Acetyl chloride Ibuprofen

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 Ibuprofen, 2-(4-iTo-butylphenyl)propionic acid (3.2.23), can be synthesized by various methods [88-98]. The simplest way to synthesize ibuprofen is by the acylation of Mo-butylbenzol by acetyl chloride. The resulting iTo-butylbenzophenone (3.2.21) is reacted with sodium cyanide, giving oxynitrile (3.2.22), which upon reaction with hydroiodic acid in the presence of phosphorus is converted into 2-(4-iTo-butylphenyl)pro-pionic acid (3.2.23), which subsequently undergoes phases of dehydration, reduction, and hydrolysis. 

The prototype for this class of compounds is ibufenac (42-3), developed by a group at Boots in the UK. This drug was to be quickly superseded by its a-methylated congener, ibuprofen, from the same laboratory [43]. The mechanistically very complex Wilgerodt reaction constitutes the key to the preparation of ibufenac. Thus, reaction of the acetylation product (42-1) from isobutyl benzene and acetyl chloride with sulfur and morpholine leads to the transposition of the oxidized function to the terminal carbon and formation of thiomorpholide (42-2). Hydrolysis of the thioamide... 

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. 

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). 

Commenls The preparation of alcoholic HCl can also be carried out in silu by the addition of acetyl chloride to the dry chiral alcohol [8]. Although the conditions used for these reactions are harsh, the authors reported no evidence of racemization during the derivatization of naproxen [54] even after an extended reaction time of 23 h. Lee el al. [64], however, observed a small peak, corresponding to approximately 2%, when enantiomeri-cally pure ibuprofen was derivatized under the conditions described in procedure C the results could have been attributed to either racemization or the presence of impurities in the substrates or reagents. 

A particularly impressive green example (Real Life 3-1) of this effect is achieved in the Friedel-Crafts acetylation of (2-methylpropyl)benzene with acetic anhydride, in an industrial approach to an ibuprofen intermediate (Chapter Opening see also Exercise 16-10). Here, a porous zeolite catalyst (see Section 3-3) provides not only the acidic surface sites necessary for the reaction to proceed, but also an environment that enhances para selectivity. This process avoids the use of the corrosive acetyl chloride and AICI3 reagents and with it the formation of the toxic HCl by-product of the classical Friedel-Crafts acetylation. Instead, the by-product is acetic acid, itself a valuable commodity. 

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