Patent GB-1011121-A (GB)
Title: Steroidal alkaloids
IPC: A61K31/57
Filed: 1962-06-01
Abstract: The invention comprises methylhola-phylline (3b  - dimethylamino - 20 - oxo - pregna - 5 - ene) having the following properties: formula C23H37ON, melting point 121 DEG  C., and (a )D= +30.4 DEG  (in CHCl3 C=0.86), and 3,5-cyclo-6b -dimethylamino - pregnan - 20 - one having the following properties: formula C23H37ON, melting point 109-110 DEG C., and (a )D=+128 DEG  (in CHCl3 C=0.86); a process for the preparation of 3 - amino-, 3 - methylamino- or 3 - dimethylamino-pregna-5-ene and the corresponding hydrochloride salts by reacting pregnenolone tosylate (obtainable by reacting pregnenolone and p-toluene sulphonyl chloride) with liquid ammonia, methylamine or dimethylamine respectively and, when required, converting the bases to hydrochloride salts; a process for the preparation of 3b  - dimethylamino - 20 - oxo - pregna-5-ene by heating the corresponding 3b -monomethylamino compound with formic acid and formaldehyde; a process for the preparation of 3,5 - cyclo - 6b  - dimethylamino - pregnan-20-one by reacting pregnanolone tosylate with dimethylamine, adding hydrochloric acid to precipitate hydrochloride salts, dissolving the hydrochlorides in methanol, diluting the resulting solution with water, making it alkaline, extracting the alkaline solution with ether, washing, drying and distilling the ether, passing the residue over alumina, eluting the alumina with ether and recrystallizing the product obtained from the ether with methanol; a process for the preparation of a hydrochloride of holaphyllamine and a hydrochloride of 3,5-cyclo - 6b  - amino - pregnan - 20 - one by reacting lithium azide in a methanolic solution with 3b  - tosyloxy - 20 - ketoximo - 5 - pregnene (obtained by the reaction of pydroxylamine hydrochloride and pregnenolone tosylate), reducing the resulting 3-azido derivative with lithium aluminium hydride, hydrolysing the 20-ketoxime group, adding hydrochloric acid, separating the hydrochloride of holaphyllamine and the hydrochloride of 3,5 - cyclo - 6b  - amino - pregnan-20-one by chromatography; a process for the preparation of 3a -amino-20-ketoximo-pregn-5-ene by reacting 3b -tosyloxy-20-ketoximo-pregn-5-ene with sodium azide in dimethylsulphoxide to form 3a -azido-20-ketoximo-pregn-5-ene, reducing this compound with lithium aluminium hydride, decomposing excess hydride with ether and water to obtain a precipitate of 3a -amino-20-ketoximo-pregn-5-ene, dissolving the precipitate in hydrochloric acid and then adding alkali; a process for the preparation of holaminol by reacting pregnenolone tosylate with sodium azide in dimethylsulphoxide at a temperature of about 90 DEG C., adding water to the reaction mixture, cooling, extracting the product with an ether-benzene mixture and reducing the dried residue obtained from the extract with lithium aluminium hydride; a process for the preparation of 3,5-cyclo-6,20-dioxo-pregnane by mixing pregnenolone tosylate and potassium acetate, refluxing this mixture in aqueous acetone, removing the acetone, extracting the residue with ether, washing, drying and distilling the extract, and recrystallizing the residue from ethanol and oxidizing the resulting 3,5 - cyclo - pregnan - 6b  - ol - 20 - one with chromium trioxide; and a process for the preparation of holaphylline by reacting dimethylamine and progesterone, reducing the resulting 3-enamine with potassium borohydride, treating the resulting 3b -dimethylamino-20-hydroxy-pregn-5-ene with acetic anhydride to form the corresponding 20b -acetoxy compound treating this compound with cyanogen bromide to form the corresponding 3-cyanamide compound, saponifying this compound and oxidizing the resulting 3b -methylamino-20-hydroxy-pregna-5-ene. In the above process using pregnenolone tosylate and ammonia as the reactants, 3b -amino-20-oxo-pregna-5-ene and the by-products D 3-5 pregnadien - 20 - one and 3b  - hydroxy - 17 - iso - D 5 - pregnen - 20 - one are formed when liquid ammonia and heating under pressure are employed in the reaction, and 3a -amino-20-oxo-pregna-5-ene is obtained when a major amount of liquid ammonia and a minor amount of toluene and heating under pressure are employed in the reaction.  Specification 948,485 is referred to.