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Bulletin of the Korean Chemical Society (BKCS)

ISSN 0253-2964(Print)
ISSN 1229-5949(Online)
Volume 24, Number 4
BKCSDE 24(4)
April 20, 2003 

Synthesis of Ketoconazole Derivatives
Jae Chun Ryu, Kwang Jae Lee, Sang Hee Lee
Drug master file (DMF), Ketoconazole, Impurities, 1,4-Dihydropyrazine
For the drug master file (DMF) of ketoconazole, four impurities (1-4) contained in ketoconazole were synthesized. During the synthesis of 2, a new synthetic method of 1,4-dihydropyrazine was established. To oxidize the aminoalcohol (2j) to the aminal (2j-1), the standard Swern oxidation condition was modified to mask the nucleophilicity of the amino group temporarily using one equivalent of acetic acid. Derivative 3 was synthesized via regioselective bromination at the 2 position of the 4-aminophenol derivative (3a) using Br2 in the presence of p-TsOH. The etherification of aryl bromide with the phenol derivative (1f) was accomplished by a modification of the general Cu-mediated reaction condition using excess 1f itself as a solvent at elevated temperature (190 oC).
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