RESUMO
The design and optimization of a novel series of renin inhibitor is described herein. Strategically, by committing the necessary resources to the development of synthetic sequences and scaffolds that were most amenable for late stage structural diversification, even as the focus of the SAR campaign moved from one end of the molecule to another, highly potent renin inhibitors could be rapidly identified and profiled.
Assuntos
Álcoois/síntese química , Anti-Hipertensivos/síntese química , Anti-Hipertensivos/uso terapêutico , Desenho de Fármacos , Hipertensão/tratamento farmacológico , Piperidinas/síntese química , Renina/antagonistas & inibidores , Álcoois/química , Álcoois/uso terapêutico , Animais , Anti-Hipertensivos/química , Estrutura Molecular , Piperidinas/química , Piperidinas/uso terapêutico , Ratos , Renina/química , Relação Estrutura-AtividadeRESUMO
A practical large-scale chromatography-free synthesis of EP4 antagonist MF-310, a potential new treatment for chronic inflammation, is presented. The synthetic route provided MF-310 as its sodium salt in 10 steps and 17% overall yield from commercially available pyridine dicarboxylate 7. The key features of this sequence include a unique regioselective reduction of succinimide 2 controlled by the electronic properties of a remote pyridine ring, preparation of cyclopropane carboxylic acid 3 via a Corey-Chaykovsky cyclopropanation, and a short synthesis of sulfonamide 5.
Assuntos
Química Orgânica/métodos , Química Farmacêutica/métodos , Ciclopropanos/síntese química , Compostos Heterocíclicos com 3 Anéis/síntese química , Receptores de Prostaglandina E/antagonistas & inibidores , Succinimidas/química , Ácidos Carboxílicos/química , Química Orgânica/instrumentação , Química Farmacêutica/instrumentação , Cristalização , Ciclopropanos/química , Desenho de Fármacos , Eletrônica , Compostos Heterocíclicos com 3 Anéis/química , Modelos Químicos , Estrutura Molecular , Receptores de Prostaglandina E Subtipo EP4 , Estereoisomerismo , Sulfonamidas/química , Tecnologia FarmacêuticaRESUMO
A novel two-step procedure for the synthesis of 3-amino-5-substituted-isoxazoles is described. In the presence of a base, readily available 3-bromoisoxazolines react with amines to afford 3-aminoisoxazolines. An oxidation protocol was developed for these heterocycles to provide 3-aminoisoxazoles in consistently high yield.
Assuntos
Aminas/química , Aminas/síntese química , Hidrocarbonetos Bromados/química , Isoxazóis/síntese química , Catálise , Técnicas de Química Combinatória , Isoxazóis/química , Estrutura Molecular , OxirreduçãoRESUMO
We describe a tandem Mitsunobu/3,3-sigmatropic rearrangement of allylic azides on a chiral auxiliary system that favors one regioisomer thanks to its exceptional steric bias. The sequence may be completed by the oxidative cleavage of the auxiliary or by a ring-closing metathesis reaction that produces a carbo- or heterocycle directly and a recyclable form of the chiral auxiliary. Applications of the methodology to the total synthesis of (+)-coniine, (+)-lentiginosin, and (+)-pumiliotoxin C are reported.
Assuntos
Alcaloides/síntese química , Compostos Alílicos/química , Azidas/química , Compostos Alílicos/síntese química , Aminoácidos/síntese química , Animais , Azidas/síntese química , Compostos Heterocíclicos/síntese química , Piperidinas/síntese química , Quinolinas/síntese química , EstereoisomerismoRESUMO
[reaction: see text] Homochiral alpha-amino acids, heterocycles, and carbocycles are efficiently constructed via a short sequence of reactions starting from the chiral auxiliary p-menthane-3-carboxaldehyde. The key feature of the sequence is a highly selective tandem Mitsunobu/3,3-sigmatropic rearrangement of hydrazoic acid that procures enantiomerically enriched allylic azides. The sequence is either terminated by oxidative cleavage to provide amino acids or by ring-closing metathesis to provide heterocycles or carbocycles bearing nitrogen.