JP4569187B2 - Process for producing 4-cyanotetrahydropyran - Google Patents
Process for producing 4-cyanotetrahydropyran Download PDFInfo
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- JP4569187B2 JP4569187B2 JP2004180107A JP2004180107A JP4569187B2 JP 4569187 B2 JP4569187 B2 JP 4569187B2 JP 2004180107 A JP2004180107 A JP 2004180107A JP 2004180107 A JP2004180107 A JP 2004180107A JP 4569187 B2 JP4569187 B2 JP 4569187B2
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本発明は、ビス(2-置換エチル)エーテルから、4-シアノテトラヒドロピランを製造する方法に関する。4-シアノテトラヒドロピラン、医薬・農薬等の原料や合成中間体として有用な化合物である。 The present invention relates to a process for producing 4-cyanotetrahydropyran from bis (2-substituted ethyl) ether. It is a useful compound as a raw material and synthetic intermediate for 4-cyanotetrahydropyran, pharmaceuticals and agricultural chemicals.
従来、ビス(2-置換エチル)エーテルから、4-シアノテトラヒドロピランを製造する方法としては、例えば、ビス(2-クロロエチル)エーテルとシアノ酢酸エチルとを反応させて4-シアノテトラヒドロピラン-4-カルボン酸エチルとした後、これを加水分解して4-シアノテトラヒドロピラン-4-カルボン酸を得、次いで、これを180〜200℃に加熱して4-シアノテトラヒドロピランを総合取得収率2.3％で製造する方法が知られている（例えば、非特許文献１参照）。しかしながら、この方法では、反応工程が多い上に、収率が極めて低く、4-シアノテトラヒドロピランの工業的な製法としては満足出来るものではなかった。 Conventionally, as a method for producing 4-cyanotetrahydropyran from bis (2-substituted ethyl) ether, for example, bis (2-chloroethyl) ether and ethyl cyanoacetate are reacted to form 4-cyanotetrahydropyran-4- After converting to ethyl carboxylate, this was hydrolyzed to obtain 4-cyanotetrahydropyran-4-carboxylic acid, which was then heated to 180-200 ° C. to obtain 4-cyanotetrahydropyran overall acquisition yield 2.3% (See, for example, Non-Patent Document 1). However, this method has many reaction steps and an extremely low yield, which is not satisfactory as an industrial production method of 4-cyanotetrahydropyran.
本発明の課題は、即ち、上記問題点を解決し、簡便な方法によって、ビス(2-置換エチル)エーテルから、4-シアノテトラヒドロピランを高収率で製造出来る、工業的に好適な4-シアノテトラヒドロピランの製法を提供することである。 The object of the present invention is to solve the above-mentioned problems and to produce 4-cyanotetrahydropyran in high yield from bis (2-substituted ethyl) ether by a simple method. It is to provide a process for producing cyanotetrahydropyran.
本発明の課題は、アルカリ金属水素化物の存在下、一般式（１）
The subject of this invention is general formula (1) in presence of alkali metal hydride.
（式中、Ｘは、脱離基を示す。）
で示されるビス(2-置換エチル)エーテルとアセトニトリルとを反応させることを特徴とする、4-シアノテトラヒドロピランの製法によって解決される。
(In the formula, X represents a leaving group.)
This is solved by a process for producing 4-cyanotetrahydropyran characterized by reacting bis (2-substituted ethyl) ether represented by formula (II) with acetonitrile.
本発明により、簡便な方法によって、ビス(2-置換エチル)エーテルから4-シアノテトラヒドロピランを高収率で製造出来る、工業的に好適な4-シアノテトラヒドロピランの製法を提供することが出来る。 According to the present invention, an industrially suitable process for producing 4-cyanotetrahydropyran, which can produce 4-cyanotetrahydropyran from bis (2-substituted ethyl) ether in a high yield by a simple method, can be provided.
本発明の反応において使用するビス(2-置換エチル)エーテルは、前記の一般式（１）で示される。その一般式（１）において、Ｘは脱離基であり、具体的には、例えば、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；メタンスルホニルオキシ基、エタンスルホニルオキシ基、トリフルオロメタンスルホニルオキシ基等のアルキルスルホニルオキシ基；ベンゼンスルホニルオキシ基、p-トルエンスルホニルオキシ基、p-ブロモベンゼンスルホニルオキシ基等のアリールスルホニルオキシ基が挙げられる。 The bis (2-substituted ethyl) ether used in the reaction of the present invention is represented by the general formula (1). In the general formula (1), X is a leaving group, specifically, for example, a halogen atom such as a fluorine atom, chlorine atom, bromine atom, iodine atom; methanesulfonyloxy group, ethanesulfonyloxy group, trifluoro Examples include alkylsulfonyloxy groups such as lomethanesulfonyloxy group; arylsulfonyloxy groups such as benzenesulfonyloxy group, p-toluenesulfonyloxy group, and p-bromobenzenesulfonyloxy group.
本発明の反応において使用する塩基としては、例えば、水酸化ナトリウム、水酸化カリウム等のアルカリ金属水酸化物；炭酸ナトリウム、炭酸カリウム等のアルカリ金属炭酸塩；炭酸水素ナトリウム、炭酸水素カリウム等のアルカリ金属炭酸水素塩；ナトリウムメトキシド、カリウムメトキシド等のアルカリ金属アルコキシド；水素化ナトリウム、水素化カリウム等のアルカリ金属水素化物；メチルリチウム、n-ブチルリチウム、sec-ブチルリチウム、t-ブチルリチウム等のアルキルアルカリ金属；リチウムジイソプロピルアミド、リチウムビス(トリメチルシリル)アミド、ナトリウムアミド、ナトリウムビス(トリメチルシリル)アミド等のアルカリ金属アミドが挙げられるが、好ましくはアルカリ金属水素化物、更に好ましくは水素化ナトリウム、水素化カリウムが使用される。なお、これらの塩基は、単独又は二種以上を混合して使用しても良い。 Examples of the base used in the reaction of the present invention include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkalis such as sodium hydrogen carbonate and potassium hydrogen carbonate Metal bicarbonates; alkali metal alkoxides such as sodium methoxide and potassium methoxide; alkali metal hydrides such as sodium hydride and potassium hydride; methyllithium, n-butyllithium, sec-butyllithium, t-butyllithium, etc. Alkali alkali metals of the following: Alkali metal amides such as lithium diisopropylamide, lithium bis (trimethylsilyl) amide, sodium amide, sodium bis (trimethylsilyl) amide, etc. are preferable, but alkali metal hydrides, more preferably sodium hydride , Potassium hydride are used. In addition, you may use these bases individually or in mixture of 2 or more types.
前記塩基の使用量は、ビス(2-置換エチル)エーテル1モルに対して、好ましくは1.0〜10モル、更に好ましくは2.1〜5.0モルである。 The amount of the base to be used is preferably 1.0 to 10 mol, more preferably 2.1 to 5.0 mol, per 1 mol of bis (2-substituted ethyl) ether.
本発明の反応において使用するアセトニトリルの使用量は、ビス(2-置換エチル)エーテル1モルに対して、好ましくは1〜100モル、更に好ましくは1〜30モルである。 The amount of acetonitrile used in the reaction of the present invention is preferably 1 to 100 mol, more preferably 1 to 30 mol, per 1 mol of bis (2-substituted ethyl) ether.
本発明の反応は、溶媒の存在下又は非存在下にて行われる。溶媒を使用する場合、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、イソプロピルアルコール、t-ブチルアルコール、エチレングリコール、トリエチレングリコール等のアルコール類；アセトン、メチルエチルケトン、メチルイソブチルケトン等のケトン類；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-メチルピロリドン等のアミド類；N,N'-ジメチルイミダゾリジノン等の尿素類；ジメチルスルホキシド等のスルホキシド類；ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン等のエーテル類；ベンゼン、トルエン、キシレン等の芳香族炭化水素類が挙げられるが、好ましくはアミド類、スルホキシド類、芳香族炭化水素類が使用される。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. When a solvent is used, the solvent is not particularly limited as long as it does not inhibit the reaction. For example, water; alcohols such as methanol, ethanol, isopropyl alcohol, t-butyl alcohol, ethylene glycol, and triethylene glycol; acetone, Ketones such as methyl ethyl ketone and methyl isobutyl ketone; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; ureas such as N, N′-dimethylimidazolidinone; dimethyl sulfoxide and the like Sulphoxides; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, and dioxane; aromatic hydrocarbons such as benzene, toluene, xylene, and the like, preferably amides, sulfoxides, and aromatic hydrocarbons are used. Is done. 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、反応液の均一性や攪拌性により適宜調節するが、ビス(2-置換エチル)エーテル1gに対して、好ましくは0〜100g、更に好ましくは0〜20gである。 The amount of the solvent used is appropriately adjusted depending on the uniformity and stirring properties of the reaction solution, but is preferably 0 to 100 g, more preferably 0 to 20 g based on 1 g of bis (2-substituted ethyl) ether.
本発明の反応は、例えば、ビス(2-置換エチル)エーテル、アセトニトリル及び塩基を混合して、攪拌しながら反応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-70〜200℃、更に好ましくは-20〜150℃であり、反応圧力は特に制限されない。 The reaction of the present invention is performed by, for example, a method of mixing bis (2-substituted ethyl) ether, acetonitrile and a base and reacting them with stirring. The reaction temperature at that time is preferably −70 to 200 ° C., more preferably −20 to 150 ° C., and the reaction pressure is not particularly limited.
本発明の反応によって得られた4-シアノテトラヒドロピランは、例えば、中和、抽出、濾過、濃縮、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-Cyanotetrahydropyran obtained by the reaction of the present invention is isolated and purified by a general method such as neutralization, extraction, filtration, concentration, distillation, column chromatography and the like.
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.
実施例１（4-シアノテトラヒドロピランの合成）
攪拌装置、温度計及び還流冷却器を備えた内容積20mlのガラス製フラスコに、ビス(2-クロロエチル)エーテル1.0g(7.0mmol)、アセトニトリル5.0ml(95mmol)及び60％水素化ナトリウム0.61(15.2mmol)を加え、攪拌しながら60℃で8時間反応させた。反応終了後、反応液をガスクロマトグラフィーで分析（内部標準法）で分析したところ、4-シアノテトラヒドロピランが0.20g生成していた(反応収率：26％)。
Example 1 (Synthesis of 4-cyanotetrahydropyran)
A glass flask equipped with a stirrer, thermometer and reflux condenser with a 20 ml internal volume was charged with 1.0 g (7.0 mmol) of bis (2-chloroethyl) ether, 5.0 ml (95 mmol) of acetonitrile and 60% sodium hydride 0.61 (15.2). mmol) was added and allowed to react for 8 hours at 60 ° C. with stirring. After completion of the reaction, the reaction mixture was analyzed by gas chromatography (internal standard method). As a result, 0.20 g of 4-cyanotetrahydropyran was formed (reaction yield: 26%).
実施例２（4-シアノテトラヒドロピランの合成）
攪拌装置、温度計及び還流冷却器を備えた内容積20mlのガラス製フラスコに、ビス(2-クロロエチル)エーテル1.0g(7.0mmol)、アセトニトリル2.5ml(48mmol)、60％水素化ナトリウム0.61(15.2mmol)及びジメチルスルホキシド2.5mlを加え、攪拌しながら60℃で8時間反応させた。反応終了後、反応液をガスクロマトグラフィーで分析（内部標準法）で分析したところ、4-シアノテトラヒドロピランが0.30g生成していた(反応収率：39％)。
Example 2 (Synthesis of 4-cyanotetrahydropyran)
Into a glass flask equipped with a stirrer, thermometer and reflux condenser, a glass flask having an internal volume of 20 ml, 1.0 g (7.0 mmol) of bis (2-chloroethyl) ether, 2.5 ml (48 mmol) of acetonitrile, 60% sodium hydride 0.61 (15.2 mmol) and 2.5 ml of dimethyl sulfoxide were added and reacted at 60 ° C. for 8 hours with stirring. After completion of the reaction, the reaction solution was analyzed by gas chromatography (internal standard method). As a result, 0.30 g of 4-cyanotetrahydropyran was formed (reaction yield: 39%).
実施例３（4-シアノテトラヒドロピランの合成）
攪拌装置、温度計及び還流冷却器を備えた内容積20mlのガラス製フラスコに、ビス(2-クロロエチル)エーテル1.0g(7.0mmol)、アセトニトリル2.5ml(48mmol)、60％水素化ナトリウム0.61g(15.2mmol)及びトルエン2.5mlを加え、攪拌しながら60℃で8時間反応させた。反応終了後、反応液をガスクロマトグラフィーで分析（内部標準法）で分析したところ、4-シアノテトラヒドロピランが0.29g生成していた(反応収率：38％)。
Example 3 (Synthesis of 4-cyanotetrahydropyran)
A glass flask having an internal volume of 20 ml equipped with a stirrer, a thermometer and a reflux condenser was charged with 1.0 g (7.0 mmol) of bis (2-chloroethyl) ether, 2.5 ml (48 mmol) of acetonitrile, and 0.61 g of 60% sodium hydride ( 15.2 mmol) and 2.5 ml of toluene were added and reacted at 60 ° C. for 8 hours with stirring. After completion of the reaction, the reaction solution was analyzed by gas chromatography (internal standard method). As a result, 0.29 g of 4-cyanotetrahydropyran was formed (reaction yield: 38%).
本発明は、ビス(2-置換エチル)エーテルから、4-シアノテトラヒドロピランを製造する方法に関する。4-シアノテトラヒドロピラン、医薬・農薬等の原料や合成中間体として有用な化合物である。 The present invention relates to a process for producing 4-cyanotetrahydropyran from bis (2-substituted ethyl) ether. It is a useful compound as a raw material and synthetic intermediate for 4-cyanotetrahydropyran, pharmaceuticals and agricultural chemicals.
Claims (1)
で示されるビス（２−置換エチル）エーテルとアセトニトリルとを反応させることを特徴とする、４−シアノテトラヒドロピランの製法。 In the presence of alkali metal hydride , general formula (1)
A process for producing 4-cyanotetrahydropyran, which comprises reacting bis (2-substituted ethyl) ether represented by formula (II) with acetonitrile.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2000191654A (en) * | 1998-12-22 | 2000-07-11 | Pfizer Prod Inc | Production of 5-lipoxygenase inhibitor and intermediate therefor |
| WO2005028410A1 (en) * | 2003-09-19 | 2005-03-31 | Ube Industries, Ltd. | Method for producing nitrile compound, carboxylic acid compound or carboxylate compound |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2000191654A (en) * | 1998-12-22 | 2000-07-11 | Pfizer Prod Inc | Production of 5-lipoxygenase inhibitor and intermediate therefor |
| WO2005028410A1 (en) * | 2003-09-19 | 2005-03-31 | Ube Industries, Ltd. | Method for producing nitrile compound, carboxylic acid compound or carboxylate compound |
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