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Synthesis of [ 14 C]CI‐980, ethyl [5‐amino‐1,2‐dihydro‐2( S )‐methyl‐3‐[ 14 C]phenylpyrido[3,4‐ 6 ]pyrazin‐7‐YL]carbamate isethionate salt, a tubulin‐binding, antimitotic, broad‐spectrum antitumor agent
Author(s) -
Woo Peter W. K.,
Lee Helen T.
Publication year - 1994
Publication title -
journal of labelled compounds and radiopharmaceuticals
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.432
H-Index - 47
eISSN - 1099-1344
pISSN - 0362-4803
DOI - 10.1002/jlcr.2580340102
Subject(s) - chemistry , sodium borohydride , catalysis , medicinal chemistry , benzene , ketone , pyridine , bromide , raney nickel , methyl isobutyl ketone , dehydrogenation , organic chemistry
[ 14 C]CI‐980 ( 14b ) was synthesized in eight steps starting from [U‐ 14 C]benzene ( 5 ), which was converted to bromo[ 14 C]benzene ( 6 ) in the presence of tetrabutylammonium bromide as catalyst. Reaction of 6 with the anion of N ‐ethoxycarbonyl‐ N ′‐methoxy‐ N ′‐methyl‐L‐alaninamide ( 4a ) gave the chiral ( S )‐ketone 8 with ee exceeding 96%. Sodium borohydride reduction of 8 , followed by sequential condensation with ethyl 6‐amino‐4‐chloro‐5‐nitro‐2‐pyridine carbamate ( 11 ), chromium trioxide oxidation, and catalytic hydrogenation over Raney nickel gave the free base form of [ 14 C]CI‐980 ( 14a ), which was extremely unstable and readily aromatized to 15 . The free base 14a was, however, isolated under specially developed conditions and converted to the crystalline isethionate salt 14b in pure form.