Ibuprofen, synthesis

Figure 9.6 Ibuprofen synthesis by Pd/tppts-catalyzed biphasic carbonylation in water.

SCHEME 80. Preparation of quarternary chiral centers and (+)-ibuprofen synthesis... 

These ketones are important intermediates in the synthesis of fragrances of the musk type, of UV absorbents and of pharmaceuticals such as paracetamol, ibuprofen, S-naproxen. Thus, in the processes of ibuprofen synthesis (9), the first classical step is the acetylation of isobutylbenzene with acetic anhydride in presence of HF (Hoechst process) or of A1C13 (Boots process) ... 

In a similar approach, naproxen is prepared from an olefin, the product of a Heck reaction (see Section 5.3.2.1). As described above, the reaction proceeds in the presence of water and HC1, additionally copper(n)chloride is added, possibly to prevent the formation of palladium black (Scheme 5.39). Addition of HC1 to the double bond and subsequent oxidative addition reaction of the benzylic chloride with the active Pd° species initiates the catalytic cycle, which proceeds similarly to the ibuprofen synthesis [70-73]. 

Scheme 5.38 Industrial carbonylation in the Ibuprofen synthesis of Celanese.

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 Boots-Hoechst-Celanese Process for Ibuprofen Synthesis... 

For example, isobutylbenzene as starting material for ibuprofen synthesis is produced by side-chain alkylation of toluene with solid super-base by Sumitomo (Eq. 8-28). 

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%. 

Immobilized Rhodococcus sp. SP 361 is an example that shows how complex stereoselective nitrile conversions might sometimes appear [57]. In the bioconversion of R,S)-2-alkylarylacetonitriles an unusual enantioselective diversity was observed. Whereas most racemic 2-alkylarylacetonitriles were converted to (S)-acids and (/ )-amides (Fig. 17), indicating the presence of an (>S)-selective amidase, ibuprofen nitrile was only converted to the ( )-acid (e.e. 32%) without any intermediate amide formation. A slow and strictly R) specific nitrile hydratase and a fast and less strict (5)-amidase were accounted for the (/ )-specific ibuprofen synthesis. The aryl-bound isobutyl moiety of ibuprofen nitrile seemed to invert the molecule orientation at the catalytic center of the nitrile hydratase. Furthermore, in the conversion of (.R,5)-2-(4-methylphenyl)propionitrile, not only the chiral S) acid (e.e. more than 95%, yield 41%) and (/ )-amide (e.e. more than 95%, yield 18%), but also enantiomerically almost pure (fi )-nitrile (e.e. more than 95%, yield 25%) was obtained. In this instance, the nitrile was hydrated with a partial (5)-selectivity. Overall, the absolute configuration of the products was rationalized according to a model assuming the presence of an (5)-selective amidase and a nitrile hydratase with (5)-, (JR)-, or nonspecificity depending on the type of substrate. 

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