Synthesis Of Intermediates For COX-2 Inhibitor Etoricoxib

Etoricoxib was identified as a very potent and specific COX-2 inhibitor having analgesic and anti-inflammatory action. It can be assembled by construction of l-(6-methyl-3-pyridinyl)-2-[(4-methylsulphonyl)phenyl] ethanone (MMPE) with vinamidinium salts. In this paper, three synthetic strategies -Grignard, Horner-Wittig, and Claisen- to MMPE were exploited starting from 2-methyl-5-ethylpyridine(MEP) and thioanisole. Several important intermediates concerned were prepared including methyl 6-methylnicotinate (MMN), Weinreb amide (N-methoxy-N,6-dimethy-l pyridine-3- formamide), 6-methylnicotinaldehyde (NTA), 4-methylsulfonylacetoph-enone, 4-methylsulphonylphenyl acetic acid. Finally, MMN was achieved by Claisen condensation of 4-methylsulphonylphenylacetic acid with MMN in 44% overall yield from thioanisole.MMN was prepared from MEP by oxidation and esterification in the presence of nitric acid as an oxidation agent and ammonium vanadate as a catalyst. In this case, 1 equiv of MEP was mixed with 2 equiv of sulfuric acid and small mounts of ammonium vanadate. Then 6 equiv of nitric acid was added dropwise at from 130 150℃ for 23 hours. After cooling the misture was estered by superfluous methanol for 2 times and MMN was isolated from the mixture in 72% yield by rectification having a content of 98.4%.4-methylsulphonylphenyl acetic acid was prepared from thioanisole by three steps. 1 equiv of thioanisole reacted with 1.3 equiv of acetyl chloride at 0℃ in the presence of 1.3 equiv of AlCl₃ as catalyst. The Friedel-Crafts reaction preceeds in 2 hours to give 4-methylthioacetophenone. The obtained 4-methylthioacetophenone was oxided by H₂O₂ in the presence of small mounts of H₂SO₄ in HAc for 2 hours at 55 60℃ to give 4-methylsulfonylacetophenone, which was converted with morpholine and sulfur by Willgerodt-Kindler reaction into 4-methylsulphonylphenyl acetic acid. The rearrangement reaction preceeds at from 126¹27℃ for 5 hours to give the intermediate compound which followed by hydrolyzation in 10% NaOH aqueous forover 10 hours. The yield was 74%(from thioanisole) having a content of 98.9%. Besides, some derivatives were achieved.MMPE was prepared by Claisen condensation of 4-methylsulphonyl-phenylacetic acid with MMN. In this case, 1 equiv of 4-methylsulphonylphenylacetic acid and MMN reacted in the presence of 3 equiv of t-butyl magnesium chloride as base at 50°C in THF to give the P -ketoester ,which followed by acid hydrolysis and decarboxylation to give MMPE in 59.3% yield having a content of 98.7%. The structure of the product was comfirmed by IR, 'H NMR and 13C NMR.MMN was reduced to NTA useful for Horner-Wittig approach to MMPE by Synhydrid as a reductant in a single step. Compared with UAIH4 or DIBAL, the adoption of Synhydrid greatly reduced the cost. In this case, Synhydrid reacted with morpholine in toluene to give amino-hydride. Then 1.2 equiv of the amino-hydride reacted with 1 equiv of MMN for 3 hours below 20°C, treated with tartaric acid, extracted by toluene and evaporated to give NTA in 89.7% yield.MMN was converted with methoxymethylamine in THF into Weinreb amide useful for Grignard approach to MMPE in the presence of isopropylmagnesium chloride. Weinreb amide was obtained in 82.6% yield and 93.2% purity. p-Methylthiobenzyl chloride was another important intermediate for Grignard approach. But its prepration by via chloromethylation of thioanisole was difFcult. It was obtained only in 52.3% purity with isomers that were not practicably separable. As a result, Grignard approach was restricted from large scale production of MMPE.