4,4'-(6-chloropyrimidine-2,4-diyl)dimorpholine -Drug Synthesis Database

【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 合成路线2

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 .

参考文献中间体

合成目标

【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 .

参考文献中间体

合成目标

【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