Paper
Robust Synthesis of Methyl 5-Chloro-4-fluoro-1H-indole-2-carboxylate: A Key Intermediate in the Preparation of an HIV NNRTI Candidate
Published Aug 16, 2010 · B. Mayes, N. Chaudhuri, Christopher P. Hencken
Organic Process Research & Development
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Abstract
A synthetic preparation of methyl 5-chloro-4-fluoro-1H-indole-2-carboxylate, a key intermediate towards phosphoindole inhibitors of HIV non-nucleoside reverse transcriptase, is described. The five-step synthesis involved Boc protection of the commercially available 4-chloro-3-fluoroaniline and regioselective iodination at C-2. After facile Boc deprotection, cyclization of the resultant o-iodoaniline gave the corresponding 5-chloro-4-fluoro-indole-2-carboxylic acid which was subsequently esterified to provide the target indole ester in 56% overall yield. Identification of 6-chloro-7-iodo-2(3H)-benzoxazolone as a significant side product in the iodination step led to the development of conditions which eliminated its formation in subsequent batches. Advantages of this alternative approach relative to existing methodologies include (1) potentially hazardous diazonium and azido species were not required, (2) regioisomeric products were not generated, and (3) chromatographic isolations were avoided, as all int...
This study presents a robust synthetic approach for preparing methyl 5-chloro-4-fluoro-1H-indole-2-carboxylate, a key intermediate in the preparation of an HIV NNRTI candidate, with advantages over existing methodologies.
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