Continuous flow Aza-Michael reaction for preparing the fast-acting synthetic opioid drug Remifentanil

Artur Vaz; João Luis Callegari Lopes; Giuliano Cesar Clososki

doi:10.1590/s2175-97902023e22764

Authors

Artur Vaz Núcleo de Pesquisa em Produtos Naturais e Sintéticos (NPPNS), Departamento de Ciências BioMoleculares, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil https://orcid.org/0000-0002-6231-5003
João Luis Callegari Lopes Núcleo de Pesquisa em Produtos Naturais e Sintéticos (NPPNS), Departamento de Ciências BioMoleculares, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil; Avita Produtos Químicos e Farmacêuticos LTDA, Supera Parque, Ribeirão Preto, SP, Brazil
Giuliano Cesar Clososki Núcleo de Pesquisa em Produtos Naturais e Sintéticos (NPPNS), Departamento de Ciências BioMoleculares, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil https://orcid.org/0000-0001-7605-4150

DOI:

https://doi.org/10.1590/s2175-97902023e22764%20%20

Keywords:

Remifentanil, Opioids, Organic synthesis, Continuous flow synthesis

Abstract

Remifentanil is a modern fentanyl analogue with ultrashort-action granted by an esterase-labile methyl propanoate chain. Here, we present the development of a continuous flow methodology for the key N-alkylation step of remifentanil preparation in a biphasic, “slug-flow” regime. We screened parameters under microwave-assisted reactions, translated conditions to flow settings, and obtained remifentanil under 15-min residence time in a 1-mL microreactor, with a space-time yield of 89 mg/mL·h and 94% yield.

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Continuous flow Aza-Michael reaction for preparing the fast-acting synthetic opioid drug Remifentanil

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