DE1643008C3 - Process for making 17 ethynyl delta to the power of 16 steroids - Google Patents

Description

C = CH

wherein R represents an ethyl or propyl group.

3. 17 - ethynyl - 18 - methyl - ι ¹ · ³ · ^{5 '10} » ¹⁶ - oestratetraen-3-ol-3-methyl ether.

4. Rac. 17-ethynyl-18-methyl-I ⁴¹⁶ -estradien-3-one.

5. 17-ethynyl-18-methyl-l ^4l6 -östradien-3-one.

östra-

40

45

The main patent 1593 521 describes the production of 17-ethynyl- ^{I 16} -steroids of the partial formula

55

described from corresponding 17 "- ethynyl - Π β - hydroxyiteroids by elimination of water with phosphorus oxychloride in the presence of 2,4-lutidine.

In a further development of the method according to the invention, it has now been found that steroids which carry an ethyl or propyl group on carbon atom C-13, implemented by this process can be.

The invention thus relates to a process according to patent 15 93521 for the production of 17-ethynyl ! '"- steroids of the general sub-formula

where R represents an ethyl or propyl group from corresponding 17 "- ethynyl -1 7ft - hydroxysteroids by splitting off water with phosphorus oxychloride in the presence of 2,4-lutidine, characterized in that instead of compounds with R = methyl, compounds with R in the meaning of an ethyl or propyl group starts out.

The elimination of water from alkynols to enynes with pyridine as the organic base is already known. For example, EB Hershberg and coworkers (J. Amer. Chem. Soc. 73, 5074 [1951]) have made ^{17'-ethynyl- l 5} -androsten-3, i, 17 /) '- diol with phosphorus oxychloride in the presence of pyridine 17-ethynyl- ^516- androstadien-3 ^ -ol produced. However, this process has the disadvantage of generally giving ^only moderate yields. Furthermore, a chlorallene derivative occurs as a by-product, the separation of which from the desired enyne is additionally associated with a great deal of work.

It has now been found that the formation of the by-product and the yield can be suppressed can be increased significantly if the elimination of water is achieved with phosphorus oxychloride instead of pyridine carried out in the presence of 2,4-lutidine. The advantages when using 2,4-lutidine were all the more surprising as it was simultaneously found that 2,6- and 3,4-lutidine as well as collidine and quinoline do not have these advantages over pyridine.

The 17a-ethynyl-17 / i-hydroxysteroids used as starting materials can be substituted on rings A, B and C in the usual way, e.g. B. by halogen, Alkyl, acyl, primary and secondary hydroxyl, acyloxy and / or alkyloxy groups. The steroid framework can also contain keto groups, heteroatoms and / or double bonds.

The new 17-Äthinyl- l ^lf> steroids are the synthesis of pregnane valuable intermediates door.

example 1

The solution of 46.9 g of 17'-ethynyl-18-methyl-, 1.3.5 (10). östratrien - 3.17 / i - diol - 3 - methyl ether in 500 ml of 2,4-lutidine (about barium distilled) is added at 0 ⁰ C and 47 ml Phosphoroxychiorid and under nitrogen for 18 hours at room temperature, then 8 hours at 70 ° C stirred. The batch is then poured into ice water with hydrochloric acid, the precipitate is filtered off, taken up in methylene chloride and the solution is washed neutral with water. After drying over sodium sulfate and evaporation, the residue is chromatographed on 800 g of silica gel with petroleum ether / acetone (from 0% acetone to 5% acetone). After recrystallization from methanol over charcoal, 18 g of 17-ethynyl-18-methyl-, 1,3.5 (10Ue. Oestratetraen-3-oil-3-methyl ether with a melting point of 94 to 96 ° C. are obtained.

Example 2

800 mg of rac 17 </ - ethynyl-18-methyl-I * - oestren - 17 / f - oil - 3 - one are dissolved in 8.5 ml of distilled 2,4-lutidine and 0.8 ml of phosphorus oxychloride is added with stirring . The mixture is stirred for a further 6 hours at 70 ^° C. under nitrogen and the reaction solution is then poured into ice-water with sulfuric acid. After extraction with ether, the organic phase is washed neutral with water, dried over sodium sulfate and evaporated. The crude product obtained is purified by column chromatography on silica gel and recrystallized from hexane / acetone. Rac. 17 - Athynyl -18 - methyl - 1 ^4α6 - estradien - 3 - one with a melting point of 125 to 128 ° C.

Example 3

51.5 g of nu-ethynyl-IS-methyl- i * - oestren - 17 / V-ol-3-one are reacted in 500 ml of 2,4-lutidine with 50 ml of phosphorus oxychloride analogously to Example 2 and worked up. Hexane / 20% acetone) on 80 pg silica gel 17-ethynyl-18-methyll ^4J6 -estradien-3-one with a melting point of 113 to 116 ° C (hexane / acetone).

Claims (2)

Patent claims: 1. Further development of the process of Patent 1,593,521 for the preparation of 17-Äthinyll ^I6-steroids of the general partial formula CsCH 15th in which R represents an ethyl or propyl group, from corresponding nn-ethynyl-l ^ -hydroxysteroids by elimination of water with phosphorus oxychloride in the presence of 2,4-lutidine, thereby I η et that instead of compounds with R = Methyl starts from compounds with R meaning an ethyl or propyl group.
2. Compounds of the general sub-formula