Ibuprofen from isobutylbenzene

Show how ou might prepare the anti-inflammatory agent ibuprofen starting from isobutylbenzene. More than one step is needed. 

A very popular alternative to aspirin and acetaminophen is ibuprofen, which has tradenames such as Motrin and Advil . It can be synthesized from isobutylbenzene by a Friedel-Crafts acylation with acetyl chloride, followed by formation of a cyanohydrin. Treatment with H2/Pd reduces the benzylic hydroxyl to a hydrogen and hydrolysis of the nitrile gives the carboxylic acid. There are at least six published syntheses of ibuprofen. This illustrates the difficulty of knowing which technology a particular company is using. At the other extreme is the proprietary nature of some syntheses, where they have not yet been published. 

Ibuprofen can be synthesized from isobutylbenzene by a Friedel-Crafts acylation with acetyl chloride, followed by formation of a cyanohydrin. Treatment with hydrogen iodide and phosphorus reduces the benzylic hydroxyl to a hydrogen and hydrolyzes the nitrile to a carboxylic acid. 

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The carbonylation reaction is the final part of a three step route to ibuprofen (shown in Figure 6a) which has superseded a less efficient six-step pathway from isobutylbenzene (Box 6).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). 

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). 

Friedel—Crafts alkylation of benzene with mesyl lactates under nonracemizing reaction conditions affords methyl or ethyl (5)-2-phenylpropionate (182) in high chemical yield and 97% optical yield [67,68]. The excellent stereoselectivity results from the ability of the Lewis acid to form a complex with 156 prior to the back-side attack of benzene with net inversion of configuration. Analogous reaction with isobutylbenzene produces a mixture of regioisomeric products from which (5)-ibuprofen is isolated. 

Give an efficient synthesis of (2-methylpropyl)benzene (isobutylbenzene, the starting material for the preparation of ibuprofen see Exercise 16-10), starting from benzene. [Hint What would you expect as the major monosubstitution product of Friedel-Crafts alkylation of benzene with l-chloro-2-methylpropane (isobutyl chloride) ]... 

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