Patent GB-927328-A (GB)
Title: New steroids and process for their manufacture
IPC: C07J75/00
Filed: 1959-06-10
Abstract: The invention comprises (1) 18,20-dihydroxy-18,20- cyclo-pregnanes and -allopregnanes; (2) 3b -acetoxy- 18,20-dioxo-allopregnane, the corresponding 18-acid and the free 3b -ol corresponding to the last-named compound; (3) 18-unsubstituted- 20-oxo-21-nor-18,20-cyclopregnane compounds; (4) the preparation of pregnanes containing a 20-keto group, an 18-formyl or -carboxyl group, and an optional 21-esterified or etherified hydroxyl group by reacting a D 18(20)-21-unsubstituted- or -21-esterified or etherified hydroxyl substituted-pregnene either with ozone and then a reducing agent or with osmium tetroxide and then a reducing agent and subsequent treatment of the glycol formed with periodic acid or a lead tetraacylate, and isolating a 13-formyl-20-oxo-pregnane so obtained or further oxidizing it with chromium trioxide, potassium permanganate, sodium bismuthate, an alkali metal periodate, hydrogen peroxide or a lead tetraacylate to form a 20-oxo-pregnane-18-acid; and (5) the preparation of pregnanes having the partial formulae <FORM:0927328/IV(a)/1> (wherein R3 is a hydrogen atom or a hydroxyl group, R4 is an oxo group or a hydroxyl group and a radical having the meaning given for R21, and R21 is a methyl group o an esterified or etherified hydroxymethyl group or, in the 18,20-cyclo-compounds, a free hydroxymethyl group) by reacting a pregnene of the partial formula <FORM:0927328/IV(a)/2> (wherein R5 is a methylene group or an esterified or etherified hydroxymethylene group) with osmium tetroxide and then a reducing agent and isolating a 20-hydroxy-18,20-cyclopregnane so obtained or further oxidising it by reaction with periodic acid or a lead tetraacylate to give a 20-oxo compound of either of the above partial formulae.  It is stated that side reactions may occur during these processes, and that some 18,20-dioxo pregnanes are formed when mild conditions are employed whereas under more drastic conditions the pregnane-18-acids or 21-nor-pregnanes are obtained as the main products.  The products of the invention may additionally contain free or functionally converted hydroxyl or oxo groups (free hydroxyl and/or oxo groups may be converted into esters, ethers, enol esters, enol ethers, acetals, corresponding thio derivatives, hydrazones, semicarbazones or oximes), fluorine or chlorine atoms and methyl groups, for example in one or more of the positions 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 14, 15, 16, 17, 19 and 21.  They may be saturated in the ring system or contain double bonds, for example in one or more of the positions 4, 5, 9(11), 11, 14 or 16.  Esters may be formed with organic carboxylic or sulphonic acids or with sulphuric, phosphoric or hydrohalic acids. In examples (1) 3b -acetoxy-20-hydroxy-18,20-cyclo-allopregnane is refluxed with acetic anhydride and acetic acid to give a mixture of D 18(20)- and D 20(21)-3b -acetoxy-18,20-cyclo-allopregnanes, these on ozonolysis and reduction give 3b -acetoxy-18,20-dioxo-allopregnane and this on oxidation gives 3b -acetoxy-20-oxo -allopregnane-18-acid (also obtainable by direct oxidative cleavage of the ozonide); (2) the acid product of (1) is prepared directly from the D 18(20)-starting material and, without isolation, is hydrolysed to the 3b -ol; (3) the D 18(20)-starting material of (1) is osmylated and reduced to give 3b ,18,20-trihydroxy- 18,20-cyclo-allopregnane (2 isomers), and similarly are prepared D 5-3-ethylenedioxy- 18,20-dihydroxy-18,20-cyclopregnene, D 5-3-ethylenedioxy- 11b ,18,20-trihydroxy-18, 20-cyclo-pregnene and D 5-3-ethylenedioxy- 11b ,18,20,21- tetrahydroxy-18, 20-cyclo-pregnene, and, from these, the corresponding D 4-3-ketones; (4) the first product of (3) with lead tetra-acetate gives, inter alia, the 3b -ol of (2); (5) D 5,18(20)-3-ethylenedioxy-11b -hydroxy-18, 20-cyclopregnadiene on ozonolysis, reduction and hydrolysis gives 21-desoxyaldosterone which on oxidation gives the corresponding (18-->11)-lactone (either of which compounds on incubation with a fungus of the species Ophiobolus herpotrichus or Sclerotinia fructicola and, if necessary, reduction of the lactone groups, gives aldosterone); (6) D 5,18(20)-3-ethylenedioxy-21-acetoxy-18, 20-cyclo-pregnadiene on ozonolysis, reduction and hydrolysis gives D 4-3,18,20-trioxo-21-acetoxy-pregnene, or by the method of (3) gives D 5-3-ethylenedioxy-18,20,21-trihydroxy-18,20-cyclo-pregnene and thence the D 4-3-ketone; (7) D 5,18(20)-ethylenedioxy- 11b -hydroxy- 21-acetoxy- 18, 20-cyclo-pregnadiene on ozonolysis and reduction gives D 5-3-ethylenedioxy-11b -hydroxy-21-acetoxy-18, 20-dioxo-pregnene and thence aldosterone-21-acetate; (8) D 20-3b -acetoxy18,20-cyclo-allopregnene on osmylation and reduction gives 18,20-cyclo-3b -acetoxy-20,21-dihydroxy-allopregnane (which on hydrolysis gives the 3b -ol and on acetylation gives the 3b ,21-diacetate), and this on oxidation gives 3b -acetoxy- 20-oxo- 21-nor- 18,20-cyclo-allopregnane (2,4-dinitrophenylhydrazone described) which can be converted to a 20-dimethyl-acetal (which in turn can be converted to the 20-ketone again) or hydrolysed to the 3b -ol; D 5-3b -acetoxy-20,21-dihydroxy-18,20-cyclo-pregnene and D 5-3b -acetoxy-20-oxo-21-nor-18,20-cyclo-pregnene are prepared similarly; (9) the processes of (3) or (8) are used to prepare D 5-3-ethylenedioxy-20,21-di-hydroxy-18,20- cyclo-pregnene, D 5-3-ethylenedioxy-20-oxo-21-nor-18,20-cyclo-pregnene and the corresponding D 4-3-ketone, and the corresponding 11a -acetoxy-compounds; and (10) osmylation replaces ozonolysis in (1) to give 3b -acetoxy- 20-oxo-21-nor-18,20- cyclo-allopregnane and 3b -acetoxy-18,20- dioxo-allopregnane, and the last-named on oxidation gives 3b -acetoxy-20-oxo-allopregnane-18-acid as the 18,20-lactol thereof.  Specification 927,327 is referred to.