Patent GB-1130115-A (GB)
Title: 16-methyl-4-pregnen-3ªß-ol-20-ones and their preparation
Inventor: IRMSCHER KLAUS
IPC: A61K31/57
Filed: 1967-07-05
Abstract: 1,130,115. 16-Methyl-4-pregnen-3#-ol-20- ones. E. MERCK A.G. 5 July, 1967 [6 Aug., 1966; 12 Aug., 1966; 9 Feb., 1967; 3 March, 1967; 20 May, 1967], No. 30884/67. Heading C2U. Novel steroids of the formula (wherein R<SP>1</SP> is F, Cl, Br, CH 3  or CF 3 ; R<SP>2</SP> and R<SP>3</SP> are each H or together are -CH 2 -; and the #<SP>6</SP> double bond is optional) are prepared by (1) liberation of the 20-keto group in corresponding steroids containing a functionally modified 20-keto group; (2) selective reduction of corresponding 3-ones with lithium aluminium tri-tert.-butoxy hydride or diborane in an inert solvent or with sodium borohydride in pyridine, methanol or anhydrous isopropanol; or (3) treatment of corresponding 3#,17α,20- trihydroxy steroid 3,20-dialkanoates with zinc and hydrolysis of the product with a strong base or a strong acid. 6α,16α - Dimethyl - 4 - pregnen - 3# - ol - 20- one 20-semicarbazone is prepared reacting 6α, 16α-dimethylprogesterone with pyrrolidine to form the 3 - pyrrolidine enamine, converting this to its 20-semicarbazone, hydrolysing this to 6α,16α - dimethylprogesterone 20 - semicarbazone and reducing this. 6α,16α - Dimethyl - 4- pregnen - 3# - ol - 20 - one 20 - ethylene ketal is prepared by Oppenauer oxidation of 6,16α-dimethyl 5 - pregnen - 3# - ol - 20 - one 20 - ethylene ketal (itself prepared from the free 20- one) to give 6α,16α - dimethyl - progesterone 20 - ethylene ketal and reduction of this. 6α,16α - Dimethyl - 4 - pregnen - 3#,17α,20- triol 3,20 - diacetate is prepared by reduction of 6α,16α - dimethyl - 17α - acetoxy - progesterone and acetylation of the product. 6- Halo - 16 - methyl - progeaterones are prepared by reacting 3-enol ethers of the corresponding 6-unsubstituted progesterones with N-halosuccinimides to give 6#-products and, when required, epimerizing these to 6α-products. These and other starting materials can be converted to the corresponding #<SP>4</SP>'<SP>6</SP>-steroids by reaction with chloranil. 1α,2α-methylene starting materials are prepared by dehydrogenation of #<SP>4</SP> or #<SP>4,6</SP> compounds to #<SP>1,4</SP> or #<SP>1</SP>'<SP>4</SP>'<SP>6</SP>-compounds and reaction of these with trimethyl sulphoxonium iodide or diazomethane. 1α,2α- Methylene - 6 - chloro - 16 - methyl - 6 - dehydroprogesterones are prepared by converting corresponding 6 - unsubstituted compounds to the 6α,7α-epoxides, reacting these with HCl to give 1α - chloromethyl - 6 - chloro - 16 - methyl - 6 - dehydroprogesterones and treating these with a base; the corresponding 6 - bromo compounds are prepared by converting the 1α-chloromethyl intermediates to their 6α,7α-epoxides, reacting these with HBr and ring closing with collidine; 6-fluoro compounds are prepared similarly by reaction with HF before dehydration with HBr and ring closure. 6α-Triluoromethyl-16- methyl-progesterones are prepared from the corresponding 6-unsubstituted 3-enol ethers and CF 3 I with subsequent acid treatment. Starting materials saturated in the 6,7-position can also be obtained by reduction of 6-dehydroprogesterones, the configuration of any 6-substituent depending on the method used. The steroids of the invention, which are stated to have ovulation-inhibiting, cycleinfluencing, anti-androgenic, gonadotrophin influencing, anti-estrogenic and/or anti-fertility properties, may be made up into pharmaceutical compositions for parenteral, enteral or topical application with suitable carriers.