Ibuprofen routes

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. 

Devise a synthesis of 5-Ibuprofen that, in terms of the principles of green chemistry, compares favourably with the commercial route outlined in Chapter 2. 

The hydrocarboxylation of styrene (Scheme 5.12) and styrene derivatives results in the formation of arylpropionic acids. Members of the a-arylpropionic acid family are potent non-steroidal anti-inflammatory dmgs (Ibuprofen, Naproxen etc.), therefore a direct and simple route to such compounds is of considerable industrial interest. In fact, there are several patents describing the production of a-arylpropionic acids by hydroxycarbonylation [51,53] (several more listed in [52]). The carbonylation of styrene itself serves as a useful test reaction in order to learn the properties of new catalytic systems, such as activity, selectivity to acids, regioselectivity (1/b ratio) and enantioselectivity (e.e.) in the branched product. In aqueous or in aqueous/organic biphasic systems complexes of palladium were studied exclusively, and the results are summarized in Table 5.2. 

Betahistine (84), a vasodilator based on the readily available feedstock a-picoline, can be synthesized by a very lengthy process (75MI20904). A shorter route employing the commercially available 2-pyridylethanol has also been described (77CZ389). Reaction of (6-hydroxymethyl-2-pyridyl)methanol with methyl isocyanate, or its bis(phenylcarbonate) with methylamine (66JAP6622185), affords anginin (85), a compound used to reduce lipids and cholesterol levels in the blood. Esterification of 2-pyridylmethanol with ibuprofen... 

Ibuprofen is effective in closing patent ductus arteriosus in preterm infants, with much the same efficacy and safety as indomethacin. The oral and intravenous routes are equally effective for this indication. A topical cream preparation appears to be absorbed into fascia and muscle an... 

S)-ibuprofen (44b Ar = 4-isobutylphenyl), (S)-naproxen (44c Ar = 6-MeO-naphthyl), and (S)-suprofen (44d Ar = 4-(2-thienylcarbonyl)phenyl) (Eq. 7.11) (10]. Thus, the asymmetric hydroformylation of vinylarenes discussed above provides potentially efficient route to these drags. 

An early example of Raman mapping by Breitenbach et al. [52] showed that when crystalline ibuprofen is formulated in a hot melt extrudate the API changes to the amorphous form. Ibuprofen is a sparingly water-soluble compound, so this formulation provides a route to better bioavailability via the more soluble amorphous form. Using confocal Raman mapping the form of the API was determined at the time of manufacture and under stress conditions and was used to assess the stability of the amorphous form. These studies also showed that the API was homogeneously distributed throughout the formulation based on the relative band intensities of the amorphous API and a formulation excipient, polyvinylpyrrolidone (PVP). 

Ibuprofen, a well-known, non-steroidal, anti-inflammatory drug (NSAID) used as a common painkiller and marketed under brand names such as Advil and Motrin , provides an example of the switching of processes from one chemical route to another. 

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... 

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.

Because ibuprofen has been a successful drug on the market for almost 30 years with no patent protection since 1985, there is a widespread competition for commercial production of this product throughout the world. As a result, several practical and economical industrial processes for the manufacture of racemic ibuprofen (14) have been developed and are in operation on commercial scales.38 Most of these processes start with isobutylbenzene (15) and go through an isobutylstyrene3 4 or an acetophenone intermediate.42 The most efficient route is believed to be the Boots-Hoechst-Celanese process, which involves 3 steps from isobutylbenzene, all catalytic, and is 100% atom-efficient (Scheme 6.1).43 44... 

The asymmetric hydroformylation of vinyl arenes can provide a route to the preparation of the profen class of drugs. Naproxen and ibuprofen, two examples in the profen class, are NSAIDs on the market.50... 

There are basically two processes for the production of ibuprofen (see Fig. 2.31). Both involve a Friedel-Crafts acylation as the first step. In the classical route, developed by Boots, the p-isobutylacetophenone is subsequently converted to ibuprofen in five steps involving conventional organic chemistry. In the catalytic route, more recently developed by Hoechst, the p-isobutylacetophenone is converted in two steps. 

The profens are non-steroidal anti-inflammatory agents based on arylpropionic acids the best known is ibuprofen. The BHC company (Boots-Hoechst-Celanese) developed a commercial route to ibuprofen which involves a... 

The carbonylation reaction is the final part of a three step route to ibuprofen (shown in Figure 6a) which has superseded a less efficient six-step pathway from isobutylbenzene (Box 6). A related profen, naproxen is made by a hydroxycarbonylation route (Figure 6b). 

Figure 6 Synthetic routes to anti-inflammatories (a) ibuprofen and (b) naproxen involving palladium catalyzed carbonylation steps.

The three step BHC route to ibuprofen supersedes a previous synthetic pathway which also started from isobutylbenzene but required six steps and was environmentally less friendly, i.e. less green (see Figure 7). 

It is instructive to compare the atom economies of the two pathways. Atom economy is a measure of the efficiency of a chemical process, defined in percentage terms as x (formula wt. of atoms utilized)/(formula wt. of all reactants). For the old six-step ibuprofen synthesis the atom economy was only 40% (with MeC02H, EtOH, NaCl, Et0C02H, 2H2O and NH3 as waste). This is dramatically improved to 77% for the new three-step route with only MeC02H as a by-product from the first step. Recovery and use of this increases the atom economy to 99%. Additionally, the catalytic amounts of HF and Pd complex used in the BHC process are recovered and reused, whereas stoichiometric quantities of AICI3 hydrate were produced as waste by the old route. 

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. 

A classic example of improving the route to a commercial product is ibuprofen (1.16), which is an analgesic (a pain reliever) and is also effective as a non-steroidal antiinflammatory drug. Ibuprofen was produced using six steps (Scheme 1.8) by the Boots Company, with an overall atom economy of just 40%. 

An interesting example is ibuprofen and naxoprofen chemistry. The 20 years of naxoprofen technology have been reviewed recently [71], and the electrochemical route has also been described [72], Ibuprofen electrochemistry has been described by SNPE [73]. 

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