Water → N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-6-(2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

HRID 1522385Notes

Reaction equation

HRID 1522385 reaction equation
Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[O:27]=[C:28]1[NH:33][C:32](=[O:34])[C:31](B(O)O)=[CH:30][NH:29]1.C(=O)(O)[O-].[Na+].O>COCCOC.O.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].C(Cl)Cl>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([C:31]2[C:32](=[O:34])[NH:33][C:28](=[O:27])[NH:29][CH:30]=2)[CH:3]=1)=[O:15]

Participants

7

Reactant 4

HCID 962WaterHCID 256205(2,4-Dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)boronic acidHCID 516892Sodium BicarbonateHCID 565974256-Chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

Product 1

HCID 56598144N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-6-(2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamideYield 43.4%

Reagents, catalysts & solvents 2

HCID 178418807HCID 178418807, compoundCatalystHCID 18180031Water 1,2-dimethoxyethaneSolvent

Conditions

Temperature
150 °C

Procedure

In a 25 mL sealable tube under nitrogen were combined 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (80 mg, 0.21 mmol) and (2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)boronic acid (50 mg, 0.32 mmol) in DME/water (3 ml:1 ml). PdCl2(dppf)-CH2Cl2 adduct (8.74 mg, 0.011 mmol) was added and the resulting mixture was degassed with nitrogen for 10 min. Sodium bicarbonate (53.9 mg, 0.64 mmol) was added, the vessel was sealed, and reaction mixture was heated in a microwave at 150° C. for 30 min. After cooling, 2 mL of water was added to the black mixture and solids that precipitated were filtered. DCM/MeOH (1:1) was added, the mixture was pre-absorbed on silica gel and purified by silica gel chromatography (eluent: gradient 0 to 90:10:1 DCM/MeOH/NH4OH). The isolated product was treated with EtOH/EtOAc (1:1) and sonicated. The solids that precipitated were filtered, washed with EtOH and DCM, and dried to afford the title compound (41 mg, 42%) as a light grey solid. LCMS E-S (M+H)=449.9. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.58 (s, 1 H), 11.52 (br. s., 1 H), 11.47 (s, 1 H), 8.75 (t, J=5.05 Hz, 1 H), 8.36 (s, 1 H), 8.31 (s, 1 H), 8.23 (s, 1 H), 5.90 (s, 1 H), 5.27 (quin, J=6.69 Hz, 1 H), 4.37 (d, J=5.05 Hz, 2 H), 2.23 (s, 3 H), 2.13 (s, 3 H), 1.52 (s, 3 H), 1.50 (s, 3 H).

Workup

  1. customIn a 25 mL sealable tube under nitrogen were combined
  2. customthe resulting mixture was degassed with nitrogen for 10 min
  3. customthe vessel was sealed
  4. customreaction mixture
  5. temperatureAfter cooling
  6. customthat precipitated
  7. filtrationwere filtered
  8. additionDCM/MeOH (1:1) was added
  9. customthe mixture was pre-absorbed on silica gel
  10. custompurified by silica gel chromatography (eluent: gradient 0 to 90:10:1 DCM/MeOH/NH4OH)
  11. additionThe isolated product was treated with EtOH/EtOAc (1:1)
  12. customsonicated
  13. customThe solids that precipitated
  14. filtrationwere filtered
  15. washwashed with EtOH and DCM
  16. customdried

Sources & evidence

ORD record
ord-4d491553e4864df496bb3bb9a3499123
Source dataset
uspto-grants-2015_07
Patent number
US09073924B2

Reaction notes

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