RESUMO
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.
Assuntos
Indústria Farmacêutica , Preparações Farmacêuticas/química , Desenho de Fármacos , Humanos , Estrutura Molecular , Preparações Farmacêuticas/síntese químicaRESUMO
Aldehyde-bisulfite adducts dervied from unstable parent aldehydes were reductively alkylated in a direct fashion with a variety of amines. This approach features the use of 2-picoline borane as the reducing agent and a protic solvent for the reaction media and has been successfully applied to the synthesis of a DPP-IV inhibitor and a variety of other amines.
Assuntos
Aminas/química , Dipeptidil Peptidase 4/agonistas , Dipeptidil Peptidase 4/química , Morfolinas/química , Picolinas/química , Sulfitos/química , Aldeídos , Alquilação , Aminação , Boranos/químicaRESUMO
Two new, reliable syntheses of a pyrido[2,3-d]-pyrimidine inhibitor of the CXCR3 receptor are described. A nine-step synthesis of the CXCR3 inhibitor (1) from 2-aminonicotinic acid was demonstrated on a multikilogram scale and incorporates a classic resolution to deliver the enantioenriched active pharmaceutical ingredient (API). A second synthesis of the CXCR3 inhibitor starts from (+)-(D)-Boc alanine and 2-chloronicotinic acid and utilizes a Goldberg coupling. This second synthesis, performed on a gram scale, intersects the former route at a common intermediate thereby completing a formal synthesis of the enantioenriched API in higher overall yield without the need for a resolution.
Assuntos
Acetamidas/síntese química , Acetamidas/farmacologia , Hidrocarbonetos Fluorados/síntese química , Hidrocarbonetos Fluorados/farmacologia , Pirimidinas/síntese química , Pirimidinas/farmacologia , Receptores CXCR3/antagonistas & inibidores , Acetamidas/química , Alanina/química , Aldeídos/química , Aminas/química , Estereoisomerismo , Tartaratos/químicaRESUMO
The discovery of novel and highly potent oxopiperazine based B1 receptor antagonists is described. Compared to the previously described arylsulfonylated (R)-3-amino-3-phenylpropionic acid series, the current compounds showed improved in vitro potency and metabolic stability. Compound 17, 2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide, showed EC(50) of 10.3 nM in a rabbit biochemical challenge model. The practical syntheses of chiral arylsulfonylated oxopiperazine acetic acids are also described.
Assuntos
Acetamidas/uso terapêutico , Antagonistas de Receptor B1 da Bradicinina , Inflamação/tratamento farmacológico , Dor/tratamento farmacológico , Piperazinas/uso terapêutico , Acetamidas/síntese química , Acetamidas/química , Animais , Cães , Concentração Inibidora 50 , Camundongos , Modelos Animais , Estrutura Molecular , Piperazinas/síntese química , Piperazinas/química , Coelhos , Ratos , Receptor B1 da Bradicinina/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The enantioselective conjugate addition of alkynyl nucleophiles has been a long-standing challenge in synthetic chemistry. This paper describes a highly practical asymmetric conjugate alkynylation of Meldrum's acid-derived acceptors using cinchonidine (<$100/kg) as the chiral mediator. The process provides practical access to chiral beta-alkynyl acids. Noteworthy attributes of the method are its broad scope, high functional-group compatibility, and ease of scalability.
Assuntos
Alcinos/síntese química , Ácidos Carboxílicos/síntese química , Dioxanos/química , Alcinos/química , Ácidos Carboxílicos/química , Estrutura Molecular , EstereoisomerismoRESUMO
Heteroarenes are important structural moieties in many chemical industry fields. A highly efficient Pd/Cu-catalyzed C-H arylation method for a range of heterocycles has been discovered. It was found that the key to the success of this transformation is a combination of a palladium catalyst and a well-defined copper cocatalyst. The efficiency and low loadings of catalyst (0.25 mol %) and cocatalyst (1 mol %) together with the mild reaction conditions demonstrate this method to be practically useful and mechanistically interesting.
Assuntos
Cobre/química , Hidrocarbonetos Aromáticos/química , Compostos Organometálicos/química , Paládio/química , Fosfinas/química , Xantenos/química , Carbono/química , Catálise , Hidrogênio/químicaRESUMO
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.
Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Tiazóis/síntese química , Álcoois/química , Cloretos/química , Ciclização , Inibidores Enzimáticos/química , Solventes/química , Estereoisomerismo , Especificidade por Substrato , Tiazóis/químicaRESUMO
p38 MAP kinase inhibitors have attracted considerable interest as potential agents for the treatment of inflammatory diseases. Herein, we describe a concise and efficient synthesis of inhibitor 1 that is based on a phthalazine scaffold. Highlights of our approach include a practical synthesis of a 1,6-disubstituted phthalazine building block 24 as well as the one-pot formation of boronic acid 27. Significant synthetic work to understand the reactivity principles of the intermediates helped in selection of the final synthetic route. Subsequent optimization of the individual steps of the final sequence led to a practical synthesis of 1.
Assuntos
Inibidores de Proteínas Quinases/síntese química , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Amidas/química , Ácido Benzoico/química , Morfolinas/química , Ftalazinas/químicaRESUMO
A mild, one-pot synthesis of 4-quinolones is described. Under the optimal conditions, a variety of 2-substituted 4-quinolones were synthesized via sequential palladium-catalyzed amidation of 2'-bromoacetophenones followed by base-promoted intramolecular cyclization.