Scaled up and telescoped synthesis of propofol under continuous-flow conditions

Author(s)

Martins, Guilherme M. ; Magalhaes, Maria F. A. ; Brocksom, Timothy J. ; Bagnato, Vanderlei S. ; de Oliveira, Kleber T.

• Document type: Journal article
• Source: JOURNAL OF FLOW CHEMISTRY; v. 12, n. 3, p. 9-pg., 2022-07-19.

Abstract

Herein we report a machine-assisted and scaled-up synthesis of propofol, a short-acting drug used in procedural sedation, which is extensively in demand during this COVID-19 pandemic. The continuous-flow protocol proved to be efficient, with great potential for industrial translation, reaching a production up to 71.6 g per day with process intensification (24 h-continuous experiments). We have successfully telescoped a continuous flow approach obtaining 5.74 g of propofol with productivity of 23.0 g/day (6 h-continuous experiment), proving the robustness of the method in both separated and telescoped modes. Substantial progress was also achieved for the in-line workup, which provides greater safety and less waste, also relevant for industrial application. Overall, the synthetic strategy is based on the Friedel-Crafts di-isopropylation of low-cost p-hydroxybenzoic acid, followed by a decarboxylation reaction, giving propofol in up to 84% overall yield and very low by-product formation. (AU)

• FAPESP's process: 13/07276-1 - CEPOF - Optics and Photonic Research Center
• Grantee: Vanderlei Salvador Bagnato
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 15/11801-0 - Development of flow chemistry synthetic platform to obtain molecules of pharmaceutical interest
• Grantee: Leandro de Carvalho Alves
• Support Opportunities: Research Grants - Innovative Research in Small Business - PIPE
• FAPESP's process: 19/27176-8 - Asymmetric photocatalysis applied to the synthesis of Brivaracetam: synthetic approaches employing enabling technologies for chemical synthesis
• Grantee: Kleber Thiago de Oliveira
• Support Opportunities: Regular Research Grants
• FAPESP's process: 20/06874-6 - Applications of technologies and synthetic methodologies developed under continuous flow conditions at LQBO-UFSCar for the preparation of molecules with biological activities and APIs
• Grantee: Kleber Thiago de Oliveira
• Support Opportunities: Regular Research Grants
• FAPESP's process: 21/01259-4 - New photosensitizers obtained from selenilation of methyl pheophorbide a and curcumin: applications in PDT and photodiagnosis
• Grantee: Guilherme Ariel Machado Martins
• Support Opportunities: Scholarships in Brazil - Post-Doctoral