Potassium Carbonate → 2-Amino-3-(3'-{5-methyl-2-[(3,4,5-trimethoxyphenyl)amino]-imidazo[5,1-f][1,2,4]triazin-7-yl}-1,1'-biphenyl-4-yl)propanoic acid

HRID 2374958Notes

Reaction equation

HRID 2374958 reaction equation
Br[C:2]1[CH:3]=[C:4]([C:8]2[N:16]3[C:11]([CH:12]=[N:13][C:14]([NH:17][C:18]4[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=4)=[N:15]3)=[C:10]([CH3:30])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.OB(O)[C:33]1[CH:44]=[CH:43][C:36]([CH2:37][C@@H:38]([C:40]([OH:42])=[O:41])[NH2:39])=[CH:35][CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COCCOC>[NH2:39][CH:38]([CH2:37][C:36]1[CH:43]=[CH:44][C:33]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:16]4[C:11]([CH:12]=[N:13][C:14]([NH:17][C:18]5[CH:19]=[C:20]([O:28][CH3:29])[C:21]([O:26][CH3:27])=[C:22]([O:24][CH3:25])[CH:23]=5)=[N:15]4)=[C:10]([CH3:30])[N:9]=3)[CH:3]=2)=[CH:34][CH:35]=1)[C:40]([OH:42])=[O:41]

Participants

6

Reactant 3

HCID 11430Potassium CarbonateHCID 150315L-p-BoronophenylalanineHCID 112135557-(3-bromophenyl)-5-methyl-N-(3,4,5-trimethoxyphenyl)-imidazo[5,1-f][1,2,4]triazin-2-amine

Product 1

HCID 112958642-Amino-3-(3'-{5-methyl-2-[(3,4,5-trimethoxyphenyl)amino]-imidazo[5,1-f][1,2,4]triazin-7-yl}-1,1'-biphenyl-4-yl)propanoic acidYield 42.2%

Reagents, catalysts & solvents 2

HCID 11979704Tetrakis(triphenylphosphine)palladiumCatalystHCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
130 °C

Procedure

To a mixture of 7-(3-bromophenyl)-5-methyl-N-(3,4,5-trimethoxyphenyl)imidazo[5,1-f][1,2,4]triazin-2-amine (Example 9) (40 mg, 0.085 mmol), 4-(dihydroxyboryl)phenylalanine (57.6 mg, 0.275 mmol), tetrakis(triphenylphosphine) palladium (0) (15.0 mg, 0.013 mmol) and potassium carbonate (52.8 mg, 0.382 mmol) was added DME (1.8 mL) and distilled water (0.6 mL). In a sealed reaction vessel, the mixture was heated with microwave radiation at 130° C. for a total time of 1.5 hours. After cooling to room temperature, removed solvent under reduced pressure, dissolved residue in methanol (25 mL), and added silica gel (1 g). Following evaporation of the volatiles under reduced pressure, the pre-adsorbed solids were loaded into a solid loading cartridge and subjected to a gradient elution using dichloromethane:methanol (100:0 to 65:35) followed by ethyl acetate:methanol (80:20) using a RediSep silica gel cartridge (12 g; ISCO). The appropriate fractions were combined and concentrated under reduced pressure to give 2-amino-3-(3′-{5-methyl-2-[(3,4,5-trimethoxyphenyl)amino]-imidazo[5,1-f][1,2,4]triazin-7-yl}-1,1′-biphenyl-4-yl)propanoic acid (0.0199 g) as a yellow solid. 1H NMR (DMSO-d6): δ9.63 (s, 1H), 9.26 (s, 1H), 8.55 (s, 1H), 8.45 (d, J=7.9 Hz, 1H), 7.73 (d, J=8.1 Hz, 1H), 7.61-7.21 (m, 5H), 7.09 (s, 2H), 3.65 (s, 6H), 3.63 (s, 3H), 3.43-3.12 (m, 1H), 2.92-2.80 (m, 2H). MS m/z 555 (M+1).

Workup

  1. distillationdistilled water (0.6 mL)
  2. customIn a sealed reaction vessel
  3. temperatureAfter cooling to room temperature
  4. customremoved solvent under reduced pressure
  5. dissolutiondissolved residue in methanol (25 mL)
  6. additionadded silica gel (1 g)
  7. customevaporation of the volatiles under reduced pressure
  8. washsubjected to a gradient elution
  9. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-f94f3c991eb84caf8a8c71b869f65a55
Source dataset
uspto-grants-2008_12
Patent number
US07462614B2

Reaction notes

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