Isobutylbenzene Ibuprofen

Isobutylbenzene Ibuprofen Pharma Nonsteroidal analgestic C (Homo Het) 1000 - 3000 STR... 

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. 

An intEiesting variant on the Wilgerodt reaction offers a simple three-step procedure that avoids the wastage involved in the schemes above, which require the incorporation of an extra carbon atom that must later be eliminated. The sequence starts with the acylation of isobutylbenzene (49-1) with propionyl chloride to give propiophenone (49-2). Reaction of that with thallium 111 nitrate and methyl ortho-formate in methanol leads in high yield to the methyl ester (49-3) of ibuprofen [50]. This would be the method of choice for preparing the dmg but for two unfortunate facts the extreme toxicity of thallium and the very high sensitivity of analytical methods for the detection of metals. It proved to be virtually impossible, in practice, to produce samples that showed zero residues of thallium. 

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). 

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... 

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) ... 

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). 

Based on the palladium-catalyzed carbonylation of l-(4-isobutylphenyl)etha-nol, which is produced via salt-free acylation of isobutylbenzene to 4-isobutyl-acetophenone and subsequent hydrogenation, the former Hoechst Celanese Corporation [33] developed an ecologically superior process to produce ibuprofen in a plant operating since 1992 on a 3500-ton scale (eq. (9) 1 bar = 0.1 MPa) [34]. 

Acylation of isobutylbenzene with acetic anhydride leads with high yield and selectivity to para-acetylisobutylbenzene (Eq. 9) which is an intermediate in the synthesis of ibuprofen, an important antiinflammatory drug [18]. With H/1 zeolite at 140 °C after 1 h the yield is 80 % with 96 % para selectivity. Acylation of tetra-lin with acid chlorides and different zeolites has also been studied [19], For this reaction again acetyl chloride is much less reactive than higher acid chlorides such as butanoyl or octanoyl chloride. The selectivity is in favor of the 2-substituted isomer (85-90%) and limited quantities of the 1 isomer (10-15%) are formed (Eq. 10). 

In the presence of Re207/Al203 that has been pretreated with Cu(N03)2 to suppress side reactions, the cross-metathesis of 2,4,4-trimethyl-2-pentene with 4-vi-nylcyclohexene (Eq. 10) proceeds with >15% selectivity [29]. The product iso-butenyl cyclohexene can be converted to isobutylbenzene, which is the starting material for the synthesis of the over-the-counter analgesic, ibuprofen. 

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. 

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). 

Similarly, acylation of isobutylbenzene with acetic anhydride over H-Beta catalyst at 140°C can afford p-acetylisobutylbenzene (Figure 11.10), which is an intermediate in the synthesis of antiinflammatory drug ibuprofen, in 80% yield and 96% para-selectivity [41]. 

Show how you could synthesize racemic ibuprofen starting with l-bromo-4-isobutylbenzene. 

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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