RESUMEN
A method for the preparation of highly functionalized 4-iodo-7-azaindazoles is reported. These valuable heterocycles are synthesized via condensation of 2-hydrazineylpyrimidines with various iodoalkynones followed by Diels-Alder/retro-Diels-Alder cyclization. The method is general to the formation of products with a variety of C3, C5, and C6 substituents while preserving the C4 iodide functional handle for further late-stage functionalization. The utility of this transformation is demonstrated through the rapid synthesis of several bioactive azaindazole targets.
RESUMEN
We report a diastereoselective, photocatalyst-free decarboxylative alkylation of (hetero)aryl sulfinimines using redox-active esters under blue light. High yields and diastereoselectivities can be achieved under mild conditions, and we demonstrate its utility as a synthetic method, especially for medicinal chemists.
Asunto(s)
Iminas , Catálisis , Estructura Molecular , AlquilaciónRESUMEN
We describe practical methods to prepare DOTAGA-DBCO and DFO-DBCO from commercially available starting materials. DOTAGA-DBCO is available in five steps from cyclen with a 33 % overall yield at gram scale. Our synthesis of DFO-DBCO also proceeds in five steps from commercially available starting materials. These bifunctional molecules possess chelating functionality for the binding of medically important radiometals and a strained alkyne suitable for Huisgen cyclization with an azide. These syntheses represent an important step toward improved radioimmunoconjugates for imaging and therapeutic applications.
Asunto(s)
Ciclamas , Inmunoconjugados , Alquinos/química , Azidas/química , Ciclización , Inmunoconjugados/farmacología , Inmunoconjugados/uso terapéuticoRESUMEN
Herein a method for the radical alkylation of heteroaryl halides that relies upon the combination of photoredox and nickel catalysis is described. The use of aliphatic N-(acyloxy)phthalimides as redox-active esters affords primary and secondary radicals for the decarboxylative dual cross-coupling with pyrimidine and pyridine heteroaryl chlorides, bromides, and iodides. The method provides an additional synthetic tool for the incorporation of medicinally relevant heterocyclic motifs.
Asunto(s)
Ésteres , Níquel , Alquilación , Estructura Molecular , Oxidación-Reducción , Procesos FotoquímicosRESUMEN
The synthesis and preclinical characterization of two novel, brain penetrating P2X7 compounds will be described. Both compounds are shown to be high potency P2X7 antagonists in human, rat, and mouse cell lines and both were shown to have high brain concentrations and robust receptor occupancy in rat. Compound 7 is of particular interest as a probe compound for the preclinical assessment of P2X7 blockade in animal models of neuro-inflammation.
RESUMEN
A POCl(3)-mediated, direct amination reaction of heterocyclic amides/ureas with NH-heterocycles or N-substituted anilines is described. Compared to the existing methods, this operationally simple protocol provides unique reactivity and functional group compatibility because of the metal-free, acidic reaction conditions. The yields are generally excellent.
Asunto(s)
Amidas/química , Química Farmacéutica/métodos , Compuestos Heterocíclicos/síntesis química , Medicamentos bajo Prescripción/síntesis química , Urea/química , Aminación , Compuestos de Anilina/química , Anticolesterolemiantes/análisis , Anticolesterolemiantes/química , Compuestos de Azabiciclo/análisis , Compuestos de Azabiciclo/química , Benzamidas , Catálisis , Clorhidrato de Erlotinib , Eszopiclona , Fluorobencenos/análisis , Fluorobencenos/química , Compuestos Heterocíclicos/análisis , Humanos , Concentración de Iones de Hidrógeno , Hipnóticos y Sedantes/análisis , Hipnóticos y Sedantes/química , Hipoglucemiantes/análisis , Hipoglucemiantes/química , Mesilato de Imatinib , Estructura Molecular , Compuestos de Fósforo/química , Piperazinas/análisis , Piperazinas/química , Medicamentos bajo Prescripción/análisis , Inhibidores de Proteínas Quinasas/análisis , Inhibidores de Proteínas Quinasas/química , Pirimidinas/análisis , Pirimidinas/química , Quinazolinas/análisis , Quinazolinas/química , Rosiglitazona , Rosuvastatina Cálcica , Sulfonamidas/análisis , Sulfonamidas/química , Tiazolidinedionas/análisis , Tiazolidinedionas/química , Urea/análogos & derivadosRESUMEN
In our pursuit of an efficient, protecting-group-free synthesis of the dual CCK1/CCK2 receptor antagonist 1, we have developed chemoselective conditions for sulfonamide formation reaction in pure water and a PhNMe(2) mediated carboxamide formation, both in the presence of a carboxylic acid. Practical synthesis of an unnatural, chiral ß-aryl-α-amino acid is also described.
Asunto(s)
Receptor de Colecistoquinina A/antagonistas & inhibidores , Receptor de Colecistoquinina B/antagonistas & inhibidores , Estructura Molecular , EstereoisomerismoRESUMEN
A novel intramolecular 1,3-dipolar cycloaddition strategy for a rapid entry into benzofuropyrazoles is described. In a three-step sequence, (E)-2-(1,2-dichlorovinyloxy)aryldiazomethanes were generated in situ from the corresponding salicylaldehydes. Intramolecular cycloaddition followed by dehydrohalogenation garnered 3-chlorobenzofuropyrazoles in excellent yields. By careful choice of solvent, base, and reaction conditions, the entire sequence can be carried out in a one-pot procedure.