Paracetamol, synthesis

Blair, LA., Boobis, A.R., Davies, D.J. and Cresp, T.M. (1980). Paracetamol oxidation, synthesis and reactivity of N-acetyl-/>-benzoquinone imine. Tetrahedron Lett. 21, 4947-4950. 

The different reactivities associated with nucleophiles and leaving groups is nicely exemplified in the synthesis of the analgesic drug paracetamol (USA acetaminophen) from 4-aminophenol. If 4-aminophenol is treated with an excess of acetic anhydride, aeetylation of both amino and phenol groups is observed, and the product is the diacetate. Paracetamol is the A-acetate of 4-aminophenol, so how might mono-acetylation be achieved There are two approaches. 

Scheme 65 Synthesis of paracetamol, Hoechst-Celanese process.

Bose and coworkers have performed known chemical processes in various kitchen microwave devices to explore microwave chemistry at a larger scale [33]. Representative examples for multigram-scale synthesis without optimization of reaction conditions have been presented, such as the rapid preparation of 500-800 g of acetylsalicylic acid (Aspirin). Another valuable pharmaceutical compound, Tylenol (acetaminophen, paracetamol), could be... 

In the synthesis of daminozide an anhydride is used out of necessity rather than out of choice, but it often turns out that there are several alternative reagents all corresponding to the same disconnection. Paracetamol, for example, is an amide that can be disconnected either to amine -I- acyl chloride or to amine -l- anhydride. 

Aspirin deals with pain that comes from any form of inflammation, but it does cause some stomach bleeding. Therefore, research was undertaken for an alternative that was cheap to manufacture and would not cause stomach bleeding. This search led to the synthesis of paracetamol (Figure 1.6). Paracetamol does not cause stomach bleeding, but large doses damage the liver. 

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) ... 

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]. 

Adverse effects. Paracetamol is usually well-tolerated by the stomach because inhibition of prostaglandin synthesis in the periphery is weak allergic reactions and skin rash sometimes occur. Heavy, long-term daily use may predispose to chronic renal disease. 

While aspirin significantly inhibits peripheral prostaglandin and thromboxane synthesis, paracetamol is less potent as a synthetase inhibitor than the NSAIDs, except in the brain, and paracetamol has only a weak anti-inflammatory action. It is simple to ascribe the analgesic activity of aspirin to its capacity to inhibit prostaglandin synthesis, with a consequent reduction in inflammatory edema and vasodilatation, since aspirin is most effective in the pain associated with inflammation or injury. However, such a peripheral effect cannot account for the analgesic activity of paracetamol, which is less well understood. 

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