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4) The oxidation of 4-(methylsulfanyl)acetophenone (X) with monoperoxyphthalic acid (MMPP) in dichloro-methane/methanol gives the corresponding sulfone (XI), which is brominated with Br2/AlCl3 in chloroform, yielding the expected phenacyl bromide (XII). Finally, this compound is cyclocondensed with phenylacetic acid (I) by means of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and triethylamine in acetonitrile. 5) Reaction of [4-(methylsulfonyl)phenyl]phenylacetyl-ene (XIII) with CO catalyzed by Rh4(CO)12 in THF at 100 C in a stainless steel autoclave at 100 Atm pressure, followed by a chromatographic separation in a silicagel column to eliminate the undesired regioisomer.

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7) The Friedel-Crafts condensation of thioanisole (XX) with acetyl chloride (XXI) by means of AlCl3 in dichlorobenzene gives the corresponding acetophenone (X), which is oxidized with H2O2/WO4Na2 to the ketosulfone (XI). The bromination of (XI) with Br2 in acetic acid/48% HBr affords the phenacyl bromide (XII), which is condensed with phenylacetic acid sodium salt (XXIII) in DMF, giving the phenacyl ester (XXII). Finally, this compound is cyclized by means of diisopropylamine in DMF.

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The Friedel Crafts acylation of thioanisole (I) with acetyl chloride (II) and AlCl3 in chloroform gives 4-(methylsulfanyl)acetophenone (III), which is oxidized with monoperoxyphthalic acid (MMPP) in methanol/dichloromethane to yield 4-(methylsulfonyl)acetophenone (IV). The bromination of (IV) with Br2 and AlCl3 in chloroform affords 4-(methylsulfonyl)phenacyl bromide (V), which is finally cyclized by means of DBU and TEA in acetonitrile to provide the target furanone derivative.

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2) Synthesis of etoricoxib via ketosulfone (XXIV): a) The reaction of 6-methylpyridine-3-carboxylic acid methyl ester (XVIII) with N,O-dimethylhydroxylamine and isopropylmagnesium chloride in toluene gives the N-methoxyamide (XIX), which is reduced with DIBAL to afford 6-methylpyridine-3-carbaldehyde (XX). Reaction of aldehyde (XX) with aniline and diphenyl phosphite provides the diphenyl phosphonate (XXI), which is condensed with 4-(methylsulfonyl)benzaldehyde (XXII) by means of potassium tert-butoxide in HF to yield the enimine (XXIII). Finally, this compound is hydrolyzed with HCl to give ketosulfone (XXIV). b) Condensation of N-methoxyamide (XIX) with 4-(methylsulfanyl)benzylmagnesium bromide (XXV) in toluene/THF gives 1-(6-methylpyridin-3-yl)-2-[4-(methylsulfanyl)phenyl]ethanone (XXVI), which is finally oxidized with Na2WO4 to yield ketosulfone (XXIV). c) Oxidation of 4'-(methylsulfonyl)acetophenone (XXVII) with S8 and morpholine, followed by esterification with ethanol, affords 2-[4-(methylsulfonyl)phenyl]acetic acid ethyl ester (XXVIII); which is condensed with 6-methylpyridine-3-carboxylic acid methyl ester (XVIII) by means of t-BuMgCl in hot THF to furnish ketosulfone (XXIV).

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6-Chloronicotinic acid (I) is converted to the corresponding acid chloride (II) employing either SOCl2 or PCl5/POCl3. Treatment of acid chloride (II) with EtOH and Et3N, followed by reduction of the resultant ethyl ester with LiAlH4, furnishes 6-chloro-3-pyridylmethanol (III). Alcohol (III) is alternatively prepared by NaBH4 reduction of acid chloride (II). Chlorination of (III) by using SOCl2 gives the chloromethyl pyridine (IV), and further chloride displacement with KCN leads to nitrile (V). Substitution of the remaining chloride group of (V) upon heating with pyrrolidine (VI) furnishes the pyrrolidinyl pyridine (VII). Then hydrolysis of the nitrile function of (VII) under acidic conditions provides carboxylic acid (VIII). Bromination of 4-(methylsulfonyl)acetophenone (IX) in the presence of AlCl3 produces the phenacyl bromide (X). Finally, condensation between acid (VIII) and bromo ketone (X) under basic conditions gives rise to the title diaryl furanone

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