Synthesis Of Naproxen As Nonsteroidal Antiinflammatory Drug And Reaction Mechanism

Naproxen is one of the most effective and toterable nonsteroidal antiinflammatoiy drug (NSAID). Naproxen is increasingly used for analgesic purposes. Twelve synthetic methods of naproxen were reviewed with 94 references. Naproxen were synthesized from 6-methoxy-2-propionylnaphthalene, via a - halogenation (CuC12 and CuBr2), 1 ,2-propanediol ketalization and rearrangement by one-pot method. 6-Methoxy-2-propionylnaphthalene was selectively halogenatin by copper(II) halide in alcohol (methanol, ethanol) to give 6-methoxy-2-(2?halopropionyl) naphthalene in high yield (CuBr2: 97%; CuC12: 98.4%). The ketalized product that 6 methoxy-2-(2挆halopropionyl) naphthalene reacted with I ,2-propanediol was directly used for the rearrangement reaction catalyzed by ZnO or Zn(OAc)2 without separation and purification; All reactions are carried out by convenient operation, in mild condition, overall yield is high (89%-.-90%, based on 6-methoxy-2- propionylnaphthalene). At the same time, syntheses of dl-naproxen were also studied by neopentyl glycol ketalization method with 74%---92.6% overall yield (based on 6-methoxy-2- propionylnaphthalene). 5-halo-6-methoxy-2-propionylnaphthalene was hydrodehalogenated with hydrogen and Pd/C catalyst under multiphase conditions to afford 6-methoxy-2-propionylnaphthalene with higti yield (98.76%). The hydrodehalogenation is mild and facile. S-Naproxen can be prepared by below two routes. One route: S-Naproxen was synthesized from 2- methoxynaphthalene, via Friedel-Crafts propionylization, ketalization, asymmetric bromination, hydrolysis, rearrangement and hydrodebromination. The overall yield of S- naproxen is 41 .3%(based on 2-methoxynaphthalene). The other route: S-Naproxen was synthesized from 2-methoxynaphthalene in 7 steps through 5-bromo-6-methoxy-2-propionylnaphthalene. 2-Methoxynaphthalene was iii ThZr~眫{~i~ brominated by I ,3-dibromo-5,5-dimethylhydantoin to give 1-bromo-2-methoxynaphthalene with 98.1% yield. 5-Bromo-6-methoxy-2-propionynaphthalene was obtained by propionylization of 1-bromo-2-methoxynaphthalene with 97.6% yield. The ketalization of 5-bromo-6-methoxy-2-propionylnaphthalene with (2R, 3R)- dimethyltartrate gave (4R, 5R)-2-ethyl-2-(5?bromo-6挆methoxy-2?naphthyl)- 1 ,3-dioxolane- 4,5-dicarboxylic acid dimethyl ester with 95% yield. (4R,5R)-2-ethyl-2-(5?bromo-6? methoxy-2?naphthyl)-l ,3-dioxolane-4,5-dicarboxylic acid dimethyl ester was brominated with bromine, hydrolysized, rearranged and hydrodebrominated to give S-naproxen with 48.8% overall yield (based on 2-methoxynaphthalene). Enantiomeric excess of S-naproxen is 94% e.e.. Although synthetic route through 5-bromo-6-methoxy-2-propionyl napbthalene has one more step than through 6-methoxy-2-propionylnaphthalene, the overall yield is increased by 7.5%. S-Naproxen, dl-naproxen and 24 intermediates were prepared by various approaches. 21 kinds of the compounds were separated, and determined by IR, NMR, MS and element analysis. Some results were disussed, and explained by nuclear halogenation mechanism, a- halogenation mechanism, asymmetric bromination mechanism and rearrangement mechanism. Resolution of dl-naproxen prepared from by 1 ,2-propanediol and neopentyl glycol ketalization methods was readily achieved by c...