Application of Flow Photochemical Bromination in the Synthesis of a 5-Bromomethylpyrimidine Precursor of Rosuvastatin: Improvement of Productivity and Product Purity

Abstract

In this report we present a flow photochemical bromination of a 5-methyl-substituted pyrimidine precursor of rosuvastatin. The study demonstrated that the reaction productivity can be increased markedly with a flow-mode approach compared to a batch-mode synthesis. Indeed, reaction times can be significantly shortened from a range of hours to a range of minutes. Moreover, in addition to process intensification, the study demonstrated that significantly lower overall levels of side products are obtained when photochemical bromination is conducted in a flow mode.

Chemical reaction engineering, process design and scale-up issues at the frontier of synthesis: Flow chemistry

“…As well, the scale-up of the continuous photobromination of 5-methylpyrimidine, a precursor of Rosuvastatin was successful, whereas it was substantially unscalable in batch due to overbromination and prolonged reaction time (16−64 h already on millimolar scale). [89].…”

Continuous‐Flow Technology—A Tool for the Safe Manufacturing of Active Pharmaceutical Ingredients

“…[120] Thetubular reactor was made from light-transparent FEP tubing wrapped around ah ousehold compact fluorescent lamp.T his setup was suitable for the selective benzylic monobromination of ab road range of substrates within residence times of 13 to 50 min at temperatures of 0t o6 08 8 C. [120] Č asar andc o-workers used as imilar tubular photoreactor for their preparation of a5-(bromomethyl)pyrimidine precursor of Rosuvastatin, ad rug mainly used for the treatment of dyslipidemia (Scheme 31). [121] The photoreactor was built using aF EP tubing with an inner diameter of 0.8 mm and a150 Wm edium-pressure Hg lamp. After ar esidence time of 5min in the photoreactor,9 8% conversion was obtained and 86 %o ft he desired product 73 was isolated after recrystallization.…”

Design Consideration of Continuous-Flow Photoreactors

“…36 An 18-mL flow reactor consisting of a 150-W medium-pressure Hg lamp was used to improve both the reaction productivity (from 130 up to 580 g day −1 when moving from batch to flow conditions) and the selectivity of the bromination of a 5-methyl substituted pyrimidine (8) to 9, precursor of the cardiovascular therapeutic Rosuvastatin (Scheme 1.1). 37 Hurevich et al 38 used a Booker-Milburn type reactor sealed in an aluminum box for performing continuous-flow solid phase synthesis (Figure 1.8). In a typical experiment, a polystyrene-based support with photolabile linkers was pre-swollen in dichloromethane and pushed through the FEP tubing using a syringe pump and then irradiated for 30 min.…”