Sodium Bicarbonate → N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-[6-(4-morpholinyl)-3-pyridinyl]-1H-indazole-4-carboxamide

HRID 1476488Notes

Reaction equation

HRID 1476488 reaction equation
Br[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:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[N:27]1([C:33]2[N:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=2)[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C(=O)(O)[O-].[Na+]>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:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=[C:2]([C:36]2[CH:37]=[N:38][C:33]([N:27]3[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)=[CH:34][CH:35]=2)[CH:3]=1)=[O:15]

Participants

6

Reactant 3

HCID 516892Sodium BicarbonateHCID 467351676-(Morpholino)pyridine-3-boronic Acid (contains varying amounts of Anhydride)HCID 545964906-bromo-N-((1,2-dihydro-4,6-dimethyl-2-oxopyridin-3-yl)methyl)-1-isopropyl-1H-indazole-4-carboxamide

Product 1

HCID 68210248N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-[6-(4-morpholinyl)-3-pyridinyl]-1H-indazole-4-carboxamideYield 94.5%

Reagents, catalysts & solvents 2

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

Conditions

Temperature
110 °C

Procedure

In a 25 mL sealable tube under nitrogen were combined 6-bromo-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-indazole-4-carboxamide (110 mg, 0.26 mmol) and [6-(4-morpholinyl)-3-pyridinyl]boronic acid (82 mg, 0.39 mmol) in DME/water (3 mL:1 mL). PdCl2(dppf)-CH2Cl2 (10.76 mg, 0.013 mmol) was added and the resulting mixture was degassed with nitrogen for 10 min. Sodium bicarbonate (66.4 mg, 0.79 mmol) was added and the insoluble mixture was heated in a microwave at 110° C. for 20 min. It was evaporated, DCM/MeOH (1:1) was added, it was pre-absorbed on silica gel and purified by SiO2 chromatography (eluent: gradient 100% DCM to 80:20:2 DCM/MeOH/NH4OH). Fractions were evaporated. EtOH was added, it was sonicated and the solids that precipitated were filtered, washed with hexanes and dried to afford the title compound (123 mg, 89%) as a light beige solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.54 (s, 1H) 8.69 (d, J=2.27 Hz, 1H) 8.61 (t, J=4.93 Hz, 1H) 8.36 (s, 1H) 8.08-8.12 (m, 2H) 7.85 (d, J=1.01 Hz, 1H) 6.98 (d, J=8.84 Hz, 1H) 5.89 (s, 1H) 5.14 (quin, J=6.57 Hz, 1H) 4.39 (d, J=5.05 Hz, 2H) 3.71-3.75 (m, 4H) 3.50-3.55 (m, 4H) 2.22 (s, 3H) 2.13 (s, 3H) 1.50 (s, 3H) 1.49 (s, 3H). MS (ES) [M+H]+ 501.1.

Workup

  1. customIn a 25 mL sealable tube under nitrogen were combined
  2. customthe resulting mixture was degassed with nitrogen for 10 min
  3. customIt was evaporated
  4. additionDCM/MeOH (1:1) was added
  5. customit was pre-absorbed on silica gel
  6. custompurified by SiO2 chromatography (eluent: gradient 100% DCM to 80:20:2 DCM/MeOH/NH4OH)
  7. customFractions were evaporated
  8. additionEtOH was added
  9. customit was sonicated
  10. customthe solids that precipitated
  11. filtrationwere filtered
  12. washwashed with hexanes
  13. customdried

Sources & evidence

ORD record
ord-893975d5ceed4da8b9b84441f8ce310d
Source dataset
uspto-grants-2015_04
Patent number
US09018382B2

Reaction notes

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