JP4734975B2 - Preparation of 2- (tetrahydropyran-4-yl) -2-oxoacetic acid - Google Patents

Description

  The present invention relates to a process for producing 2- (tetrahydropyran-4-yl) -2-oxoacetic acid. 2- (Tetrahydropyran-4-yl) -2-oxoacetic acid is a useful compound as a raw material and synthetic intermediate for pharmaceuticals and agricultural chemicals.

  The 2- (tetrahydropyran-4-yl) -2-oxoacetic acid of the present invention is a novel compound, and its existence and production method have never been known so far.

  The object of the present invention is to solve the above-mentioned problems and to produce 2- (tetrahydropyran-4-yl) -2-oxoacetic acid in a high yield by a simple method. It is to provide a process for the preparation of (tetrahydropyran-4-yl) -2-oxoacetic acid.

  In view of the above problems, as a result of intensive studies by the present inventors, a method that can produce 2- (tetrahydropyran-4-yl) -2-oxoacetic acid in a high yield by the following simple method was found, The present invention has been completed.

  That is, the subject of this invention is general formula (1).

（式中、Ｒは、炭化水素基を示す。）
で示される2-(4-シアノテトラヒドロピラン-4-イル)-2-オキソ酢酸エステル（以下、化合物（１）と称する）と酸とを反応させることを特徴とする、式（２）

(In the formula, R represents a hydrocarbon group.)
Wherein 2- (4-cyanotetrahydropyran-4-yl) -2-oxoacetic acid ester represented by the following formula (2) is reacted with an acid:

で示される2-(テトラヒドロピラン-4-イル)-2-オキソ酢酸（以下、化合物（２）と称する）の製法によって解決される。

This is solved by a process for producing 2- (tetrahydropyran-4-yl) -2-oxoacetic acid (hereinafter referred to as compound (2)).

  According to the present invention, 2- (tetrahydropyran-4-yl) -2-oxoacetic acid can be produced in a high yield by a simple method, and industrially suitable 2- (tetrahydropyran- A process for producing 4-yl) -2-oxoacetic acid can be provided.

  The compound (1) of the present invention is represented by the general formula (1). In the general formula (1), R is a hydrocarbon group, specifically, for example, methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group. Alkyl groups such as decyl group; cycloalkyl groups such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, cyclononyl group, and cyclodecyl group; aralkyl groups such as benzyl group and phenethyl group; An aryl group such as a phenyl group, a tolyl group, a xylyl group, and a naphthyl group is exemplified, and a methyl group and an ethyl group are preferable. These groups include various isomers.

  In addition, compound (1) of this invention is reaction process formula (1).

(In the formula, X represents a halogen atom, an alkoxy group, an aralkyloxy group or an aryloxy group, and R has the same meaning as described above.)
As shown in the above, it is obtained by reacting 4-cyanotetrahydropyran (compound (3)) with an oxalic acid compound (compound (4)) in the presence of a base (described in Reference Example 1 below).

  Examples of the acid used in the reaction of the present invention include carboxylic acids such as formic acid, acetic acid, and trifluoroacetic acid; and organic sulfones such as methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid. Acids; Hydrohalic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid; sulfuric acid; nitric acid; phosphoric acid, preferably hydrohalic acid, sulfuric acid, nitric acid, phosphoric acid, more preferably hydrochloric acid, Hydrobromic acid, hydroiodic acid, sulfuric acid, particularly preferably hydrochloric acid and sulfuric acid are used. In addition, you may use these bases individually or in mixture of 2 or more types.

  The amount of the acid to be used is preferably 0.8 to 100 mol, more preferably 1.0 to 50 mol, per 1 mol of compound (1).

  The reaction of the present invention is preferably carried out in a solvent, and the solvent to be used is not particularly limited as long as it does not inhibit the reaction. For example, water; amines such as triethylamine and tributylamine; pyridine, methyl Pyridines such as pyridine and dimethylaminopyridine; Quinolines such as quinoline, isoquinoline and methylisoquinoline; Amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; N, N'-dimethyl Ureas such as imidazolidinone; Sulfoxides such as dimethyl sulfoxide and sulfolane; Alcohols such as n-propyl alcohol and n-butyl alcohol; Ethers such as diisopropyl ether, dioxane and cyclopropyl methyl ether; Toluene and xylene Aromatic hydrocarbons; ethyl acetate, butyl acetate, etc. The carboxylic acid esters are preferably water and alcohols. In addition, you may use these solvents individually or in mixture of 2 or more types.

  Although the usage-amount of the said solvent is suitably adjusted with the uniformity and stirring property of a reaction liquid, Preferably it is 0.5-100g with respect to 1g of compounds (1), More preferably, it is 1-60g.

  The reaction of the present invention is performed by, for example, a method of mixing the compound (1), an acid and a solvent and reacting them while stirring. The reaction temperature at that time is preferably -20 to 200 ° C, more preferably 0 to 150 ° C, particularly preferably 10 to 130 ° C, and the reaction pressure is not particularly limited.

  In addition, although compound (2) is obtained by reaction of this invention, this is isolated and refine | purified by general methods, such as neutralization, extraction, filtration, concentration, distillation, column chromatography, after completion | finish of reaction. .

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

Reference Example 1 (Compound (1) [R = ethyl group]; synthesis of concentrate mainly composed of 2- (4-cyanotetrahydropyran-4-yl) -2-oxoacetate)
To a glass flask having an internal volume of 50 ml equipped with a stirrer, a thermometer and a dropping funnel, 18.9 ml (18.0 mmol) of 1.0 mol / l lithium bis (trimethylsilyl) amide in tetrahydrofuran was added, and the liquid temperature was −10 to 0 ° C. While maintaining the solution at the same temperature, 2.0 g (18.0 mmol) of 4-cyanotetrahydropyran was added dropwise and the mixture was stirred at the same temperature for 1 hour. Next, 6.23 g (135 mmol) of diethyl oxalate was added dropwise and reacted at the same temperature for 1 hour with stirring. After completion of the reaction, 1.24 g (81 mmol) of formic acid was added and stirred for 1 hour while maintaining the temperature of the reaction solution at 0 ° C. or lower, and 9 ml of acetonitrile was added. The precipitated solid was filtered and the filtrate was concentrated under reduced pressure to obtain 3.75 g of a concentrate mainly composed of ethyl 2- (4-cyanotetrahydropyran-4-yl) -2-oxoacetate.

Example 1 (Compound (2); Synthesis of 2- (tetrahydropyran-4-yl) -2-oxoacetic acid)
Concentrate 3.75 which is composed mainly of ethyl 2- (4-cyanotetrahydropyran-4-yl) -2-oxoacetate synthesized in Reference Example 1 in a glass flask having an internal volume of 50 ml equipped with a stirrer and a thermometer. g and 40 ml (480 mmol) of 12 mol / l hydrochloric acid were added and reacted at 90 to 110 ° C. for 3 hours with stirring. After completion of the reaction, the reaction mixture was concentrated, and 40 ml of dimethoxyethane was added to the concentrate and filtered. The filtrate was concentrated to give 2.0 g of 2- (tetrahydropyran-4-yl) -2-oxoacetic acid as a brown oil (isolated yield based on 4-cyanotetrahydropyran; 70%).
Incidentally, 2- (tetrahydropyran-4-yl) -2-oxopropionic acid is a novel compound represented by the following physical property values.

¹ H-NMR (CDCl ₃ , δ (ppm)); 1.44 to 1.53 (2H, m), 1.72 to 1.78 (2H, m), 2.09 (1H, s), 3.16 to 3.29 (1H, m), 3.39 ( 2H, dt, J = 11.7,3.0Hz), 3.82 to 3.88 (2H, m)
CI-MS (m / e); 159 (M + 1)

Reference Example 2 (Compound (1) [R = ethyl group]; Synthesis of ethyl 2- (4-cyanotetrahydropyran-4-yl) -2-oxoacetate)
To a glass flask having an internal volume of 100 ml equipped with a stirrer, a thermometer and a dropping funnel, 56.7 ml (56.8 mmol) of 1.0 mol / l lithium bis (trimethylsilyl) amide in tetrahydrofuran was added, and the liquid temperature was −10 to 0 ° C. Then, 6.0 g (54.0 mmol) of 4-cyanotetrahydropyran was added dropwise, and the mixture was stirred at the same temperature for 1 hour. Next, 18.7 g (135 mmol) of diethyl oxalate was added dropwise and reacted at the same temperature for 1 hour with stirring. After the reaction was completed, 3.72 g (81 mmol) of formic acid was added and stirred for 1 hour while maintaining the temperature of the reaction solution at 0 ° C. or lower, and then 26 ml of acetonitrile was added. The precipitated solid was filtered, and the filtrate was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (developing solvent; hexane / ethyl acetate = 9/1 → 7/3) to give 2- 3.78 g of ethyl (4-cyanotetrahydropyran-4-yl) -2-oxoacetate was obtained (isolation yield; 33%).

Example 2 ((Compound (2); Synthesis of 2- (tetrahydropyran-4-yl) -2-oxoacetic acid)
By reacting ethyl 2- (tetrahydropyran-4-yl) -2-oxoacetate obtained in Reference Example 2 with an acid in the same manner as in Example 1, 2- (tetrahydropyran-4 -Yl) -2-oxoacetic acid is obtained.

Reference Example 3 (Synthesis of 4-tetrahydropyranylglycine)
In the presence of a palladium catalyst, 2- (tetrahydropyran-4-yl) -2-oxoacetic acid synthesized in Example 1 was stirred in an aqueous ammonia solution in a hydrogen atmosphere, whereby 4-tetrahydropyranylglycine was obtained. Good yield is obtained.

  The present invention relates to a process for producing 2- (tetrahydropyran-4-yl) -2-oxoacetic acid. 2- (Tetrahydropyran-4-yl) -2-oxoacetic acid is a useful compound as a raw material and synthetic intermediate for pharmaceuticals and agricultural chemicals.

Claims (1)

General formula (1)

(In the formula, R represents a hydrocarbon group.)
Wherein 2- (4-cyanotetrahydropyran-4-yl) -2-oxoacetic acid ester represented by formula (2) is reacted with an acid.

A method for producing 2- (tetrahydropyran-4-yl) -2-oxoacetic acid represented by the formula: