JP2006001880A - Method for producing 4-cyanotetrahydropyran - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an industrially suitable method for producing 4-cyanotetrahydropyran from a bis(2-substituted ethyl) ether in high yield by a simple means. <P>SOLUTION: The method for producing 4-cyanotetrahydropyran comprises carrying out a reaction between the bis(2-substituted ethyl) ether of general formula(1)( wherein, X is an eliminable group ) and acetonitrile in the presence of a base. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  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.

  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 give 4-cyanotetrahydropyran-4-carboxylic acid, which was then heated to 180-200 ° C. to give 4-cyanotetrahydropyran as a total 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.

J. Chem. Soc., 1930, 2525

  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.

  The subject of the present invention is the general formula (1) in the presence of a base.

(In the formula, X represents a leaving group.)
This can be solved by a process for producing 4-cyanotetrahydropyran characterized by reacting bis (2-substituted ethyl) ether represented by formula (II) with acetonitrile.

  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.

  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.

  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 such as lithium diisopropylamide, lithium bis (trimethylsilyl) amide, sodium amide, sodium bis (trimethylsilyl) amide, and the like. Preferred are 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.

  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.

  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.

  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.

  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, relative to 1 g of bis (2-substituted ethyl) ether.

  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.

  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.

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

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 solution was analyzed by gas chromatography (internal standard method). As a result, 0.20 g of 4-cyanotetrahydropyran was formed (reaction yield: 26%).

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 mixture was analyzed by gas chromatography (internal standard method). As a result, 0.30 g of 4-cyanotetrahydropyran was formed (reaction yield: 39%).

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%).

  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)

In the presence of a base, general formula (1)

(In the formula, X represents a leaving group.)
A process for producing 4-cyanotetrahydropyran, which comprises reacting bis (2-substituted ethyl) ether represented by formula (II) with acetonitrile.