Androstenedione (II) was converted to the C-17 cyanohydrin (III) by treatment with either KCN and AcOH or with acetone cyanohydrin and NaOH. Ketalization of the remaining 3-keto group with ethylene glycol and trimethyl orthoformate led to (IV). The C-17 hydroxyl was then protected by formation of the acetaldehyde mixed ketal (V) by treatment with butyl vinyl ether. Addition of methyllithium to the cyano group, followed by acidic ketal hydrolysis furnished the pregnenedione (VI). Subsequent iodination of (VI) by means of iodine and calcium oxide gave iodo ketone (VII), which was further displaced by potassium acetate yielding the C-21 acetate ester (VIII). Finally, dehydration of the C-17 alcohol employing 70% aqueous sulfuric acid produced the title compound.
The title compound was prepared by dehydration of 11-hydroxyl group of hydrocortisone acetate (I) by means of methanesulfonyl chloride and pyridine in hot DMF. Dehydration of (I) has also been reported by treatment with N,N'-sulfinyldiimidazole, prepared from imidazole and thionyl chloride.
Reaction of 9a-hydroxyandrost-4-ene-3,17-dione (I) with benzenesulfinyl chloride and pyridine gives the corresponding sulfinate (II), which by treatment with TsOH in refluxing chloroform yields androsta-4,9(11)-diene-3,17-dione (III). Reaction of the androstadienedione (III) with acetylene by means of potassium tert-butoxide in THF affords the 17a-ethynyl derivative (IV), which is treated with phenylsulfenyl chloride and TEA at ?0 C to provide the sulfenate ester (V). Rearrange-ment of sulfenate (V) by warming at ?0 C gives the allene sulfoxide (VI), which is treated with sodium methoxide in methanol at 25 C to yield the enol ether sulfoxide (VII). Then, by refluxing in methanol, an equilibrium between sulfoxide (VII) and sulfenate (VIII) occurs. Reaction of the non-isolated sulfenate (VIII) with the thiophile trimethyl phosphite affords the 17a-hydroxy enol ether (IX), which is finally converted to anecortave acetate by either treatment with peracetic acid and NaHCO3 in dichloromethane or bromination with Br2 and pyridine in dichloromethane to give compound (X) followed by treatment with KOAc, KI and AcOH in refluxing acetone.
Condensation of 3-methoxyandrosta-3,5,9(11)-trien-17-one (XI) with (E)-1,2-dichloroethylene (XII) by means of BuLi in toluene gives 17a-[(E)-1,2-dichloro-vinyl]-17b-hydroxyandrosta-4,9(11)-dien-3-one (XXX), which is treated with phenylsulfenyl chloride and TEA in dichloromethane to yield 20,21-dichloro-21-(phenylsulfinyl)pregna-4,9(11),17(20)-trien-3-one (XXXI). Reac-tion of compound (XXXI) with MeONa in acetone/MeOH at 0 C affords 21-chloro-20-methoxy-21-(phenylsulfinyl)-pregna-4,9(11),17(20)-trien-3-one (XXXII), which by treatment with more MeONa at 35 C provides 21-chloro-17a-hydroxy-20-methoxypregna-4,9(11),20-trien-3-one (XXXIII). Hydrolysis of the enol ether of (XXXIII) with HCl in THF/acetone/MeOH gives the 3,20-dione derivative (XVI), which is finally treated with AcOK and KI in hot acetone/dichloromethane.
Condensation of 3-methoxyandrosta-3,5,9(11)-trien-17-one (XI) with 3-hydroxypropionitrile (XXV) by means of LDA in THF provides 17a-(1-cyano-2- hydroxyethyl)-17b-hydroxyandrosta-4,9(11)-dien-3-one (XXVI), which is selectively monoacetylated by means of Ac2O in pyridine to yield monoacetate (XXVII). Dehydration of (XXVII) by means of SOCl2 in pyridine gives 20-cyano-21-acetoxypregna-4,9(11),17(20)-trien-3-one (XXVIII), which is treated with ethylene glycol, trimethyl orthoformate and TsOH in dichloromethane to afford the ethylene ketal (XXIX). Finally, compound (XXIX) is oxidized with KMnO4 in acetone/ethylene glycol and treated with NaHSO3 and HCOOH.
In a different approach, irradiation of (IX) in the presence of phenyliodine dichloride produced selectively the 9-chloro derivative (X). This was dechlorinated to the 9(11) olefin (XI) with AgBF4 in acetone. Hydrolysis of the ester groups of (XI) by K2CO3 in MeOH afforded diol (XII), which was finally converted to the title compound by selective reacetylation of the C-21 hydroxyl group.
Reaction of 4,9(11)-androstadien-3,17-dione (III) with trimethyl orthoformate and TsOH in dioxane gives 3-methoxy-3,5,9(11)-androstatrien-17-one (XI), which is condensed with 1,2-dichloroethylene (XII) by means of MeLi in ethyl ether/THF to yield 17a-(chloroethynyl)-17b-hydroxy-4,9(11)-androstadien-3-one (XIII). Esterification of the OH group of (XIII) with fuming HNO3 and acetic anhydride affords the 17b-(nitrooxy) derivative (XIV), which is treated with formic acid and AgNO3 in N-methylpyrrolidone to provide 21-chloro-17a-(formyloxy)-4,9(11)-pregnadien-3,20-dione (XV). Hydrolysis of the formyloxy group of (XV) by means of KHCO3 in methanol/water gives 21-chloro-17a-hydroxy-4,9(11)-pregnadien-3,20-dione (XVI), which is finally acetylated by means of AcOK and KI in hot DMF.
Reaction of 17a-ethynyl-9,11-didehydrotestosterone (IV) with phenylsulfinyl chloride and TEA in dichloromethane gives 21-(phenylsulfinyl)pregna-4,9(11),17(20),20-tetraen-3-one (VI), which is treated with phenol and NaOH in refluxing toluene to provide 20-(phenoxy)-21-(phenylsulfinyl)pregna-4,9(11),20-trien-3-one (XXXIV). The reaction of compound (XXXIV) with trimethyl phosphite and TEA in hot methanol affords 17a-hydroxy-20-(phenoxy)pregna-4,9(11),20-trien-3-one (XXXV), which is finally treated with Oxone and KOH in hot dichloromethane, and then acetylated with Ac2O, TEA and DMAP in THF/water.
Condensation of 3-methoxyandrosta-3,5,9(11)-trien-17-one (XI) with 2-chlorovinyl ethyl ether (XXXVI) by means of BuLi in THF gives 20-chloro-3-oxopregna-4,9(11),17(20)-trien-21-al (XXXVII), which is treated with Ac2O and AcOK in hot DMF to yield 21-(acetoxy)pregna-4,9(11),16-triene-3,20-dione (XXXVIII), Reaction of compound (XXXVIII) with RhCl(PPh3)3 and triethylsilane in hot dichloromethane affords 21-(acetoxy)-20-(triethyl-silyloxy)pregna-4,9(11),17(20)-trien-3-one (XXXIX), which is finally oxidized with peracetic acid in toluene, quenched with SO2 and treated with TEA.
Reaction of 3-methoxyandrosta-3,5,9(11)-trien-17-one (XI) with KCN and AcOH in methanol gives a 1:1 mixture of the epimeric cyanohydrins (XVII) and (XVIII) and the desired b-cyano epimer (XVIII) is obtained in a 95% yield by selective crystallization under equilibrating conditions. Protection of the 17-OH group of (XVIII) with TMS-Cl and imidazole yields the silyl ether (XIX), which is reduced with DIBAL and AcOH to afford the carbaldehyde (XX). Reaction of compound (XX) with dibromomethane and LDA provides the dibromo derivative (XXI), which by reaction with more LDA gives the lithium enolate (XXII). Hydrolysis of enolate (XXII) in acid medium yields the a-bromoketone (XXIII), which is acylated with AcOH and TEA in hot acetone to afford the silylated steroid (XXIV). Finally, compound (XXIV) is deprotected by means of HF and TEA in dichloromethane.