Patent GB-641618-A (GB)
Title: Manufacture of pregnane derivatives substituted in the 21-position
IPC: C07J75/00
Filed: 1947-12-13
Abstract: Pregnane derivatives substituted in the 21-position are obtained by treating a D 20 : 23-21-halogen-choladiene in either order of succession with (a) an agent known to be capable of exchanging an aliphatically bound halogen for a free, esterified or etherified hydroxyl group, e.g. a hydrolysing agent such as an aqueous solvent, a re-esterifying agent such as a salt of a carboxylic or sulphonic acid or an etherifying agent such as an alcohol, a phenol, a tetracyl-glucose or a heptacyl-lactose, and (b) an agent known to be capable of bringing about the oxidative degradation of the side-chain to form a 20-ketone, e.g. a compound of hexavalent chromium, such as chromic acid; permanganate; ozonisation and splitting of the ozonide, the action of peroxides and the oxidation of the glycol formed by the hydrolysis of the oxido ring or by the direct addition of two hydroxyl groups to each of the double bonds.  During the oxidation the double bonds in the cyclopentano-polyhydrophenanthrene nucleus are preferably protected by reaction with halogen or halogen hydride and oxidizable substituents such as hydroxyl groups particularly a free hydroxyl group in the 21-position may also be protected, e.g. by esterification or etherification. These groups may be wholly or partly regenerated at any desired reaction stage.  A free carbinol group in the ring may be converted to a keto group concurrently with the oxidative degradation of the side chain, or in a separate reaction.  In examples: (1) D 20 : 23-3 : 12-diacetoxy-21-bromo-24 : 24-diphenylcholadiene is converted to the 21-acetoxy derivative and oxidized to 3 : 12 : 21-triacetoxy-pregnane-20-one which may be hydrolysed to the 3 : 12 : 21-trioxy compound; (2) D 20 : 23-3 : 12-diacetoxy-21-bromo-24 : 24-diphenylcholadiene is oxidized and treated with potassium acetate and glacial acetic acid to give 3 : 12 : 21 - triacetoxy-pregnane-20-one; (3) D 20 : 23-3-keto-12-acetoxy-21 - bromo - 24 : 24 - diphenylcholadiene is converted to 3 : 20-diketo-12 : 21-diacetoxy-pregnane; (4) D 20 : 23-3-keto-12-p-toluenesulphoxy-21 - bromo - 24 : 24 - diphenylcholadiene is converted to D 11-21-acetoxy-pregnene-3 : 20-dione; (5) D 20 : 23-3 : 12-diacetoxy-21-bromo-24 : 24-diphenylcholadiene is converted to 3 : 12-diketo-21-ethoxy-pregnane-20-one; (6) D 20 : 23-3-acetoxy-5-chloro-21-bromo-24 : 24-diphenylcholadiene is converted to D 4-21-methoxy-pregnene-3 : 20-dione; (7) D 20 : 23-3-oxy-5-chloro-21-methoxy-24 : 24-diphenylcholadiene, obtained from the 21-bromo compound is converted to the product of (6); (8) D 4 : 20 : 23-3-keto-21-bromo-24 : 24-diphenylcholatriene is converted to D 4-21-acetoxy-pregnene-3 : 20-dione; (9) D 11 : 20 : 23-3-keto-21-bromo-24 : 24-diphenylcholatriene is converted to D 11-21-acetoxy-pregnene-3 : 20-dione; (10 D 20 : 23-3 : 11-diketo-21 - bromo - 24 : 24 - diphenylcholadiene is converted to 21-acetoxy-pregnene-3 : 11 : 20-trione and (11) D 4 : 20 : 23-3 : 11-diketo-21-bromo-24 : 24-diphenylcholatriene is converted to D 4-21-acetoxy-pregnene-3 : 11 : 20-trione.  Samples have been furnished under Sect. 2 (5) of the Acts which are prepared as follows: (1) D 20 : 23-3-keto-12 : 21 - diacetoxy - 24 : 24-di-phenyl-choladiene prepared as in example (3) is hydrolysed to the 12 : 21-dioxy compound, partially esterified to the 12-oxy-21-succinyloxy compound which is then completely esterified on the 12-position with p-toluene sulphonic acid chloride and this mixed ester oxidized with chromium trioxide to D 11-3 : 20-diketo-21-succinyloxy-pregnene.  This is hydrolysed and re-esterified to D 11-3 : 20-diketo-21-acetoxy-pregnene.  (2) The methyl ester of 3 : 20-diketo-12-p-toluene sulphoxy-21-succinyloxy pregnane obtained is brominated, treated to remove hydrobromic acid to obtain D 4 : 11-3 : 20-diketo-21-oxy-pregnadiene which is then acetylated to the corresponding 21-acetoxy compound.  Specifications 624,047 and 641,617 are referred to.