Patent GB-869511-A (GB)
Title: Improvements in or relating to steroids and the manufacture thereof
IPC: C07J43/00
Filed: 1959-04-24
Abstract: The invention comprises compounds having the formulae:  wherein R is hydrogen or the acyl radical of a hydrocarbon carboxylic acid of from 1-12 carbon atoms, inclusive; R1 is b -hydroxy or keto; X111 is hydrogen, bromine, iodine, fluorine or chlorine; Ac is the acyl radical of a carboxylic acid; M is hydrogen or an alkali metal and the lower alkyl contains 1-8 carbon atoms inclusive, X is chlorine or bromine, and wherein the carbon atoms joined by the dotted line are single or double bonded; and a process for preparing such compounds by treating the 3-enmine of 11-keto-16-dehydroprogesterone with a Grignard reagent and hydrolysing to form 11-keto-16-methylprogesterone IV; reacting IV with oxalic acid diester and a base, and with halogen to obtain 2,21-dialkoxyoxalyl-2,21,21-trihalo 11-keto-16a methylprogesterone VI; rearranging with a strong base and removing the 2-halo group to produce 3,11-diketo-16a -methyl-4,17(20)-[cis]pregnadien-21-oic acid alkyl ester VIII; forming the 3-ketal from VIII, reducing with LiA1H4 and hydrolysing gives 11b ,21-dihydroxy-16a - methyl-4,17(20)- [cis]- pregnadiene-3-one XI; dehydrogenating with SeO2 followed by oxidative hydroxylation gives 11b , 17a - dihydroxy-21- acyloxy-16a - methyl-1,4pregnadiene-3, 20-dione XIV; hydrolysing or oxidising XIV gives the corresponding 21hydroxy and 11-keto compounds; treating XIV with a dehydrating agent and a source of hypohalous acid gives 11b ,17a -dihydroxy-9a -halo-21- acyloxy-16a - methyl-1, 4- pregnadiene3,20-dione XVII; reacting this compound with a base gives the 9,11-epoxy compound which with HF gives the corresponding 9a -fluoro11b -hydroxy compound.  Illustrative products of the invention are 11b ,17a ,21-trihydroxy16a -methyl-4-pregnene-3,20-dione and the 21-acetate thereof, 9a -fluor-11b ,17a ,21-trihydroxy-16a -methyl-4-pregnene-3, 20-dione and the 21-acetate thereof, the corresponding 1,4-pregnadienes,3,11-diketo- 16a -methyl- 4,17(20) [cis]-pregnadiene-21-oic acid methyl ester, 11-keto-16a -methylprogesterone and the 3-pyrrolidyl enamine thereof, 11b ,21-dihydroxy-16a -methyl-4,17(20)-[cis]-pregnadiene-3-one and the 3-pyrrolidyl enamine thereof and 11b ,21-dihydroxy- 16a - methyl- 1,4,17(20) - [cis]-pregnatriene-3-one.  Specifications 761,490, 771,344, 779,002 and 781,712 are referred to.ALSO:Pharmaceutical compositions comprise 11b , 17a ,21 - trihydroxy - 16a  - methyl - 4 - pregnene-3,20 - dione, 16a  - methyl - 17a ,21 - dihydroxy - 4 - pregnene - 3,11,20 - trione, 11b ,17a ,21 - trihydroxy - 16a  - methyl - 1,4 - pregnadiene - 3,20-dione, 16a -methyl-17a ,21-dihydroxy-1,4-pregnadiene - 3,11,20 - trione, 9a  - fluoro - 11b ,17a , 21 - trihydroxy - 16a  - methyl - 4 - pregnene - 3,20 - dione, 9a  - fluoro - 16a  - methyl - 17a ,21 - dihydroxy - 4 - pregnene - 3,11,20 - trione, 9a -fluoro - 11b ,17a ,21 - trihydroxy - 16a  - methyl - 1,4 - pregnadiene - 3,20 - dione, 9a  - fluoro - 16a  - methyl - 17a ,21 - dihydroxy - 1,4 - pregnadiene - 3,11,20-dione and their 21-esters incorporated in an inert ointment, cream, lotion or spray.  In addition, antibiotics, e.g. penicillins, neomycin, tetracycline, chloramphenicol and novobiocin, may be present. Specification 761,490, 771,344, 779,002 and 781,712 are referred to.