Ibuprofen process

The Boots Hoechst Celanese (BHC) ibuprofen process involves palladium-catalyzed carbonylation of a benzylic alcohol (IBPE). More recently, we performed this reaction in an aqueous biphasic system using Pd/tppts as the catalyst (Figure 9.6 tppts = triphenylphosphinetrisulfonate). This process has the advantage of easy removal of the catalyst, resulting in less contamination of the product. 

The novel BHC ibuprofen process with its three catalytic steps and 80% atom utilization (99% with recycle) replaces a process with six stoichiometric steps at < 40% atom utilization. 

The BHC ibuprofen process is an innovative, efficient technology that revolutionized bulk pharmaceutical manufacturing. The new technology with its three catalytic steps achieves approximately 80% atom utilization, which is increased to almost 99% if recovery of the by-product acetic acid is included. It replaces a pro-... 

Figure 20.2 Ibuprofen processes (http //www.chm.bris.ac.uk/motm/ibuprofen/synthesisc.htm).

Figure 9 Conversion of the S-ibuprofen process with and without the ultrafiltration unit.

The BHC ibuprofen process is an innovative, efficient technology that has revolutionized bulk pharmaceutical manufacture. The process provides an elegant solution to a prevalent problem encountered in bulk pharmaceutical synthesis It avoids the large quantities of solvents and waste (especially aqueous salt waste... 

Figure 4.12 Hypothetical cycle for Hoechst-Celanase ibuprofen process. For all the proposed intermediates cis geometry is assumed.

Considerable advances in asymmetric hydroformylation, a process which, among other things, provides a potential route to enantiomericaHy pure biologically active compounds, have occurred. Of particular interest are preparations of nonsteroidal antiinflammatory (NSAI) pharmaceuticals such as Naproxen (8) and Ibuprofen (9), where the represents a chiral center. 

Lipase-catalyzed kinetic resolutions are often practical for the preparation of optically active pharmaceuticals (61). For example, suprofen [40828-46-4] (45), which is a nonsteroidal antiinflamatory dmg, can be resolved by Candida glindracea]i 2Lse in >95% ee at 49% conversion (61). Moreover, hpase-based processes for the resolution of naproxen [22204-53-1] and ibuprofen [15687-27-1] (61) have also been developed. 

Although very efficient, the broad application of the direct preparation is restricted due to the limited number of pure starting enantiomers. The design of a multistep process that includes asymmetric synthesis is cumbersome and the development costs may be quite high. This approach is likely best suited for the multi-ton scale production of commodity enantiomers such as the drugs ibuprofen, naproxen, atenolol, and albuterol. However, even the best asymmetric syntheses do not lead to products in an enantiomerically pure state (100 % enantiomeric excess). Typically, the product is enriched to a certain degree with one enantiomer. Therefore, an additional purification step may be needed to achieve the required enantiopurity. 

The 12 principles won t all be met in most real-world applications, but they provide a worthy goal to aim for and they can make chemists think more carefully about the environmental implications of their work. Success stories are already occurring, and more are in progress. Approximately 7 million pounds per year of ibuprofen (6 billion tablets ) is now made by a "green" process that produces approximately 99% less waste than the process it replaces. Only three steps are needed, the anhydrous HF solvent used in the first step is recovered and reused, and the second and third steps are catalytic. 

The most important removal pathways of PhACs during wastewater treatment are biotransformation/biodegradation and abiotic removal by adsorption to the sludge. The efficiency of their removal at WWTP depends on their physico-chemical properties, especially hydrophobicity and biodegradability, and process operating parameters (i.e., HRT, SRT, and temperature). For certain NSAIDs (e.g., ibuprofen, acetaminophen), high removals (>90%) are consistently reported in literature... 

Figure 4.21 Multiphase membrane reactor synthesis of ibuprofen from ibuprofen methoxyethyl ester applying a multiphase membrane reactor in batch mode followed by extraction and distillation for downstream processing...

An example of monotropic behavior consists of the system formed by anhydrous ibuprofen lysinate [41,42], Figure 4.12 shows the DSC thermogram of this compound over the temperature range of 20-200°C, where two different endothermic transitions were noted for the substance (one at 63.7°C and the other at 180.1°C). A second cyclical DSC scan from 25 to 75°C demonstrated that the 64°C endotherm, generated on heating, had a complementary 62°C exotherm, formed on cooling (see Fig. 4.13). The superimposable character of the traces in the thermograms demonstrates that both these processes were reversible, and indicates that the observed transition is associated with an enantiotropic phase interconversion [41]. X-ray powder (XRPD) diffraction patterns acquired at room temperature, 70°C, and... 

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