合成路线1

Two related routes for the synthesis of pemirolast potassium have been reported: 1) The condensation of 2-amino-3-methylpyridine (I) with ethoxymethylenemalonodinitrile (II) gives the monocyclic intermediate (III), which is in tautomeric equilibrium with the pyridopyrimidine derivative (IV). The reaction of (IV) with aluminum azide (AlCl3.NaN3) in refluxing THF yields 4-imino-9-methyl-3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidine (V). Finally, this compound is first hydrolyzed with 1N HCl and then treated with KOH. 2) Compound (IV) can be converted to the final product by a one-pot reaction: (VI) is treated first with NaN3 in refluxing acetic acid, then hydrolyzed with HCl and finally treated with KOH.

合成路线2

Palladium-catalyzed coupling of methyl 5-iodosalycilate (I) with trimethylsilyl acetylene (II) produced the ethynyl salycilate (III). The trimethylsilyl protecting group of (III) was then cleaved by treatment with KF in DMF to give (IV). On the other hand, sulfonamide (VII) was obtained by condensation of 4-iodobenzenesulfonyl chloride (V) with 2-amino-3-methylpyridine (VI). A further Suzuki coupling between acetylene (IV) and iodosulfonamide (VII) furnished diaryl acetylene (VIII). The methyl ester group of (VIII) was finally saponified with NaOH to provide the target carboxylic acid.

合成路线3

Condensation of carboxylic acid (I) with dipropylamine (II) in the presence of ethyl 1,2-dihydro-2-ethoxy-1-quinolinecarboxylate (EEDQ) yields amide (III), which is then brominated with Br2 in CCl4 to provide derivative (IV). Finally, bromoketoamide (IV) is cyclized with to 3-methyl-2-aminopyridine (V) in DMF to furnish the target product.

合成路线4

合成路线5