RESUMO
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
Aryl carboxylic esters were synthesized by Pd-catalyzed carbonylation of aryl p-fluorobenzenesulfonates or -tosylates. A unique Josiphos ligand was discovered through high-throughput catalyst screening, which was the key for the successful carbonylation of various substrates. This catalyst is effective and works well for both electron-rich and electron-poor aryl arenesulfonates. Isolated yields of up to 90% were obtained for aryl p-fluorobenzenesulfonates and -tosylates. [reaction: see text]
Assuntos
Sulfonatos de Arila/química , Hidrocarbonetos Fluorados/química , Compostos de Tosil/química , Catálise , Técnicas de Química Combinatória , Ésteres , Estrutura Molecular , PaládioRESUMO
A scalable synthesis of a potent renin inhibitor (1) is described. The absolute stereochemistry is set via an unprecedented diastereoselective Dieckmann cyclization directed by a remote chiral protecting group. This transformation enables preparation of chiral 1,3-[3.3.1]-diazabicyclononenes by desymmetrization of alkyl-esters, with selectivities ranging from 4 to 17:1.
Assuntos
Compostos Azo/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Renina/antagonistas & inibidores , Tolueno/análogos & derivados , Compostos Azo/química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Cristalografia por Raios X , Ciclização , Conformação Molecular , Estrutura Molecular , Inibidores de Proteases/química , Estereoisomerismo , Tolueno/síntese química , Tolueno/química , Tolueno/farmacologiaRESUMO
An expedient, five step synthesis of caprolactam 1 is reported starting from natural L-homoserine. The key step is a chemoselective reductive cyclization of alpha,beta-unsaturated nitrile 10 mediated by Raney-Co type metals. This hydrogenation is extensively investigated in order to account for the observed product distribution and yields.
Assuntos
Cobalto/química , Nitrilas/química , Aldeídos/síntese química , Aldeídos/química , Caprolactama/química , Ciclização , Homosserina/síntese química , Homosserina/química , Isomerismo , Metionina/química , Estrutura Molecular , Oxirredução , TemperaturaRESUMO
The in vitro metabolism of MK-0767 [(+/-)-5-[(2,4-dioxothiazolidin-5-yl) methyl]-2-methoxy-N-[[(4-trifluoromethyl)-phenyl] methyl]benzamide], a novel 2,4-thiazolidinedione (TZD)-containing peroxisome proliferator-activated receptor alpha/gamma agonist, was studied in rat, dog, monkey, and human liver microsomes and hepatocytes, as well as in recombinant human CYP3A4-containing microsomes. Twenty-two metabolites (some at trace levels) were detected by liquid chromatography-tandem mass spectrometry analysis. All appeared to be phase I metabolites except for a glucuronide conjugate of a hydroxylated metabolite that was detected at trace levels. A constant neutral loss scan experiment performed on a triple quadrupole mass spectrometer proved to be very useful for resolving the metabolites from endogenous compounds. It was observed that the initial site of metabolism of MK-0767 was at the TZD ring leading to two major metabolites, namely the 5-hydroxy-TZD metabolite (M24) and the mercapto metabolite (M22). The latter was formed via the cleavage of the TZD ring with the elimination of the carbonyl adjacent to the sulfur atom. The structure of M24 was established by accurate mass measurements and NMR analysis. This hydroxy-TZD metabolite might represent an important precursor for a group of metabolites formed by TZD ring opening and subsequent loss of the sulfur moiety. The mercapto metabolite, on the other hand, is probably the key precursor for the TZD ring-opened metabolites with retention of the sulfur, even though the detailed mechanism of the ring scission remains to be characterized. From these studies, it was concluded that the TZD ring was the major site of metabolism of MK-0767. All the metabolites produced in vitro from human preparations were detected in the corresponding preparations from the nonclinical species.