RESUMO
Olanzapine is a marketed antipsychotic agent for treatment of both positive and negative symptoms of schizophrenia. The chemical synthesis of olanzapine drug substance involved the reaction of thienobenzodiazepine hydrochloride with N-methylpiperazine. During the manufacture of olanzapine, two unknown impurities were present in pilot batches in the range of 0.08-0.22% based upon HPLC analysis. These unknown impurities were enriched from the mother liquor of reaction by preparative HPLC, and characterized by UV, FT-IR, LC-MS/TOF, 1D-NMR (1H, 13C, DEPT), 2D-NMR (1H-1H COSY, HSQC, HMBC, ROESY) and single-crystal X-ray diffraction analysis. Based on the complete spectral analysis and knowledge of the synthetic route of olanzapine, these two new impurities were identified as 2-methyl-4-(4-methyl piperazin-1-yl)-10-((methylthio)methyl)-thieno[2,3-b][1,5] benzodiazepine (impurity-I) and 10-(3-(1H-benzo[d]imidazol-2-yl)-5-methylthiophen-2-yl)-2-methyl-4-(4-methyl piperazin-1-yl)-thieno[2,3-b][1,5]benzodiazepine (impurity-II). Finally, prospects to the formation and controlling of impurity-I and II were discussed in detail.
Assuntos
Benzodiazepinas/química , Benzodiazepinas/isolamento & purificação , Contaminação de Medicamentos/prevenção & controle , Azepinas/química , Cromatografia Líquida de Alta Pressão/métodos , Espectroscopia de Ressonância Magnética/métodos , Olanzapina , Piperazina , Piperazinas/química , Espectrometria de Massas por Ionização por Electrospray/métodos , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Espectrometria de Massas em Tandem/métodosRESUMO
A highly diastereoselective domino reaction of 2,6-diaminopyrimidine-4-one with structurally diverse aryl aldehydes and various barbituric acids in water under microwave irradiation is described. The products are 6-spiro-substituted pyrido[2,3-d]pyrimidines with high diastereoselectivities (up to 99: 1) in which the major diastereomer bears a cis relationship between substituents at the 5- and 7-positions. Furthermore, the mechanism for diastereoselectivity was confirmed by DFT (B3LYP) calculations.
Assuntos
Técnicas de Química Combinatória/métodos , Pirimidinas/síntese química , Compostos de Espiro/síntese química , Água/química , Aldeídos/química , Barbitúricos/química , Micro-Ondas , Modelos Moleculares , Pirimidinas/química , Compostos de Espiro/química , EstereoisomerismoRESUMO
A series of pyrido[2,3-d]pyrimidine derivatives and related compounds were synthesized via the condensation reaction of an aldehyde, 2,6-diaminopyrimidine-4(3H)-one and either tetronic acid or 1,3-indanedione under ultrasonic irradiation without catalyst. This protocol has the advantages of higher yields, lower cost and convenient procedure.
Assuntos
Pirimidinas/química , Pirimidinas/síntese química , Ultrassom , Aldeídos/química , Catálise , Desenho de Fármacos , Inibidores Enzimáticos , Etilenoglicol/química , Furanos/química , Indanos/química , Modelos Químicos , Estrutura Molecular , Piridonas , Solventes/químicaRESUMO
A series of unusual fused heterocyclic compound derivatives, consisting of a pyridine and a imidazole or pyrimidine core, with a bridgehead nitrogen, were successfully synthesized by a microwave-assisted, three-component domino reaction of aldehydes, enaminones, and malononnitrile. In this one-pot reaction, up to five new bonds were formed accompanied by generating the lactam group. This method has the advantages of short synthetic route, operational simplicity, increased safety for small-scale high-speed synthesis, and minimal environment impact.
