Patent GB-946659-A (GB)
Title: 18-oxygenated steroids and process for their manufacture
IPC: C07J71/00
Filed: 1960-02-12
Abstract: The invention comprises (1) a process for the preparation of 18-hydroxy-20-oxo-pregnanes, 18, 20-dioxo-pregnanes and 18, 20- or 18, 11-lactones of pregnane-18-acids wherein an 18, 20-dihydroxy-pregnane is treated with an oxidizing agent capable of dehydrogenating an alcohol to form a carbonyl compound and, if desired, in a resulting oxidation product, if desired, after the introduction of a 4, 5-double bond by bromination and dehydrobromination and/or ketalization in the 3-, 18- and/or 20-positions of oxo groups formed, any 11-oxo group present is reduced to the 11 b -hydroxy group and, if desired, an 18, 11-lactone of an 11b , 20-dihydroxy-pregnane-18-acid formed is oxidized to a corresponding 20-oxo compound; and (2) 3, 18, 20-trioxo-5a -pregnane; 3, 11, 18, 20-tetraoxo-5 b -pregnane and ketals thereof; 3, 18, 20-trioxo-11b -acetoxy-5a -pregnane and ketals thereof; the 18-->20-cyclohemiketal of 3, 11, 20-trioxo-18-hydroxy-5 b -pregnane; and 18, 20-lactones of 20-hydroxy-pregnane-18-acids saturated in the 20-position. Oxidizing agents referred to are compounds of hexavalent chromium and N-halogen carboxylic acid amides and imides, the products depending on the agent and conditions used.  The use of chromium trioxide in acetic acid or in acetone and sulphuric acid gives, as main product, lactones of 20-hydroxy-pregnane-18-acids, and, in smaller quantities, 18, 20-dioxo compounds and 18-hydroxy-20-ketones (which may be present in the form of their 18-->20 cyclo-hemiketals) the last two groups of compounds being formed primarily when mild oxidation with chromium trioxide in pyridine is used.  Free 3- and 11-hydroxy groups are oxidized in these processes, the starting materials for which may be steroids of the 5a - or 5b -pregnane series which may contain further substituents in the ring system, such as free, esterified or etherified hydroxyl groups or free or ketalized oxo groups. Products unsubstituted in the 11-position may be oxidized with the aid of microorganisms.  In examples (1) 3b , 18, 20-trihydroxy-5a -pregnane is oxidized to 3, 18, 20-trioxo-5a -pregnane; 3b , 18, 20-trihydroxy-11b -acetoxy-5a -pregnane is oxidized to 3, 18, 20-trioxo-11b -acetoxy-5a -pregnane, this is converted to 3, 18, 20-tris-ethylenedioxy-11b -acetoxy-5a -pregnane, the 11b -acetoxy group and then the ketal groups are hydrolysed to give the 11-->18-hemiacetal of 3, 18, 20-trioxo-11b -hydroxy-5a -pregnane and this is oxidized to the 11-->18-lactone of 3, 20-diketo-11b -hydroxy-5a -pregnane-18-acid; and 3a , 11a , 18, 20-tetrahydroxy-5b -pregnane is oxidized to 3, 11, 18, 20-tetraoxo-5b -pregnane, this is converted to 3, 18, 20-trisethylenedioxy-11-keto-5b -pregnane, this is reduced to the 11 b -ol, this is hydrolyzed to the 11-->18-hemiacetal of 3, 18, 20-trioxo-11b -hydroxy-5b -pregnane, this is oxidized to the 11-->18-lactone of 3, 20-diketo-11b -hydroxy-5b -pregnane-18-acid, this is brominated to the 4-bromo compound, and this dehydrobrominated to give the 11-->18-lactone of D 4-3, 20-diketo-11b -hydroxy-pregnene-18-acid; (2) D 4-3-keto-11b , 18, 20-trihydroxy-pregnene is oxidized to D 4-3, 11, 18, 20-tetraoxo-pregnene; (3) 3a , 11a , 18, 20a -tetrahydroxy-5b -pregnane is oxidized to the 18-->20-lactone of 3, 11-diketo-20a -hydroxy-5b -pregnane-18-acid, this is brominated and dehydrobrominated to the 18-->20-lactone of D 4-3, 11-diketo-20a -hydroxy-pregnene-18-acid, this is converted to the 18-->20-lactone of D 5-3-ethylenedioxy-11-keto-20a -hydroxy-pregnene-18 -acid, this is reduced to the 18-->11-lactone of D 5-3-ethylenedioxy-11b , 20a -dihydroxy - pregnene-18-acid this is oxidized to the 18-->11-lactone of D 5-3-ethylenedioxy-11b -hydroxy-20-keto-pregnene-18 -acid and this is converted to aldosterone 21-acetate via the 21-oxalo-ester, the 21-acetate and the 18-->11-lactone of D 4-3, 20-diketo-11b , 21-dihydroxy-pregnene-18-acid which is ketalized, reduced, acetylated and hydrolysed in known manner; (4) the starting material of (3) is oxidized to the first-mentioned product of (3), the 18-->20-cyclohemiketal of 3, 11, 20-triketo-18-hydroxy-5b -pregnane and 3, 11, 18, 20-tetraoxo-5b -pregnane; (5) 3, 11-diketo-18, 20a -dihydroxy-5b -pregnane is oxidized to the first-named product of (3); and (6) the starting material of (1) is oxidized to 20a -hydroxy-3-keto-5a -pregnane-18-acid-lactone, this is reduced and acetylated to 3b -acetoxy-20a -hydroxy-5a -pregnane-18-acid-lactone and this is reduced to the starting material viz. 3b , 18, 20a -trihydroxy-5a -pregnane. Specifications 946,656, 946,657, 946,658 and 946,659 are referred to.