ABSTRACT
Visible-light-promoted organic reactions can offer increased reactivity and selectivity via unique reaction pathways to address a multitude of practical synthetic problems, yet few practical solutions exist to employ these reactions for multikilogram production. We have developed a simple and versatile continuous stirred tank reactor (CSTR) equipped with a high-intensity laser to drive photochemical reactions at unprecedented rates in continuous flow, achieving kg/day throughput using a 100 mL reactor. Our approach to flow reactor design uses the Beer-Lambert law as a guideline to optimize catalyst concentration and reactor depth for maximum throughput. This laser CSTR platform coupled with the rationale for design can be applied to a breadth of photochemical reactions.
ABSTRACT
Understanding impurity rejection in a drug substance crystallization process is valuable for establishing purity specifications for the starting materials used in the process. Impurity rejection has been determined for all known ABT-510 impurities and for many of the reasonable & conceivable impurities. Based on this study, a very high purity specification (e.g., > 99.7%) can be set for ABT-510 with a high level of confidence.
Subject(s)
Angiogenesis Inhibitors/chemistry , Oligopeptides/chemistry , CrystallizationABSTRACT
Dipeptidyl peptidase-IV (DPP-IV) inhibitors are poised to be the next major drug class for the treatment of type 2 diabetes. Structure-activity studies of substitutions at the C5 position of the 2-cyanopyrrolidide warhead led to the discovery of potent inhibitors of DPP-IV that lack activity against DPP8 and DPP9. Further modification led to an extremely potent (Ki(DPP)(-)(IV) = 1.0 nM) and selective (Ki(DPP8) > 30 microM; Ki(DPP9) > 30 microM) clinical candidate, ABT-279, that is orally available, efficacious, and remarkably safe in preclinical safety studies.
Subject(s)
Adenosine Deaminase Inhibitors , Dipeptidyl-Peptidase IV Inhibitors , Glycoproteins/antagonists & inhibitors , Hypoglycemic Agents/chemical synthesis , Pyridines/chemical synthesis , Pyrrolidines/chemical synthesis , Adenosine Deaminase/chemistry , Administration, Oral , Animals , Binding Sites , Caco-2 Cells , Crystallography, X-Ray , Diabetes Mellitus, Type 2/drug therapy , Dipeptidyl Peptidase 4/chemistry , Dogs , Female , Glucose Intolerance/drug therapy , Glycoproteins/chemistry , Humans , Hypoglycemic Agents/pharmacokinetics , Hypoglycemic Agents/pharmacology , Macaca fascicularis , Models, Molecular , Molecular Structure , Pyridines/pharmacokinetics , Pyridines/pharmacology , Pyrrolidines/pharmacokinetics , Pyrrolidines/pharmacology , Rats , Rats, Sprague-Dawley , Rats, Zucker , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Ketoester 1 is cyclized to give pyran-3,5-dione 2 in 78% yield using a parallel addition of ketoester 1 and base NaO(t)Bu in refluxing THF. Compared to the previously reported procedures, these optimized conditions have significantly increased the yield of this transformation and the quality of pyran 2 and prove to be suitable for large-scale preparation. An application of 2 to the synthesis of ABT-598, a potassium channel opener, is demonstrated.
Subject(s)
Potassium Channels/agonists , Pyrans/chemical synthesis , Pyrones/chemical synthesis , Cyclization , Esters/chemistry , tert-Butyl AlcoholABSTRACT
The enantioselective synthesis of endothelin-A antagonist ABT-546 has been accomplished via the discovery and development of a highly selective catalytic asymmetric conjugate addition of ketoesters to nitroolefins. Employing just 4 mol % bis(oxazoline)-Mg(OTf)(2) complex with an amine cocatalyst, we obtained the product nitroketone with 88% selectivity at the aryl-bearing stereocenter and in good yield on scales ranging to 13 mol. The effects of ligand structure, metal salt, and solvent on the reaction are described. Particularly important to the reaction is the water content. While water is necessary during the generation of the catalyst, the water must be then removed to maximize stereoselectivity and reactivity. The reaction has been extended to other dicarbonyl substrates, and a variety of substitution patterns are tolerated on the nitroolefin partner. The reaction has also been employed in the synthesis of the antidepressant rolipram. Investigations relating to the mechanism of the reaction are also described.
Subject(s)
Alkenes/chemistry , Nitro Compounds/chemistry , Pyrrolidines/chemical synthesis , Rolipram/chemical synthesis , Antidepressive Agents/chemical synthesis , Catalysis , Endothelin Receptor Antagonists , Receptor, Endothelin A , Stereoisomerism , Styrenes/chemistryABSTRACT
[reaction: see text]. A highly diastereoselective coupling reaction between TBSOP (3) and trityl sulfenimine 4 was developed which provided influenza neuraminidase inhibitor intermediate 7 in 80% yield and >99% de after crystallization. The reaction was shown to be reversible with the high diastereoselectivity resulting from a favorable H-bonding interaction in the major diastereomer.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Neuraminidase/antagonists & inhibitors , Orthomyxoviridae/enzymology , Pyrrolidines/chemical synthesis , Pyrrolidines/pharmacology , Chromatography, High Pressure Liquid , Crystallization , Crystallography, X-Ray , Hydrogen Bonding , Indicators and Reagents , Magnetic Resonance Spectroscopy , Mass Spectrometry , StereoisomerismABSTRACT
[reaction: see text] Treatment of a variety of alcohols, amines, and N-hydroxylamines with 2,2,2-trifluoroethyl formate gave the corresponding formylated adducts in high yields.
