Romaric Gérardy

Assessing inter- and intramolecular continuous-flow strategies towards methylphenidate (Ritalin) hydrochloride

The batch-to-flow translation of inter- and intramolecular strategies for the diastereoselective preparation of the active pharmaceutical ingredient threo-methylphenidate hydrochloride is presented. Both inter- and intramolecular strategies imply the telescoping of multiple processing steps and the generation of unstable diazo species under continuous-flow conditions. The intermolecular strategy relies on an unprecedented continuous-flow Rh-catalyzed intermolecular C–H carbene insertion, providing enriched threo-N-Boc methylphenidate in 38% or 19% isolated yield according to sequential or fully telescoped processes, respectively. Quantitative Boc-deprotection is carried out off-line. The intramolecular strategy relies on a continuous-flow thermal intramolecular C–H carbene insertion, providing enriched threo-methylphenidate hydrochloride in 70% isolated yield. A continuous-flow photochemical alternative is also presented. The critical step of the most promising intramolecular strategy is implemented on the mesoscale in a pilot-scale continuous-flow reactor.

Multistep Continuous-Flow Processes for the Preparation of Heterocyclic Active Pharmaceutical Ingredients

Flow chemistry has many fascinating facets, among which the most challenging is arguably the implementation of complex multistep processes within one uninterrupted fluidic network. This document provides a thorough overview of some of the most representative examples of multistep continuous-flow strategies in the specific context of preparing heterocyclic active pharmaceuticals. Selected examples emphasizing the implementation of multistep sequences, including various combinations of chemical transformations, purifications, or in-line analysis, are discussed.

A versatile biobased continuous flow strategy for the production of 3-butene-1,2-diol and vinyl ethylene carbonate from erythritol

A versatile, tunable and robust continuous flow procedure for the deoxydehydration (DODH) of biobased erythritol toward 3-butene-1,2-diol is described. The procedure relies on specific assets of multistep continuous flow processing. Detailed mechanistic and computational studies on erythritol show that either 3-butene-1,2-diol or butadiene are obtained in high selectivity and yield on demand, as a function of the DODH reagent/substrate ratio and of the process parameters. Short reaction times (1–15 min) at high temperature (225–275 °C) and moderate pressure are reported. 3-Butene-1,2-diol is then further converted downstream into its corresponding carbonate, i.e. 4-vinyl-1,3-dioxolan-2-one (vinyl ethylene carbonate), an important industrial building block. The carbonation step uses a supported organocatalyst, and could be directly concatenated to the first DODH step. This unprecedented procedure also relies on a unique combination of on- and off-line analytical protocols for reaction monitoring and product quantification, and offers a biobased strategy toward important industrial building blocks otherwise petrosourced.

Preparation, Reactivity, and Synthetic Utility of Simple Benzotriazole Derivatives

The benzotriazole fragment is known to behave as (1) an excellent leaving group, (2) an electron-donating or an electron-withdrawing group, (3) an anion precursor, and (4) a radical precursor. It confers unique physicochemical properties to its immediate vicinity on various molecular scaffolds. This review covers the preparation and synthetic utility of versatile benzotriazole derivatives. The selected compounds are conveniently prepared from 1H-benzotriazole and are characterized by a huge synthetic potential. Their specific reactivity is discussed and illustrated with various examples ranging from methodology in organic chemistry to the total synthesis of complex structures.