JP2002363171A - Method of producing 4-substituted-3-amino-isoxazole derivative - Google Patents

Method of producing 4-substituted-3-amino-isoxazole derivative

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Publication number
JP2002363171A
JP2002363171A JP2001166541A JP2001166541A JP2002363171A JP 2002363171 A JP2002363171 A JP 2002363171A JP 2001166541 A JP2001166541 A JP 2001166541A JP 2001166541 A JP2001166541 A JP 2001166541A JP 2002363171 A JP2002363171 A JP 2002363171A
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JP
Japan
Prior art keywords
reaction
mmol
added
reduced pressure
under reduced
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
Application number
JP2001166541A
Other languages
Japanese (ja)
Inventor
Akio Matsushita
明生 松下
Kiyotaka Yoshii
清隆 吉井
Masayoshi Ogami
雅良 大上
Taku Nakamura
卓 中村
Shuji Yamada
修二 山田
Original Assignee
Ube Ind Ltd
宇部興産株式会社
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Ube Ind Ltd, 宇部興産株式会社 filed Critical Ube Ind Ltd
Priority to JP2001166541A priority Critical patent/JP2002363171A/en
Publication of JP2002363171A publication Critical patent/JP2002363171A/en
Pending legal-status Critical Current

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Abstract

PROBLEM TO BE SOLVED: To provide a method of producing an industrially suitable 4- substituted-3-aminoisoxazole derivative in high yield, from a readily available dialkoxyamide oxime derivative through a simple process. SOLUTION: The 4-substituted-3-aminoisoxazole derivative is produced characteristically by subjecting a dialkoxyamide oxime to the cyclization reaction in the presence of an acid.

Description

【発明の詳細な説明】DETAILED DESCRIPTION OF THE INVENTION

【0001】[0001]

【発明の属する技術分野】本発明は、医薬・農薬の合成
原料として有用な4-置換-3-アミノイソオキサゾール誘
導体に関する。特に、4-置換-3-アミノイソオキサゾー
ル誘導体は、血圧降下剤や抗動脈硬化剤として有用なス
ルホンアミドエンドセリンアンタゴニスト化合物の合成
原料として利用出来る(例えば、特開平6-9598号公
報)。
TECHNICAL FIELD The present invention relates to a 4-substituted-3-aminoisoxazole derivative useful as a raw material for synthesizing pharmaceuticals and agricultural chemicals. In particular, a 4-substituted-3-aminoisoxazole derivative can be used as a raw material for synthesizing a sulfonamide endothelin antagonist compound useful as a hypotensive agent or an anti-atherosclerotic agent (for example, JP-A-6-9598).

【0002】[0002]

【従来の技術】従来、4-置換-3-アミノイソオキサゾー
ル誘導体を製造する方法としては、炭酸水素ナトリウム
水溶液中、2-(トリフルオロアセト)プロピオニトリルに
ヒドロキシルアミンを還流下で反応させて2-(トリフル
オロアセト)プロピオンアミドオキシムとし、引き続
き、これに濃塩酸を加えて再度還流下で反応させて5-ト
リフルオロメチル-4-メチル-3-アミノイソオキサゾール
を得る方法が知られている(特開昭62-96479号公報)。
しかしながら、この方法では、目的とする5-トリフルオ
ロメチル-4-メチル-3-アミノイソオキサゾールの収率が
31.7%と極めて低い上に、目的物と分離が困難な3-トリ
フルオロメチル-4-メチル-5-アミノイソオキサゾール
(位置異性体)が2.6%副生するという問題があった。
2. Description of the Related Art Conventionally, as a method for producing a 4-substituted-3-aminoisoxazole derivative, hydroxylamine is reacted with 2- (trifluoroaceto) propionitrile under reflux in an aqueous sodium hydrogen carbonate solution. It is known that 2- (trifluoroaceto) propionamide oxime is obtained, followed by adding concentrated hydrochloric acid thereto and reacting again under reflux to obtain 5-trifluoromethyl-4-methyl-3-aminoisoxazole. (JP-A-62-96479).
However, in this method, the yield of the desired 5-trifluoromethyl-4-methyl-3-aminoisoxazole is low.
In addition to the extremely low 31.7%, there is a problem that 2.6% of 3-trifluoromethyl-4-methyl-5-aminoisoxazole (positional isomer) which is difficult to separate from the target product is by-produced.

【0003】[0003]

【発明が解決しようとする課題】本発明の課題は、上記
問題点を解決し、入手が容易なジアルコキシアミドオキ
シム誘導体から、簡便な方法によって、高収率で4-置換
-3-アミノイソオキサゾール誘導体を得る、工業的に好
適な4-置換-3-アミノイソオキサゾール誘導体の製法を
提供するものである。
SUMMARY OF THE INVENTION The object of the present invention is to solve the above-mentioned problems, and to obtain a 4-substituted dialkoxyamide oxime derivative by a simple method in a high yield.
An object of the present invention is to provide an industrially suitable method for producing a 4-substituted-3-aminoisoxazole derivative, which can obtain a 3-aminoisoxazole derivative.

【0004】[0004]

【課題を解決するための手段】本発明の課題は、酸の存
在下、一般式(1)
The object of the present invention is to provide a compound of the general formula (1) in the presence of an acid.

【0005】[0005]

【化3】 Embedded image

【0006】で示されるジアルコキシアミドオキシム誘
導体を環化反応させることを特徴とする、一般式(2)
A cyclization reaction of a dialkoxyamide oxime derivative represented by the general formula (2):

【0007】[0007]

【化4】 Embedded image

【0008】(式中、R1及びR2は、前記と同義であ
る。)で示される4-置換-3-アミノイソオキサゾール誘
導体の製法によって解決される。
(In the formula, R 1 and R 2 have the same meanings as described above.) This is solved by a method for producing a 4-substituted-3-aminoisoxazole derivative represented by the formula:

【0009】[0009]

【発明の実施の形態】本発明の反応において使用するジ
アルコキシアミドオキシム誘導体は、前記の一般式
(1)で示される。
BEST MODE FOR CARRYING OUT THE INVENTION The dialkoxyamide oxime derivative used in the reaction of the present invention is represented by the above general formula (1).

【0010】一般式(1)において、R1は、反応に関
与しない基であるが、特に、水素原子、置換基を有して
いても良いアルキル基又はアリール基であり、具体的に
は、例えば、水素原子;メチル基、エチル基、プロピル
基、ブチル基等のアルキル基;フェニル基、ナフチル
基、アントリル基等のアリール基が挙げられる。なお、
これらは各種異性体を含む。
In the general formula (1), R 1 is a group which does not participate in the reaction, but is particularly a hydrogen atom, an alkyl group or an aryl group which may have a substituent, and specifically, Examples include a hydrogen atom; an alkyl group such as a methyl group, an ethyl group, a propyl group, and a butyl group; and an aryl group such as a phenyl group, a naphthyl group, and an anthryl group. In addition,
These include various isomers.

【0011】前記の置換基としては、メトキシル基、エ
トキシル基、プロポキシル基、ブトキシル基等のアルコ
キシル基;フッ素原子、塩素原子、臭素原子、ヨウ素原
子等のハロゲン原子が挙げられる。なお、置換基の数や
位置は特に限定されない。
Examples of the substituent include an alkoxyl group such as a methoxyl group, an ethoxyl group, a propoxyl group and a butoxyl group; and a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. The number and position of the substituent are not particularly limited.

【0012】一般式(1)において、R2は、反応に関
与しない基であるが、特に、置換基を有していても良い
アルキル基又はアリール基であり、具体的には、例え
ば、メチル基、エチル基、プロピル基、ブチル基等のア
ルキル基;フェニル基、ナフチル基、アントリル基等の
アリール基が挙げられる。なお、これらは各種異性体を
含む。
In the general formula (1), R 2 is a group which does not participate in the reaction, but is particularly an alkyl group or an aryl group which may have a substituent. Alkyl groups such as a group, ethyl group, propyl group and butyl group; and aryl groups such as a phenyl group, a naphthyl group and an anthryl group. These include various isomers.

【0013】前記の置換基としては、メトキシル基、エ
トキシル基、プロポキシル基、ブトキシル基等のアルコ
キシル基;フッ素原子、塩素原子、臭素原子、ヨウ素原
子等のハロゲン原子が挙げられる。なお、置換基の数や
位置は特に限定されない。
Examples of the substituent include an alkoxyl group such as a methoxyl group, an ethoxyl group, a propoxyl group and a butoxyl group; and a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. The number and position of the substituent are not particularly limited.

【0014】一般式(1)において、R3及びR4は、同
一又は異なっていても良く、反応に関与しない基である
が、特に、炭素数1〜4のアルキル基であり、具体的に
は、例えば、メチル基、エチル基、プロピル基、ブチル
基が挙げられるが、好ましくはメチル基、エチル基であ
る。なお、これらは各種異性体を含む。また、R3及び
4は、連結して環を形成していても良く、連結して成
る基としては、例えば、エチレン基、トリメチレン基、
テトラメチレン基が挙げられるが、好ましくはエチレン
基である。
In the general formula (1), R 3 and R 4 may be the same or different and are groups which do not participate in the reaction. In particular, they are alkyl groups having 1 to 4 carbon atoms. Is, for example, a methyl group, an ethyl group, a propyl group, or a butyl group, preferably a methyl group or an ethyl group. These include various isomers. R 3 and R 4 may be linked to each other to form a ring. Examples of the linked group include an ethylene group, a trimethylene group,
Although a tetramethylene group is mentioned, an ethylene group is preferable.

【0015】本発明の反応において使用するジアルコキ
シアミドオキシム誘導体は、例えば、一般式(3)
The dialkoxyamide oxime derivative used in the reaction of the present invention is, for example, a compound represented by the following general formula (3):

【0016】[0016]

【化5】 Embedded image

【0017】(式中、R1、R2、R3及びR4は、前記と
同義である。)に示すような反応工程によって、シアノ
ケトン類から、容易に合成出来る化合物である(後の参
考例に記載)。
(Wherein R 1 , R 2 , R 3 and R 4 have the same meanings as described above), and are compounds which can be easily synthesized from cyanoketones by the following reaction steps (see the following reference). Described in the example).

【0018】本発明の反応において使用する酸として
は、例えば、塩酸、硫酸、リン酸等の鉱酸類;ギ酸、酢
酸等のカルボン酸類;メタンスルホン酸、エタンスルホ
ン酸、ベンゼンスルホン酸、p-トルエンスルホン酸等の
スルホン酸類が挙げられるが、好ましくは鉱酸類、更に
好ましくは塩酸、硫酸が使用される。
Examples of the acid used in the reaction of the present invention include mineral acids such as hydrochloric acid, sulfuric acid and phosphoric acid; carboxylic acids such as formic acid and acetic acid; methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid and p-toluene. Sulfonic acids such as sulfonic acid may be mentioned, but preferably mineral acids, more preferably hydrochloric acid and sulfuric acid are used.

【0019】前記酸の使用量は、ジアルコキシアミドオ
キシム誘導体1molに対して、好ましくは0.001〜20mol、
更に好ましくは0.005〜10molである。
The amount of the acid used is preferably 0.001 to 20 mol per 1 mol of the dialkoxyamide oxime derivative,
More preferably, it is 0.005 to 10 mol.

【0020】本発明の反応は溶媒中で行うのが好まし
く、使用する溶媒は反応を阻害しないものならば特に限
定されないが、例えば、水;メタノール、エタノール、
n-プロピルアルコール、イソプロピルアルコール、n-ブ
チルアルコール、イソブチルアルコール、t-ブチルアル
コール等のアルコール類;N,N-ジメチルホルムアミド、
N,N-ジメチルアセトアミド、N,N'-ジメチル-2-イミダゾ
リドン等のアミド類;アセトニトリル、プロピオニトリ
ル、ベンゾニトリル等のニトリル類;トルエン、キシレ
ン、クメン等の芳香族炭化水素類;酢酸メチル、酢酸エ
チル、酢酸n-プロピル、酢酸イソプロピル、酢酸n-ブチ
ル、酢酸イソブチル、酢酸t-ブチル等のカルボン酸エス
テル類;シクロヘキサン、シクロヘプタン、シクロオク
タン等の脂肪族炭化水素類が挙げられるが、好ましくは
アルコール類、芳香族炭化水素類、カルボン酸エステル
類が使用される。なお、これら溶媒は、単独又は二種以
上を混合して使用しても良い。
The reaction of the present invention is preferably carried out in a solvent, and the solvent used is not particularly limited as long as it does not inhibit the reaction. For example, water; methanol, ethanol,
alcohols such as n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, t-butyl alcohol; N, N-dimethylformamide;
Amides such as N, N-dimethylacetamide and N, N'-dimethyl-2-imidazolidone; nitriles such as acetonitrile, propionitrile and benzonitrile; aromatic hydrocarbons such as toluene, xylene and cumene; methyl acetate , Ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, carboxylic acid esters such as t-butyl acetate; cyclohexane, cycloheptane, aliphatic hydrocarbons such as cyclooctane, Preferably, alcohols, aromatic hydrocarbons and carboxylic esters are used. In addition, you may use these solvents individually or in mixture of 2 or more types.

【0021】前記溶媒の使用量は、反応液の均一性や攪
拌性により適宜調節するが、ジアルコキシアミドオキシ
ム誘導体1gに対して、好ましくは1〜1000ml、更に好ま
しくは1〜100mlである。
The amount of the solvent to be used is appropriately adjusted depending on the uniformity and stirring properties of the reaction solution, but is preferably 1 to 1000 ml, more preferably 1 to 100 ml, per 1 g of the dialkoxyamide oxime derivative.

【0022】本発明の反応は、例えば、不活性ガスの雰
囲気にて、ジアルコキシアミドオキシム誘導体、酸及び
溶媒を混合して、攪拌させる等の方法によって行われ
る。その際の反応温度は、好ましくは20〜200℃、更に
好ましくは50〜150℃であり、反応圧力は特に制限され
ない。
The reaction of the present invention is carried out, for example, by a method in which a dialkoxyamide oxime derivative, an acid and a solvent are mixed and stirred in an inert gas atmosphere. The reaction temperature at that time is preferably 20 to 200 ° C, more preferably 50 to 150 ° C, and the reaction pressure is not particularly limited.

【0023】本発明の反応によって得られる4-置換-3-
アミノイソオキサゾール誘導体は、反応終了後、例え
ば、中和、抽出、濃縮、濾過等の処理を行った後に、再
結晶、蒸留、カラムクロマトグラフィー等による一般的
な方法によって単離・精製される。
4-Substituted-3- obtained by the reaction of the present invention
After completion of the reaction, the aminoisoxazole derivative is subjected to, for example, neutralization, extraction, concentration, filtration, and the like, and then isolated and purified by a general method such as recrystallization, distillation, or column chromatography.

【0024】[0024]

【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。
EXAMPLES Next, the present invention will be described specifically with reference to examples, but the scope of the present invention is not limited to these examples.

【0025】参考例1(3-シアノ-2-ブタノンのナトリ
ウム塩の合成) 攪拌装置、温度計及び還流冷却器を備えた内容積300ml
のガラス製フラスコに、ナトリウムメトキシド13.0g(0.
24mol)、プロピオニトリル19.9g(0.36mol)、酢酸n-ブチ
ル37.2g(0.32mol)及びトルエン100mlを加え、窒素雰囲
気にて、90℃で24時間反応させた。反応終了後、室温ま
で冷却し、析出物を濾過して乾燥させ、無色粉末として
3-シアノ-2-ブタノンのナトリウム塩12.0gを得た(単離
収率;41.7%)。3-シアノ-2-ブタノンのナトリウム塩の
物性値は以下の通りであった。
Reference Example 1 (Synthesis of sodium salt of 3-cyano-2-butanone) 300 ml in internal volume equipped with a stirrer, thermometer and reflux condenser
13.0 g of sodium methoxide (0.
24 mol), 19.9 g (0.36 mol) of propionitrile, 37.2 g (0.32 mol) of n-butyl acetate and 100 ml of toluene were added and reacted at 90 ° C. for 24 hours in a nitrogen atmosphere. After the completion of the reaction, the mixture is cooled to room temperature, and the precipitate is filtered and dried to obtain a colorless powder.
12.0 g of sodium salt of 3-cyano-2-butanone was obtained (isolation yield; 41.7%). Physical properties of the sodium salt of 3-cyano-2-butanone were as follows.

【0026】1H-NMR(DMSO-d6,δ(ppm));1.45(3H,s)、
1.75(3H,s)
1 H-NMR (DMSO-d 6 , δ (ppm)); 1.45 (3H, s),
1.75 (3H, s)

【0027】参考例2(2-(β-エチレンジオキシアセ
ト)プロピオニトリルの合成) 攪拌装置、温度計、滴下漏斗、還流冷却器及びDean-Sta
rk装置を備えた内容積200mlのガラス製フラスコに、参
考例1と同様な方法で合成した3-シアノ-2-ブタノンの
ナトリウム塩16.7g(0.14mol)、エチレングリコール17.4
g(0.28mol)及びトルエン72mlを加え、5℃まで冷却して
攪拌しながら、濃硫酸12.5g(0.12mol)を滴下した。その
後、反応で生成する水を留去させながら、窒素雰囲気に
て、加熱還流下(105〜110℃)で7時間反応させた。反
応終了後、室温まで冷却して、反応液を、水10ml、2mol
/L水酸化ナトリウム水溶液15mlの順で洗浄した。次い
で、有機層を取り出し、有機層を減圧下で濃縮して、無
色液体として2-(β-エチレンジオキシアセト)プロピオ
ニトリル18.4gを得た(単離収率;93%)。2-(β-エチレ
ンジオキシアセト)プロピオニトリルの物性値は以下の
通りであった。。
Reference Example 2 (Synthesis of 2- (β-ethylenedioxyaceto) propionitrile) Stirrer, thermometer, dropping funnel, reflux condenser, Dean-Sta
In a 200 ml glass flask equipped with an rk device, 16.7 g (0.14 mol) of sodium salt of 3-cyano-2-butanone synthesized in the same manner as in Reference Example 1 and 17.4 g of ethylene glycol
g (0.28 mol) and 72 ml of toluene were added, and 12.5 g (0.12 mol) of concentrated sulfuric acid was added dropwise while cooling to 5 ° C. and stirring. Thereafter, the reaction was carried out for 7 hours under heating and refluxing (105 to 110 ° C.) in a nitrogen atmosphere while distilling off water generated in the reaction. After completion of the reaction, the reaction solution was cooled to room temperature,
Washing was performed in the order of 15 ml of a 1 / L aqueous sodium hydroxide solution. Next, the organic layer was taken out, and the organic layer was concentrated under reduced pressure to obtain 18.4 g of 2- (β-ethylenedioxyaceto) propionitrile as a colorless liquid (isolation yield; 93%). Physical properties of 2- (β-ethylenedioxyaceto) propionitrile were as follows. .

【0028】1H-NMR(CDCl3,δ(ppm));1.30(3H,d)、1.4
0(3H,s)、2.90(1H,q)、4.0〜4.1(4H,m)
1 H-NMR (CDCl 3 , δ (ppm)); 1.30 (3H, d), 1.4
0 (3H, s), 2.90 (1H, q), 4.0 ~ 4.1 (4H, m)

【0029】参考例3(2-(β-エチレンジオキシアセ
ト)プロピオンアミドオキシムの合成) 攪拌装置、温度計、滴下漏斗及び還流冷却器を備えた内
容積100mlのガラス製フラスコに、4mol/L水酸化ナトリ
ウム水溶液10ml(40mmol)及びメタノール8.7mlを混合
し、氷冷下、ヒドロキシルアミン塩酸塩2.33g(33.6mmo
l)を加え、10分間攪拌させた。次いで、室温まで昇温
し、参考例2と同様な方法で合成した2-(β-エチレンジ
オキシアセト)プロピオニトリル2.12g(15mmol)をゆるや
かに滴下し、窒素雰囲気にて、加熱還流下(70〜75℃)
で5時間反応させた。反応終了後、室温まで冷却し、酢
酸エチル30mlで抽出した。有機層を取り出し、有機層を
減圧下で濃縮して、無色粉末として2-(β-エチレンジオ
キシアセト)プロピオンアミドオキシム2.30gを得た(単
離収率;87%)。2-(β-エチレンジオキシアセト)プロピ
オンアミドオキシムの物性値は以下の通りであった。
Reference Example 3 (Synthesis of 2- (β-ethylenedioxyaceto) propionamide oxime) 4 mol / L was placed in a 100 ml glass flask equipped with a stirrer, thermometer, dropping funnel and reflux condenser. A mixture of 10 ml (40 mmol) of an aqueous sodium hydroxide solution and 8.7 ml of methanol was mixed under ice-cooling with 2.33 g of hydroxylamine hydrochloride (33.6 mmo).
l) was added and allowed to stir for 10 minutes. Then, the temperature was raised to room temperature, and 2.12 g (15 mmol) of 2- (β-ethylenedioxyaceto) propionitrile synthesized in the same manner as in Reference Example 2 was slowly added dropwise. (70-75 ℃)
For 5 hours. After completion of the reaction, the mixture was cooled to room temperature and extracted with 30 ml of ethyl acetate. The organic layer was removed, and the organic layer was concentrated under reduced pressure to obtain 2.30 g of 2- (β-ethylenedioxyaceto) propionamide oxime as a colorless powder (isolation yield: 87%). Physical properties of 2- (β-ethylenedioxyaceto) propionamide oxime were as follows.

【0030】1H-NMR(CDCl3,δ(ppm));1.18(3H,d,J=7.4
Hz)、1.32(3H,s)、2.60(1H,q,J=7.4Hz)、3.95〜5.00(4
H,m)、5.0(2H,brs)、5.7〜6.4(1H,brs)
[0030] 1 H-NMR (CDCl 3, δ (ppm)); 1.18 (3H, d, J = 7.4
Hz), 1.32 (3H, s), 2.60 (1H, q, J = 7.4Hz), 3.95 to 5.00 (4
H, m), 5.0 (2H, brs), 5.7-6.4 (1H, brs)

【0031】実施例1(3-アミノ-4,5-ジメチルイソオ
キサゾールの合成) 攪拌装置、温度計及び還流冷却器を備えた内容積50mlの
ガラス製フラスコに、参考例3と同様な方法で合成した
2-(β-エチレンジオキシアセト)プロピオンアミドオキ
シム1.74g(10mmol)、エタノール10ml及び濃硫酸0.1ml
(1.8mmol)を加え、窒素雰囲気にて、加熱還流下(75〜7
8℃)で12時間反応させた。反応終了後、室温まで冷却
し、反応液を減圧下で濃縮した。その後、濃縮物に酢酸
エチル10ml及び15質量%炭酸ナトリウム水溶液3mlを加
え、有機層を取り出した。次いで、水層を酢酸エチル5m
lで抽出して、先の有機層と合わせ、無水硫酸マグネシ
ウムで乾燥させた。濾過後、濾液を減圧下で濃縮し、得
られた濃縮物をトルエン/n-ヘキサン(=3/1(容量比))
で再結晶させて、無色針状結晶として3-アミノ-4,5-ジ
メチルイソオキサゾール0.90gを得た(単離収率;80
%)。3-アミノ-4,5-ジメチルイソオキサゾールの物性値
は以下の通りであった。
Example 1 (Synthesis of 3-amino-4,5-dimethylisoxazole) A 50 ml glass flask equipped with a stirrer, thermometer and reflux condenser was prepared in the same manner as in Reference Example 3. Synthesized
1.74 g (10 mmol) of 2- (β-ethylenedioxyaceto) propionamide oxime, ethanol 10 ml and concentrated sulfuric acid 0.1 ml
(1.8 mmol) and heated under reflux in a nitrogen atmosphere (75 to 7
(8 ° C.) for 12 hours. After the completion of the reaction, the resultant was cooled to room temperature, and the reaction solution was concentrated under reduced pressure. Thereafter, 10 ml of ethyl acetate and 3 ml of a 15% by mass aqueous sodium carbonate solution were added to the concentrate, and the organic layer was taken out. Then, the aqueous layer was ethyl acetate 5m
Extracted with l, combined with the previous organic layer and dried over anhydrous magnesium sulfate. After filtration, the filtrate is concentrated under reduced pressure, and the obtained concentrate is toluene / n-hexane (= 3/1 (volume ratio))
To give 0.90 g of 3-amino-4,5-dimethylisoxazole as colorless needle crystals (isolation yield; 80).
%). Physical properties of 3-amino-4,5-dimethylisoxazole were as follows.

【0032】1H-NMR(CDCl3,δ(ppm));1.80(3H,s)、2.2
0(3H,s)、3.80(2H,s)
1 H-NMR (CDCl 3 , δ (ppm)); 1.80 (3H, s), 2.2
0 (3H, s), 3.80 (2H, s)

【0033】実施例2(3-アミノ-4,5-ジメチルイソオ
キサゾールの合成) 攪拌装置、温度計及び還流冷却器を備えた内容積200ml
のガラス製フラスコに、参考例3と同様な方法で合成し
た2-(β-エチレンジオキシアセト)プロピオンアミドオ
キシム19.4g(110mmol)、イソプロピルアルコール77ml及
び濃塩酸13.3ml(160mmol)を加え、窒素雰囲気にて、加
熱還流下(80〜82℃)で7時間反応させた。反応終了
後、室温まで冷却し、反応液を減圧下で濃縮した。その
後、濃縮物に酢酸エチル400ml及び飽和炭酸水素ナトリ
ウム水溶液170mlを加え、有機層を取り出し、無水硫酸
マグネシウムで乾燥させた。濾過後、濾液を減圧下で濃
縮し、得られた濃縮物をイソプロピルアルコール13mlで
再結晶させて、無色粉末として3-アミノ-4,5-ジメチル
イソオキサゾール11.4gを得た(単離収率;92%)。
Example 2 (Synthesis of 3-amino-4,5-dimethylisoxazole) 200 ml in internal volume equipped with a stirrer, thermometer and reflux condenser
19.4 g (110 mmol) of 2- (β-ethylenedioxyaceto) propionamide oxime synthesized in the same manner as in Reference Example 3, 77 ml of isopropyl alcohol and 13.3 ml (160 mmol) of concentrated hydrochloric acid were added to The reaction was carried out in an atmosphere under heating and reflux (80 to 82 ° C) for 7 hours. After the completion of the reaction, the resultant was cooled to room temperature, and the reaction solution was concentrated under reduced pressure. Thereafter, 400 ml of ethyl acetate and 170 ml of a saturated aqueous solution of sodium hydrogen carbonate were added to the concentrate, and the organic layer was taken out and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained concentrate was recrystallized from 13 ml of isopropyl alcohol to obtain 11.4 g of 3-amino-4,5-dimethylisoxazole as a colorless powder (isolation yield) ; 92%).

【0034】実施例3(3-アミノ-4,5-ジメチルイソオ
キサゾールの合成) 攪拌装置、温度計及び還流冷却器を備えた内容積100ml
のガラス製フラスコに、参考例3と同様な方法で合成し
た2-(β-エチレンジオキシアセト)プロピオンアミドオ
キシム7.98g(45.8mmol)、酢酸エチル40ml及び濃塩酸4.4
ml(53mmol)を加え、窒素雰囲気にて、加熱還流下(75〜
77℃)で7時間反応させた。反応終了後、室温まで冷却
し、15%炭酸ナトリウム水溶液39mlを加えた。有機層と
水層を分液した後、水層を酢酸エチル20mlで抽出し、抽
出液を有機層と合わせ、無水硫酸マグネシウムで乾燥さ
せた。濾過後、濾液にトルエン50gを加え、内容物が15g
になるまで減圧下で濃縮した。その後、得られた濃縮物
を70℃まで過熱した後に5℃まで冷却して結晶を析出さ
せた。結晶を濾過し、乾燥させて、無色針状結晶として
3-アミノ-4,5-ジメチルイソオキサゾール4.20gを得た
(単離収率;82%)。
Example 3 (Synthesis of 3-amino-4,5-dimethylisoxazole) An inner volume of 100 ml equipped with a stirrer, a thermometer and a reflux condenser.
7.98 g (45.8 mmol) of 2- (β-ethylenedioxyaceto) propionamide oxime synthesized in the same manner as in Reference Example 3, 40 ml of ethyl acetate and 4.4 ml of concentrated hydrochloric acid.
ml (53 mmol) and heated under reflux in a nitrogen atmosphere (75-
(77 ° C.) for 7 hours. After the completion of the reaction, the mixture was cooled to room temperature, and 39 ml of a 15% aqueous sodium carbonate solution was added. After separating the organic layer and the aqueous layer, the aqueous layer was extracted with 20 ml of ethyl acetate, and the extract was combined with the organic layer and dried over anhydrous magnesium sulfate. After filtration, 50 g of toluene was added to the filtrate, and the content was 15 g.
It was concentrated under reduced pressure until. Thereafter, the obtained concentrate was heated to 70 ° C. and then cooled to 5 ° C. to precipitate crystals. The crystals are filtered and dried to give colorless needles
4.20 g of 3-amino-4,5-dimethylisoxazole was obtained.
(Isolation yield; 82%).

【0035】実施例4(3-アミノ-4,5-ジメチルイソオ
キサゾールの合成) 実施例3と同様な装置に、参考例3と同様な方法で合成
した2-(β-エチレンジオキシアセト)プロピオンアミド
オキシム7.98g(45.8mmol)、トルエン50ml及び濃塩酸4.4
ml(53mmol)を加え、窒素雰囲気にて、加熱還流下(105
〜110℃)で5時間反応させた。反応終了後、室温まで冷
却し、15%炭酸ナトリウム水溶液20mlと酢酸エチル100m
lを加えた。有機層を取り出し、無水硫酸マグネシウム
で乾燥させた。濾過後、濾液を減圧下で濃縮し、得られ
た濃縮物をイソプロピルアルコールで再結晶させて、無
色針状結晶として3-アミノ-4,5-ジメチルイソオキサゾ
ール3.80gを得た(単離収率;74%)。
Example 4 (Synthesis of 3-amino-4,5-dimethylisoxazole) 2- (β-ethylenedioxyaceto) synthesized in the same apparatus as in Example 3 by the same method as in Reference Example 3. 7.98 g (45.8 mmol) of propionamide oxime, 50 ml of toluene and 4.4 of concentrated hydrochloric acid
ml (53 mmol) and heated under reflux in a nitrogen atmosphere (105
〜110 ° C.) for 5 hours. After completion of the reaction, the reaction solution was cooled to room temperature, and 20 ml of a 15% aqueous sodium carbonate solution and 100 ml of ethyl acetate
l was added. The organic layer was taken out and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained concentrate was recrystallized from isopropyl alcohol to obtain 3.80 g of 3-amino-4,5-dimethylisoxazole as colorless needles (isolated yield). Rate; 74%).

【0036】参考例4(3-シアノ-2-ブタノンの合成) 内容積300mlのガラス製フラスコに、参考例1と同様な
方法で合成した3-シアノ-2-ブタノンのナトリウム塩30.
0g(0.25mol)、水40ml及び酢酸エチル100mlを加えた。次
いで、濃塩酸21.7ml(0.26mol)を加えた後、有機層を取
り出して無水硫酸マグネシウムで乾燥させた。濾過後、
濾液を減圧下で濃縮して、無色液体として3-シアノ-2-
ブタノン22.3gを得た(単離収率;92%)。3-シアノ-2-ブ
タノンの物性値は以下の通りであった。
Reference Example 4 (Synthesis of 3-cyano-2-butanone) A sodium flask of 3-cyano-2-butanone synthesized in the same manner as in Reference Example 1 was placed in a glass flask having an internal volume of 300 ml.
0 g (0.25 mol), 40 ml of water and 100 ml of ethyl acetate were added. Next, after adding 21.7 ml (0.26 mol) of concentrated hydrochloric acid, the organic layer was taken out and dried over anhydrous magnesium sulfate. After filtration,
The filtrate was concentrated under reduced pressure to give 3-cyano-2- as a colorless liquid.
22.3 g of butanone was obtained (isolation yield; 92%). Physical properties of 3-cyano-2-butanone were as follows.

【0037】1H-NMR(DMSO-d6,δ(ppm));1.50(3H,d)、
2.38(3H,s)、3.60(1H,q)
1 H-NMR (DMSO-d 6 , δ (ppm)); 1.50 (3H, d),
2.38 (3H, s), 3.60 (1H, q)

【0038】参考例5(2-メチルブチロニトリル-3-オ
ン-ジエチルアセタールの合成) 攪拌装置及び温度計を備えた内容積25mlのガラス製フラ
スコに、濃硫酸10mg(0.1mmol)、参考例4と同様な方法
で合成した3-シアノ-2-ブタノン1.94g(20mmol)、オルト
ギ酸エチル3.56g(24mmol)及びエタノール5mlを加え、窒
素雰囲気にて、室温で7時間反応させた。反応終了後、
反応液に、炭酸カリウム0.75g(5mmol)を加えて、更に室
温で1時間攪拌させた。析出物を濾過し、濾液を減圧下
で濃縮して、薄黄色液体として2-メチルブチロニトリル
-3-オン-ジエチルアセタール2.91gを得た(単離収率;85
%)。2-メチルブチロニトリル-3-オン-ジエチルアセタ
ールの物性値は以下の通りである。
REFERENCE EXAMPLE 5 (Synthesis of 2-methylbutyronitrile-3-one-diethylacetal) 10 mg (0.1 mmol) of concentrated sulfuric acid was placed in a 25-ml glass flask equipped with a stirrer and a thermometer. 1.94 g (20 mmol) of 3-cyano-2-butanone, 3.56 g (24 mmol) of ethyl orthoformate and 5 ml of ethanol synthesized in the same manner as in Example 4 were added, and the mixture was reacted at room temperature for 7 hours in a nitrogen atmosphere. After the reaction,
0.75 g (5 mmol) of potassium carbonate was added to the reaction solution, and the mixture was further stirred at room temperature for 1 hour. The precipitate is filtered and the filtrate is concentrated under reduced pressure to give 2-methylbutyronitrile as a pale yellow liquid
2.91 g of -3-one-diethyl acetal was obtained (isolation yield; 85
%). The physical properties of 2-methylbutyronitrile-3-one-diethylacetal are as follows.

【0039】1H-NMR(CDCl3,δ(ppm));1.0〜1.3(9H,
m)、1.40(3H,s)、3.2〜3.6(4H,m)、4.10(1H,q)
1 H-NMR (CDCl 3 , δ (ppm)); 1.0 to 1.3 (9H,
m), 1.40 (3H, s), 3.2-3.6 (4H, m), 4.10 (1H, q)

【0040】参考例6(2-メチルブチルアミドオキシム
-3-オン-ジエチルアセタールの合成) 攪拌装置、温度計、滴下漏斗及び還流冷却器を備えた内
容積25mlのガラス製フラスコに、水酸化ナトリウム1.46
g(36.5mmol)、水7ml及びヒドロキシルアミン塩酸塩1.97
g(28.3mmol)を混合し、氷冷下、参考例5と同様な方法
で合成した2-メチルブチロニトリル-3-オン-ジエチルア
セタール2.40g(14.0mmol)をメタノール7mlに溶解した液
ををゆるやかに滴下し、窒素雰囲気にて、10℃で2時
間、室温で13時間、更に加熱還流下(70〜75℃)で1.5
時間反応させた。反応終了後、室温まで冷却し、酢酸エ
チル20mlで3回抽出した。有機層を取り出し、無水硫酸
マグネシウムで乾燥させた。濾過後、濾液を減圧下で濃
縮して、薄黄色液体として2-メチルブチルアミドオキシ
ム-3-オン-ジエチルアセタール2.45gを得た(単離収率;
86%)。2-メチルブチルアミドオキシム-3-オン-ジエチ
ルアセタールの物性値は以下の通りである。
Reference Example 6 (2-methylbutyramide oxime
Synthesis of 3-one-diethyl acetal) A sodium flask (1.46) was placed in a 25-ml glass flask equipped with a stirrer, a thermometer, a dropping funnel and a reflux condenser.
g (36.5 mmol), water 7 ml and hydroxylamine hydrochloride 1.97
g (28.3 mmol), and a solution prepared by dissolving 2.40 g (14.0 mmol) of 2-methylbutyronitrile-3-one-diethylacetal synthesized in the same manner as in Reference Example 5 in 7 ml of methanol under ice cooling. Slowly in a nitrogen atmosphere at 10 ° C. for 2 hours, at room temperature for 13 hours, and further under heating and refluxing (70-75 ° C.) for 1.5 hours.
Allowed to react for hours. After completion of the reaction, the mixture was cooled to room temperature and extracted three times with 20 ml of ethyl acetate. The organic layer was taken out and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 2.45 g of 2-methylbutyramidooxime-3-one-diethylacetal as a pale yellow liquid (isolation yield;
86%). The physical property values of 2-methylbutyramidooxime-3-one-diethylacetal are as follows.

【0041】1H-NMR(CDCl3,δ(ppm));1.1〜1.3(9H,
m)、1.40(3H,s)、2.8〜3.2(1H,m)、3.2〜4.3(5H,m)、5.
0〜5.2(2H,brs)
1 H-NMR (CDCl 3 , δ (ppm)); 1.1 to 1.3 (9H,
m), 1.40 (3H, s), 2.8-3.2 (1H, m), 3.2-4.3 (5H, m), 5.
0-5.2 (2H, brs)

【0042】実施例5(3-アミノ-4,5-ジメチルイソオ
キサゾールの合成) 攪拌装置及び温度計を備えた内容積25mlのガラス製フラ
スコに、参考例6と同様な方法で合成した2-メチルブチ
ルアミドオキシム-3-オン-ジエチルアセタール2.25g(11
mmol)、エタノール13ml及び濃硫酸20mg(0.2mmol)を加
え、窒素雰囲気にて、室温で15時間反応させた。反応終
了後、反応液を減圧下で濃縮し、濃縮物をイソプロピル
アルコール1mlで再結晶させて、無色粉末として3-アミ
ノ-4,5-ジメチルイソオキサゾール1.00gを得た(単離収
率;81%)。
Example 5 (Synthesis of 3-Amino-4,5-dimethylisoxazole) A 25-ml glass flask equipped with a stirrer and a thermometer was synthesized in the same manner as in Reference Example 6 to obtain a 2-amino-4,5-dimethylisoxazole. 2.25 g of methylbutylamidooxime-3-one-diethylacetal (11
mmol), 13 ml of ethanol and 20 mg (0.2 mmol) of concentrated sulfuric acid, and reacted at room temperature for 15 hours in a nitrogen atmosphere. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the concentrate was recrystallized from 1 ml of isopropyl alcohol to obtain 1.00 g of 3-amino-4,5-dimethylisoxazole as a colorless powder (isolation yield; 81%).

【0043】参考例7(2-アセチルベンジルシアニドの
合成) 攪拌装置、温度計及び還流冷却器を備えた内容積300ml
のガラス製フラスコに、ナトリウムメトキシド10.8g(0.
20mol)、ベンジルシアニド11.7g(0.10mol)、酢酸n-ブチ
ル17.4g(0.15mol)及びトルエン100mlを加え、窒素雰囲
気にて、加熱還流下(105〜110℃)で6時間反応させ
た。反応終了後、室温まで冷却し、水120ml及び濃塩酸1
7ml(0.2mol)を加えた。次いで、有機層を取り出し、無
水硫酸マグネシウムで乾燥させた。濾過後、濾液を減圧
下で濃縮し、薄肌色粉末として2-アセチルベンジルシア
ニド15.4gを得た(単離収率;97%)。2-アセチルベンジ
ルシアニドの物性値は以下の通りであった。
Reference Example 7 (Synthesis of 2-acetylbenzyl cyanide) 300 ml in internal volume equipped with a stirrer, thermometer and reflux condenser
10.8 g of sodium methoxide (0.
20 mol), 11.7 g (0.10 mol) of benzyl cyanide, 17.4 g (0.15 mol) of n-butyl acetate and 100 ml of toluene were added, and the mixture was reacted in a nitrogen atmosphere under reflux with heating (105 to 110 ° C.) for 6 hours. After completion of the reaction, the mixture was cooled to room temperature, and water (120 ml) and concentrated hydrochloric acid (1) were added.
7 ml (0.2 mol) were added. Next, the organic layer was taken out and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 15.4 g of 2-acetylbenzyl cyanide as a light flesh-colored powder (isolation yield; 97%). Physical properties of 2-acetylbenzyl cyanide were as follows.

【0044】1H-NMR(CDCl3,δ(ppm));2.30(3H,s)、4.7
0(1H,s)、7.4〜7.6(5H,m)
1 H-NMR (CDCl 3 , δ (ppm)); 2.30 (3H, s), 4.7
0 (1H, s), 7.4 to 7.6 (5H, m)

【0045】参考例8(2-(β-エチレンジオキシアセ
ト)ベンジルシアニドの合成) 攪拌装置、温度計、還流冷却器及びDean-Stark装置を備
えた内容積100mlのガラス製フラスコに、p-トルエンス
ルホン酸・一水和物950mg(5mmol)、参考例7と同様な方
法で合成した2-アセチルベンジルニトリル7.95g(50mmo
l)、エチレングリコール4.97g(80mol)及びトルエン25ml
を加え、反応で生成する水を留去させながら、窒素雰囲
気にて、加熱還流下(105〜110℃)で15時間反応させ
た。反応終了後、室温まで冷却して、反応液を、飽和食
塩水3ml、2mol/L水酸化ナトリウム水溶液10ml、水3mlの
順で洗浄した。次いで、有機層を取り出し、有機層を減
圧下で濃縮した。この濃縮物をシリカゲルカラムクロマ
トグラフィー(充填剤;ワコーゲルC-200(和光純薬社
製)、展開溶媒;n-ヘキサン/酢酸エチル=4/1(容量比))
で精製して、薄茶色液体として2-(β-エチレンジオキシ
アセト)ベンジルシアニド8.51gを得た(単離収率;84
%)。2-(β-エチレンジオキシアセト)ベンジルシアニド
の物性値は以下の通りであった。
Reference Example 8 (Synthesis of 2- (β-ethylenedioxyaceto) benzyl cyanide) A 100 ml glass flask equipped with a stirrer, a thermometer, a reflux condenser, and a Dean-Stark apparatus was charged with p. -950 mg (5 mmol) of toluenesulfonic acid monohydrate, 7.95 g (50 mmo) of 2-acetylbenzylnitrile synthesized in the same manner as in Reference Example 7.
l), ethylene glycol 4.97 g (80 mol) and toluene 25 ml
Was added thereto, and the mixture was allowed to react for 15 hours under a reflux atmosphere (105 to 110 ° C.) in a nitrogen atmosphere while distilling off water produced by the reaction. After completion of the reaction, the reaction solution was cooled to room temperature, and the reaction solution was washed with 3 ml of saturated saline, 10 ml of a 2 mol / L aqueous sodium hydroxide solution, and 3 ml of water in this order. Next, the organic layer was taken out, and the organic layer was concentrated under reduced pressure. This concentrate is subjected to silica gel column chromatography (filler: Wakogel C-200 (manufactured by Wako Pure Chemical Industries, Ltd.), developing solvent: n-hexane / ethyl acetate = 4/1 (volume ratio))
To give 8.51 g of 2- (β-ethylenedioxyaceto) benzyl cyanide as a light brown liquid (isolation yield; 84
%). Physical properties of 2- (β-ethylenedioxyaceto) benzyl cyanide were as follows.

【0046】1H-NMR(CDCl3,δ(ppm));1.36(3H,s)、3.8
5〜3.91(1H,m)、3.93〜4.10(4H,m)、7.35〜7.45(5H,m)
1 H-NMR (CDCl 3 , δ (ppm)); 1.36 (3H, s), 3.8
5 to 3.91 (1H, m), 3.93 to 4.10 (4H, m), 7.35 to 7.45 (5H, m)

【0047】参考例9(2-(β-エチレンジオキシアセ
ト)-2-フェニルアセトアミドオキシムの合成) 攪拌装置、温度計、滴下漏斗及び還流冷却器を備えた内
容積25mlのガラス製フラスコに、ヒドロキシルアミン塩
酸塩0.43g(6.2mmol)及びメタノール3mlを混合し、氷冷
下、トリエチルアミン0.79g(8.8mmol)を加えて攪拌させ
た。次いで、実施例8と同様な方法で合成した2-(β-エ
チレンジオキシアセト)ベンジルシアニド0.63g(3.1mmo
l)をメタノール1mlに溶解した液をゆるやかに滴下し、
窒素雰囲気にて、加熱還流下(60〜64℃)で20時間反応
させた。反応終了後、室温まで冷却し、反応液を減圧下
で濃縮した。次いで、濃縮物に酢酸エチル15ml及び飽和
炭酸水素ナトリウム水溶液5mlを加え、有機層を取り出
し、無水硫酸マグネシウムで乾燥させた。濾過後、濾液
を減圧下で濃縮した。この濃縮物をシリカゲルカラムク
ロマトグラフィー(充填剤;ワコーゲルC-200(和光純薬
社製)、展開溶媒;n-ヘキサン/酢酸エチル=1/3(容量
比))で精製して、無色粉末として2-(β-エチレンジオ
キシアセト)-2-フェニルアセトアミドオキシム0.60gを
得た(単離収率;81%)。2-(β-エチレンジオキシアセ
ト)-2-フェニルアセトアミドオキシムの物性値は以下の
通りであった。
Reference Example 9 (Synthesis of 2- (β-ethylenedioxyaceto) -2-phenylacetamidooxime) A 25-ml glass flask equipped with a stirrer, a thermometer, a dropping funnel and a reflux condenser was placed in a flask. 0.43 g (6.2 mmol) of hydroxylamine hydrochloride and 3 ml of methanol were mixed, and 0.79 g (8.8 mmol) of triethylamine was added thereto under ice-cooling, followed by stirring. Then, 0.63 g (3.1 mmo) of 2- (β-ethylenedioxyaceto) benzyl cyanide synthesized in the same manner as in Example 8.
l) A solution of 1) dissolved in 1 ml of methanol is slowly added dropwise.
The reaction was carried out in a nitrogen atmosphere under reflux with heating (60 to 64 ° C.) for 20 hours. After the completion of the reaction, the resultant was cooled to room temperature, and the reaction solution was concentrated under reduced pressure. Next, 15 ml of ethyl acetate and 5 ml of a saturated aqueous solution of sodium hydrogen carbonate were added to the concentrate, and the organic layer was taken out and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. This concentrate was purified by silica gel column chromatography (filler: Wakogel C-200 (manufactured by Wako Pure Chemical Industries, Ltd.), developing solvent: n-hexane / ethyl acetate = 1/3 (volume ratio)) to give a colorless powder. 0.60 g of 2- (β-ethylenedioxyaceto) -2-phenylacetamidooxime was obtained (isolation yield; 81%). Physical properties of 2- (β-ethylenedioxyaceto) -2-phenylacetamidooxime were as follows.

【0048】1H-NMR(CDCl3,δ(ppm));1.44(3H,s)、3.3
3〜3.40(1H,m)、3.65〜4.00(5H,m)、4.50(1H,brs)、5.2
4(2H,brs)、7.20〜7.50(5H,m)
1 H-NMR (CDCl 3 , δ (ppm)); 1.44 (3H, s), 3.3
3 to 3.40 (1H, m), 3.65 to 4.00 (5H, m), 4.50 (1H, brs), 5.2
4 (2H, brs), 7.20 ~ 7.50 (5H, m)

【0049】実施例6(3-アミノ5-メチル-4-フェニル
メチルイソオキサゾールの合成) 攪拌装置、温度計及び還流冷却器を備えた内容積50mlの
ガラス製フラスコに、参考例9と同様な方法で合成した
2-(β-エチレンジオキシアセト)-2-フェニルアセトアミ
ドオキシム3.1g(13.0mmol)、イソプロピルアルコール10
ml及び濃塩酸1.3ml(16mmol)を加え、窒素雰囲気にて、
還流下(80〜82℃)で10時間反応させた。反応終了後、
反応液を減圧下で濃縮し、濃縮物に酢酸エチル50ml及び
飽和炭酸水素ナトリウム水溶液20mlを加え、有機層を取
り出し、無水硫酸マグネシウムで乾燥させた。濾過後、
濾液を減圧下で濃縮し、薄黄色粉末として3-アミノ5-メ
チル-4-フェニルメチルイソオキサゾール2.0gを得た(単
離収率;88%)。3-アミノ5-メチル-4-フェニルメチルイ
ソオキサゾールの物性値は以下の通りであった。
Example 6 (Synthesis of 3-amino-5-methyl-4-phenylmethylisoxazole) A 50 ml glass flask equipped with a stirrer, a thermometer and a reflux condenser was charged in the same manner as in Reference Example 9. Synthesized by the method
3.1 g (13.0 mmol) of 2- (β-ethylenedioxyaceto) -2-phenylacetamidooxime, isopropyl alcohol 10
ml and concentrated hydrochloric acid 1.3 ml (16 mmol) were added, and in a nitrogen atmosphere,
The reaction was performed under reflux (80-82 ° C) for 10 hours. After the reaction,
The reaction solution was concentrated under reduced pressure, 50 ml of ethyl acetate and 20 ml of a saturated aqueous solution of sodium hydrogen carbonate were added to the concentrate, and the organic layer was taken out and dried over anhydrous magnesium sulfate. After filtration,
The filtrate was concentrated under reduced pressure to obtain 2.0 g of 3-amino-5-methyl-4-phenylmethylisoxazole as a pale yellow powder (isolation yield: 88%). Physical properties of 3-amino-5-methyl-4-phenylmethylisoxazole were as follows.

【0050】1H-NMR(CDCl3,δ(ppm));2.34(3H,s)、4.0
0(2H,brs)、7.30〜7.55(5H,m)
1 H-NMR (CDCl 3 , δ (ppm)); 2.34 (3H, s), 4.0
0 (2H, brs), 7.30 ~ 7.55 (5H, m)

【0051】参考例10(2-ホルミルベンジルシアニド
の合成) 攪拌装置、温度計及び還流冷却器を備えた内容積200ml
のガラス製フラスコに、ナトリウムメトキシド8.1g(0.1
5mol)、ベンジルシアニド17.6g(0.15mol)、ギ酸エチル1
2.3g(0.17mol)及びメタノール70mlを加え、窒素雰囲気
にて、室温で6時間反応させた。反応終了後、固体が析
出して来たので、濾過して乾燥させた。この固体を水20
0mlに溶解させ、濃塩酸5.8ml(70mol)を加えた。析出し
て来た結晶を濾過して乾燥させ、無色粉末として2-ホル
ミルベンジルシアニド9.0gを得た(単離収率;41%)。2-
ホルミルベンジルシアニドの物性値は以下の通りであっ
た。
Reference Example 10 (Synthesis of 2-formylbenzyl cyanide) 200 ml of internal volume equipped with a stirrer, thermometer and reflux condenser
8.1 g of sodium methoxide (0.1 g
5mol), benzyl cyanide 17.6g (0.15mol), ethyl formate 1
2.3 g (0.17 mol) and 70 ml of methanol were added, and reacted at room temperature for 6 hours in a nitrogen atmosphere. After the completion of the reaction, a solid precipitated, and was filtered and dried. This solid in water 20
The solution was dissolved in 0 ml, and 5.8 ml (70 mol) of concentrated hydrochloric acid was added. The precipitated crystals were filtered and dried to obtain 9.0 g of 2-formylbenzyl cyanide as a colorless powder (isolation yield; 41%). 2-
The physical properties of formylbenzyl cyanide were as follows.

【0052】1H-NMR(DMSO-d6,δ(ppm));7.32〜7.70(6
H,m)、8.06(1H,s)
1 H-NMR (DMSO-d 6 , δ (ppm)); 7.32 to 7.70 (6
H, m) 、 8.06 (1H, s)

【0053】参考例11(2-(β-エチレンジオキシホル
ミル)ベンジルシアニドの合成) 攪拌装置、温度計、還流冷却器及びDean-Stark装置を備
えた内容積100mlのガラス製フラスコに、p-トルエンス
ルホン酸・一水和物950mg(5mmol)、参考例10と同様な
方法で合成した2-ホルミルベンジルシアニド4.10g(28.2
mmol)、エチレングリコール2.81g(45.2mmol)及びトルエ
ン40mlを加え、反応で生成する水を留去させながら、窒
素雰囲気にて、加熱還流下(105〜110℃)で16時間反応
させた。反応終了後、室温まで冷却して、反応液を、飽
和食塩水10ml、2mol/L水酸化ナトリウム水溶液10ml、水
5mlの順で洗浄した。次いで、有機層を取り出し、有機
層を減圧下で濃縮した。この濃縮物をシリカゲルカラム
クロマトグラフィー(充填剤;ワコーゲルC-200(和光純
薬社製)、展開溶媒;n-ヘキサン/酢酸エチル=4/1(容量
比))で精製して、薄黄色液体として2-(β-エチレンジ
オキシホルミル)ベンジルシアニド4.00gを得た(単離収
率;75%)。2-(β-エチレンジオキシホルミル)ベンジル
シアニドの物性値は以下の通りであった。
Reference Example 11 (Synthesis of 2- (β-ethylenedioxyformyl) benzyl cyanide) A 100 ml glass flask equipped with a stirrer, a thermometer, a reflux condenser, and a Dean-Stark apparatus was charged with p. -950 mg (5 mmol) of toluenesulfonic acid monohydrate, 4.10 g (28.2 g) of 2-formylbenzyl cyanide synthesized in the same manner as in Reference Example 10.
mmol), 2.81 g (45.2 mmol) of ethylene glycol, and 40 ml of toluene, and the mixture was reacted under a refluxing atmosphere (105 to 110 ° C.) for 16 hours in a nitrogen atmosphere while distilling off water produced by the reaction. After completion of the reaction, the reaction solution was cooled to room temperature, and the reaction solution was diluted with 10 ml of a saturated saline solution, 10 ml of a 2 mol / L aqueous sodium hydroxide solution, and water
Washing was performed in the order of 5 ml. Next, the organic layer was taken out, and the organic layer was concentrated under reduced pressure. This concentrate was purified by silica gel column chromatography (filler: Wakogel C-200 (manufactured by Wako Pure Chemical Industries, Ltd.), developing solvent: n-hexane / ethyl acetate = 4/1 (volume ratio)) to give a pale yellow liquid. As a result, 4.00 g of 2- (β-ethylenedioxyformyl) benzyl cyanide was obtained (isolation yield; 75%). The physical properties of 2- (β-ethylenedioxyformyl) benzyl cyanide were as follows.

【0054】1H-NMR(CDCl3,δ(ppm));3.85〜3.95(2H,
m)、4.00〜4.15(3H,m)、5.17(1H,d)、7.30〜7.45(5H,m)
1 H-NMR (CDCl 3 , δ (ppm)); 3.85 to 3.95 (2H,
m), 4.00-4.15 (3H, m), 5.17 (1H, d), 7.30-7.45 (5H, m)

【0055】参考例12(2-(β-エチレンジオキシホル
ミル)-2-フェニルアセトアミドオキシムの合成) 攪拌装置、温度計、滴下漏斗及び還流冷却器を備えた内
容積100mlのガラス製フラスコに、ヒドロキシルアミン
塩酸塩2.78g(40mmol)及びメタノール18mlを混合し、氷
冷下、トリエチルアミン5.06g(50mmol)を加えて攪拌さ
せた。次いで、参考例11と同様な方法で合成した2-
(β-エチレンジオキシホルミル)ベンジルシアニド3.79g
(20mmol)をメタノール5mlに溶解した液をゆるやかに滴
下し、窒素雰囲気にて、加熱還流下(60〜64℃)で6時
間反応させた。反応終了後、室温まで冷却し、反応液を
減圧下で濃縮した。次いで、濃縮物に酢酸エチル60ml及
び水10mlを加え、有機層を取り出し、無水硫酸マグネシ
ウムで乾燥させた。濾過後、濾液を減圧下で濃縮した。
この濃縮物をシリカゲルカラムクロマトグラフィー(充
填剤;ワコーゲルC-200(和光純薬社製)、展開溶媒;n-
ヘキサン/酢酸エチル=1/2(容量比))で精製して、無色
粉末として2-(β-エチレンジオキシホルミル)-2-フェニ
ルアセトアミドオキシム0.60gを得た(単離収率;14
%)。2-(β-エチレンジオキシホルミル)-2-フェニルア
セトアミドオキシムの物性値は以下の通りであった。
Reference Example 12 (Synthesis of 2- (β-ethylenedioxyformyl) -2-phenylacetamidooxime) A 100 ml glass flask equipped with a stirrer, a thermometer, a dropping funnel and a reflux condenser was placed in a flask. 2.78 g (40 mmol) of hydroxylamine hydrochloride and 18 ml of methanol were mixed, and 5.06 g (50 mmol) of triethylamine was added thereto under ice cooling, followed by stirring. Then, 2-synthesized in the same manner as in Reference Example 11
(β-ethylenedioxyformyl) benzyl cyanide 3.79 g
A solution of (20 mmol) dissolved in 5 ml of methanol was slowly added dropwise, and the mixture was reacted under a refluxing atmosphere (60 to 64 ° C.) for 6 hours in a nitrogen atmosphere. After the completion of the reaction, the resultant was cooled to room temperature, and the reaction solution was concentrated under reduced pressure. Next, 60 ml of ethyl acetate and 10 ml of water were added to the concentrate, and the organic layer was taken out and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure.
This concentrate was subjected to silica gel column chromatography (filler: Wakogel C-200 (manufactured by Wako Pure Chemical Industries, Ltd.), developing solvent: n-
Hexane / ethyl acetate = 1/2 (volume ratio)) to give 0.60 g of 2- (β-ethylenedioxyformyl) -2-phenylacetamidooxime as a colorless powder (isolation yield; 14).
%). Physical properties of 2- (β-ethylenedioxyformyl) -2-phenylacetamidooxime were as follows.

【0056】1H-NMR(CDCl3,δ(ppm));3.75(1H,d,J=3.9
Hz)、3.81〜3.90(4H,m)、4.83(2H,brs)、5.40(1H,d,J=
3.9Hz)、7.25〜7.44(6H,m)
1 H-NMR (CDCl 3 , δ (ppm)); 3.75 (1 H, d, J = 3.9
Hz), 3.81 to 3.90 (4H, m), 4.83 (2H, brs), 5.40 (1H, d, J =
(3.9Hz), 7.25 to 7.44 (6H, m)

【0057】実施例7(3-アミノ-4-フェニルイソオキ
サゾールの合成) 攪拌装置、温度計及び還流冷却器を備えた内容積25mlの
ガラス製フラスコに、参考例12と同様な方法で合成し
た2-(β-エチレンジオキシホルミル)-2-フェニルアセト
アミドオキシム0.34g(1.5mmol)、イソプロピルアルコー
ル3ml及び濃塩酸0.2ml(2.4mmol)を加え、窒素雰囲気に
て、還流下(80〜82℃)で20時間反応させた。反応終了
後、反応液を減圧下で濃縮し、濃縮物に酢酸エチル20ml
及び飽和炭酸水素ナトリウム水溶液5mlを加え、有機層
を取り出し、有機層を無水硫酸マグネシウムで乾燥させ
た。濾過後、濾液を減圧下で濃縮し、この濃縮物をシリ
カゲルカラムクロマトグラフィー(充填剤;ワコーゲル
C-200(和光純薬社製)、展開溶媒;n-ヘキサン/酢酸エチ
ル=1/1→1/2(容量比))で精製して、無色針状結晶とし
て3-アミノ-4-フェニルイソオキサゾール0.10gを得た
(単離収率;41%)。3-アミノ-4-フェニルイソオキサゾ
ールの物性値は以下の通りであった。
Example 7 (Synthesis of 3-amino-4-phenylisoxazole) A 25 ml glass flask equipped with a stirrer, thermometer and reflux condenser was synthesized in the same manner as in Reference Example 12. 0.34 g (1.5 mmol) of 2- (β-ethylenedioxyformyl) -2-phenylacetamidooxime, 3 ml of isopropyl alcohol and 0.2 ml (2.4 mmol) of concentrated hydrochloric acid were added, and the mixture was refluxed under a nitrogen atmosphere (80 to 82 ° C.). ) For 20 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure.
Then, 5 ml of a saturated aqueous sodium hydrogen carbonate solution was added, the organic layer was taken out, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the filtrate is concentrated under reduced pressure, and the concentrate is subjected to silica gel column chromatography (filler: Wakogel).
Purified with C-200 (manufactured by Wako Pure Chemical Industries, Ltd.), developing solvent: n-hexane / ethyl acetate = 1/1 → 1/2 (volume ratio), and 3-amino-4-phenyl was obtained as colorless needle crystals. 0.10 g of isoxazole was obtained.
(Isolation yield; 41%). Physical properties of 3-amino-4-phenylisoxazole were as follows.

【0058】1H-NMR(CDCl3,δ(ppm));4.08(2H,brs)、
7.35〜7.48(5H,m)、8.19(1H,s)
1 H-NMR (CDCl 3 , δ (ppm)); 4.08 (2H, brs),
7.35 to 7.48 (5H, m), 8.19 (1H, s)

【0059】参考例13(2-ホルミルプロピオニトリル
の合成) 攪拌装置及び温度計を備えた内容積300mlのガラス製フ
ラスコに、37.5%水素化ナトリウム15.5g(0.24mol)、プ
ロピオニトリル13.2g(0.24mol)及びエーテル100mlを加
えた。次いで、氷冷下、ギ酸エチル40ml(0.50mol)をゆ
るやかに滴下した後、室温で20時間反応させた。反応終
了後、水50ml及び濃塩酸25.5ml(0.31mol)を加え、有機
層を取り出して、無水硫酸マグネシウムで乾燥させた。
濾過後、濾液を減圧下で濃縮し、得られた濃縮液の内下
層を分離して、無色液体として2-ホルミルプロピオニト
リル3.5gを得た(単離収率;18%)。2-ホルミルプロピオ
ニトリルの物性値は以下の通りであった。
Reference Example 13 (Synthesis of 2-formylpropionitrile) In a 300-ml glass flask equipped with a stirrer and a thermometer, 15.5 g (0.24 mol) of 37.5% sodium hydride and 13.2 g of propionitrile were placed. (0.24 mol) and 100 ml of ether were added. Then, under ice-cooling, 40 ml (0.50 mol) of ethyl formate was slowly added dropwise, followed by reaction at room temperature for 20 hours. After the completion of the reaction, 50 ml of water and 25.5 ml (0.31 mol) of concentrated hydrochloric acid were added, and the organic layer was taken out and dried over anhydrous magnesium sulfate.
After filtration, the filtrate was concentrated under reduced pressure, and the inner lower layer of the obtained concentrated liquid was separated to obtain 3.5 g of 2-formylpropionitrile as a colorless liquid (isolation yield; 18%). Physical properties of 2-formylpropionitrile were as follows.

【0060】EI-MS(m/e);83(M+) CI-MS(m/e);84(M+1)EI-MS (m / e); 83 (M +) CI-MS (m / e); 84 (M + 1)

【0061】参考例14(2-(β-エチレンジオキシホル
ミル)プロピオニトリルの合成) 攪拌装置、温度計、還流冷却器及びDean-Stark装置を備
えた内容積100mlのガラス製フラスコに、p-トルエンス
ルホン酸・一水和物40mg(0.2mmol)、参考例13と同様
な方法で合成した2-ホルミルプロピオニトリル1.90g(2
2.9mmol)、エチレングリコール2.28g(36.7mmol)及びト
ルエン20mlを加え、反応で生成する水を留去させなが
ら、窒素雰囲気にて、加熱還流下(105〜110℃)で9時
間反応させた。反応終了後、室温まで冷却して、反応液
を、飽和食塩水5ml、飽和炭酸水素ナトリウム水溶液5ml
の順で洗浄し、無水硫酸マグネシウムで乾燥させた。濾
過後、濾液を減圧下で濃縮して、無色液体として2-(β-
エチレンジオキシホルミル)プロピオニトリル1.20gを得
た(単離収率;41%)。2-(β-エチレンジオキシホルミ
ル)プロピオニトリルの物性値は以下の通りであった。
Reference Example 14 (Synthesis of 2- (β-ethylenedioxyformyl) propionitrile) A 100 ml glass flask equipped with a stirrer, a thermometer, a reflux condenser, and a Dean-Stark apparatus was charged with p. -Toluenesulfonic acid monohydrate 40 mg (0.2 mmol), 2-formylpropionitrile 1.90 g (2
2.9 mmol), 2.28 g (36.7 mmol) of ethylene glycol and 20 ml of toluene were added, and the mixture was reacted for 9 hours under heating and refluxing (105 to 110 ° C.) in a nitrogen atmosphere while distilling off water produced by the reaction. After completion of the reaction, the reaction solution was cooled to room temperature, and the reaction solution was diluted with 5 ml of a saturated saline solution,
And dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give 2- (β-
1.20 g of ethylenedioxyformyl) propionitrile was obtained (isolation yield; 41%). Physical properties of 2- (β-ethylenedioxyformyl) propionitrile were as follows.

【0062】1H-NMR(CDCl3,δ(ppm));1.36(3H,d),2.80
〜2.95(1H,m)、3.90〜4.20(4H,m)、4.95(1H,d)
1 H-NMR (CDCl 3 , δ (ppm)); 1.36 (3H, d), 2.80
~ 2.95 (1H, m), 3.90 ~ 4.20 (4H, m), 4.95 (1H, d)

【0063】参考例15(2-(β-エチレンジオキシホル
ミル)プロピオンアミドオキシムの合成) 攪拌装置、温度計、滴下漏斗及び還流冷却器を備えた内
容積25mlのガラス製フラスコに、ヒドロキシルアミン塩
酸塩0.82g(12mmol)及びメタノール8mlを混合し、氷冷
下、トリエチルアミン1.45g(14mmol)を加えて攪拌させ
た。次いで、参考例14と同様な方法で合成した2-(β-
エチレンジオキシホルミル)プロピオニトリル0.75g(5.9
mmol)をメタノール2mlに溶解した液をゆるやかに滴下
し、窒素雰囲気にて、加熱還流下(60〜64℃)で20時間
反応させた。反応終了後、室温まで冷却し、反応液を減
圧下で濃縮した。次いで、濃縮物に酢酸エチル20ml及び
水2mlを加え、有機層を取り出し、無水硫酸マグネシウ
ムで乾燥させた。濾過後、濾液を減圧下で濃縮した。こ
の濃縮物をシリカゲルカラムクロマトグラフィー(充填
剤;ワコーゲルC-200(和光純薬社製)、展開溶媒;n-ヘ
キサン/酢酸エチル=1/2(容量比))で精製して、無色液
体として2-(β-エチレンジオキシホルミル)プロピオン
アミドオキシム0.60gを得た(単離収率;63%)。2-(β-
エチレンジオキシホルミル)プロピオンアミドオキシム
の物性値は以下の通りであった。
Reference Example 15 (Synthesis of 2- (β-ethylenedioxyformyl) propionamidoxime) Hydroxylamine hydrochloride was placed in a 25-ml glass flask equipped with a stirrer, thermometer, dropping funnel and reflux condenser. 0.82 g (12 mmol) of a salt and 8 ml of methanol were mixed, and 1.45 g (14 mmol) of triethylamine was added thereto under ice cooling, followed by stirring. Then, 2- (β-
Ethylenedioxyformyl) propionitrile 0.75 g (5.9
(mmol) in 2 ml of methanol was slowly added dropwise, and the mixture was reacted under a nitrogen atmosphere under reflux with heating (60 to 64 ° C) for 20 hours. After the completion of the reaction, the resultant was cooled to room temperature, and the reaction solution was concentrated under reduced pressure. Next, 20 ml of ethyl acetate and 2 ml of water were added to the concentrate, and the organic layer was taken out and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. This concentrate was purified by silica gel column chromatography (filler: Wakogel C-200 (manufactured by Wako Pure Chemical Industries, Ltd.), developing solvent: n-hexane / ethyl acetate = 1/2 (volume ratio)) to give a colorless liquid. 0.60 g of 2- (β-ethylenedioxyformyl) propionamide oxime was obtained (isolation yield; 63%). 2- (β-
Physical properties of (ethylenedioxyformyl) propionamide oxime were as follows.

【0064】1H-NMR(CDCl3,δ(ppm));1.20(3H,d,J=7.3
Hz)、2.58〜2.68(1H,m)、3.83〜4.04(5H,m)、4.87(2H,b
rs)、4.92(1H,d,J=3.4Hz)
1 H-NMR (CDCl 3 , δ (ppm)); 1.20 (3H, d, J = 7.3
Hz), 2.58-2.68 (1H, m), 3.83-4.04 (5H, m), 4.87 (2H, b
rs), 4.92 (1H, d, J = 3.4Hz)

【0065】実施例8(3-アミノ-4-メチルイソオキサ
ゾールの合成) 攪拌装置、温度計及び還流冷却器を備えた内容積25mlの
ガラス製フラスコに、参考例15と同様な方法で合成し
た2-(β-エチレンジオキシホルミル)プロピオンアミド
オキシム0.50g(3.1mmol)、イソプロピルアルコール5ml
及び濃塩酸0.5ml(6.0mmol)を加え、窒素雰囲気にて、還
流下(80〜82℃)で20時間反応させた。反応終了後、反
応液を減圧下で濃縮し、濃縮物に酢酸エチル20ml及び飽
和炭酸水素ナトリウム水溶液5mlを加え、有機層を取り
出し、有機層を無水硫酸マグネシウムで乾燥させた。濾
過後、濾液を減圧下で濃縮し、この濃縮物をシリカゲル
カラムクロマトグラフィー(充填剤;ワコーゲルC-200
(和光純薬社製)、展開溶媒;n-ヘキサン/酢酸エチル=1/
1→1/2(容量比))で精製して、無色液体として3-アミノ
-4-メチルイソオキサゾール0.23gを得た(単離収率;76
%)。3-アミノ-4-メチルイソオキサゾールの物性値は以
下の通りであった。
Example 8 (Synthesis of 3-amino-4-methylisoxazole) A 25 ml glass flask equipped with a stirrer, thermometer and reflux condenser was synthesized in the same manner as in Reference Example 15. 0.50 g (3.1 mmol) of 2- (β-ethylenedioxyformyl) propionamide oxime, 5 ml of isopropyl alcohol
And 0.5 ml (6.0 mmol) of concentrated hydrochloric acid was added, and the mixture was reacted under reflux (80 to 82 ° C.) for 20 hours in a nitrogen atmosphere. After completion of the reaction, the reaction solution was concentrated under reduced pressure, 20 ml of ethyl acetate and 5 ml of a saturated aqueous solution of sodium hydrogen carbonate were added to the concentrate, the organic layer was taken out, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the filtrate is concentrated under reduced pressure, and the concentrate is subjected to silica gel column chromatography (filler: Wakogel C-200).
(Manufactured by Wako Pure Chemical Industries, Ltd.), developing solvent: n-hexane / ethyl acetate = 1 /
1 → 1/2 (volume ratio)) to give 3-amino as a colorless liquid
0.23 g of 4-methylisoxazole was obtained (isolation yield: 76
%). Physical properties of 3-amino-4-methylisoxazole were as follows.

【0066】1H-NMR(CDCl3,δ(ppm));1.91(3H,s)、3.9
6(2H,brs)、7.85(1H,s)
1 H-NMR (CDCl 3 , δ (ppm)); 1.91 (3H, s), 3.9
6 (2H, brs), 7.85 (1H, s)

【0067】参考例16(2-メチルブチロニトリル-3-
オン-ジメチルアセタールの合成) 攪拌装置及び温度計を備えた内容積50mlのガラス製フラ
スコに、濃硫酸10mg(0.1mmol)、参考例4と同様な方法
で合成した3-シアノ-2-ブタノン7.14g(73.5mmol)、オル
トギ酸メチル15.6g(147mmol)及びメタノール30mlを加
え、窒素雰囲気にて、室温で23時間反応させた。反応終
了後、反応液に、炭酸カリウム1.02g(6.8mmol)を加え
て、更に室温で1時間攪拌させた。析出物を濾過し、濾
液を減圧下で濃縮して、濃縮物をシリカゲルカラムクロ
マトグラフィー(充填剤;ワコーゲルC-200(和光純薬社
製)、展開溶媒;n-ヘキサン/酢酸エチル=3/1(容量比))
で精製して、薄黄色液体として2-メチルブチロニトリル
-3-オン-ジメチルアセタール9.5gを得た(単離収率;90
%)。2-メチルブチロニトリル-3-オン-ジメチルアセタ
ールの物性値は以下の通りであった。
Reference Example 16 (2-methylbutyronitrile-3-
Synthesis of on-dimethyl acetal) In a 50 ml glass flask equipped with a stirrer and a thermometer, 10 mg (0.1 mmol) of concentrated sulfuric acid, 3-cyano-2-butanone 7.14 synthesized in the same manner as in Reference Example 4. g (73.5 mmol), 15.6 g (147 mmol) of methyl orthoformate and 30 ml of methanol were added, and the mixture was reacted at room temperature for 23 hours in a nitrogen atmosphere. After completion of the reaction, 1.02 g (6.8 mmol) of potassium carbonate was added to the reaction solution, and the mixture was further stirred at room temperature for 1 hour. The precipitate is filtered, the filtrate is concentrated under reduced pressure, and the concentrate is subjected to silica gel column chromatography (filler: Wakogel C-200 (manufactured by Wako Pure Chemical Industries, Ltd.), developing solvent: n-hexane / ethyl acetate = 3 / 1 (volume ratio))
Purified with 2-methylbutyronitrile as a pale yellow liquid
9.5 g of 3-one-dimethylacetal was obtained (isolation yield; 90
%). The physical properties of 2-methylbutyronitrile-3-one-dimethylacetal were as follows.

【0068】1H-NMR(CDCl3,δ(ppm));1.23(3H,d)、1.4
0(3H,s)、3.02(1H,q)、3.17(3H,s)、3.28(3H,s)
1 H-NMR (CDCl 3 , δ (ppm)); 1.23 (3H, d), 1.4
0 (3H, s), 3.02 (1H, q), 3.17 (3H, s), 3.28 (3H, s)

【0069】参考例17(2-メチルブチルアミドオキシ
ム-3-オン-ジメチルアセタールの合成) 攪拌装置、温度計、滴下漏斗及び還流冷却器を備えた内
容積50mlのガラス製フラスコに、ヒドロキシルアミン塩
酸塩3.48g(50.0mmol)及びメタノール10mlを混合し、氷
冷下、トリエチルアミン6.33g(62.6mmol)、参考例16
と同様な方法で合成した2-メチルブチロニトリル-3-オ
ン-ジメチルアセタール3.58g(25.0mmol)をメタノール5m
lに溶解した液をを順次ゆるやかに滴下し、窒素雰囲気
にて、加熱還流下(60〜64℃)で8時間反応させた。反
応終了後、室温まで冷却し、反応液を減圧下で濃縮し、
濃縮物に酢酸エチル120ml及び水40mlを加えた。次い
で、有機層を取り出し、無水硫酸マグネシウムで乾燥さ
せた。濾過後、濾液を減圧下で濃縮して、無色粉末とし
て2-メチルブチルアミドオキシム-3-オン-ジメチルアセ
タール3.15gを得た(単離収率;72%)。2-メチルブチル
アミドオキシム-3-オン-ジメチルアセタールの物性値は
以下の通りであった。
Reference Example 17 (Synthesis of 2-methylbutylamidooxime-3-one-dimethylacetal) A hydroxylamine hydrochloride was placed in a 50-ml glass flask equipped with a stirrer, a thermometer, a dropping funnel and a reflux condenser. 3.48 g (50.0 mmol) of a salt and 10 ml of methanol were mixed, and under ice-cooling, 6.33 g (62.6 mmol) of triethylamine, Reference Example 16
3.58 g (25.0 mmol) of 2-methylbutyronitrile-3-one-dimethylacetal synthesized in a similar manner to methanol 5m
The solution dissolved in l was slowly and gradually added dropwise, and the mixture was reacted for 8 hours in a nitrogen atmosphere under heating and refluxing (60 to 64 ° C). After completion of the reaction, the mixture was cooled to room temperature, and the reaction solution was concentrated under reduced pressure.
120 ml of ethyl acetate and 40 ml of water were added to the concentrate. Next, the organic layer was taken out and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 3.15 g of 2-methylbutylamidooxime-3-one-dimethylacetal as a colorless powder (isolation yield; 72%). Physical properties of 2-methylbutyramidooxime-3-one-dimethylacetal were as follows.

【0070】1H-NMR(CDCl3,δ(ppm));1.12(3H,d,J=7.1
Hz)、1.25(3H,s)、2.73(1H,q,J=7.1Hz)、3.20(1H,br
s)、3.21(3H,s)、3.26(3H,s)、5.03(2H,br)
1 H-NMR (CDCl 3 , δ (ppm)); 1.12 (3H, d, J = 7.1
Hz), 1.25 (3H, s), 2.73 (1H, q, J = 7.1Hz), 3.20 (1H, br
s), 3.21 (3H, s), 3.26 (3H, s), 5.03 (2H, br)

【0071】実施例9(3-アミノ-4,5-ジメチルイソオ
キサゾールの合成) 攪拌装置、温度計及び還流冷却器を備えた内容積25mlの
ガラス製フラスコに、参考例17と同様な方法で合成し
た2-メチルブチルアミドオキシム-3-オン-ジメチルアセ
タール2.98g(17mmol)、イソプロピルアルコール13ml及
び濃塩酸2ml(24mmol)を加え、窒素雰囲気にて、還流下
(80〜82℃)で3時間反応させた。反応終了後、反応液
を減圧下で濃縮し、濃縮物に酢酸エチル50ml及び飽和炭
酸水素ナトリウム水溶液20mlを加え、有機層を取り出
し、有機層を無水硫酸マグネシウムで乾燥させた。濾過
後、濾液を減圧下で濃縮し、無色固体として3-アミノ-
4,5-ジメチルイソオキサゾール1.60gを得た(単離収率;
84%)。
Example 9 (Synthesis of 3-amino-4,5-dimethylisoxazole) A 25-ml glass flask equipped with a stirrer, a thermometer and a reflux condenser was prepared in the same manner as in Reference Example 17. 2.98 g (17 mmol) of the synthesized 2-methylbutyramidooxime-3-one-dimethylacetal, 13 ml of isopropyl alcohol and 2 ml (24 mmol) of concentrated hydrochloric acid are added, and the mixture is refluxed (80 to 82 ° C.) for 3 hours in a nitrogen atmosphere. Reacted. After completion of the reaction, the reaction solution was concentrated under reduced pressure, 50 ml of ethyl acetate and 20 ml of a saturated aqueous solution of sodium hydrogen carbonate were added to the concentrate, the organic layer was taken out, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give 3-amino- as a colorless solid.
1.60 g of 4,5-dimethylisoxazole was obtained (isolation yield;
84%).

【0072】参考例18(2-ホルミルベンジルシアニド
の合成) 攪拌装置、温度計及び還流冷却器を備えた内容積200ml
のガラス製フラスコに、ナトリウムメトキシド8.1g(0.1
5mol)、ベンジルシアニド17.6g(0.15mol)、ギ酸エチル1
2.3g(0.17mol)及びメタノール70mlを加え、窒素雰囲気
にて、室温で6時間反応させた。反応終了後、固体が析
出して来たので、反応液を濾過して乾燥させた。この固
体を水200mlに溶解させ、濃塩酸5.8ml(70mol)を加え
た。析出して来た結晶を濾過して乾燥させ、無色粉末と
して2-ホルミルベンジルシアニド9.0gを得た(単離収
率;41%)。2-ホルミルベンジルシアニドの物性値は以
下の通りであった。
Reference Example 18 (Synthesis of 2-formylbenzyl cyanide) 200 ml of internal volume equipped with a stirrer, thermometer and reflux condenser
8.1 g of sodium methoxide (0.1 g
5mol), benzyl cyanide 17.6g (0.15mol), ethyl formate 1
2.3 g (0.17 mol) and 70 ml of methanol were added, and reacted at room temperature for 6 hours in a nitrogen atmosphere. After the completion of the reaction, a solid precipitated, and the reaction solution was filtered and dried. This solid was dissolved in 200 ml of water, and 5.8 ml (70 mol) of concentrated hydrochloric acid was added. The precipitated crystals were filtered and dried to obtain 9.0 g of 2-formylbenzyl cyanide as a colorless powder (isolation yield; 41%). Physical properties of 2-formylbenzyl cyanide were as follows.

【0073】1H-NMR(DMSO-d6,δ(ppm));7.32〜7.70(6
H,m)、8.06(1H,s)
1 H-NMR (DMSO-d 6 , δ (ppm)); 7.32 to 7.70 (6
H, m) 、 8.06 (1H, s)

【0074】参考例19(2-(β-ジエトキシホルミル)
ベンジルシアニドの合成) 攪拌装置及び温度計を備えた内容積100mlのガラス製フ
ラスコに、濃硫酸10mg(0.1mmol)、参考例18と同様な
方法で合成した2-ホルミルベンジルシアニド5.81g(40mm
ol)、オルトギ酸メチル17.76g(120mmol)及びエタノール
40mlを加え、窒素雰囲気にて、室温で15時間反応させ
た。反応終了後、反応液に、炭酸カリウム4.0g(5mmol)
を加えて、更に室温で1時間攪拌させた。析出物を濾過
し、濾液を減圧下で濃縮して、濃縮物をシリカゲルカラ
ムクロマトグラフィー(充填剤;ワコーゲルC-200(和光
純薬社製)、展開溶媒;n-ヘキサン/酢酸エチル=4/1(容
量比))で精製して、無色粉末として2-(β-ジエトキシ
ホルミル)ベンジルシアニド4.1gを得た(単離収率;47
%)。2-(β-ジエトキシホルミル)ベンジルシアニドの物
性値は以下の通りであった。
Reference Example 19 (2- (β-diethoxyformyl)
Synthesis of benzyl cyanide) In a 100-ml glass flask equipped with a stirrer and a thermometer, 10 mg (0.1 mmol) of concentrated sulfuric acid and 5.81 g of 2-formylbenzyl cyanide synthesized by the same method as in Reference Example 18 ( 40mm
ol), 17.76 g (120 mmol) of methyl orthoformate and ethanol
After adding 40 ml, the mixture was reacted at room temperature for 15 hours in a nitrogen atmosphere. After the reaction, 4.0 g (5 mmol) of potassium carbonate was added to the reaction solution.
Was added and further stirred at room temperature for 1 hour. The precipitate is filtered, the filtrate is concentrated under reduced pressure, and the concentrate is subjected to silica gel column chromatography (filler: Wakogel C-200 (manufactured by Wako Pure Chemical Industries, Ltd.), developing solvent: n-hexane / ethyl acetate = 4 / 1 (volume ratio)) to obtain 4.1 g of 2- (β-diethoxyformyl) benzyl cyanide as a colorless powder (isolated yield; 47).
%). The physical properties of 2- (β-diethoxyformyl) benzyl cyanide were as follows.

【0075】1H-NMR(CDCl3,δ(ppm));1.09(3H,t)、1.2
2(3H,t)、3.30〜3.80(4H,m)、4.00(2H,d)、4.62(2H,
d)、7.30〜7.41(5H,m)
1 H-NMR (CDCl 3 , δ (ppm)); 1.09 (3H, t), 1.2
2 (3H, t), 3.30-3.80 (4H, m), 4.00 (2H, d), 4.62 (2H,
d), 7.30-7.41 (5H, m)

【0076】参考例20(2-(β-ジエトキシホルミル)-
2-フェニルアセトアミドオキシムの合成) 攪拌装置、温度計、滴下漏斗及び還流冷却器を備えた内
容積25mlのガラス製フラスコに、ヒドロキシルアミン塩
酸塩695mg(10mmol)及びメタノール5mlを混合し、氷冷
下、トリエチルアミン1.52g(15mmol)、参考例19と同
様な方法で合成した2-(β-ジエトキシホルミル)ベンジ
ルシアニド1.1g(5mmol)をメタノール1mlに溶解した液を
を順次ゆるやかに滴下し、窒素雰囲気にて、加熱還流下
(60〜64℃)で4時間反応させた。反応終了後、室温ま
で冷却し、反応液を減圧下で濃縮し、濃縮物に酢酸エチ
ル30ml及び飽和炭酸水素ナトリウム水溶液3mlを加え
た。次いで、有機層を取り出し、無水硫酸マグネシウム
で乾燥させた。濾過後、濾液を減圧下で濃縮して、濃縮
物をシリカゲルカラムクロマトグラフィー(充填剤;ワ
コーゲルC-200(和光純薬社製)、展開溶媒;n-ヘキサン/
酢酸エチル=1/2(容量比))で精製して、無色粉末として
2-(β-ジエトキシホルミル)-2-フェニルアセトアミドオ
キシム0.8gを得た(単離収率;64%)。2-(β-ジエトキシ
ホルミル)-2-フェニルアセトアミドオキシムはの物性値
は以下の通りであった。
Reference Example 20 (2- (β-diethoxyformyl)-
Synthesis of 2-phenylacetamido oxime) A hydroxylamine hydrochloride (695 mg, 10 mmol) and methanol (5 ml) were mixed in a 25-ml glass flask equipped with a stirrer, a thermometer, a dropping funnel, and a reflux condenser. A solution prepared by dissolving 1.52 g (15 mmol) of triethylamine and 1.1 g (5 mmol) of 2- (β-diethoxyformyl) benzyl cyanide synthesized in the same manner as in Reference Example 19 in 1 ml of methanol was slowly and gradually added dropwise. The reaction was carried out in a nitrogen atmosphere under reflux with heating (60 to 64 ° C.) for 4 hours. After completion of the reaction, the reaction solution was cooled to room temperature, the reaction solution was concentrated under reduced pressure, and 30 ml of ethyl acetate and 3 ml of a saturated aqueous solution of sodium hydrogen carbonate were added to the concentrate. Next, the organic layer was taken out and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the concentrate was subjected to silica gel column chromatography (filler: Wakogel C-200 (manufactured by Wako Pure Chemical Industries, Ltd.), developing solvent: n-hexane /
Ethyl acetate = 1/2 (volume ratio)) as a colorless powder
0.8 g of 2- (β-diethoxyformyl) -2-phenylacetamidooxime was obtained (isolation yield; 64%). The physical properties of 2- (β-diethoxyformyl) -2-phenylacetamidooxime were as follows.

【0077】1H-NMR(CDCl3,δ(ppm));1.12(3H,t,J=7.1
Hz)、1.20(3H,t,J=7.1Hz)、3.50〜3.85(5H,m)、4.84(1
H,d,J=4.9Hz)、5.03(2H,br)、7.25〜7.45(6H,m)
1 H-NMR (CDCl 3 , δ (ppm)); 1.12 (3H, t, J = 7.1
Hz), 1.20 (3H, t, J = 7.1Hz), 3.50-3.85 (5H, m), 4.84 (1
(H, d, J = 4.9Hz), 5.03 (2H, br), 7.25-7.45 (6H, m)

【0078】実施例10(3-アミノ-4-フェニルイソオ
キサゾールの合成) 攪拌装置、温度計及び還流冷却器を備えた内容積25mlの
ガラス製フラスコに、参考例20と同様な方法で合成し
た2-(β-ジエトキシホルミル)-2-フェニルアセトアミド
オキシム1.48g(5.9mmol)、イソプロピルアルコール13ml
及び濃塩酸0.7ml(8.4mmol)を加え、窒素雰囲気にて、還
流下(80〜82℃)で7.5時間反応させた。反応終了後、
反応液を減圧下で濃縮し、濃縮物に酢酸エチル50ml及び
飽和炭酸水素ナトリウム水溶液20mlを加え、有機層を取
り出し、有機層を無水硫酸マグネシウムで乾燥させた。
濾過後、濾液を減圧下で濃縮し、この濃縮物をシリカゲ
ルカラムクロマトグラフィー(充填剤;ワコーゲルC-20
0(和光純薬社製)、展開溶媒;n-ヘキサン/酢酸エチル=3
/1(容量比))で精製して、無色粉末として3-アミノ-4-
フェニルイソオキサゾール0.70を得た(単離収率;74
%)。
Example 10 (Synthesis of 3-amino-4-phenylisoxazole) A 25 ml glass flask equipped with a stirrer, a thermometer and a reflux condenser was synthesized in the same manner as in Reference Example 20. 1.48 g (5.9 mmol) of 2- (β-diethoxyformyl) -2-phenylacetamidooxime, 13 ml of isopropyl alcohol
Then, 0.7 ml (8.4 mmol) of concentrated hydrochloric acid was added, and the mixture was reacted in a nitrogen atmosphere under reflux (80 to 82 ° C.) for 7.5 hours. After the reaction,
The reaction solution was concentrated under reduced pressure, 50 ml of ethyl acetate and 20 ml of a saturated aqueous sodium hydrogen carbonate solution were added to the concentrate, the organic layer was taken out, and the organic layer was dried over anhydrous magnesium sulfate.
After filtration, the filtrate is concentrated under reduced pressure, and the concentrate is subjected to silica gel column chromatography (filler: Wakogel C-20).
0 (manufactured by Wako Pure Chemical Industries), developing solvent: n-hexane / ethyl acetate = 3
/ 1 (volume ratio)) to give 3-amino-4- as a colorless powder.
0.70 of phenylisoxazole was obtained (isolation yield: 74)
%).

【0079】1H-NMR(CDCl3,δ(ppm)); 1 H-NMR (CDCl 3 , δ (ppm));

【0080】参考例21(2-ベンゾイルベンジルシアニ
ドの合成) 攪拌装置、温度計及び還流冷却器を備えた内容積300ml
のガラス製フラスコに、ナトリウムメトキシド10.8g(0.
20mol)、ベンジルシアニド11.7g(0.10mol)、安息香酸メ
チル20.4g(0.15mol)及びトルエン60mlを加え、加熱還流
下(105〜110℃)で2.5時間反応させた。反応終了後、
水120ml及び濃塩酸17ml(0.2mol)を加え、有機層を取り
出して、無水硫酸マグネシウムで乾燥させた。濾過後、
濾液を減圧下で濃縮した。濃縮物をトルエン15mlで再結
晶させ、無色針状結晶として2-ベンゾイルベンジルシア
ニド15.4gを得た(単離収率;70%)。2-ベンゾイルベン
ジルシアニドの物性値は以下の通りであった。
Reference Example 21 (Synthesis of 2-benzoylbenzyl cyanide) 300 ml in internal volume equipped with a stirrer, thermometer and reflux condenser
10.8 g of sodium methoxide (0.
20 mol), 11.7 g (0.10 mol) of benzyl cyanide, 20.4 g (0.15 mol) of methyl benzoate and 60 ml of toluene were added, and reacted under reflux with heating (105 to 110 ° C.) for 2.5 hours. After the reaction,
120 ml of water and 17 ml (0.2 mol) of concentrated hydrochloric acid were added, and the organic layer was taken out and dried over anhydrous magnesium sulfate. After filtration,
The filtrate was concentrated under reduced pressure. The concentrate was recrystallized from 15 ml of toluene to obtain 15.4 g of 2-benzoylbenzyl cyanide as colorless needles (isolation yield; 70%). Physical property values of 2-benzoylbenzyl cyanide were as follows.

【0081】1H-NMR(CDCl3,δ(ppm));5.60(1H,s)、7.3
5〜8.20(10H,m)
1 H-NMR (CDCl 3 , δ (ppm)); 5.60 (1 H, s), 7.3
5 to 8.20 (10H, m)

【0082】参考例22(2-(β-エチレンジオキシベン
ゾイル)ベンジルシアニドの合成) 攪拌装置、温度計、還流冷却器及びDean-Stark装置を備
えた内容積100mlのガラス製フラスコに、p-トルエンス
ルホン酸・一水和物950mg(5mmol)、参考例21と同様な
方法で合成した2-ベンゾイルベンジルニトリル4.43g(2
0.0mmol)、エチレングリコール4.97g(80.0mmol)及びキ
シレン40mlを加え、反応で生成する水を留去させなが
ら、窒素雰囲気にて、加熱還流下(135〜140℃)で25時
間反応させた。反応終了後、室温まで冷却して、10%炭
酸ナトリウム水溶液60mlを加えた。固体が析出して来た
ので反応液を濾過し、濾液に水10mlを加え、有機層を取
り出して無水硫酸マグネシウムで乾燥させた。濾過後、
濾液を減圧下で濃縮して、濃縮物をシリカゲルカラムク
ロマトグラフィー(充填剤;ワコーゲルC-200(和光純薬
社製)、展開溶媒;n-ヘキサン/酢酸エチル=4/1(容量
比))で精製して、薄黄色液体として2-(β-エチレンジ
オキシベンゾイル)ベンジルシアニド1.51gを得た(単離
収率;29%)。2-(β-エチレンジオキシベンゾイル)ベン
ジルシアニドの物性値は以下の通りであった。
Reference Example 22 (Synthesis of 2- (β-ethylenedioxybenzoyl) benzyl cyanide) A 100 ml glass flask equipped with a stirrer, thermometer, reflux condenser and Dean-Stark apparatus was charged with p -Toluenesulfonic acid monohydrate 950 mg (5 mmol), 4.43 g of 2-benzoylbenzylnitrile synthesized in the same manner as in Reference Example 21 (2
(0.0 mmol), 4.97 g (80.0 mmol) of ethylene glycol, and 40 ml of xylene, and the mixture was allowed to react under a nitrogen atmosphere under heating and refluxing (135 to 140 ° C.) for 25 hours while distilling off water produced by the reaction. After completion of the reaction, the mixture was cooled to room temperature, and 60 ml of a 10% aqueous sodium carbonate solution was added. Since a solid was deposited, the reaction solution was filtered, 10 ml of water was added to the filtrate, and the organic layer was taken out and dried over anhydrous magnesium sulfate. After filtration,
The filtrate is concentrated under reduced pressure, and the concentrate is subjected to silica gel column chromatography (filler: Wakogel C-200 (manufactured by Wako Pure Chemical Industries, Ltd.), developing solvent: n-hexane / ethyl acetate = 4/1 (volume ratio)) To give 1.51 g of 2- (β-ethylenedioxybenzoyl) benzyl cyanide as a pale yellow liquid (isolation yield; 29%). Physical properties of 2- (β-ethylenedioxybenzoyl) benzyl cyanide were as follows.

【0083】1H-NMR(CDCl3,δ(ppm));3.82〜4.20(4H,
m)、4.23(1H,s),7.10〜7.40(10H,m)
[0083] 1 H-NMR (CDCl 3, δ (ppm)); 3.82~4.20 (4H,
m), 4.23 (1H, s), 7.10 ~ 7.40 (10H, m)

【0084】参考例23(2-(β-エチレンジオキシベン
ゾイル)-2-フェニルアセトアミドオキシムの合成) 攪拌装置、温度計、滴下漏斗及び還流冷却器を備えた内
容積25mlのガラス製フラスコに、ヒドロキシルアミン塩
酸塩0.23g(3.3mmol)及びメタノール3mlを混合し、氷冷
下、トリエチルアミン0.41g(4.1mmol)を加えて攪拌させ
た。次いで、参考例22と同様な方法で合成した2-(β-
エチレンジオキシベンゾイル)ベンジルシアニド0.43g
(1.6mmol)をメタノール1mlに溶解した液をゆるやかに滴
下し、窒素雰囲気にて、加熱還流下(60〜64℃)で20時
間反応させた。反応終了後、室温まで冷却し、反応液を
減圧下で濃縮した。次いで、濃縮物に酢酸エチル20ml及
び飽和炭酸水素ナトリウム水溶液5mlを加え、有機層を
取り出し、無水硫酸マグネシウムで乾燥させた。濾過
後、濾液を減圧下で濃縮した。この濃縮物に酢酸エチル
3mlを加えて還流させた後、析出物を濾過して乾燥し、
無色粉末として2-(β-エチレンジオキシベンゾイル)-2-
フェニルアセトアミドオキシム0.30gを得た(単離収率;
63%)。2-(β-エチレンジオキシベンゾイル)-2-フェニ
ルアセトアミドオキシムの物性値は以下の通りであっ
た。
Reference Example 23 (Synthesis of 2- (β-ethylenedioxybenzoyl) -2-phenylacetamidooxime) A 25 ml glass flask equipped with a stirrer, a thermometer, a dropping funnel and a reflux condenser was placed in a flask. 0.23 g (3.3 mmol) of hydroxylamine hydrochloride and 3 ml of methanol were mixed, and under ice-cooling, 0.41 g (4.1 mmol) of triethylamine was added and stirred. Then, 2- (β-
0.43 g of ethylenedioxybenzoyl) benzyl cyanide
A solution prepared by dissolving (1.6 mmol) in 1 ml of methanol was slowly added dropwise, and the mixture was reacted under a refluxing atmosphere (60 to 64 ° C.) for 20 hours in a nitrogen atmosphere. After the completion of the reaction, the resultant was cooled to room temperature, and the reaction solution was concentrated under reduced pressure. Next, 20 ml of ethyl acetate and 5 ml of a saturated aqueous solution of sodium hydrogen carbonate were added to the concentrate, and the organic layer was taken out and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. Ethyl acetate is added to this concentrate.
After adding 3 ml and refluxing, the precipitate was filtered and dried,
2- (β-ethylenedioxybenzoyl) -2- as a colorless powder
0.30 g of phenylacetamidooxime was obtained (isolation yield;
63%). Physical properties of 2- (β-ethylenedioxybenzoyl) -2-phenylacetamidooxime were as follows.

【0085】1H-NMR(CDCl3,δ(ppm));3.74〜3.86(3H,
m)、3.95〜4.00(2H,m)、5.23(2H,brs)、5.72(1H,brs)、
7.19〜7.44(10H,m)
1 H-NMR (CDCl 3 , δ (ppm)); 3.74 to 3.86 (3H,
m), 3.95-4.00 (2H, m), 5.23 (2H, brs), 5.72 (1H, brs),
7.19 to 7.44 (10H, m)

【0086】実施例11(3-アミノ-4,5-ジフェニルイ
ソオキサゾールの合成) 攪拌装置、温度計及び還流冷却器を備えた内容積25mlの
ガラス製フラスコに、参考例23と同様な方法で合成し
た2-(β-エチレンジオキシベンゾイル)-2-フェニルアセ
トアミドオキシム0.50(1.7mmol)、イソプロピルアルコ
ール5ml及び濃塩酸0.5ml(6.0mmol)を加え、窒素雰囲気
にて、還流下(80〜82℃)で30時間反応させた。反応終
了後、反応液を減圧下で濃縮し、濃縮物に酢酸エチル30
ml及び飽和炭酸水素ナトリウム水溶液10mlを加え、有機
層を取り出し、有機層を無水硫酸マグネシウムで乾燥さ
せた。濾過後、濾液を減圧下で濃縮し、無色粉末として
3-アミノ-4,5-ジフェニルイソオキサゾール0.30gを得た
(単離収率;76%)。
Example 11 (Synthesis of 3-amino-4,5-diphenylisoxazole) A 25-ml glass flask equipped with a stirrer, a thermometer and a reflux condenser was prepared in the same manner as in Reference Example 23. 0.50 (1.7 mmol) of the synthesized 2- (β-ethylenedioxybenzoyl) -2-phenylacetamidooxime, 5 ml of isopropyl alcohol and 0.5 ml (6.0 mmol) of concentrated hydrochloric acid were added, and the mixture was refluxed (80 to 82 C) for 30 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure.
ml and a saturated aqueous solution of sodium bicarbonate (10 ml) were added, the organic layer was taken out, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the filtrate is concentrated under reduced pressure to give a colorless powder
0.30 g of 3-amino-4,5-diphenylisoxazole was obtained.
(Isolation yield; 76%).

【0087】1H-NMR(CDCl3,δ(ppm));5.33(2H,brs)、
7.10〜7.40(10H,m)
1 H-NMR (CDCl 3 , δ (ppm)); 5.33 (2H, brs),
7.10 to 7.40 (10H, m)

【0088】[0088]

【発明の効果】本発明により、入手が容易なジアルコキ
シアミドオキシム誘導体から、簡便な方法によって、高
収率で4-置換-3-アミノイソオキサゾール誘導体を得
る、工業的に好適な4-置換-3-アミノイソオキサゾール
誘導体の製法を提供することが出来る。
According to the present invention, an industrially suitable 4-substituted 4-substituted-3-aminoisoxazole derivative is obtained from a readily available dialkoxyamide oxime derivative by a simple method in a high yield. A method for producing a -3-aminoisoxazole derivative can be provided.

フロントページの続き (72)発明者 中村 卓 山口県宇部市大字小串1978番地の5 宇部 興産株式会社宇部研究所内 (72)発明者 山田 修二 山口県宇部市大字小串1978番地の5 宇部 興産株式会社宇部研究所内 Fターム(参考) 4C056 AA01 AB01 AC01 AD01 AE03 AF01 FA03 FA04 FB10 FC01 4H039 CA42 CH10 Continuing from the front page (72) Inventor Taku Nakamura 5-1978 Kogushi, Oji, Ube City, Yamaguchi Prefecture Inside Ube Research Laboratories (72) Inventor Shuji Yamada 5 1978 Kogushi, Oji City, Ube City, Yamaguchi Ube F-term in the laboratory (reference) 4C056 AA01 AB01 AC01 AD01 AE03 AF01 FA03 FA04 FB10 FC01 4H039 CA42 CH10

Claims (2)

【特許請求の範囲】[Claims] 【請求項1】酸の存在下、一般式(1) 【化1】 (式中、R1及びR2は、反応に関与しない基(但し、R
2は、水素原子を除く)、R3及びR4は、同一又は異な
っていても良く、反応に関与しない基を示す。なお、R
3及びR4は、連結して環を形成していても良い。)で示
されるジアルコキシアミドオキシム誘導体を環化反応さ
せることを特徴とする、一般式(2) 【化2】 (式中、R1及びR2は、前記と同義である。)で示され
る4-置換-3-アミノイソオキサゾール誘導体の製法。
(1) In the presence of an acid, a compound represented by the following general formula (1): (Wherein R 1 and R 2 are groups not participating in the reaction (provided that R 1 and R 2 are
2 excludes a hydrogen atom), R 3 and R 4 may be the same or different and represent a group which does not participate in the reaction. Note that R
3 and R 4 may be linked to form a ring. ), Wherein the dialkoxyamide oxime derivative represented by the general formula (2) is subjected to a cyclization reaction. (Wherein, R 1 and R 2 have the same meanings as described above.) A method for producing a 4-substituted-3-aminoisoxazole derivative represented by the formula:
【請求項2】反応を溶媒中で行う請求項1記載の4-置換
-3-アミノイソオキサゾール誘導体の製法。
2. The 4-substitution according to claim 1, wherein the reaction is carried out in a solvent.
Production method of -3-aminoisoxazole derivative.
JP2001166541A 2001-06-01 2001-06-01 Method of producing 4-substituted-3-amino-isoxazole derivative Pending JP2002363171A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107200729A (en) * 2017-05-27 2017-09-26 无锡捷化医药科技有限公司 One kind 4(2 methoxyphenyls)‑5‑(2 pyridine radicals) 3 amido isoxazoles preparation method

Cited By (2)

* Cited by examiner, † Cited by thir