JP2007077161A - Dialkoxy nitrile derivative and method for producing the same - Google Patents

Dialkoxy nitrile derivative and method for producing the same Download PDF

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JP2007077161A
JP2007077161A JP2006290105A JP2006290105A JP2007077161A JP 2007077161 A JP2007077161 A JP 2007077161A JP 2006290105 A JP2006290105 A JP 2006290105A JP 2006290105 A JP2006290105 A JP 2006290105A JP 2007077161 A JP2007077161 A JP 2007077161A
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derivative
reaction
orthoformate
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dialkoxynitrile
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JP4518066B2 (en
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Akio Matsushita
明生 松下
Kiyotaka Yoshii
清隆 吉井
Masayoshi Ogami
雅良 大上
Shuji Yamada
修二 山田
Taku Nakamura
卓 中村
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Ube Corp
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Ube Industries Ltd
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Abstract

<P>PROBLEM TO BE SOLVED: To provide a new dialkoxy nitrile derivative useful as a synthetic raw material for a medicine and an agrochemical; and to provide a method for producing the derivative. <P>SOLUTION: The new dialkyl acetal derivative of 2-methylbutyronitrile-3-one can be synthesized by reacting 3-cyano-2-butanone with an orthoformic ester in an acidic condition. The compound can, for example, be introduced to a 4-substituted-3-aminoisoxazole derivative by reacting the compound with a hydroxylamine. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

本発明は、例えば、医薬・農薬の合成原料として有用な、ジアルコキシニトリル誘導体及びその製法に関する。   The present invention relates to a dialkoxynitrile derivative useful as, for example, a synthetic raw material for pharmaceuticals and agricultural chemicals and a method for producing the same.

本発明のジアルコキシニトリル誘導体は、新規な化合物であり、従来までにその製法は全く知られていなかった。   The dialkoxynitrile derivative of the present invention is a novel compound, and its production method has never been known so far.

本発明の課題は、即ち、ジアルコキシニトリル誘導体及びその製法を提供するものである。   An object of the present invention is to provide a dialkoxynitrile derivative and a method for producing the same.

本発明の課題は、   The subject of the present invention is

(式中、R1は、炭素数1〜4のアルキル基を示す。)
ジアルコキシニトリル誘導体によって解決される。
(In the formula, R 1 represents an alkyl group having 1 to 4 carbon atoms.)
This is solved by dialkoxynitrile derivatives.

本発明の課題は、又、酸性条件下、一般式(2)   The subject of this invention is also general formula (2) under acidic conditions.

で示されるシアノケトン類に、一般式(3) A cyano ketone represented by general formula (3)

(式中、Rは、前記と同義である。)
で示されるオルトギ酸エステルを反応させて、一般式(1)
(Wherein R 1 has the same meaning as described above.)
Is reacted with an orthoformate represented by the general formula (1)

(式中、R1は、前記と同義である。)
で示される請求項1記載のジアルコキシニトリル誘導体の製法によっても解決される。
(In the formula, R 1 has the same meaning as described above.)
It can also be solved by the method for producing a dialkoxynitrile derivative according to claim 1 represented by

本発明により、新規なジアルコキシニトリル誘導体及びその製法を提供することが出来る。   According to the present invention, a novel dialkoxynitrile derivative and a method for producing the same can be provided.

本発明のジアルコキシニトリル誘導体は、前記の一般式(1)で示される。   The dialkoxynitrile derivative of the present invention is represented by the general formula (1).

一般式(1)において、Rは、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、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。 In the general formula (1), R 1 is an alkyl group having 1 to 4 carbon atoms, specifically, 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.

なお、前記のジアルコキシニトリル誘導体は、ヒドロキシルアミンを反応させた後、酸と反応させることによって、一般式(4)   The dialkoxynitrile derivative is reacted with hydroxylamine and then reacted with an acid to give a general formula (4)

(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に導くことが出来(後の参考例3に記載)、導かれた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6-9585号公報)。
(In the formula, R 1 and R 2 are as defined above.)
Can be led to the 4-substituted-3-aminoisoxazole derivative (described in Reference Example 3 below), and the derived 4-substituted-3-aminoisoxazole derivative can be used as a hypotensive agent or anti-arteriosclerosis. It can be used as a raw material for the synthesis of sulfonamide endothelin antagonist compounds useful as agents (for example, JP-A-6-9585).

本発明のジアルコキシアミドオキシム誘導体は、酸性条件下、一般式(2)で示されるシアノケトン類に、一般式(3)で示されるオルトギ酸エステルを反応させることによって得ることが出来る。   The dialkoxyamidooxime derivative of the present invention can be obtained by reacting an orthoformate represented by the general formula (3) with a cyanoketone represented by the general formula (2) under acidic conditions.

本発明の反応は、酸性条件下、一般式(2)で示されるシアノケトン類に、一般式(3)で示されるオルトギ酸エステルを反応させて、一般式(4)で示されるジアルコキシニトリル誘導体とする工程である。   In the reaction of the present invention, a dialkoxynitrile derivative represented by the general formula (4) is obtained by reacting an orthoformate represented by the general formula (3) with the cyanoketone represented by the general formula (2) under acidic conditions. It is a process.

本発明の反応において使用するオルトギ酸エステルは、前記の一般式(3)で示されるが、例えば、オルトギ酸メチル、オルトギ酸エチル、オルトギ酸プロピル、オルトギ酸イソプロピル、オルトギ酸ブチル等が挙げられるが、好ましくはオルトギ酸メチル、オルトギ酸エチルである。   The orthoformate used in the reaction of the present invention is represented by the general formula (3), and examples thereof include methyl orthoformate, ethyl orthoformate, propyl orthoformate, isopropyl orthoformate, and butyl orthoformate. Preferably, methyl orthoformate and ethyl orthoformate are used.

前記オルトギ酸エステルの使用量は、シアノケトン類1molに対して、好ましくは0.1〜50mol、更に好ましくは0.5〜10molである。   The amount of the orthoformate used is preferably 0.1 to 50 mol, more preferably 0.5 to 10 mol, relative to 1 mol of the cyanoketones.

本発明の反応は、酸性条件下で行われる。反応系を酸性にするために、系内に酸を存在させるが、使用する酸としては、塩酸、硫酸、リン酸等の鉱酸類;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;酢酸、プロピオン酸、酪酸等のカルボン酸類が挙げられるが、好ましくは鉱酸類、スルホン酸類が使用される。なお、これらの酸は、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 carried out under acidic conditions. In order to make the reaction system acidic, an acid is present in the system. Examples of the acid used include mineral acids such as hydrochloric acid, sulfuric acid and phosphoric acid; sulfonic acids such as benzenesulfonic acid and p-toluenesulfonic acid; acetic acid Carboxylic acids such as propionic acid and butyric acid are preferable, and mineral acids and sulfonic acids are preferably used. In addition, you may use these acids individually or in mixture of 2 or more types.

前記酸の使用量は、反応系を酸性にする量であれば特に制限はされないが、シアノケトン類1molに対して、好ましくは0.001〜10mol、更に好ましくは0.005〜5molである。   The amount of the acid used is not particularly limited as long as it makes the reaction system acidic, but is preferably 0.001 to 10 mol, more preferably 0.005 to 5 mol, with respect to 1 mol of the cyanoketones.

本発明の反応は、溶媒の存在下又は非存在下で行われる。使用される溶媒は反応に関与しないものならば特に限定されず、例えば、シクロヘキサン、シクロヘプタン、シクロオクタン等の環状脂肪族炭化水素類;トルエン、キシレン、クメン等の芳香族炭化水素類;クロロベンゼン、ブロモベンゼン等のハロゲン化芳香族炭化水素類;ニトロベンゼン等のニトロ化芳香族炭化水素類;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;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が挙げられるが、好ましくは環状脂肪族炭化水素類、芳香族炭化水素類、カルボン酸エステル類、アルコール類が使用される。なお、これらの溶媒は、単独又は二種以上を混合して使用しても良い。   The reaction of the present invention is carried out in the presence or absence of a solvent. The solvent used is not particularly limited as long as it does not participate in the reaction. For example, cycloaliphatic hydrocarbons such as cyclohexane, cycloheptane and cyclooctane; aromatic hydrocarbons such as toluene, xylene and cumene; chlorobenzene, Halogenated aromatic hydrocarbons such as bromobenzene; nitrated aromatic hydrocarbons such as nitrobenzene; methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, t-butyl acetate, etc. Carboxylic acid esters of: alcohols such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, t-butyl alcohol, preferably cyclic aliphatic hydrocarbons, aromatic Used by hydrocarbons, carboxylic acid esters, and alcohols It is. In addition, you may use these solvents individually or in mixture of 2 or more types.

前記溶媒の使用量は、溶液の均一性や攪拌性により適宜調節するが、シアノケトン類1gに対して、好ましくは0.5〜100ml、更に好ましくは1〜50mlである。   The amount of the solvent used is appropriately adjusted depending on the uniformity and agitation of the solution, but is preferably 0.5 to 100 ml, more preferably 1 to 50 ml with respect to 1 g of cyanoketones.

本発明の反応は、例えば、不活性ガスの雰囲気にて、酸、シアノケトン類、オルトギ酸エステル及び溶媒を混合して、攪拌す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0〜200℃、更に好ましくは5〜160℃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 of mixing an acid, a cyanoketone, an orthoformate ester and a solvent in an inert gas atmosphere and stirring. The reaction temperature at that time is preferably 0 to 200 ° C., more preferably 5 to 160 ° C., and the reaction pressure is not particularly limited.

本発明の反応によって得られるジアルコキシニトリル誘導体は、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・精製することができる。   The dialkoxynitrile derivative obtained by the reaction of the present invention is treated by a general method such as recrystallization, distillation, column chromatography, etc. after the reaction is completed, for example, after neutralization, extraction, concentration, filtration, etc. It can be isolated and purified.

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

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)
In a glass flask having an internal volume of 300 ml equipped with a stirrer, thermometer and reflux condenser, sodium methoxide 13.0 g (0.24 mol), propionitrile 19.9 g (0.36 mol), n-butyl acetate 37.2 g (0.32 mol) ) And 100 ml of toluene, and reacted at 90 ° C. for 24 hours in a nitrogen atmosphere. After completion of the reaction, the reaction mixture was cooled to room temperature, and the precipitate was filtered and dried to obtain 12.0 g of a sodium salt of 3-cyano-2-butanone as a colorless powder (isolation yield; 41.7%).
The physical properties of sodium salt of 3-cyano-2-butanone were as follows.

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)

参考例2(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 2 (Synthesis of 3-cyano-2-butanone)
To a glass flask having an internal volume of 300 ml, 30.0 g (0.25 mol) of sodium salt of 3-cyano-2-butanone synthesized in the same manner as in Reference Example 1, 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 obtain 22.3 g of 3-cyano-2-butanone as a colorless liquid (isolated yield; 92%).
The physical properties of 3-cyano-2-butanone were as follows.

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)

実施例1(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2と同様な方法で合成した3-シアノ-2-ブタノン1.94g(24mmol)、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は、以下の物性値で示される新規な化合物である。
Example 1 (Synthesis of 2-methylbutyronitrile-3-one-diethylacetal)
Concentrated sulfuric acid 10 mg (0.1 mmol), 1.94 g (24 mmol) 3-cyano-2-butanone synthesized in the same manner as in Reference Example 2, orthoformatic acid in a glass flask with an internal volume of 25 ml equipped with a stirrer and a thermometer Ethyl 3.56 g (24 mmol) and ethanol 5 ml were added, and the mixture was reacted at room temperature for 7 hours in a nitrogen atmosphere. After completion of 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 was filtered and the filtrate was concentrated under reduced pressure to give 2.91 g of 2-methylbutyronitrile-3-one-diethylacetal as a pale yellow liquid (isolated yield; 85%).
2-Methylbutyronitrile-3-one-diethylacetal is a novel compound represented by the following physical property values.

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 to 3.6 (4H, m), 4.10 (1H, q)

実施例2(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1.46g(36.5mmol)、水7ml及びヒドロキシルアミン塩酸塩1.97g(28.3mmol)を混合し、氷冷下、実施例1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、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は、以下の物性値で示される新規な化合物である。
Example 2 (Synthesis of 2-methylbutyramideoxime-3-one-diethylacetal)
1.46 g (36.5 mmol) of sodium hydroxide, 7 ml of water and 1.97 g (28.3 mmol) of hydroxylamine hydrochloride were mixed in a glass flask having an internal volume of 25 ml equipped with a stirrer, thermometer, dropping funnel and reflux condenser. Under ice-cooling, a solution of 2.40 g (14.0 mmol) of 2-methylbutyronitrile-3-one-diethylacetal synthesized in the same manner as in Example 1 was slowly dropped into 7 ml of methanol, and a nitrogen atmosphere was added. The mixture was reacted at 10 ° C. for 2 hours, at room temperature for 13 hours, and further heated under reflux (70 to 75 ° C.) for 1.5 hours. After completion of the reaction, the reaction 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-methylbutylamidooxime-3-one-diethylacetal as a pale yellow liquid (isolation yield; 86%).
2-Methylbutlamidooxime-3-one-diethylacetal is a novel compound represented by the following physical property values.

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 to 3.2 (1H, m), 3.2 to 4.3 (5H, m), 5.0 to 5.2 (2H, brs)

参考例3(3-アミノ-4,5-ジメチルイソオキサゾールの合成)
攪拌装置及び温度計を備えた内容積25mlのガラス製フラスコに、実施例2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(11mmol)、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、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、白色粉末として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%)。
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。
Reference Example 3 (Synthesis of 3-amino-4,5-dimethylisoxazole)
In a glass flask equipped with a stirrer and a thermometer and having an internal volume of 25 ml, 2.25 g (11 mmol) of 2-methylbutamidooxime-3-one-diethylacetal synthesized in the same manner as in Example 2, ethanol 13 ml and concentrated 20 mg (0.2 mmol) of sulfuric acid was added, and the mixture was reacted at room temperature for 15 hours in a nitrogen atmosphere. After completion of the reaction, the reaction mixture 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 white powder (isolated yield; 81%) .
The physical properties of 3-amino-4,5-dimethylisoxazole were as follows.

1H-NMR(CDCl3,δ(ppm));1.80(3H,s)、2.20(3H,s)、3.80(2H,s) 1 H-NMR (CDCl 3 , δ (ppm)); 1.80 (3H, s), 2.20 (3H, s), 3.80 (2H, s)

実施例3(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2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は、以下の物性値で示される新規な化合物である。
Example 3 (Synthesis of 2-methylbutyronitrile-3-one-dimethylacetal)
In a glass flask equipped with a stirrer and a thermometer and having an internal volume of 50 ml, 10 mg (0.1 mmol) of concentrated sulfuric acid, 7.14 g (73.5 mmol) of 3-cyano-2-butanone synthesized in the same manner as in Reference Example 2, 15.6 g (147 mmol) of methyl acid 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 was filtered, the filtrate was concentrated under reduced pressure, and the concentrate was subjected to silica gel column chromatography (filler; Wako Gel C-200 (manufactured by Wako Pure Chemical Industries, Ltd.), developing solvent; n-hexane / ethyl acetate = 3 / 1 (volume ratio)) to give 9.5 g of 2-methylbutyronitrile-3-one-dimethylacetal as a pale yellow liquid (isolation yield; 90%).
2-Methylbutyronitrile-3-one-dimethyl acetal is a novel compound represented by the following physical property values.

1H-NMR(CDCl3,δ(ppm));1.23(3H,d)、1.40(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), 1.40 (3H, s), 3.02 (1H, q), 3.17 (3H, s), 3.28 (3H, s)

実施例4(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)、実施例3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5ml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、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、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は、以下の物性値で示される新規な化合物である。
Example 4 (Synthesis of 2-methylbutyramideoxime-3-one-dimethylacetal)
Hydroxylamine hydrochloride (3.48 g, 50.0 mmol) and methanol (10 ml) were mixed in a glass flask equipped with a stirrer, thermometer, dropping funnel and reflux condenser with an internal volume of 50 ml. Under ice-cooling, triethylamine (6.33 g, 62.6 g) was mixed. mmol), and a solution prepared by dissolving 3.58 g (25.0 mmol) of 2-methylbutyronitrile-3-one-dimethylacetal synthesized in the same manner as in Example 3 in 5 ml of methanol was gradually and gradually dropped into a nitrogen atmosphere. And reacted for 8 hours under heating and reflux (60 to 64 ° C.). After completion of the reaction, the reaction mixture was cooled to room temperature, concentrated under reduced pressure, and 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%).
2-Methylbutlamidooxime-3-one-dimethylacetal is a novel compound represented by the following physical property values.

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

参考例4(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(0.15mol)、ベンジルシアニド17.6g(0.15mol)、ギ酸エチル12.3g(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 4 (Synthesis of 2-formylbenzylcyanide)
In a glass flask having an internal volume of 200 ml equipped with a stirrer, a thermometer and a reflux condenser, sodium methoxide 8.1 g (0.15 mol), benzyl cyanide 17.6 g (0.15 mol), ethyl formate 12.3 g (0.17 mol) and 70 ml of methanol was added and reacted at room temperature in a nitrogen atmosphere for 6 hours. After completion of the reaction, a solid was precipitated, and 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-formylbenzylcyanide as a colorless powder (isolation yield: 41%).
The physical properties of 2-formylbenzylcyanide were as follows.

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

実施例5(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4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(40mmol)、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。
Example 5 (Synthesis of 2- (β-diethoxyformyl) benzyl cyanide)
In a 100 ml glass flask equipped with a stirrer and a thermometer, 10 mg (0.1 mmol) of concentrated sulfuric acid, 5.81 g (40 mmol) of 2-formylbenzylcyanide synthesized in the same manner as in Reference Example 4, methyl orthoformate 17.76 g (120 mmol) and 40 ml of ethanol were added and reacted at room temperature for 15 hours in a nitrogen atmosphere. After completion of the reaction, 4.0 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 was filtered, the filtrate was concentrated under reduced pressure, and the concentrate was subjected to silica gel column chromatography (filler; Wako Gel 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 (isolation yield; 47%).
The physical properties of 2- (β-diethoxyformyl) benzyl cyanide were as follows.

1H-NMR(CDCl3,δ(ppm));1.09(3H,t)、1.22(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), 1.22 (3H, t), 3.30 to 3.80 (4H, m), 4.00 (2H, d), 4.62 (2H, d) 7.30-7.41 (5H, m)

実施例6(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)、実施例5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、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、以下の物性値で示される新規な化合物である。
Example 6 (Synthesis of 2- (β-diethoxyformyl) -2-phenylacetamidooxime)
Hydroxylamine hydrochloride 695 mg (10 mmol) and methanol 5 ml were mixed in a glass flask having an internal volume of 25 ml equipped with a stirrer, thermometer, dropping funnel and reflux condenser, and 1.52 g (15 mmol) of triethylamine under ice cooling, A solution prepared by dissolving 1.1 g (5 mmol) of 2- (β-diethoxyformyl) benzylcyanide synthesized in the same manner as in Example 5 in 1 ml of methanol was gradually added dropwise and heated under reflux in a nitrogen atmosphere. (60 to 64 ° C.) for 4 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, concentrated under reduced pressure, and 30 ml of ethyl acetate and 3 ml of a saturated aqueous sodium hydrogen carbonate solution 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; Wako Gel C-200 (manufactured by Wako Pure Chemical Industries, Ltd.), developing solvent; n-hexane / ethyl acetate = 1/2 (volume) Ratio)) to give 0.8 g of 2- (β-diethoxyformyl) -2-phenylacetamidooxime as a colorless powder (isolation yield; 64%).
2- (β-Diethoxyformyl) -2-phenylacetamidooxime is a novel compound represented by the following physical property values.

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

本発明は、例えば、医薬・農薬の合成原料として有用な、ジアルコキシニトリル誘導体及びその製法に関する。   The present invention relates to a dialkoxynitrile derivative useful as, for example, a synthetic raw material for pharmaceuticals and agricultural chemicals and a method for producing the same.

Claims (4)

一般式(1)
(式中、Rは、炭素数1〜4のアルキル基を示す。)
で示されるジアルコキシニトリル誘導体。
General formula (1)
(In the formula, R 1 represents an alkyl group having 1 to 4 carbon atoms.)
A dialkoxynitrile derivative represented by:
が、メチル基又はエチル基である請求項1記載のジアルコキシニトリル誘導体。 The dialkoxynitrile derivative according to claim 1, wherein R 1 is a methyl group or an ethyl group. 酸性条件下、一般式(2)
で示されるシアノケトン類に、一般式(3)
(式中、Rは、前記と同義である。)
で示されるオルトギ酸エステルを反応させて、一般式(1)
(式中、R1は、前記と同義である。)
で示される請求項1記載のジアルコキシニトリル誘導体の製法。
Under acidic conditions, general formula (2)
A cyano ketone represented by general formula (3)
(Wherein R 1 has the same meaning as described above.)
Is reacted with an orthoformate represented by the general formula (1)
(In the formula, R 1 has the same meaning as described above.)
A process for producing a dialkoxynitrile derivative according to claim 1,
オルトギ酸エステルが、オルトギ酸メチル又はオルトギ酸エチルである請求項3記載ジアルコキシニトリル誘導体の製法。   The process for producing a dialkoxynitrile derivative according to claim 3, wherein the orthoformate is methyl orthoformate or ethyl orthoformate.
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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5470217A (en) * 1977-11-09 1979-06-05 Sogo Yatsuko Kk Novel amidoxime derivative
JPS5731672A (en) * 1980-06-19 1982-02-20 Lilly Co Eli Urea derivative and insecticide containing same
JPS5781476A (en) * 1980-09-16 1982-05-21 Lilly Co Eli Isooxazolylbenzamide derivative
JPS58170772A (en) * 1983-03-11 1983-10-07 Sogo Yatsukou Kk Preparation of isoxazole derivative
JPH069585A (en) * 1992-02-24 1994-01-18 E R Squibb & Sons Inc Sulfonamideendoserine antagonist
JP2002523369A (en) * 1998-08-24 2002-07-30 ブリストルーマイヤーズ スクイブ カンパニー New isoxazolinone antibacterial agent

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5470217A (en) * 1977-11-09 1979-06-05 Sogo Yatsuko Kk Novel amidoxime derivative
JPS5731672A (en) * 1980-06-19 1982-02-20 Lilly Co Eli Urea derivative and insecticide containing same
JPS5781476A (en) * 1980-09-16 1982-05-21 Lilly Co Eli Isooxazolylbenzamide derivative
JPS58170772A (en) * 1983-03-11 1983-10-07 Sogo Yatsukou Kk Preparation of isoxazole derivative
JPH069585A (en) * 1992-02-24 1994-01-18 E R Squibb & Sons Inc Sulfonamideendoserine antagonist
JP2002523369A (en) * 1998-08-24 2002-07-30 ブリストルーマイヤーズ スクイブ カンパニー New isoxazolinone antibacterial agent

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