Potassium Carbonate → 4-[4-(2-Fluoro-4-{[1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarbonyl]-amino}-phenoxy)-6-methoxy-quinazolin-7-yloxymethyl]-piperidine-1-carboxylic acid tert-butyl ester

HRID 705648Notes

Reaction equation

HRID 705648 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[C:33]5[C:28](=[CH:29][C:30]([OH:36])=[C:31]([O:34][CH3:35])[CH:32]=5)[N:27]=[CH:26][N:25]=4)=[C:19]([F:37])[CH:18]=3)=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[C:38]([O:42][C:43]([N:45]1[CH2:50][CH2:49][CH:48]([CH2:51]OS(C)(=O)=O)[CH2:47][CH2:46]1)=[O:44])([CH3:41])([CH3:40])[CH3:39].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[C:38]([O:42][C:43]([N:45]1[CH2:50][CH2:49][CH:48]([CH2:51][O:36][C:30]2[CH:29]=[C:28]3[C:33]([C:24]([O:23][C:20]4[CH:21]=[CH:22][C:17]([NH:16][C:14]([C:11]5([C:9](=[O:10])[NH:8][C:5]6[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=6)[CH2:13][CH2:12]5)=[O:15])=[CH:18][C:19]=4[F:37])=[N:25][CH:26]=[N:27]3)=[CH:32][C:31]=2[O:34][CH3:35])[CH2:47][CH2:46]1)=[O:44])([CH3:41])([CH3:39])[CH3:40]

Participants

6

Reactant 3

HCID 11430Potassium Carbonate2×HCID 2765838Tert-butyl 4-(methylsulfonyloxymethyl)piperidine-1-carboxylate2×HCID 136168662Cyclopropane-1,1-dicarboxylic acid (3-fluoro-4-(7-hydroxy-6-methoxy-quinazolin-4-yloxy)-phenyl]-amide (4-fluoro-phenyl)-amide

Product 1

HCID 588305724-[4-(2-Fluoro-4-{[1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarbonyl]-amino}-phenoxy)-6-methoxy-quinazolin-7-yloxymethyl]-piperidine-1-carboxylic acid tert-butyl esterYield 60.6%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
80 °C

Procedure

Cyclopropane-1,1-dicarboxylic acid [3-fluoro-4-(7-hydroxy-6-methoxy-quinazolin-4-yloxy)-phenyl]-amide (4-fluoro-phenyl)-amide (325 mg, 0.64 mmol), 4-methanesulfonyloxymethyl-piperidine-1-carboxylic acid tert-butyl ester (193 mg, 0.66 mmol), K2CO3 (181 mg, 1.31 mmol) were combined in DMF (5 ml) and heated to 80° C. overnight. The reaction was not complete and more 4-methanesulfonyloxymethyl-piperidine-1-carboxylic acid tert-butyl ester (90 mg, 0.31 mmol) and K2CO3 (90 mg, 0.65 mmol) were added and heating at 80° C. continued for another night. The reaction mixture was allowed to cool to room temperature, then diluted with EtOAc and washed with H2O (3×), sat'd NaCl (1×), dried (Na2SO4) and concentrated in vacuo. The resulting crude material was purified by flash chromatography (1:1 hexanes:EtOAc, followed by 1:3 hexanes:EtOAc) to give 4-[4-(2-fluoro-4-{[1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarbonyl]-amino}-phenoxy)-6-methoxy-quinazolin-7-yloxymethyl]-piperidine-1-carboxylic acid tert-butyl ester (273 mg, 60%). LC/MS Calcd for [M+H]+ 704.3. found 704.4.

Workup

  1. temperatureheating at 80° C.
  2. waitcontinued for another night
  3. temperatureto cool to room temperature
  4. washwashed with H2O (3×), sat'd NaCl (1×)
  5. dry with materialdried (Na2SO4)
  6. concentrationconcentrated in vacuo
  7. customThe resulting crude material was purified by flash chromatography (1:1 hexanes:EtOAc, followed by 1:3 hexanes:EtOAc)

Sources & evidence

ORD record
ord-58fbbc4c4d3a4a97a64134b62051d69d
Source dataset
uspto-grants-2015_11
Patent number
US09174947B2

Reaction notes

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