Lithium Hexamethyldisilazide → 4-(2-(5-Fluoro-6-methoxypyridin-3-ylamino)-5-(morpholinomethyl)pyridin-3-yl)-n,n-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine

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Reaktionsgleichung

F[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[N:9]=2)=[CH:6][C:5]([CH2:34][N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)=[CH:4][N:3]=1.[F:41][C:42]1[CH:43]=[C:44]([NH2:50])[CH:45]=[N:46][C:47]=1[O:48][CH3:49].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1.O>[F:41][C:42]1[CH:43]=[C:44]([NH:50][C:2]2[C:7]([C:8]3[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([CH2:25][C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=4)[CH2:16][C:17]4[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=4)[N:9]=3)=[CH:6][C:5]([CH2:34][N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[CH:4][N:3]=2)[CH:45]=[N:46][C:47]=1[O:48][CH3:49]

Komponenten

Reaktionsbedingungen

Temperatur: -20 °C

Versuchsvorschrift

A mixture of 4-(2-fluoro-5-(morpholinomethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.500 g, 0.918 mmol) and 5-fluoro-6-methoxypyridin-3-amine (0.261 g, 1.836 mmol) in THF (20 mL) was cooled to −20° C. and treated with a 1.0 M solution of lithium bis(trimethylsilyl)amide (3.21 mL, 3.21 mmol) added dropwise. The mixture was allowed to slowly warm to ambient temperature over 1 h. The reaction mixture was diluted with water (50 mL) and extracted with CH2Cl2 (3×50 mL). The combined organic extracts were dried over sodium sulfate and concentrated to give the crude product as a tan solid. This was purified by chromatography through a SiliCycle SiliaSep pre-packed silica-gel column (80 gram) eluting with a gradient of 0% to 100% EtOAc in hexane over 30 min to give 4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-(morpholinomethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.095 g) as a tan oil. This was treated with trifluoroacetic acid (1.8 mL, 23.36 mmol) and trifluoromethanesulfonic acid (0.2 mL, 2.252 mmol) and heated at 70° C. for 20 min. The mixture was cooled to ambient temperature and concentrated to give a tan oil. This was dissolved in DCM (10 mL) and allowed to stir for 5 min, then sodium carbonate (1.6 g) was slowly added to the mixture and stirred vigorously for 20 min. The mixture was filtered and concentrated. The mixture was diluted with ethyl acetate and filtered. The filtrate was concentrated and the residue was diluted with diethyl ether (20 mL) and placed in a sonicator for 2 min. The precipitate was collected by filtration. The solid was recrystallized from hot ethyl acetate to give 4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-(morpholinomethyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (0.025 g, 0.059 mmol, 6.39% yield) as a tan solid. 1H NMR (400 MHz, d6-DMSO) δ 11.94 (s, 1H); 8.72 (s, 1H); 8.41 (s, 1H); 8.36 (d, J=12.91 Hz, 1H); 8.24 (s, 1H); 7.90 (s, 1H); 7.75 (s, 1H); 3.93 (s, 3H); 3.57 (s, 4H); 3.43 (s, 2H); 2.44 (s, 7H). m/z (ESI, +ve ion) 427 (M+H)+.

Aufarbeitung

additionadded dropwise
temperatureto slowly warm to ambient temperature over 1 h
extractionextracted with CH2Cl2 (3×50 mL)
dry with materialThe combined organic extracts were dried over sodium sulfate
concentrationconcentrated
customto give the crude product as a tan solid
customThis was purified by chromatography through a SiliCycle SiliaSep pre-packed silica-gel column (80 gram)
washeluting with a gradient of 0% to 100% EtOAc in hexane over 30 min

Quellen und Nachweise

ORD-Eintrag: ord-76a7fbd0eb724b549e32a268b6d50fb6
Quelldatensatz: uspto-grants-2014_07
DOI: 10.6084/m9.figshare.5104873.v1
Patentnummer: US08772480B2

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