Coupling biocatalysis with high-energy flow reactions for the synthesis of carbamates and β-amino acid derivatives

Abstract

A continuous flow process is presented that couples a Curtius rearrangement step with a biocatalytic impurity tagging strategy to produce a series of valuable Cbz-carbamate products. Immobilized CALB was exploited as a robust hydrolase to transform residual benzyl alcohol into easily separable benzyl butyrate. The resulting telescoped flow process was effectively applied across a series of acid substrates rendering the desired carbamate structures in high yield and purity. The derivatization of these products via complementary flow-based Michael addition reactions furthermore demonstrated the creation of β-amino acid species. This strategy thus highlights the applicability of this work towards the creation of important chemical building blocks for the pharmaceutical and speciality chemical industries.

Development and Manufacture of a Curtius Rearrangement Using Continuous Flow towards the Large-Scale Manufacture of AZD7648

“…To avoid going through over 50 manufacturing batches for a typical 30 kg campaign, a continuous processing set-up strategy was explored. The advantages of using continuous flow have been well documented in the literature and have been routinely used for Curtius rearrangements. − Due to the excellent heat and mass transfer of continuous flow reactors, a higher degree of control was predicted to reduce the overall impurity formation. Furthermore, as these reactors are typically smaller in volume, the overall inventory of explosive intermediates at elevated temperatures would be significantly less and could be adequately cooled before leaving the pressurized system, further reducing the risk to the operator.…”

Continuous-Flow Technology for Chemical Rearrangements: A Powerful Tool to Generate Pharmaceutically Relevant Compounds

“…The most recent work at the time this review was compiled comes from Mallia et al, 23 who developed a flow-based CR for Scheme 6. A) Flow Protocol for CR and Biocatalytic Impurity Tagging by Baumann, 20 large-scale synthesis of AZD7648, an anticancer agent acting as a selective inhibitor of DNA-dependent protein kinase. Flow chemistry could overcome issues related to scale-up of batch synthesis, including the high quantity of explosive intermediates and the increased levels of impurities.…”

“…In 2021, Baumann and co-workers developed a merging protocol between CR and a biocatalytic impurity tagging strategy. 20 A solution containing different carboxylic acids, an excess of benzyl alcohol (1.8 equiv), and triethylamine in toluene was loaded in the first sample loop; the second loop was filled with DPPA in toluene. The reaction takes place in a reactor coil heated to 120 °C, followed by a 100 psi BPR to control the pressure after the release of nitrogen.…”