Batch processing supported synthesis

Divinylbenzene copolymers with styrene are produced extensively as supports for the active sites of ion-exchange resins and in biochemical synthesis. About 1—10 wt % divinylbenzene is used, depending on the required rigidity of the cross-linked gel, and the polymerization is carried out as a suspension of the monomer-phase droplets in water, usually as a batch process. Several studies have been reported on the reaction kinetics (200,201). 

Despite the breakthrough associated with Merrifield s approach, there are several limitations such as the discontinuous nature of the reaction, the need for large excesses of reagent and the mechanical instability of the polymer matrix. An early solution to the restrictions imposed by Merrifield s polystyrene supported batch process was the use of commercially available benzyl alcohol-functionalized silica (used for H PLC columns). This was initially derivatized with the first member of the peptide chain to be propagated. The synthesis of a tetrapeptide in flow was completed in half the time required for the equivalent batch mode assembly and required significantly smaller excesses of the solution-phase reagent [92],... 

The in situ membrane growth technique cannot be applied using the zeolite-based ceramic porous membrane as support, under hydrothermal conditions in a solution containing sodium hydroxide. The high pH conditions will cause membrane amorphization and lead to final dissolution. Therefore, we tried to synthesize an aluminophosphate zeolite such as AlP04-5 [105] over a zeolite porous ceramic membrane. For the synthesis of the AlP04-5-zeolite-based porous membrane composite, the in situ membrane growth technique [7,13,22] was chosen. Then, the support, that is, the zeolite-based porous ceramic membrane, was placed in contact with the synthesis mixture and, subsequently, subjected to a hydrothermal synthesis process [18]. The batch preparation was as follows [106] ... 

In addition, supported reagents have been demonstrated to be effective under reaction conditions when either thermal or microwave heating - is employed. They have also been utilised in traditional batch synthesis, stop-flow methods and continuous flow processes. ° However, one caveat is that the immobilisation of reagents can change their reactivity. For example, polymer-supported borohydride selectively reduces a,P-unsaturated carbonyl compounds to the a,P-unsaturated alcohoF in contrast to the behaviour of the solution-phase counterpart, which additionally causes double bond reduction. 

Even if the problems of poor crystal intergrowth due to local exhaustion of reactants in the autoclave and synthesis of zeolite material in the bulk of the solution were solved, an important problem remains, related to the fact that several batch synthesis cycles (with their associated heating and cooling processes) are often required to achieve a zeolite membrane of good quality. Thus, a synthesis procedure in which reactants are continuously supplied to the synthesis vessel while this is maintained at a constant temperature would clearly be desirable not only for performance but also for the feasibility of the scale-up. This type of approaches has already been tested for inner MFI and NaA zeolite membranes [33-35], and the results obtained indicate that the formation of concomitant phases and the amount of crystals forming in the liquid phase are greatly reduced. Similarly, the continuous seeding of tubular supports by cross-flow filtration of aqueous suspensions [36-37] has been carried out for zeolite NaA membrane preparation. 

In contrast to most chemical reagents, which are usually of the same quality regardless of the supplier, the source of solid support is extremely important. Thus, distinct solid supports from different manufacturers or even from the same one, but from separate batches, may differ in performance. Consequently, the choice of the solid support source can have a significant influence on the result of the chemical process. If the large-scale synthesis of a molecule or the production of a library is preceded by an optimization step, both steps should be carried out with the same batch of solid support. 

In addition to demonstrating the synthesis of dipeptides, the authors also reported the preparation of a tripeptide (59% yield, 95% purity), with an overall processing time of 6-7 h compared with batch protocols which take 24h to complete. The authors noted that an additional advantage associated with the use of a continuous flow process is that the reagents spend very little time in contact with the supported reagents, hence racemization is negligible. 

Recently there has been considerable interest in the use of supported catalysts in fine chemical synthesis. Compared to homogeneously catalyzed systems, it is easier to separate the product fi om a supported system. This leads to faster processing, higher purity products and the possibility of re-using the catalyst in batch or continuous flow systems. These factors are environmental, economic and labor-saving advantages on multi-kilo manufacturing scale syntheses. 

A production process for the synthesis of carboxylic nucleoside precursors, which can be used for the manufacture of anti-HIV-1 agents such as carbovir (128) and analogs, has been developed by Chiroscience (Scheme 39) [ 114]. The process uses jS-lactamhydrolase from Aureobacterium sp, immobilized on a glu-taraldehyde-activated solid support for the optical resolution of lactam rac-126. The biotransformation is conducted as a batch reaction and an aqueous solution of rac-126 is cycled through a fixed bed of immobilized enzyme. This setup guarantees that the enzyme can be used in a steady-state production for more than six months, limited only by the mechanical stability of the carrier. The reaction stops when (-)-126 is completely hydrolyzed and a simple addition of acetone causes only the amino acid (-)-127 to crystallize. The latter can be used... 

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