Practical synthesis of a (N)-(S)-2-hydroxy-3-methyl butyryl-1- (S)-alaninyl –(S)-1-amino-3-methyl-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one

ORGN 774

Sathish Boini, Boini_Sathish@lilly.com, Radhe Vaid, vaid_radhe_k@lilly.com, Ken Moder, John Pu, and David Mitchell, dmit@lilly.com. Chemical Product Research and Development, Eli Lilly and Company, Indianaplois, IN 46285
Abstract: Synthesis of the title compound was accomplished via acylation of (S)-alaninyl-(S)-1-amino-3-methyl-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one with activated trimethylsilyl ester of (S)-2-trimethylsilyloxy-3-methylbutyric acid, followed by in situ de-protection and crystallization. (S)-alaninyl-(S)-1-amino-3-methyl-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one was prepared by coupling of (S)-1-amino-3-methyl-4,5,6,7-tetrahydro-2H-3-benzazepi-2-one with activated N-(2-methoxycarbonyl-1-methyl-vinyl)-(S)-alanine sodium salt or N-BOC-(S)-alanine in form of mixed carboxylic carbonic anhydride followed by de-protection of protecting group under acidic conditions.