DE2517770C3 - Process for the production of - Google Patents

Description

CsCH

(D

where R ₁ denotes methyl or ethyl and St denotes the following partial steroid structures

where R ₁ denotes methyl or ethyl and St denotes the following partial steroid structures

15th

20th

25 R, O

R ₂ O

and

30th

35 R ₂ O

with R2 meaning lower acyl with 1-6 C atoms or lower alkyl with 1 -3 C atoms, by splitting off water with phosphorus oxychloride in Presence of an aromatic base from corresponding 17 /? - hydroxy-17Ä-äthinyIsteroiden in an aromatic hydrocarbon, thereby characterized in that the starting materials are 17 /? - Hydroxy-17 <x -ethinyl steroids of the general Sub-formula II

with R2 meaning lower acyl with 1-6 C atoms or lower alkyl with 1-3 C atoms from 17 <x -ethynyl-17j3-hydroxysteroids by elimination of water with phosphorus oxychloride in the presence of an aromatic base in an aromatic hydrocarbon proposed as a solvent.

In a further development of the process it has now been found that the process proposed in the patent application can be applied not only to steroids that are either saturated or arcimatic in the Α-ring, but also to those steroids in which the Α-ring Δ * - or ^ '^ - is unsaturated.

The present invention thus relates to a further development of the method according to patent 22 38 586 for the production of ^416-17 -ethinyl steroids of the general sub-formula I.

CsCH

55

CsCH

(ID

60 in which R _{1 is} methyl or ethyl and St is the following steroid, where Ri and St have the meanings given above for partial structures, use !.

65

and

with R2 meaning lower acyl
with 1 - 6 carbon atoms or lower alkyl
with 1-3 carbon atoms, by elimination of water with phosphorus oxychloride in the presence of an aromatic base from corresponding 17 /? - hydroxy-17a-ethinyl steroids by elimination of water in an aromatic "hydrocarbon, which is characterized in that 17 / f-hydroxy -17 «-ethinyl steroids of the general sub-formula II

C = CH

(H)

Produce ketopregnane which by hydrogenation after protection of the 4 ⁴ -3-keto function, for example by partial ketalization, for example with palladium / carbon in dimethylformamide, for example progesterone, or by methylation with methylmagnesium iodide in the presence of copper (I) chloride to give the 16ot-methyl lead compounds, which in turn are the starting material for the production of known corticoids.
The following examples are intended to explain the process according to the invention.

example 1

100 g of 17oc-ethynylestosterone (ethisterone) are mixed in 700 ml of toluene and 300 ml of 2,4-lutidine with 100 ml of phosphorus oxychloride and the reaction mixture is ^{heated under nitrogen for 3 hours at 100 °} C. After cooling, the reaction mixture is in a mixture of 1.8 liters Water and 400 ml of concentrated hydrochloric acid precipitated, then stirred for 2 hours. It is extracted several times with methylene chloride and the organic phase is washed neutral with water and saturated sodium chloride solution. After drying the solution over sodium sulfate, it is concentrated to dryness. The crude product (102.3 g) is refluxed with 6 liters of isopropyl ether and 10 g of charcoal for one hour, filtered and concentrated to approx. 400 ml. 73.43 g of 17- ethynyl-4.16-androstadien-3-one with a melting point of 165-170 ⁰ C, [ «]" + 174.8 ° (chloroform) and a purity of about 98% according to TLC.

Example 2

where Ri and St have the meaning given above, used

It was quite surprising that under the conditions of dehydration with phosphorus oxychloride the Δ ⁴ - and ^ '^ - double bonds are retained, since it would have been expected that the corresponding 3-enolphosphere would be formed.

As aromatic hydrocarbons are all those in question, which are compared to the rest Behave reactants inert. Examples include benzene, toluene and XyIoL

The inventive method is advantageously at elevated temperature, preferably in the temperature range above room temperature to the boiling temperature, preferably at 80-100 ⁰ C, the reaction mixture carried out In this case, it is not excluded that the inventive method can be carried out also at room temperature with a correspondingly extended reaction time The elimination of water is complete after a few hours at higher temperatures

The 17'-ethynyl-17jS-hydroxysteroids used as starting materials can be substituted in the usual way. Suitable substituents are lower alkyl groups in the 1-, 6- or 16-position gen annt.

The compounds which can be prepared according to the invention are intermediates for the preparation of valuable medicaments. So can be prepared from the ^{4416-Äthiny3steroiden} -17 by addition of water in the presence of mercury salts easily the corresponding ⁴⁴¹⁶ -20-20 g norethindrone (19-nor-17 "-äthinyltestosteron) are dissolved in 60 ml of toluene and 140 ml of 2,4- 12 ml of phosphorus oxychloride are added to lutidine and the mixture is heated at 100 ° C. for 3 hours under nitrogen.

After cooling, the reaction mixture is concentrated in a mixture of 900 ml of water and 200 ml Hydrochloric acid precipitated, then stirred for one hour. It is extracted several times with methylene chloride and washes the organic phase neutral with water. The solution is concentrated to dryness and the residue taken up in 50 ml of methylene chloride. 600 ml of isopropyl ether are added, 200 ml are distilled off, filtered and concentrated to approx. 40 ml. It crystallizes

15.65 g of pure 17-ethynyl-4.16-estradiene-3-one with a melting point of 148-152 ⁰ C; [<%] "+ 111.5 ° (chloroform), UV: 6235 = 24,850.

Example 3

Analogously to Example 1, 17'-ethynyl-17j3-hydroxy-18-methyl-19-norandrost-4-en-3-one is used (d-Norgestrel) converted to 17-ethynyl-18-methyl-4.16-estradien-3-one and recrystallized from acetone-hexane

Melting point 130-132 ° C. Yield 77.2% of theory. Th.

Example 4

4 g of 17'-ethynyl-17 /? - hydroxy-1,4-androstadien-3-one are reacted under the same conditions as in Example 1 and recrystallized from isopropyl ether. 3.02 g of 17-ethynyl-1.4.16-androstatrien-3-one with a melting point of 179-182 ° C. are obtained; [a] "+ 129.2 ° (dioxane), UV: e> _J6 =

Claims (1)

Claim: According to patent 22 38 586 for the preparation of 4 ¹⁶ -17-äthinylsteroiden further embodiment of the method of the general partial formula I In the patent 22 38 586 describes a process for the preparation of 4 ¹⁶ -17-äthinylsteroiden the general partial formula