ABSTRACT
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.
ABSTRACT
An efficient synthesis of the 2-aminocarbonylpyrrolidin-4-ylthio containing side chain of ertapenem (MK-0826) is described. Starting material N-(O,O-diisopropyl phosphoryl)-trans-4-hydroxy-L-proline is converted in a one-pot process to (2S)-cis-3-[[(4-mercapto-2-pyrrolidinyl)carbonyl]amino]benzoic acid monohydrochloride in 70-75% overall yield via a series of six reactions. The development of each of these reactions and the isolation of the product is discussed in detail.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Infective Agents/chemical synthesis , Carbapenems/chemical synthesis , Combinatorial Chemistry Techniques , Lactams , Anti-Bacterial Agents/chemistry , Anti-Infective Agents/chemistry , Carbapenems/chemistry , Chromatography, High Pressure Liquid , Ertapenem , Molecular Structure , Pyrrolidines/chemistry , Stereoisomerism , beta-LactamsABSTRACT
The synthesis of a spirobicyclic NK-1 receptor (Substance-P) antagonist 1 antipode is described. Retrosynthetic analysis reveals an allylic halide A bearing the cyclopropoxy-substituted aryl group and a 2-phenyl-3-piperidone B. The stereochemistry in the spirobicyclic system bearing three chiral centers is initially set via a highly diastereoselective zinc-mediated coupling of the allylic bromide 23 to the optically active ketopiperidine 3. The remaining benzylic asymmetric center is set by a diastereoselective hydroboration followed by cyclization to the spirobicyclic system.
