ABSTRACT
[reaction: see text] A newly developed synthesis of a NO-releasing prodrug of rofecoxib is described. The highly productive process consists of five chemical steps and produces prodrug 1 in an overall 64% yield from commercially available 3-phenyl-2-propyn-1-ol (4). The synthesis is highlighted by the carbometalation reaction of propargyl alcohol 4 to generate the tetrasubstituted olefin core, sulfone acid 2. Additionally, two alternate end-game strategies to prepare NO-COXIB 1 from this intermediate were explored and developed: (1) a convergent synthesis where a bromonitrate side chain is introduced in one step and (2) a two-step sequence that first installs the requisite six-carbon ester side chain followed by chemoselective nitration.
Subject(s)
Cyclooxygenase Inhibitors/chemical synthesis , Lactones/chemical synthesis , Nitric Oxide/analysis , Sulfones/chemical synthesis , Carbon Dioxide , Cyclooxygenase Inhibitors/chemistry , Indicators and Reagents , Lactones/chemistry , Models, Molecular , Molecular Conformation , Prodrugs/chemical synthesis , Prodrugs/chemistry , Sulfones/chemistryABSTRACT
Two asymmetric syntheses of the NK(1) receptor antagonist 1-[2-(R)-{1-(R)-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-3-(R)-(3,4-difluorophenyl)-4-(R)-tetrahydro-2H-pyran-4-ylmethyl]-3-(R)-methylpiperidine-3-carboxylic acid (1) were developed. In both routes, the core tetrahydropyran stereochemistry was established by asymmetric conjugate addition to an alpha,beta-unsaturated ester (6), using an amide of the chiral auxiliary pseudoephedrine. Selective ester reduction then allowed formation of lactone 2 with the thermodynamically preferred trans geometry. The chiral ether side chain (3) was attached by stereoselective acetal substitution. In the first route, the chiral piperidine ester fragment was installed at the end by N-alkylation. In the shorter second synthesis, this piece was appended to the Michael acceptor at the beginning.
Subject(s)
Combinatorial Chemistry Techniques , Neurokinin-1 Receptor Antagonists , Piperidines/chemical synthesis , Pyrans/chemical synthesis , Alkylation , Molecular Structure , Piperidines/chemistry , Piperidines/pharmacology , Pyrans/chemistry , Pyrans/pharmacology , StereoisomerismABSTRACT
Access to a key 3-aryl-delta-lactone intermediate in enantiopure form using preparative chiral chromatography allowed expedited preparation of an important drug discovery target. A preclinical drug discovery strategy that combines rapid route discovery with effective use of preparative chiral chromatography can result in significant savings of both time and labor.
Subject(s)
Pharmaceutical Preparations/chemistry , Pharmaceutical Preparations/chemical synthesis , Amides/chemical synthesis , Amides/chemistry , Chromatography, High Pressure Liquid , Chromatography, Supercritical Fluid , Drug Design , Esters/chemical synthesis , Esters/chemistry , Indicators and Reagents , Lactones/chemical synthesis , Lactones/chemistry , Magnetic Resonance Spectroscopy , StereoisomerismABSTRACT
The concise synthesis of a potent thrombin inhibitor was accomplished by a mild lactone aminolysis between an orthogonally protected bis-benzylic amine and a diastereomerically pure lactone. The lactone was synthesized by the condensation of l-proline methyl ester with an enantiomerically pure hydroxy acid, which in turn was synthesized by a highly stereoselective (>500:1 er) and productive (100,000:1, S/C) enzymatic reduction of an alpha-ketoester. In addition, a second route to the enantiomerically pure lactone was accomplished by a diastereoselective ketoamide reduction.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Lactones/chemistry , Thrombin/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Molecular Structure , StereoisomerismABSTRACT
An efficient stereoselective synthesis of the orally active NK(1) receptor antagonist Aprepitant is described. A direct condensation of N-benzyl ethanolamine with glyoxylic acid yielded a 2-hydroxy-1,4-oxazin-3-one which was activated as the corresponding trifluoroacetate. A Lewis acid mediated coupling with enantiopure (R)-1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-ol afforded a 1:1 mixture of acetal diastereomers which was converted into a single isomer via a novel crystallization-induced asymmetric transformation. The resulting 1,4-oxazin-3-one was converted via a unique and highly stereoselective one-pot process to the desired alpha-(fluorophenyl)morpholine derivative. Interesting and unexpected [1,2]-Wittig and [1,3]-sigmatropic rearrangements were identified during the optimization of these key steps. In the final step, a triazolinone side chain was appended to the morpholine core. The targeted clinical candidate was thus obtained in 55% overall yield over the longest linear sequence.
Subject(s)
Morpholines/chemical synthesis , Neurokinin-1 Receptor Antagonists , Aprepitant , Crystallography, X-Ray , Lactams/chemical synthesis , Lactams/chemistry , Molecular Structure , Morpholines/chemistry , Oxazines/chemistry , StereoisomerismABSTRACT
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
The palladium-catalyzed N-(hetero)arylation of a number of heteroarylamines including 2-aminopyridines, 2-aminothiazoles, and their analogues has been realized using Xantphos as the ligand. Weak bases such as Cs(2)CO(3), Na(2)CO(3), and K(3)PO(4) were used in most cases to allow for the introduction of functional groups. Choice of the base and solvent was critical for the success of these reactions. [reaction: see text]
