合成路线1

Reduction of 2-fluoro-6-(trifluoromethyl)benzonitrile (I) with BH3/THF in refluxing THF gives the benzylamine derivative (II), which by treatment with urea in the presence of HCl in refluxing water yields N-[2-fluoro-6-(trifluoromethyl)benzyl]urea (III). Cyclization of the urea (III) with diketene (IV) by means of NaI and TMSCl in acetonitrile provides the pyrimidine-2,4-dione derivative (V), which is then brominated with Br2 in AcOH to afford the 5-bromopyrimidine-2,4-dione derivative (VI). N-Alkylation of intermediate (VI) with N-Boc-D-phenylglycinol (VII) by means of PPh3 and DBAD in THF gives the 3-[2(R)-amino-2-phenylethyl]pyrimidine-2,4-dione derivative (VIII), which upon Suzuki condensation with 2-fluoro-3-methoxyphenylboronic acid (IX) in the presence of Na2CO3 and Pd(PPh3)4 in H2O/dioxane at 90 °C yields the 5-(2-fluoro-3-methoxyphenyl)pyrimidine-2,4-dione derivative (X). Deprotection of the N-protected benzylamine (X) by means of TFA in CH2Cl2 affords the benzylamine derivative (XI), which is finally N-alkylated with methyl (XIIa) or ethyl (XIIb) 4-bromobutyrate and DIEA or Et3N, respectively, in refluxing acetonitrile and the resulting methyl or ethyl esters, (XIIIa) or (XIIIb), saponified with NaOH or LiOH in THF/H2O or MeOH/H2O at 45-50 °C .