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【结 构 式】 
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【分子编号】68698 【品名】5-bromo-3-[1(R)-(2,6-dichloro-3-fluorophenyl)ethyl]-pyridin-2-amine;(R)-5-bromo-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine 【CA登记号】 |
【 分 子 式 】C13H10BrCl2FN2O 【 分 子 量 】380.043 【元素组成】C 41.09% H 2.65% Br 21.02% Cl 18.66% F 5.00% N 7.37% O 4.21% |
合成路线1
该中间体在本合成路线中的序号：(I)Reaction of 5-bromo-3-[1(R)-(2,6-dichloro-3-fluorophenyl)ethyl]-pyridin-2-amine (I) with Boc2O by means of DMAP in DMF gives the protected aniline (II), which is condensed with bis(pinacolato)-diboron (III) by means of a Pd catalyst and KOAc in DMSO to yield the N-protected boronic ester (IV). Deprotection of the amino group of compound (IV) by means of HCl in dioxane/dichloromethane affords the boronic ester (V), which is condensed with 1-(1-Boc-piperidin-4-yl)-4-bromo-1H-pyrazole (VI) by means of PdCl2(PPh3)2 and Na2CO3 in hot DME/water to provide the adduct (VII). Finally, this compound is N-deprotected by means of HCl in dioxane/dichloromethane, as before .
| 【1】 Cui, J.J., Funk, L.A., Jia, L. et al. (Pfizer, Inc.; Agouron Pharmaceuticals, Inc.). Enantiomerically pure aminoheteroaryl compounds as protein kinase inhibitors. EP 1786785, JP 2008510790, US 2006046991, WO 2006021884. |
| 【2】 Cui, J.J., Funk, L.A., Jia, L. et al. (Pfizer, Inc.). Pyrazole-substituted aminoheteroaryl compounds as protein kinase inhibitors. EP 1784396, JP 2008510788, WO 2006021881. |
| 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) | 68698 | 5-bromo-3-[1(R)-(2,6-dichloro-3-fluorophenyl)ethyl]-pyridin-2-amine;(R)-5-bromo-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine | C13H10BrCl2FN2O | 详情 | 详情 | |
| (II) | 68697 | C23H26BrCl2FN2O5 | 详情 | 详情 | ||
| (III) | 53342 | 4,4,4',4',5,5,5',5'-Octamethyl-2,2'-bi-1,3,2-dioxaborolane; Bis(pinacolato)diboron; Diboron pinacol ester | 73183-34-3 | C12H24B2O4 | 详情 | 详情 |
| (IV) | 68696 | C29H38BCl2FN2O7 | 详情 | 详情 | ||
| (V) | 68695 | (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine | C19H22BCl2FN2O3 | 详情 | 详情 | |
| (VI) | 68694 | 1-(1-Boc-piperidin-4-yl)-4-bromo-1H-pyrazole;4-(4-Bromopyrazol-1-yl)piperidine-1-carboxylicacid tert-butyl ester | 877399-50-3 | C13H20BrN3O2 | 详情 | 详情 |
| (VII) | 68693 | (R)-tert-butyl 4-(4-(6-amino-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate | C26H30Cl2FN5O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)Mitsunobu coupling between 1(S)-(2,6-dichloro-3-fluorophenyl) ethanol (VIII) and 3-hydroxy-2-nitropyridine (IX) in the presence of DIAD and PPh3 affords ether (X), which by subsequent nitro group reduction using iron and HCl in EtOH yields the aminopyridine (XI). Bromination of compound (XI) by treatment with N-bromosuccinimide provides the bromopyridine (I), which is then submitted to palladium-catalyzed coupling with the pyrazolyl boronate (XII) to give adduct (VII). Finally, the N-Boc protecting group is removed by treatment with HCl .
| 【1】 Tran-Dube, M., Shen, H., Yamazaki, S. et al. Lead optimization of 2-amino-3-benzyloxy-5-pyrazol-4-yl-pyridine for the discovery of clinical candidate PF-2341066 as potent and highly selective c-Met inhibitor. 235th ACS Natl Meet (April 6-10, New Orleans) 2008, Abst MEDI 105. |
| 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) | 68698 | 5-bromo-3-[1(R)-(2,6-dichloro-3-fluorophenyl)ethyl]-pyridin-2-amine;(R)-5-bromo-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine | C13H10BrCl2FN2O | 详情 | 详情 | |
| (VII) | 68693 | (R)-tert-butyl 4-(4-(6-amino-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate | C26H30Cl2FN5O3 | 详情 | 详情 | |
| (VIII) | 68699 | 1(S)-(2,6-dichloro-3-fluorophenyl)ethanol;(S)-1-(2,6-dichloro-3-fluorophenyl)ethanol | 877397-65-4 | C8H7Cl2FO | 详情 | 详情 |
| (IX) | 26207 | 2-nitro-3-pyridinol | 15128-82-2 | C5H4N2O3 | 详情 | 详情 |
| (X) | 68700 | (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-2-nitropyridine | C13H9Cl2FN2O3 | 详情 | 详情 | |
| (XI) | 68701 | (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine | C13H11Cl2FN2O | 详情 | 详情 | |
| (XII) | 68702 | tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate | C19H32BN3O4 | 详情 | 详情 |