Potassium Carbonate → 4-(6,7-Dimethoxy-quinazolin-4-yl)-piperidine-1-carboxylic acid (4-isopropoxy-phenyl)-amide

HRID 657186Notes

Reaction equation

HRID 657186 reaction equation
[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[N+](C1C=CC([O:30][C:31](=O)[NH:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH:40]([CH3:42])[CH3:41])=[CH:35][CH:34]=2)=CC=1)([O-])=O.CCN(C(C)C)C(C)C.C([O-])([O-])=O.[K+].[K+]>CC#N.CC(C)=O>[CH:40]([O:39][C:36]1[CH:37]=[CH:38][C:33]([NH:32][C:31]([N:18]2[CH2:19][CH2:20][CH:15]([C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH2:16][CH2:17]2)=[O:30])=[CH:34][CH:35]=1)([CH3:42])[CH3:41]

Participants

7

Reactant 4

HCID 11430Potassium CarbonateHCID 81531DiisopropylethylamineHCID 58769998(4-Isopropoxy-phenyl)-carbamic acid 4-nitrophenyl esterHCID 595517346,7-Dimethoxy-4-(piperidin-4-yl)quinazoline

Product 1

HCID 587707614-(6,7-Dimethoxy-quinazolin-4-yl)-piperidine-1-carboxylic acid (4-isopropoxy-phenyl)-amideYield 72.1%

Reagents, catalysts & solvents 2

HCID 180AcetoneSolventHCID 6342AcetonitrileSolvent

Procedure

To a mixture of 6,7-dimethoxy-4-piperidin-4-yl-quinazoline (1.86 g, 6.80 mmol), prepared essentially as described in the previous step, and (4-isopropoxy-phenyl)-carbamic acid 4-nitro-phenyl ester (2.28 g, 7.22 mmol), prepared essentially as described in Example 1a, in CH3CN (13 mL) was added DIEA (1.24 mL, 7.50 mmol). The homogeneous solution was refluxed for 4 h, allowed to cool to rt, shaken with 1 M K2CO3, and extracted with EtOAc (2×25 mL). The organic layers were combined, washed with 0.5 M NaH2PO4 (1×50 mL), 4 M NaCl (1×25 mL), dried three times (Na2SO4), and concentrated under reduced pressure to give crude title compound as a beige semisolid (3.5 g). Flash chromotography (3:4→1:2 hex/acetone) afforded the title compound as an off-white foam (2.21 g, 72%). 1H-NMR (300 MHz, CDCl3) 9.08 (s, 1H), 7.34 (s, 1H), 7.28-7.22 (m, 3H), 6.83 (m, 2H), 6.46 (br s, 1H), 4.47 (heptet, J=6.1 Hz, 1H), 4.27 (br m, 2H), 4.07 (s, 3H), 4.06 (s, 3H), 3.59 (tt, J=11.0 Hz, 3.7 Hz, 1H), 3.15 (td, J=12.8 Hz, 2.4 Hz, 2H), 2.22-2.06 (m, 2H), 2.04-1.92 (m, 2H), 1.31 (d, J=6.1 Hz, 6H). LC/MS (ESI): calcd mass 450.2, found 451.3 (MH)+. Anal. Calcd for C25H30N4O4: C, 66.65; H, 6.71; N, 12.44. Found: C, 66.41; H, 6.68; N, 12.22.

Workup

  1. customprepared essentially
  2. customprepared essentially
  3. temperatureThe homogeneous solution was refluxed for 4 h
  4. extractionextracted with EtOAc (2×25 mL)
  5. washwashed with 0.5 M NaH2PO4 (1×50 mL), 4 M NaCl (1×25 mL)
  6. dry with materialdried three times (Na2SO4)
  7. concentrationconcentrated under reduced pressure
  8. customto give crude title compound as a beige semisolid (3.5 g)

Sources & evidence

ORD record
ord-3fa3b77a721a43fab9e7d94515baafee
Source dataset
uspto-grants-2011_12
Patent number
US08071768B2

Reaction notes

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