DE1244178B - Process for the preparation of alpha, beta-methylene keto steroids - Google Patents

Description

FUNDAMENTAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Int. Cl .:

C07C C O 7 J

German class: 12 ο -25/05

Number: 1244 178

File number: Sch 36654IV b / 12 ο

Filing date: March 9, 1965

Opened on: July 13, 1967

The invention relates to a process for the preparation of new 17-carboxylic acid esters of a J- methylcnketosteroids of the general formula

CH ₃

CH ₂

CH ₃

Process for the production of
Λ, / J-methylene keto steroids

Applicant:

Schering Aktiengesellschaft,

Berlin 65, Mullerstr. 170/172

Named as inventor:

Dr. Josef Hader,

Dr. Rudolf Wiechert, Berlin

in which X is a hydrogen, a fluorine or chlorine atom or the methyl group, R is preferably the radical of one means lower or middle aliphatic carboxylic acid.

The process according to the invention consists in the 1,2-methylenation of unsaturated 3-keto steroids general formula

CH,

at room temperature. The yield of the process can be increased considerably by using an excess of methylenating agent (for example 2 to 10 molar equivalents of trimethylsulfoxonium iodide).
The course of the reaction according to the invention is surprising. Although the methylenation process described above is known per se, it has been shown that cyclizations to γ-lactones occur in the case of 17-acyloxy-20-ketosteroids under the alkaline reaction conditions. In the German patent 1,218,440, for example, compounds with the partial steroid formula have been proposed

CH ₃

C = O
...- OCO - CH ₂ - alkyl

Alkyl

in which X and R have the above meaning. 40 under the alkaline conditions of the invention

As methylenation reagents, trimethyl-appropriate conversion at room temperature in y-laksulfoxonium salts are used, in the presence of a base in a dipolar aprotic solvent with the mentioned steroids are implemented in a manner known per se. 45

Suitable solvents for the reaction are, in particular, dimethyl sulfoxide and dimethylformamide. Alkali hydrides, amides, hydroxides and alcoholates are preferably used as bases, in particular the relevant sodium 50 links. The reaction is carried out at temperatures between about 0 and 70 ° C., primarily to convert.

tone of the sub-formula

CH ₃

C = O

709 610/575

Also had to be the possibility of saponification of the 17-Estergruppiemng, especially when using of alkali hydroxides or alkali alcoholates as bases.

Accordingly, it was not to be expected that the methylenation according to the invention of 16-methyl-17-acyloxy-20-ketosteroids would give α , β -methylene ketones while maintaining the esterified hydroxyketone soap chain.

The compounds according to the invention have excellent gestagenic and ovulation-inhibiting properties Effect of great therapeutic interest.

example 1

960 mg of trimethylsulfoxone iodide are dissolved in 7 ml of dimethylsulfoxide, and 120 mg of sodium hydride (50% oil suspension) are added under nitrogen. The mixture is stirred for about 2 hours under nitrogen, then transmits 383mg 16a-methyl-zl ¹ - ^{4 (i} -pregnatriene-17a-ol-3,20-dione-17-acetate and stirred at room temperature under nitrogen for 17 more hours.

The reaction mixture is stirred into ice water, acidified with dilute hydrochloric acid, taken up in methylene chloride, washed neutral with water, dried over sodium sulfate and evaporated to dryness in vacuo. The crude product obtained is purified by preparative thin-layer chromatography (S1O2) [benzene-ethyl acetate 60-1-40] and recrystallized from isopropyl ether. 250 mg of 1,2a-methylene-16a-methyl- / i ¹⁰ -pregnadien-17a-ol-3,20-dione-17-acetate are obtained. F. 201 to 203 ⁰ C. UV: £ 282 = 21,300.

Example 2

960 mg of trimethylsulfoxonium iodide are dissolved in 10 ml of dimethylsulfoxide and, after the addition of 160 mg of powdered sodium hydroxide, stirred for 2 hours under nitrogen. Then 417 mg of 6-chloro-16a-methyl-zl ¹ · ⁴ · ⁶ -pregnatriene-17a-ol-3,20-dione-17-acetate are introduced and stirring is continued overnight under nitrogen. The reaction mixture is stirred into ice water, acidified with dilute hydrochloric acid and extracted with methylene chloride. After washing, drying and concentrating in vacuo, it is chromatographed on SiO2 + 10% H2O and eluted with methylene chloride. This gives 6-Chlorl, 2a-methylene-16a-methyl-z) ⁴ - ⁶ -Pregnadien-17a-ol-3,20-dione-17-acetate. After recrystallization from isopropyl ether, the analytically pure substance melts at 208 to 209 ° C. UV: _i282 = 17,400.

Example 3

60 + 40) purified and recrystallized from isopropyl ether. 6-fluoro-1,2'-methylene-16a-methyl-J ⁴ · ⁶ -pregnadiene-17α-oil-3.20-dione-17-acetate is obtained.
5

Example 4

500 mg of trimethylsulfoxonium iodide are dissolved in 6 ml of dimethylsulfoxide, 65 mg of sodium hydride (50%) are added and the mixture is stirred for 5 hours under nitrogen. 200 mg of 6,16a-dimethyl- ^{I 1} ' ^{4 (i} -pregnatrien-17ct-ol-3,20-dione-17-acetate are then introduced and the mixture is stirred for 40 hours at room temperature under nitrogen. The reaction mixture is stirred into ice water with The organic phase is washed neutral with water, dried over sodium sulfate and concentrated in vacuo. The crude product is purified on SiO ₂ (preparative thin-layer chromatography) with benzene-ethyl acetate 60 + 40 and recrystallized from isopropyl ether. 1,2a - methylene - 6,16a - dimethyl - Λ ⁴ · ⁶ - pregnadien-17a-ol-3,20-dione-17-acetate is obtained. F. 204 to 206 ^° C. UV:

«287 = 18 100.

25th

Example 5

720 mg of trimethylsulfoxonium iodide are dissolved in 7 ml of dimethylsulfoxide and 100 mg of sodium hydride are added under nitrogen. After 3 hours' stirring, 214 mg carries loa-methyl-J ^{1-4 G} -pregnatriene-17a-ol-3,20-dione 17-caproate, and stirred at room temperature under nitrogen for 20 hours.

The reaction mixture is stirred into ice water, acidified with dilute hydrochloric acid and extracted with methylene chloride. It is washed, dried and evaporated. The crude product is purified by preparative thin-layer chromatography (S1O2, benzene-ethyl acetate 60 + 40) and recrystallized from isopropyl ether. 1,2a-methylene-16a-methyl-J ⁴ · ⁶ -pregnadiene-17a-3,20-dione-17-capronate is obtained. The 1,2a-methylene-16a-methyl-zl ⁴ ' ⁶ -pregnadiene-17nr-3,20-dione-17-enanthate is obtained analogously. UV: t-282 = 21,000 (capronate).

45

50

55

480 mg of trimethylsulfoxonium iodide are dissolved in 5 ml of dimethylsulfoxide; 60 mg of sodium hydride (50 ⁰ / oig) was added and the mixture is stirred under nitrogen for 1 hour. Then, 203 mg of 6 are - fluoro - 16a - methyl - Δ ^1-4 · ⁶ - pregnatrien -17α - ol-3,20-dione-17-acetate is added and stirred for 18 hours under nitrogen at room temperature. The reaction mixture is then stirred into ice water, acidified with dilute hydrochloric acid and extracted with methylene chloride. After washing, drying and concentrating, the crude product is purified by preparative thin-layer chromatography (benzene-ethyl acetate

Claims (1)

Claim: Process for the preparation of α, / 3-methylene keto steroids the general formula CH ₃ CH ₂ in which X is a hydrogen, fluorine or chlorine atom or the methyl group, R the radical of a preferably lower or middle aliphatic group Carboxylic acid means that 5 6 indicates that one is an unsaturated steroid of the general formula in which X and R have the above meaning, in a manner known per se in a dipolar aprotic Solvent, preferably in dimethylsulfoxide or dimethylformamide, with a Trimethylsulfoxonium salt in the presence of a base, in particular an alkali hydride or amide, hydroxide or alcoholate, in particular the sodium compounds concerned, preferably Reacts at room temperature. 709 610/575 7.67 O Bundesdruckerei Berlin