Patent GB-872201-A (GB)
Title: Improvements in or relating to steroids and the manufacture thereof
IPC: C07J5/00
Filed: 1958-11-25
Abstract: The invention comprises compounds having the formulae: - <FORM:0872201/IV (b)/1> wherein the 1,2-carbon atom linkage is a single or double bond linkage and R and R1 are hydrogen or the acyl radical of a hydrocarbon carboxylic acid containing 1-12 carbon atoms inclusive, wherein R11 is <FORM:0872201/IV (b)/2> or keto and wherein R111 is hydrogen, chlorine, bromine or fluorine and a process which comprises reacting 6 - methyl - 11b ,21 - dihydroxy - 4,16 - pregnadiene-3,20-dione 21-acylate, wherein the acyl group is of a hydrocarbon carboxylic acid, with osmium tetroxide and hydrolysing to obtain 6-methyl-11b ,16a ,17a ,21-tetrahydroxy4-pregnene-3,20-dione 21-acylate; hydrolysing the monoester to obtain 6-methyl-16a -hydroxyhydrocortisone, and esterifying the free diol to yield the diester; treating the diester 6-methyl - 16a  - hydroxyhydrocortisone 16,21 - diacylate with an N-haloacylamide and SO2 to obtain 6 - methyl - 16a ,17a ,21 - trihydroxy - 4,9(11)-pregnadiene-3,20-dione 16,21-diacylate which with hypohalous acid gives 6-methyl-9-halo - 11b ,16a ,17a ,21 - tetrahydroxy - 4 - pregnene-3,20-dione 16,21-diacylate; treating said 9a -halo compound with a mild base to obtain 6 - methyl - 9b ,11b  - oxido - 16a ,17a ,21 - tri - hydroxy-4-pregnene-3,20-dione; treating the thus obtained oxido compound with HF to produce the corresponding 6-methyl-9a -fluoro-11b ,16a ,17a ,21 - tetrahydroxy - 4 - pregnene - 3,20-dione 16,21-diacylate; said 9a -fluoro compound is subjected to fermentation e.g. with Septomyxa to produce 6-methyl-9a -fluoro11b ,16a ,17a ,21 - tetrahydroxy - 1,4 - pregnadiene-3,20-dione which may be esterified to obtain the diester.  Alternatively the D 1 double bond may be introduced into 6-methyl11b ,16a ,17a ,21 - tetrahydroxy - 4 - pregnene - 3,20-dione or its mono or diacylate and a similar series of reactions to those described above effected for the introduction of a 9-halo substituent.  The corresponding 11 - keto analogues may be obtained either by employing an 11-keto starting compound or by oxidising the 11 - hydroxy product e.g. with chromic anhydride in acetic acid.  The process is applicable to both 6a  and 6b -epimers.  Illustrative products of the invention are 6a -methyl-16a -hydroxyhydrocortisone, 1-dehydro6a  - methyl - 16a  - hydroxyhydrocortisone, 6a  - methyl-9a -fluoro-16a -hydroxyhydrocortisone, 1-dehydro - 6a  - methyl - 9a  - fluoro - 16a - hydroxyhydrocortisone, 6a -methyl-16a -hydroxycortisone, 1-dehydro-6-methyl-16a -hydroxycortisone, 6a  - methyl - 9a  - fluoro - 16a  - hydroxycortisone, 1 - dehydro - 6a  methyl - 9a -fluoro-16a -hydroxycortisone and their 16,21-diacetates.ALSO:Pharmaceutical compositions comprise 6-methyl - 16a  - hydroxyhydrocortisone, 1-dehydro - 6 - methyl - 16a  - hydroxyhydrocortisone, 6 - methyl - 9a  - fluoro - 16a  - hydroxyhydrocortisone, 1 - dehydro - 6 - methyl - 9a  - fluoro - 16a  - hydroxyhydrocortisone, the 21 - esters and 16,21-diesters thereof, the 11-keto analogues or the 16,21-diesters thereof, and a pharmaceutical diluent.  They may be employed orally as tablets which may also incorporate antibiotics, e.g. tetracycline, chlorotetracycline, chloramphenicol, penicillin, novobiocin or oxytetracycline, and sulpha drugs and aspirin.  For topical use they may be in the forms of ointments, bougies, lotions, jellies, solutions or suspensions, or as an aerosol for nasal use.  They may also be used parenterally.