Nabumetone synthesis

Nabumetone selectively inhibits COX-2. It is metabolised into 6-methoxy-2-naphthylacetic acid (MNA), that is a potent inhibitor of COX-2. It has no inhibitory effect on COX-1 which is responsible for prostaglandin synthesis in gastric mucosa, thereby minimising the risk of problems like ulcers and hypertension. After oral administration 80% of dose is excreted in the urine. Peak plasma concentration is reached after 2.5 to 4 hours. 

Scheme 13.2 Synthesis of nabumetone (4-(6-methoxy-2-naphthenyl)-2-butanone.

Problem 24.7 a published synthesis of the analgesic nabumetone uses a crossed aldol reaction to form X. What is the structure of X X is converted to nabumetone in one step by hydrogenation with H2 and Pd-C. (See Problem 23.28 for another way to make nabumetone.)... 

This reaction was particularly applied [23] to the one-step synthesis of nabumetone... 

Using a developed method, laser irradiation of colloidal mixtures of the three metals, these authors dispersed Au/Ag/Pd nanoparticles with average diameters 4.4 1.5 nm. These tri-metallic nanoparticles were assessed for activity in the synthesis of nabumetone [4-(6-methoxy-2-naphthalenyl)-2-butanone], a non-steroidal anti-inflammatory drug that has greater activity than aspirin and is comparable to naproxen and indomethacin. The 0.45-mol% Au/Ag/Pd was sufficient to catalyse the coupling of the 3-buten-2-ol... 

The synthesis of the nonsteroidal anti-inflammatory drug nabumetone (9) was developed by Hoechst-Celanese [71]. It was prepared via a Heck coupling of 2-bromo-6-methoxy-naphthalene (1) with methyl vinyl ketone in the presence of palladium catalyst [71]. Further reduction of unsaturated ketone provided 9. Nabumetone was also obtained in a one-step coupling reaction of 2-bromo-6-methoxy-naphthalene with 3-buten-2-ol followed by isomerization of enol [72]. 

Figure 2.67 Synthesis of nabumetone with a multifunctional base/acid/Pd catalyst through a cascade reaction.

Nabumetone is a NSAID that decreases inflammation, pain and fever, probably through inhibition of cyclooxygenase activity and prostaglandin synthesis. 

Other examples for which homogeneously catalyzed Heck reactions have been exploited toward an industrial production include the preparation of the fragrance Lihal developed by Givaudan, the synthesis of the nonsteroidal anti-inflammatory drug Nabumeton by Hoechst-Celanese, ° and the synthesis of the sunscreen agent 2-ethylhexyl p-methoxy-cinnamate (EHMC) by Hoechst AG and other companies (Scheme 6). Noteworthy, Nabumeton is obtained in one step via coupling and domino isomerization reaction of 2-bromo-6-methoxynaphthalene with 3-buten-2-ol. ° ... 

One potential synthesis of the anti-inflammatory and analgesic drug nabumetone is chloromethylation (Problem 22.48) of 2-methoxynaphthalene followed by an acetoacetic ester synthesis (Section 19.6). 

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