ABSTRACT
An efficient general methodology for the synthesis of 4-quinolinyl ethers is demonstrated via a highly reactive SNAr reaction of 4-quinolinyl sulfones with a range of structurally diversified 1°, 2°, and 3° alcohols with a wide substrate scope and high yields. By adapting this methodology, a convergent synthesis of a complex target of HCV NS3/4a protease inhibitor BI 201420 was accomplished.
Subject(s)
Hepatitis C , Viral Nonstructural Proteins , Antiviral Agents , Ethers , Hepacivirus , Humans , Protease Inhibitors/pharmacology , SulfonesABSTRACT
A potent reversible inhibitor of the cysteine protease cathepsin-S was prepared on large scale using a convergent synthetic route, free of chromatography and cryogenics. Late-stage peptide coupling of a chiral urea acid fragment with a functionalized aminonitrile was employed to prepare the target, using 2-hydroxypyridine as a robust, nonexplosive replacement for HOBT. The two key intermediates were prepared using a modified Strecker reaction for the aminonitrile and a phosphonation-olefination-rhodium-catalyzed asymmetric hydrogenation sequence for the urea. A palladium-catalyzed vinyl transfer coupled with a Claisen reaction was used to produce the aldehyde required for the side chain. Key scale up issues, safety calorimetry, and optimization of all steps for multikilogram production are discussed.
Subject(s)
Alkenes/chemical synthesis , Cathepsins/antagonists & inhibitors , Cathepsins/chemistry , Enzyme Inhibitors/chemical synthesis , Urea/chemical synthesis , Vinyl Compounds/chemical synthesis , Alkenes/chemistry , Calorimetry/methods , Catalysis , Cyclization , Enzyme Inhibitors/pharmacology , Indicators and Reagents/chemistry , Models, Molecular , Molecular Structure , Palladium/chemistry , Rhodium/chemistry , Stereoisomerism , Urea/chemistry , Vinyl Compounds/chemistryABSTRACT
A sequential allyl vinyl ether formation-Claisen rearrangement process catalyzed by a palladium(II)-phenanthroline complex is reported. The effects of allylic alcohol structure, type of vinylating agent, and palladium catalysts are discussed. This method provides a convenient approach to gamma,delta-unsaturated aldehydes under mild conditions that avoid the use of toxic Hg(II) catalysts. The new methodology has been successfully demonstrated on the kilogram scale.
Subject(s)
Aldehydes/chemical synthesis , Palladium/chemistry , Phenanthrolines/chemistry , Propanols/chemistry , Vinyl Compounds/chemistry , Aldehydes/chemistry , Catalysis , Stereoisomerism , ThermodynamicsABSTRACT
[reaction: see text] The 5-bromopyridyl-2-magnesium chloride (2), which was not accessible previously, was efficiently synthesized for the first time via an iodo-magnesium exchange reaction with 5-bromo-2-iodopyridine (1). This reactive intermediate was allowed to react with a variety of electrophiles to afford a range of useful functionalized pyridine derivatives. Application of this methodology to 5-bromo-2-iodo-3-picoline provided a simple and economical synthesis of a key intermediate for the preparation of Lonafarnib, a potent anticancer agent.
Subject(s)
Magnesium Chloride/chemistry , Organometallic Compounds/chemical synthesis , Pyridines/chemical synthesis , Magnesium Chloride/chemical synthesis , Molecular Structure , Organometallic Compounds/chemistry , Pyridines/chemistryABSTRACT
The tyrosine kinase p56lck (lck) is essential for T cell activation; thus, inhibitors of lck have potential utility as autoimmune agents. Our initial disclosure of a new class of lck inhibitors based on the phenylaminoimidazoisoquinolin-9-one showed reasonable cellular activity but did not work in vivo upon oral administration. Our current work highlights the further use of rational drug design and molecular modeling to produce a series of lck inhibitors that demonstrate cellular activity below 100 nM and are as efficacious as cyclosporin A in an in vivo mouse model of anti-CD3-induced IL-2 production.
Subject(s)
Benzimidazoles/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Immunosuppressive Agents/chemical synthesis , Isoquinolines/chemical synthesis , Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/antagonists & inhibitors , Administration, Oral , Animals , Antibodies, Monoclonal/pharmacology , Benzimidazoles/chemistry , Benzimidazoles/pharmacology , CD3 Complex/immunology , Crystallography, X-Ray , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Female , Humans , Immunosuppressive Agents/chemistry , Immunosuppressive Agents/pharmacology , Interleukin-2/antagonists & inhibitors , Interleukin-2/biosynthesis , Interleukin-2/blood , Isoquinolines/chemistry , Isoquinolines/pharmacology , Jurkat Cells , Mice , Mice, Inbred BALB C , Models, Molecular , Molecular Conformation , Protein Binding , Structure-Activity RelationshipABSTRACT
A practical and improved synthesis of (3S,5S)-3-[(tert-butyloxycarbonyl)methyl]-5-[(methanesulfonyloxy)methyl]-2-pyrrolidinone (1) is described. The key transformations involve a highly efficient reaction sequence consisting of ethoxycarbonylation, alkylation, hydrolysis, and decarboxylation to produce compound 10. The process described herein is practical, robust, and cost-effective, and it has been successfully implemented in a pilot plant to produce a multikilogram quantity of mesylate 1.
ABSTRACT
An imidazo[4,5-h]isoquinolin-7,9-dione (1) was identified as an adenosine 5'-triphosphate competitive inhibitor of lck by high throughput screening. Initial structure-activity relationship studies identified the dichlorophenyl ring and the imide NH as important pharmacophores. A binding model was constructed to understand how 1 binds to a related kinase, hck. These results suggested that removing the gem-dimethyl group and flattening the ring would enhance activity. This was realized by converting 1 to the imidazo[4,5-h]isoquinolin-9-one (20), resulting in an 18-fold improvement in potency against lck and a 50-fold increase in potency in a cellular assay.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Imidazoles/chemical synthesis , Isoquinolines/chemical synthesis , Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/antagonists & inhibitors , Animals , Antibodies/pharmacology , Binding Sites , CD3 Complex/immunology , Crystallography, X-Ray , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Female , Humans , Imidazoles/chemistry , Imidazoles/pharmacology , Interleukin-2/biosynthesis , Isoquinolines/chemistry , Isoquinolines/pharmacology , Jurkat Cells , Mice , Mice, Inbred BALB C , Models, Molecular , Molecular Conformation , Structure-Activity Relationship , T-Lymphocytes/drug effects , T-Lymphocytes/metabolismABSTRACT
A new and efficient enantioselective synthesis of the (S)-alpha,alpha-disubstituted phenethylamine 1 via Lipase resolution of the esters 3 and 4 is described. The effect of pH, enzyme load, and solubilizing additives has been studied and optimized. Conversion of the carboxylic acid 10 to the desired thiazole 1 is accomplished in high overall yield via an intermediate oxazolinone 13. This facile process requires only a single chromatographic step, and multigram quantities of 1 have been prepared.
