Dichloromethane → N-[6-(6-amino-pyrid-3-yl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide

HRID 497719Notes

Reaction equation

HRID 497719 reaction equation
[NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:17]2[CH:25]=[C:24]3[C:20]([C:21]([NH:34][C:35](=[O:39])[CH2:36][CH2:37][CH3:38])=[N:22][N:23]3[CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])=[CH:19][CH:18]=2)O1.ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C(OCC)(=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]>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:17]2[CH:25]=[C:24]3[C:20]([C:21]([NH:34][C:35](=[O:39])[CH2:36][CH2:37][CH3:38])=[N:22][N:23]3[CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:31])[CH3:32])=[CH:19][CH:18]=2)=[CH:6][CH:7]=1

Participants

9

Reactant 4

HCID 6344DichloromethaneHCID 10340Sodium CarbonateHCID 706222-Amino-5-bromopyridineHCID 22319493N-[6-(4,4,5,5-tetramethyl [1,3,2]dioxaborolan-2-yl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide

Product 1

HCID 22319508N-[6-(6-amino-pyrid-3-yl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamideYield 0.1%

Reagents, catalysts & solvents 4

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolvent2×HCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Procedure

0.45 g of 2-amino-5-bromopyridine is added to 1.0 g of N-[6-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, prepared in Example 56, in 50 cm3 of dioxane, 142 mg of dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium, dichloromethane and 646 mg of sodium carbonate in 10 cm3 of water are added to the pale yellow solution, and the mixture is refluxed for 2 hours. The reaction medium is diluted with 50 cm3 of ethyl acetate and 50 cm3 of water, and then filtered through a sinter funnel packed with Celite. The filtrate is separated by settling and the aqueous phase is washed with 2×50 cm3 of saturated sodium chloride solution, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2 kPa; 50° C.). The crude product obtained is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 3 cm), eluting with a cyclohexane/ethyl acetate gradient mixture (70/30 to 50/50 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.) to give 0.53 mg of N-[6-(6-amino-pyrid-3-yl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide in the form of a solid melting at 138° C.

Workup

  1. temperaturethe mixture is refluxed for 2 hours
  2. filtrationfiltered through a sinter funnel
  3. customThe filtrate is separated
  4. washthe aqueous phase is washed with 2×50 cm3 of saturated sodium chloride solution
  5. dry with materialdried over magnesium sulphate
  6. filtrationfiltered
  7. concentrationconcentrated to dryness under reduced pressure (2 kPa; 50° C.)
  8. customThe crude product obtained
  9. customis purified by chromatography under an argon pressure of 50 kPa
  10. washon a column of silica gel (particle size 40-60 μm; diameter 3 cm), eluting with a cyclohexane/ethyl acetate gradient mixture (70/30 to 50/50 by volume)
  11. additionThe fractions containing the expected product
  12. customevaporated under reduced pressure (2 kPa; 50° C.)

Sources & evidence

ORD record
ord-95fb729b27a84d819ce9f0cc4b9b862c
Source dataset
uspto-grants-2005_09
Patent number
US06949579B2

Reaction notes

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