Patent GB-952085-A (GB)
Title: 16-methylene-steroids and processes for the manufacture thereof
IPC: C07J7/00
Filed: 1960-09-22
Abstract: Steroids of the general formula: <FORM:0952085/C2/1> wherein R1 represents <FORM:0952085/C2/2> or O = and X represents hydrogen or fluorine, and the corresponding 1, 2-dehydro steroids, are prepared (i) by treating the corresponding 11-unsubstituted steroid with an 11-hydroxylating microorganism to form the 11a - or 11b -hydroxy steroid, (ii) by treating 16-methylene-11a , 17a -dihydroxy-progesterone or the corresponding 1, 2-dehydro-compound with a dehydrating agent to form the corresponding D  9(11)-steroid unsubstituted at the 11-position, treating the D  9(11)-steroid with an acylating agent to form the corresponding D  9(11)-17a -acylate, treating this compound with hypobromous or hypochlorous acid or with agents which liberate hypobromous or hypochlorous acid such as an N-halo-acetamide or an N-halosuccinimide, to form the corresponding 9a -bromo (or chloro)-11b -hydroxy-steroid, treating this compound with an agent to split off hydrogen halide to form the corresponding 9b , 11b -epoxide, and treating the epoxide with hydrofluoric acid, and hydrolysing the 17-acyloxy group at any stage following treating with hypobromous or hypochlorous acid to form a 9a -fluoro-11b -hydroxy steroid of the above general formula, (iii) by dehydrogenating the corresponding D  4-steroid with chemical or microbiological dehydrogenating agents such as 2, 3-dichloro-5, 6-dicyano-p-benzoquinone or the microorganisms Bacillus sphaericus Var. fusiformis and Corynebacterium simplex, and (iv) the preparation of an 11-keto-steroid of the above general formula by oxidizing the corresponding 11-hydroxy steroid.  The 11-hydroxylation process referred to above may be carried out with any microorganisms of the genera Curvularia (for 11b -hydroxylation), and of the order Mucorales such as the genera Mucor, Streptomyces, Fusarium, Aspergillus, Penicillium, Rhizopus and Bacillus (for 11a -hydroxylation).  The dehydration step may be carried out by esterifying the 11a -hydroxy group, for example, to form an 11a -tosyloxy compound, and splitting off the corresponding acid by heating or by reacting with a basic agent. The dehydration step may also be carried out using 16-methylene-11b , 17a -dihydroxy-progesterone or the corresponding 1,2-dehydrocompound and carrying out the dehydration with phosphorus oxychloride or with thionyl chloride in pyridine to form the corresponding D 9(11)-steroid.  16-Methylene-17a -hydroxy-progesterone is prepared by converting 16-methyl-pregnadienolone acetate into 16a , 17a -oxido-16b -methyl-4-pregnene -3, 20-dione by alkaline hydrogen peroxide and subsequent Oppenauer oxidation, and splitting the 16a , 17a -oxido compound with a strong acid in an inert solvent, for example, p-toluene sulphonic acid in benzene.  Therapeutic compositions having anti-inflammatory action contain as the active ingredient steroids of the above general formula. The compositions may be in the form of powders, ointments, emulsions or lotions. Specification 941,553 is referred to.  Reference has been directed by the Comptroller to Specification 857,114.