Potassium Phosphate, Tribasic → N-(5-(3-formyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)propionamide

HRID 2096952Notes

Reaction equation

HRID 2096952 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:10]([CH:11]=[O:12])=[N:9][N:8]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)[C:5]2=[N:6][CH:7]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.CC([O-])=O.[K+].Br[C:43]1[CH:44]=[C:45]([NH:49][C:50](=[O:53])[CH2:51][CH3:52])[CH:46]=[N:47][CH:48]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C(Cl)Cl>[CH:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:43]3[CH:44]=[C:45]([NH:49][C:50](=[O:53])[CH2:51][CH3:52])[CH:46]=[N:47][CH:48]=3)[CH:3]=2)[N:8]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[N:9]=1)=[O:12]

Participants

10

Reactant 5

HCID 62657Potassium Phosphate, TribasicHCID 517044Potassium AcetateHCID 2733548Bis(pinacolato)diboraneHCID 583775865-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbaldehydeHCID 68737458N-(5-bromopyridin-3-yl)propionamide

Product 1

HCID 58377773N-(5-(3-formyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)propionamide

Reagents, catalysts & solvents 4

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
90 °C

Procedure

A solution of 5-bromo-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-carbaldehyde (XI) (0.218 g, 0.70 mmol), bis(pinacolato)diboron (0.213 g, 0.84 mmol), and KOAc (0.206 g, 2.1 mmol) in DMF (10 ml) was purged with argon. PdCl2(dppf)2. DCM was added to the solution and purged again with argon. The solution was heated at 90° C. for 2 h under argon and cooled to the room temperature. N-(5-bromopyridin-3-yl)propionamide (XXXIII) (0.70 mmol), potassium phosphate (0.223 g, 1.05 mmol) and water (1 mL) was added to the solution and purged with argon. Pd(PPh3)4 was added to the solution and again purged with the argon. The solution was heated at 90° C. for 4 h under argon. The solution was filtered through a bed of Celite and the solvent was distilled under vacuum. The residue was treated with water and extracted with DCM. The combined organic phase was dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (100% DCM→5:95 MeOH:DCM) to get N-(5-(3-formyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)propionamide (LX) as a off white solid (45% yield). 1H NMR (DMSO-d6) δ ppm 1.13 (t, J=7.55 Hz, 3H), 1.51-1.74 (m, 2H), 1.96-2.18 (m, 2H), 2.41 (q, J=7.55 Hz, 2H), 3.68 (m, 1H), 3.92 (m, 1H), 6.26 (dd, J=10.20, 2.14, 1H), 8.48 (m, 1H), 8.70 (m, 2H), 8.77 (m, 1H), 9.07 (m, 1 Hz), 10.17 (s, 1H), 10.24 (s, 1H); ESIMS found C20H21N5O3 m/z 380 (M+H).

Workup

  1. custompurged again with argon
  2. temperaturecooled to the room temperature
  3. custompurged with argon
  4. additionPd(PPh3)4 was added to the solution
  5. customagain purged with the argon
  6. temperatureThe solution was heated at 90° C. for 4 h under argon
  7. filtrationThe solution was filtered through a bed of Celite
  8. distillationthe solvent was distilled under vacuum
  9. additionThe residue was treated with water
  10. extractionextracted with DCM
  11. dry with materialThe combined organic phase was dried over MgSO4
  12. filtrationfiltered
  13. concentrationconcentrated
  14. customThe residue was purified by flash chromatography (100% DCM→5:95 MeOH:DCM)

Sources & evidence

ORD record
ord-b0c4c692a82d462db721cfbcafd326f4
Source dataset
uspto-grants-2013_05
Patent number
US08450340B2

Reaction notes

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