Patent GB-948545-A (GB)
Title: C-nor-steroids
IPC: C07J5/00
Filed: 1962-01-01
Abstract: The invention comprises (1) a process for the preparation of C-nor-steroids oxygenated in the 11-position wherein an 11, 12- diketo-steroid is treated with a strong base and the thus obtained 11-carboxy-11-hydroxy-C-nor-steroid is oxidized in an acid medium to give an 11-keto-C-nor-steroid; (2) compounds of the formula: <FORM:0948545/C2/1> wherein Y is H(b OH) or =O; R1 is H, OH or O acyl; R2 is H, OH or O acyl; and C1-C2 is saturated or unsaturated; and (3) compounds of the formula: <FORM:0948545/C2/2> wherein X is a halogen atom; Y is H(b OH) or =O; R1 is OH or O acyl; R2 is OH; and C1-C2 is saturated or unsaturated. The starting material in process (1) may be, for example, 11, 12-diketo-tigogenin which is converted to 11-keto-C-nor-tigogenin. In this product the spirostan side-chain may be degraded, for example, by reaction with a mixture of acetic anhydride, pyridine and methylamine hydrochloride (giving 11-keto-C-nor-pseudo-tigogenin), followed by oxidation with chromic acid to give 3b ,16b -dihydroxy-11,20-diketo-C-nor-allopregnane 3-acetate 16 - (gamma - methyl - delta - acetoxy) - valerate, boiling with methanolic sodium acetate to give D 16-11, 20-diketo -3b -acetoxy-C-nor-allopregnane and reducing this to 3b -acetoxy-11, 20-diketo -C-nor-allopregnane. This may then be enol-acylated to give D 17-3,20-diacetoxy-11-keto -C-nor-allopregnane, this oxidized with an organic per-acid to 3b , 20-diacetoxy-11-keto-17, 20-oxido-C-nor-allopregnane, and this hydrolysed to 3b , 17a -dihydroxy-11, 20-diketo-C-nor-allopregnane. This may then be iodated or brominated to give the 21-halo compound which on reaction with, for example, sodium acetate gives 3b , 17a , 21-trihydroxy-11, 20-diketo-C-nor-allopregnane 21-acetate which on hydrolysis gives the 21-ol.  The acetate may be oxidized to the 3-ketone, and this may be reduced, by halogenation and dehydrohalogenation or by means of selenium dioxide, to give D  1,4-3, 11, 20-triketo -17a , 21-dihydroxy-C-nor-pregnadiene-21-acetate which on hydrolysis gives the 21-ol. A halogen atom can be introduced into the 9-position by reduction of the 11-keto group and dehydration to the D 9(11)-compound which by reaction with for example, N-bromo-acetamide, followed by treatment with, for example, potassium acetate gives the 9, 11-oxido-compound which is subsequently converted to the desired 11b -hydroxy -9-halogen compound by reaction with hydrochloric or hydrofluoric acid. On oxidation this compound gives the 11-keto-9a -halogen compound. The thus prepared compounds can be esterified at the 17a - and 21-positions with carboxylic acids or inorganic acids such as phosphoric.  Examples describe the above-detailed process for the preparation of C-nor-prednisone and in further examples (1) 3a -hydroxy-11,12-diketo-cholanic acid methyl ester 3-formate gives 3a ,11-dihydroxy-11-carboxy-C-nor-cholanic acid and then the 11-keto compound, this with phenyl magnesium bromide gives D 23-3a -hydroxy -11- keto-24, 24-diphenyl-C-nor-cholene, this with N-bromo-succinimide gives D 23-3a -hydroxy-11-keto-22-bromo-24, 24-diphenyl-C-nor-cholene and this on oxidation gives 3a -hydroxy-11, 20-diketo-C-nor-pregnane; (2) 3b , 12b -diacetoxy-11, 20-diketo-allopregnane (prepared by hydrogenation of the D 16-compound) is converted to its 20-ethylene ketal, this is hydrolysed to the 3b , 12b -diol, this is oxidized to the corresponding 11, 12-diketo-allopregnane compound and this by the process of the invention gives 3b -hydroxy-11,20-diketo-C-nor-allopregnane; (3) the acetate of the last-named product is hydrolysed to that product and this by the process outlined above is converted into D 1,4-3,11,20-triketo-C-nor-pregnadiene; (4) D 1,4-3,11, 20-triketo-17a -hydroxy-C-nor-pregnadiene, prepared similarly, is converted to the 17-acetate and other esters; (5) the product of (1) is oxidized to the 3-ketone, this is brominated to 4-bromo-3,11,20-triketo-C-nor-pregnane, this is converted to D 4-3, 11, 20-triketo-C-nor-pregnane, this is ketalized at the 3- and 20-positions, the diketal reduced to the 11-ol, and the keto groups again liberated, and the thus obtained 11-keto and 11-hydroxy compounds are converted into the corresponding 17a -hydroxy and 17a , 21-dihydroxy compounds, to obtain 11-keto-17a -hydroxy-C-nor-progesterone, 11-hydroxy -17a - hydroxy -C-nor-progesterone, C-nor-cortisone and C-nor-cortisol, which may then be esterified; (6) 3, 11, 20-triketo -17a , 21-dihydroxy-C-nor-allopregnane-21-acetate is converted to the 3, 20-disemicarbazone, this is reduced and hydrolysed to 3, 20-diketo-11b , 17a , 21-trihydroxy -C-nor-allopregnane -21-acetate, this is dehydrated to the corresponding D 9(11)-compound, this is converted via the 9a -bromo-11 b -hydroxy compound and the 9, 11-oxido-compound to 3, 20-diketo-11 b , 17a , 21-trihydroxy -9a - fluoro -C-nor-allopregnane -21-acetate, this is reduced to 9a -fluoro-C-nor-prednisolone -21- acetate, this is oxidized to the corresponding prednisone compound, and this is hydrolysed and converted to various other 21-esters; and (7) 3, 11, 20-triketo-17a , 21-dihydroxy -C-nor-pregnane -21- acetate is similarly converted to 9a -fluoro-C-nor-cortisone and -hydrocortisone and 21-esters thereof.