Fajkos J, Cerný I, Pouzar V
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Prague, The Czech Republic.
Steroids. 1996 Nov;61(11):634-8. doi: 10.1016/s0039-128x(96)00136-5.
The key intermediate, 15-oxandrost-5-en-3 beta, 17 beta-diyl 3-acetate 17-benzoate (10), was prepared by a five-step procedure based on the addition of 4-methoxybenzyl alcohol to 3 beta-hydroxyandrosta-5, 15-dien-17-one (1). The resulting C-15 isomers were separated as acetates. In both series, the 17-ketones were reduced to 17 beta-hydroxy derivatives, and after benzoylation, the protecting methoxyphenylmethyl group at position 15 was removed with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, leaving 15 beta-hydroxyandrost-5-ene-3 beta, 17 beta-diyl 3-acetate 17-benzoate (6) and its 15 alpha-isomer 9. After Jones oxidation, both benzoates afforded the identical ketone 10. The reaction of 10 with (O-carboxymethyl)hydroxylamine in pyridine followed by diazomethane esterification gave (15E)-15-oxandrost-5-ene-3 beta, 17 beta-diyl 3-acetate 17-benzoate 15-(O-carboxymethyl)oxine methyl ester (11). Methyl ester 11 was successively submitted to acidic deacetylation, Oppenauer oxidation, potassium hydroxide treatment and reesterification with diazomethane to give (15E)-17 beta-hydroxyandrost-4-ene-3,15-dione 15-(O-carboxymethyl) oxine methyl ester (14). After purification, ester 14 was hydrolyzed with potassium hydrogen carbonate in aqueous methanol at elevated temperature into fee testosterone 15-(O-carboxymethyl)oxine (15).
关键中间体15-氧代雄甾-5-烯-3β,17β-二醇3-乙酸酯17-苯甲酸酯（10）是通过基于4-甲氧基苄醇加成到3β-羟基雄甾-5,15-二烯-17-酮（1）的五步程序制备的。所得的C-15异构体以乙酸酯形式分离。在两个系列中，17-酮被还原为17β-羟基衍生物，并且在苯甲酰化之后，用2,3-二氯-5,6-二氰基-1,4-苯醌除去15位的保护甲氧基苯基甲基，得到15β-羟基雄甾-5-烯-3β,17β-二醇3-乙酸酯17-苯甲酸酯（6）及其15α-异构体9。经琼斯氧化后，两种苯甲酸酯均得到相同的酮10。10与（O-羧甲基）羟胺在吡啶中反应，然后用重氮甲烷酯化，得到（15E）-15-氧代雄甾-5-烯-3β,17β-二醇3-乙酸酯17-苯甲酸酯15-（O-羧甲基）肟甲酯（11）。甲酯11依次进行酸性脱乙酰化、欧芬脑尔氧化、氢氧化钾处理并用重氮甲烷进行再酯化，得到（15E）-17β-羟基雄甾-4-烯-3,15-二酮15-（O-羧甲基）肟甲酯（14）。纯化后，酯14在高温下用碳酸氢钾在甲醇水溶液中水解，得到游离睾酮15-（O-羧甲基）肟（15）。
