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Synthesis of three isotopically labeled versions and a metabolite of Aurora A kinase inhibitor

✍ Scribed by Yuexian Li; Shimoga R. Prakash

Publisher
John Wiley and Sons
Year
2009
Tongue
French
Weight
131 KB
Volume
52
Category
Article
ISSN
0022-2135

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✦ Synopsis

Abstract

Sodium ring‐[^14^C]‐4‐[[9‐chloro‐7‐(2,6‐difluorophenyl)‐5H‐pyrimido[5,4‐d][2]benzazepin‐2‐yl]amino]‐benzoate (1A, MLN8054), an Aurora A kinase inhibitor, was synthesized from [^14^C]‐cyanamide in two steps in an overall radiochemical yield of 7%. The intermediate, [^14^C]‐4‐guanidinobenzoic acid, was prepared by coupling [^14^C]‐cyanamide with 4‐aminobenzoic acid. Sodium carboxyl‐[^14^C]‐4‐[[9‐chloro‐7‐(2,6‐difluorophenyl)‐5H‐pyrimido[5,4‐d][2]benzazepin‐2‐yl]amino]‐benzoate (1B) was synthesized from carboxyl‐[^14^C]‐4‐guanidinobenzoic acid in one step in a radiochemical yield of 35%. [D~4~,^15^N]‐4‐[[9‐chloro‐7‐(2,6‐difluorophenyl)‐5H‐pyrimido[5,4‐d][2]benzazepin‐2‐yl]amino]‐benzoic acid (1C) was synthesized from [^15^N~2~]‐cyanamide and [D~4~]‐4‐aminobenzoic acid in two steps in an overall yield of 37%. The major metabolite, β‐acyl glucuronide of 4‐[[9‐chloro‐7‐(2,6‐difluorophenyl)‐5H‐pyrimido[5,4‐d][2]benzazepin‐2‐yl]amino]‐benzoic acid (14), was synthesized from D‐glucuronic acid in three steps in an overall yield of 1%. The key intermediate for synthesis of glucuronide was prepared by HATU catalyzed coupling of 4‐[[9‐chloro‐7‐(2,6‐difluorophenyl)‐5H‐pyrimido[5,4‐d][2]benzazepin‐2‐yl]amino]‐benzoic acid with allyl glucuronate. Copyright © 2009 John Wiley & Sons, Ltd.

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