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【结 构 式】

【分子编号】67960

【品名】4,4'-(6-chloropyrimidine-2,4-diyl)dimorpholine

【CA登记号】 

【 分 子 式 】C12H17ClN4O2

【 分 子 量 】284.745

【元素组成】C 50.62% H 6.02% Cl 12.45% N 19.68% O 11.24%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(VI)

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

合成路线2

该中间体在本合成路线中的序号:(VI)

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
Extended Information