Patent GB-748236-A (GB)
Title: A steroid compound and the preparation thereof
IPC: C07J75/00
Filed: 1953-10-26
Abstract: The invention comprises 11b ,17a -dihydroxy-4-pregnene-3,20-dione and the preparation thereof by heating 17a  - hydroxypregnane - 3,11,20-trione with an alkanediol in the presence of an acid catalyst to produce the 3,20-cyclic diketal thereof which is reduced with an alkali metal aluminium hydride or an alkali metal borohydride or by means of hydrogen in the presence of a hydrogenation catalyst to produce an 11b ,17a -dihydroxy-dihydroxy-pregnane - 3,20 - dione 3,20 - cyclic diketal, the diketal is hydrolysed with dilute mineral acid or a strong organic acid in the presence of water to form 11b , 17a -dihydroxypregnane-3,20-dione which is reacted with chlorine or bromine to produce 4-chloro (or bromo)-11b ,17a -dihydroxy-pregnane-3,2;-dione, the 4-halo compound is treated with a substituted hydrazine one primary amino nitrogen atom in the hydrazine group to form a 3-hydrazone derivative of 11b , 17a  - dihydroxy - 4 - pregnene - 3,20 - dione which is then treated with pyruvic acid or aldehyde or a substituted benzaldehyde, such as the p- and m-hydroxy- and the p- and m-carboxy-benzaldehyde, to form the desired 11b ,17a -dihydroxy - 4 - pregnene - 3,20 - dione.  Suitable alkane diols for use in the first step of the above process may be of the formula <FORM:0748236/IV(a)/1> wherein R and R1 represent hydrogen or alkyl radicals (preferably alkyl radicals containing 1 to 6 carbon atoms such as the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, amyl and hexyl radicals), n is 0 or an integer-preferably the alcohol contains not more than 8 carbon atoms, diols mentioned being ethylene glycol propane - 1,2 - and - 1,3 - diol, butane - 1,3 -, -2,3- and -1,2-diol, pentane-1,2- and -1,3-diol, 3 - methyl - pentane - 1,2 - diol, hexane - 1,2 - and -1,3-diol, heptane-1,2- and -1,3-diol and octane-1,2- and -1,3-diol.  The acid catalyst may be a mineral acid, e.g. hydrochloric or sulphuric acid or an organic sulphonic acid, e.g. m- and p-toluenesulphonic acid, naphthalenesulphonic acid, benzenesulphonic acid and o-chlorobenzensulphonic acid.  The first step of the process is preferably carried out in an inert organic solvent-a solvent which co-distills with water being particularly useful.  The reduction may be carried out with lithium aluminium hydride, lithium or sodium borohydride or hydrogen in the presence of platinum or Raney nickel. Suitable acids to hydrolyse the ketal groups are dilute hydrochloric, sulphuric and phosphoric acids, or p-toluenesulphonic acid in the presence of water.  The halogenation to introduce the 4-chloro- or-bromo-substituent is preferably carried out by dissolving the 11b ,17a  dihydroxypregnane - 3,20 - dione in an organic solvent such as acetic acid, dichloromethane, chloroform, carbon tetrachloride, t.-butyl alcohol, N,N-dimethylformamide; N,N-dimethylacetamide or other N,N-dialkylacylamide, and to this solution is added the halogen, either as such or as a solution in the same solvent.  The dehydrohalogenation step may be carried out with semicarbazide, phenylhydrazine, 2,4-nitrophenylhydrazine, p-nitrophenylhydrazine, a - or b -naphthylsemicarbazide or 2,4- or 3,5-dinitrophenylsemicarbazide-preferably using an inert organic solvent such as acetic acid, acetone, dioxane, t.-butyl alcohol, methylene dichloride or mixtures of these solvents.  The last step is preferably carried out with pyruvic acid in aqueous organic solvents such as dioxane-water solution.  It is preferred to use the substituted benzaldehydes in acetic acid solution for the last step. Detailed examples are given in which ethylene glycol and 1,3- and 1,2-propylene glycol are used as the ketal forming agents and semicarbazide is used to form the 3-hydrazone derivative. The Specification also refers to a number of 17a -hydroxypregnane-3,11,20-trione, 3,20-cyclic diketal and 11b ,17a -dihydroxypregnane - 3,20 - dione, 3,20 - cyclic diketal intermediates obtainable by the process referred to above. Specification 748,237 is referred to.