Patent GB-735568-A (GB)
Title: Process of preparing and manufacture of 16-hetero-substituted steroids
IPC: C07J41/00
Filed: 1952-05-13
Abstract: The invention comprises N-substituted 16-amino-10 : 13-dimethylsteroids of the general formula <FORM:0735568/IV (b)/1> (wherein X represents methyl, hydroxymethy or an alkoxy group of 1-3 carbon atoms and Y represents an oxygen atom, or X and Y together represent a nitrogen atom, and <FORM:0735568/IV (b)/2> represents the residue of a primary or secondary amine, and wherein the nucleus may contain a double bond in the 4(5)- or 5(6)-position and/or a keto or hydroxy group or a group hydrolysable to hydroxy in the 3-position), and their salts (e.g. bitartrates, maleates, succinates, hydrochlorides or sulphates), and a process for the manufacture of N-substituted 16-aminosteroids by an addition reaction between a primary or secondary amine and a D 16-steroid containing the group <FORM:0735568/IV (b)/3> in the 17-position, in the presence of a catalyst selected from hydroxides and carbonates of sodium and potassium, sodamide, potassamide, lithamide and their lower (1-3C) alkyl derivatives, quaternary ammonium hydroxides, hydrochloric acid and acetic acid.  When the group <FORM:0735568/IV (b)/4> is -COO Alkyl or -CN it may subsequently be converted to -COCH3 (which is the preferred 17-substituent) by the reaction of methyl magnesium bromide, whilst the nuclear double bond (if any) may be selectively hydrogenated in the presence of a palladium catalyst.  An esterified hydroxy group in the 3-position will be hydrolysed in the course of the reaction, and the resulting hydroxy group, or one present from the start, may be subsequently esterified.  Examples describe the preparation of (1) D 5-16-benzylaminopregnen - 3 - ol - 20 - one from D 5,16-pregnadien-3-ol-20-one and benzylamine in the presence of benzyltrimethylammonium hydroxide; (2) D 5 - 16 - anilinopregnen - 3 - ol-20 - one from D 5,16 - pregnadien - 3 - ol - 20-one acetate and aniline in the presence of caustic potash; (6) to (11) the corresponding a -methylpiperidino, octylamino, pyrrolidino, diethylamino, di-n-heptylamino and isohexylamino compounds similarly; (3) 16-benzylaminoallopregnan - 3b  - ol - 20 - one from D 16-allopregnen-3b -ol-20-one and benzylamine in the presence of caustic potash; (4) D 5-16-methylaminopregnen - 3b  - ol - 20 - one from D 5,16 - pregnadien - 3b  - ol - 20 - one acetate and methylamine in the presence of benzyltrimethylammonium hydroxide; (5) 16 - pentadecylaminoprogesterone from D 5,16 - pregnadien - 3 : 20 - dione and pentadecylamine in the presence of caustic potash; (12) D 5 - 16-piperidinopregnen - 3 - ol - 20 - one from D 5,16-pregnadien - 3b  - ol - 20 - one acetate and piperidine in the presence of caustic potash; (13) D 5 - 16 - (b  - pipecolino) - pregnen - 3 - ol-20 - one from D 5,16 - pregnadien - 3 - ol - 20-one and b -pipecoline in the presence of choline; (14) D 5 - 16 - morpholinopregnen - 3 - ol - 20-one from D 5,16 - pregnadien - 3 - ol - 20 - one acetate and morpholine in the presence of caustic potash; (15) the bi-d-tartrate of the product of (12); (16) the veratric ester of the product of (12) by esterification with veratroyl chloride and pyridine; (17) and (18) the hydrochloride and bi-d-tartrate of the product of (16); (19) 16 - piperidinoallopregnan - 3b  - ol - 20-one by hydrogenating the product of (12) in the presence of 10 per cent palladium-charcoal; (20) D 5 - 16 - piperidinopregnen - 3 - ol - 20 - one 3-glucoside acid maleate from D 5,16 - pregnadien-3 - ol - 20 - one 3 - glucoside - tetracetate and piperidine in the presence of caustic potash, with subsequent treatment with maleic acid; (21) 16-piperidinoallopregnanolone by treating 16 - dehydroallopregnan - 3b  - ol - 20 - one acetate as in (12); (22) 16-g -pipecolinopregnenolone by replacing the b -pipecoline in (13) by g -pipecoline; (23) the acetic ester of the product of (22) by esterification with acetic anhydride and pyridine; (24) 16-piperidino-17-cyano - 5 - androsten - 3 - ol acetate from 17-cyano - 5 : 16 - androstadien - 3 - ol acetate and piperidine in the presence of acetic acid, with-subsequent reacetylation; (25) 16-piperidinopregnane - 3 : 11 - diol - 20 - one (and its hydrochloride) from 16-pregnene-3 : 11-diol-20-one diacetate and piperidine in the presence of caustic potash; (26) 16-cyclohexylamino-4-pregnen-3 : 10 - dione from 4 : 16 - pregnadiene - 3 : 20-dione and cyclohexylamine in the presence of caustic potash; (27) 16-cyclohexylaminoallopregnan - 3 - ol - 20 - one similarly from D 16-allopregnen - 3 - ol - 20 - one; (28) 16 - piperidino - 3 - hydroxy - D 5 - etiocholenic acid methyl ester (and its hydrochloride) from 3-hydroxy - D 5,16 - etiochloadienic acid methyl ester and piperidine in the presence of acetic acid; (29) 16-cyclohexylamino-3-hydroxyetioallocholanic acid methyl ester (and its hydrochloride) similarly from 3-hydroxy-D 16-etioallocholenic acid methyl ester and cyclohexylamine.  D 5,16 - Pregnadien - 3 - ol - 20 - one 3 - glucoside tetracetate is prepared by heating and stirring D 5,16 - pregnadien - 3 - ol - 20 - one with silver carbonate in benzene and gradually adding a benzene solution of tetracetobromoglucose.