Patent GB-784855-A (GB)
Title: Manufacture of methyl steroids
IPC: C07J5/00
Filed: 1954-01-28
Abstract: The invention comprises saturated and unsaturated 14-methylpregnane compounds containing free or functionally converted hydroxy or oxo groups in the 3- and 20-positions (with or without other substituents, viz., further free or functionally converted hydroxy or oxo groups, especially in the 21- and/or 11-position, or a free or esterified hydroxy group or a hydrocarbon radical in the 17-position); and the preparation thereof by treating a D 3(5)-3 : 14-dimethyl-A-norpregnene compound, containing a free or functionally converted hydroxy or oxo group in the 20-position, with an oxidizing agent suitable for splitting a C-to-C double bond, and condensing the 5-oxo group in the resulting 4 : 5-seco-3 : 5-dioxo-14-methylpregnane compound with the 4-methyl group by means of an alkaline condensing agent, followed, if desired, by interconversion of any free or functionally converted hydroxy or oxo group (especially conversion of a D 4-3-oxo compound into a D 5-3-hydroxy compound by formation of the 3-enol acetate and subsequent reduction), and/or by saturation of the 4 : 5- or 5 : 6-double bond with hydrogen.  Suitable oxidizing agents are hexavalent chromium compounds, permanganate, ozone, or peroxide compounds (advantageously in the presence of osmium tetroxide), and, depending on the agent chosen, the 3 : 5-double bond is split up directly or with intermediate formation of ozonides, glycols or oxides, the ozonides being split hydrolytically or oxidatively, the oxides hydrolysed to glycols, and the glycols split by means of, for example, chromic acid, lead tetracetate or periodic acid. As alkaline condensing agents, which may be used in an anhydrous solvent or in aqueous solution, are specified alkali and alkaline-earth metal hydroxides and alcoholates, and strong organic bases such as secondary and tertiary amines and quaternary ammonium hydroxides.  In examples: (1) D 3(5)-3 : 4-dimethyl-11-oxo-20 - acetoxy - A - norpregnene is treated with osmium tetroxide in pyridine, the product is refluxed with mannitol and potassium hydroxide in benzene and ethanol, the resulting glycol is oxidized with lead tetracetate in chloroform and glacial acetic acid, and the oxidation product is shaken with potassium hydroxide in dioxane to form D 4 - 3 : 11 - dioxo - 14 - methyl - 20 - hy - droxypregnene, which is oxidized with chromic acid in acetic acid to 14-methyl-11-oxoprogesterone (purified by chromatography); the D 4-3-oxo compound can be converted to the corresponding D 5-3-hydroxy compound via the D 3(4) : 5(6)-3-enol acetate; (2) 14-methyl-11-oxoprogesterone is shaken with palladiumbarium sulphate catalyst in ethyl acetate in a hydrogen atmosphere to produce 14-methyl3 : 11 : 20-trioxopregnane.  Starting materials.  D 3(5)-3 : 14 - Dimethyl-Anorpregnene compounds are obtainable by conversion of the 3-hydroxy-4 : 4-dimethyl grouping present in the tetracyclic triterpenes (e.g. lanosterol and its derivatives degraded in the side chain) according to the following reaction scheme: <FORM:0784855/IV (a)/1> The preparation of the starting material of Example (1) from 4 : 4 : 14-trimethyl-3-hydroxy11 : 20-dioxopregnane (obtainable from lanosterol by the process of Specification 779,941) is described in detail, the intermediate products being 3-isopropylidene-14-methyl-11 : 20-dioxo-A - norpregnane, 3 - isopropylidene - 14 - methyl - 11b  - hydroxy - 20 - acetoxy - A - norpregnanes (by an intermediate partial reduction and esterification, not shown above), 14-methyl-3-oxo-11b - hydroxy - 20 - acetoxy - A - norpregnanes and 3 : 14 - dimethyl - 11 - oxo - 3 - hydroxy-20-acetoxy-A-norpregnane (after reoxidation of the 11b -hydroxy group).