Patent GB-994745-A (GB)
Title: Cyclopentanophenanthrene compounds and process for their production
IPC: C07J75/00
Filed: 1961-06-28
Abstract: The invention comprises 16a -mono-, di- and tri-fluoromethyl pregnanes of the general formula <FORM:0994745/C2/1> in which Y represents b -hydroxy or keto; X is hydrogen, chlorine, or fluorine; Z is a double bond or saturated linkage between C1 and C2; R1 is hydrogen, methyl, fluorine or chlorine; R2 represents fluorine or chlorine; and R is hydrogen or an acyl radical of a hydrocarbon carboxylic acid of less than 12 carbon atoms, which may be straight, branched, cyclic, and may be substituted by functional groups, e.g. acetyl, benzoyl, trimethylacetyl, phenoxyacetyl, aminoacetyl, b -chloropropionyl.  The 16a -trifluoromethyl compounds may be prepared from 16a  - trifluoromethyl - D 5 - pregnene - 3b ,17a -diol-20 -one by oxidation to the corresponding D 4-3-ketone, iodination at C21 and formation of the 21-acetoxy derivative, which may then be dehydrogenated with selenium dioxide or 2,3-dichloro - 5,6 - dicyano - 1,4 - benzoquinone the resulting D 1,4-compound saponified to yield the 21-hydroxy compound and the latter incubated with Curvularia lurata ATCC 13935 or with adrenal glands to give 16a -trifluoromethyl prednisolone which may be acylated at C21 to give the corresponding 21-esters.  Alternatively the 21-acetoxy derivative mentioned above is saponified and hydroxylated at C11 with C lunata to give 16a -trifluoromethyl-hydrocortisone, which may be dehydrogenated at C1-C2 and/or acylated at C21.  A halogen atom may be introduced at C-9a  by dehydration at C9,11 with mesyl chloride, formation of the halohydrin, conversion to the 9b ,11b -oxide and cleavage with hydrohalic acid.  The corresponding 16a -monofluoromethyl compounds are prepared from 16a -monofluoromethyl-D 5-pregnene - 3b , 17a  - diol - 20 - one.  Likewise the 6-methyl analogues of these compounds are prepared from 6-methyl-16a -monofluoro- (or trifluoro) - methyl - D 5 - pregnene 3b ,17a  - diol-20-one, or the 6a -methyl group may be introduced subsequently by protecting the keto group of 16a -mono or trifluoromethyl-D 5-pregnene - 3b ,17a  - diol - 20 - one with ethylene glycol, epoxidizing the D 5 bond, treating the oxido derivative with methyl magnesium halide and dehydrating the 6b -methyl-5a -hydroxy compound obtained. Compounds of the invention possessing a 6a -fluoro substituent are prepared by treating 16a -mono- or trifluoromethyl - D 5 - pregnene - 3b ,17a  - diol - 20 - one with N-bromoacetamide and HF, oxidizing the 5a  - bromo - 6b  - fluoro derivative and dehydrobrominating the resultant 3-ketone followed by inversion at C6 to yield 6a -fluoro-16a -mono- or trifluoromethyl-D 4-pregnen-17a -ol-3, 20-dione, which is then modified by standard procedures.  Alternatively the fluoro group or a chloro group may be introduced at C6 by treating 16a  - monofluoro - or trifluoromethyl - D 5-pregnene - 3b ,17a  - diol - 20 - one with a peracid and reacting the 5a ,6a -oxide produced with fluoroboric acid.  The resulting 6b -fluoropregnane - 3b ,5a ,17a  - triol derivative is then oxidized with chromic acid, dehydrated and epimerized at C6 with concentrated HCl, and thereafter modified by standard procedues outlined above the yield the novel compounds. Compounds of the invention that possess a 16a -difluoromethyl group are prepared by treating 16a  - cyano - D 5 - pregnen - 3b  - ol - 20 - one acetate with sodium borohydride, etherifying the 20-hydroxyl group thus formed, saponifying the 3-acetate, benzoylating, hydrolysing the protective ether group, acetylating, and treating the resulting 3-benzoate 20-acetate of D 5-pregnene - 3b ,20b  - diol - 16a  - carboxylic acid with oxalyl chloride, reducing the 16a -acid halide by Rosenmund method to the 16a -carboxaldehyde and treating it with SF4 to give 16a -difluoromethyl - D 5 - pregnene - 3b ,20b  - diol - 3-benzoate - 20 - acetate.  Subsequent saponification and Oppanauer oxidation yields 16a -difluoromethyl progesterone, which is treated by standard procedues to yield compounds of the invention. The processes are illustrated in thirty-one detailed examples. Specifications 776,848,959,016, 994,743 and 994,744 are referred to.