JPH07126261A - Production of 4-methylenetetrahydropyran - Google Patents

Abstract

PURPOSE:To efficiently obtain the compound useful as a raw material for medicines, etc., in a high yield by intermittently or continuously feeding hydroxymethyltetrahydropyran into a reactor and reacting the hydroxymethyltetrahydropyran under specific conditions. CONSTITUTION:This method for producing the objective 4- methylenetetrahydropyran expressed by formula II is to intermittently or continuously feed 4-hydroxy-4-methyltetrahydropyran expressed by formula I into a reactor and dehydrating the 4-hydroxy-4-methyltetrahydropyran in the presence of a sulfate such as copper sulfate while distilling off the resultant product in the reactor.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an advantageous method for economically producing 4-methylenetetrahydropyran useful as a raw material for pharmaceuticals and agricultural chemicals on an industrial scale.

[0002]

BACKGROUND OF THE INVENTION 4-Methylenetetrahydropyran is a compound which is effectively used as a raw material for pharmaceuticals and agricultural chemicals. For example, it is produced as a by-product from isobutene and formaldehyde during the synthesis of isoprene (Ch
em. Abstr. 77, 134876, 1971)
Alternatively, 4,4-dimethyl-1,3-dioxa-
Upon thermal decomposition of cyclohexane, the isomer 4-methyl-1-oxa-cyclohex-3- which is represented by (Chemical formula 3)
Generated in a state of being mixed with Ene (Pet. Chem. U.
SSR (Engl., Transl,) 7 (1967)
92).

[0003]

[Chemical 3]

In general production of pyrans, (1) a method of utilizing a ring-closing reaction of a diol represented by the chemical formula 4, for example, a method of forming a sulfonic acid ester and then ring-closing with a base ( JP-A-3-77879),

[0005]

[Chemical 4]

(2) The alcohol represented by (Chemical formula 1) is
There is a method of dehydrating with a solid catalyst such as neutral alumina or alumina impregnated with a base.

[0007]

[Chemical 5]

[0008]

By the way, in the above-mentioned conventional general method for producing pyrans, the method utilizing the ring-closing reaction of diols in the above item (1) requires an equivalent amount or more of sulfonyl halide. Moreover, since the sulfonate salt precipitates after the ring-closing reaction, it is not practical as a method for producing pyrans on an industrial scale.

Further, the method using a solid catalyst such as the neutral alumina or the alumina impregnated with a base in the item (2) has a drawback that isoprene and formaldehyde are produced by decomposition of the produced pyran.

On the other hand, the present invention provides a method for efficiently obtaining 4-methylenetetrahydropyran on an industrial scale without the above-mentioned problems.

[0011]

[Means for Solving the Problems] The above object is represented by (Formula 2) by dehydrating 4-hydroxy-4-methyltetrahydropyran represented by (Formula 1) in the presence of a sulfate salt. The 4-methylenetetrahydropyran represented by the formula (1) is intermittently or continuously supplied to the reactor to produce 4-methylenetetrahydropyran, and the product in the reactor is produced. Can be achieved by carrying out a dehydration reaction while distilling.

[0012]

[Chemical 6]

[0013]

[Chemical 7]

In the method for producing 4-methylenetetrahydropyran of the present invention having the above structure, the alcohol represented by (Chemical formula 1), ie, 4-hydroxy-4-methyltetrahydropyran, which is a starting material, is represented by (Chemical formula 3) The 4-methylenetetrahydropyran isomer can be easily obtained by hydration in the presence of a mineral acid such as sulfuric acid or phosphoric acid, or a solid acid such as an acidic ion exchange resin, zeolite or activated clay.

[0015]

[Chemical 8]

[0016]

[Chemical 9]

4-Hydroxy-4-methyltetrahydropyran is obtained by hydrating 4-methylenetetrahydropyran isomer under acidic conditions, neutralizing the system, and then extracting with an organic solvent. It can be easily purified to sufficient purity for the next step reaction by cutting and subsequent mono-evaporation.

The sulfate used as a catalyst in the method of the present invention is, for example, copper sulfate, sodium sulfate, nickel sulfate, magnesium sulfate, zirconium sulfate, and hydrogen sulfate such as sodium hydrogen sulfate and potassium hydrogen sulfate.

These sulfates may be hydrates or anhydrides, commercially available products may be used as powders or crystals, and further commercially available products may be melted, It may be solidified and crushed to an appropriate size.

In carrying out the dehydration reaction of 4-hydroxy-4-methyltetrahydropyran, 4-hydroxy-4-methyltetrahydropyran is used as it is or diluted with a solvent. Examples of the solvent when diluted and used include hydrocarbons such as toluene, xylene and hexane, ethers such as diethyl ether and diisopropyl ether, and halogenated hydrocarbons such as carbon tetrachloride.

However, the method for producing 4-methylenetetrahydropyran of the present invention is a method by liquid layer reactive distillation, that is, 4-hydroxy-4-methyltetrahydropyran is intermittently or continuously supplied to the reactor. In view of the reaction conditions and the volumetric efficiency, it is preferable to carry out the reaction without a solvent, because it is a liquid layer reactive distillation which comprises performing a dehydration reaction while distilling the product in the reactor. It is suitable.

The reaction temperature for the dehydration reaction of 4-hydroxy-4-methyltetrahydropyran differs depending on the catalyst used. For example, when using sodium sulfate as a catalyst, 1
The temperature is about 40 ° C., and about 170 ° C. when using copper sulfate as a catalyst.

The reaction can be carried out under atmospheric pressure to reduced pressure. The reaction under reduced pressure is suitable for distilling the product out of the reaction system faster, and sufficient results can be obtained at atmospheric pressure for more easily carrying out the reaction.

The amount of sulfate as a reaction catalyst is about 0.001 to 100 parts by weight with respect to 100 parts by weight of 4-hydroxy-4-methyltetrahydropyran, and in order to obtain higher selectivity, it is 0. 0.01 to 10 parts by weight is preferable.

The dehydration reaction of 4-hydroxy-4-methyltetrahydropyran is carried out by the liquid layer reactive distillation system as described above.

More specifically, 4-hydroxy-4-methyltetrahydropyran and a catalyst are initially charged in a reactor and the temperature is raised to a predetermined temperature. Along with this temperature rise, a dehydration reaction proceeds, and 4-methylenetetrahydropyran, which is a product, 4-methyl-1-oxa-cyclohex-3-ene, which is an isomer, and water start to distill.

At this time, 4-hydroxy-4-methyltetrahydropyran is fed to the reaction system so that the catalyst concentration in the system does not change, whereby a stable selectivity can be obtained.

The reaction product obtained by liquid layer reactive distillation is 4-methylenetetrahydropyran and 4-methyl-1-oxa-cyclohex-3- which is an isomer of the compound.
An organic layer composed of a mixture with ene and an aqueous layer.

4-methylenetetrahydropyran and 4-methyl-1-oxa-cyclohex-3- in the organic layer
The separation from ene can be easily carried out by distillation under normal pressure. Therefore, the desired 4-methylenetetrahydropyran is obtained by distilling the organic layer obtained as a reaction product and then distilling it.

The 4-isomer of the isomer produced by the reaction
Methyl-1-oxa-cyclohex-3-ene is converted to 4-hydroxy-4-methyltetrahydropyran by returning to the hydration step, and used as a starting material in the method for producing 4-methylenetetrahydropyran of the present invention. You can

[0031]

The method for producing 4-methylenetetrahydropyran according to the present invention comprises dehydrating 4-hydroxy-4-methyltetrahydropyran in the presence of a sulfate, which is used in the reactor. It comprises a process for producing 4-methylenetetrahydropyran in which hydroxy-4-methyltetrahydropyran is intermittently or continuously supplied and a dehydration reaction is carried out while distilling the product in the reactor.

In the method of the present invention having the above structure,
The selectivity between 4-methylenetetrahydropyran and the isomer 4-methyl-1-oxa-cyclohex-3-ene is high, and the isomer 4-methyl-1-oxa-cyclohex-3-ene is 4 by returning to the hydration process
-Hydroxy-4-methyltetrahydropyran can be used as a starting material in the method for producing 4-methylenetetrahydropyran of the present invention.

Therefore, the method of the present invention is extremely useful as a method for economically and industrially obtaining 4-methylenetetrahydropyran.

[0034]

EXAMPLES The specific constitution of the method for producing 4-methylenetetrahydropyran of the present invention will be described below based on examples.

Reference Example Production of 4-hydroxy-4-methyltetrahydropyran:

50 g of 4-methyl-5,6-dihydro-2Hpyran and 150 g of 35% aqueous sulfuric acid were charged in a reactor at 50 g.
The mixture was warmed to ° C and stirred for 70 hours.

Next, the inside of the reaction system was neutralized, extracted with ethyl acetate, ethyl acetate was cut off, and then evaporated to obtain 106 g of 4-hydroxy-4-methyltetrahydropyran (yield 90%). .

Example 1 40 g of 4-hydroxy-4-methyltetrahydropyran and 0.2 g of copper sulfate pentahydrate were placed in a 100 ml three-necked flask, and 1
The temperature was raised to 70 ° C.

With the distillation of the product after the start of the reaction, 4
-Hydroxy-4-methyltetrahydropyran was fed.

By carrying out the reaction for 2 hours, 96 g of distillate was obtained. The organic layer in the distillate was 80.7 g.
Met. The concentration of the mixture of 4-methylenetetrahydropyran and the isomer 4-methyl-1-oxa-cyclohex-3-ene in this organic layer is 99.5% by weight, and 4-methylenetetrahydropyran and 4-methyl- 1
The weight ratio with -oxa-cyclohex-3-ene is 3
It is 1:69.

The previous 80.7 g of organic layer was distilled under normal pressure to obtain 24.3 g of 4-methylenetetrahydropyran (purity 99% or more).

Example 2 40 g of 4-hydroxy-4-methyltetrahydropyran and 0.1 g of potassium hydrogen sulfate were placed in a 100 ml three-necked flask, and the temperature was raised to 150 ° C.

With the distillation of the product after the start of the reaction, 4
-Hydroxy-4-methyltetrahydropyran was fed.

By carrying out the reaction for 2 hours, 102.
5 g of distillate was obtained. The organic layer in the distillate is 8
It was 6.2 g. In this organic layer, 4-methylenetetrahydropyran and the isomeric 4-methyl-1-oxa-
The concentration of the mixture with cyclohex-3-ene is 99.6% by weight, and the weight ratio of 4-methylenetetrahydropyran to 4-methyl-1-oxa-cyclohex-3-ene is 37:63.

By distilling 86.2 g of the above organic layer under atmospheric pressure, 30.8 g of 4-methylenetetrahydropyran (purity 99% or more) was obtained.

Example 3 In a 100 ml three-necked flask, 40 g of 4-hydroxy-4-methyltetrahydropyran and 0.05 g of sodium hydrogensulfate were charged, and the temperature was raised to 150 ° C.

With the distillation of the product after the start of the reaction, 4
-Hydroxy-4-methyltetrahydropyran was fed.

By carrying out the reaction for 2 hours, 109.
2 g of distillate was obtained. The organic layer in the distillate is 9
It was 2.0 g. In this organic layer, 4-methylenetetrahydropyran and the isomeric 4-methyl-1-oxa-
The concentration of the mixture with cyclohex-3-ene is 99.6% by weight, and the weight ratio of 4-methylenetetrahydropyran to 4-methyl-1-oxa-cyclohex-3-ene is 41:59.

By distilling 92.0 g of the above organic layer under atmospheric pressure, 36.6 g of 4-methylenetetrahydropyran (purity 99% or more) was obtained.

[0050]

Industrial Applicability According to the method of the present invention, 4-methylenetetrahydropyran, which is useful as a raw material for pharmaceuticals and agricultural chemicals, can be industrially obtained efficiently.

Claims (1)

[Claims] 1. 4-hydroxy-represented by the formula
A method for producing 4-methylenetetrahydropyran represented by (Chemical formula 2), which comprises dehydrating 4-methyltetrahydropyran in the presence of a sulfate, which is represented by (Chemical formula 1) in a reactor. 4-hydroxy-4-methyltetrahydropyran is intermittently or continuously supplied, and a dehydration reaction is carried out while distilling the product in the reactor, thereby producing 4-methylenetetrahydropyran. . [Chemical 1] [Chemical 2]