【结 构 式】 |
【分子编号】68111 【品名】methyl 3-(bromomethyl)-2-nitrobenzoate 【CA登记号】 |
【 分 子 式 】C9H8BrNO4 【 分 子 量 】274.07086 【元素组成】C 39.44% H 2.94% Br 29.15% N 5.11% O 23.35% |
合成路线1
该中间体在本合成路线中的序号:(III)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 |