Synthesis of etoricoxib via dichloropyridine (VIII): a) The bromination of 5-chloro-2-hydroxypyridine (I) with Br2 in acetic acid gives 3-bromo-5-chloro-2-hydroxypyridine (II), which is treated with benzyl bromide and Ag2CO3 in hot benzene to yield benzyl ether (III). Condensation of (III) with 4-(methylsulfanyl)phenylboronic acid (IV) by means of Pd(PPh3)4 and Na2CO3 in refluxing ethanol/benzene affords 2-(benzyloxy)-5-chloro-3-[4-(methylsulfanyl)phenyl]pyridine (V), which is oxidized with OsO4 and sodium sulfite to furnish sulfone (VI). Treatment of (VI) with TFA provides the 2-hydroxypyridine (VII), which is reacted with POCl3 to yield 2,5-dichloro-3-[4-(methylsulfonyl)phenyl]pyridine (VIII). b) Bromination of 2-amino-5-chloropyridine (IX) with Br2 in acetic acid provides 2-amino-3-bromo-5-chloropyridine (X), which is condensed with 4-(methylsulfanyl)phenylboronic acid (IV) by means of Pd(PPh3)4 and Na2CO3 in refluxing ethanol/benzene to give 2-amino-5-chloro-3-[4-(methylsulfanyl)phenyl]pyridine (XI). Oxidation of compound (XI) with OsO4 as before yields sulfone (XII), which is converted into compound (VIII) by treatment first with NaNO2 and HCl and then chlorination with POCl3.

Finally, compound (VIII) is condensed with either trimethyl(6-methyl-3-pyridyl)tin (XIII) or the boronate ester lithium salt (XIV) by means of Pd(PPh3)4 to afford etoricoxib. The metalated pyridine (XIII) is obtained by esterification of 3-hydroxy-6-methylpyridine (XV) with triflic anhydride to give the corresponding triflate (XVI), which is treated with hexamethylditin to afford the target tin intermediate (XIII). The boronate lithium salt (XIV) is prepared by treatment of 5-bromo-2-methylpyridine (XVII) with n-BuLi followed by addition of triisopropyl borate.

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).

Finally, etoricoxib is obtained by several related ways: Cyclization of ketosulfone (XXIV) with 2-chloromalondialdehyde (XXIX) or the aniline derivative (XXX) and ammonium acetate in hot propionic acid. Cyclization of ketosulfone (XXIV) with aminoacrolein (XXXI) in the absence of ammonium acetate. Aminoacrolein (XXXI) is prepared by treatment of chloromalondialdehyde (XXIX) with isopropanol, yielding the ether (XXXII) and followed by reaction with ammoniun hydroxide. Cyclization of the lithium enolate of ketosulfone (XXIV) with 2,3-dichloroacrolein (XXXIII) -- obtained by treatment of chloromalondialdehyde (XXIX) with oxalyl chloride and DMF in toluene -- followed by reaction with ammonium acetate or anhydrous ammonia. Reaction of ketosulfone (XXIV) with 2-chloro-1,3-bis(dimethylamino)trimethinium hexaflourophosphate salt (XXXIV) in the presence of an equimolar amount of t-BuOK followed by treatment with HOAc/TFA and then heating at reflux with an excess of ammonium hydroxide. 2-Chloro-1,3-bis(dimethylamino)trimethinium hexaflourophosphate salt (XXXIV) is obtained by reaction of chloroacetic acid (XXXV) with hot dimethylformamide (XXXVI) and POCl3, and then the reaction mixture is treated with 5N NaOH and hexafluorophosphoric acid in water.

Synthesis of etoricoxib via dichloropyridine (VIII): a) The bromination of 5-chloro-2-hydroxypyridine (I) with Br2 in acetic acid gives 3-bromo-5-chloro-2-hydroxypyridine (II), which is treated with benzyl bromide and Ag2CO3 in hot benzene to yield benzyl ether (III). Condensation of (III) with 4-(methylsulfanyl)phenylboronic acid (IV) by means of Pd(PPh3)4 and Na2CO3 in refluxing ethanol/benzene affords 2-(benzyloxy)-5-chloro-3-[4-(methylsulfanyl)phenyl]pyridine (V), which is oxidized with OsO4 and sodium sulfite to furnish sulfone (VI). Treatment of (VI) with TFA provides the 2-hydroxypyridine (VII), which is reacted with POCl3 to yield 2,5-dichloro-3-[4-(methylsulfonyl)phenyl]pyridine (VIII). b) Bromination of 2-amino-5-chloropyridine (IX) with Br2 in acetic acid provides 2-amino-3-bromo-5-chloropyridine (X), which is condensed with 4-(methylsulfanyl)phenylboronic acid (IV) by means of Pd(PPh3)4 and Na2CO3 in refluxing ethanol/benzene to give 2-amino-5-chloro-3-[4-(methylsulfanyl)phenyl]pyridine (XI). Oxidation of compound (XI) with OsO4 as before yields sulfone (XII), which is converted into compound (VIII) by treatment first with NaNO2 and HCl and then chlorination with POCl3.

Finally, compound (VIII) is condensed with either trimethyl(6-methyl-3-pyridyl)tin (XIII) or the boronate ester lithium salt (XIV) by means of Pd(PPh3)4 to afford etoricoxib. The metalated pyridine (XIII) is obtained by esterification of 3-hydroxy-6-methylpyridine (XV) with triflic anhydride to give the corresponding triflate (XVI), which is treated with hexamethylditin to afford the target tin intermediate (XIII). The boronate lithium salt (XIV) is prepared by treatment of 5-bromo-2-methylpyridine (XVII) with n-BuLi followed by addition of triisopropyl borate.

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).

Finally, etoricoxib is obtained by several related ways: Cyclization of ketosulfone (XXIV) with 2-chloromalondialdehyde (XXIX) or the aniline derivative (XXX) and ammonium acetate in hot propionic acid. Cyclization of ketosulfone (XXIV) with aminoacrolein (XXXI) in the absence of ammonium acetate. Aminoacrolein (XXXI) is prepared by treatment of chloromalondialdehyde (XXIX) with isopropanol, yielding the ether (XXXII) and followed by reaction with ammoniun hydroxide. Cyclization of the lithium enolate of ketosulfone (XXIV) with 2,3-dichloroacrolein (XXXIII) -- obtained by treatment of chloromalondialdehyde (XXIX) with oxalyl chloride and DMF in toluene -- followed by reaction with ammonium acetate or anhydrous ammonia. Reaction of ketosulfone (XXIV) with 2-chloro-1,3-bis(dimethylamino)trimethinium hexaflourophosphate salt (XXXIV) in the presence of an equimolar amount of t-BuOK followed by treatment with HOAc/TFA and then heating at reflux with an excess of ammonium hydroxide. 2-Chloro-1,3-bis(dimethylamino)trimethinium hexaflourophosphate salt (XXXIV) is obtained by reaction of chloroacetic acid (XXXV) with hot dimethylformamide (XXXVI) and POCl3, and then the reaction mixture is treated with 5N NaOH and hexafluorophosphoric acid in water.

Finally, etoricoxib is obtained by several related ways: Cyclization of ketosulfone (XXIV) with 2-chloromalondialdehyde (XXIX) or the aniline derivative (XXX) and ammonium acetate in hot propionic acid. Cyclization of ketosulfone (XXIV) with aminoacrolein (XXXI) in the absence of ammonium acetate. Aminoacrolein (XXXI) is prepared by treatment of chloromalondialdehyde (XXIX) with isopropanol, yielding the ether (XXXII) and followed by reaction with ammoniun hydroxide. Cyclization of the lithium enolate of ketosulfone (XXIV) with 2,3-dichloroacrolein (XXXIII) -- obtained by treatment of chloromalondialdehyde (XXIX) with oxalyl chloride and DMF in toluene -- followed by reaction with ammonium acetate or anhydrous ammonia. Reaction of ketosulfone (XXIV) with 2-chloro-1,3-bis(dimethylamino)trimethinium hexaflourophosphate salt (XXXIV) in the presence of an equimolar amount of t-BuOK followed by treatment with HOAc/TFA and then heating at reflux with an excess of ammonium hydroxide. 2-Chloro-1,3-bis(dimethylamino)trimethinium hexaflourophosphate salt (XXXIV) is obtained by reaction of chloroacetic acid (XXXV) with hot dimethylformamide (XXXVI) and POCl3, and then the reaction mixture is treated with 5N NaOH and hexafluorophosphoric acid in water.

Synthesis of etoricoxib via dichloropyridine (VIII): a) The bromination of 5-chloro-2-hydroxypyridine (I) with Br2 in acetic acid gives 3-bromo-5-chloro-2-hydroxypyridine (II), which is treated with benzyl bromide and Ag2CO3 in hot benzene to yield benzyl ether (III). Condensation of (III) with 4-(methylsulfanyl)phenylboronic acid (IV) by means of Pd(PPh3)4 and Na2CO3 in refluxing ethanol/benzene affords 2-(benzyloxy)-5-chloro-3-[4-(methylsulfanyl)phenyl]pyridine (V), which is oxidized with OsO4 and sodium sulfite to furnish sulfone (VI). Treatment of (VI) with TFA provides the 2-hydroxypyridine (VII), which is reacted with POCl3 to yield 2,5-dichloro-3-[4-(methylsulfonyl)phenyl]pyridine (VIII). b) Bromination of 2-amino-5-chloropyridine (IX) with Br2 in acetic acid provides 2-amino-3-bromo-5-chloropyridine (X), which is condensed with 4-(methylsulfanyl)phenylboronic acid (IV) by means of Pd(PPh3)4 and Na2CO3 in refluxing ethanol/benzene to give 2-amino-5-chloro-3-[4-(methylsulfanyl)phenyl]pyridine (XI). Oxidation of compound (XI) with OsO4 as before yields sulfone (XII), which is converted into compound (VIII) by treatment first with NaNO2 and HCl and then chlorination with POCl3.

Finally, compound (VIII) is condensed with either trimethyl(6-methyl-3-pyridyl)tin (XIII) or the boronate ester lithium salt (XIV) by means of Pd(PPh3)4 to afford etoricoxib. The metalated pyridine (XIII) is obtained by esterification of 3-hydroxy-6-methylpyridine (XV) with triflic anhydride to give the corresponding triflate (XVI), which is treated with hexamethylditin to afford the target tin intermediate (XIII). The boronate lithium salt (XIV) is prepared by treatment of 5-bromo-2-methylpyridine (XVII) with n-BuLi followed by addition of triisopropyl borate.

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).

Finally, etoricoxib is obtained by several related ways: Cyclization of ketosulfone (XXIV) with 2-chloromalondialdehyde (XXIX) or the aniline derivative (XXX) and ammonium acetate in hot propionic acid. Cyclization of ketosulfone (XXIV) with aminoacrolein (XXXI) in the absence of ammonium acetate. Aminoacrolein (XXXI) is prepared by treatment of chloromalondialdehyde (XXIX) with isopropanol, yielding the ether (XXXII) and followed by reaction with ammoniun hydroxide. Cyclization of the lithium enolate of ketosulfone (XXIV) with 2,3-dichloroacrolein (XXXIII) -- obtained by treatment of chloromalondialdehyde (XXIX) with oxalyl chloride and DMF in toluene -- followed by reaction with ammonium acetate or anhydrous ammonia. Reaction of ketosulfone (XXIV) with 2-chloro-1,3-bis(dimethylamino)trimethinium hexaflourophosphate salt (XXXIV) in the presence of an equimolar amount of t-BuOK followed by treatment with HOAc/TFA and then heating at reflux with an excess of ammonium hydroxide. 2-Chloro-1,3-bis(dimethylamino)trimethinium hexaflourophosphate salt (XXXIV) is obtained by reaction of chloroacetic acid (XXXV) with hot dimethylformamide (XXXVI) and POCl3, and then the reaction mixture is treated with 5N NaOH and hexafluorophosphoric acid in water.

Finally, etoricoxib is obtained by several related ways: Cyclization of ketosulfone (XXIV) with 2-chloromalondialdehyde (XXIX) or the aniline derivative (XXX) and ammonium acetate in hot propionic acid. Cyclization of ketosulfone (XXIV) with aminoacrolein (XXXI) in the absence of ammonium acetate. Aminoacrolein (XXXI) is prepared by treatment of chloromalondialdehyde (XXIX) with isopropanol, yielding the ether (XXXII) and followed by reaction with ammoniun hydroxide. Cyclization of the lithium enolate of ketosulfone (XXIV) with 2,3-dichloroacrolein (XXXIII) -- obtained by treatment of chloromalondialdehyde (XXIX) with oxalyl chloride and DMF in toluene -- followed by reaction with ammonium acetate or anhydrous ammonia. Reaction of ketosulfone (XXIV) with 2-chloro-1,3-bis(dimethylamino)trimethinium hexaflourophosphate salt (XXXIV) in the presence of an equimolar amount of t-BuOK followed by treatment with HOAc/TFA and then heating at reflux with an excess of ammonium hydroxide. 2-Chloro-1,3-bis(dimethylamino)trimethinium hexaflourophosphate salt (XXXIV) is obtained by reaction of chloroacetic acid (XXXV) with hot dimethylformamide (XXXVI) and POCl3, and then the reaction mixture is treated with 5N NaOH and hexafluorophosphoric acid in water.