Citric Acid → 1,1-Dimethylethyl 2-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-6-(methyloxy)-1-oxo-1,2,3,4-tetrahydro-9H-beta-carboline-9-carboxylate

HRID 1874792Notes

Reaction equation

HRID 1874792 reaction equation
CO[C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[CH2:8][CH2:9][NH:10][C:11](=[O:23])[C:12]=3[N:13]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:27][C:28]1[C:29]([F:45])=[C:30]([O:35][C:36]2[CH:37]=[C:38]([CH:41]=[C:42]([Cl:44])[CH:43]=2)[C:39]#[N:40])[C:31]([Cl:34])=[CH:32][CH:33]=1.C(O)(=O)C[C:48](CC(O)=O)(C(O)=O)[OH:49]>C1COCC1.CCOC(C)=O>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([CH2:27][N:10]2[CH2:9][CH2:8][C:7]3[C:6]4[C:14](=[CH:15][CH:3]=[C:4]([O:49][CH3:48])[CH:5]=4)[N:13]([C:16]([O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:17])[C:12]=3[C:11]2=[O:23])=[C:29]([F:45])[C:30]=1[O:35][C:36]1[CH:37]=[C:38]([C:39]#[N:40])[CH:41]=[C:42]([Cl:44])[CH:43]=1

Participants

7

Reactant 4

HCID 311Citric AcidHCID 24758Sodium hydrideHCID 594515763-{[3-(Bromomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrileHCID 709371861,1-Dimethylethyl 7-(methyloxy)-1-oxo-1,2,3,4-tetrahydro-9H-beta-carboline-9-carboxylate

Product 1

HCID 594515721,1-Dimethylethyl 2-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-6-(methyloxy)-1-oxo-1,2,3,4-tetrahydro-9H-beta-carboline-9-carboxylateYield 24%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

1,1-Dimethylethyl 7-(methyloxy)-1-oxo-1,2,3,4-tetrahydro-9H-β-carboline-9-carboxylate (0.075 g, 0.23 mmol) was dissolved in THF (2 mL) and cooled to 0° C. Sodium hydride (60% dispersion in oil, 0.01 g, 0.25 mmol) was added and the mixture was stirred for 15 min. 3-{[3-(Bromomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.09 g, 0.23 mmol) was added. The reaction mixture was allowed to warm to RT and stirred for 1 h. 10% Aqueous citric acid and EtOAc were added. The layers were separated and the aqueous layer extracted with EtOAc (3×5 mL). The organic extracts were combined, dried over Na2SO4, filtered and evaporated. Purification was accomplished by column chromatography (hexane/EtOAc) to afford the title compound (0.034 g, 24%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 7.83 (s, 1H), 7.81 (d, 1H), 7.52 (d, 1H), 7.45-7.51 (m, 2H), 7.34 (t, 1H), 7.20 (d, 1H), 7.07 (dd, 1H), 4.79 (s, 2H), 3.79 (s, 3H), 3.71 (t, 2H), 2.94 (t, 2H), 1.48 (s, 9H). MS: m/z 632.2 (M+23).

Workup

  1. temperatureto warm to RT
  2. stirringstirred for 1 h
  3. customThe layers were separated
  4. extractionthe aqueous layer extracted with EtOAc (3×5 mL)
  5. dry with materialdried over Na2SO4
  6. filtrationfiltered
  7. customevaporated
  8. customPurification

Sources & evidence

ORD record
ord-62a8d91dc3e2483c854836804c758a77
Source dataset
uspto-grants-2012_11
Patent number
US08304419B2

Reaction notes

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