Potassium Carbonate → 1-(1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-1H-pyrazolo[3,4-b]pyridin-3-yl)-N,N-dimethylpiperidin-4-amine

HRID 2241315Notes

Reaction equation

HRID 2241315 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]([CH3:37])[CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.N1CCC[C@H]1C(O)=O.C([O-])([O-])=O.[K+].[K+]>[Cu]I.CN(C=O)C>[NH2:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][C:16]2[CH:15]=[CH:14][N:13]=[C:12]3[N:8]([CH2:7][C:6]4[CH:27]=[CH:28][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[N:9]=[C:10]([N:34]4[CH2:35][CH2:36][CH:31]([N:30]([CH3:37])[CH3:29])[CH2:32][CH2:33]4)[C:11]=23)=[C:19]([F:25])[CH:20]=1

Participants

7

Reactant 4

HCID 11430Potassium CarbonateHCID 145742L-ProlineHCID 417391N,N-Dimethylpiperidin-4-amineHCID 672210033-Fluoro-4-((3-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)oxy)aniline

Product 1

HCID 685138871-(1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-1H-pyrazolo[3,4-b]pyridin-3-yl)-N,N-dimethylpiperidin-4-amineYield 71.6%

Reagents, catalysts & solvents 2

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
100 °C

Procedure

A 100 mL round-bottomed flask was charged with 4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorobenzenamine (50.0 mg, 0.102 mmol, prepared in Example 7, step B), N,N-dimethylpiperidin-4-amine (39.2 mg, 0.306 mmol), copper(I)iodide (3.88 mg, 0.0204 mmol), (S)-pyrrolidine-2-carboxylic acid (4.70 mg, 0.0408 mmol), K2CO3 (70.5 mg, 0.510 mmol) and DMF (10 mL). The reaction mixture was stirred at 100° C. overnight. Then the reaction was cooled to room temperature and partitioned between EtOAc and H2O. The phases were separated and the aqueous phase was re-extracted with EtOAc. 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 50/1 to 10/1, v/v) to afford product (35.8 mg, 71.6%). LRMS (APCI pos): >98% purity, 254 nm, m/e 491 (M+1).

Workup

  1. temperatureThen the reaction was cooled to room temperature
  2. custompartitioned between EtOAc and H2O
  3. customThe phases were separated
  4. extractionthe aqueous phase was re-extracted with EtOAc
  5. dry with materialThe combined organic layers were dried (Na2SO4)
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customto yield a crude product
  9. customThe crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 50/1 to 10/1

Sources & evidence

ORD record
ord-307c54952fc74f3d850b12e226d0dbbc
Source dataset
uspto-grants-2010_05
Patent number
US07723330B2

Reaction notes

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