DE1072991B - Process for the preparation of 1,2-methylene-3-keto steroids - Google Patents

Description

GERMAN

It has been found that diazomethane when acting on Zl ¹ ' ⁴ ' ⁶ -3-keto steroids attaches itself to the ^ double bond of the keto steroid in a smooth reaction:

Method of manufacture
of 1,2-methylene-3-keto steroids

Applicant:

Schering Aktiengesellschaft,
Berlin N 65, Müllerstr. 170-172

Dr. Rudolf Wiechert, Berlin-Lichterfelde,

Dr. Emanuel Kaspar, Berlin-Wilmersdorf,

and Dr. Martin Schenck, Berlin-Frohnau,

have been named as inventors

Here, Z means grouping

- N ₅ .

-CH,

"N

This strange reaction could by no means be foreseen, since it was not known how the individual double bonds would behave towards diazomethane, especially since A MS keto steroids had shown themselves to be inert towards diazomethane (own experiments).

The 1,2-diazomethylene-Zl *> ⁶ -3-ketosteroids obtainable in this way are valuable intermediates for syntheses in the steroid series.

For example, if they are subjected to thermal cleavage, as has also been found, instead of the expected (cf. German Patent 1 023 764) 1-methyl-Zl ¹ ' ⁴ ' ⁶ -3-ketosteroids, the corresponding 1,2- Methylene-Zl ⁴ > ⁶ -3-ketosteroids:

In these 1,2-methylene compounds, as was finally found, the Δ ^ double bond can be selectively hydrogenated. This leads to the 1,2-methylene-zl ⁴ -3-keto steroids, which cannot be obtained directly from the Zl ¹ ' ⁴ -3-keto steroids or the associated diazomethane addition products because of the above-mentioned absence of diazomethane addition:.

CH,

The above general formulas are only intended to provide a schematic explanation of the process according to the invention and are not intended to represent any restriction. ^{The / d 1} >*> ^e -3-Kstosteroids serving as starting materials can, as the following examples show, other substituents such as hydroxyl groups in free or functionally modified form and / or side chains such as Alkyl groups containing acetyl or hydroxyacety group.

909 709/468

The addition of diazomethane to double bonds and the thermal cleavage of the pyrazolines obtained with formation of the corresponding methylene compounds is known per se (cf. Journ. Amer. Chem. Soc., Vol. 73, 1951, pp. 2383 ff).

The ^ l ⁵ -16,17-methylen-3ß-ol-20-one is only obtained as a by-product in the previously known reaction sequence, however. Since ./IM-S- ketosteroids had already been shown to be inert to diazomethane in our own experiments, the transferability of the previously known reaction sequence to ^!. ^ ES-ketosteroids is quite surprising.

example 1

a) 1,2-Diazomethylene- ^ ⁴ · ⁶ -androstadien-17β-ol-3-one-17-acetate

5.7 g of nitrosomethylurea is added with 100 ml of ether with 17.2 ml of 40% potassium hydroxide solution at -5 ⁰ C. The ethereal phase is added to 1 g of ^{I 1} > ⁴ < ⁶ -Ar.drostatrien-17 /? - ol-3-one-17-acetate and this solution is kept closed for 6 days at room temperature. A precipitated polymer is then filtered off and the ether is stripped off in vacuo at room temperature. After chromatography on silica gel, 1,2-diazomethylene-Zl ⁴ · ⁶ -androstadien-17 ^ -ol-3-one-17-acetate is obtained.

F. = 154 to 158 ° C. UV: ε ₂₉₀ = 23 700.

b) 1,2-methylene-zl ⁴ > ^e -androstadien-

17j8-ol-3-one-17-acetate

200 mg of the above diazomethylene compound are heated to 140 ° C. in a high vacuum. The substance begins to melt and the pressure in the apparatus increases from 10 ~ ³ mm to 5 x 10 ~ ² mm. The reaction has ended after about 10 minutes.

It is recrystallized from isopropyl ether.

F. = 174 to 176 ° C. UV: ε ₂₈₂ = 20 540.

c) 1,2-Methylen-Zl ⁴ -androsten-l 7ß-ol-3-one-17-acetate

322 mg 1,2-methylene-I ⁴ . ^6- androstadien-17 / S-ol-3-one-17-acetate are hydrogenated in 9 ml of anhydrous methanol containing 0.1% potassium hydroxide with the addition of 160 mg of 10% palladium-carbon catalyst until 1 mmol of hydrogen is absorbed. The catalyst is then filtered off, evaporated to dryness and recrystallized from isopropyl ether.

F. = 174 to 175 ° C. UV: ε ₂₃₉ = 14000.

Example 2

a) 1,2-Diazomethylene-Zl ⁴ » ⁶ -pregnadien-17a-ol-3,20-dione-17-acetate

It is produced from .d ¹ ' ⁴ ' ⁶ -Preg-natrien-17a-ol-3,20-dione-17-acetate, as with Δ ^x > ⁴ > ^e -Androstatrien-17 / S-ol-3-one -17-acetate described.

F. = 183 to 185 ° C. UV: ε ₂₈₈ = 22 400.

b) 1,2-methylene-zl ⁴ > ⁶ -pregnadien-17a-ol-3,20-dione-17-acetate

The 1,2-diazomethylene compound is obtained by heating it in a high vacuum to 180 ° C., as described for 1,2-diazomethylene- / l ⁴ > ^e -androstadien-17 / S-ol-3-one-17-acetate above connection. It is recrystallized from methanol.

F. = 279.5 to 280.5 ° C. UV: ε ₂₈₂ = 20 790.

Claims (3)

PATENT CLAIMS: 1. A process for the preparation of 1,2-methylene-3-ketosteroids, characterized in that diazomethane is allowed to act on JM ^ -S-ketosteroids, expediently in an inert organic solvent, the 1,2-diazomethylene / J ⁴ > ⁶ -3-ketosteroids are subjected to thermal cleavage and the resulting ^{1,2-methylene / l 4} > ^e -3-keto steroids are optionally hydrogenated selectively to give the corresponding 1,2-methylene-Zl ⁴ -3-keto steroids. 2. A process for the preparation of 1,2-diazomethylene-zl ⁴ ' ^e -3-ketosteroids, characterized in that diazomethane is allowed to act on Zl ¹ '^{4> e} -3-keto steroids in an inert organic solvent. 3. A process for the preparation of Δ ⁴ · ⁶ - or ./^- unsaturated l ^ -Methylene-S-ketosteroids, characterized in that the l, 2-diazomethylene / f ⁴ > ⁶ available in particular according to claim 2 - Subjects 3-ketosteroids to thermal cleavage and, if necessary, ^{selectively hydrogenates their Zl e} double bond. 35 40 © 909 709/468 1.6tt