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【结 构 式】 
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【药物名称】MK-4827；Niraparib 【化学名称】2-[4-[3(S)-Piperidinyl]phenyl]-2H-indazole-7-carboxamide hydrochloride 【CA登记号】1038915-64-8;1038915-60-4 (free base) 【 分 子 式 】C19H20N4O.HCl 【 分 子 量 】356.849 |
【开发单位】Merck & Co. (US); licensed to Tesaro, Inc. (US) 【药理作用】Poly [ADP-Ribose] Polymerase (PARP) Inhibitor;Oncolytic |
合成路线1
Esterification of 3-methyl-2-nitrobenzoic acid (I) with MeOH in the presence of AcCl at reflux gives methyl 3-methyl-2-nitrobenzoate (II), which is then brominated with NBS in the presence of (PhCO)2O2 in refluxing CCl4 to yield methyl 3-(bromomethyl)-2-nitrobenzoate (III). Oxidation of the bromo derivative (III) with NMMO in acetonitrile leads to methyl 3-formyl-2-nitrobenzoate (IV), which is then condensed with 4-(N-Boc-3-piperidinyl)aniline (V) in refluxing EtOH to afford the corresponding imine (VI). Ring closure of the imine derivative (VI) by means of NaN3 in DMF at 90 °C provides the indazole derivative (VII), which is then treated with NH3 in MeOH at 60 °C to give the carboxamide derivative (VIII). Deprotection of compound (VIII) by means of HCl leads to the hydrochloride salt of the corresponding amine, which is finally resolved by chiral supercritical fluid chromatography (chiral SFC) and treated with HCl .
Aldehyde intermediate (IV) can be prepared in a large-scale synthesis by treatment of methyl 3-methyl-2-nitrobenzoate (II) with DMFA in DMF at 130 °C to give enamine (X), which is finally oxidized with NaIO4 in DMF/H2O .
| 【1】 Jones, P., Ontoria Ontoria, J.M., Scarpelli, R., Schultz-Fademrecht, C. (Istituto di Ricerche di Biologia Molecolare P. Angeletti SpA). Amide substituted indazoles as poly(ADP-ribose)polymerase (PARP) inhibitors. EP 2109608, EP 2336120, JP 2010515715, US 2008167345, WO 2008084261. |
| 【2】 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. |
| 【3】 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 |
|---|---|---|---|---|---|---|
| (I) | 68109 | 3-methyl-2-nitrobenzoic acid；2-Nitro-m-toluic acid | 5437-38-7 | C8H7NO4 | 详情 | 详情 |
| (II) | 68110 | methyl 3-methyl-2-nitrobenzoate；2-Nitro-3-methylbenzoic acid methyl ester;3-methyl-2-nitrobenzoic acid methyl ester | 5471-82-9 | C9H9NO4 | 详情 | 详情 |
| (III) | 68111 | methyl 3-(bromomethyl)-2-nitrobenzoate | C9H8BrNO4 | 详情 | 详情 | |
| (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 | |
| (VI) | 68114 | tert-butyl 3-(4-((3-(methoxycarbonyl)-2-nitrobenzylidene)amino)phenyl)piperidine-1-carboxylate | C25H29N3O6 | 详情 | 详情 | |
| (VII) | 68115 | methyl 2-(4-(1-(tert-butoxycarbonyl)piperidin-3-yl)phenyl)-2H-indazole-7-carboxylate | C25H29N3O4 | 详情 | 详情 | |
| (VIII) | 68116 | tert-butyl 3-(4-(7-carbamoyl-2H-indazol-2-yl)phenyl)piperidine-1-carboxylate | C24H28N4O3 | 详情 | 详情 | |
| (IX) | 68117 | 2-[4-[3(S)-Piperidinyl]phenyl]-2H-indazole-7-carboxamide | 1038915-64-8 | C19H20N4O | 详情 | 详情 |
| (X) | 68126 | (E)-methyl 3-(2-(dimethylamino)vinyl)-2-nitrobenzoate | C12H14N2O4 | 详情 | 详情 | |
| (X) | 68126 | (E)-methyl 3-(2-(dimethylamino)vinyl)-2-nitrobenzoate | C12H14N2O4 | 详情 | 详情 |
合成路线2
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 |