Efficient Asymmetric Synthesis of N-[(1R)-6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl]-2-pyridinecarboxamide for Treatment of Human Papillomavirus Infections

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• 作者：Sharon D. Boggs ; Jeremy D. Cobb ; Kristjan S. Gudmundsson ; Lynda A. Jones ; Richard T. Matsuoka ; Alan Millar ; Daniel E. Patterson ; Vicente Samano ; Mark D. Trone ; Shiping Xie ; Xiao-ming Zhou
• 刊名：Organic Process Research & Development
• 出版年：2007
• 出版时间：May 2007
• 年：2007
• 卷：11
• 期：3
• 页码：539 - 545
• 全文大小：106K
• 年卷期：v.11,no.3(May 2007)
• ISSN：1520-586X

文摘

An efficient asymmetric synthesis of N-[(1R)-6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl]-2-pyridinecarboxamide 1, a potential treatment for human papillomavirus infections, isdescribed. The key step in the synthesis of this molecule is anasymmetric reductive amination directed by chiral (phenyl)ethylamines resulting in up to 96% disastereo facial selectivity.The synthesis is also highlighted by isolation of a unique2-picolinic acid salt of (1R)-6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-amine (13). Subsequent application of 1-propylphosphonic acid cyclic anhydride (T3P) for convenient amideformation from the two components of the salt provides theproduct 1 in high yield. The process research work leading tothe final synthesis includes a racemic synthesis followed byresolution with chiral supercritical fluid chromatography, andan enantioselective reductive amination via chiral transferhydrogenation catalyzed by Ru(II) complexes of N-[(1S,2S)-2-amino-1,2-diphenylethyl]-1-naphthalenesulfonamide or (R)-BINAP. Highlighting the practicality of the synthesis, the processhas been scaled up in 200-gallon reactors for delivery ofmultikilograms of the target compound 1 in over 99.5%enantiomeric purity.