合成路线1

Cyclization of 1-(2-fluoro-4-iodophenyl)-3-cyclopropyl-6-(methylamino)uracil (I) (optionally containing some 1-cyclopropyl regioisomer) with either diethyl 2-methylmalonate (II) in Ph2O at 220 °C or with 2-methylmalonic acid (III) in Ac2O at 100 °C yields the 5-hydroxypyrido[2,3-d]pyrimidine-2,4,7-trione derivative (IV) , which can be separated from its regioisomeric byproduct by crystallization from acetone . Treatment of compound (IV) with Tf2O in the presence of 2,6-lutidine in CHCl3 gives the corresponding triflate (V) . Similarly, reaction of (IV) with p-TsCl in the presence of Et3N and Me3N·HCl in acetonitrile produces tosylate (VI) . The condensation of triflate (V) with 3-nitroaniline (VII) at 130 °C furnishes the 5-(arylamino)pyrido[2,3-d]pyrimidine derivative (VIII), which undergoes rearrangement to the isomeric pyrido[4,3-d]pyrimidine (IX) in the presence of K2CO3 in MeOH/THF at 80 °C. Reduction of nitro compound (IX) by means of Na2S2O4 in DMF/H2O at 90 °C, followed by acetylation of the resulting amine with Ac2O in pyridine/CHCl3, leads to trametinib (X). Finally, crystallization of (X) from DMSO produces trametinib dimethyl sulfoxide solvate .
In an alternative procedure, condensation of either triflate (V) or tosylate (VI) with N-(3-aminophenyl)acetamide (XI) by means of 2,6-lutidine in DMA at 130 °C affords intermediate (XII), which upon rearrangement in the presence of NaOMe in THF/MeOH gives rise to the pyrido[4,3-d]pyrimidine compound (IX) .