Continuous separation ibuprofen

Taking advantage of the ready availability of racemic ibuprofen, the resolution approach for production of (S)-(+)-ibuprofen becomes an attractive alternative. Merck s resolution process involves the formation of a diastereomeric salt of ibuprofen with (S)-lysine, an inexpensive and readily available natural amino acid.45 The racemic ibuprofen is mixed with 1.0 equivalent of (5)-lysine in aqueous ethanol. The slurry is agitated to allow full dissolution. The supernatant, which is a supersaturated solution of ibuprofen-lysine salt, is separated from the solid and seeded with (.S )-ibuprofcn-(.S )-lysine to induce crystallization. The precipitated solid is collected by filtration, and the mother liquor is recycled to the slurry of racemic ibuprofen and (S)-lysine. This process is continued until essentially all (S)-ibuprofen in the original slurry is recovered, resulting in the... 

OperationaUy, there are several ways to start up the system (1) ibuprofen and lysine can be mixed in a separate tank/transfer vessel and then added or (2) the contents of the system at the end of one run can be saved for the next. It was decided to charge a slurry of diastereomers to be separated to the dissolver at the beginning. The slurry in the dissolver was continuously filtered via a ceramic crossflow filter of 0.2 p,m pore size. The supersaturated permeate was transferred to the crystallizer. Simultaneously, the slurry in the crystallizer could be filtered via another ceramic filter, and the clear saturated (with respect to S-ibu-S-lys) permeate filtrate could be sent to the dissolver. Both permeates would be kept at the same rate to maintain the volumes in both the dissolver and crystallizer. However, fluidized bed operation was clearly more convenient. Table 7-3 summarizes the results of two kilogram-scale experiments. As shown in the table, the final optical purity of S-ibu-S-lys is greater than 98%, starting with 50% S-ibu-S-lys and 50% R-ibu-S-lys in the dissolver. 

A pioneering work on the multi-step flow chemistry is the continuous synthesis of ibuprofen, a h h-volume, nonsteroidal anti-inflammatory drug. The assembly of the three-step synthesis into one continuous system was envisioned. The researchers first optimized the three reactions separately and then assembled the three steps into a single continuous system. The synthesis of ibuprofen was however seen as an entity, instead of a series of independent reactions. In the design of each reaction, it was taken into account that the synthesized byproducts and excess reagents would not interfere in the subsequent reactions, which eventually eliminated the need for purification and isolation steps. The Friedel—Crafts acylation. 

Interesting KRs of ibuprofen were performed in single chaimel three-phase continuous-flow microreactors [108, 109]. Laminar streams of two phases were separated by an interposed third stream of an IL. Selective esterification of (S)-ibuprofen by CrL in the ethanoUc stream was followed by transportation of the (S)-ester through the IL serving as a pseudo-membrane and finally the (S)-acid was recovered by hydrolysis catalyzed by porcine pancreas lipase (PPL) in the aqueous stream. 

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