Synthesis of Paracetamol

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. 

In the green synthesis of paracetamol p-hydroxyacetophenone is reacted with ammonia and hydrogen peroxide in presence of titanium(IV)-silicate (TS-1) catalyst to give the oxime of p-hydroxyacetophenone. In fact, in the above reaction, ammoximation proceeds via in situ formation of hydroxylamine by titanium-catalysed oxidation of ammonia with in the micropores of 

---

Scheme 65 Synthesis of paracetamol, Hoechst-Celanese process.

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. 

Many preparative methods have since been described for the synthesis of paracetamol, mostly emplo3ring the acetylation ofpara-aminophenol with acetic anhydride as indicated above. However, a number of other routes of synthesis have also been discovered and used commercially, namely ... 

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. 

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. 

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]. 

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. 

Dicoumarol, warfarin + paracetamol With especially large doses, increase in anticoagulant effect Possibly displacement from protein. Depression of clotting factor synthesis Use low doses of paracetamol. Probably the safest mild analgesic to use with oral anticoagulants... 

Richard AM, Hongslo JK, Boone PF, et al. 1991. Structure-activity study of paracetamol analogues Inhibition of replicative DNA synthesis in V79 Chinese hamster cells. Chem Res Toxicol 4 151-156. 

One synthesis of the analgesic paracetamol (acetaminophen, 12) involves the nitrosation of phenol followed by reduction of the 4-nitrosophenol. Subsequent selective acetylation of the more reactive amino group completes the process ... 

The para isomer is a key intermediate in the Hoechst Celanese process for the manufacture of paracetamol (p-acetaminophenol) [2] the ortho isomer can be used for the synthesis of salicylic acid. Other hydroxyarylketones of commercial importance also result from the Fries rearrangement, e. g. 2,4-dihydroxybenzophe-none, an intermediate in the preparation of UV absorbents [3], and diphenol monomers which can be used for the manufacture of advaneed polymers [4], etc. 

Paracetamol (acetaminophen) was synthesised first in 1888 as an intermediate in the synthesis of phenacetin. Unfortunately, the organic chemists at Bayer never tested this compoimd for its medicinal properties. The prevailing thought at the time was that phenols were too toxic for clinical use. It was the Swedish physiological chemist, Karl Morner in 1891 who discovered that paracetamol (acetaminophen) was a urinary metabolite of phenacetm. This is a result of the 0-de-ethylation of phenacetin... 

To mention some examples, benzoylation of xylenes was particularly studied because of the use of dimethylbenzophenones as UV-light stabilizers in plastics. Moreover, 2-acetyl-6-methoxynaphthalene represents the precursor to the antirheumatic Naproxen.i ortho- and para-Hydroxy-acetophenones are widely used for the synthesis of aspirin and paracetamol (4-acetamidophenol), respectively. orf/zo-Hydroxyacetophenone is also a key intermediate in the production of 4-hydroxycoumarin and warfarin, both used as anticoagulant drugs in the therapy of thrombotic diseases, and it is also employed in the synthesis of flavonones. ... 

---