Synthesis of Ibuprofen

Ibuprofen is one of the products used in large quantities for making pharmaceutical drugs, in particular various kinds of analgesics (pain killers). 

The above synthesis results in only small amount of unwanted products and has very good atom economy (77%). 

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Scheme 5.4-2 Synthesis of ibuprofen by asymmetric, Ru-cataiyzed hydrogenation in...

Hydroformylation has been extensively studied since it produces optically active aldehydes which could be important precursors for pharmaceutical and fine chemical compounds. Thus, asymmetric hydroformylation of styrene (Scheme 27) is a model reaction for the synthesis of ibuprofen or naproxen. Phosphorus ligands were used for this reaction with excellent results, espe-... 

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...

Similar chemistry been used by Faigl and Schlosser in an elegant and simple synthesis of ibuprofen 632 using only superbase chemistry (Scheme 245). Starting with para-xylene 630, two successive metallations and alkylations give 631, which is once more metallated at the less hindered benzylic site and carbonated to give ibuprofen 632. 

Lastly, Cann featured Colin Baird s Environmental Chemistry as an example of a text that has green chemistry integrated throughout every chapter. In addition, the preface is an introduction to green chemistry, atom economy, and the synthesis of ibuprofen. 

Figure 3.4 The synthesis of ibuprofen is initiated by a Friedel-Crafts acylation of an aUcyl-substituted benzene ring. The resulting ketone is then reduced to an alcohol with sodium boro-hydride. The alcohol functionality then undergoes a functional group interchange by conversion to a bromide. In turn, this permits the introduction of an additional carbon atom in the form of a nitrile introduced via an 8, 2 nucleophilic displacement. This is then hydrolyzed to give the target molecule.

There have been many commercial and laboratory publications on the synthesis of ibuprofen. Two of the most popular ways to obtain ibuprofen are the Boots process and the Hoechst process. The Boots process is an older commercial process developed by the Boots Pure Dmg Company, the discoverers of ibuprofen in the 1960s, and the Hoechst process is a newer process developed by the Hoechst Company. Most of these routes to Ibuprofen begin with isobutylbenzene and use Friedel-Crafts acylation. The Boots process requires six steps, while the Hoechst process, with the assistance of catalysts, is completed in only three steps (Figure 20.2). 

The original reported synthesis of ibuprofen (13.87) was patented in the late 1960s by the Boots Pure Drug Company in England.27 The route is shown in Scheme 13.15. Side products are shown... 

SCHEME 13.16 Atom economy information for Boots synthesis of ibuprofen... 

The BHC synthesis of ibuprofen has a high atom economy. Does this fact make the process green ... 

The Boots synthesis of ibuprofen (Scheme 13.15) uses ethyl chloroacetate and sodium ef/toxide in the step going from 13.83 to 13.84. In theory, changing these reagents to methyl chloroacetate and sodium methoxide should have... 

In 1992, BASF opened a 35 000 tons per year ibuprofen production plant in Bishop, Texas. This plant was the result of the elegant green chemistry route developed by the BHC consortium. The clean synthesis of ibuprofen is an excellent example of how combining catalysis and green chemistry can yield both commercial success and environmental benefits. Ibuprofen is a nonsteroidal, anti-inflammatory painkiller. It is a popular over-the-counter drug against headache, toothache, and muscular pains. You may know it better as Advil , Motrin , or Nurofen. 

Figure 1.20 Synthesis of ibuprofen a the six-step Boots route b the three-step BHC route. In each case, the catalysts are highlighted in gray.

The relative reactivity of different alkyl groups on a phenyl ring parallels the one encountered in alkenes methyl > methylene > methine. This discrimination between benzylic position has been used to design a one-pot synthesis of ibuprofene, an analgesic with both anti-inflammatory and anti-rheumatic properties. The synthesis has been accomplished196 by sequential LIC-KOR deprotonation-alkylation starting with /wra-xylene. 

Futhermore an enantioselective synthesis of (+)-ibuprofen could be achieved by this methodology (Scheme 130,130a... 

The salt production can be circumvented by performing the selective Pd/ tppts-catalysed carbonylation of benzyl alcohol in an acidic aqueous biphasic system (Fig. 1.36) [106]. This methodology was also applied to the synthesis of ibuprofen (see earlier) by biphasic carbonylation of l-(4-isobutylphenyl)ethanol [107] and to the biphasic hydrocarboxylation of olefins [108]. 

Figure 7 The older, classical six-step synthesis of ibuprofen not involving metal-catalyzed carbonylation.

The synthesis of ibuprofen will now be used as an example of the determination of atom economy (see Cann, 2000). This synthesis results in rather small amounts of unwanted by-products, thus lessening the need for disposal and remediation of waste products. Ibuprofen is widely used for the relief of headache (including migraine). It is marketed as an analgesic agent for general pain conditions that arise from various injuries. The synthetic route commonly used is shown in Figure 12.13. 

Ibuprofen is the generic name for the pain reliever known by the trade names of Motrin and Advil. Like aspirin, ibuprofen acts as an anti-inflammatory agent by blocking the synthesis of prostaglandins from ara-chidonic acid. One step in a commercial synthesis of ibuprofen involves the reaction of a nucleophilic eno-late with an electrophilic carbonyl group. In Chapter 24, we learn about the carbon-carbon bond-forming reactions of enolates with carbonyl electrophiles. 

The most frequently discussed green chemistry topic was catalysts, followed by the synthesis of ibuprofen, ionic liquids, supercritical solvents, atom economy, pesticides, polymers, renewable feedstocks, and the principles of green chemistry. Other green chemistry topics that were found included... 

Since this method allows us easily to construct structures branched at benzylic positions, it was applied to the synthesis of -arylpropionic acids, including anti-inflammatory agents. An example is the facile synthesis of ibuprofen by such an allyl-aryl coupling and subsequent oxidation (Scheme 10-8) [29]. The cross-coupling was more effective when the substrate had an electron-withdrawing group. 

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