1-Methyl-5-(tri-n-butylstannyl)imidazole → 3-fluoro-4-(1-(4-methoxybenzyl)-3-(1-methyl-1H-imidazol-5-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)aniline

HRID 2241430Notes

Reaction equation

HRID 2241430 reaction equation
[CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10](I)=[N:9]2)=[CH:5][CH:4]=1.[CH3:29][N:30]1[C:34]([Sn](CCCC)(CCCC)CCCC)=[CH:33][N:32]=[CH:31]1>[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.C1(C)C=CC=CC=1>[F:25][C:19]1[CH:20]=[C:21]([CH:22]=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[N:8]([CH2:7][C:6]3[CH:27]=[CH:28][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:9]=[C:10]([C:34]3[N:30]([CH3:29])[CH:31]=[N:32][CH:33]=3)[C:11]=12)[NH2:24]

Participants

5

Reactant 2

HCID 109156511-Methyl-5-(tri-n-butylstannyl)imidazoleHCID 672210033-Fluoro-4-((3-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)oxy)aniline

Product 1

HCID 685107133-fluoro-4-(1-(4-methoxybenzyl)-3-(1-methyl-1H-imidazol-5-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)anilineYield 78.3%

Reagents, catalysts & solvents 2

HCID 11979704Tetrakis(triphenylphosphine)palladiumCatalystHCID 1140TolueneSolvent

Conditions

Temperature
100 °C

Procedure

4-(1-(4-Methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorobenzenamine (300 mg, 0.612 mmol, prepared in Example 7, step B), 1-methyl-5-(tributylstannyl)-1H-imidazole (681 mg, 1.84 mmol) (Org. Proc. Res. & Dev., 2003, 7(5), 676-683), tetrakis (triphenylphosphine) palladium (0) (141 mg, 0.122 mmol) and toluene (5 mL) were charged in a 25 mL, single-neck, round-bottomed flask. The reaction mixture was stirred at 100° C. until the starting material had been consumed (2 days). Then the reaction was cooled to room temperature and then partitioned between EtOAc (50 mL) and water (50 mL). The phases were separated and the aqueous phase was extracted with EtOAc (3×50 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 100/1 to 10/1, v/v) to afford product (213 mg, 78.3%). LRMS (APCI pos): >95% purity, 254 nm, m/e 445 (M+1). 1H NMR (400 MHz, CDCl3 δ 8.32 (d, 1H), 7.71 (m, 1H), 7.50 (m, 1H), 7.36 (m, 2H), 6.96 (m, 1H), 6.83 (m, 2H), 6.52 (m, 1H), 6.46 (m, 1H), 6.28 (d, 1H), 5.65 (s, 2H), 3.92 (s, 3H), 3.77 (s, 3H), 3.67 (s, 2H, NH2),

Workup

  1. customhad been consumed (2 days)
  2. temperatureThen the reaction was cooled to room temperature
  3. custompartitioned between EtOAc (50 mL) and water (50 mL)
  4. customThe phases were separated
  5. extractionthe aqueous phase was extracted with EtOAc (3×50 mL)
  6. dry with materialThe combined organic layers were dried (Na2SO4)
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customto yield a crude product
  10. customThe crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 100/1 to 10/1

Sources & evidence

ORD record
ord-fd50180032ae4aefb1315d3d8be45c1d
Source dataset
uspto-grants-2010_05
Patent number
US07723330B2

Reaction notes

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