合成路线1

Suzuki coupling of 3-piperidinylboronic acid (X) with 1-iodo-4-nitrobenzene (XI) by means of Pd(PPh3)4 and Na2CO3 in THF , or with 1-bromo-4-nitrobenzene (XII) in the presence of PdCl2(dppf) and Na2CO3 in THF at 60 °C , gives 3-(4-nitrophenyl)piperidine (XIII), which is reduced with H2 over PtO2 in the presence of HCl in MeOH to yield 4-(3-piperidinyl)aniline (XIV) . Resolution of 4-(3-piperidinyl)aniline (XIV) with L-tartaric acid in refluxing EtOH affords 4-[3(S)-piperidinyl]aniline L-tartrate (XV), which is then N-protected by means of Boc2O in CH2Cl2, followed by basification with NH3 in MeOH to provide 4-[N-Boc-3(S)-piperidyl]aniline (XVI) . Condensation of aniline derivative (XVI) with the benzaldehyde derivative (IV) in refluxing EtOH or in MTBE at 50 °C leads to azomethine (XVII) , which then undergoes initial substitution of the nitro group and subsequent cyclization by means of NaN3 in DMF at 90 °C to result in the indazole derivative (XVIII) . Alternatively, cyclization of (XVII) with NaN3 in the presence of 2,6-lutidine in DMF at 110 °C, followed by ester hydrolysis with NaOH, affords indazole derivative (XVIII) . Amidation of methyl ester (XVIII) with NH3 in MeOH or sequential treatment with Boc2O in the presence of pyridine and reaction with NH4HCO3 gives the corresponding carboxamide (XIX) , which is finally N-deprotected with HCl in AcOEt .
Alternatively, intermediate (XVI) can be prepared by N-protection of 4-(3-piperidinyl)aniline (XIV) with Boc2O in CH2Cl2 to give tert-butyl 3-(4-aminophenyl)piperidine-1-carboxylate (V), which is finally resolved into enantiomer using chiral HPLC .