ABSTRACT
An organocatalyzed, formal (3+3) cycloaddition reaction is described for the practical synthesis of substituted pyridines. Starting from readily available enamines and enal/ynal/enone substrates, the protocol affords tri- or tetrasubstituted pyridine scaffolds bearing various functional groups. This method was demonstrated on a 50 g scale, enabling the synthesis of 2-isopropyl-4-methylpyridin-3-amine, a raw material used for the manufacture of sotorasib. Mechanistic analysis using two-dimensional nuclear magnetic resonance (NMR) spectrometry revealed the transformation proceeds through the reversible formation of a stable reaction off-cycle species that precedes pyridine formation. In situ reaction progress kinetic analysis and control NMR studies were employed to better understand the role of FeCl3 and pyrrolidine hydrochloride in promoting the reaction.
Subject(s)
Aldehydes , Ketones , Aldehydes/chemistry , Catalysis , Cycloaddition Reaction , Ketones/chemistry , Kinetics , Pyridines/chemistryABSTRACT
The ipso nitration of aryl boronic acid derivatives has been developed using fuming nitric acid as the nitrating agent. This facile procedure provides efficient and chemoselective access to a variety of aromatic nitro compounds. While several activating agents and nitro sources have been reported in the literature for this synthetically useful transformation, this report demonstrates that these processes likely generate a common active reagent, anhydrous HNO3. Kinetic and mechanistic studies have revealed that the reaction order in HNO3 is >2 and indicate that the â¢NO2 radical is the active species.
Subject(s)
Boronic Acids , Nitric Acid , NitratesABSTRACT
Experimental and computational studies of the unexpected racemization of enantiopure fused cyclopropyl isoxazolines are reported. These studies offer insights into the mechanism of racemization, quantify the position of the transition state on the dipolar-diradical continuum, and establish a relationship between the structure and stability of this class of compounds. Experimental and computed energy barriers for racemization are also presented.
ABSTRACT
A Perspective of our work in the development of innovative synthetic methods within the discipline of Process Research and Development is presented. Through an overview of some of the programs that we have worked on during the past decade, we have selected cases studies to illustrate the challenges faced in development of robust chemical processes for molecules on a multi-kilogram scale. The examples have been selected to demonstrate the innovative chemistry being developed within our laboratories with a focus on fragment design, asymmetric synthesis, new synthetic reagents, and the methods that have allowed us to deliver cost-effective syntheses under reduced timelines in an increasingly competitive environment. The technical challenges are presented in the context of molecule complexity that while increasing in the portfolio of small molecules being developed inspires us to deliver new solutions. Overall, our goal is to highlight the exciting work that can be done within our field to support the discovery and delivery of medicines to patients.
Subject(s)
Drug Industry , Pharmaceutical Preparations/chemistry , Drug Design , Humans , Molecular Structure , Pharmaceutical Preparations/chemical synthesisABSTRACT
A robust process to manufacture AMG 232 was developed to deliver drug substance of high purity. Highlights of the commercial process development efforts include the following: (i) use of a novel bench-stable Vilsmeier reagent, methoxymethylene- N, N-dimethyliminium methyl sulfate, for selective in situ activation of a primary alcohol intermediate; (ii) use of a new crystalline and stable isopropyl calcium sulfinate reagent ensuring robust preparation of a sulfone intermediate; (iii) development of a safe ozonolysis process conducted in an aqueous solvent mixture in either batch or continuous manufacturing mode; and (iv) control of the drug substance purity by crystallization of a salt rejecting impurities effectively. The new process was demonstrated to afford the drug substance (99.9 LC area %) in 49.8% overall yield from starting material DLAC (1).
Subject(s)
Acetates/chemical synthesis , Ozone/chemistry , Piperidones/chemical synthesis , Acetates/chemistry , Acetates/isolation & purification , Molecular Structure , Piperidones/chemistry , Piperidones/isolation & purificationABSTRACT
The efficacy of therapeutic antibodies that induce antibody-dependent cellular cytotoxicity can be improved by reduced fucosylation. Consequently, fucosylation is a critical product attribute of monoclonal antibodies produced as protein therapeutics. Small molecule fucosylation inhibitors have also shown promise as potential therapeutics in animal models of tumors, arthritis, and sickle cell disease. Potent small molecule metabolic inhibitors of cellular protein fucosylation, 6,6,6-trifluorofucose per-O-acetate and 6,6,6-trifluorofucose (fucostatin I), were identified that reduces the fucosylation of recombinantly expressed antibodies in cell culture in a concentration-dependent fashion enabling the controlled modulation of protein fucosylation levels. 6,6,6-Trifluorofucose binds at an allosteric site of GDP-mannose 4,6-dehydratase (GMD) as revealed for the first time by the X-ray cocrystal structure of a bound allosteric GMD inhibitor. 6,6,6-Trifluorofucose was found to be incorporated in place of fucose at low levels (<1%) in the glycans of recombinantly expressed antibodies. A fucose-1-phosphonate analog, fucostatin II, was designed that inhibits fucosylation with no incorporation into antibody glycans, allowing the production of afucosylated antibodies in which the incorporation of non-native sugar is completely absent-a key advantage in the production of therapeutic antibodies, especially biosimilar antibodies. Inhibitor structure-activity relationships, identification of cellular and inhibitor metabolites in inhibitor-treated cells, fucose competition studies, and the production of recombinant antibodies with varying levels of fucosylation are described.
Subject(s)
Fucose/metabolism , Hydro-Lyases/metabolism , Small Molecule Libraries , Animals , CHO Cells , Cricetinae , Cricetulus , Crystallography, X-Ray , Fucose/antagonists & inhibitors , Guanosine Diphosphate Mannose/metabolism , Mass Spectrometry , Molecular Structure , Surface Plasmon ResonanceABSTRACT
IgG1 monoclonal antibodies with reduced glycan fucosylation have been shown to improve antibody-dependent cellular cytotoxicity (ADCC) by allowing more effective binding of the Fc region of these proteins to T cells receptors. Increased in vivo efficacy in animal models and oncology clinical trials has been associated with the enhanced ADCC provided by these engineered mAbs. 6,6,6-Trifluorofucose (1) is a new inhibitor of fucosylation that has been demonstrated to allow the preparation of IgG1 monoclonal antibodies with lower fucosylation levels and thus improve the ADCC of these proteins. A new process has been developed to support the preparation of 1 on large-scale for wide mAb manufacture applications. The target fucosylation inhibitor (1) was synthesized from readily available d-arabinose in 11% overall yield and >99.5/0.5 dr (diastereomeric ratio). The heavily telescoped process includes seven steps, two crystallizations as purification handles, and no chromatography. The key transformation of the sequence involves the diastereoselective preparation of the desired trifluoromethyl-bearing alcohol in >9/1 dr from a trimethylsilylketal intermediate via a ruthenium-catalyzed tandem ketal hydrolysis-transfer hydrogenation process.
Subject(s)
Antibodies, Monoclonal/chemistry , Fucose/analogs & derivatives , Fucose/chemistry , Antibody-Dependent Cell Cytotoxicity , Catalysis , Crystallization , Hydrogenation , Immunoglobulin G/chemistry , Oxidation-Reduction , Ruthenium , StereoisomerismABSTRACT
An expeditious synthetic approach to chiral phenol 1, a key building block in the preparation of a series of drug candidates, is reported. The strategy includes a cost-effective and readily scalable route to cyclopentanone 3 from isobutyronitrile (10). The sterically hindered and enolizable ketone 3 was subsequently employed in a challenging Grignard addition mediated by LaCl(3)·2LiCl. A novel preparation of the lanthanide reagent required for this transformation is described. To complete the process, a highly enantioselective hydrogenation step afforded the target (1). The importance of the phenol group to the success of this asymmetric transformation is discussed.
Subject(s)
Alkenes/chemistry , Phenols/chemical synthesis , Catalysis , Hydrogenation , Molecular Structure , Phenols/chemistry , StereoisomerismABSTRACT
A new synthetic strategy that turns styrene-type olefins into excellent substrates for Rh-catalyzed asymmetric hydrogenation by installing a 2'-hydroxyl substituent is described. This methodology accommodates trisubstituted olefinic substrates in various E/Z mixtures, leading to valuable benzylic chiral compounds including (R)-tolterodine. It is also demonstrated that the 2'-hydroxyl groups could be readily removed in high yield without loss of ee from the products. Thus, this technology represents an attractive alternative to the Ir(P-N) catalyst system for the asymmetric hydrogenation of unfunctionalized olefins.
Subject(s)
Hydroxyl Radical/chemistry , Styrene/chemistry , Hydrogenation , Molecular Structure , StereoisomerismABSTRACT
The synthesis and SAR of a series of 4,4-disubstituted cyclohexylbenzamide inhibitors of 11ß-HSD1 are described. Optimization rapidly led to potent, highly selective, and orally bioavailable inhibitors demonstrating efficacy in both rat and non-human primate ex vivo pharmacodynamic models.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Benzamides/chemistry , Enzyme Inhibitors/chemical synthesis , 11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism , Administration, Oral , Animals , Benzamides/chemical synthesis , Benzamides/pharmacokinetics , Binding Sites , Crystallography, X-Ray , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , Humans , Macaca fascicularis , Microsomes, Liver/metabolism , Rats , Structure-Activity RelationshipABSTRACT
Two asymmetric syntheses of AMG 221 (2), an inhibitor of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) discovered in our laboratories, are reported. One of the syntheses utilizes chiral trimethylsilyl cyanohydrin 12 as starting material and the other utilizes its enantiomer ent-12. The displacement approach involves the conversion of 12 to 2 via a six-step sequence, occurs with net inversion of configuration, and employs amine 6 as starting material. This route features a novel approach toward chiral dialkylsubstituted alpha-mercaptoacids. The cyclization approach entails the synthesis of 2 from ent-12 in 2 steps, takes place with net retention of configuration, and uses thiourea 8 as starting material. The final step of this route exemplifies a novel synthesis of chiral C-5 dialkylsubstituted 2-aminothiazolones from chiral alpha-hydroxyacids and thioureas. Insights into the mechanism of this transformation and study of the effect of the medium on the stereochemical outcome of the reaction are presented.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Thiazoles/chemical synthesis , Alcohols/chemistry , Chlorides/chemistry , Cyclization , Enzyme Inhibitors/chemistry , Solvents/chemistry , Stereoisomerism , Substrate Specificity , Thiazoles/chemistryABSTRACT
Novel 4,4-disubstituted cyclohexylbenzamide inhibitors of 11beta-HSD1 were optimized to account for liabilities relating to in vitro pharmacokinetics, cytotoxicity and protein-related shifts in potency. A representative compound showing favorable in vivo pharmacokinetics was found to be an efficacious inhibitor of 11beta-HSD1 in a rat pharmacodynamic model (ED(50)=10mg/kg).
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Benzamides/chemistry , 11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism , Animals , Benzamides/pharmacology , Dose-Response Relationship, Drug , HeLa Cells , Humans , Macaca fascicularis , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
A diastereoselective palladium-catalyzed arylation of 4-substituted cyclohexyl esters has been developed. The reaction proceeds at room temperature in the presence of [(t-Bu3P)PdBr]2 providing products in up to 37:1 dr.
ABSTRACT
We report the discovery of potent benzamide inhibitors of 11beta-hydroxysteroid dehydrogenase (11beta-HSD1). The optimization and correlation of in vitro and in vivo metabolic stability will be described. Through modifications to our initial lead 2, we discovered pyridyl compound 13. This compound has a favorable pharmacokinetic profile across three species and showed a dose-dependent decrease in adipose 11beta-HSD1 activity in a monkey ex vivo pharmacodynamic model.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Benzamides/administration & dosage , Benzamides/chemical synthesis , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemical synthesis , 11-beta-Hydroxysteroid Dehydrogenase Type 1/chemistry , 11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism , Administration, Oral , Animals , Benzamides/chemistry , Benzamides/metabolism , Cell Line , Crystallography, X-Ray , Dogs , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/metabolism , Humans , Macaca fascicularis , Models, Animal , Models, Molecular , Molecular Structure , Rats , Structure-Activity RelationshipABSTRACT
Two new methods for the synthesis of 2-aminothiazolones from 2-(4-methoxybenzylthio)acetic acids are described. A single reagent and simple experimental conditions are used in the key tandem deprotection-cyclization process. In the first approach 2-aminothiazolones are directly accessed via cyclization of the corresponding N-acylisothioureas. The second complementary approach provides access to a variety of 2-thiomethylthiazolones via cyclization of N-acyldithioimidates. The product 2-thiomethylthiazolones are then efficiently converted to 2-aminothiazolones via amine displacement.