JPS6355517B2 - - Google Patents

Description

[Detailed Description of the Invention] The present invention provides 19-norethisterone (hereinafter referred to as "NET")
).

For more details, see 19-Nor-Androst-4-
En-3,17-dione (hereinafter referred to as "NAD")
This paper relates to a method for producing NET, which is useful as a progestin agent.

NAD is synthesized via 3β-hydroxyandrost-5-en-17-one, which is derived from diosgenin, as well as androster-1,4-diene, which is produced by fermentation of sterols. It can also be synthesized from 3,17-dione via estrone.

NET is synthesized by ethynylation of NAD, and traditionally potassium tert-butoxy was used together with acetylene as a reagent.

The present inventors have discovered that high yield and high purity NETs can be easily obtained from NAD by using cheaper caustic potash and using a specific post-treatment method, and have arrived at the present invention. That is, the present invention involves reacting caustic potash with a purity of 90% or higher with alcohol in an aprotic organic solvent at 20°C to 60°C, and then supplying acetylene to the reaction product to combine the resulting acetylene adduct and NAD. A method for producing NET, which is characterized by producing NET by reacting at 20°C or lower, then maintaining the resulting reaction mixture at 25 to 60°C, making it acidic and subjecting it to acid contact reaction, and further neutralizing.

The present invention will be explained in detail below.

In the method of the present invention, first, acacis potash and alcohol are reacted in an aprotic organic solvent.
Examples of the aprotic organic solvent include tetrahydrofuran, dioxane, N-methylpyrrolidone, dimethylformamide, etc., but tetrahydrofuran is commonly used industrially.

Caustic potash with a purity of 90% or more, preferably 93% or more, is used.

On the other hand, examples of alcohol include methanol, ethanol, propanol, isopropanol, n-
Lower aliphatic alcohols such as butanol, sec-butanol, and tert-butanol, and ethylene glycol monoalkyl ethers such as ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monopropyl ether, and ethylene glycol monobutyl ether are commonly used. Considering the recovery and purification of the solvent, it is preferable to select an alcohol whose boiling point is sufficiently different from that of the solvent.

The reaction temperature between caustic potash and alcohol is 10℃
to about reflux temperature, preferably 20 to 50°C. The reaction time is usually about several minutes to several hours.

Next, acetylene is supplied to the obtained reaction product to cause the reaction to occur. The reaction temperature is usually about -20 to +20°C, preferably about -5 to +10°C, and the reaction time is usually about several minutes to several hours.

Furthermore, the obtained acetylene adduct is reacted with NAD. NAD can also be used as the organic solvent solution described above.

The reaction time is usually about several minutes to several hours.

If the reaction temperature exceeds 20°C, there is a risk that the conversion rate will decrease and the product may start to form.
In the present invention, a temperature of 20° C. or lower is employed in the above reaction.

In the above reaction, the amount of caustic potash and alcohol used is 4 to 30, respectively, relative to NAD.
It is selected from about twice the molar amount and about 2 to 15 times the molar amount. The aprotic organic solvent contains 5 to 1 g of NAD.
Approximately 50ml is used.

Note that it is preferable to have acetylene present in the reaction between NAD and the acetylene adduct, since this further improves the reaction yield.

The resulting reaction mixture is then heated to and maintained at 25-60°C. The time usually ranges from several minutes to 10 hours.

This retention ensures that the by-products in the reaction mixture are
It is converted into a substance that can be converted into NETs after a subsequent neutralization process, resulting in an improved yield of NETs.

The reaction mixture is then made acidic with a mineral or organic acid such as hydrochloric acid, sulfuric acid, nitric acid, or an aqueous solution thereof, and stirred at a temperature of 10°C to 80°C, preferably 25°C to 60°C, for several minutes to several hours. An acid catalytic reaction is carried out.

Furthermore, it is neutralized with an alkaline aqueous solution such as caustic soda.

After the reaction is completed, extract from the reaction mixture by a conventional method.
NET is separated. Examples of this separation method include a method in which the solvent is distilled off, followed by filtration or extraction, followed by crystallization. In this way, NET can be produced with good yield.

Hereinafter, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited to these Examples unless the gist thereof is exceeded.

Example 1 95% caustic potash in 25 ml of tetrahydrofuran
Add 7.5g and then add 4.5ml of ethanol to 40°C.
Stir for 30 minutes. The flaky caustic potash turned into a kayu-like one. It was cooled to 10°C and acetylene was passed through it for 20 minutes. Furthermore, while continuing to pass acetylene, a solution of 2.38 g of NAD with a purity of 97.8% dissolved in 25 ml of THF was added dropwise over 5 minutes. After 3 hours, the temperature was raised to 30°C and stirring was continued for 30 minutes. Then, 50 ml of 18% aqueous hydrochloric acid solution was added and stirred at 30°C for 30 minutes.

After neutralizing with a 20% caustic soda aqueous solution and distilling off tetrahydrofuran, the suspended crystals were collected and dried. The crude crystal weight was 2.45g and the NET purity was 95.3%. (Yield 94.7%).

Claims (1)

[Claims] 1. After reacting caustic potash with a purity of 90% or higher with alcohol in an aprotic organic solvent at 20°C to 60°C, acetylene is supplied to the reaction product, and the resulting acetylene adduct and 19-nor-androst -4
-Ene-3,17-dione is reacted at below 20℃,
A method for producing 19-norethisterone, which is characterized in that the obtained reaction mixture is then maintained at 25 to 60°C, then acidified, subjected to an acid contact reaction, and further neutralized to produce 19-norethisterone.