ABSTRACT
This paper describes a remarkably efficient process for the preparation of gamma-secretase inhibitor 1. The target is synthesized in only five steps with an overall yield of 58%. The key operation is a highly selective and practical, crystallization-driven transformation for the conversion of a mixture of tertiary benzylic alcohols into the desired sulfide diastereomer with 94:6 dr. This unprecedented process is based upon a reversible carbon-sulfur bond formation under acidic conditions.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Carbon/chemistry , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Sulfur/chemistry , Amyloid Precursor Protein Secretases/metabolism , Crystallization , Fluorine/chemistry , Keto Acids/chemical synthesis , Keto Acids/chemistry , Magnesium/chemistry , Molecular Structure , Oxidation-Reduction , Protease Inhibitors/chemistry , Solubility , Stereoisomerism , Sulfides/chemistry , TemperatureABSTRACT
The development of a practical and highly convergent synthesis of an alpha(v)beta3 antagonist is described. The two key fragments present in this compound, a tetrahydropyrido[2,3-b]azepine ring system and a chiral 3-aryl-5-oxopentanoic acid, were constructed independently and then coupled at a late stage using a Wittig reaction. The pyridoazepine moiety was prepared from N-Boc 6-chloro-2-aminopyridine via directed ortho-metalation/alkylation followed by in situ cyclization. A Suzuki reaction was then used to attach the propionaldehyde side-chain required for Wittig coupling. The coupling partner was prepared from asymmetric methanolysis of a 3-substituted glutaric anhydride followed by elaboration of the acid moiety to the requisite beta-keto phosphorane. Using this route, kilogram quantities of the desired drug candidate were prepared.
Subject(s)
Azepines/chemical synthesis , Azepines/pharmacology , Integrin alphaVbeta3/antagonists & inhibitors , Pentanoic Acids/chemical synthesis , Pentanoic Acids/pharmacology , Azepines/chemistry , Cyclization , Molecular Structure , Pentanoic Acids/chemistry , Structure-Activity RelationshipABSTRACT
A streamlined and high-yielding synthesis of aprepitant (1), a potent substance P (SP) receptor antagonist, is described. The enantiopure oxazinone 16 starting material was synthesized via a novel crystallization-induced dynamic resolution process. Conversion of 16 to the penultimate intermediate cis-sec-amine 9 features a highly stereoselective Lewis acid-catalyzed trans acetalization of chiral alcohol 3 with trichloroacetimidate 18 followed by inversion of the adjacent chiral center on the morpholine ring. The six-step process for the synthesis of 9 was accomplished in extremely high overall yield (81%) and with only two isolations.
