Potassium Carbonate → Cyclopropane-1,1-dicarboxylic acid [4-(7-benzyloxy-6-methoxy-quinazolin-4-yloxy)-3-fluoro-phenyl]-amide (4-fluoro-phenyl)-amide

HRID 1924166Notes

Reaction equation

HRID 1924166 reaction equation
[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([C:32]2([C:35]([NH:37][C:38]3[CH:43]=[CH:42][C:41]([OH:44])=[C:40]([F:45])[CH:39]=3)=[O:36])[CH2:34][CH2:33]2)=[O:31])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[F:22][C:23]1[CH:24]=[CH:25][C:26]([NH:29][C:30]([C:32]2([C:35]([NH:37][C:38]3[CH:43]=[CH:42][C:41]([O:44][C:13]4[C:12]5[C:17](=[CH:18][C:9]([O:8][CH2:1][C:2]6[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=6)=[C:10]([O:20][CH3:21])[CH:11]=5)[N:16]=[CH:15][N:14]=4)=[C:40]([F:45])[CH:39]=3)=[O:36])[CH2:34][CH2:33]2)=[O:31])=[CH:27][CH:28]=1

Participants

5

Reactant 3

HCID 11430Potassium CarbonateHCID 106619987-(Benzyloxy)-4-chloro-6-methoxyquinazolineHCID 46899431N-(3-Fluoro-4-hydroxyphenyl)-N'-(4-fluorophenyl)-1,1-cyclopropanedicarboxamide

Product 1

HCID 57810122Cyclopropane-1,1-dicarboxylic acid [4-(7-benzyloxy-6-methoxy-quinazolin-4-yloxy)-3-fluoro-phenyl]-amide (4-fluoro-phenyl)-amideYield 76%

Reagents, catalysts & solvents 1

HCID 31374DimethylacetamideSolvent

Conditions

Temperature
50 °C

Procedure

A mixture of 7-benzyloxy-4-chloro-6-methoxy-quinazoline (5 g, 16.67 mmol), cyclopropane-1,1-dicarboxylic acid (3-fluoro-4-hydroxy-phenyl)-amide (4-fluoro-phenyl)-amide (8.3 g, 25 mmol), potassium carbonate (125 mmol, 17.25 g), and dimethylacetamide (125 ml) was heated 50° C. with stirring for 16 h. Reaction mixture was poured onto ice/water (600 ml) and stirred for 30 minutes, and filtered. The solid was dissolved in ethyl acetate and washed with water (1×), brine, and concentrated. The crude was purified on silica get column eluting with 30% acetone in hexanes to yield cyclopropane-1,1-dicarboxylic acid [4-(7-benzyloxy-6-methoxy-quinazolin-4-yloxy)-3-fluoro-phenyl]-amide (4-fluoro-phenyl)-amide (7.5 g, 76%). 1H NMR (CDCl3): 8.64 (1H, br. s), 8.55 (1H, s), 8.33 (1H, br. s), 7.74-7.71 (1H, dd), 7.54 (1H, s), 7.48-7.33 (8H, m), 7.31-7.24 (2H, m), 7.06-7.02 (2H, m), 5.32 (2H, s), 4.06 (3H, s), 1.77-1.74 (2H, m), 1.63-1.61 (2H, m).

Workup

  1. customReaction mixture
  2. additionwas poured onto ice/water (600 ml)
  3. stirringstirred for 30 minutes
  4. filtrationfiltered
  5. dissolutionThe solid was dissolved in ethyl acetate
  6. washwashed with water (1×), brine
  7. concentrationconcentrated
  8. customThe crude was purified on silica
  9. customget column
  10. washeluting with 30% acetone in hexanes

Sources & evidence

ORD record
ord-20f2427e024d419f9ae67209d10d80a0
Source dataset
uspto-grants-2012_05
Patent number
US08178532B2

Reaction notes

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