【结 构 式】 |
【分子编号】68124 【品名】tert-butyl 3(S)-(4-(7-carbamoyl-2H-indazol-2-yl)phenyl)piperidine-1-carboxylate 【CA登记号】 |
【 分 子 式 】C24H28N4O3 【 分 子 量 】420.511 【元素组成】C 68.55% H 6.71% N 13.32% O 11.41% |
合成路线1
该中间体在本合成路线中的序号:(XIX)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 .
【1】 Jones, P., Altamura, S., Boueres, J. et al. Discovery of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (MK-4827): A novel oral poly(ADP-ribose)polymerase (PARP) inhibitor efficacious in BRCA-1 and -2 mutant tumors. J Med Chem 2009, 52(22): 7170-85. |
【2】 Wallace, D.J., Baxter, C.A., Brands, K.J.M. et al. Development of a fit-forpurpose large-scale synthesis of an oral PARP inhibitor. Org Process Res Dev 2011, 15(4): 831-40. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(IV) | 68112 | methyl 3-formyl-2-nitrobenzoate | C9H7NO5 | 详情 | 详情 | |
(V) | 68113 | tert-butyl 3-(4-aminophenyl)piperidine-1-carboxylate | C16H24N2O2 | 详情 | 详情 | |
(X) | 68118 | (1,3-azaborinan-3-yl)methanediol | C5H12BNO2 | 详情 | 详情 | |
(XI) | 21845 | 1-iodo-4-nitrobenzene | 636-98-6 | C6H4INO2 | 详情 | 详情 |
(XII) | 26628 | 1-bromo-4-nitrobenzene | 99-99-0 | C6H4BrNO2 | 详情 | 详情 |
(XIII) | 68119 | 3-(4-nitrophenyl)piperidine | C11H14N2O2 | 详情 | 详情 | |
(XIV) | 68120 | 4-(3-piperidinyl)aniline | C11H16N2 | 详情 | 详情 | |
(XV) | 68121 | 4-[3(S)-piperidinyl]aniline L-tartrate | C11H16N2.C4H6O6 | 详情 | 详情 | |
(XVI) | 68122 | tert-butyl 3(S)-(4-aminophenyl)piperidine-1-carboxylate | C16H24N2O2 | 详情 | 详情 | |
(XVII) | 68125 | (E)-tert-butyl 3(S)-(4-((3-(methoxycarbonyl)-2-nitrobenzylidene)amino)phenyl)piperidine-1-carboxylate | C25H29N3O6 | 详情 | 详情 | |
(XVIII) | 68123 | (S)-methyl 2-(4-(1-(tert-butoxycarbonyl)piperidin-3-yl)phenyl)-2H-indazole-7-carboxylate | C25H29N3O4 | 详情 | 详情 | |
(XIX) | 68124 | tert-butyl 3(S)-(4-(7-carbamoyl-2H-indazol-2-yl)phenyl)piperidine-1-carboxylate | C24H28N4O3 | 详情 | 详情 |