No abstract

Capecitabine is an important anticancer drug whose synthesis comprises late-stage carbamoylation and ester hydrolysis. Herein we report the use of the Schotten–Baumann reaction in order to perform these transformation in one pot both in batch and under continuous flow. In batch, capecitabine was obtained in 82% yield in 5 h, while under continuous flow it was obtained in 81% yield in 30 min. This one-pot reaction reduces the chemical waste produced, labor, time, and cost and additionally comprises the use of environmentally friendly solvents and reagents as well as energy-efficient and safe methods, all of which fulfill the requirements of a green process.

O Crizotinibe é um agente anticancerígeno aprovado para tratamento de carcinoma de pulmão de células grandes. Segundo a análise retrossintética (FRANÇA e col., in press), o 1-(2,6-dicloro-3-fluorofenil) etanol é um intermediário importante, que pode ser produzido por diferentes abordagens biocatalíticas (CUI e col., 2011). Logo, o objetivo foi preparar este intermediário na sua forma enantiomericamente pura desejada. A metodologia usada foi a mesma do 1-feniletanol, descrita por Koning e col. (2011), que apresenta a estratégia de produção do álcool racêmico por redução clássica com borohidreto de sódio, seguida de acetilação via resolução cinética. Uma vez que o 1-(2,6-dicloro-3-fluorofenil) etanol contém substituintes nas posições orto, são esperados longos tempos de reação para esta transformação. Deste modo, deu-se início por rastrear a influência de doadores de acila (acetato de etila, acetato de vinila e o acetato de isopropenila) sobre o resultado da reação quando se utiliza a lipase comercial Novozyme 435 a 60 °C e ciclohexano como solvente com tempo reacional de 10 dias. Dentre os doadores de acila avaliados, o acetato de isopropenila levou aos melhores resultados, em boas conversões e alta seletividade (conv. 44%, 99% e.e.). Palavras Chave: Resolução Cinética; Crizotinibe.The Crizotinib is an anticancer agent approved for treatment of lung cancer large cells. According to the retrosynthetic analysis (France et al., in press), 1-(2,6-Dichloro-3-fluoro-phenyl)-ethanol is an important intermediary, which can be produced by different biocatalytic approaches (CUI et al., 2011). Therefore, the objective was to prepare this intermediary in its desired enantiomerically pure form. The methodology used was the same as the 1-phenylethanol, described by Koning and col. (2011), which presents a strategy for the production of the racemic alcohol by a classic reduction with sodium borohydride, followed by acetylation via kinetic resolution. Once the 1-(2,6-Dichloro-3-fluorophenyl)-ethanol contains substituents in the ortho positions, long reaction times are expected for this transformation. In this way, it was iniciated the tracing of the influence of acyl donors (ethyl acetate, vinyl acetate and isopropyl acetate) on the outcome of the reaction when using commercial lipase Novozyme 435 at 60 °C and cyclohexane as solvent with reaction time of 10 days. Among the acyl donors evaluated, the isopropyl acetate led to the best results, in good conversions and high selectivity (conv. 44%, 99% e.e.).