JPS6241520B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for purifying estrone. More specifically, the present invention deals with impurities contained in crude estrone, such as 1-methylestrone, 2-methylestrone, 4-methylestrone, seco-
The present invention relates to a method for purifying estrone by removing estrone and the like.

Estrone is used as an estrogen itself, as well as estradiol and its derivatives,
It is important as a raw material for manufacturing pharmaceuticals with hormonal activity such as 19-norethisterone, and high quality is required. For example, according to Volume 14 of the US National Formulary (commonly known as NF), the purity of estrone is
It is required that the content is 97.0 to 103.0%, the color is white to milky white, and the content of impurities is 3% or less.

Conventionally, crude estrone is obtained from tetrahydrofuran,
Estrone is dissolved in a solvent such as alcohol that dissolves it relatively well, and after removing insoluble matter, it is purified by recrystallization, etc. Among the relatively inexpensive solvents currently used industrially, Even tetrahydrofuran, which dissolves estrone best, has 30
Only 5.1 g of estrone dissolves in 100 g of tetrahydrofuran at ℃. Therefore, in industrial purification of estrone, when crude estrone is passed through a filtration device not equipped with a heating device to remove insoluble matter, the minimum amount of tetrahydrofuran required is determined by the solubility of estrone mentioned above. , there is an upper limit to the amount of preparation per batch.

In view of the above circumstances, the inventors of the present invention have conducted intensive studies on a method that can increase the amount of estrone refining using ordinary equipment, and have found that the amount of estrone refining can be increased by approximately 2
We have arrived at the present invention, which allows twice the amount of preparation.

The gist of the present invention is to contain 2 to 14% by weight of crude estrone.
If insoluble matter remains, it is dissolved in tetrahydrofuran containing water, and after filtration, the resulting solution is concentrated in the presence or absence of aromatic hydrocarbons, or after concentrating the solution, aromatic hydrocarbons are dissolved. The present invention consists in a method of crystallizing estrone by treatment with a hydrocarbon and separating solid estrone.

Next, the present invention will be explained in more detail.

The method for producing estrone, which is the target of purification in the method of the present invention, is not particularly limited, but for example, a method of thermally decomposing androsta-1,4,6-diene-3,17-dione (hereinafter abbreviated as ADD) (Refer to JP-A-51-26865 and JP-A-52-48655), using crude estrone obtained by the method of producing from ADD using an alkali metal (Refer to JP-A-42-1226), etc. can do.

According to the pyrolysis method, after mixing a hydrocarbon (toluene, xylene, etc.) solution or suspension of ADD with a preheated hydrocarbon (kerosene, diesel oil, etc.),
Pyrolysis of ADD at 450-700°C yields estrone.

Note that the estrone obtained by this method may contain hydrocarbons such as kerosene used in the reaction when the temporary washing is insufficient, but this does not impede the application of the method of the present invention.

According to the method of using alkali metals, ADD
17-ethylene acetal was dissolved in diphenylmethane,
The 17-ethylene acetal of estrone obtained by coexisting methylnaphthalene etc. as a methyl alkali metal scavenger and treating it with polycyclic aromatic compounds such as 1-methylnaphthalene and biphenyl and alkali metals such as lithium and sodium is Hydrolysis yields estrone.

According to the method of the present invention, crude estrone is dissolved in tetrahydrofuran containing 2 to 14% by weight of water;
If insoluble matter is present, after removing it by filtration, tetrahydrofuran and water are distilled off by concentration in the presence or absence of aromatic hydrocarbons to crystallize estrone, or estrone is crystallized by concentration. After the addition treatment of aromatic hydrocarbons, the solid estrone containing estrone to be crystallized is filtered.

As the solvent used to dissolve the crude estrone, tetrahydrofuran containing 2-14% by weight of water is chosen, preferably tetrahydrofuran containing 5-11% by weight of water, more preferably 8-14% by weight of water.
Tetrahydrofuran containing 9% by weight of water is chosen.
The amount of these solvents to be used depends on the temperature, but it is easy to use about 5 to 15 ml per gram of crude estrone.

The aromatic hydrocarbon to be added to the solution or suspension obtained by dissolving or suspending estrone in the above-mentioned solvent usually has 6 to 20 carbon atoms, such as benzene, toluene, ethylbenzene, xylene, and tetralin.
aromatic hydrocarbons and mixtures of aromatic hydrocarbons such as kerosene. In terms of boiling point, preferred aromatic hydrocarbons are toluene and xylene. The amount of these aromatic hydrocarbons used is not particularly limited, but 5 to 1 g of crude estrone
~30ml is easy to handle.

The gist of the present invention is that the solubility of estrone in aqueous tetrahydrofuran is greatest in tetrahydrofuran with a water content of 8 to 9% by weight.
The figure shows the solubility curve of estrone in hydrous tetrahydrofuran at 30°C. for example,
Approximately 5.1 g of estrone is dissolved in 100 g of tetrahydrofuran, but the solubility increases as water is added, and up to about 9.3 g of estrone is dissolved in approximately 8.5 wt.% water-containing tetrahydrofuran. As more water is added, the solubility decreases.

As detailed above, according to the present invention, crude estrone is dissolved by a simple method suitable for industrial implementation, consisting of crystallization and washing operations using a combination of specific solvents, and further, When filtering insoluble matter, estrone can be obtained in high yield and purity by using only about half the amount of solvent used in the past, without using any special equipment such as heating piping or filtering equipment.

EXAMPLES Hereinafter, the present invention will be explained in detail with reference to examples, but the present invention is not limited to the following examples unless it exceeds the gist thereof.

In the examples described below, the purity of crude estrone and purified estrone was determined by n-
This is a value determined by gas chromatography for octacosane, and there is a possibility of an error of ±1%.

Example 1 In a 100 ml eggplant flask equipped with a stirring device and a nitrogen inlet tube, ADD thermal decomposition (Japanese Patent Application Laid-open No. 51-26865
Purity obtained by the method described in Example 1 of the publication
Prepare 2.00g of 75.5% crude estrone, 17g of 8
Add wt % water-containing tetrahydrofuran and stir for 1 hour over the aqueous solution at 30°C. During this time the crystals dissolve. Pass this solution through a glass filter to remove insoluble matter (solid matter other than estrone),
A stirring device was equipped with a distillation tube, a thermometer, and a nitrogen introduction tube. Pour into a 100ml four-necked flask. Add 60ml of toluene to this, immerse it in an oil bath, and adjust the temperature of the oil bath.
Raise the temperature to 120°C and distill off tetrahydrofuran and water. Crystals precipitate during distillation, but distillation is continued until the distillation temperature reaches 111°C, then cooled to room temperature with stirring in an oil bath, and then placed in a constant temperature bath at 20°C for 2 hours. put. Collect the precipitated crystals and
After drying under reduced pressure at ℃ for 3 hours, the purity of the crystals was measured by gas chromatography to be 93.9%, and the crystallization rate was 96.5%.

Example 2 Into the same eggplant flask as in Example 1, 2.00 g of the same crude estrone was charged, and 5% by weight of 18 g was added.
Add aqueous tetrahydrofuran and stir on a 30°C water bath for 1 hour. During this time the crystals dissolve. This solution is placed in the same four-necked flask as in Example 1, immersed in a water bath at 80°C, and tetrahydrofuran and water are distilled off. When 12.5 g of solvent has been distilled off, the distillation is stopped, the mixture is allowed to stand under stirring, and the mixture is left in a constant temperature bath at 20°C for 2 hours. The precipitated crystals were collected and dried under reduced pressure at 100°C for 3 hours, and the purity of the crystals was measured by gas chromatography, and it was 92.1%, and the crystallization rate was
It was 87.1%.

[Brief explanation of the drawing]

The figure shows the solubility of estrone in hydrous tetrahydrofuran at 30°C. The vertical axis is
The number of grams of estrone dissolved in 100 g of hydrous tetrahydrofuran is shown, and the horizontal axis shows the weight percent of water contained in tetrahydrofuran.

Claims (1)

[Claims] 1. Dissolve crude estrone in tetrahydrofuran containing 2 to 14% by weight of water, and if any insoluble matter remains, after filtration, concentrate the resulting solution in the presence or absence of aromatic hydrocarbons, or Alternatively, a method for purifying estrone, which comprises concentrating the solution and then treating it with an aromatic hydrocarbon to crystallize estrone and separate solid estrone.