Patent GB-852847-A (GB)
Title: Improvements in or relating to 6-methyl steroid compounds
Inventor: KIRK DAVID NEVILLE
IPC: C07J1/00
Filed: 1958-03-04
Abstract: The invention comprises (a) a process for the preparation of 3-oxo-D 1:4-6-methyl and 3-oxo-D 1:4:6-6-methyl steroids by reacting the corresponding 3-oxo-D 4-6-methyl or 3-oxo-D 4:6-6-methyl steroids with 2:3-dicyano-p-benzoquinone, which may additionally be substituted by one or two chlorine atoms, in a solvent; (b) steroids having apart from substituents in the 16- and 17-positions, the general formula:  <FORM:0852847/IV(b)/1> wherein A is hydrogen or a keto or hydroxyl group; and (c) the specific steroids 6a -methylcholesta-1:4-dien-3-one, 6-methylcholesta-1:4:6-trien-3-one, 6a -methyl-25D-spirosta-1:4-dien-3-one, 6-methyl-25D-spirosta-1:4:6-trien-3-one, 6-hydroxy-6-methyl-25D-spirosta-1:4-dien-3-one, 17b -hydroxy-6a -and-6b -methylandrosta-1:4-dien-3-ones, 17b -hydroxy-6-methylandrosta-1:4:6-trien-3-one, 6a - and 6b -methylandrosta-1:4: diene-3:17-diones, 6a  and 6b :17a -dimethyl-17b -hydroxy-androsta-1:4-dien-3-ones, 17b -hydroxy-6:17a -dimethylandrosta-1:4:6-trien-3-one, 17a -Y-17b -hydroxy-6a -methylandrosta-1:4-dien-3-ones (wherein Y is ethynyl ethyl,, vinyl, prop-1-ynyl and but-1-ynyl), 17a -ethynyl-17b -hydroxy-6-methyl-androsta-1:4:6-trien-3-one, 17b -acetoxy-4:6a -dimethylandrosta-1:4-dien-3-one, 17b -acetoxy-2:6a -dimethylandrosta-1:4-dien-3-one, 9a -fluoro-11b :17b -dihydroxy-6a :17a -dimethylandrosta-1:4-dien -3-one, 6a -methyl-pregna-1:4-diene-3:20-dione, 6-methyl-pregna-1:4:6-triene-3:20-dione, 17a -hydroxy-6a -methylpregna-1:4-diene-3:20-dione and the hexanoyl esther thereof, 11a -hydroxy-6a -methylpregna-1:4-diene-3:20-dione, 11-oxo-6a -methylpregna-1:4-diene-3:20-dione, 6a :16a -dimethylpregna-1:4-diene-3:20-dione, 6a -methylpregna-1:4:16-triene-3:20-dione, 6a -methyl-16a :17a -isopropylidenedioxypregna-1:4-diene-3:20 -dione, 20b -hydroxy-6a -methyl pregna-1:4-diene-3-one, 20:20-bisethylenedioxy-6a -methylpregna-1:4-dien-3-one, ethyl 6a -methyl-3-oxopregna-1:4:17(20)-trien-21-oate and 17a -acetoxy-6a -methylpregna-1:4-diene-3:20-dione.  The preferred hydrogenating agent is 2:3-dicyano -5:6-dichloro-1:4-benzoquinone, the process advantageously being effected in benzene, dioxan, propyl acetate or acetic acid at 80 DEG  to 110 DEG C. in the presence of a catalytic quantity of p-nitrophenol.  It is stated that the process may, in general, be applied to steroids of the andostane, pregnane, cholestane and spirostane series containing additional substituents which do not interfere with the reaction, such as oxo groups at positions 11, 17 and 20, hydroxy, alkoxy and acyloxy groups at positions 6, 11, 16, 17, 20 and 21, fluorine atoms at position 9, alkyl groups at positions 2, 4, 16 and 17, and vinyl, ethynyl and substituted ethynyl groups at position 17.  Examples describe the preparation of all the steroids referred to above and of 17a :21-dihydroxy-6a -methylpregna-1:4-diene-3:11:20-trione and the 21-acetate thereof, and the corresponding 11b -hydroxy compounds. 17b -Acetoxy-4:6a -dimethylandrost-4-en-3-one is prepared by heating 6a -methyl-testosterone, thiophenol and formaldehyde in triethylamine and ethanol to give 6a -methyl-4-phenylthiomethyltestosterone, acetylating this with acetic anhydride in pyridine and heating the product with Raney nickel and acetone. 17b -Acetoxy-2a :6a -dimethylandrost-4-en-3-one is prepared by reacting 6a -methyltestosterone with ethyl oxalate and sodium hydride in benzene, treating the product with methyl iodide, potassium carbonate and dimethylformamide at 100 DEG C. reacting the so formed compound with sodium in methanol and acetylating the product. 6-Hydroxy-6-methyl-25 D-spirost-4-en-3-one is prepared by heating 3b -acetoxy-5a :6a -epoxy-5a :25D-spirostane with periodic acid to form 3b -acetoxy-5a :25D-spirostane-5a :6b -diol, oxidizing this with chromium dioxide in pyridine to give 3b -acetoxy-5-hydroxy5a :25D-spirostan-6-one, reacting this with methyl magnesium iodide to form 3b :5:6-trihydroxy-6-methyl-5a :25D-spirostane, oxidizing this with chromium trioxide in pyridine to give 5:6-dihydroxy-6-methyl-5a :25D-spirostan-3-one and heating this with methanol and sodium hydroxide.  6a  - Methyl-16a :17a -isopropylidenedioxypregn-4-ene-3:20-dione is prepared by reacting 6a -methyl-pregna-4:16-diene-3:20-dione with potassium permanganate, acetone and acetic acid to form 16a :17a -dihydroxy-6a -methylpregn-4-ene-3:20-dione and treating this with one drop of perchloric acid in acetone. 20b -Hydroxy-6a -methylpregn-4-en-3-one is prepared by treating 6a -methylpregn-4-ene-3b :20b -diol with 2:3-dichloro-5:6-dicyano-1:4-benzoquinone in dioxan at room temperature.  20:20-Bisethylenedioxy-6a -methylpregn-4-en-3-one is prepared by treating 3b -hydroxy-6-methylpregn-5-en-20-one with ethylene glycol and toluene p-sulphonic acid to form 20:20 bisethylenedioxy-3b -hydroxy-6-methylpregn-5-ene and oxidizing this by the Oppenauer method.  In the Provisional Specification it is stated that the dehydrogenation process may be applied to steroids of the androstane, pregnane, cholestane and spirostane series additionally substituted by such groups as oxo, hydroxy, alkoxy, acyloxy, fluoro, alkyl and ethynyl ; and the preparation of 21-fluoro-6a -methylpregna-1:4-diene-3:20-dione is additionally specifically referred to.  Specifications 820,004, 802,005, 809,465, 843,353 and 852,683 are referred to in the Provisional Specification.ALSO:Pharmaceutical preparations contain certain 6-methyl-1:4-dien-3-ones and 6-methyl-1:4:6-trien-3-ones of the cholestane, spirostane, androstane and pregnane series.  Tablets, elixirs, injections and implants are referred to.  The compounds, apart from substituents in the 16-and 17- positions may be represented by the general formula:  <FORM:0852847/VI/1> wherein A represents hydrogen, keto or hydroxyl.