合成路线1

Chlorination of 3,3,3-trifluoro-2,2-dimethylpropanoic acid (I) using (COCl)2 in refluxing CHCl3 gives the corresponding acid chloride (II) , which by condensation with 4-methoxy-3-buten-2-one (III) by means of LiHMDS in THF at –78 °C affords the hepta-1,4-dien-3-one derivative (IV) . Cyclization of intermediate (IV) in the presence of TFA in toluene or benzene produces the pyranone (V) (1-5), which is treated with aqueous NH3 at 65 °C to provide pyridinone (VI). Bromination of compound (VI) with POBr3 in toluene at 80 °C or in dichloroethane at 85 °C leads to the 4-bromopyridine derivative (VII). Subsequent coupling of bromopyridine (VII) with 2-acetamido-4-methylthiazole (VIII) by means of Pd(OAc)2, t-Bu3P·HBF4 and Cs2CO3 in refluxing DMF yields the pyridylthiazole adduct (IX), which by deacetylation using HCl in refluxing EtOH affords the 2-aminothiazole derivative (X) . Acylation of amine (X) with phenyl chloroformate (XI), optionally in the presence of DIEA in THF gives the thiazolylcarbamate (XII), which is finally condensed with L-prolinamide (XIII), optionally in the presence of Et3N in H2O .
Similarly, reaction of amine (X) with carbonyldiimidazole (XIV) in refluxing CH2Cl2 gives the carbamoyl imidazolide (XV), which is finally coupled with L-prolinamide (XIII) in the presence of Et3N in DMF or in DMAc at 65°C .