Patent GB-910768-A (GB)
Title: Aminosteroid compounds and process for their manufacture
IPC: C07J41/00
Filed: 1958-12-11
Abstract: The invention comprises (1) a process wherein a 20-(N-halogen-secondary amino)-pregnane is treated with a concentrated mineral acid and the 18-halogeno-20-secondary amino-pregnane formed is isolated or treated with an alkaline agent to give an 18,20-iminopregnane; and (2) as new compounds, the starting materials and intermediates of the above process, and the final products containing in the 3-position a free or functionally converted hydroxyl or oxo group, and, additionally, 18,20-imino-N-methyl-allopregnane.  The treatment with concentrated mineral acid may be effected with sulphuric acid in an anhydrous organic acid, and may be performed in the presence of ultraviolet light and/or a metal salt catalyst.  The alkaline agent used for the second stage is preferably an alkali metal alcoholate.  The starting materials are prepared from corresponding non-halogenated 20-secondary amino-pregnanes and hypohalous acids or N-halogen amides or imides.  They may be of the pregnane, allopregnane or 21-norpregnane series and may contain free or functionally converted hydroxyl or oxo groups i.e. esterified or etherified hydroxyl groups or ketalized or enolized oxo groups or oximes, hydrazones or semicarbazones, or the corresponding thio analogues, halogen atoms or alkyl groups in one or more of the positions 2, 3, 4, 6, 9, 11, 12, 17 or 21 and/or double bonds in one or more of the positions 1, 4, 5, 9(11), 11, 14 or 16.  In Examples (1) 3b -acetoxy-20-keto-allopregnane and hydroxylamine hydrochloride give 3b -acetoxy-20-keto-allopregnane oxime, this on catalytic hydrogenation gives 3b  - acetoxy - 20a  - amino-allopregnane acetate, from which the free base is isolated and converted to 20a -formylamino-3b -acetoxy-allopregnane, this is reduced to 20a -N-methylamino - 3b  - hydroxy - allopregnane, this is oxidized to 20a -N-methyl-amino-3-keto-allopregnane, this with N-chlorosuccinimide gives 20a  - (N - chloro-N-methyl-amino)-3-oxo-allopregnane and this with sulphuric acid and then sodium hydroxide gives 18,20-imino-N-methyl-3-oxo-allopregnane, separated from the 18-unsubstituted secondary amine also formed by conversion of the latter to 20a -(N-acetyl-N-methyl-amino)-3-oxo-allopregnane; (2) methylamine and D 5-3b -acetoxy-etiocholenic acid chloride (prepared from the acid) give D 5-3b -acetoxy-etiocholenic acid N-methylamide, this on reduction gives D 5-20-methylamino-3b -hydroxy-21-nor-pregnene, this is oxidized to D 4-20-methylamino-3-oxo-21-nor-pregnene, this with N-chlorosuccinimide gives D 4-20-(N-chloro-N-methyl-amino)-3-oxo-21-nor-pregnene and this as in (1) gives the 18,20-imino product; (3) and (4) 20a -N-methylamino-3-oxo-allopregnane is heated in ethanol and ethylene glycol with hydrazine hydrate and KOH to give 20a -N-methylamino-allopregnane, this with N-chlorosuccinimide gives 20a -(N-chloro-N-methyl-amino)-allopregnane and this by the process of the invention gives 18-chloro-20a -methylamino-allopregnane (which is isolated as a sulphate and which with sodium nitrite in hydrochloric acid gives 18-chloro-20a -N-nitroso-N-methyl-allopregnane) and 18,20-imino-N-methyl-allopregnane (also prepared by treating dihydroisoconessimine with N-chlorosuccinimide to give a steroid of the formula <FORM:0910768/IV (b)/1> heating this with sodium in methanol and then treating with sulphuric acid to give 18,20-imino-N-methyl-3-oxo-allopregnane and removing the 3-keto group from this by the hydrazine hydrate method outlined above); and (5) 20a -N-methyl-amino-3b -acetoxy-allopregnane is prepared from the 3b -ol and is converted to the N-chloro-compound and then this by the process of the invention to the 18,20-imino-compound, and D 5-20a -(N-chloro-N - methyl - amino)-3b -acetoxy-pregnene (prepared as in (1) from D 5-3b -acetoxy-pregnene-20-one) is also converted by the process of the invention to the 18,20-imino-compound.  Some of the above processes are also described in more general terms, and a list of acylating acids and ether-, enol-ether- and acetal-forming groups is provided.