Cesium carbonate → HCID 89813063, compound

HRID 1481104Notes

Reaction equation

HRID 1481104 reaction equation
[CH2:1]([O:3][C:4](=[O:31])[C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][C:6]=1[CH2:12][N:13]([CH2:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=1[O:29][CH3:30])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:2].[Cl:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=1[OH:40].C([O-])([O-])=O.[Cs+].[Cs+].CC(C)(C(=O)CC(=O)C(C)(C)C)C>CN1C(=O)CCC1>[CH2:1]([O:3][C:4](=[O:31])[C:5]1[CH:10]=[CH:9][C:8]([O:40][C:34]2[CH:35]=[CH:36][C:37]([F:39])=[CH:38][C:33]=2[Cl:32])=[CH:7][C:6]=1[CH2:12][N:13]([CH2:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=1[O:29][CH3:30])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:2]

Participants

6

Reactant 4

HCID 10796Cesium carbonateHCID 707002,2,6,6-Tetramethyl-3,5-heptanedioneHCID 748142-Chloro-4-fluorophenolHCID 89813124HCID 89813124, compound

Product 1

HCID 89813063HCID 89813063, compoundYield 53.2%

Reagents, catalysts & solvents 1

HCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
130 °C

Procedure

To a mixture of 4-bromo-2-{[(2,5-dimethoxy-benzyl)-ethoxycarbonylmethyl-amino]-methyl}-benzoic acid ethyl ester (3.44 g, 6.96 mmol) and 2-chloro-4-fluorophenol (2.04 g, 13.9 mmol) in NMP (6.8 mL) was added Cs2CO3 (4.53 g, 13.9 mmol). The resultant mixture was degassed and re-filled with N2 gas prior to the addition of 2,2,6,6-tetramethyl-heptane-3,5-dione (128 mg, 0.70 mmol) and Cu(I)Cl (344 mg, 3.48 mmol). It was de-gassed and filled with N2 gas again. The resultant mixture was heated in a 130° C. oil bath for 24 h. Reaction mixture was filteredthrough a pad of celite and washed with EtOAc until no UV active spot was detected from the filtrate. Filtrate was washed with 1 N HCl (100 mL and 50 mL), water and brine. It was dried over MgSO4, filtered and concentrated. Crude product was purified by silica gel chromatography, eluting with CH2Cl2, to provide the title compound 2.07 g (3.70 mmol) in 44% yield. 1H NMR (200 MHz) in CDCl3, δ ppm: 7.80 (d, J=8.4 Hz, 1H), 7.38 (d, J=2.6 Hz, 1H), 7.20 (m, 1H), 7.03 (m, 3H), 6.73 (dd, J=8.4, 2.6 Hz, 1H), 6.38 (m, 2H), 4.29 (q, J=7.2 Hz, 2H), 4.18 (s, 2H), 4.11 (q, J=7.0 Hz, 2H), 3.79 (s, 3H), 3.72 (s, 3H), 3.70 (s, 2H), 3.28 (s, 2H), 1.4-1.2 (m, 6H).

Workup

  1. customThe resultant mixture was degassed
  2. additionre-filled with N2 gas
  3. customIt was de-gassed
  4. additionfilled with N2 gas again
  5. customReaction mixture
  6. washwashed with EtOAc until no UV active spot
  7. washFiltrate was washed with 1 N HCl (100 mL and 50 mL), water and brine
  8. dry with materialIt was dried over MgSO4
  9. filtrationfiltered
  10. concentrationconcentrated
  11. customCrude product was purified by silica gel chromatography
  12. washeluting with CH2Cl2

Sources & evidence

ORD record
ord-6ac53a0479464c7b9a989acd4f89341a
Source dataset
uspto-grants-2016_08
Patent number
US09409892B2

Reaction notes

Loading…