Ibuprofen, oxidation

The benzyl hydroxyl containing API cyclandelate undergoes oxidation to the corresponding ketone, 3,3,5-trimethylcyclohexyl phenylglyoxalate (143). Low level benzylic oxidation is observed for the API ibuprofen. Oxidation to form the ketone derivatives at both benzylic sites to yield isobutyl acetophenone and 2-(4-isobutyrylphenyl)-propionic acid has been reported (144). 

The hydrolysis of various para-substituted a-methylstyrene oxides was studied using 10 EHs [184]. The hydrolysis of the isobutyl compound with the enzyme from A. niger WHS the key step in the synthesis of (S)-ibuprofen (Figure 6.65). The (R)-diol was recycled via chemical racemization. 

A number of papers have appeared on the use of layered double hydroxides (e.g. Mg and Al containing oxides). A meixnerite-like catalyst has been reported to give 100% selectivity for diacetone alcohol from acetone at 0 C at close to thermodynamic equilibrium conversion of 23% (Tichit and Fajula, 1999). The side-chain alkylation of toluene with propylene to give isobutyl benzene (for ibuprofen) is a well-known example where Na/K alloy on Na2C03/K2C03 is used as the catalyst. 

Kennedy, T.P., Rao, N.V., Noah, W., Michael, J.R., Jaffri, M.H., Gurtner, G.H. and Hoidal, J.K (1990). Ibuprofen prevents oxidant lung injury and in vitro lipid peroxidation by chelating iron. J. Clin. Invest. 86, 1565-1573. 

Asymmetric Hydroformylation of Vinylarenes a-Arylpropanals, the products of asymmetric hydroformylation of vinylarenes, serve as useful intermediates for pharmaceutical drugs. For example, (5)-2-arylpropanals can be oxidized to the corresponding (5)-2-arylpropanoic acids, such as (5)-ibuprofen (Ar = 4-isobutylphe-nyl), (5)-naproxen (Ar = 6-methoxynaphthalen-2-yl), and (5)-suprofen (Ar = 4-(2-thienylcarbonyl)phenyl) (see later in chapter. Scheme 4.4). Styrene is thus one of the most popular substrates used to test new catalyst systems. Representative ligands and their use as Pt or Rh complexes in the asymmetric hydroformylation are summarized in Figure 4.1 and Table 4.1. (See also Scheme 4.3.)... 

The synthesis of (S)-ibuprofen (S)-34 utilizing allylic alkylation was undertaken to determine the stereochemical course of this process. The reaction of the enantiomeri-cally enriched allylic carbonate (S)-32 (95% ee) with the requisite aryl zinc bromide (Scheme 10.7) [32], under optimized reaction conditions, furnished the 3-aryl propenyl derivative (R)-33 in 90% yield (2° 1°=10 1) with inversion of configuration (100% cee). The synthesis of (S)-ibuprofen (S)-34 was then completed through the oxidative cleavage of the aUcene (R)-33 in 74% yield [33]. 

Impairment of mitochondrial jj-oxidation leads to accumulation of fat, resulting in steatosis. Examples are various tetracycline derivatives, valproic acid (used to treat seizures) and overdoses of aspirin [64—66]. Certain NSAIDs such as ibuprofen, ketoprofen and naproxen also have the ability to inhibit jj-oxidation [67-69]. 

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... 

Cleij, M., Archelas, A., Furstoss, R. Microbiological Transformations 43. Epoxide Hydrolases as Tools for the Synthesis of Enantiopure Methylstyrene Oxides A New and Efficient Synthesis of (S)-Ibuprofen, J. Org. Chem. 1999, 64, 5029-5035. 

Caviglioli G, Valeria P, Brunella P, Sergio C, Attilia A, Gaetano B. Identification of degradation products of Ibuprofen arising from oxidative and thermal treatments. J Pharm Biomed Anal 2002 30 499-509. 

Figure 12.20 A designer C H oxidation catalyst the positions the reactive CH-bond over the catalyst active site using molecular recognition. The ibuprofen substrate is oxidised to the 2-(4-Isobutyryl-phenyl) -propionic acid product in > 98 % selectivity (reproduced by permission of The Royal Society of Chemistry).

Hydroformylation of styrene and its analogues has attracted particular attention, since this provides a general method for the preparations of optically pure arylpropionic acids. Apart from Naproxen , the drug ibuprofen is another ar-ylpropionic acid-based nonsteroidal anti-inflammatory agent. As shown by 9.9, ibuprofen may in principle be synthesized by enantioselective hydroformylation reactions followed by oxidation of the aldehydic functionality. 

PdCl2(PPh3)2 was applied. After initial reduction of the palladium to obtain the active species, an oxidative addition of the benzylic chloride takes place. Migration of the benzylic group leads to the formation of the new carbon-carbon bond a reductive elimination then releases ibuprofen as its acid chloride which is hydrolysed, closing the second catalytic cycle, too. This process is used to produce 3500 t/year of ibuprofen and TON of 10000 have been reached for the palladium catalyst (Scheme 5.38). 

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]. 

FIGURE 9 (A) Molecular structures of ibuprofen and its oxidation products (B) ter-... 

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