Cesium carbonate → 3-(3-Methoxy-phenylamino)-phthalic acid dimethyl ester

HRID 448409Notes

Reaction equation

HRID 448409 reaction equation
[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10](I)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].C(=O)([O-])[O-].[Cs+].[Cs+].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.[CH3:68][O:69][C:70]1[CH:75]=[CH:74][CH:73]=[C:72]([NH2:76])[CH:71]=1>C1(C)C=CC=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([NH:76][C:72]2[CH:73]=[CH:74][CH:75]=[C:70]([O:69][CH3:68])[CH:71]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 108243-MethoxyanilineHCID 634876Binap, (A+-)-HCID 2326127Dimethyl 3-iodophthalate

Product 1

HCID 583072403-(3-Methoxy-phenylamino)-phthalic acid dimethyl esterYield 47%

Reagents, catalysts & solvents 2

HCID 1140TolueneSolventHCID 6344DichloromethaneSolvent

Procedure

A mixture of 3-iodo-phthalic acid dimethyl ester (1.0 g, 3.1 mmol), cesium carbonate (1.4 g, 4.3 mmol), Pd2(dba) (0.13 g, 0.14 mmol) and rac-BINAP (0.058 g, 0.093 mmol) in toluene (6 mL) was stirred at room temperature for 5 minutes. m-Anisidine (0.38 g, 3.1 mmol) was then added, and the reaction mixture was refluxed for 48 hours. The reaction mixture was diluted with methylene chloride (20 mL) and filtered through celite. The filter was washed with additional methylene chloride (25 mL). The combined filtrates were evaporated, and the residue was purified by ISCO silica gel flash chromatography using a hexanes-ethyl acetate gradient, eluting the product at 7:3 hexanes-ethyl acetate. It was then purified by preparative HPLC using an acetonitrile-water gradient, eluting the product at 6:4 acetonitrile:water to give the title product, 0.46 g in 47% yield; 1H NMR (CDCl3) δ 3.79 (s, 3H), 3.87 (s, 3H), 3.89 (s, 3H), 6.59-6.75 (m, 3H), 7.09-7.46 (m, 4H), 8.00 (s, 1H).

Workup

  1. temperaturethe reaction mixture was refluxed for 48 hours
  2. filtrationfiltered through celite
  3. washThe filter was washed with additional methylene chloride (25 mL)
  4. customThe combined filtrates were evaporated
  5. customthe residue was purified by ISCO silica gel flash chromatography
  6. washeluting the product at 7:3 hexanes-ethyl acetate
  7. customIt was then purified by preparative HPLC
  8. washeluting the product at 6:4 acetonitrile

Sources & evidence

ORD record
ord-ad2b172bc34b4986be1c2d375ad0537f
Source dataset
uspto-grants-2013_07
Patent number
US08481568B2

Reaction notes

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