Synthesis of 6β-[(2′-aminoethyl)carboxamidomethyl]estradiol and preparation of estradiol probes

被引:14
作者
Adamczyk, M [1 ]
Johnson, DD [1 ]
Reddy, RE [1 ]
机构
[1] Abbott Labs, Div Organ Chem Res, Div Diagnost, Abbott Pk, IL 60064 USA
关键词
D O I
10.1021/bc970203l
中图分类号
Q5 [生物化学];
学科分类号
071010 ; 081704 ;
摘要
Reformatsky reaction of 3,17 beta-bis[(2-trimethylsilyl)ethoxymethyl]-1,3,5(10)-estratrien-6-one (2) with bromoethyl acetate and zinc gave the ester (3) in 60% yield which upon treatment with methanesulfonyl chloride in pyridine afforded the olefinic esters (4 and 5) as an endo and exo mixture (67:33 ratio) in 81% yield. Hydrolysis of the SEM protective groups in compounds 4 and 5 followed by hydrogenation of the resulting hydroxy compounds 6 and 7 using 10% Pd/C afforded an epimeric mixture (beta:alpha = 79:21) of 6-[(ethoxycarbonyl)methyl]estradiol (8a and 8b) in 95% yield. Hydrolysis of the ethyl esters (8a and 8b) using sodium hydroxide gave the acid (9a and 9b) in 81% yield. The epimeric mixture of acids (9a and 9b) was activated, treated with tert-butyl-N-(2-aminoethyl)carbamate (10), and purified by HPLC to afford 6 beta-[[[(2-tert-butoxycarbonyl)amino]ethyl]carboxamidomethyl]estradiol (11) in 39% yield as the major isomer. Hydrolysis of the BOC group in compound 11 using TFA afforded the desired 6 beta-[(2-aminoethyl)carboxamidomethyl]estradiol 12 in 50% yield. The biotinylated estradiol probe 14, fluorescent probe 16, and chemiluminescent probe 18 were prepared from 6 beta-[(2-aminoethyl)carboxamidomethyl]estradiol (12) and the corresponding biotin, 5-carboxyfluorescein, and 10-(3-sulfopropyl)-N-tosyl-N-(3-carboxypropyl)acridium-9-carboxamide N-succinimidyl esters (13, 15, and 17) in 65-74% yield and 99% purity.
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页码:403 / 408
页数:6
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