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Synthesis of 1,2,4‐triazole and thiazole analogs of ketoconazole
Author(s) -
Huang LiangFu,
Kim JangWoo,
Bauer Ludwig,
Doss George
Publication year - 1997
Publication title -
journal of heterocyclic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.321
H-Index - 59
eISSN - 1943-5193
pISSN - 0022-152X
DOI - 10.1002/jhet.5570340219
Subject(s) - chemistry , diastereomer , thiazole , bromide , alkylation , piperazine , ketone , methylene , stereochemistry , organic chemistry , medicinal chemistry , catalysis
The synthesis of 1,2,4‐triazole and thiazole analogs of ketoconazole is described in which one of the α azole ring carbons is linked to C‐2 of the ketal by means of a three methylene tether. Lithiation of 1‐methyl‐1,2,4‐triazole and thiazole and subsequent alkylation with 2‐(2,4‐dichlorophenyl)‐2‐(3‐iodopropyl)‐1,3‐dioxolane produced, after an aqueous acidic workup, 2,4‐dichlorophenyl 3‐[5‐(1‐methyl‐1,2,4‐triazolyl) and 2‐thiazolyl]propyl ketones, respectively. Ketalization with glycerol furnished the corresponding diastereomeric pairs of cis and trans 1,3‐ dioxolanes. The reaction of 2,4‐dichlorophenyl 3‐[5‐(1‐methyl‐1,2,4‐triazolyl)]propyl ketone with 3‐mercapto‐1,2‐propanediol produced the corresponding diastereomeric cis and trans hydroxymethyl 1,3‐oxathiolanes. The diastereomeric racemates were separated by column chromatography and their stereochemistry established by nOe nmr experiments. Some of these racemic cis ketal alcohols were converted by benzyl bromide to the corresponding benzyl ethers. Several of these racemic cis ‐ketals were reacted, first with methanesulfonyl chloride, then with 1‐acetyl‐4‐(4‐hydroxyphenyl)piperazine, to furnish the title compounds.