Recently, application of the flow technologies for the preparation of fine chemicals, such as natural products or Active Pharmaceutical Ingredients (APIs), has become very popular, especially in academia. Although pharma industry still relies on multipurpose batch or semibatch reactors, it is evident that interest is arising toward continuous flow manufacturing of organic molecules, including highly functionalized and chiral compounds. Continuous flow synthetic methodologies can also be easily combined to other enabling technologies, such as microwave irradiation, supported reagents or catalysts, photochemistry, inductive heating, electrochemistry, new solvent systems, 3D printing, or microreactor technology. This combination could allow the development of fully automated process with an increased efficiency and, in many cases, improved sustainability. It has been also demonstrated that a safer manufacturing of organic intermediates and APIs could be obtained under continuous flow conditions, where some synthetic steps that were not permitted for safety reasons can be performed with minimum risk. In this review we focused our attention only on very recent advances in the continuous flow multistep synthesis of organic molecules which found application as APIs, especially highlighting the contributions described in the literature from 2013 to 2015, including very recent examples not reported in any published review. Without claiming to be complete, we will give a general overview of different approaches, technologies, and synthetic strategies used so far, thus hoping to contribute to minimize the gap between academic research and pharmaceutical manufacturing. A general outlook about a quite young and relatively unexplored field of research, like stereoselective organocatalysis under flow conditions, will be also presented, and most significant examples will be described; our purpose is to illustrate all of the potentialities of continuous flow organocatalysis and offer a starting point to develop new methodologies for the synthesis of chiral drugs. Finally, some considerations on the perspectives and the possible, expected developments in the field are briefly discussed.

A simple procedure to convert protein data bank files (.pdb) into a stereolithography file (.stl) using VMD software (Virtual Molecular Dynamic) is reported. This tutorial allows generating, with a very simple protocol, threedimensional customized structures that can be printed by a low-cost 3D-printer, and used for teaching chemical education topics. With the use of the free licensed and multiplatform software, colored input geometries can be obtained by a simple-click modification procedure in order to generate .obj and .mtl files. An easy protocol to create personal .pdb files for 3D-printing technology is also reported.

Radical copolymerisation of divinylbenzene and a properly modified enantiomerically pure imidazolidinone inside a stainless steel column in the presence of dodecanol and toluene as porogens afforded the first example of a chiral organocatalyst immobilized onto a monolithic reactor. Organocatalyzed cycloadditions between cyclopentadiene and cinnamic aldehyde were performed under continuous-flow conditions; by optimizing the experimental set up, excellent enantioselectivities (90% ee at 25 [degree]C) and high productivities (higher than 330) were obtained, thus showing that a catalytic reactor may work efficiently to continuously produce enantiomerically enriched compounds. The same catalytic reactor was also employed to carry out three different stereoselective transformations in continuo, sequentially, inside the chiral column (Diels-Alder, 1,3-dipolar nitrone-olefin cycloaddition, and Friedel-Crafts alkylation); excellent results were obtained in the case of the former two reactions (up to 99% yield, 93% ee and 71% yield, 90% ee, at 25 [degree]C, respectively). In addition to simplify the product recovery, the monolithic reactor performed better than the same supported organocatalyst in a stirred flask and could be kept working continuously for more than 8 days

3D-printed flow reactors were designed, fabricated from different materials (PLA, HIPS, nylon), and used for a catalytic stereoselective Henry reaction. The use of readily prepared and tunable 3D-printed reactors enabled the rapid screening of devices with different sizes, shapes, and channel dimensions, aimed at the identification of the best-performing reactor setup. The optimized process afforded the products in high yields, moderate diastereoselectivity, and up to 90 % ee. The method was applied to the continuous-flow synthesis of biologically active chiral 1,2-amino alcohols (norephedrine, metaraminol, and methoxamine) through a two-step sequence combining the nitroaldol reaction with a hydrogenation. To highlight potential industrial applications of this method, a multistep continuous synthesis of norephedrine has been realized. The product was isolated without any intermediate purifications or solvent switches.

Continuous flow processes have recently emerged as a powerful technology for performing chemical transformations since they ensure some advantages over traditional batch procedures. In this work, the use of commercially available and affordable PEEK (Polyetheretherketone) and PTFE (Polytetrafluoroethylene) HPLC (High Performance Liquid Chromatography) tubing as microreactors was exploited to perform organic reactions under continuous flow conditions, as an alternative to the commercial traditional glass microreactors. The wide availability of tubing with different sizes allowed quickly running small-scale preliminary screenings, in order to optimize the reaction parameters, and then to realize under the best experimental conditions a reaction scale up for preparative purposes. The gram production of some Active Pharmaceutical Ingredients (APIs) such as (S)-Pregabalin and (S)-Warfarin was accomplished in short reaction time with high enantioselectivity, in an experimentally very simple procedure.

Polystyrene‐supported 9‐amino‐9‐deoxy‐epi‐quinine was synthesized through co‐polymerization of an ad hoc‐designed chiral monomer with divinylbenzene, in the presence of azobis(isobutyronitile) (AIBN) as radical initiator and toluene and 1‐dodecanol as porogenic solvents. The heterogenized catalyst efficiently promoted the reaction of isobutyric aldehyde with β‐nitrostyrene, in very high yield and enantioselectivity, comparable or even higher than that of the homogeneous counterpart (up to 95% ee). The recyclability of the catalyst, its general applicability and its successful application to other reactions was also demonstrated. Finally, for the first time, a 9‐amino‐epi‐quinine derivative was employed to perform an enantioselective Michael reaction under continuous‐flow conditions; by using a home‐made, packed‐bed catalytic reactor, the aldehyde addition to nitrostyrene was successfully realized in flow mode, leading to the product in up to 93% ee.magnified image

The synthesis of chiral imidazolidinones on mesoporous silica nanoparticles, exploiting two different anchoring sites and two different linkers, is reported. Catalysts 1-4 were prepared starting from l-phenylalanine or l-tyrosine methyl esters and supporting the imidazolidinone onto silica by grafting protocols or azide-alkyne copper(I)-catalyzed cycloaddition. The four catalysts were fully characterized by solid-state NMR, N2 physisorption, SEM, and TGA in order to provide structural assessments, including an evaluation of surface areas, pore dimensions, and catalyst loading. They were used in organocatalyzed Diels-Alder cycloadditions between cyclopentadiene and different aldehydes, affording results comparable to those obtained with the nonsupported catalyst (up to 91% yield and 92% ee in the model reaction between cyclopentadiene and cinnamic aldehyde). The catalysts were recovered from the reaction mixture by simple filtration or centrifugation. The most active catalyst was recycled two times with some loss of catalytic efficiency and a small erosion of ee.

Silica nanoparticles of different morphological properties were functionalized with enantiomerically pure imidazolidinones, through different immobilization techniques; stainless‐steel columns were then loaded with silica bearing chiral organocatalysts to realize chiral “homemade” reactors. The influence of the material properties and immobilization procedures on the chemical and stereochemical activities of the chiral HPLC columns was studied by performing organocatalyzed DielsAlder reactions between cyclopentadiene and α,β‐unsaturated aldehydes under continuous‐flow conditions. In some cases, excellent enantioselectivities were obtained, thus showing that a catalytic reactor may work efficiently to continuously produce enantiomerically enriched cycloadducts for more than 200 h. Regeneration of the organocatalytic column was also partially accomplished, although associated with a slightly lower enantioselectivity, thus prolonging the “life” of the reactor to more than 300 h.