Tri-o-tolylphosphine → 4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)benzoic acid

HRID 77720Notes

Reaction equation

HRID 77720 reaction equation
C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C([O-])(=O)C.[Na+].I[C:29]1[C:30]([NH:35][C:36]2[CH:37]=[C:38]([C:42]3[C:47]([CH3:48])=[CH:46][CH:45]=[C:44]([C:49]([OH:51])=[O:50])[CH:43]=3)[CH:39]=[CH:40][CH:41]=2)=[N:31][CH:32]=[N:33][CH:34]=1>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:48][C:47]1[CH:46]=[CH:45][C:44]([C:49]([OH:51])=[O:50])=[CH:43][C:42]=1[C:38]1[CH:37]=[C:36]2[C:41]([C:29]3[CH:34]=[N:33][CH:32]=[N:31][C:30]=3[NH:35]2)=[CH:40][CH:39]=1

Participants

6

Reactant 3

HCID 80271Tri-o-tolylphosphineHCID 517045Sodium AcetateHCID 690440573'-[(5-Iodopyrimidin-4-yl)amino]-6-methylbiphenyl-3-carboxylic acid

Product 1

HCID 690470684-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)benzoic acid

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
20 °C

Procedure

tri-o-Tolylphosphine (18 mg, 0.060 mmol) was stirred in DMF (3 mL). The mixture was degassed by bubbling nitrogen through it until all additions were complete. To the mixture was added palladium acetate (6.8 mg, 0.030 mmol), and the resulting mixture was stirred at 20° C. for 5 min. To this mixture was added sodium acetate (37.1 mg, 0.452 mmol) and 3′-[(5-iodopyrimidin-4-yl)amino]-6-methylbiphenyl-3-carboxylic acid (0.13 g, 0.30 mmol). The resulting mixture was heated to reflux for 2 h. LCMS showed complete reaction to give the desired product, M+H 304; and a small amount of reduction product (M+H 306). The mixture was cooled to 20° C. The product was isolated by prep HPLC/MS using a 30 mm×100 mm C18 column; 25% CH3CN—H2O (0.1% TFA), 1.75 min, to 40% at 6 min; 60 mL/min; detector set at m/z 304; retention time, 3.2 min; reduction product, 4.3 min. The HPLC fractions were freeze dried to yield 45 mg of the TFA salt, a white solid. 1H NMR (d6-DMSO) δ 13.0 (br s, 1H, NH); 9.6 (s, 1H); 9.1 (s, 1H); 8.3 (d, 1H); 7.8 (m, 2H); 7.5 (s, 1H); 7.4 (m, 2H); 2.3 (s, 3H).

Workup

  1. customThe mixture was degassed
  2. customby bubbling nitrogen through it until all additions
  3. temperatureThe resulting mixture was heated
  4. temperatureto reflux for 2 h
  5. customreaction

Sources & evidence

ORD record
ord-817826fdef344207a0ff8b421340fae9
Source dataset
uspto-grants-2014_09
Patent number
US08841318B2

Reaction notes

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