and cyanoarenes has also been optimized using an HTE approach. [63] Other Photochemical TransformationsNon-activated alkyl bromides were coupled with Michael acceptors in a photoredox Giese-type reaction. [64] Reaction optimization was performed by studying the effect of photocatalyst, solvent, base, and varying amounts of radical initiator (Me 3 Si) 3 SiH on product and by-product profile. Another study of conjugate addition using photocatalytic methodology was shown for the synthesis of unnatural β-alkyl α-amino acid derivatives via decarboxylative photocatalysis. [65] Photocatalysis was performed with oxime and cyanopyridine precursors (Scheme 4g) to form primary amine products. [66] Four different solvents (acetone, DCE, ACN, DMSO), nine different photocatalysts, and two reductants were used to evaluate 45 unique reactions. DMSO with diisopropylamine and Ir[dF(Me) ppy] 2 dtbbpyPF 6 gave the highest yield by UPLC, although many Scheme 4. Photocatalytic transformations in HTE.

Developing continuous syntheses of lead compounds to support in vivo studies and preclinical evaluation remains an underdeveloped area. We report a telescoped continuous flow synthesis of an alkynylnaphthyridine lead compound for the treatment of FLT3 mutations in acute myeloid leukemia. Different strategies were used to develop the route, including Design of Experiments (DoE), high-throughput experimentation (HTE), and application of desorption electrospray ionization mass spectrometry (DESI-MS) to optimize and telescope the amidation and Sonogashira couplings to prepare the target compound, HSN608, a potent FLT3 inhibitor. Findings from these statistical design and automation studies helped streamline our workflow to achieve 10-fold and 5-fold reductions in the catalyst and cocatalyst loadings, respectively, in the synthesis. The application of high-throughput tools combined with a telescoped continuous synthesis method enabled an efficient and safe synthesis of this lead compound using the hazardous coupling reagent HATU while minimizing byproduct formation.

Desorption electrospray ionization-mass spectrometry (DESI-MS) was used as a high-throughput experimentation (HTE) tool to rapidly identify derivatives of the biobased platform molecule triacetic acid lactone (TAL). TAL is a platform molecule capable of conversion to a wide range of useful commodity chemicals, agrochemicals, and advanced pharmaceutical intermediates. In the present study, a diverse family of aldol reaction mixtures were prepared in high-density microtiter plates with a liquid handling robot, then printed with a pin tool onto a PTFE surface for analysis by DESI-MS. Our DESI-MS results indicate that aldol products of TAL were obtained for each substrate tested, in good agreement with previously reported TAL reactivity. These HTE experiments also revealed solvent-dependent reactivity trends that facilitated reaction scale up. Our findings suggest that DESI-MS analysis can rapidly inform the selection of optimal reaction conditions from a wide variety of conditions for scale up using continuous synthesis conditions.

Lorazepam, a widely used sedative that appears on the World Health Organization list of essential medicines, experiences periodic shortages. Using a workflow involving route scouting, high-throughput experimentation, and impurity profiling to develop an optimal sequence, we report a novel 5-step route for synthesis of lorazepam in flow. The five steps comprise Nacylation, diazepine ring closure, imine N-oxidation, Polonovski-type rearrangement, and ester hydrolysis to give lorazepam. Each step was optimized and translated to continuous flow. The mean residence times for each of the individual flow reactions summed to a total of 72.5 min for the 5-step sequence. We also report a comprehensive analysis of the purity and byproduct profile to maximize the desired product purity in each step, leading to over 99% pure lorazepam.