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【结 构 式】 
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【分子编号】67966 【品名】(6-acetamido-4-(trifluoromethyl)pyridin-3-yl)boronic acid 【CA登记号】 |
【 分 子 式 】C8H8BF3N2O3 【 分 子 量 】247.969 【元素组成】C 38.75% H 3.25% B 4.36% F 22.98% N 11.30% O 19.36% |
合成路线1
该中间体在本合成路线中的序号：(XIV)Bromination of 2-amino-4-(trifluoromethyl)pyridine (X) with nBS in THF affords 2-amino-5-bromo-4-(trifluoromethyl)pyridine (XI), which by N-acetylation with Ac2o and DMAP in EtoAc yields the corresponding acetamide (XIII), which by sequential metalation with BuLi in THF, borylation with (i-Pro)3B and hydrolysis with HCl affords the boronic acid (XIV). Suzuki cross-coupling of boronic acid (XIV) with 4-chloro-2,6-di(morpholin-4-yl)pyrimidine (VI) in the presence of Pd(PPh3)4 and K2Co3 in DME at 70 °C results in N-[4-trifluoro methyl-5-(2,6-dimorpholinopyrimidin-4-yl)pyridin-2-yl]acetamide (XV), which is finally deacetylated by treatment with HCl .
. Alternatively, Miyaura borylation of 4-chloro-2,6-di(morpholin-4-yl)pyrimidine (VI) with bis(pinacolato)diboron (XII) by means of Pd2dba3, KoAc and Cy3P in acetonitrile gives boronate ester (XVI), which is finally submitted to Suzuki cross-coupling with 2-amino-5-bromo-4-(trifluoromethyl)pyridine (XI) in the presence of Pd(dppf)Cl2 and Cs2Co3 in THF .
| 【1】 Calienni, J.V., De La Cruz, M., Flubacher, D. et al. (novartis AG). Manufacturing process for pyrimidine derivatives. Wo 2012044727. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 67960 | 4,4'-(6-chloropyrimidine-2,4-diyl)dimorpholine | C12H17ClN4O2 | 详情 | 详情 | |
| (X) | 67963 | 4-(trifluoromethyl)pyridin-2-amine | 106447-97-6 | C6H5F3N2 | 详情 | 详情 |
| (XI) | 67964 | 5-bromo-4-(trifluoromethyl)pyridin-2-amine | C6H4BrF3N2 | 详情 | 详情 | |
| (XI) | 67964 | 5-bromo-4-(trifluoromethyl)pyridin-2-amine | C6H4BrF3N2 | 详情 | 详情 | |
| (XII) | 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 |
| (XIII) | 67965 | N-(5-bromo-4-(trifluoromethyl)pyridin-2-yl)acetamide | C8H6BrF3N2O | 详情 | 详情 | |
| (XIV) | 67966 | (6-acetamido-4-(trifluoromethyl)pyridin-3-yl)boronic acid | C8H8BF3N2O3 | 详情 | 详情 | |
| (XV) | 67967 | N-[4-trifluoro methyl-5-(2,6-dimorpholinopyrimidin-4-yl)pyridin-2-yl]acetamide | C20H23F3N6O3 | 详情 | 详情 | |
| (XVI) | 67968 | 4,4'-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine-2,4-diyl)dimorpholine | C18H29BN4O4 | 详情 | 详情 |