Patent GB-815692-A (GB)
Title: Improvements in or relating to 12a-aza-c-homopregnane-12,20-dione derivatives
Filed: 1957-07-10
Abstract: The invention comprises 12a-aza-C-homo-5a -pregnanes of the general formula <FORM:0815692/IV (b)/1> and the 16-dehydro, 16,17-epoxy and 17-hydroxy derivatives thereof, wherein X represents an hydroxymethylene or carbonyl radical or an alkanoyloxymethylene radical in which the alkanoyl portion is of the formula <FORM:0815692/IV (b)/2> lower alkyl, the alkyl radical being of the CnH2n+1 type wherein n is less than 7.  The pregnanes and the 16-dehydro derivatives thereof may be prepared by forming the oxime of hecogenin acetate, subjecting the oxime to the Beckmann rearrangement to form 3b -acetoxy-12a-aza-C-homo - 5a  - spirostan - 12 - one, reacting the spirostan with acetic anhydride, chromic oxide and sodium acetate successively to form 3b -acetoxy - 12a - aza - C - homo - 5a  - pregn - 16 - ene-12,20-dione (optionally hydrolysing this compound to form the corresponding 3-hydroxy compound and, if necessary, esterifying the 3-hydroxy group to form 16-dehydro-compounds of the above general formula in which X is an hydroxymethylene or an alkanoyloxymethylene radical), hydrogenating the 3b -acetoxy-12a-aza - C - homo - 5a  - pregn - 16 - ene - 12,20-dione to form the corresponding pregnanes (optionally hydrolysing this compound to form 12a - aza - 3b  - hydroxy - C - homo - 5a  - pregnane - 12,20 - dione and, if necessary, esterifying the 3-hydroxy group as above), and oxidizing the 12a-aza-3b -hydroxy-C-homo-5a -pregnane-12,20-dione by treatment with t-butyl hypochlorite, the resulting 12a-aza-C-homo-N-chloro-5a -pregnane-3,12,20-trione being treated with sodium bisulphite or a similar reducing agent to replace the N-chlorine atom by an N-hydrogen atom to form 12a-aza-C-homo-5a -pregnane-3,12,20-trione. The 16,17-epoxy-3-alcohol derivative is prepared by treating the 16-dehydro-3-acetate of the above general formula with alkaline peroxide, and, if necessary, esterifying or oxidizing as above through the N-chloro-compound to form the desired 3-ester or 3-ketone respectively thereof.  The 3,17-diol of the above general formula is prepared by treating the 16-17-epoxy-3-alcohol with hydrobromic acid and hydrogen, the hydrogenation being carried out in the presence of a hydrogenation catalyst such as palladium on calcium carbonate.  The 3,17-diols may be converted to the corresponding 3-oxo compound by treating with t-butyl hypochlorite as above through the N-chloro-compound.  In the examples: (1) 3b -acetoxy - 12a - aza - C - homo - 5a  - pregn - 16-ene-12,20-dione is prepared by treating hecogenin acetate with hydroxylamine hydrochloride to form 3b -acetoxy-5a -spirostan-12-one oxime, then applying the Beckmann rearrangement to the oxime to form 3b -acetoxy-12a-aza-C-homo-5a -spirostan-12-one, and finally treating this compound successively with acetic anhydride, chromic trioxide and sodium acetate; (2) 12a-aza - 3b  - hydroxy - C - homo - 5a  - pregn - 16-ene-12,20-dione is prepared by hydrolysing the final product of (1) with caustic potash; (3) 3b  - acetoxy - 12a - aza - C - homo - 5a  - pregnone-12,20-dione is prepared by hydrogenating the product of (1) in the presence of pre-reduced palladium on charcoal, and then hydrolysing to the corresponding free 3-hydroxy compound as in (2); (4) 12a-aza-C-homo-5a -pregnone-3,12,20-trione is prepared by treating the free hydroxy compound of (3) with t-butyl hypochlorite in t-butyl alcohol and then sodium bisulphite; (5) 12a - aza - 16a ,17a  - epoxy - 3b -hydroxy - C - homo - 5a  - pregnane - 12,20-dione is prepared by treating the final product of (1) with hydrogen peroxide in the presence of aqueous caustic potash; (6) 12a-aza-16a ,17a -epoxy - C - homo - 5a  - pregnane - 3,12,20-trione is prepared by treating the product of (5) with t-butyl hypochlorite in the presence of t-butyl alcohol to form 12a-aza-N-chloro-16a , 17a  - epoxy - C - homo - 5a  - pregnane - 3,12,20-trione and treating this compound with potassium acetate, glacial acetic acid and sodium bisulphite; (7) 12a - aza - 3b  - acetoxy - 17a  - hydroxy - C - homo - 5a  - pregnane - 12,20 - dione is prepared by treating the product of (5) with hydrobromic acid in the presence of glacial acetic acid to form 3b  - acetoxy - 12a - 16b -bromo - 17a  - hydroxy - C - homo - 5a  - pregnane-12,20-dione, treating this compound with hydrogen in the presence of alcohol and palladium on calcium carbonate to form 12a-aza-3b ,17a -dihydroxy - C - homo - 5a  - pregnane - 12,20-dione and acetylating this compound at the 3-position; (3) 12a - aza - 17a - hydroxy - C-homo - 5a  - pregnane - 3,12,20 - trione is prepared by oxidizing the corresponding 3-hydroxy compound as in (4); (9) 12a-aza-C-homo-5a  - pregn - 16 - ene - 3,12,20 - trione is prepared by refluxing 12a-aza-C-homo-5a -spirostane - 3,12 - dione with acetic anhydride and pyridine hydrochloride to form 12a-aza-26-hydroxy - 5a - furost - 20(22) - ene - 3,12 - dione of the formula <FORM:0815692/IV (b)/3> and treating this compound successively with chromium trioxide and sodium acetate.