JP3864763B2 - 3-halo-2-hydrazono-1-hydroxyiminopropane derivative and process for producing the same - Google Patents

Description

〔式中、Ｒ^１、Ｒ^２及びＸは前記と同様である。〕
【０００８】
第２の発明は、次式（２）で示される３−ハロ−２−オキソ−１−ヒドロキシイミノプロパン誘導体と
【０００９】
【化６】

〔式中、Ｒ^１及びＸは前記と同様である。〕
次式（３）で示されるヒドラジン誘導体を反応させることを特徴とする
【００１０】
【化７】

〔式中、Ｒ^２は前記と同様である。〕
次式（１）に示される３−ハロ−２−ヒドラゾノ−１−ヒドロキシイミノプロパン誘導体の製造法である。
【００１１】
【化８】

〔式中、Ｒ^１、Ｒ^２及びＸは前記と同様である。〕
【００１２】
【発明の実施の形態】
本発明における化合物（１）及びその原料化合物である化合物（２）、化合物（３）における置換基は以下の通りである。
【００１３】
Ｒ^１はＣＯＯＲ^３基（但し、Ｒ^３は、炭素原子数１〜４個の低級アルキル基、又はシクロアルキル基を表す。）又はシアノ基を表す。
Ｒ^３としては、メチル基、エチル基、ｎ−プロピル基、イソプロピル基、ｎ−ブチル基、イソブチル基、ｓｅｃ−ブチル基、ｔ−ブチル基などの炭素原子数１〜４個の低級アルキル基、又はシクロプロピル基などのシクロアルキル基が挙げられるが、好ましくはメチル基、又はエチル基である。
Ｒ^１として、ＣＯＯＭｅ基、ＣＯＯＥｔ基又はシアノ基が好ましい。
【００１４】
Ｘとしては、フッ素原子、塩素原子、臭素原子及びヨウ素原子などのハロゲン原子が挙げられるが、塩素原子が好ましい。
Ｒ^２としては、アセチル基、プロピオニル基、ブチリル基、イソブチリル基、バレリル基、イソバレリル基、ピバロイル基などの炭素原子数２〜５個のアシル基が挙げられるが、好ましくはアセチル基である。
【００１５】
化合物（１）にはヒドラゾン基及びオキシム基が存在するため、その幾何異性などに基づく異性体が存在するが、いずれの異性体も本発明に含まれる。
【００１６】
〔化合物（１）の製法〕
化合物（１）は、以下に示すように、化合物（２）と化合物（３）を無溶媒又は溶媒中、必要により酸の存在下、反応させることによって製造することができる。
【００１７】
【化９】

（式中、Ｒ^１，Ｒ²及びＸは前記と同義である）
【００１８】
原料化合物（２）は、例えばＪ．Ｏｒｇ．Ｃｈｅｍ．，４７，１１６（１９８２）に記載の方法等に準じて、対応する４−ハロ−アセト酢酸誘導体等をニトロソ化することによって製造することができる。
原料化合物（３）は、市販のものを使用できるが、例えばＪ．Ｐｒａｋｔ．Ｃｈｅｍ．，６４，４０４（１９０１）に記載の合成法により得ることもできる。
【００１９】
化合物（１）の合成で用いる溶媒としては、本反応に直接関与しないものであれば特に限定されず、例えば、ジエチルエーテル、テトラヒドロフラン、ジオキサンなどのエーテル類、Ｎ，Ｎ−ジメチルホルムアミド、ジメチルスルホキシドなどの非プロトン性極性溶媒類、ペンタン、ヘキサン、シクロヘキサン、ヘプタンなどの脂肪族炭化水素類、ベンゼン、トルエン、キシレンなどの芳香族炭化水素類、アセトニトリル、プロピオニトリルなどのニトリル類、塩化メチレン、クロロホルム、１，２−ジクロロエタンなどの塩素化炭化水素類、メタノール、エタノール、イソプロパノールなどのアルコール類、酢酸エチル、酢酸ブチル、プロイオン酸エチルなどの脂肪族エステル類、水及びこれらの混合溶媒などを挙げることができる。
前記溶媒の使用量は、反応液の均一性や攪拌性により適宜調製するが、化合物（２）１ｇに対して０〜１００ｇ、好ましくは０〜５０ｇである。
【００２０】
化合物（１）の製造に用いる酸としては、塩酸、硝酸、硫酸などの無機酸類、パラトルエンスルホン酸などのスルホン酸類、酢酸、プロピオン酸などの脂肪族カルボン酸などが挙げられるが、好ましくは脂肪族カルボン酸であり、特に好ましくは酢酸である。
酸の使用量は化合物(２)１ｍｏｌに対し、０．００５〜２０ｍｏｌである。
【００２１】
反応温度は使用する溶媒の沸点以下で行う限り特に限定されず、−３０℃〜１１０℃で行うことができるが、好ましくは−２０℃〜６０℃である。
反応圧力は通常大気圧中であるが、加圧又は減圧状態でも良く、特に制限されない。
反応時間は、前記の溶媒の使用量、温度によって変化するが、通常０．５〜２４時間で行うことができる。
得られた化合物（１）は、常法（カラムクロマトグラフィー、再結晶など）にて分離、精製して得ることができる。
【００２２】
【実施例】
実施例１
３−アセチルヒドラゾノ−４−クロロー２−ヒドロキシイミノブタン酸エチルの合成
４−クロロ−３−オキソ−２−ヒドロキシイミノブタン酸エチル０．５ｇ（２．６ｍｍｏｌ）及びアセトヒドラジド０．１９ｇ（２．６ｍｍｏｌ）を１，２−ジクロロエタン５ｍｌに溶解し、２０時間室温攪拌した。
反応液に水を加え、酢酸エチルで抽出した。無水硫酸ナトリウムで乾燥後、減圧下で溶媒を留去した。得られた固体をトルエン３ｍｌで洗浄して、濾取し、微黄色粉末である目的物０．３２ｇ（収率４９．６％）を得た。
得られた目的物の物性は以下の通りであった。
ｍ．ｐ．１２６〜１２７℃
ＣＩ−ＭＳ（ｍ／ｚ）；２５０（ＭＨ^＋）、２１４
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３、δｐｐｍ）；１．３６（３Ｈ，ｔ）
２．２０（３Ｈ，ｓ），４．３６（２Ｈ，ｍ），４．５２（２Ｈ，ｓ），
１０．３３（１Ｈ，ｓ），１１．０３（１Ｈ，ｓ）
【００２３】
実施例２
３−アセチルヒドラゾノ−４−クロロ−２−ヒドロキシイミノブタン酸エチルの合成
４−クロロ−３−オキソ−２−ヒドロキシイミノブタン酸エチル４．０ｇ（２０．７ｍｍｏｌ）、アセトヒドラジド１．５３ｇ（２０．７ｍｍｏｌ）及び酢酸１．２ｍｌをトルエン２．８ｍｌに溶解し、４時間室温にて攪拌した。
反応液に水１５ｍｌを加え、析出結晶を濾取して、水５ｍｌで２回洗浄した。４０℃で真空乾燥し、無色結晶の目的物４．０５ｇ（収率７８．５％）を得た。
【００２４】
実施例３
３−アセチルヒドラゾノ−４−クロロ−２−ヒドロキシイミノブタン酸エチルの合成
４−クロロ−３−オキソ−２−ヒドロキシイミノブタン酸エチル１９．３ｇ（０．１ｍｏｌ）、アセトヒドラジド７．４ｇ（０．１ｍｏｌ）を酢酸１５ｍｌに溶解し、４時間室温にて攪拌した。
反応液に水７０ｍｌを加え、析出結晶を濾取して、水５０ｍｌで洗浄した。４０℃で真空乾燥し、目的物１７．９ｇ（収率７１％）を得た。
【００２５】
実施例４
３−アセチルヒドラゾノ−４−クロロ−２−ヒドロキシイミノブチロニトリルの合成
４−クロロ−３−オキソ−２−ヒドロキシイミノブチロニトリル４ｇ（２７．３ｍｍｏｌ）、アセトヒドラジド２．４ｇ（３２．４ｍｍｏｌ）を酢酸４ｍｌに溶解し、室温で２４時間攪拌した。
反応液に水３０ｍｌを加え、析出結晶を濾取して、水５ｍｌで２回洗浄した。得られた結晶をトルエンに溶解し、無水硫酸ナトリウムで乾燥後、溶媒を減圧下で留去した。残渣をカラムクロマトグラフィー（Ｍｉｃｒｏ Ｓｐｈｅｒｅ Ｇｅｌ Ｄ−１５０−６０Ａ、展開溶媒：トルエン／酢酸エチル＝３／１）で精製し、白色粉末３．６ｇを得た。得られた白色粉末をさらに、水、少量のトルエン、ヘキサンの順に洗浄し、白色結晶である目的物３．２ｇ（収率５７．９％）を得た。
得られた目的物の物性は以下の通りであった。
ｍ．ｐ．１３６〜１５２℃（ｄｅｃ．）
ＣＩ−ＭＳ（ｍ／ｚ）；２０３（ＭＨ^＋）、１６９
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６、δｐｐｍ）；２．２２（３Ｈ，ｓ），
４．６５（２Ｈ，ｓ），１１．４９（１Ｈ，ｓ），１４．０３（１Ｈ，ｓ）
【００２６】
【発明の効果】
本発明の新規な３−ハロ−２−ヒドラゾノ−１−ヒドロキシイミノプロパン誘導体は、医薬、農薬等の中間体として有用である。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a novel 3-halo-2-hydrazono-1-hydroxyiminopropane derivative useful as an intermediate for pharmaceuticals, agricultural chemicals and the like, and a method for producing the same.
[0002]
[Prior art]
2-Hydrazono-1-hydroxyiminopropane derivatives are useful as intermediates for medicines and agricultural chemicals, and some are known. For example, Japanese Patent Application Laid-Open No. 10-25271 discloses DE 2810922 and Indian. J. et al. Chem. Sect. B. 16B (7), 638 (1978), which are described as intermediates of cephalosporins antibiotic derivatives. However, unlike the present invention, 2-hydrazono-1-hydroxyiminopropane derivatives described in these publications do not have a halogen atom at the 3-position. Further, EP 412849 discloses a 2-hydrazono-1-hydroxyiminopropane derivative as an intermediate of a triazole insecticide, but the 3-position is a trifluoromethyl group, as in the present invention, No compound having a monohalogenated methyl group at the 3-position was disclosed.
[0003]
In general, a trifluoromethyl group in which a carbon atom is substituted with all fluorine atoms is poor in reactivity and is known as a stable substituent. Therefore, the substitution by the nucleophilic group hardly occurs.
On the other hand, monohalogenated methyl groups are greatly different from trifluoromethyl groups in terms of their reactivity, such as being easily attacked by nucleophilic groups and being able to be replaced with various substituents. Therefore, in order to synthesize a compound having a monohalogenated methyl group, it is necessary to carry out the reaction while carefully controlling the nucleophilic reaction of the monohalogenated methyl group to the halogen atom. In addition, the compound having a monohalogenated methyl group of the present invention is highly useful as an intermediate for medical and agricultural chemicals and the like. For example, various substituents can be introduced by utilizing this reactivity. Thus, the compound having a monohalogenated methyl group of the present invention is greatly different from the compound having a trifluoromethyl group in the production and utility value.
[0004]
As described above, the 2-hydrazono-1-hydroxyiminopropane derivative is widely useful as an intermediate for medical and agricultural chemicals and the like, and has a monohalogenated methyl group shown in the present invention despite being widely used. The 3-halo-2-hydrazono-1-hydroxyiminopropane derivative has not been known so far, and the production method thereof has not been disclosed at all.
[0005]
[Problems to be solved by the invention]
An object of the present invention is to provide a novel 3-halo-2-hydrazono-1-hydroxyiminopropane derivative useful as an intermediate for pharmaceuticals, agricultural chemicals and the like, and a method for producing the same.
[0006]
[Means for Solving the Problems]
The first invention is a 3-halo-2-hydrazono-1-hydroxyiminopropane derivative useful as an intermediate for pharmaceuticals, agricultural chemicals and the like represented by the following formula (1).
[0007]
[Chemical formula 5]

[Wherein, R ¹ , R ² and X are the same as defined above. ]
[0008]
A second invention relates to a 3-halo-2-oxo-1-hydroxyiminopropane derivative represented by the following formula (2):
[Chemical 6]

[Wherein, R ¹ and X are the same as defined above. ]
A hydrazine derivative represented by the following formula (3) is reacted:
[Chemical 7]

[Wherein R ² is the same as defined above. ]
This is a method for producing a 3-halo-2-hydrazono-1-hydroxyiminopropane derivative represented by the following formula (1).
[0011]
[Chemical 8]

[Wherein, R ¹ , R ² and X are the same as defined above. ]
[0012]
DETAILED DESCRIPTION OF THE INVENTION
The substituents in the compound (1) and the starting compound (2) and compound (3) in the present invention are as follows.
[0013]
R ¹ represents a COOR ³ group (where R ³ represents a lower alkyl group having 1 to 4 carbon atoms or a cycloalkyl group) or a cyano group.
R ³ includes a lower alkyl group having 1 to 4 carbon atoms such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, and a t-butyl group; Alternatively, a cycloalkyl group such as a cyclopropyl group can be mentioned, and a methyl group or an ethyl group is preferable.
R ¹ is preferably a COOMe group, a COOEt group or a cyano group.
[0014]
X includes halogen atoms such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, and a chlorine atom is preferred.
Examples of R ² include an acyl group having 2 to 5 carbon atoms such as acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group, and pivaloyl group, and is preferably an acetyl group.
[0015]
Since compound (1) has a hydrazone group and an oxime group, isomers based on geometric isomerism and the like exist, and any isomer is included in the present invention.
[0016]
[Production Method of Compound (1)]
As shown below, compound (1) can be produced by reacting compound (2) and compound (3) in the absence of a solvent or in the presence of an acid, if necessary.
[0017]
[Chemical 9]

(Wherein R ¹ , R ² and X are as defined above)
[0018]
The starting compound (2) is, for example, J.I. Org. Chem. 47, 116 (1982), etc., by nitrosating the corresponding 4-halo-acetoacetic acid derivative or the like.
As the raw material compound (3), commercially available compounds can be used. Prakt. Chem. 64, 404 (1901).
[0019]
The solvent used in the synthesis of compound (1) is not particularly limited as long as it does not directly participate in this reaction, and examples thereof include ethers such as diethyl ether, tetrahydrofuran, dioxane, N, N-dimethylformamide, dimethyl sulfoxide and the like. Aprotic polar solvents, aliphatic hydrocarbons such as pentane, hexane, cyclohexane and heptane, aromatic hydrocarbons such as benzene, toluene and xylene, nitriles such as acetonitrile and propionitrile, methylene chloride and chloroform , Chlorinated hydrocarbons such as 1,2-dichloroethane, alcohols such as methanol, ethanol and isopropanol, aliphatic esters such as ethyl acetate, butyl acetate and ethyl proionate, water and mixed solvents thereof be able to.
Although the usage-amount of the said solvent is suitably prepared with the uniformity and stirring property of a reaction liquid, it is 0-100g with respect to 1g of compound (2), Preferably it is 0-50g.
[0020]
Examples of the acid used for the production of the compound (1) include inorganic acids such as hydrochloric acid, nitric acid and sulfuric acid, sulfonic acids such as paratoluenesulfonic acid, and aliphatic carboxylic acids such as acetic acid and propionic acid. Group carboxylic acid, particularly preferably acetic acid.
The usage-amount of an acid is 0.005-20 mol with respect to 1 mol of compounds (2).
[0021]
The reaction temperature is not particularly limited as long as the reaction temperature is not higher than the boiling point of the solvent to be used, and it can be carried out at -30 ° C to 110 ° C, preferably -20 ° C to 60 ° C.
The reaction pressure is usually atmospheric pressure, but it may be pressurized or reduced pressure and is not particularly limited.
Although reaction time changes with the usage-amounts and temperature of the said solvent, it can carry out normally in 0.5 to 24 hours.
The obtained compound (1) can be obtained by separation and purification by conventional methods (column chromatography, recrystallization, etc.).
[0022]
【Example】
Example 1
Synthesis of ethyl 3-acetylhydrazono-4-chloro-2-hydroxyiminobutanoate 0.5 g (2.6 mmol) of ethyl 4-chloro-3-oxo-2-hydroxyiminobutanoate and 0.19 g of acetohydrazide (2. 6 mmol) was dissolved in 5 ml of 1,2-dichloroethane and stirred at room temperature for 20 hours.
Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained solid was washed with 3 ml of toluene and collected by filtration to obtain 0.32 g (yield 49.6%) of the target product as a slightly yellow powder.
The physical properties of the obtained target product were as follows.
m. p. 126-127 ° C
CI-MS (m / z); 250 (MH ^<+> ), 214
¹ H-NMR (CDCl ₃ , δ ppm); 1.36 (3H, t)
2.20 (3H, s), 4.36 (2H, m), 4.52 (2H, s),
10.33 (1H, s), 11.03 (1H, s)
[0023]
Example 2
Synthesis of ethyl 3-acetylhydrazono-4-chloro-2-hydroxyiminobutanoate 4.0 g (20.7 mmol) of ethyl 4-chloro-3-oxo-2-hydroxyiminobutanoate, 1.53 g of acetohydrazide (20 0.7 mmol) and 1.2 ml of acetic acid were dissolved in 2.8 ml of toluene and stirred at room temperature for 4 hours.
15 ml of water was added to the reaction solution, and the precipitated crystals were collected by filtration and washed twice with 5 ml of water. By vacuum drying at 40 ° C., 4.05 g (yield 78.5%) of the target product as colorless crystals was obtained.
[0024]
Example 3
Synthesis of ethyl 3-acetylhydrazono-4-chloro-2-hydroxyiminobutanoate 19.3 g (0.1 mol) of ethyl 4-chloro-3-oxo-2-hydroxyiminobutanoate, 7.4 g of acetohydrazide (0 0.1 mol) was dissolved in 15 ml of acetic acid and stirred at room temperature for 4 hours.
70 ml of water was added to the reaction solution, and the precipitated crystals were collected by filtration and washed with 50 ml of water. Vacuum drying at 40 ° C. gave 17.9 g (yield 71%) of the desired product.
[0025]
Example 4
Synthesis of 3-acetylhydrazono-4-chloro-2-hydroxyiminobutyronitrile 4-chloro-3-oxo-2-hydroxyiminobutyronitrile 4 g (27.3 mmol), acetohydrazide 2.4 g (32.4 mmol) ) Was dissolved in 4 ml of acetic acid and stirred at room temperature for 24 hours.
30 ml of water was added to the reaction solution, and the precipitated crystals were collected by filtration and washed twice with 5 ml of water. The obtained crystals were dissolved in toluene and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (Micro Sphere Gel D-150-60A, developing solvent: toluene / ethyl acetate = 3/1) to obtain 3.6 g of a white powder. The obtained white powder was further washed with water, a small amount of toluene, and hexane in this order to obtain 3.2 g (yield 57.9%) of the target product as white crystals.
The physical properties of the obtained target product were as follows.
m. p. 136-152 ° C. (dec.)
CI-MS (m / z); 203 (MH ^<+> ), 169
¹ H-NMR (DMSO-d ₆ , δ ppm); 2.22 (3H, s),
4.65 (2H, s), 11.49 (1H, s), 14.03 (1H, s)
[0026]
【The invention's effect】
The novel 3-halo-2-hydrazono-1-hydroxyiminopropane derivative of the present invention is useful as an intermediate for pharmaceuticals, agricultural chemicals and the like.

Claims (2)

A 3-halo-2-hydrazono-1-hydroxyiminopropane derivative represented by the following formula (1):

[Wherein, R ¹ represents a COOR ³ group (where R ³ represents an alkyl group having 1 to 4 carbon atoms or a cycloalkyl group) or a cyano group, and R ² represents ² carbon atoms. Represents ˜5 acyl groups, and X represents a halogen atom. ] A 3-halo-2-oxo-1-hydroxyiminopropane derivative represented by the following formula (2):

[Wherein, R ¹ and X are the same as defined above. ]
It is characterized by reacting a hydrazine derivative represented by the following formula (3)

[Wherein R ² is the same as defined above. ]
A method for producing a 3-halo-2-hydrazono-1-hydroxyiminopropane derivative represented by the following formula (1):

[Wherein, R ¹ , R ² and X are the same as defined above. ]