Acetic Acid → N-(2-(dimethylamino)ethyl)-8-(1-(4-fluorophenylamino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxamide

HRID 572712Notes

Reaction equation

HRID 572712 reaction equation
[C:1]([C:4]1[CH:5]=[C:6]([C:21]([NH:23][CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])=[O:22])[CH:7]=[C:8]2[C:13]=1[O:12][C:11]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[CH:10][C:9]2=[O:20])(=O)[CH3:2].[F:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1.C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+].C(O)(=O)C.[B-]C#N.[Na+]>C(Cl)Cl.CO.[Ti](Cl)(Cl)(Cl)Cl>[CH3:28][N:26]([CH3:27])[CH2:25][CH2:24][NH:23][C:21]([C:6]1[CH:7]=[C:8]2[C:13](=[C:4]([CH:1]([NH:34][C:33]3[CH:35]=[CH:36][C:30]([F:29])=[CH:31][CH:32]=3)[CH3:2])[CH:5]=1)[O:12][C:11]([N:14]1[CH2:15][CH2:16][O:17][CH2:18][CH2:19]1)=[CH:10][C:9]2=[O:20])=[O:22]

Participants

10

Reactant 6

HCID 176Acetic AcidHCID 8471TriethylamineHCID 97314-FluoroanilineHCID 10340Sodium Carbonate2×HCID 20587905Sodium cyanoborohydride [MI]HCID 582349798-acetyl-N-(2-(dimethylamino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxamide

Product 1

HCID 52913589N-(2-(dimethylamino)ethyl)-8-(1-(4-fluorophenylamino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxamideYield 58.6%

Reagents, catalysts & solvents 3

HCID 24193Titanium TetrachlorideCatalystHCID 887MethanolSolventHCID 6344DichloromethaneSolvent2×

Conditions

Temperature
23 °C

Procedure

Titanium(IV) chloride (0.129 mL, 0.13 mmol) was added to a stirred suspension of 8-acetyl-N-(2-(dimethylamino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxamide (100 mg, 0.26 mmol), 4-fluoroaniline (0.042 mL, 0.44 mmol) and triethylamine (0.108 mL, 0.77 mmol) in DCM (2 mL) under nitrogen at 10° C. The resulting solution was stirred at 23° C. for 2 days. A saturated solution of sodium carbonate was added and extracted with DCM. The organic phase was washed with water, brine, dried over magnesium sulfate, and concentrated to afford the crude imine. The imine was diluted with DCM and MeOH, and acetic acid (0.030 mL, 0.52 mmol) and sodium cyanotrihydroborate (32.4 mg, 0.52 mmol) were added. The resulting solution was stirred at room temperature for 30 min. A solution of sodium carbonate was added and extracted with DCM. The organic phase was washed with water, brine, dried over magnesium sulfate, and concentrated to dryness. The crude product was purified by flash chromatography on silica gel eluting with 5% methanol in DCM followed by 5% methanolic ammonia (7 N) in DCM. The solvent was evaporated to dryness and a second purification was done on a preparative HPLC using a Waters X-Terra reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length, flow rate of 40 mL/minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to give a white solid which was triturated in MTBE then dried under vacuum to afford N-(2-(dimethylamino)ethyl)-8-(1-(4-fluorophenylamino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxamide (73.0 mg, 58.6%). Mass Spectrum: M+H+ 483. NMR Spectrum: (CDCl3) 1.60 (d, 3H), 2.25 (s, 6H), 2.50 (t, 2H), 3.45-3.58 (m, 6H), 3.79-3.89 (m, 4H), 4.02 (bs, 1H), 4.88-4.98 (m, 1H), 5.56 (s, 1H), 6.40 (dd, 2H), 6.81 (dd, 2H), 6.91 (bs, 1H), 8.27 (d, 1H), 8.34 (d, 1H).

Workup

  1. extractionextracted with DCM
  2. washThe organic phase was washed with water, brine
  3. dry with materialdried over magnesium sulfate
  4. concentrationconcentrated
  5. customto afford the crude imine
  6. additionwere added
  7. stirringThe resulting solution was stirred at room temperature for 30 min
  8. extractionextracted with DCM
  9. washThe organic phase was washed with water, brine
  10. dry with materialdried over magnesium sulfate
  11. concentrationconcentrated to dryness
  12. customThe crude product was purified by flash chromatography on silica gel eluting with 5% methanol in DCM
  13. customThe solvent was evaporated to dryness
  14. customa second purification
  15. additionThe fractions containing the desired compound
  16. customwere evaporated to dryness
  17. customto give a white solid which
  18. customwas triturated in MTBE
  19. customthen dried under vacuum

Sources & evidence

ORD record
ord-120584da75a74657b03bcd73bc8cb8fe
Source dataset
uspto-grants-2015_05
Patent number
US09029374B2

Reaction notes

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