Patent GB-1043995-A (GB)
Title: Improvements in or relating to 5,10-methylene-19-nor-steroids and 5,10-seco-5,19-cyclo-10-fluoro-steroids
IPC: C07J75/00
Filed: 1963-08-21
Abstract: Novel steroids and 5,10-seco-5,19-cyclo-steroids of the formulae <FORM:1043995/C2/1> (wherein R is hydrogen or an acyl group containing less than 12 carbon atoms which is optionally substituted; R1 is hydrogen, C1- 8 alkyl, C2- 8 alkenyl or C2- 8 alkynyl; R3 is hydrogen, hydroxyl or acyloxy of less than 12 carbon atoms which is optionally substituted; R4 is hydrogen, a -methyl, b -methyl or a -hydroxyl; or R3 and R4 together are a ,a -methylenedioxy which may be alkyl-, alkaryl-, aralkyl- or aryl-substituted; X is hydrogen, fluorine or chlorine; Y is hydrogen, b -hydroxyl or keto, X being hydrogen when Y is hydrogen; and R7 is hydrogen or acyl of less than 12 carbon atoms which is optionally substituted) are prepared by treating the corresponding D 4-3-keto-19-hydroxy-steroids with about 1 to 2 molar equivalents of a reagent of the formula ACF2N(A1)2, wherein A is fluorinated or halo-fluorinated C1- 8 alkyl group, and A1 is C1- 8 alkyl in an inert organic solvent containing no acidic hydrogen.  This process is a general one applicable to any D 4-3-keto-19-hydroxy-steroids of the androstane or pregnane series. The two products may be separated by chromatography. If the reaction conditions are made milder, e.g. room temperature for 30 minutes to 1 hour or about 50 DEG  to about 90 DEG  C. for about 5 to 10 minutes instead of reflux temperature for about 30 minutes to about 1 hour or about 0 DEG  to 20 DEG  C. for about 16 to 24 hours, 5,10 - seco - 5,19 - cyclo - 10b  - fluoro compounds and a small amount of the 10a -fluoro-isomers are obtained.  Groups other than those in the above formulae which may be present in the starting materials are 17-keto and 6-methyl, and corticoid side-chains are preferably protected by conversion to bis-methylenedioxy derivatives.  In the products an 11-hydroxyl group may be introduced by microbiological methods and 11-hydroxy compounds may be oxidized to 11-ketones or converted to 9a -halo-11-oxygenated compounds, a 16-hydroxyl group may be introduced by incubation with Streptomyces roseochromogenus, and a 21-hydroxyl group may be eliminated by known methods. 17a  - Methyl - D 4 - androstene - 17b ,19 - diol-3-one is prepared by reacting D 5-androstene-3b ,19-diol-17-one with methyl magnesium bromide to give 17a  - methyl - D 5 - androstene - 3b ,17b ,19-triol and then oxidizing this by the Oppenauer method.  Similarly prepared by Oppenauer oxidation are 16a  - and 16b  - methyl - D 4-pregnen - 19 - ol - 3,20 - dione; 16a ,17a -isopropylidenedioxy - D 4 - pregnen - 19 - ol - 3,20 - dione, the 17-acetates of D 4-pregnene-17a ,19-diol - 3,20 - dione, 16a  - methyl - D 4 - pregnene-17a ,19 - diol - 3,20 - dione and 17a  - ethynyl-D 4-androstene - 17b ,19 - diol - 3 - one; the free 17-ol of the last-named compound and the corresponding 17a -vinyl compound; and 17,20; 20,21-bismethylenedioxy - D 4 - pregnen - 19 - ol - 3 - one and the corresponding 11-one.  17a  - Ethynyl-D 5 - androstene - 3b ,17b ,19 - triol and the corresponding 17a -vinyl compound are prepared from the corresponding 17-ones and Grignard reagents, and the first-named is converted to the triacetate and this hydrolysed to the 17-monoacetate.