合成路线1

Chlorination of 5-fluorouracil (I) by means of POCl3 gives 2,4-dichloro-5-fluoropyrimidine (II), which is condensed with the pyrido-[3,2-b][1,4]oxazin-3-one derivative (III) to afford the secondary amine (IV). Then, subsequent displacement of the remaining chlorine of pyrimidine (IV) with 3,4,5-trimethoxyaniline (V) yields the substituted pyrimidine-2,4-diamine (VI) . Condensation of pyridooxazinone derivative (VI) with di-tert-butyl chloromethyl phosphate (VII) prepared by chlorination of potassium di-tert-butylphosphate (VIII) with ClSO3CH2Cl by means of Bu4NHSO4 in CH2Cl2/H2O – in the presence of Cs2CO3 in acetone or DMF gives a mixture of three N-substituted regioisomers, which are then subjected to either column chromatography or crystallization on MTBE to provide the major N-substituted oxazinone (IX). Hydrolysis of the t-butyl ester groups of (IX) by means of AcOH in H2O or TFA in CH2Cl2 affords free acid (X) , which is finally treated with aqueous or IPA/H2O NaOH .
Alternatively, condensation of pyridooxazinone (VI) and chloromethyl phosphate (VII) with Cs2CO3 in DMAC at 40 °C affords the N-substituted oxazinone (IX), which is directly hydrolyzed by means of AcOH in H2O, and the phosphoric acid (X) is submitted to purification by crystallization on DMF .