Scale microwave-assisted synthesis

The strategies explored and defined in the various examples presented open a way for wider application of microwave chemistry in industry. The most important problem for chemists today (in particular, drug discovery chemists) is to scale-up microwave chemistry reactions for a large variety of synthetic reactions with minimal optimization of the procedures for scale-up. At the moment, there is a growing demand from industry to scale-up microwave-assisted chemical reactions, which is pushing the major suppliers of microwave reactors to develop new systems. In the next few years, these new systems will evolve to enable reproducible and routine kilogram-scale microwave-assisted synthesis. 

In the next few years, these new systems will evolve to enable reproducible and routine kilogram-scale microwave-assisted synthesis. 

A microwave-assisted preparation of a series of l-alkyl-3-methylimidazolium halide ILs has been described [17]. The reaction is run in solvent-free conditions with a near-stoichiometric amount of reactants, and the imidazolium halides are obtained in high yield. It is also possible to perform the subsequent metathesis reaction with sodium hexafluorophosphate by means of microwave radiation and then to form the final product in a one-pot reaction [18]. Due to the fact that ILs absorb microwave energy in a very efficient way, they are believed to be well suited for large-scale microwave-assisted synthesis (that is, for reaction mixtures of more than 100 L). 

Most examples of microwave-assisted chemistry published to date and presented in this book (see Chapters 6 and 7) were performed on a scale of less than 1 g (typically 1-5 mL reaction volume). This is in part a consequence of the recent availability of single-mode microwave reactors that allow the safe processing of small reaction volumes under sealed-vessel conditions by microwave irradiation (see Chapter 3). While these instruments have been very successful for small-scale organic synthesis, it is clear that for microwave-assisted synthesis to become a fully accepted technology in the future there is a need to develop larger scale MAOS techniques that can ultimately routinely provide products on a multi kg (or even higher) scale. 

Whereas batch synthesis on the small scale is the standard procedure in microwave-assisted synthesis and has been extensively reviewed ( [50-52] and references cited therein), protocols in the 50 mL range are rather rare. In this section, scale-up of volumes > 50 mL in sealed vessels will be discussed. An important issue for the process chemist is the potential of direct scalability of microwave reactions, allowing rapid translation of previously optimized small-scale conditions to a larger scale. Several authors have reported independently the feasibility of directly scaling reaction conditions from small-scale single-mode (typically 0.5-5 mL) to larger scale multimode... 

Most of the single-mode reactors commercially available have been designed for small to medium scale reactions (250 L-120 mL). Single mode and multi-mode batch reactors that allow for microwave-assisted synthesis up to 500 mL have been recently introduced. Importantly, reactions optimized in smaller cavities can be directly reproduced in these larger reactors. 

The development of a support/linker system for the microwave-assisted synthesis of dihydropyrimidine test libraries, and methods for solid-phase scale-up on cellulose were recently described [101]. 

One possible difficulty with the commercialization of microwave-assisted synthesis of polymers could be the scale-up, as higher energy input is required for larger quantities. 

Traditionally, the synthesis of MOFs follows a solvothermal route, heating a ligand (typically in protonated form) and metal salt mixture in solvents such as dimethylformamide (DMF) for hours or up to several days. However, this often produces small amounts of the desired crystals (ca. 1 g or less) and the amount of solvent required limits feasible scale-up. Other methods have been examined, such as sonochemical and microwave assisted synthesis, with both of these methods and others covered in an in-depth review by Meek. These methods are outside the scope of this report, which is limited to an electrosynthetic focus. 

Microwave technology has now matured into an established technique in laboratory-scale organic synthesis. In addition, the application of microwave heating in microreactors is currently being investigated in organic synthesis reactions [9-11] and heterogeneous catalysis [12, 13]. However, most examples of microwave-assisted chemistry published until now have been performed on a... 

Komatsu K (2005) The Mechanochemical Solid-State Reaction of Fullerenes. 254 185-206 Kremsner JM, Stadler A, Kappe CO (2006) The Scale-Up of Microwave-Assisted Organic Synthesis. 266 233-278... 

A specialized application of microwave-assisted organic synthesis involves the preparation of radiopharmaceuticals labeled with short-lived radionuclides, particularly for use in positron emission tomography [70-72]. This represented an excellent application of microwave technology, where the products must be prepared quickly and in high radiochemical yield, on a small scale. 

Another synthesis technology which has just started to impact and change the way chemical synthesis is performed in many laboratories is microwave assisted organic synthesis. Using microwave reactors, reaction times often can be reduced from hours or days to minutes or even seconds. Selectivities and yields often can be increased drastically. Therefore, this technology has the potential to increase the output of chemical drug discovery units enormously. An important question in this field is how to scale up these transformations in microwave reactors up to kilogram scale. 

Besson and co-workers have investigated the microwave-assisted multi-step (seven steps) synthesis of thiazoloquinazolinone derivatives, utilising commercially available nitroanthranilic acids as the initial precursors69. Comparison of the conventional thermal heating and microwave heating approaches demonstrated that the overall time for the multi-step synthesis could be considerably reduced (by a factor of 8) by adopting the microwave-heated reaction methods (Scheme 3.44). In addition, the reactions were cleaner and the products could be purified rapidly. For the microwave-heated multi-step synthesis, the overall yield of the final product was increased by a factor of 2, which enabled the scale of the overall synthesis to be increased from 0.2 to 1 g. 

Microwave-assisted stepwise imine formation and subsequent reduction with NaBH4 were also used as the key steps in the synthesis of ephedrine from L-phenylacetylcarbinol. The reactions were performed on a multigram scale in a domestic microwave oven to provide the product in satisfactory yield within a total reaction time of 19 min (Scheme 4.27)49. 

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