4-Isopropylaniline → 2-[4-(6,7-Dimethoxy-quinazolin-4-yl)-piperidin-1-yl]-N-(4-isopropyl-phenyl)-acetamide

HRID 657197Notes

Reaction equation

HRID 657197 reaction equation
[CH:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C([O-])([O-])=O.[Ca+2].Br[CH2:17][C:18](Br)=[O:19].[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[N:29]=[CH:28][N:27]=[C:26]2[CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>CC#N>[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[N:29]=[CH:28][N:27]=[C:26]2[CH:35]1[CH2:40][CH2:39][N:38]([CH2:17][C:18]([NH:8][C:7]2[CH:9]=[CH:10][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=2)=[O:19])[CH2:37][CH2:36]1

Participants

6

Reactant 4

HCID 74644-IsopropylanilineHCID 10112Calcium CarbonateHCID 61147Bromoacetyl bromideHCID 595517346,7-Dimethoxy-4-(piperidin-4-yl)quinazoline

Product 1

HCID 587707972-[4-(6,7-Dimethoxy-quinazolin-4-yl)-piperidin-1-yl]-N-(4-isopropyl-phenyl)-acetamideYield 57%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Procedure

A mixture of 4-isopropylaniline (17.7 mg, 131 μmol), CaCO3 (33.1 mg, 331 μmol) (10 micron powder), and CH3CN (240 μL) was stirred in an ice bath for 2-3 min before adding bromoacetyl bromide (10.3 μL, 119 μmol) dropwise over 10-15 s with stirring at 0° C. After an additional 2-3 min stirring at 0° C., the ice bath was removed and the slurry was stirred at rt for 30 min. Then 6,7-dimethoxy-4-piperidin-4-yl-quinazoline (35.1 mg, 129 μmol), as prepared in Example 1d, was added in one portion and the mixture was stirred at 100° C. for 40 min. The reaction was then allowed to cool to rt, quenched with 2 M K2CO3 (2 mL), and extracted with DCM (2×2 mL). The organic layers were combined, dried (Na2SO4), and concentrated under reduced pressure. Flash chromatography of the residue (1:1 hex/acetone) provided the title compound (30.3 mg, 57%). 1H-NMR (300 MHz, CDCl3) δ 9.11 (s, 2H), 7.51 (m, 2H), 7.33 (s, 1H), 7.25 (s, 1H), 7.19 (m, 2H), 4.05 (s, 6H), 3.41 (tt, 1H), 3.21 (s, 2H), 3.18-3.10 (m, 2H), 2.88 (heptet, 1H), 2.51 (td, 2H), 2.24 (qd, 2H), 2.02-1.92 (m, 2H), 1.22 (d, 6H). LC/MS (ESI): calcd mass 448.3, found 449.3 (MH)+.

Workup

  1. stirringwith stirring at 0° C
  2. stirringAfter an additional 2-3 min stirring at 0° C.
  3. customthe ice bath was removed
  4. stirringthe slurry was stirred at rt for 30 min
  5. additionwas added in one portion
  6. stirringthe mixture was stirred at 100° C. for 40 min
  7. customquenched with 2 M K2CO3 (2 mL)
  8. extractionextracted with DCM (2×2 mL)
  9. dry with materialdried (Na2SO4)
  10. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-dd5762b18fbe4fd19287868044b295e0
Source dataset
uspto-grants-2011_12
Patent number
US08071768B2

Reaction notes

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