Patent GB-906443-A (GB)
Title: Steroid compounds
IPC: A61K31/57
Filed: 1958-12-18
Abstract: The invention comprises steroids of the general formula <FORM:0906443/IV (b)/1> wherein R represents an alkyl radical, R1 represents hydrogen or an acyl radical, R11 represents a hydroxy or oxo group, and X represents hydrogen or a halogen, and the dotted line represents the optional presence of a 1,2-double bond and of the general formulae <FORM:0906443/IV (b)/2> wherein R, R1 and R11 have the above significance and Ac represents an acyl radical, and processes that comprise each stage and processes that may commence at any stage in the following synthesis:- 16b -alkyl-4-bromo-17a ,21 - dihydroxypregnane -3,11,20 - trione 21-acylate (which may be prepared by a process set out below) is reacted with semicarbazide hydrochloride to form the 3-semicarbazone of 16b -alkyl-17a ,21-dihydroxy-4-pregnene-3,11,20-trione 21-acylate; the 3-semicarbazone is reacted with pyruvic acid to form 16b -alkyl-17a ,21-dihydroxy-4-pregnene-3,11,20-trione 21-acylate; the latter compound or the corresponding free 21-hydroxy compound is reacted with semicarbazide hydrochloride to form the 3,20-disemicarbazone of 16b -alkyl-17a ,21-dihydroxy-4-pregnene-3,11,20-trione or the 21-acylate thereof; the 3,20-disemicarbazone or the 21-acylate thereof is reacted with an alkali metal borohydride to form the 3,20-disemicarbazone of 16b -alkyl-11b ,17a ,21-trihydroxy-4-pregnene-3,20-dione (this compound may be reacylated at the 21-position); the 21-hydroxy-compound is reacted with pyruvic acid to form 16b -alkyl-11b ,17a ,21-trihydroxy-4-pregnene - 3,20 - dione; the resulting 21-hydroxy compound is reacted with an acyl anhydride to form the corresponding 21-acylate; the 21-acylate is reacted with an organic sulphonyl chloride to form 16b -alkyl-17a ,21-dihydroxy-4,9(11)-pregnadiene-3,20-dione 21-acylate; the 4,9(11)-pregnadiene is reacted with an N-bromo-acylamide to form 16b -alkyl - 9a  - bromo-11b ,17a ,21-trihydroxy-4-pregnene-3,20-dione 21-acylate; the 9a -bromo compound is reacted with sodium methoxide to form 16b  - alkyl - 9b ,11b  - epoxy-17a ,21-dihydroxy-4-pregnene-3,20-dione, and then with an acyl anhydride to form 16b -alkyl-9b ,11b -epoxy - 17a ,21-dihydroxy-4-pregnene-3,20-dione 21-acylate; and the 9b ,11b -epoxy compound is reacted with a hydrogen halide to form a 16b  - alkyl - 9a  - halo-11b ,17a ,21-trihydroxy-4-pregnene-3,20-dione 21-acylate. The invention also includes processes for the preparation of steroids of the general formula <FORM:0906443/IV (b)/3> wherein R, R1, R11 and X have the above significance, by dehydrogenating steroids of the general formula <FORM:0906443/IV (b)/4> wherein R, R1, R11 and X have the above significance, with selenium dioxide; for the preparation of steroids of the general formula <FORM:0906443/IV (b)/5> wherein R, and R11 have the above significance by dehydrogenating steroids of the general formula <FORM:0906443/IV (b)/6> wherein R, R1, R11 and X have the above significance, by growing Bacillus sphaericus micro-organisms; for the preparation of steroids of the general formula <FORM:0906443/IV (b)/7> wherein R, R11 and X have the above significance and Ac represents an acyloxy radical, by treating steroids of the general formula <FORM:0906443/IV (b)/8> wherein R, R11 and X have the above significance and Ac represents an acyloxy radical, with bromine to form 2,4-dibromo-steroids of the general formula <FORM:0906443/IV (b)/9> wherein R, R11 and X have the above significance and Ac represents an acyloxy radical, and dehydrobrominating the 2,4 - dibromo-steroids with dimethyl-aniline in dimethyl formamide; and for the preparation of 21-hydroxy steroids by the alkaline hydrolysis of steroids of the general formula <FORM:0906443/IV (b)/100> wherein R, R11 and X have the above significance and Ac represents an acyloxy radical. 16b -Alkyl-4-bromo-17a ,21-dihydroxypregnane-3,11,20-trione 21-acylate is prepared by reacting 3a -acyloxy-16-pregnene-11,20-dione with diazoalkanes such as diazomethane and diazoethane, to form 3a -acyloxy-16a ,17a -alkylene-azopregnane-11,20-dione, heating this compound to form 3a -acyloxy-16-alkyl-16-pregnene-11,20-dione (and a small quantity of each of the two isomeric compounds, namely a 3-acyloxy - 16a ,17a  - alkylenepregnane-11,20-dione and a 3-acyloxy-16-alkylene-pregnane-11,20-dione having respectively the general formulae <FORM:0906443/IV (b)/111> wherein R111 represents hydrogen or an alkyl radical, the latter compound may be converted to a 16a -alkyl-3a -hydroxy-16-pregnene-11,20-dione by treating the said compound with an alkali metal hydroxide), epoxidising the 3a -acyloxy - 16 - alkyl-16-pregnene-11,20-dione to form 16b  - alkyl - 16a ,17a - epoxy - 3a  - hydroxypregnane-11,20-dione (this compound may then be acylated at the 3-position), treating the 16a , 17a -epoxy compound with a strong inorganic acid such as perchloric acid, to form a mixture of 16-alkyl-3a ,17a -dihydroxy-15-pregnene-11,20-dione and 16-alkylene-3a ,17a -dihydroxy-pregnane - 11,20 - dione having respectively the formulae <FORM:0906443/IV (b)/122> wherein R has the above significance and R111 represents hydrogen or an alkyl radical, treating the 16b -alkyl-16a ,17a -epoxy-3a -hydroxypregnane-11,20-dione referred to above with hydrogen bromide in a carboxylic acid forms 3a  - acyloxy-16-alkylene-17a -hydroxy-pregnane-11,20-dione uncontaminated with the 15-pregnene isomer but there is also produced 3a  - acyloxy - 16 - alkyl-15-bromo-16-pregnene-11,20-dione of the formula <FORM:0906443/IV (b)/133> wherein R represents an alkyl radical, hydrogenating the mixture of 16-alkyl-3a ,17a -dihydroxy - 15 - pregnene - 11,20 - dione and 16-alkylene-3a ,17a -dihydroxy-pregnane-11,20-dione with hydrogen in the presence of a hydrogenation catalyst forms a mixture of 16a -alkyl- and 16b  - alkyl - 3a ,17a  - dihydroxypregnane-11,20-dione (the same mixture is also obtained by hydrogenating 16b  - alkyl - 16a ,17a  - epoxy-3a -hydroxypregnane-11,20-dione referred to above under acidic conditions, or by hydrogenating the 16 - alkylene - 3a ,17a  - dihydroxypregnane-11,20-dione referred to above under acidic conditions), brominating the mixture or the separated components at the 21-position to form 16a  - alkyl- and 16b  - alkyl - 21 - bromo-3a ,17a -dihydroxypregnane-11,20-dione, reacting these components with potassium acylate to form the corresponding 21-acylates (at this stage the epimeric mixture may be separated or carried further), oxidising the epimers to form 16a -alkyl-and 16b -alkyl-17a ,21-dihydroxypregnane-3,11,20-trione 21-acylates (an epimeric mixture may be separated at this stage), and finally treating the 16b -alkyl-17a ,21-dihydroxypregnane-3,11,20-trione with bromine to form the desired 16b -alkyl-4-bromo-17a ,21-dihydroxypregnane-3,11,20-trione 21-acylate.