Optimization and Scale-Up of a Continuous Flow Synthesis of Dapagliflozin

Abstract

Dapagliflozin is a selective inhibitor of sodium-dependent glucose cotransporter 2 (SGLT2). The traditional synthesis method of dapagliflozin needs ultralow temperature (−78 °C) and is greatly affected by the environment. Here we report a continuous flow synthesis process for dapagliflozin. The mild and efficient synthesis of Br/Li exchange reaction and C-arylation was achieved with the aid of efficient mixing and heat transfer in the microreactor, and the reaction temperature could be increased from −78 °C to −20 °C. The closed environment can reduce the environmental interference of moisture in the ambient air in the methoxy reduction reaction, thereby minimizing the formation of impurities, meeting the quality requirements. The continuous flow synthesis method for dapagliflozin reported in this paper not only greatly shortened the reaction time (from 26 h to 43 min) but also significantly improved the safety of the process and increased the yield. The final product quality is improved, the purity of the product is 99.83%, and the existing scale output is as high as 4.13 kg/day.

Synthetic Approaches to Gliflozins: A Comprehensive Overview

“…In 2023, Tiemin Sun and colleagues published an article on the continuous flow synthesis of dapagliflozin (3) (Scheme 13). 33 This novel approach allows the Br/Li exchange reaction, C-arylation, methoxylation, and demethoxylation reactions to be successfully carried out in continuous flow. Compared to the traditional batch process, the continuous flow synthesis of dapagliflozin (3) is accomplished in a significantly shorter reaction time (26 hours reduced to 43 minutes).…”

“…In 2023, Tiemin Sun and colleagues published an article on the continuous flow synthesis of dapagliflozin ( 3 ) (Scheme 13 ). 33…”

“…Scheme 34 A reported commercial process for the synthesis of sotagliflozin (9) Scheme 33 The first reported synthesis of sotagliflozin ( 9) by Zhao, Wu and co-workers…”

Efficient Cleaning Method for Flow Reactors in Flow Lithiation Reactions Under Water-free Conditions

“…In addition, if water is not removed efficiently from the channel, there is an increased risk of fouling by inorganic lithium salts when the reaction is restarted. 18 Our research group has adopted the lithiation reaction for preparing acetal 5, an intermediate of the type 2 diabetes drug dapagliflozin, 19,20 switching the process from batch to flow mode to avoid cryogenic conditions (jacket temperature can be increased from −78 °C in batch mode to −20 °C in flow mode) (Scheme 1). The reaction was performed by using the flow reactor system (Figure 1).…”

Continuous flow reactions in the preparation of active pharmaceutical ingredients and fine chemicals

“…In the last decade, a significant increase in the use of flow technologies for the production of fine chemicals has been observed, particularly for the synthesis of natural products and active pharmaceutical ingredients (APIs). [1][2][3][4] Flow chemistry is widely recognized as a more effective technology compared to conventional batch approaches and has gained prominence owing to its various benefits, especially in enhancing the safety of protocols. 5 In addition, it is considered a much more environmentally friendly methodology, adding a sustainable aspect to its appeal.…”