Patent GB-679743-A (GB)
Title: Manufacture of unsaturated 17ª‡-methyl pregnene compounds
IPC: C07J75/00
Filed: 1950-01-30
Abstract: The invention comprises D 4-17a -methyl-3 : 20-diketopregnene and its derivatives substituted in the 21-position by a hydroxy group or a substituent convertible thereto by hydrolysis, and the manufacture of these compounds p  from halides of 17a -methylactiocholanic acids, saturated or unsaturated in rings A and B and containing in the 3-position a keto or hydroxy group or a group convertible thereto by hydrolysis (e.g. an ester, ether, enol, thioenol, acetal or mercaptal group).  The methods of manufacture consist in: (a) treating the acid halide (if desired with protection of any double bond present) with diazomethane to form a methyl ketone substituted in the 21-position by a diazo group (if the diazomethane is used in excess) or a halogen atom (if the diazomethane is added gradually), replacing the 21-substituent by hydrogen or a free or esterified hydroxy group, if necessary converting into a keto or hydroxy group a 3-substituent so convertible at any desired stage in the process, if necessary oxidizing a free hydroxy group in the 3-position to a keto group, and if necessary introducing a double bond in the 4 : 5-position by halogenation and elimination of hydrogen halide; or (b) treating the acid halide with a methyl-metal compound to produce directly the methyl ketone, if desired converting this directly or indirectly into its 21-hydroxy or 21-acyloxy derivative (e.g. by the action of oxidizing agents such as lead tetracylates or aryl-iodoso acylates, or by halogenation and replacement of the halogenatom), and if necessary carrying out the last three steps set out under (a). Replacement of the halogen atom or diazo group in the 21-position by hydrogen may be effected by reduction, e.g. with metals such as zinc, copper, magnesium or their alloys and solvents such as alcohols, aqueous alcohols, acetic acid, acetic and hydrohalic acids, or alkalis, with catalytically activated hydrogen, with aluminium or sodium amalgam, zinc-palladium, alkali iodides and glacial acetic acid, sodium and alcohols, disubstituted anilines, or combinations of these agents, or electrolytically.  The diazo group may be replaced by a hydroxy group by hydrolysis (e.g. with water or dilute acids), and by esterified hydroxy groups by the action of organic or inorganic acids having a low water content (e.g. acetic, propionic, butyric, crotonic, palmitic, benzoic, phenylacetic, hydrochloric, hydrobromic, hydriodic, phosphoric or boric acid).  Halogen may be replaced by a hydroxy or esterified hydroxy group by treatment with, respectively, alkaline agents (e.g. bicarbonates) or salts of the aforementioned acids.  Oxidation of a 3-hydroxy group may be effected with chromic acid in glacial acetic acid, with a dehydrogenating agent (e.g. by heating with copper powder), or with a metal alcoholate or phenolate in the presence of a ketone. In examples: (1) D 5-3b -acetoxy-17a -methylactiocholenic acid chloride is treated with excess of diazomethane in ether, the resulting 21-diazo compound is treated with hydrobromic or hydrochloric acid in ether, the 21-halogen substituent so introduced is replaced by hydrogen by the action of zinc and acetic acid, the acetoxy group is hydrolysed with methanolic caustic potash, and the product is oxidized with cyclohexanone and aluminium tert.-butylate to D 4-17a -methyl-3 : 20-diketopregnene; (2) D 5-3b  - acetoxy - 17a  - methyl - 20 - keto - 21 - chloro - pregnene is prepared as in (1), the acetoxy group is hydrolysed and the resulting free hydroxy group oxidized as in (1), and then the chlorine atom is replaced by hydrogen by the action of potassium iodide and potassium acetate in glacial acetic acid; (3) D 5-3b -acetoxy-17a -methyl-20-keto-21-diazopregnene is treated with methanolic caustic potash to hydrolyse the acetoxy group, then with benzoic or acetic acid in benzene to replace the diazo group by benzoyloxy or acetoxy, the 3-hydroxy group in the 21-acetoxy compound is oxidized with cyclohexanone and aluminium tert.-butylate, and the product is hydrolysed to D 4-17#-methyl - 21 - hydroxy - 3 : 20 - diketopregnene; (4) D 5 - 3b  - acetoxy - 17a  - methylactiocholenic acid chloride is treated with cadmium dimethyl, and the product is hydrolysed with methanolic caustic potash to D 5-3b -hydroxy-17a -methyl-pregnene-20-one, which is oxidized as in (1).  Other methyl-metal compounds which may be used are those of magnesium, zinc, mercury, copper, aluminium, tin and alkali metals, whilst D 4 - 17a  - methyl - 3 - ketoactiocholenic acid chloride is specified as an additional starting material.  D 4 - 17a  - Methyl - 3 - keto- and D 5 - 17a  - methyl-3-acyloxy-actiochenic acid halides are obtainable by halogenating the corresponding 20-ketopregnanes in the 17-position and rearranging the product by the action of sodium bicarbonate in methanol, or by treating a 21-halogen-20-ketopregnane compound with an alkali alcoholate. D 5-3b -acetoxy-17a -methyl-acetiocholenic acid chloride is alternatively prepared by acetylating D  - 3b  - hydroxy - 17a  - methylacetiocholenic acid with acetic acid in pyridine and treating the product with thionyl chloride.