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【结 构 式】 
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【分子编号】67962 【品名】4,4'-(6-iodopyrimidine-2,4-diyl)dimorpholine 【CA登记号】 |
【 分 子 式 】C12H17IN4O2 【 分 子 量 】376.197 【元素组成】C 38.31% H 4.55% I 33.73% N 14.89% O 8.50% |
合成路线1
该中间体在本合成路线中的序号：(IX)Cyclization of morpholine-4-carboximidamide hydrobromide (I) with diethyl malonate (II) by means of naoEt in refluxing EtoH gives 2-(morpholin-4-yl)pyrimidine-4,6-diol (III), which by chlorination with PoCl3 at 120 °C affords 4,6-dichloro-2-(morpholin-4-yl)pyrimidine (IV). nucleophilic substitution of the dichloropyrimidine (IV) with morpholine (V) in the presence of Et3n in refluxing N-methyl-2-pyrrolidone provides 2,4-di(morpholin-4-yl)-6-chloropyrimidine (VI) . Alternatively, dimorpholinopyrimidine (VI) is prepared by reaction of 2,4,6-trichloropyrimidine (VII) with morpholine (V) in THF, followed by chromatographic separation . Finally, chloropyrimidine derivative (VI) is submitted to a Suzuki cross-coupling reaction with boronate ester (VIII) in the presence of Pd(dppf)2Cl2·CH2Cl2 or Pd(dppf)2Cl2 and na2Co3 in 1,2-dimethoxyethane at 90-95 °C .
Alternatively, iodination of chloride (VI) with HI and naI yields the corresponding iodide (IX) , which is also coupled with boronate (VIII) in the presence of Pd(dppf)Cl2·CH2Cl2 and K2Co3 in 1,4-dioxane/H2o at 100 °C .
Boronate ester (VIII) is obtained by bromination of 4-(trifluoromethyl) pyridin-2-amine (X) with nBS in CHCl3 or CH2Cl2 to afford 5-bromo-4-(trifluoromethyl)pyrimidin-2-amine (XI), which is finally condensed with bis(pinacolato)diboron (XII) in the presence of Pd(dppf)2Cl2·CH2Cl2 and KoAc in refluxing dioxane or DMSO .
| 【1】 Pick, T., Barsanti, P., Iwanowicz, E. et al. (novartis AG). Pyrimidine derivatives used as PI-3 kinase inhibitors. EP 1984350, EP 2261223, JP 200952764, US 2010249126, US 8217035, US 2012225859, Wo 2007084786. |
| 【2】 Burger, M.T., Pecchi, S., Wagman, A. et al. Discovery of BKM120, a pan class I PI3 kinase inhibitor in phase I/II clinical trials. 240th ACS natl Meet (Aug 22-26, Boston) 2010, Abst MEDI 489. |
| 【3】 Vu, A.T., Morris, J. Malhotra, S.V. Efficient and improved synthesis of a PI3K inhibitor anticancer agent. 241st ACS natl Meet (March 27-31, Anaheim) 2011, Abst oRGn 115. |
| 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) | 67957 | morpholine-4-carboximidamide hydrobromide | C5H11N3O.HBr | 详情 | 详情 | |
| (II) | 16829 | Diethyl malonate | 105-53-3 | C7H12O4 | 详情 | 详情 |
| (III) | 67958 | 2-morpholinopyrimidine-4,6-diol | C8H11N3O3 | 详情 | 详情 | |
| (IV) | 67959 | 4,6-dichloro-2-(morpholin-4-yl)pyrimidine | 10397-13-4 | C8H9Cl2N3O | 详情 | 详情 |
| (V) | 10388 | Morpholine | 110-91-8 | C4H9NO | 详情 | 详情 |
| (VI) | 67960 | 4,4'-(6-chloropyrimidine-2,4-diyl)dimorpholine | C12H17ClN4O2 | 详情 | 详情 | |
| (VII) | 43734 | 2,4,6-trichloropyrimidine | 3764-01-0 | C4HCl3N2 | 详情 | 详情 |
| (VIII) | 67961 | 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)pyridin-2-amine | C12H16BF3N2O2 | 详情 | 详情 | |
| (IX) | 67962 | 4,4'-(6-iodopyrimidine-2,4-diyl)dimorpholine | C12H17IN4O2 | 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 | |
| (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 |