Patent GB-843215-A (GB)
Title: Improvements in or relating to steroid compounds
IPC: C07J5/00
Filed: 1955-08-03
Abstract: The invention comprises a 1,4,9(11)-pregnatriene which is substituted at least by a 17 a -hydroxy group, by a 21-hydroxy group and by keto groups at the 3- and 20- positions and the preparation thereof by treating a correspondingly substituted 11(a  or b )-hydroxy- or 11 a -organo sulphonate-1,4-pregnadiene with an agent known to be capable of removing the 11-substituent and the 9-hydrogen to introduce the 9(11) double bond.  The 21-hydroxy group in the product and reactant may be esterified with an acyl radical e.g. an alkanoyl radical containing not more than 8 carbon atoms.  The preferred 1,4,9(11)-pregnatrienes have the general formula: <FORM:0843215/IV(b)/1> wherein R represents hydrogen or an acyl radical such as an alkanoyl radical containing not more than 8 carbon atoms.  The 21-ester group may be an acetate, propionate, cyclopentylpropionate or enanthate.  The 9(11)-double bond may be formed by treating the 11-hydroxy compound with phosphorus oxychloride in pyridine, or by treating the 11 a -hydroxy compound with an organo-sulphonyl chloride such as p-toluenesulphonyl chloride in pyride, to form the 11 a -organo-sulphonate such as the 11 a -p-toluenesulphonate, and treating the sulphonate with a basic compound e.g., the salt of a strong base and a weak acid such as sodium or potassium acetate or lithium propionate in acetic acid or other alkali metal alkanoate having up to 8 carbon atoms.  The 11 a -methane-sulphonate and the 11 a -benzene-sulphonate may be similarly treated.  It is preferred to carry out the process to form the 9(11) double bond using a reactant containing the 21-ester group obtained by selectively acylating with a carboxylic anhydride in pyridine which may be subsequently hydrolysed to form a free 21-hydroxy compound containing the 9(11)-double bond e.g. by hydrolysis with aqueous methanolic sodium bicarbonate solution under nitrogen.  The invention also includes a process for the preparation of a 21-ester of 9 a -bromo - 1,4 - pregnadiene - 11b ,17 a ,21 - triol -3, 20-dione by treating the 21-esters of 1,4,9(11)-pregnatriene-17 a ,21-diol-3,20-dione of the above general formula with a compound which provides a bromine ion, e.g. N-bromacetamide or N-bromosuccinimide in the presence of a strong acid such as perchloric or sulphuric acid, a process for the preparation of the corresponding 9 a -fluoro-and 9 a -chloro-compounds by treating the 21-esters of 9 a -bromo-1,4-pregnadiene-11b , 17 a ,21-triol-3,20-dione with a weakly basic alkali metal compound to form the corresponding 9,11 - oxido - 1,4 - pregnadiene - 17 a ,21 - diol - 3, 20-dione 21-ester and treating the oxido compound with hydrofluoric and hydrochloric acid respectively, a process for the preparation of 21-ester of 9 a -fluoro-, 9 a -chloro- and 9 a -bromo-1,4-pregnadiene-17 a ,21-diol-3,11,20-trione by treating the above corresponding 11b -hydroxy compounds with chromic acid, and a process for the preparation of the free 21-hydroxy compounds corresponding to all the 9 a -fluoro-, 9 a -chloro-, and 9 a -bromocompounds by hydrolysing the corresponding 21-esters e.g. by means of aqueous acid or sodium bicarbonate.  In the examples:-(1) 1,4,9(11)-pregnatriene-17 a ,21-diol-3,20-dione is prepared by acetylating 1,4-pregnadiene-11b , 17 a ,21-triol-3,20-dione to form the 21-acetate thereof, treating the 21-acetate with phosphorus oxychloride to form 1,4,9(11)-pregnatriene-17 a , 21-diol-3,20-dione 21-acetate, and hydrolysing the 21-acetate; (2) 9 a -fluoro-1,4-pregnadiene11b ,17 a ,21-triol-3,20-dione is prepared by acetylating 1,4-pregnadiene-11 a , 17 a ,21-triol-3,20-dione, treating the resulting 21-acetate with p-toluene-sulphonyl chloride to form 1,4-pregnadiene-11 a ,17 a ,21-triol-3,20-dione 11 a -p-toluene-sulphonate, treating the p-toluene-sulphonate with acetic acid and sodium acetate to form 1,4,9 (11)-pregnatriene-17 a ,21-diol-3,20-dione 21-acetate, treating the 1,4,9(11)-pregnatriene with N-bromacetamide to form 9 a -bromo-1,4-pregnadiene-11 b ,17 a ,21-triol-3, 20 - dione 21 - acetate, treating the 9 a -bromo-compound with anhydrous potassium acetate in methanol to form 9,11-oxido - 1,4-pregnadiene-17 a ,21-diol-3,20-dione 21-acetate, treating the oxido compound with hydrogen fluoride to form 9 a -fluoro-1,4-pregnadiene-11 b ,17 a ,21-triol 21-acetate and hydrolysing to form the corresponding free 21-hydroxy compound; 9 a -fluoro-1,4-pregnadiene-17 a ,21-diol-3,11,20-trione 21-acetate is prepared by oxidizing the corresponding 11 b -hydroxy compound with chromium trioxide and the free 21-hydroxy compound is prepared by hydrolysing the 21-acetate; (3) 9 a -chloro-1,4-pregnadiene-11 b ,17 a ,21-triol-3,20-dione is prepared by treating 9(11)-oxido-1,4-pregnadiene-17 a ,21-diol-3, 20-dione 21-acetate with anhydrous hydrogen chloride to form 9 a -chloro-1,4-pregnadiene 11 b , 17 a ,21-triol-3,20-dione 21-acetate, and hydrolysing the 21-acetate; 9 a -chloro-1,4-pregnadiene-17 a ,21-diol-3,11,20-trione 21-acetate is prepared by oxidizing the corresponding 11 b -hydroxy compound, and the free 21-hydroxy compound is prepared by hydrolysing the 21-acetate.  Specifications 843,213 and 843,217 are referred to.