Dimethylformamide → 1-[4(6-Fluoro-4-morpholin-4-yl-7-pyridin-3-yl-quinazolin-2-yl)-phenyl]-3-[4-(4-methyl-piperazine-1-carbonyl)-phenyl]-urea

HRID 517452Notes

Reaction equation

HRID 517452 reaction equation
Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[C:7]([F:18])[CH:8]=2)[N:3]=1.[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([C:32]([C:34]2[CH:39]=[CH:38][C:37]([NH:40][C:41]([NH:43][C:44]3[CH:49]=[CH:48][C:47](B4OC(C)(C)C(C)(C)O4)=[CH:46][CH:45]=3)=[O:42])=[CH:36][CH:35]=2)=[O:33])[CH2:28][CH2:27]1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[F:18][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[N:3]=[C:2]([C:47]1[CH:48]=[CH:49][C:44]([NH:43][C:41]([NH:40][C:37]3[CH:38]=[CH:39][C:34]([C:32]([N:29]4[CH2:28][CH2:27][N:26]([CH3:25])[CH2:31][CH2:30]4)=[O:33])=[CH:35][CH:36]=3)=[O:42])=[CH:45][CH:46]=1)[N:11]=[C:10]2[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1

Participants

7

Reactant 4

HCID 6228DimethylformamideHCID 10796Cesium carbonateHCID 675174421-[4-(4-Methyl-piperazine-1-carbonyl)-phenyl]-3-[4-(4,4,5,5,-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ureaHCID 866657642-Chloro-6-fluoro-4-morpholin-4-yl-7-pyridin-3-yl-quinazoline

Product 1

HCID 573348751-[4(6-Fluoro-4-morpholin-4-yl-7-pyridin-3-yl-quinazolin-2-yl)-phenyl]-3-[4-(4-methyl-piperazine-1-carbonyl)-phenyl]-ureaYield 9%

Reagents, catalysts & solvents 2

HCID 178418476HCID 178418476, compoundCatalystHCID 962WaterSolvent

Conditions

Temperature
95 °C

Procedure

To a 50 mL round bottom flask, 2-chloro-6-fluoro-4-morpholin-4-yl-7-pyridin-3-yl-quinazoline (90 mg, 0.000259 mol), 1-[4-(4-methyl-piperazine-1-carbonyl)-phenyl]-3-[4-(4,4,5,5,-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-urea (144.7 mg, 0.0003114 mol), cesium carbonate (212.3 mg, 0.000647 mol), DMF (5 mL) and water (2.5 mL) were added. The reaction mixture was degassed with nitrogen for 5-10 min. To the same reaction flask, Pd(PPh3)2Cl2 (9.07 mg, 0.0000131 mol) was added and again degassed with nitrogen for 5-10 min. The reaction mixture was stirred at 95° C. for 2 h. The reaction mixture was cooled and diluted with ethyl acetate. The organic layer was washed with water, brine and dried over sodium sulfate. The solvent was removed under reduced pressure to afford the crude product. The crude product was purified using column chromatography (60-120 silica gel, 5% MeOH in chloroform) to yield the title compound (15 mg, 6%) 1H NMR (300 MHz, DMSO-d6): δ 9.05 (s, 1H), 9.0 (s, 1H), 8.93 (brs, 1H), 8.68-8.72 (m, 1H), 7.92-8.73 (m, 5H), 7.52-7.64 (m, 5H), 7.35 (d, J=8.1 Hz, 2H), 3.85 (s, 8H), 3.46-3.57 (m, 4H), 2.24-2.37 (m, 4H), 2.19 (s, 3H); LC-MS (ESI): Calculated mass: 646.2; Observed mass: 647.2 (RT: 0.11 min).

Workup

  1. customThe reaction mixture was degassed with nitrogen for 5-10 min
  2. customagain degassed with nitrogen for 5-10 min
  3. temperatureThe reaction mixture was cooled
  4. additiondiluted with ethyl acetate
  5. washThe organic layer was washed with water, brine
  6. dry with materialdried over sodium sulfate
  7. customThe solvent was removed under reduced pressure
  8. customto afford the crude product
  9. customThe crude product was purified

Sources & evidence

ORD record
ord-4ce9e69a147d4ad4abef9ee1212bcac3
Source dataset
uspto-grants-2015_08
Patent number
US09115092B2

Reaction notes

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