合成路线1

Condensation of indole-6-carboxylic acid (VI) with cyclopentanone (VII) in the presence of aqueous NaOH and glycerol at 100 °C or KOH in aqueous MeOH at 75 °C yields the cyclopentene derivative (VIII), which is reduced to the corresponding cyclopentane (IX) by catalytic hydrogenation over Pd/C in THF or Pd(OH)2 in MeOH . Simultaneous esterification and N-methylation of the indole-carboxylic acid (IX) with CO(OMe)2 by means of K2CO3 in NMP at 130 °C , or sequential esterification with MeI and K2CO3 in DMF, followed by Nmethylation of the resultant indolyl-carboxylate with MeI using NaH in DMF , affords methyl 3-cyclopentyl-1-methylindole-6-carboxylate (X) . Bromination of intermediate (X) with Br2, optionally in the presence of NaOAc in acetonitrile or i-PrOAc, gives the 2-bromoindole derivative (XI) , which is then condensed with 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (XII) in the presence of Pd(OAc)2, TFP and Et3N in DME at 68 °C to provide boronate (XIIIa) . In an alternative procedure, transesterification of the methyl ester (X) with i-PrOLi in i-PrOH at 65 °C produces the more stable isopropyl ester (XIV), which is then brominated with Br2 in acetonitrile or i-PrOAc to afford the bromoindole derivative (XV). Condensation of bromide (XV) with 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (XII) using Pd(TFP)2Cl2 or Pd(OAc)2, TFP and Et3N in acetonitrile at 82 °C yields boronate (XIIIb) . Finally, Suzuki coupling of pinacol boronates (XIIIa) or (XIIIb) with 5-bromo-2-iodopyrimidine (XVI) in the presence of K3PO4 at 76 °C, followed by ester hydrolysis of the resulting adducts (XVIIa) or (XVIIb) with NaOH in NMP, DMSO or i-PrOH , affords carboxylic acid (I) .