Patent GB-821777-A (GB)
Title: Oxygenated steroids and process for their manufacture
IPC: C07J75/00
Filed: 1956-05-18
Abstract: The invention comprises D 4-3,20-dioxo-11b -hydroxy-21-halogenpregnenes having a ring C of the partial formula <FORM:0821777/IV (a)/1> in which X represents an oxo group, or <FORM:0821777/IV (a)/2> , and their functional derivatives, e.g. esters, ethers, thioesters, thioethers, thiol or thione esters, acetals, mercaptals, ketals, enol esters, ethers and enamines, hydrazones and semicarbazones, and also a process for the preparation of the corresponding compounds having a free or functionally converted hydroxy-acetyl side chain in position 17 by reacting a 21-unsubstituted D 4-3,20-dioxopregnene containing a ring C of the above partial formula with an oxalic acid ester, treating the resulting 21-oxalo-acid ester in the form of an enol salt with a halogenating agent; subjecting the 21-halo-21-oxalo-acid ester to acid splitting with an alkaline agent, e.g. an alkali metal hydroxide or alcoholate, and converting the resulting 21-halide into the 21-acyloxy or 21-hydroxy compound by treatment with a metal salt of an organic acid or with an hydrolysing agent.  The condensation with oxalic esters is carried out in the presence of basic agents, e.g. sodium methylate or ethylate or potassium t-butylate; the resulting racemic 21-oxalo-acid esters can be resolved into their optical isomers, e.g. by hydrolysis and crystallization of the brucine or strychnine salts; the halogenation is effected with free halogen, particularly iodine, or with N-halogen amides or imides.  Specified 21-esters prepared by the process include those with acetic, propionic, butyric, trimethylacetic, crotonic, oenanthic, palmitic, benzoic, phenylacetic, b -cyclopentylpropionic, and phosphoric acids. In examples: (1) the (18 --> 11b )-lactone of d:l - D 5 - 3:3 - ethylenedioxy - 11b  - hydroxy - 20 - ketopregnene - 18 - acid is condensed with dimethyl oxalate using sodium methylate and the resulting lactone of d:l- D 5-3:3 - ethylenedioxy - 11b  - hydroxy - 20 - oxo-pregnene-18-acid-21-oxalo acid methyl ester treated with methanolic sodium methylate and iodine yielding the corresponding 20-oxo-21-iodo-pregnene 18-acid, which is boiled with potassium acetate in acetone giving the (18 --> 11b )-lactone of d, l- D 5-3:3-ethylenedioxy-11b -hydroxy-20-oxo-21 -acetoxypregnene-18-acid (I) and subsequently the ketal group is removed yielding the free 3,20-dione, also prepared in an optically-active form aldosterone 21-acetate by chromium trioxide oxidation; hydrolysis of the latter gives the 21-hydroxy compound, whose racemate is also obtained from I by treatment with HClO4; (2) the (18 --> 11b )-lactone of d,l- D 5 - 3:3 - ethylenedioxy - 11b  - hydroxy - 20 - oxo - pregnene - 18 - acid is converted to its 3:3:20:20 - bis - ethylenedioxy derivative (II) and then reduced with lithium aluminium hydride to d,l- D 5-3:3:20:20-bis-ethylenedioxy - 11b  - hydroxy - 18 - oxo - pregnene or its 18:11-cyclosemiacetal (III) and the ketal groups then removed, giving d,l- D 4-3,18,20 - trioxo - 11b  - hydroxypregnene or its 18:11-cyclosemiacetal; (3) III is acetylated, the ketal groups removed and then reacted with methylethyldioxolane and p-toluene sulphonic acid giving acetylated 18:11-cyclosemiacetal of d,l- D 5 - 3:3 - ethylenedioxy - 11b  - hydroxy - 18:20-dioxopregnene, which is then reacted with dimethyl oxalate and sodium methylate, the resulting 21-oxalo acid methyl ester treated with methanolic iodine solution and the resulting 21-iodo compound converted to the acetylated 18:11 - cyclosemiacetal of d,l- D 5 - 3:3 - ethylenedioxy - 11b  - hydroxy - 18:20 - dioxo-21-acetoxypregnene; subsequent treatment with aqueous acetic acid yields the free 3:18:20-trioxo compound, which on saponification with methanolic potassium bicarbonate gives d,l-aldosterone; (4) II is reduced to III as in (2); (5) III is acetylated and the ketal groups removed, yielding d,l- D 4-3,18,20-trioxo-11b -hydroxy-pregnene or its 18:11-cyclo-semiacetal which can be converted to d,l-aldosterone as in (3); (6) the (18 --> 11b )-lactone of d,l- D 5-3:3-ethylenedioxy - 11b  - hydroxy - 20 - oxopregnene - 18 - acid - 21 - oxalo - acid methyl ester is treated with KOH and the enol-salt acidified, giving the corresponding 21-oxalo-acid, which is resolved with strychnine into the d- and l-forms; subsequent treatment of the d- and l-forms with potassium bicarbonate gives the (18 --> 11b )-lactones of d- and l- D 5-3:3-ethylenedioxy - 11b  - hydroxy - 20 - oxo - pregnene-18-acid and cleavage of the ketals with perchloric acid the (18 --> 11b )-lactones of d- and l- D 4 - 3,20 - dioxo - 11b  - hydroxy - pregnene - 18-acid; the d-form is then monoketalized as in (3) and treated as in (1), giving the (18 --> 11b )-lactone of d- D 4-3,20-dioxo-11b -hydroxy-21-acetoxypregnene-18-acid, identical with that prepared by oxidation of d-aldosterone 21-mono-acetate. Specifications 805,603, 821,778 and 821,779 are referred to.