Paracetamol, Beckmann rearrangement

The ammoximation reaction involves the in situ formation of hydroxylamine via TS-1 catalysed oxidation of NH3 with H2O2. Hence, there are no size restrictions with regard to the ketone substrate, because the reaction of NH2OH with the latter occurs in the bulk solution. For example, TS-1 catalyses the ammoximation of / -hydroxyacetophenone (Le Bars et al., 1996). Beckmann rearrangement of the oxime product (see Fig. 2.18) affords the analgesic paracetamol (4-acetaminophenol). 

A serious shortcoming of TS-1, in the context of fine chemicals manufacture, is the restriction to substrates that can be accommodated in the relatively small (5.lx5.5 A2) pores of this molecular sieve, e.g. cyclohexene is not epoxidised. This is not the case, however, with ketone ammoximation which involves in situ formation of hydroxylamine by titanium-catalysed oxidation of NH3 with H202. The NH2OH then reacts with the ketone in the bulk solution, which means that the reaction is, in principle, applicable to any ketone (or aldehyde). Indeed it was applied to the synthesis of the oxime of p-hydroxyacetophenone, which is converted, via Beckmann rearrangement, to the analgesic, paracetamol (Fig. 1.24) [75]. 

Paracetamol is used in broad spectrum of arthritic and rheumatic conditions linked with musculoskeletal pain, headaches, neuralgias and dysmenorrhea. It is generally prepared from p-nitrophenol by reduction (Sn + HCl) followed by reaction with acetic anhydride-acetic acid mixture. Alternatively it is obtained by the Beckmann rearrangement of oxime of p-hydroxyacetophenone. 

The oxime of p-hydroxyacetophenone (obtained above) on Beckmann rearrangement gives paracetamol (Scheme 24). 

Paracetamol (a widely used over-the-counter analgesic and antipyretic) was synthesized by the environmentally benign liquid-phase Beckmann rearrangement of 4-hydroxyacetophenone oxime over Al-MCM-41 modified with HjPO [158]. The conversion of 4-hydroxyacetophenone oxime to paracetamol increased with the HjPO loading in the catalysts with the maximum at 30wt.%. 

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