Ethyl Bromide → HCID 11751862, compound

HRID 1442999Notes

Reaction equation

HRID 1442999 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[F:34])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([OH:30])=[CH:13][C:14]=2[O:16][CH2:17][C@H:18]2[CH2:22][CH2:21][CH2:20][N:19]2[C:23](OC(C)(C)C)=[O:24])[N:9]=[CH:8][N:7]=1.Br[CH2:36][CH3:37].[C:38](=O)([O-])[O-:39].[K+].[K+].FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>CC(N(C)C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[F:34])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:30][CH2:36][CH3:37])=[CH:13][C:14]=2[O:16][CH2:17][C@H:18]2[CH2:22][CH2:21][CH2:20][N:19]2[C:23](=[O:24])[CH2:38][OH:39])[N:9]=[CH:8][N:7]=1

Participants

7

Reactant 5

HCID 6332Ethyl BromideHCID 6422Trifluoroacetic acid2×HCID 11430Potassium CarbonateHCID 516892Sodium BicarbonateHCID 136344272HCID 136344272, compound

Product 1

HCID 11751862HCID 11751862, compound

Reagents, catalysts & solvents 1

HCID 31374DimethylacetamideSolvent

Conditions

Temperature
40 °C

Procedure

The crude tert-butyl (2R)-2-[({4-[3-chloro-4-fluoroanilino]-7-hydroxy-quinazolin-5-yl}oxy)methyl]pyrrolidine-1-carboxylate (120 mg) was dissolved in DMA (1 ml), and bromoethane (27 μl) and potassium carbonate (68 mg) were each added in one portion. The reaction mixture was heated at 40° C. for 16 hours and then cooled to room temperature. Trifluoroacetic acid (0.5 ml) was then added and the reaction mixture was stirred for 4 hours at room temperature. Further trifluoroacetic acid (1 ml) was added and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was then poured onto saturated aqueous sodium hydrogen carbonate and then extracted with ethyl acetate. The organic layer was dried (MgSO4) and then concentrated in vacuo to leave a green oil. Purification by flash chromatography, using 2-5% methanol in DCM as eluent, gave the N-(3-chloro-4-fluorophenyl)-7-ethoxy-5-[(2R)-pyrrolidin-2-ylmethoxy]quinazolin-4-amine as a pale green solid (83 mg, 52% over three steps); NMR Spectrum (DMSO-d6) 10.2 (s, 1H), 9.50 (s, 1H), 8.30-8.20 (m, 1H), 7.90-7.80 (m, 1H), 7.50-7.40 (m, 1H), 6.80-6.70 (m, 1H), 4.50-4.40 (m, 1H), 4.30-4.20 (m, 1H), 4.30-4.10 (m, 3H), 3.90-3.80 (m, 1H), 3.15-3.05 (m, 2H), 2.10-2.00 (m, 1H), 1.90-1.80 (m, 2H), 1.70-1.60 (m, 1H), 1.40 (t, 3H); Mass spectrum MH+ 417.

Workup

  1. additioneach added in one portion
  2. temperaturecooled to room temperature
  3. stirringthe reaction mixture was stirred at room temperature for 16 hours
  4. extractionextracted with ethyl acetate
  5. dry with materialThe organic layer was dried (MgSO4)
  6. concentrationconcentrated in vacuo
  7. customto leave a green oil
  8. customPurification by flash chromatography

Sources & evidence

ORD record
ord-d85ca80c226146bfa63440273d816b2b
Source dataset
uspto-grants-2010_02
Patent number
US07659279B2

Reaction notes

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