Ibuprofen three-step synthesis

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. 

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). 

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.

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 modern industrial-scale synthesis of ibuprofen has very high atom efficiency, and it has been modified from the original synthesis to be both more environmentally friendly and more cost effective. The original method involved six synthetic steps but used stoichiometric (as opposed to catalytic) quantities of reagents, had lower atom efficiency, and produced undesirable quantities of waste. The modern alternative, on the other hand, requires just three steps, each of which is catalytic in nature. The first step employs a recyclable catalyst (hydrogen fluoride, HF) and produces almost no waste. The second and third steps each achieve 100% atom efficiency (wow ). This process truly represents an idetd benchmark for excellence in green synthesis on the industrial scale. 

The original synthesis of the pain reliever ibuprofen required six reactions that together sent 23 H atoms, 7 C atoms, 8 O atoms, and 1 Cl, 1 Na, and 1 N atoms into waste products. A new green synthesis using the same starting materials requires only three steps and creates waste products containing only 4 H atoms, 2 C atoms, and 2 O atoms. 

Ibuprofen, an analgesic (marketed under the brand names Advil and Matrix ), was traditionally synthesized in six stoichiometric steps involving an atom-efficiency of less than 40%. A new catalytic process designed for the synthesis of Ibuprofen by BHC (BHC, 1997) involves three steps, with an atom-efficiency of 80%. Though the usage of HF, a toxic substance, is a drawback of the process, the recovery of HF is effected with 99.9% efficiency. This is a fine example of an eco-efficient process being commercialized. 

The BHC company developed a new greener commercial synthesis of ibuprofen that consists of only three steps s (Scheme 23). 

The syntheses of ibuprofen, (S)-metolachlor, and (-)-menthol represent only three of the numerous uses of soluble transition metal complexes to catalyze, often stereoselectively, key steps in the production of biologically important compounds in the laboratory or on an industrial scale. Discussions in Chapter 12, especially with regard to asymmetric conditions, will explore more fully the use of these catalysts in the synthesis of other organic compounds. 

In 1997, the Presidential Green Chemistry Challenge Greener Synthetic PathwaysAward was given to BHC Company (now BASF) for a novel method of ibuprofen synthesis.The new process consists of three catalytic steps, with the only byproduct being acetic acid, and has overall atom efficiency of about 80%. Since the acetic acid byproduct does not end up in the waste but is recovered, the process can be considered virtually 99% atom efficient. The older process, replaced by the award-winning one, consisted of six stoichiometric steps with an overall atom efficiency of less than 40%. 

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