1-Methyl-2-(tributylstannyl)-1H-imidazole → 3-Fluoro-4-(1-(4-methoxybenzyl)-3-(1-methyl-1H-imidazol-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)aniline

HRID 2241425Notes

Reaction equation

HRID 2241425 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[CH:34]=[CH:33][N:32]=[C:31]1[Sn](CCCC)(CCCC)CCCC>[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:31]3[N:30]([CH3:29])[CH:34]=[CH:33][N:32]=3)[C:11]=12)[NH2:24]

Participants

5

Reactant 2

HCID 27632521-Methyl-2-(tributylstannyl)-1H-imidazoleHCID 672210033-Fluoro-4-((3-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)oxy)aniline

Product 1

HCID 685150213-Fluoro-4-(1-(4-methoxybenzyl)-3-(1-methyl-1H-imidazol-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)anilineYield 79%

Reagents, catalysts & solvents 2

HCID 11979704Tetrakis(triphenylphosphine)palladiumCatalystHCID 1140TolueneSolvent

Conditions

Temperature
60 °C

Procedure

4-(1-(4-Methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorobenzenamine (200 mg, 0.408 mmol, prepared in Example 7, step B), 1-methyl-2-(tributylstannyl)-1H-imidazole (908.4 mg, 2.45 mmol), tetrakis (triphenylphosphine) palladium (94.28 mg, 0.0816 mmol) and toluene (4 mL) were charged in a 25 mL, single-neck, round-bottomed flask. The reaction mixture was stirred at 60° C. until the starting material had been consumed (4 hours). Then the reaction mixture was cooled to room temperature and partitioned between EtOAc (100 mL) and H2O (50 mL). The phases were separated, and the aqueous phase was re-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 (0.143 g, 79%). LRMS (APCI pos): >99% purity, 254 nm, m/e 445 (M+1). 1H NMR (400 MHz, CDCl3 δ 8.31 (m, 1H), 7.71 (m, 1H), 7.50 (m, 1H), 7.35 (m, 2H), 6.94 (m, 1H), 6.84 (m, 2H), 6.50 (m, 1H), 6.43 (m, 1H), 6.28 (d, 1H), 5.64 (s, 2H), 3.90 (s, 3H), 3.75 (s, 3H), 3.67 (s, 2H, NH2).

Workup

  1. customhad been consumed (4 hours)
  2. temperatureThen the reaction mixture was cooled to room temperature
  3. custompartitioned between EtOAc (100 mL) and H2O (50 mL)
  4. customThe phases were separated
  5. extractionthe aqueous phase was re-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-cff8a33fd8f74453b99e77e9570c8f72
Source dataset
uspto-grants-2010_05
Patent number
US07723330B2

Reaction notes

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