Ethyl Acetate → HCID 57810271, compound

HRID 455876Notes

Reaction equation

HRID 455876 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([NH:32][C:33]([C@:35]2([C:39]([NH:41][C:42]3[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=3)=[O:40])[CH2:37][C@H:36]2[CH3:38])=[O:34])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:22][CH2:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[C:16]([O:19][CH:20]=O)[CH:17]=2)[N:12]=[CH:11][CH:10]=1.Cl.ClCCCN1CCOCC1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:32][C:33]([C@:35]2([C:39]([NH:41][C:42]3[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=3)=[O:40])[CH2:37][C@H:36]2[CH3:38])=[O:34])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:22][CH2:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[C:16]([O:19][CH3:20])[CH:17]=2)[N:12]=[CH:11][CH:10]=1

Participants

6

Reactant 4

HCID 8857Ethyl AcetateHCID 11430Potassium CarbonateHCID 122962834-(3-Chloropropyl)morpholinium chlorideHCID 86661497HCID 86661497, compound

Product 1

HCID 57810271HCID 57810271, compound

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
80 °C

Procedure

To a solution of the 7-hydroxyquinoline (80 mg, 0.15 mmol) in DMF (2 mL) was added 4-(3-chloropropyl)morpholine hydrochloride (62 mg, 0.31 mmol) and K2CO3 (64 mg, 0.46 mmol). The reaction mixture was then stirred at 80° C. for 5 h. After cooling, EtOAc (20 mL) was added. The EtOAc solution was washed twice with brine, and dried over Na2SO4. Removal of EtOAc and purification by column chromatography (CH2Cl2:MeOH=10:1) gave ′(1R,2R)—N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)-2-methylcyclopropane-1,1-dicarboxamide. The product was then dissolved in ethyl ether, and treated with 1.5 equiv. of 1N HCl/ether. Filtration and lyophilization gave the HCl salt of ′(1R,2R)—N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)-2-methylcyclopropane-1,1-dicarboxamide: 1H NMR (400 MHz, DMSO-d6) δ 10.65 (br s, 1H), 10.54 (br s, 1H), 9.74 (s, 1H), 8.75 (br s, 1H), 8.01 (br d, J=12.9 Hz, 1H), 7.80-7.50 (m, 6H), 7.20-7.10 (m, 2H), 6.84 (br s, 1H), 4.34 (br t, J=5 Hz, 2H), 4.04 (s, 3H), 4.05-3.95 (m, 2H), 3.77 (br t, J=11 Hz, 2H), 3.52 (br d, J=12.7 Hz, 4H), 3.12 (br q, J=9.0 Hz, 2H), 2.40-2.30 (m, 2H), 2.10-1.95 (m, 1H), 1.40-1.30 (m, 2H), 1.10 (d, J=6.2 Hz, 3H).

Workup

  1. temperatureAfter cooling
  2. washThe EtOAc solution was washed twice with brine
  3. dry with materialdried over Na2SO4
  4. customRemoval of EtOAc and purification by column chromatography (CH2Cl2:MeOH=10:1)

Sources & evidence

ORD record
ord-f117b5df927843349aeee9fbc3587b93
Source dataset
uspto-grants-2013_07
Patent number
US08497284B2

Reaction notes

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