Cesium carbonate → 3-[4-(2-Morpholin-4-yl-ethoxy)-phenylamino]-phthalic acid dimethyl ester

HRID 448394

Reaction equation

HRID 448394 reaction equation
[N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:17][O:18][C:19](=[O:31])[C:20]1[C:21](=[C:26](I)[CH:27]=[CH:28][CH:29]=1)[C:22]([O:24][CH3:25])=[O:23].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:25][O:24][C:22](=[O:23])[C:21]1[C:20](=[C:29]([NH:16][C:13]2[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[CH:11][CH:12]=2)[CH:28]=[CH:27][CH:26]=1)[C:19]([O:18][CH3:17])=[O:31]

Participants

8

Reactant 4

HCID 10796Cesium carbonateHCID 634876Binap, (A+-)-HCID 2326127Dimethyl 3-iodophthalateHCID 64847114-(2-Morpholinoethoxy)aniline

Product 1

HCID 583073333-[4-(2-Morpholin-4-yl-ethoxy)-phenylamino]-phthalic acid dimethyl esterYield 70%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolventHCID 6344DichloromethaneSolvent

Procedure

A mixture of 4-(2-morpholin-4-yl-ethoxy)-phenylamine (1.4 g, 6.2 mmol), 3-iodophthalic acid dimethyl ester (2.0 g, 6.2 mmol), Pd2(dba)3 (0.26 g, 0.28 mmol), rac-BINAP (0.12 g, 0.19 mmol), and cesium carbonate (2.8 g, 8.6 mmol), in 12 mL toluene was heated to reflux under nitrogen for 16 hours. The reaction mixture was cooled, diluted with CH2Cl2 (20 mL), and filtered through Celite, and the filter was washed with additional CH2Cl2 (60 mL). The filtrate was evaporated in vacuo, and the residue was purified by ISCO silica gel flash chromatography using a methylene chloride-methanol gradient, eluting 1.8 g of the product at 95:5 methylene chloride-methanol, in 70% yield, as a pale yellow solid; 1H NMR (CDCl3) δ 3.00-3.51 (m, 6H), 3.87 (s, 3H), 3.88 (s, 3H), 4.08-4.34 (m, 4H), 4.52-4.62 (m, 2H), 6.89 (d, J=8.7 Hz, 2H), 6.99 (d, J=7.1, 1H), 7.09-7.12 (m, 3H), 7.23-7.28 (m, 1H), 8.08 (s, 1H).

Workup

  1. temperatureto reflux under nitrogen for 16 hours
  2. temperatureThe reaction mixture was cooled
  3. filtrationfiltered through Celite
  4. washthe filter was washed with additional CH2Cl2 (60 mL)
  5. customThe filtrate was evaporated in vacuo
  6. customthe residue was purified by ISCO silica gel flash chromatography
  7. washeluting 1.8 g of the product at 95:5 methylene chloride-methanol

Sources & evidence

ORD record
ord-41db7f6487b5439ba7499b8d7a4761a8
Source dataset
uspto-grants-2013_07
Patent number
US08481568B2

Linked notes

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