Sodium Bicarbonate → N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-(4-(2-(dimethylamino)ethoxy)phenyl)-1-isopropyl-1H-indazole-4-carboxamide

HRID 85422Notes

Reaction equation

HRID 85422 reaction equation
[CH:1]([N:4]1[C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([C:13]([NH2:15])=[O:14])[C:7]=2[CH:6]=[N:5]1)([CH3:3])[CH3:2].[CH3:16][N:17]([CH3:36])[CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][CH:22]=1.[C:37](=[O:40])(O)[O-].[Na+]>O1CCOCC1.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>[CH3:13][C:8]1[CH:7]=[C:12]([CH3:11])[NH:4][C:37](=[O:40])[C:9]=1[CH2:10][NH:15][C:13]([C:8]1[C:7]2[CH:6]=[N:5][N:4]([CH:1]([CH3:3])[CH3:2])[C:12]=2[CH:11]=[C:10]([C:24]2[CH:23]=[CH:22][C:21]([O:20][CH2:19][CH2:18][N:17]([CH3:16])[CH3:36])=[CH:26][CH:25]=2)[CH:9]=1)=[O:14]

Participants

6

Reactant 3

HCID 516892Sodium BicarbonateHCID 425989244-(2-(Dimethylamino)ethoxy)benzeneboronic acid, pinacol esterHCID 674646471-isopropyl-1H-indazole-4-carboxamide

Product 1

HCID 54596556N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-(4-(2-(dimethylamino)ethoxy)phenyl)-1-isopropyl-1H-indazole-4-carboxamide

Reagents, catalysts & solvents 2

HCID 178418807HCID 178418807, compoundCatalystHCID 218864351,4-Dioxane--water (1/1)Solvent

Procedure

6-bromo-N-(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-1H-indazole-4-carboxamide (80 mg, 0.19 mmol), N,N-dimethyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethanamine (84 mg, 0.29 mmol) and PdCl2(dppf)-CH2Cl2 adduct (7.8 mg, 0.009 mmol) in dioxane/water (3 ml:1 ml) were stirred for 10 min under nitrogen. Sodium bicarbonate (48.3 mg, 0.58 mmol) was added and the insoluble mixture was irradiated in a microwave at 100° C. for 20 min. The reaction mixture was evaporated, dissolved in DCM/MeOH (1:1), and preabsorbed on silica gel and purified using silica gel chromatography (eluent: DCM/MeOH/NH4OH; gradient 0 to 80:20:2 in DCM). The isolated product was dissolved in hot DMSO/MeOH and purified using reversed-phase HPLC (25-80% gradient of MeCN in water with 0.1% TFA). Most of the solvent from the combined product fractions were evaporated and sat. sol. NaHCO3 was added, solids that crashed out were filtered, air-dried for 15 min, and dried in vacuum-oven overnight. The product was collected as a white solid (56 mg, 56%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.54 (br. s., 1H) 8.64 (t, J=4.80 Hz, 1H) 8.35 (s, 1H) 8.05 (s, 1H) 7.81-7.84 (m, 2H). LC-MS (ES) m/z=528.1 [M+H]+

Workup

  1. customthe insoluble mixture was irradiated in a microwave at 100° C. for 20 min
  2. customThe reaction mixture was evaporated
  3. dissolutiondissolved in DCM/MeOH (1:1)
  4. custompreabsorbed on silica gel
  5. custompurified
  6. dissolutionThe isolated product was dissolved in hot DMSO/MeOH
  7. custompurified
  8. customMost of the solvent from the combined product fractions were evaporated
  9. additionsat. sol. NaHCO3 was added
  10. filtrationsolids that crashed out were filtered
  11. customair-dried for 15 min
  12. customdried in vacuum-oven overnight
  13. customThe product was collected as a white solid (56 mg, 56%)

Sources & evidence

ORD record
ord-a47176ce20fd4dc7936f2f033c04f98c
Source dataset
uspto-grants-2014_09
Patent number
US08846935B2

Reaction notes

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