Trifluoroacetic acid → 2-[4-{3-(4-Dimethycarbamoyl-phenyl)-Ureido]-phenyl}-4-morpholin-4-yl-quinazoline-7-carboxylic acid (2-dimethylamino-ethyl)-amide

HRID 517460Notes

Reaction equation

HRID 517460 reaction equation
[CH3:1][N:2]([CH3:25])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:17]=[C:16]2[C:11]([C:12]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[N:13][C:14](Cl)=[N:15]2)=[CH:10][CH:9]=1)=[O:7].[CH3:26][N:27]([CH3:55])[C:28](=[O:54])[C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]([NH:38][C:39]2[CH:44]=[CH:43][C:42](B3OC(C)(C)C(C)(C)O3)=[CH:41][CH:40]=2)=[O:37])=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(O)(C(F)(F)F)=O>O.C(#N)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.CN(C=O)C>[CH3:1][N:2]([CH3:25])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:17]=[C:16]2[C:11]([C:12]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[N:13][C:14]([C:42]3[CH:41]=[CH:40][C:39]([NH:38][C:36]([NH:35][C:32]4[CH:33]=[CH:34][C:29]([C:28](=[O:54])[N:27]([CH3:26])[CH3:55])=[CH:30][CH:31]=4)=[O:37])=[CH:44][CH:43]=3)=[N:15]2)=[CH:10][CH:9]=1)=[O:7]

Participants

9

Reactant 4

HCID 6422Trifluoroacetic acidHCID 10796Cesium carbonateHCID 67517701N,N-Dimethyl-4-{3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]-ureido}-benzamideHCID 876218732-Chloro-4-morpholine-4-yl-quinazoline-7-carboxylic acid (2-dimethylamino-ethyl)-amide

Product 1

HCID 689128652-[4-{3-(4-Dimethycarbamoyl-phenyl)-Ureido]-phenyl}-4-morpholin-4-yl-quinazoline-7-carboxylic acid (2-dimethylamino-ethyl)-amideYield 10%

Reagents, catalysts & solvents 4

HCID 178418476HCID 178418476, compoundCatalystHCID 962WaterSolvent2×HCID 6228DimethylformamideSolventHCID 6342AcetonitrileSolvent

Conditions

Temperature
95 °C

Procedure

To a 50 mL round bottom flask, 2-chloro-4-morpholine-4-yl-quinazoline-7-carboxylic acid (2-dimethylamino-ethyl)-amide (0.08 g, 0.00022 mol), N,N-dimethyl-4-{3-{4-(4,4,5,5,-tetramethyl-[1,3,2] dioxaborolan-2-yl)-phenyl]-ureido}-benzamide (0.108 g, 0.000264 mol), cesium carbonate (0.143 g, 0.00044 mol), DMF (4 mL), water (1 mL) were added. The reaction mixture was degassed with nitrogen for 5-10 min. To the same reaction flask, Pd(PPh3)2Cl2 (8 mg, 0.000011 mol) was added and again degassed with nitrogen for 5-10 min. The reaction mixture was stirred at 95° C. for 5 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, 15-20% MeOH in chloroform) to yield the crude title compound in 50% yield, followed by preparative HPLC (0.1% TFA in water and ACN) to yield the title compound [0.013 g, 10%]. 1H NMR; (400 MHz, DMSO-d6): δ 9.65 (brs, 1H), 9.55 (s, 1H), 9.17 (s, 1H), 8.45 (brs, 1H), 8.43 (d, 2H, J=8.8 Hz), 8.16 (d, 1H, J=8.4 Hz), 7.96 (brs, 1H), 7.67 (d, 2H, J=8.0 Hz), 7.54 (d, 2H, J=8.4 Hz), 7.38 (d, 2H, J=8.4 Hz), 3.85-3.94 (m, 8H), 3.70 (d, 2H, J=5.2 Hz), 3.43 (brs, 2H), 2.95 (s, 6H), 2.86 (s, 6H): LC-MS (ESI): Calculated mass: 610.3; Observed mass: 611.1 [M+H]+ (RT: 0.08 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
  10. customto yield the crude title compound in 50% yield

Sources & evidence

ORD record
ord-c44f51af21e84c2892dd4d6df8664e9d
Source dataset
uspto-grants-2015_08
Patent number
US09115092B2

Reaction notes

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