4-morpholino-N-(4-nitrophenoxycarbonyl)aniline → 4-(6,7-Dimethoxy-quinazolin-4-yl)-piperidine-1-carboxylic acid (4-morpholin-4-yl-phenyl)-amide

HRID 657210Notes

Reaction equation

HRID 657210 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]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[CH:35][CH:34]=2)=CC=1)([O-])=O>C(Cl)Cl.CO.N.C(Cl)Cl>[N:39]1([C:36]2[CH:35]=[CH:34][C:33]([NH:32][C:31]([N:18]3[CH2:19][CH2:20][CH:15]([C:6]4[C:5]5[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=5)[N:9]=[CH:8][N:7]=4)[CH2:16][CH2:17]3)=[O:30])=[CH:38][CH:37]=2)[CH2:40][CH2:41][O:42][CH2:43][CH2:44]1

Participants

6

Reactant 2

HCID 227075274-morpholino-N-(4-nitrophenoxycarbonyl)anilineHCID 595517346,7-Dimethoxy-4-(piperidin-4-yl)quinazoline

Product 1

HCID 587706784-(6,7-Dimethoxy-quinazolin-4-yl)-piperidine-1-carboxylic acid (4-morpholin-4-yl-phenyl)-amideYield 86%

Reagents, catalysts & solvents 3

HCID 222AmmoniaSolventHCID 6344DichloromethaneSolvent2×HCID 21226129Dichloromethane methanolSolvent

Procedure

A mixture of 6,7-dimethoxy-4-piperidin-4-yl-quinazoline (111.4 mg, 408 μmol), prepared as described in Example 1d, but with purification by silica flash chromatography (9:1 DCM/MeOH saturated with NH3), (4-morpholin-4-yl-phenyl)-carbamic acid 4-nitro-phenyl ester (147 mg, 429 μmol), prepared as described in the previous step, and DCM (700 μL) was treated with TEA (63 μL, 449 μmol) in one portion at rt. The homogeneous amber solution was stirred at rt for 3.5 h, diluted with DCM (1.3 mL), and washed with 2 M K2CO3 (2 mL). The aqueous layer was extracted with DCM (2×2 mL), the organic layers were combined, dried (Na2SO4), and concentrated, and the residue was purified with silica flash chromatography (1:1 DCM/acetone) to afford the title compound (167.1 mg, 86%). 1H-NMR (300 MHz, CDCl3): δ 9.08 (s, 1H), 7.34 (s, 1H), 7.31-7.24 (m, 3H), 6.88 (m, 2H), 6.31 (br s, 1H), 4.32-4.22 (m, 2H), 4.07 (s, 3H), 4.06 (s, 3H), 3.86 (m, 4H), 3.59 (m, 1H), 3.23-3.07 (m, 6H), 2.24-2.07 (m, 2H), 2.05-1.93 (m, 2H). LC/MS (ESI): calcd mass 477.2, found 478.3 (MH+). Select fractions of this material were combined (112.5 mg) and submitted for combustion analysis: Anal. Calcd for C26H31N5O4: C, 65.39; H, 6.54; N, 14.67. Found: C, 65.26; H, 6.58; N, 14.51.

Workup

  1. customprepared
  2. customprepared
  3. washwashed with 2 M K2CO3 (2 mL)
  4. extractionThe aqueous layer was extracted with DCM (2×2 mL)
  5. dry with materialdried (Na2SO4)
  6. concentrationconcentrated
  7. customthe residue was purified with silica flash chromatography (1:1 DCM/acetone)

Sources & evidence

ORD record
ord-1abb7af8b7c947d3a16925ab528316fd
Source dataset
uspto-grants-2011_12
Patent number
US08071768B2

Reaction notes

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