れでもよいが、式（１）で表されるジブロモホルムオキシム（原料化合物）１モルに対して塩基が０．５〜２０モル、好ましくは０．５〜１０モル、より好ましくは１．０〜３．０モルの範囲を例示できる。 The amount of the base used may be any as long as the reaction proceeds sufficiently, but the base is 0.5 to 20 mol with respect to 1 mol of dibromoformoxime (raw material compound) represented by formula (1), The range is preferably 0.5 to 10 mol, more preferably 1.0 to 3.0 mol.
当反応で使用する２−メチルプロペンの使用量は、反応が充分に進行する量であれば何れでもよいが、式（１）で表されるジブロモホルムオキシム１モルに対して２−メチルプロペンが通常１．０〜１０.０モル、好ましくは１．０〜５．０モル、更に好ましくは１.５〜３．０モルの範囲を例示できる。 The amount of 2-methylpropene used in the reaction may be any amount as long as the reaction proceeds sufficiently. However, 2-methylpropene is added to 1 mol of dibromoformoxime represented by the formula (1). The range is usually 1.0 to 10.0 mol, preferably 1.0 to 5.0 mol, and more preferably 1.5 to 3.0 mol.
２−メチルプロペンは常温でガスであり、反応系への導入は液面吸収や吹き込みによって行なうことができるが、吹込みによるのが好ましい。反応系への２−メチルプロペンの導入速度は、未反応のガス（２−メチルプロペン）が反応系外に逃げてしまわないような導入速度であれば何れでもよく、反応系内に存在するジブロモホルムオキシムに対して過剰〜小過剰となるような量を導入できるような導入速度とした場合に収率が高くなる傾向が見られる。２−メチルプロペンの導入速度の範囲を例示するならば、０．０２〜０．７ｍｏｌ／時間といった速度を例示することはできるが、実際には、この２−メチルプロペンの導入速度は反応スケールの大小にも依存するので一概には言えないため、この例示範囲にとらわれることなく実際の反応スケールに合わせて適宜設定すればよい。 2-Methylpropene is a gas at normal temperature and can be introduced into the reaction system by liquid level absorption or blowing, but blowing is preferred. The introduction rate of 2-methylpropene into the reaction system may be any introduction rate so long as unreacted gas (2-methylpropene) does not escape from the reaction system. When the introduction rate is such that an amount that is excessive to small excess with respect to bromoform oxime can be introduced, the yield tends to increase. If the range of the introduction rate of 2-methylpropene is exemplified, a rate such as 0.02 to 0.7 mol / hour can be exemplified. However, in practice, the introduction rate of 2-methylpropene depends on the reaction scale. Since it depends on the size, it cannot be said unconditionally. Therefore, it may be appropriately set according to the actual reaction scale without being limited to this exemplary range.
当反応に用いうる溶媒としては、反応を阻害しないものであれば良く、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；例えば、トルエン、キシレン、クロロベンゼン等の芳香族炭化水素類；例えば、ジクロロメタン、クロロホルム等のハロゲン化脂肪族炭化水素類；例えば、酢酸メチル、酢酸エチル、酢酸ブチル等の酢酸エステルに代表される脂肪酸エステル類；例えば、ジメチルホルムアミド、ジメチルアセトアミド、Ｎ−メチルピロリドン、テトラメチル尿素、ヘキサメチルホスホリックトリアミド（ＨＭＰＡ）、プロピレンカーボネート等の非プロトン性極性溶媒類；例えば、エチルエーテル、イソプロピルエーテル、テトラヒドロフラン、ジオキサン等のエーテル系溶媒類；例えば、ペンタン、ｎ−ヘキサン等の脂肪族炭化水素類等が挙げられる。好ましくは、式（１）で表されるジハロゲノホルムオキシム化合物（原料化合物）を原料合成する際に、抽出に使用した溶媒をそのまま当反応に用いるのが簡便で、特に、酢酸エチル等の酢酸エステル類やイソプロピルエーテル等のエーテル系溶媒中で行うのが好ましい。ここで、溶媒は単独で、又は任意の混合割合の混合溶媒として用いることができ、例えばイソプロピルアルコール等のアルコール類等の極性の高い溶媒を、極性の低い溶媒に混合した混合溶媒系で当反応を実施すると反応が加速され、多くの場合、反応時間が短縮できたり収率が向上するといった、より好ましい結果を示す。 Solvents that can be used for this reaction are not particularly limited as long as they do not inhibit the reaction, for example, water; alcohols such as methanol, ethanol, isopropyl alcohol; for example, aromatic hydrocarbons such as toluene, xylene, chlorobenzene; Halogenated aliphatic hydrocarbons such as dichloromethane, chloroform; fatty acid esters typified by acetate such as methyl acetate, ethyl acetate, butyl acetate; for example, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetra Aprotic polar solvents such as methylurea, hexamethylphosphoric triamide (HMPA), and propylene carbonate; for example, ether solvents such as ethyl ether, isopropyl ether, tetrahydrofuran, and dioxane; - aliphatic hydrocarbons such as hexane and the like. Preferably, when synthesizing the dihalogenoform oxime compound (raw material compound) represented by the formula (1) as a raw material, it is simple to use the solvent used for the extraction as it is in this reaction, and in particular, acetic acid such as ethyl acetate. It is preferable to carry out in an ether solvent such as esters and isopropyl ether. Here, the solvent can be used alone or as a mixed solvent of any mixing ratio. For example, the reaction is performed in a mixed solvent system in which a highly polar solvent such as alcohols such as isopropyl alcohol is mixed with a less polar solvent. The reaction is accelerated, and in many cases, the reaction time can be shortened and the yield is improved.
溶媒量としては、反応系の攪拌が充分にできる量であれば良いが、式（１）で表されるジブロモホルムオキシム１モルに対して溶媒が通常０．０５〜１０ｌ、好ましくは０．５〜２ｌの範囲であれば良い。 The amount of the solvent may be an amount that can sufficiently stir the reaction system, but the amount of the solvent is usually 0.05 to 10 l, preferably 0.5 to 1 mol of dibromoformoxime represented by the formula (1). It may be in the range of ~ 2l.
当反応においては、極性が低い溶媒のみを用い、かつ塩基として無機塩基を用いる場合無機塩基の溶解性や反応性の向上を意図して添加剤を加えることにより反応が加速され、より好ましい結果を示す場合がある。 In this reaction, when only a solvent with low polarity is used and an inorganic base is used as the base, the reaction is accelerated by adding an additive with the intention of improving the solubility and reactivity of the inorganic base, and a more preferable result is obtained. May show.
添加剤としての相間移動触媒としては、例えば、塩化テトラブチルアンモニウム（ＴＢＡＢ）、塩化ベンジルトリエチルアンモニウム等の四級アンモニウム塩；塩化テトラブチルホスホニウム、臭化テトラフェニルホスホニウム（ＴＰＰＢ）等の四級ホスホニウム塩；１８−クラウン−６、ジベンゾ−１８−クラウン−６等のクラウンエーテル類等を例示できる。 Examples of the phase transfer catalyst as an additive include, for example, quaternary ammonium salts such as tetrabutylammonium chloride (TBAB) and benzyltriethylammonium chloride; quaternary phosphonium salts such as tetrabutylphosphonium chloride and tetraphenylphosphonium bromide (TPPB). And crown ethers such as 18-crown-6 and dibenzo-18-crown-6.
また、添加剤としての界面活性剤としては、例えばポリエチレングリコール−３００（ＰＥＧ−３００、数平均分子量２８５−３１５）、ポリエチレングリコール−６００（ＰＥＧ−６００、数平均分子量５７０−６３０）等のポリエチレングリコール類や、例えばポリプロピレングリコール−３００（ＰＰＧ−３００、数平均分子量 約３００等）のポリプロピレングリコール類を包含する、ポリアルキレングリコール類を例示することができる。 Examples of the surfactant as an additive include polyethylene glycols such as polyethylene glycol-300 (PEG-300, number average molecular weight 285-315) and polyethylene glycol-600 (PEG-600, number average molecular weight 570-630). And, for example, polyalkylene glycols including polypropylene glycols of polypropylene glycol-300 (PPG-300, number average molecular weight of about 300, etc.).
当反応における添加剤の使用量は、反応が充分に進行する量であれば何れでも良いが、一般式（１）で表される原料化合物１モルに対して０．００５〜０．５モル、好ましくは０．０１〜０．１モルの範囲を例示できる。 The amount of the additive used in the reaction may be any amount as long as the reaction proceeds sufficiently, but 0.005 to 0.5 mol with respect to 1 mol of the raw material compound represented by the general formula (1), Preferably the range of 0.01-0.1 mol can be illustrated.
当反応の反応温度は、−１０℃〜使用する溶媒の還流温度、の範囲を例示できるが、好ましくは０℃〜２０℃で反応させると、短時間で反応が完結し、収率も良い。 Although the reaction temperature of this reaction can illustrate the range of -10 degreeC-the reflux temperature of the solvent to be used, Preferably when it is made to react at 0 degreeC-20 degreeC, reaction is completed in a short time and a yield is also good.
当反応の反応時間は特に制限されないが、反応速度は、２−メチルプロペンの導入速度にも依存するが、通常は１時間〜１０時間で反応は終了する。 Although the reaction time of this reaction is not particularly limited, the reaction rate depends on the introduction rate of 2-methylpropene, but the reaction is usually completed in 1 hour to 10 hours.
当反応によれば、簡便な操作方法且つ穏やかな条件下で、収率よく、且つジクロロホルムオキシムを使う場合と比較して安全に、式（２）で表される３−ブロモ−５，５−ジメチル−４，５−ジヒドロイソオキサゾールを製造することができる。得られる、式（２）で表される３−ブロモ−５，５−ジメチル−４，５−ジヒドロイソオキサゾールは、医農薬等の中間原料として有用な化合物である。 According to this reaction, 3-bromo-5,5 represented by the formula (2) can be obtained in a simple operation method and under mild conditions with a good yield and more safely than in the case of using dichlorochloroform oxime. -Dimethyl-4,5-dihydroisoxazole can be produced. The obtained 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole represented by the formula (2) is a useful compound as an intermediate raw material for medical and agricultural chemicals.
次に、実施例を挙げて本発明化合物の製造方法を具体的に説明するが、本発明は、これら実施例によって何ら限定されるものではない。 Next, although the Example is given and the manufacturing method of this invention compound is demonstrated concretely, this invention is not limited at all by these Examples.
（参考例１）：ジブロモホルムオキシムの合成
５０％グリオキシル酸水溶液８８．８ｇ（０．６ｍｏｌ）を水１２０ｍｌに希釈し、水浴攪拌下、５０％ヒドロキシルアミン水溶液３９．６ｇ（０．６ｍｏｌ）を０．５時間かけて滴下した。滴下後、室温で１時間攪拌した。次いで、４８％水酸化ナトリウム水溶液５０ｇ（０．６ｍｏｌ）を反応液が２５℃以下になるように水浴で冷却しながら、徐々に滴下した。この際、反応液のｐＨが７であることを確認した。この反応液に、リン酸二水素ナトリウム・２水和物１８７．２ｇ（１．２ｍｏｌ）を加えた後、５℃以下まで冷却した。反応液に、臭素１９１．８ｇ（１．２ｍｏｌ）を反応液が１０℃以下を保つよう、４時間かけて滴下した。滴下後、２時間熟成し、次いで数滴の１０％重亜硫酸ナトリウム水溶液を加え、過剰の臭素を分解した。分解は反応液の色が消失することで確認した。反応液にイソプロピルエーテル１８０ｍｌを加え、有機層を分取した。さらに水層をイソプロピルエーテル６０ｍｌで再抽出した。合わせた有機層を飽和食塩水２０ｍｌで洗浄し、無水硫酸ナトリウムで乾燥させた。溶媒を減圧留去し、表題化合物１２０．１ｇ（純度７９％；収率７６．７％）を淡黄色結晶として得た。これをｎ−ヘキサンで洗浄することで表題化合物を白色結晶(純度９９％)として得た。
(Reference Example 1): Synthesis of dibromoform oxime 88.8 g (0.6 mol) of 50% glyoxylic acid aqueous solution was diluted with 120 ml of water, and 39.6 g (0.6 mol) of 50% hydroxylamine aqueous solution was reduced to 0 with stirring in a water bath. Added dropwise over 5 hours. After dropping, the mixture was stirred at room temperature for 1 hour. Next, 50 g (0.6 mol) of a 48% sodium hydroxide aqueous solution was gradually added dropwise while cooling with a water bath so that the reaction solution was 25 ° C. or lower. At this time, it was confirmed that the pH of the reaction solution was 7. To this reaction solution, 187.2 g (1.2 mol) of sodium dihydrogen phosphate dihydrate was added, and then cooled to 5 ° C. or lower. To the reaction solution, 191.8 g (1.2 mol) of bromine was added dropwise over 4 hours so that the reaction solution kept at 10 ° C. or lower. After dropping, the mixture was aged for 2 hours, and then a few drops of 10% aqueous sodium bisulfite solution were added to decompose excess bromine. Decomposition was confirmed by the disappearance of the color of the reaction solution. 180 ml of isopropyl ether was added to the reaction solution, and the organic layer was separated. Further, the aqueous layer was re-extracted with 60 ml of isopropyl ether. The combined organic layers were washed with 20 ml of saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 120.1 g (purity 79%; yield 76.7%) of the title compound as pale yellow crystals. This was washed with n-hexane to give the title compound as white crystals (purity 99%).
ＧＣ−ＭＳ（ＥＩ）ｍ／ｚ＝２０３（Ｍ＋），１２２（Ｂａｓｅ）
融点は６５−６６℃で、文献値と一致した。
GC-MS (EI) m / z = 203 (M + ), 122 (Base)
Melting point was 65-66 ° C., consistent with literature values.
（参考例２）：ジブロモホルムオキシムの合成
５０％グリオキシル酸水溶液７４．０ｇ（０．５ｍｏｌ）を水１００ｍｌに希釈し、水浴攪拌下、５０％ヒドロキシルアミン水溶液３３．０ｇ（０．５ｍｏｌ）を０．５時間かけて滴下した。滴下後、室温で１時間攪拌した。次いで、４８％水酸化ナトリウム水溶液４２ｇ（０．５ｍｏｌ）を反応液が２５℃以下になるように水浴で冷却しながら、徐々に滴下した。この際、反応液のｐＨが７であることを確認した。この反応液に、リン酸二水素ナトリウム・２水和物１５６．０ｇ（１．０ｍｏｌ）を加えた後、５℃以下まで冷却した。反応液に、臭素１５９．８ｇ（１．０ｍｏｌ）を反応液が１０℃以下を保つよう、４時間かけて滴下した。滴下後、２時間熟成し、次いで数滴の１０％重亜硫酸ナトリウム水溶液を加え、過剰の臭素を分解した。分解は反応液の色が消失することで確認した。反応液にイソプロピルエーテル１５０ｍｌを加え、有機層を分取した。さらに水層をイソプロピルエーテル１００ｍｌで再抽出した。合わせた有機層を飽和食塩水２０ｍｌで洗浄し、無水硫酸ナトリウムで乾燥させた。ガスクロマトグラフィーによる分析の結果、このイソプロピルエーテル溶液２６５．３ｇ中には表題化合物８１．２ｇが含まれており（濃度３０．６％）、収率は８０．１％であった。
(Reference Example 2): Synthesis of dibromoform oxime 74.0 g (0.5 mol) of 50% glyoxylic acid aqueous solution was diluted with 100 ml of water, and 33.0 g (0.5 mol) of 50% hydroxylamine aqueous solution was added to 0 with stirring in a water bath. Added dropwise over 5 hours. After dropping, the mixture was stirred at room temperature for 1 hour. Subsequently, 42 g (0.5 mol) of a 48% aqueous sodium hydroxide solution was gradually added dropwise while cooling with a water bath so that the reaction solution was 25 ° C. or lower. At this time, it was confirmed that the pH of the reaction solution was 7. To this reaction liquid, 156.0 g (1.0 mol) of sodium dihydrogen phosphate dihydrate was added, and then cooled to 5 ° C. or lower. To the reaction solution, 159.8 g (1.0 mol) of bromine was added dropwise over 4 hours so that the reaction solution kept at 10 ° C. or lower. After dropping, the mixture was aged for 2 hours, and then a few drops of 10% aqueous sodium bisulfite solution were added to decompose excess bromine. Decomposition was confirmed by the disappearance of the color of the reaction solution. 150 ml of isopropyl ether was added to the reaction solution, and the organic layer was separated. Further, the aqueous layer was re-extracted with 100 ml of isopropyl ether. The combined organic layers were washed with 20 ml of saturated brine and dried over anhydrous sodium sulfate. As a result of analysis by gas chromatography, 265.3 g of this isopropyl ether solution contained 81.2 g of the title compound (concentration: 30.6%), and the yield was 80.1%.
（実施例１）：３−ブロモ−５，５−ジメチル−４，５−ジヒドロイソオキサゾールの合成
イソプロピルエーテル３５０ｍｌにビーズ状の９９％水酸化ナトリウム８４．０ｇ（２．１ｍｏｌ）を懸濁し、５℃以下に冷却した。氷冷下で攪拌しながら、２−メチルプロペン７８．６ｇ（１．４ｍｏｌ）を約３時間で終了する速度で吹き込みを開始した。１時間後、２−メチルプロペン２６．２ｇ（０．４７ｍｏｌ；想定量の１／３）が吹き込まれていることを確認した後、引き続き同一速度で２−メチルプロペンを導入しながら、参考例２で合成したジブロモホルムオキシムのイソプロピルエーテル溶液４６４．０ｇ（濃度３０．６％）を５℃以下に冷却攪拌下、３時間かけて滴下した。滴下終了後、同温で２時間熟成した。反応液に水３５０ｍｌを加え、室温で０．５時間撹拌し、有機層を分取した。得られた有機層を水１４０ｍｌで２回、飽和食塩水７０ｍｌで１回洗浄し、無水硫酸ナトリウムで乾燥した。溶媒を留去し、得られた黄色の油状物をさらに蒸留することにより透明液体８４．７ｇ（純度９９．０％、収率６８％）を得た。
(Example 1): Synthesis of 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole 84.0 g (2.1 mol) of 99% sodium hydroxide in the form of beads was suspended in 350 ml of isopropyl ether. Cooled below ℃. While stirring under ice cooling, 78.6 g (1.4 mol) of 2-methylpropene was started to be blown at a speed that was completed in about 3 hours. One hour later, after confirming that 26.2 g (0.47 mol; 1/3 of the expected amount) of 2-methylpropene was blown in, Reference Example 2 was carried out while continuously introducing 2-methylpropene at the same rate. 464.0 g (concentration: 30.6%) of the isopropyl ether solution of dibromoform oxime synthesized in (3) was added dropwise to 5 ° C. or less over 3 hours with cooling and stirring. After completion of dropping, the mixture was aged at the same temperature for 2 hours. 350 ml of water was added to the reaction solution, and the mixture was stirred at room temperature for 0.5 hour to separate the organic layer. The obtained organic layer was washed twice with 140 ml of water and once with 70 ml of saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off, and the resulting yellow oil was further distilled to obtain 84.7 g of a transparent liquid (purity 99.0%, yield 68%).
１Ｈ−ＮＭＲ値（３００ＭＨｚ，ＣＤＣｌ３）：σ＝２．９５（ｓ，２Ｈ），１．４４（ｓ，３Ｈ）ｐｐｍ
ＧＣ−ＭＳ（ＥＩ）：ｍ／ｚ＝１７８（Ｍ＋），１６２（ｂａｓｅ）
沸点：４０℃／０．３ｋＰａ
1 H-NMR value (300 MHz, CDCl 3 ): σ = 2.95 (s, 2H), 1.44 (s, 3H) ppm
GC-MS (EI): m / z = 178 (M + ), 162 (base)
Boiling point: 40 ° C / 0.3kPa
以下の実施例では、実施例１で得られた化合物（３−ブロモ−５，５−ジメチル−４，５−ジヒドロイソオキサゾール）を標品とし、内部標準分析法（内部標準；ジ−ｐ−トリルエーテル）により反応収率を算出した。 In the following examples, the compound (3-bromo-5,5-dimethyl-4,5-dihydroisoxazole) obtained in Example 1 was used as a standard, and an internal standard analysis method (internal standard; di-p- The reaction yield was calculated by (tolyl ether).
（実施例２）：３−ブロモ−５，５−ジメチル−４，５−ジヒドロイソオキサゾールの製造（収率確認実験）
イソプロピルエーテル２５ｍｌにジ−ｐ−トリルエーテル０．５ｇ（内部標準物質）、ビーズ状の９９％水酸化ナトリウム１０．０ｇ（０．２５ｍｏｌ）を懸濁し、５℃以下に冷却した。氷冷下で攪拌しながら、２−メチルプロペン８．４ｇ（０．１５ｍｏｌ）を約３時間で終了する速度で吹き込みを開始した。１時間後、２−メチルプロペン２．８ｇ（０．０５ｍｏｌ；想定量の１／３）が吹き込まれていることを確認した後、引き続き同一速度で２−メチルプロペンを導入しながら、参考例２で合成したジブロモホルムオキシムのジイソプロピルエーテル溶液３３．１ｇ（濃度３０．６％）を５℃以下に冷却攪拌下、３時間かけて滴下した。１時間後、反応液をサンプリングして、ガスクロマトグラフィーを用いた内部標準分析法にて反応収率を算出した結果、収率は８０．２％であった。
Example 2 Production of 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole (Yield Confirmation Experiment)
0.5 g of di-p-tolyl ether (internal standard substance) and 10.0 g (0.25 mol) of bead-like 99% sodium hydroxide were suspended in 25 ml of isopropyl ether and cooled to 5 ° C. or lower. While stirring under ice-cooling, 8.4 g (0.15 mol) of 2-methylpropene was started to be blown at a speed that ended in about 3 hours. One hour later, after confirming that 2.8 g (0.05 mol; 1/3 of the expected amount) of 2-methylpropene was blown in, Reference Example 2 was carried out while continuously introducing 2-methylpropene at the same rate. 33.1 g (concentration: 30.6%) of dibromoform oxime synthesized in 1 above was added dropwise over 3 hours under cooling and stirring to 5 ° C. or lower. After 1 hour, the reaction solution was sampled, and the reaction yield was calculated by an internal standard analysis method using gas chromatography. As a result, the yield was 80.2%.
実施例３〜１１
実施例２と同様の操作にて、各種溶媒と塩基の組み合わせで反応を行った。結果を（表１）に纏めた。
Examples 3-11
The reaction was carried out in the same manner as in Example 2 using combinations of various solvents and bases. The results are summarized in (Table 1).
＊２：「ＰＰＧ−３００」はポリプロピレングリコール−３００（数平均分子量 約３００）を示す。
* 2: “PPG-300” indicates polypropylene glycol-300 (number average molecular weight of about 300).
（比較例１）：３−クロロ−５，５−ジメチル−４，５−ジヒドロイソオキサゾールの合成
エタノール５００ｍｌ、炭酸水素ナトリウム６３．０ｇ（０．７５ｍｏｌ）を加え、室温で撹拌させた。２−メチルプロペン８４．２ｇ（１．５０ｍｏｌ）を吹き込みながら０．５時間後、７０℃に昇温し、ジクロロホルムオキシムの４０％イソプロピルエーテル溶液１３１．３ｇ（０．５ｍｏｌ）を反応液に徐々に滴下し、同温度で８時間攪拌した。２５℃以下まで放冷し、ろ過により無機固体を除去した後、溶媒を留去した。得られた黄色溶液を６２℃／１．１ｋＰａで減圧蒸留し、無色透明液体の３−クロロ−４，５−ジヒドロイソキサゾール３２．３ｇ（収率４１％）を無色透明液体として得た。
(Comparative Example 1): Synthesis of 3-chloro-5,5-dimethyl-4,5-dihydroisoxazole 500 ml of ethanol and 63.0 g (0.75 mol) of sodium hydrogen carbonate were added and stirred at room temperature. After 0.5 hours while blowing 2-methylpropene (84.2 g, 1.50 mol), the temperature was raised to 70 ° C., and 131.3 g (0.5 mol) of a 40% isopropyl ether solution of dichlorochloroform oxime was gradually added to the reaction solution. And stirred at the same temperature for 8 hours. The mixture was allowed to cool to 25 ° C. or lower, the inorganic solid was removed by filtration, and then the solvent was distilled off. The obtained yellow solution was distilled under reduced pressure at 62 ° C./1.1 kPa to obtain 32.3 g (yield 41%) of 3-chloro-4,5-dihydroisoxazole as a colorless transparent liquid as a colorless transparent liquid.
１Ｈ−ＮＭＲ値（３００ＭＨｚ，ＣＤＣｌ３）：σ＝２．８８（ｓ，２Ｈ），１．４１（ｓ，３Ｈ）ｐｐｍ
ＧＣ−ＭＳ（ＥＩ）：ｍ／ｚ＝１３３（Ｍ＋），１１８（ｂａｓｅ）
沸点：５０℃／０．７ｋＰａ
1 H-NMR value (300 MHz, CDCl 3 ): σ = 2.88 (s, 2H), 1.41 (s, 3H) ppm
GC-MS (EI): m / z = 133 (M + ), 118 (base)
Boiling point: 50 ° C / 0.7kPa
３−ブロモ−５，５−ジメチル−４，５−ジヒドロイソオキサゾールの新規な工業的製造法が提供される。本発明方法によれば、式（１）で表されるジブロモホルムオキシムから、簡便な操作方法且つ穏やかな条件下で、収率よく、式（２）で表される３−ブロモ−５，５−ジメチル−４，５−ジヒドロイソオキサゾールを製造することができる。しかも、原料の取り扱いも簡単で、作業安全性もジクロロホルムオキシムより向上しており、工業的製造方法としてきわめて有用である。 A new industrial process for the production of 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole is provided. According to the method of the present invention, 3-bromo-5,5 represented by the formula (2) can be obtained from the dibromoform oxime represented by the formula (1) with a good yield under a simple operation method and mild conditions. -Dimethyl-4,5-dihydroisoxazole can be produced. In addition, the handling of the raw material is simple and the work safety is improved from that of dichloroform oxime, which is extremely useful as an industrial production method.
Claims (2)
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2004293715A JP2008001597A (en) | 2004-10-06 | 2004-10-06 | Method for producing 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole |
| PCT/JP2005/018453 WO2006038657A1 (en) | 2004-10-06 | 2005-10-05 | 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole and method for producing same |
| TW094134986A TW200630351A (en) | 2004-10-06 | 2005-10-06 | 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole and method for producing same |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2004293715A JP2008001597A (en) | 2004-10-06 | 2004-10-06 | Method for producing 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JP2008001597A true JP2008001597A (en) | 2008-01-10 |
Family
ID=36142729
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2004293715A Pending JP2008001597A (en) | 2004-10-06 | 2004-10-06 | Method for producing 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole |
Country Status (3)
| Country | Link |
|---|---|
| JP (1) | JP2008001597A (en) |
| TW (1) | TW200630351A (en) |
| WO (1) | WO2006038657A1 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2013512201A (en) * | 2009-11-26 | 2013-04-11 | ビーエーエスエフ ソシエタス・ヨーロピア | Process for producing 5,5-disubstituted 4,5-dihydroisoxazole-3-thiocarboxamidine salt |
| WO2021002484A2 (en) | 2019-10-31 | 2021-01-07 | クミアイ化学工業株式会社 | Herbicide and production method for intermediate thereof |
| CN116102510A (en) * | 2021-11-10 | 2023-05-12 | 江西仰立新材料有限公司 | Preparation method of 3-bromo-5, 5-dimethyl-4, 5-dihydro-isoxazole |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1799657B1 (en) | 2004-10-05 | 2009-12-02 | Syngenta Limited | Isoxazoline derivatives and their use as herbicides |
| CN111574511A (en) * | 2020-06-28 | 2020-08-25 | 安徽久易农业股份有限公司 | Synthesis method and application of sulfuryl pyraflufen |
| EP3936503A1 (en) | 2020-07-10 | 2022-01-12 | Adama Agan Ltd. | Process and intermediates for the preparation of pyroxasulfone, fenoxasulfone and various sulfone analogs of 5,5-dimethyl-4h-1,2-oxazole |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP4465133B2 (en) * | 2001-02-08 | 2010-05-19 | クミアイ化学工業株式会社 | Isoxazoline derivatives and herbicides containing the same as active ingredients |
-
2004
- 2004-10-06 JP JP2004293715A patent/JP2008001597A/en active Pending
-
2005
- 2005-10-05 WO PCT/JP2005/018453 patent/WO2006038657A1/en active Application Filing
- 2005-10-06 TW TW094134986A patent/TW200630351A/en unknown
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2013512201A (en) * | 2009-11-26 | 2013-04-11 | ビーエーエスエフ ソシエタス・ヨーロピア | Process for producing 5,5-disubstituted 4,5-dihydroisoxazole-3-thiocarboxamidine salt |
| US8921572B2 (en) | 2009-11-26 | 2014-12-30 | Basf Se | Method for producing 5,5-disubstituted 4,5-dihydroisoxazol-3-thiocarboxamidine salts |
| WO2021002484A2 (en) | 2019-10-31 | 2021-01-07 | クミアイ化学工業株式会社 | Herbicide and production method for intermediate thereof |
| CN116102510A (en) * | 2021-11-10 | 2023-05-12 | 江西仰立新材料有限公司 | Preparation method of 3-bromo-5, 5-dimethyl-4, 5-dihydro-isoxazole |
Also Published As
| Publication number | Publication date |
|---|---|
| TW200630351A (en) | 2006-09-01 |
| WO2006038657A1 (en) | 2006-04-13 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| RU2378261C2 (en) | Method of preparing salt compound (4,5-dihydroisoxazol-3-yl)thiocarboxamidine | |
| WO2006038657A1 (en) | 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole and method for producing same | |
| JPS60231645A (en) | Synthesis of o-substituted oxime compound and conversion thereof to corresponding hydroxylamine o-substituted compound | |
| JP2008208111A (en) | Bis(2-alkoxyethyl) azodicarboxylate ester compound and intermediate for producing the same | |
| JP2000044541A (en) | Production of 1,3-dialkylpyrazole-4-carboxylic acid ester | |
| JP6197868B2 (en) | Method for producing pyridazinone compound | |
| JP5001144B2 (en) | Process for producing 2-isopropenyl-5-methyl-4-hexen-1-yl 3-methyl-2-butenoate | |
| JP2007533703A (en) | Method for producing dialkyl dicarbonate | |
| JP5188475B2 (en) | Process for producing 2- (3-nitrobenzylidene) isopropyl acetoacetate | |
| JP4833419B2 (en) | Production of cyclic acids | |
| JP5009306B2 (en) | Process for producing 2-isopropenyl-5-methyl-4-hexen-1-yl 3-methyl-2-butenoate | |
| JP4030289B2 (en) | Process for producing β-ketonitriles | |
| CN113754602B (en) | Synthesis method of 5, 5-dimethyl-4, 5-dihydro-isoxazole-3-one | |
| CN110003111B (en) | Preparation method of 2-aryl-3-ether-3-pyrazole acrylonitrile compound | |
| CN1272320C (en) | Method for producing 4-haloalkylnicotinic acid esters | |
| RU2702121C1 (en) | Method of producing 2-amino-nicotinic acid benzyl ester derivative | |
| JP2007182426A (en) | Method for producing tetrafluoroterephthalic acid difluoride | |
| CN118164920A (en) | Synthesis method of polysubstituted isoxazoline | |
| JP2003104974A (en) | Method for producing 5-phenoxycarbonylbenzotriazole | |
| JP2020083797A (en) | Method for producing aromatic halogen derivative | |
| CN109422706A (en) | A kind of method of continuous production 4- phenylmorpholine | |
| JP2013121923A (en) | Method of producing 4,4-difluoro-3,4-dihydroisoquinolines | |
| JPH02258754A (en) | Preparation of alpha-chloro-alpha-oxyimino-4- hydroxyacetophenone | |
| JP2005112810A (en) | Method for producing benzyl(difluoromethyl) sulfide compound | |
| JP2006321788A (en) | Method for producing nicotinic acid derivative or its salt |