Patent GB-900173-A (GB)
Title: New steroids and process for preparing same
IPC: C07J75/00
Filed: 1958-07-04
Abstract: The invention comprises steroids of the following structure in ring C <FORM:0900173/IV (b)/1> <FORM:0900173/IV (b)/2> or <FORM:0900173/IV (b)/3> (wherein R is alkyl and X is hydrogen or halogen, except that X is halogen only if ring C is part of an 11a -alkyl-hydrocortisone or a 21-ester thereof).  The 11-methyl steroids, which are preferred, are prepared by reacting an 11-keto steroid with a methyl metal compound, and, if desired, splitting off the 11-hydroxyl group in the product to form a 9,11-double bond, combining hydrogen, a hypohalous acid or oxygen at this bond, and, if desired, splitting off hydrogen halide from a 9,11-halohydrin so obtained and hydrolysing a 9,11-oxido compound so obtained to a 9,11-halohydrin.  The steroids may be of the spirostane, cholestane, ergostane, stigmastane, pregnane or androstane series, including the 19-nor compounds, and may contain, for example, 16,17-double bonds or 16,17-oxido groups. If they contain keto groups not intended to react with the metal compound, these may be protected or reduced prior to the reaction and subsequently reconverted.  Reactive hydroxyl groups may also be protected and then reformed and, if desired, esterified after the reaction. 17a -Hydroxyl groups may be introduced into pregnane products by, for example, enol-acetylation followed by oxidation with a per-acid and alkaline hydrolysis, and 21-hydroxyl groups may be introduced, for example, by 21-halogenation and then reaction with a salt of an organic acid and alkaline hydrolysis, or by microbiological hydroxylation.  Oxo groups may be formed in ring A by, for example, saponification of an esterified hydroxyl groups and subsequent oxidation, or by splitting of a ketalized oxo or enol-ether group.  Double bonds may be introduced into the 1,2 and/or 4,5-positions by, for example, halogenation followed by splitting off of hydrogen halide, by selenium dehydrogenation or by microbiological methods.  In Examples (1) 11-keto-tigogenin (or 3-esters thereof) and methyl magnesium bromide give 11a -methyl-11b -hydroxy-tigogenin; (2) allopregnan-3b -ol-11,20-dione-3-acetate-20-ethylene-ketal similarly gives 11a -methyl-allopregnane-3b ,11b -diol-20-one-20-ethylene ketal which is re-acetylated in the 3-position and is also hydrolysed to the 20-one which is subsequently also esterified in the 3-position with acetic or succinic anhydride; (3) and (4) the 20-one-3-acetate of (2) is converted to D 9,11-11-methyl-allopregnen-3b -ol-20-one-3-acetate, this is hydrogenated to 11-methyl - allopregnane-3b ,20-diol-3-acetate and this is oxidized to the corresponding 20-one; (5) and (6) the D 9,11-product of (3) is converted to 11a  - methyl - allopregnane - 3b ,11b -diol-9a -bromo-20-one-3-acetate and this to 9b ,11b -oxido-11a -methyl-allopregnan-3b -ol-20-one; (7) to (11) the D 9,11-product of (3) is converted to the 20-enol-acetate, this to D 9,11-11-methyl-allopregnene-3b ,17a -diol-20-one, this is 21-brominated, the 21-bromo compound converted to the acetate of the 21-ol, this oxidized to D 9,11-11-methyl-allopregnene-17a ,21-diol-3, 20-dione-21-acetate, this converted via the 9a -bromo-11b -hydroxy-compound to the 9b ,11b -oxido-compound, this to the 9a -fluoro-11b -hydroxy-compound, this to the corresponding D 1,4-compound and this by hydrolysis to D 1,4-11a -methyl - 9a  - fluoro-pregnadiene-11b ,17a ,21-triol-3,20-dione, which may subsequently be esterified in the 21-position; (12) the D 9,11-product of (3) and HCN give D 9,11-11-methyl-20-cyano-allopregnene-3b ,20-diol-3-acetate, this with phosphorus oxychloride gives D 9,11;17, 20-11-methyl-20-cyano-allopregnadien-3b -ol-3-acetate and this is converted to D 9,11-11-methyl-allopregnene-3b -17a -diol-20-one; (13) the 9a -bromo-compound of (9) is 2,4-dibrominated, the product dehydrobrominated to 11a -methyl-9a -bromo-hydrocortisone-acetate and this converted via the 9b ,11b -oxido compound to the corresponding 9a -fluoro-compound; (14) the D 9,11-product of (3) is converted to D 9,11-11-methyl - allopregnen-3b -ol-20-one-21-oxalo-acid methyl ester, this to the 21-iodo compound, this to the 21-acetate of the 21-ol and this by acetylation to D 9,11-11-methyl-allopregnene-3b , 21-diol-20-one-3,21-diacetate; and (15) D 5-3-ethylenedioxy - 11-keto-17a -methyl-17b -acetoxy-androstene (prepared by acetylating 11-keto-17a -methyl-testosterone to give 11-keto-17a -methyl-testosterone acetate and ketalizing this) is converted to the 11a -methyl-11b -hydroxy-compound and this split to give 11a ,17a -dimethyl-11b -hydroxy-testosterone.  Reference has been directed by the Comptroller to Specifications 873,605 and 877,585.