RESUMO
BMS-317180 (1) is a potent, orally active agonist of the human growth hormone secretagogue (GHS) receptor. This manuscript details the process research and development efforts that enabled the synthesis of the phosphate salt of 1 on a multi-kilogram scale. Key considerations in the development of this process focused on safe execution and the requirement for telescoped synthetic transformations (i.e., without isolation of intermediate products) to contend with a lack of suitably crystalline products.
Assuntos
Descoberta de Drogas/métodos , Receptores de Grelina/agonistas , Tetrazóis , Carbamatos , Humanos , Projetos de PesquisaRESUMO
A ligand-free Suzuki-Miyaura reaction for the cross-coupling of aryl and heteroaryl bromides with aryl and heteroarylboronic acids has been developed utilizing catalytic polyethylene glycol 2000 (PEG 2000). This preparatively convenient system afforded the corresponding cross-coupled products in good to excellent isolated yields after a simple aqueous workup. Transmission electron microscopy (TEM) analysis of the Pd-PEG 2000 catalyst system revealed in situ-generated palladium nanoparticles after only 1 min of reaction.
Assuntos
Compostos de Bifenilo/síntese química , Ácidos Borônicos/química , Bromobenzenos/química , Polietilenoglicóis/química , Compostos de Bifenilo/química , Catálise , Ligantes , Paládio/químicaRESUMO
[reaction: see text] A practical, large-scale synthesis of a beta-amino ester 1 was developed. A chiral imine derived from (S)-phenylglycinol and 3-trimethylsilylpropanal was coupled with the Reformatsky reagent 3 with high diastereoselectivity (de > 98%) to give (SS)-4a as the major isomer. The amino alcohol residue of the coupling product 4 was oxidatively cleaved with sodium periodate in the presence of methylamine. An unusual selective oxidative cleavage of the (SS)-isomer was observed and the imine 6 was obtained with ee > 99% while the (RS)-4b isomer was not cleaved. Reaction with p-toluenesulfonic acid monohydrate allowed for the hydrolysis of the imine and the isolation of the amine as its salt. The title compound 1 was then obtained by transesterification, desilylation, and hydrochloride salt formation in a one-pot process. The method was successfully applied toward the synthesis of a wide variety of beta-amino esters.
Assuntos
Aminoácidos/síntese química , Ésteres/síntese química , Aldeídos/química , Amino Álcoois/química , Benzenossulfonatos/química , Etanolaminas , Glicina/análogos & derivados , Hidrólise , Iminas/química , Metilaminas/química , Modelos Químicos , Ácido Periódico/química , Estereoisomerismo , Compostos de Trimetilsilil/químicaRESUMO
A survey of several electrophilic ammonia reagents for the N-amination of indole- and pyrrole-containing heterocycles revealed that monochloramine (NH(2)Cl) is an excellent reagent for this transformation. Pyrroles and indoles containing a variety of substitution were aminated on nitrogen with isolated yields ranging from 45% to 97%.