ORGN 410 |
| An integral part of our program to develop a practical, convergent and safe process for the synthesis of HCV (Hepatitis C Virus) protease inhibitor BILN2061 (1) was the development of suitable processes for the multi-kilogram preparation of its individual components, such as quinoline 3. Herein, we describe the development of an efficient, safe and practical process for the synthesis of 7-Methoxy-2-(2-amino-4-thiazolyl)-quinoline (3) and its coupling to macrocycle (2). Our new process for the synthesis of 3 allowed for a more convergent approach to BILN2061 (1) and eliminated the use of potentially dangerous reagents such as diazomethane used in the Medicinal Chemistry approach. Key aspects of the work described here are the optimization of the reaction conditions for the acetylation of m-anisidine via a Sugasawa reaction, as well as the optimization of the coupling of 2 and 3 by means of a brosylate displacement. Development of a process for the efficient synthesis of 3 allowed for the subsequent preparation of BILN2061 (1) in multi-kilogram amounts for toxicology, formulation and clinical studies.
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Process R&D, Practical Synthesis, and Methodology
1:00 PM-4:20 PM, Tuesday, 15 March 2005 Convention Center -- Room 11A, Oral
Division of Organic Chemistry |