Patent GB-594878-A (GB)
Title: Manufacture of compounds of the suprarenal cortex hormone series
IPC: A61K31/573
Filed: 1943-10-07
Abstract: Compounds of the suprarenal cortex hormone series are prepared by treating a compound of the cyclopentanopolyhydrophenanthrene series which contains, in the 3-position a free nuclear hydroxyl group, in the 17-position an acyl group having at least one hydrogen atom in a -position to the keto group, and in the 11-position an oxo-group or a hydroxyl group, or a group convertible into a hydroxyl group by hydrolysis or a nuclear double bond at the 11 carbon atom, with a lead tetra-acylate, followed by the oxidation of the 3-hydroxyl group into a keto group if necessary with temporary protection of nuclear double bonds.  If desired the product so obtained may be treated to introduce a double bond in the a -position to the 3-keto group, and also if desired treating the product so obtained with a hydrolysing and/or esterifying agent.  The treatment with the lead tetra-acylate is preferably carried out in a solvent especially the carboxylic acid which corresponds to the acid residue of the lead tetra-acylate used. If desired an inert solvent such as benzene may also be added.  The subsequent oxidation of the 3-hydroxyl group is carried out by any of the usual oxidizing or dehydrogenating methods or agents.  Specified agents and methods include chromic acid in glacial acetic acid, permanganates, heating with a metal or metal oxide, treatment with a metal alcoholate or phenolate in the presence of carbonyl compound, or by the thermal splitting of triarylmethyl ethers.  Any carbon to carbon double bonds may be protected during the above operations by saturation with halogen or halogen hydride and its subsequent removal effected afterwards.  If powerful oxidizing agents are used, any other free hydroxyl groups present may be converted into keto groups, but if complete oxidation of all hydroxyl groups is not desired, a selective oxidation may be carried out by using only a calculated quantity of the oxidizing agent, or more particularly by using a metal alcoholate or phenolate.  If it is desired to introduce a double bond in a -position to the 3-keto group, this may be done by halogenation followed by splitting off of hydrogen halide.  In any subsequent hydrolysis step there are used only acids or very weak alkalies such as bicarbonates. Finally an esterification process may be carried out.  Acid residues mentioned include those of carboxylic acids such as acetic, propionic, butyric, crotonic, palmitic, benzoic or phenyl-acetic acids, polycarboxylic acids such as phthalic or succinic acids, or sulphonic acids methane or toluene sulphonic acids, or carbonic acid, or acids of sulphur, phosphorus or boron. In examples: (1) Pregnane-3 : 11 : 20-trione obtained according to Specification 561,566 is hydrogenated to form pregnane-3b -ol-11 : 20-dione, which is then treated with lead tetra-acetate in glacial acetic acid solution and the chromatographed product oxidized with chromium trioxide in glacial acetic acid to form pregnane 3 : 11 : 20-trione-21-ol-acetate. This is brominated in glacial acetic acid and hydrogen bromide removed with pyridine to give D 4-pregnene-3 : 11 : 20-trione - 21 - ol - acetate (dehydro - corticosterone acetate). Saponification with methyl alcoholic hydrochloric acid gives corticosterone, which may if desired be esterified.  (2) Pregnane-3b  : 11a  - diol - 20 - one obtained from 3b  : 11a -dioxy-bisnorcholonic acid by side chain degradation, is treated with lead tetra-acetate in glacial acetic acid solution as in example (1) and the product oxidized with aluminium phenolate in the presence of acetone to form pregnane-11a  - 21-diol-3 : 20-dione-21-mono-acetate. This is brominated, and hydrogen bromide removed by pyridine to form corticosterone.  If chromic acid is used as the oxidizing agent there is obtained the corresponding 11-keto compound.  (3) 11-Pregnene-3-ol-20-one is heated with an acetic acid solution of lead tetracetate and the product oxidized with chromic acid to form 11-pregnene-3 : 20-dione and 11-pregnene-3 : 20-dione-21-ol-acetate. Specifications 502,474, 524,006 and 536,210 also are referred to.  A sample has been furnished under Sect. 2 (5) of corticosterone acetate prepared as follows:-Pregnane-3a  : 11a -diol-20-one is treated with lead tetra-acetate in glacial acetic acid, and the compound so formed oxidized with aluminium phenolate and acetone to form pregnane-11a  : 21-diol-3 : 20-dione-21-monoacetate, which is then brominated, hydrogen bromide removed with pyridine.  The Specification as open to inspection under Sect. 91 includes also the use in addition to lead tetra-acylates of aryl iodoso acylates as oxidizing agents.  This subject-matter does not appear in the Specification as accepted.