JPS5855438A - Separating method of cis-dihydro-alpha-terpineol - Google Patents

Abstract

PURPOSE:To obtain the titled pure compound useful as a raw material for medicines easily, by dissolving a mixture of the cis- and trans-isomers of the titled compound in petroleum ether, n-pentane or/and dichloroethane, and intensively cooling the resultant solution to crystallize the cis-isomer. CONSTITUTION:A mixture of the cis- and trans-isomers of dihydro-alpha-terpineol is dissolved in an organic solvent selected from petroleum ether, n-pentane and dichloroethane in an amount of preferably 2-10 times that of the compound, and the resultant solution is then cooled to -10 deg.C or below, preferably about -30 deg.C, to crystallize the cis-dihydro-alpha-terpineol of formulaI, which is then filtered while cold and taken out to afford the cis-isomer of formulaIin high purity by easy operations. The resultant compound has antiarteriosclerotic action, and is useful as a raw material for the cis-isomer of formula II capable of increasing the alpha-lipoprotein and reducing the beta-lipoprotein.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for separating pure cis-dihydro-α-terpineol from a cis-trans mixture of dihydro-α-terpineol.

Cis-dihydro-α-terpineol obtained by the present invention exhibits anti-arteriosclerotic activity and α-riboprotein-increasing behavior, and exhibits α-liphoprotein-decreasing behavior.
-Menthan-8-yloxy)benzanilide (Japanese Unexamined Patent Publication No. 54-92926).

Conventionally, as a method for obtaining cis-dihydro-α-terpineol, (1) esterifying cis-4-methylcyclohexanecarbo/acid to obtain methylcis-4-methylcyclohexanecarboxylate, and then reacting with methylmagnesium iodide. (RecueH, 81, 27
4 (1962): 1 and (2) A method for obtaining a cis-trans mixture of dihydro-α-terpineol by catalytic reduction of α-terpineol.
1960)] was known.

In these conventional methods, the former method uses pure system
Although it is possible to obtain pure cis-dihydro-α-f lupineol using 4-methylcyclohexa7carboxylic acid, the starting material itself must be separated from the cis-trans mixture and pure Because it is difficult to obtain and requires several synthesis steps, it is not suitable for industrial production of pure cis-dihydro-α-terpineol (and the latter method It was not possible to obtain pure cis-dihydro-α-terpineol.

As a result of intensive research in order to obtain pure cis-α-dihydroterpineol, the present inventors have discovered that a cis-trans mixture of dihydro-α-terpineol can be prepared using an organic solvent selected from the group consisting of petroleum ether, n-pentane, and dichloroethane. High purity cis-
Crystals of dihydro-α-terpineol were obtained.

They discovered that a pure product could be obtained by repeating this operation, and completed the present invention.

By the method of the present invention, it has become possible to obtain pure cis-dihydro-α-terpineol, which can be used as a pharmaceutical preparation, with a very simple operation.

Specifically, the method of the present invention comprises dissolving a cis-trans mixture of dihydro-α-terpineol in one or more organic solvents from the group consisting of petroleum ether, n-pe/tane and dichloroethane; This is preferably carried out by cooling to about -3°C to crystallize cis-dihydro-α-terpineol, and collecting the crystals while cold. The amount of solvent is not particularly limited, but is preferably 2 to 10 times the amount of dihydro-α-terpineol. The cis-trans mixture of dihydro-α-terpineol used here may be rectified once to increase the content of the cis isomer.

Highly pure cis-dihydro-
α-Terpineol can be obtained, and pure product can be obtained by repeating the process several times.

The table below shows the increase in the content of cis isomer in dihydro-α-terpineol by the method of the present invention (however.

(if the separation operation of the present invention is applied once).

In addition, the cis isomer content was measured by gas chromatography (column used: 0V-101, 20m×0.2mm, open temperature 80C).

Next, the method of the present invention will be explained in more detail with reference to Examples.

Example 1 48 g of cis-dihydro-α-terpineol having a cis isomer content of 86% was dissolved in petroleum ether 100[11ZK.

Then, it is cooled by immersing it in a bathtub with a bath temperature of -30 to -40C. When crystals begin to precipitate, stir occasionally to equalize the internal temperature and keep it at -30 to -40C. After crystal precipitation is complete, the crystals are collected in a pre-cooled filtration device and dried under reduced pressure over phosphorus pentoxide in a desiccator, resulting in cis-dihydro-α- with a cis isomer content of 92%. Terpineol 38g
was gotten. (Yield 79.2%) Example 2 200 g of cis-dihydro-α-terpineol with a cis isomer content of 92% was dissolved in 1000 m7 of n-pentane and soaked in a bath with a bath temperature of -40 to -50C. Cooling. The internal temperature was set to -40 to -50 C, and the same procedure as in Example 1 was carried out to obtain 123 g of cis-dihydro α-terpineol with a cis-isomer content of 96%. (yield
61.5%) Example 3 73 g of cis-dihydro-α-terpineol with a 96% cis isomer content was dissolved in 600 ml of dichloroethane.

Then, it is cooled by placing it in a bathtub with a bath temperature of -30 to -35C. Crystals begin to precipitate when the internal temperature reaches 2 to 3°C, so stir occasionally to equalize the internal temperature and maintain it at -20 to -30°C. Example 1 below. Treated in the same manner as Ruto, cis isomer content 99.3
52.5 g of % cis-dihydro-α-terpineol were obtained.

This product was redissolved in 250 ml of dichloroethane and treated in the same manner as before to obtain 45.4 g of pure cis-dihydro-α-terpineol.

Melting point 43-440 Nuclear magnetic resonance spectrum (CDC-13s) (internal standard TMS) δ (ppm): 0.94 (CH)
〈), 3')l, d)shi113 Agent Akira Sasaki - Procedural amendment (spontaneous) November 1980 Commissioner of the Japanese Patent Office Haruki Shimada 1 Indication of case Patent application No. 153393 of 1988
No. 26 Name of the invention Separation method of cis-dihydro-α-terpineol 3, Relationship with the case of the person making the amendment Patent applicant address 2-5-1 Nihonbashi Honmachi, Chuo-ku, Tokyo Name ('667) Yamanouchi Pharmaceutical Co., Ltd. representative
Shigeo Morioka 4, Agent Address: 1-1-8 Azukizawa, Itabashi-ku, Tokyo 6゜(Detailed Description of the Invention) in the Specification

Claims (1)

[Claims] A cis-trans mixture of dihydro-α-terpineol, which is dissolved in an organic solvent selected from the group consisting of petroleum ether, n-peethane and dichloroethane, and then strongly cooled to crystallize and extract the cis form. - Method for separating dihydro-α-terpineol.