Patent GB-941140-A (GB)
Title: 18- and 19-oxygenated steroids and a process for their manufacture
IPC: C07J5/00
Filed: 1961-04-14
Abstract: The invention comprises (1) a process for the preparation of steroids of the partial formulae <FORM:0941140/C2/1> <FORM:0941140/C2/2> (wherein X is an oxo group, or a hydrogen atom together with a hydroxyl group or an acyloxy group) which may contain a double bond in the 4, 5- or 5, 6-position, wherein an 11b -hydroxy steroid containing 10- and 13-unsubstituted methyl groups is treated with a lead tetraacylate in the presence of iodine and the product is oxidized, hydrolysed or acylated and, if desired, an 18- or 19-acyloxy compound so obtained is hydrolysed and/or a corresponding hydroxy compound so obtained is oxidized; and (2) as new classes of steroids, 18-unsubstituted 19-hydroxy-11b , 19-oxido-steroids and their 19-esters; 19, 11-lactones of 18-unsubstituted 11b -hydroxy-steroid-19-acids; 19, 21-unsubstituted 3, 18-dihydroxy-11b , 18-oxido-20-oxo-pregnanes and their 20-ethylene ketals, and esters thereof; 19-unsubstituted 3, 20-dioxo-11b , 18-oxido-18, 21-dihydroxy-pregnanes saturated in the 5-position and their ethyleneketals, and esters thereof; 18, 11-lactones of 9, 19-unsubstituted 3, 20-dioxo-11b , 21-dihydroxy-pregnane-18-acids saturated in the 5-position and their ethylene-ketals, and esters thereof; and the 18, 11-lactone of 3a -hydroxy-11 b -hydroxy-20-oxo-5b -pregnane-18-acid and the 3-acetate thereof.  It is state that in the process of the invention there are obtained 18-iodo-18, 11 b -oxido- and 19-iodo-19, 11 b -oxido-steroids, the main product depending primarily on the conformation of the A and B rings, which by direct hydrolysis or by replacement of the iodine atom by an acyloxy group followed by hydrolysis are converted to 18-hydroxy-18, 11 b -oxido- and 19-hydroxy-19, 11 b -oxido-steroids. These, or the iodo compounds, may then be oxidized to 18, 11b -lactones of the steroid 18-acids or 19, 11b -lactones of the steroids 19-acids. The process may be applied to steroids of the androstane, pregnane, cholane, cholestane, stigmastane, spirostane and cardanolide series which may contain free or functionally converted oxo groups (ketals, enol ethers and enol esters), esterified or etherified hydroxyl groups, alkyl groups or halogen atoms in one or more of positions 1, 2, 3, 4, 5, 6, 7, 8, 9, 12, 14, 15, 16, 17 and 21.  In examples (1) 3a -acetoxy-11, 20-dioxo-5 b -pregnane is partially ketalized to the 20-monoethylene-ketal, this is reduced to, 3a -11 b -dihydroxy-20-ethylenedioxy-5- b pregnane this is converted to the 3a -acetate, this by the process of the invention gives 3a -acetoxy-11b , 18-oxido-18-iodo-20-oxo-5b -pregnane and this on oxidation gives the 18, 11-lactone of 3a -acetoxy-11 b -hydroxy-20-oxo-5b -pregnane-18-acid, 3a -acetoxy-20-oxo-11 b , 19-oxido-5 b -pregnane and 3a -acetoxy-18-hydroxy-20-oxo-11b , 18-oxido-5b -and the 18-glycol ether thereof; (2) the last named product (free ol) of (1) is oxidized to the first named product, which on hydrolysis gives the 3a -ol and then, on oxidation, the 3-one; (3) D 5-3, 20-bis-ethylenedioxy-11 b -hydroxy-pregnan (prepared by reduction of the 11-one) by the process of the invention gives D 5-3, 20-bis-ethylenedioxy-11 b , 19-oxido-19-iodo pregnane, this on hydrolysis gives D 4-3, 20-dioxo-11 b , 19-oxido-19-hydroxy-pregnene and this on oxidation gives the 19, 11-lactone of D 4-3, 20-dioxo-11B-hydroxy-pregnene-19-acid; hydrolysis of the first-named product under different conditions gives 3-ethylenedioxy-11 b , 19-oxido-20-oxo-D 5-pregnene (which on hydrolysis gives 3, 20-dioxo-11b - 19-oxido-D 4-pregnene) and some 3-ethylenedioxy-11-hydroxy - 20 - oxo - D 5-pregnene; (4) corticosterone acetate gives, by the process of the invention, D 4-3, 20-dioxo-11 b , 19-oxido-19 21-diacetoxy-pregnene and the 19, 11-lactone of D 4-3, 20-dioxo-11 b -hydroxy-21-acetoxy-pregnene-19-acid (5) 3, 20-dioxo-11b , 21-dihydroxy-5a -pregnene is ketalized and acetylated to give 3, 20-bis-ethylenedioxy-11 b -hydroxy-21-acetoxy-5a -pregnane, this by the process of the invention gives 3, 20-bis-ethylenedioxy-11b , 18-oxido-18, 21-diacetoxy-5a -pregnane, and this on hydrolysis gives 3, 20-dioxo-11 b , 18-oxido-18-hydroxy-21-acetoxy-5a -pregnane and then the 18, 21-diol; (6) the second named product of (5) is oxidized to the 18, 11-lactone of 3, 20-bisethylenedioxy-11b -hydroxy-21-acetoxy-5a -pregnane-18 -acid and this is hydrolysed to the 18, 11 - lactone of 3, 20 - dioxo - 11b  - hydroxy - 21 -acetoxy-5a -pregnane-18-acid and then the 21-ol; and (7) 3b -acetoxy-11b -hydroxy-20-ethylene-dioxy-5a -pregnane gives, by the process of the invention, 3b -acetoxy-11 b , 19-oxido-20-ethylene-dioxy-5a -pregnane, 3b -acetoxy-11 b , 18-oxido-20-ethylenedioxy-5a -pregnane, 3b , 18a -diacetoxy-11b -18-oxido-20-ethylenedioxy-5a -pregnane, and 3b  - acetoxy - 19 - hydroxy - 11b , 19 - oxido -20-ethylenedioxy-5a -pregnane, all of which are then converted to the corresponding 20-ones, two of these ketones then being oxidized to the 18, 11-lactone of 3b -acetoxy-11b -hydroxy-20-oxo-5a -pregnane-18-acid and the 11, 19-lactone of 3b -acetoxy -11b  - hydroxy - 20-oxo-5a  - pregnane-19-acid. Reference is also made to (a) the formation of D 4-3 - oxo - 11b , 19 - oxido-17, 19-dihydroxy-androsten or the 19, 11-lactone of D 4-3-oxo-11b -17b -dihydroxy-androstene-19-acid by the process of the invention and the conversion of the latter to D 4-3-oxo-11b , 17b -dihydroxy-19-nor-androstene, which, via the 11-ketone of the D 5-3-ketal is converted to 19-nor-testosterone; (b) the similar conversion of the 19, 11-lactone of D 4-3, 20-dioxo-11b -hydroxy-pregnene-19-acid to 11 b -hydroxy-19-nor-progesterone, and of 11 b -hydroxy-diosgenin via D 5-3b -acetoxy-11 b , 19-oxido-19-hydroxy-spirostene and D 4-3-oxo-11b -hydroxy-19-nor-spirostene to 11 b -hydroxy-19-nor-progesterone; (c) bromination and dehydro bromination of the 3-one of (2) to give the 18, 11-lactone of D 4-3, 20-dioxo-11 b -hydroxy-pregnene-18-acid, similar conversion of the penultimate product of (6) to the corresponding D 4-3-ketone which on ketalization yields the 18, 11-lactone of D 5- 3 - ethylenedioxy - 11b  -hydroxy-2b -oxo-21-acetoxy-pregnene-18-acid; (d) conversion of 3, 20-dioxo-11 b , 18-oxido-18, 21-dihydroxy-5b -pregnane into an aldosterone 18, 21-diacylate by esterification, bromination and dehydrobromination; (e) similar conversion of the final product of (5) into aldosterone; and (f) reduction of the final product of (6) to 4, 5-dihydro-aldosterone, esters of which are also referred to.