Patent GB-805604-A (GB)
Title: Novel aldosterone intermediates
IPC: C07J71/00
Filed: 1955-01-14
Abstract: The invention comprises steroids of the general formula <FORM:0805604/IV (b)/1> in which R1 is a free or esterified hydroxyl group, a hydroxyl group acetalized with an 18-oxo group or lactonized with a 13-carboxy group, or an oxo group, R2 is a lactonised carboxyl or an acetalized aldehyde group or a free or esterified hydroxymethyl group, R3 is a free or esterified carboxyl group, and X is a free or esterified hydroxyl group, or a free or ketalized oxo group, and in which formula there may also be a 4:5 or 5:6 double bond.  Specified compounds include (18 --> 11b )-lactones of D 4 - 3 - oxo - 11b  - hydroxy - 18 - oic acid etienic acids and their esters, (11b  --> 18)-cyclosemiacetals of D 4 - 3,18 - dioxo - 11b  - hydroxy etienic acids, their 20,18-lactones and corresponding functional derivatives, e.g. 3-ketals and esters, and their saturated analogues and the (18 --> 11b )-lactone of 3b ,11b -dihydroxy-allo-etianic acid-18-acid, its methyle ster and the corresponding 3b -acetate.  The compounds may be prepared by oxidation of the corresponding 17-formyl compounds, or by synthesis from 3-oxygenated-13,17-seco-steroid 17,13-lactones themselves obtained from 3,11-dioxygenated 17- or 20-oxo steroids by treatment with per-acids, hydrogen peroxide or with microorganisms, e.g. Mucorales, Actinomycetes or Fungi imperfecti.  A synthesis of this type is given in detail (c.f. "Starting material" below) and it is stated that the alternative procedures known in steroid syntheses can be used for the individual steps.  The compounds of the invention may subsequently be converted into 21-hydroxypregnenes.  In examples: (1) D 2 : 8a-4 - keto - 1b  - (21 - tosyloxyethyl) - 2 - (ethylenedioxy-methyl) - 7 - ethylenedioxy - 4bb  - methyl-4aa ,10ab -decahydrophenanthrene in ethanol is condensed with sodium malonic ester, the product cyclised with potassium t-butylate giving D 5 - 3,18 - bis - ethylenedioxy - 11 - keto - androstene - 17,17 - dicarboxylic acid diethyl ester, which is saponified and decarboxylated in ethylene glycol to D 5-3,18-bis-ethylenedioxy-11-keto-etienic acid, which (2), is reduced with sodium borohydride and the resulting D 5-3,18-bis-ethylenedioxy-11b -hydroxy-etienic acid converted to the 11b -trifluoracetate; (3) aldosterone hydrate is oxidized with sodium periodate, giving <FORM:0805604/IV (b)/2> together with D 4-3,18-dioxo-11b -hydroxy-etienic acid, which (4), on sublimation yields II; (5) and (12), hydrogenation of II over platinum oxide gives a mixture of the (20 --> 18)-lactones of 18,11-cyclosemiacetals of the 3,11-dihydroxy-18-oxo-etianic acids (5a  and 5b ), which on acetylation yield the (20 --> 18)-lactone of the 18,11 - cyclosemiacetal of 3b  - acetoxy - 11b  - hydroxy - 18 - oxo - alloethianic acid; treatment of the isomeric mixture of acids with hydrazine, sodium and ethanol gives the 18,11-lactone of 3b ,11b -dihydroxy-allo-etianic-acid-18-acid (III), secondly an amorphous acid fraction which on methylation with CH2N2 and oxidation with chromic acid gives the methyl ester of 3,11-dioxo-allo-etianic acid, and thirdly the 20,18-lactone of 3b ,11b ,18-trihydroxy-allo-etianic acid (IV); (6) esterification of III with CH2N2 and oxidation of the ester (characterized as its 3b -acetate) with chromic acid gives the 18,11-lactone of 3-oxo-11b -hydroxy-allo-etianic acid methyl ester-18-acid; (7) and (11) oxidation of aldosterone mono-acetate gives the 18,11-lactone of D 4 - 3,20 - dioxo - 11b  - hydroxy - 21 - acetoxy - pregnen - 18 - acid, which is saponified with methanolic bicarbonate and oxidized with periodate to give the 18,11-lactone of D 4 - 3 - oxo - 11b  - hydroxy - etienic - acid - 18-acid (characterized as its methyl ester); subsequent hydrogenation yields III, and hydrogenation of the methyl ester gives the ester of III; (8) and (9), aldosterone hydrate is oxidized with periodate to give II and D 4,3,18-dioxo-11b -hydroxy-etienic acid; (10) aldosterone hydrate is oxidized with chromic acid in acetic acid giving II; (13) the 18,11-lactone of 3b ,11b -dihydroxy-alloetianic acid-methyl ester-18-acid is obtained as in (6), converted to its 3b -acetate (V), and the mother-liquors from the esterification also acetylated and chromatographed, yielding the same acetate and also 3b -acetoxy-11b -hydroxy-allo-etianic acid methyl ester; (14) the mother liquors from the isolation of the 20,18-lactone of the 18,11-cyclosemiacetal of 3b -acetoxy - 11b  - hydroxy - 18 - oxo - etianic acid are treated with hydrazine as in (5), giving IV, and subsequently V, and 3b -acetoxy-11b -hydroxy-allo-etianic acid methyl ester; (15) chromic acid oxidation of IV gives the 20,18-lactone of 3,11-dioxo-18-hydroxy-allo-etianic acid.  Starting material.  D 2:8a-4-keto-1b -(21-tosyloxy - ethyl) - 2 - (ethylenedioxy - methyl) - 7 - ethyl-enedioxy - 4bb  - methyl - 4aa  - 10ab  - decahydrophenanthrene is prepared in twenty stages from 3a -acetoxy-testane by reaction with peracetic acid, treatment of the resulting 3a -acetoxy-11-keto - 13a  - hydroxy - 13,17 - seco-testane - 17 - acid-17,13-lactone (also obtained by microbiological treatment of 3a -acetoxy-11,20-diketo-pregnane) with phenyl magnesium bromide and hyhydration of the resulting carbinol, giving D 2-1b -(31,31-diphenylallyl) - 7a  - acetoxy - 4 - keto - 2,4bb  - dimethyl-4aa :8ab :10ab -dodecahydrophenanthrene, which is oxidized and methylated to D 2-7a -acetoxy - 4 - keto - 2:4bb  - dimethyl - 4aa :8ab : 10ab  - dodecahydro - phenanthryl - 1b  - acetic acid methyl ester, treated with N-bromo-succinimide and the 2-bromo-methyl derivative so obtained hydrolysed with HBr and then potassium acetate in acetone giving D 2-7a -hydroxy-4-keto-2 - acetoxymethyl - 4bb  - methyl - 4aa :8ab :10ab  - dodecahydro - phenanthryl - 1b  - acetic acid methyl ester which is oxidized with chromic acidpyridine to the 4,7-dione, brominated in the 8a -position and dehydrobrominated with semicarbazide to D 2:8 - 4,7 - diketo - 2 - acetoxymethyl - 4bb  - methyl - 4aa :10ab  - decahydrophenanthryl - 1b  - acetic acid methyl ester; subsequent treatment with p-toluene sulphonic acid and ethylene glycol gives D 2:8a - 4 - keto - 2 - hydroxymethyl - 7 - ethylenedioxy - 4bb  - methyl - 4aa :10ab  - decahydro - phenanthryl - 1b  - acetic acid methyl ester, which is reduced to the 4b -hydroxy - 1b  - (21 - hydroxy - ethyl) - derivative with LiAlH4, acetylated to the 1b -(21-acetoxyethyl) - 2 - (acetoxymethyl) - derivative, oxidized to the 4-ketone and hydrolysed to D 2:8a - 4 - keto - 1b  - (21 - hydroxyethyl) - 2 - (hydroxymethyl) - 7 - ethylenedioxy - 4bb - methyl - 4aa : 10ab -decahydrophenanthrene, which is tosylated and the corresponding pyridinium bromide or tosylate salt treated with p-nitroso-dimethylaniline, giving [D 2:8a - 4 - keto - 1b  - (21 - tosyl oxy - ethyl) - 7 - ethylenedioxy - 4bb  - methyl - 4aa :10ab  - decahydrophenanthryl - (2)] - N - p - dimethylaminophenyl nitrone, which is decomposed to the 4,7-diketo-2-formyl compound and converted to the corresponding 2,7-bis-ethylenedioxy derivative.  Specification 805,603 is referred to.