4-Bromopyridinium chloride → 2-[1-[(4-ethoxy-2,6-difluorophenyl)methyl]-5,6-dihydro-4H-cyclopenta[c]pyrazol-3-yl]-5-methoxy-N-pyridin-4-ylpyrimidin-4-amine

HRID 1482930Notes

Reaction equation

HRID 1482930 reaction equation
[CH2:1]([O:3][C:4]1[CH:27]=[C:26]([F:28])[C:7]([CH2:8][N:9]2[C:13]3[CH2:14][CH2:15][CH2:16][C:12]=3[C:11]([C:17]3[N:22]=[C:21]([NH2:23])[C:20]([O:24][CH3:25])=[CH:19][N:18]=3)=[N:10]2)=[C:6]([F:29])[CH:5]=1)[CH3:2].Cl.Br[C:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([F:29])[C:7]([CH2:8][N:9]2[C:13]3[CH2:14][CH2:15][CH2:16][C:12]=3[C:11]([C:17]3[N:22]=[C:21]([NH:23][C:32]4[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=4)[C:20]([O:24][CH3:25])=[CH:19][N:18]=3)=[N:10]2)=[C:26]([F:28])[CH:27]=1)[CH3:2]

Participants

6

Reactant 3

HCID 881004-Bromopyridinium chlorideHCID 634876Binap, (A+-)-HCID 900126782-[1-(4-Ethoxy-2,6-difluorobenzyl)-1,4,5,6-tetrahydrocyclopenta-[c]pyrazol-3-yl]-5-methoxypyrimidin-4-amine

Product 1

HCID 722022542-[1-[(4-ethoxy-2,6-difluorophenyl)methyl]-5,6-dihydro-4H-cyclopenta[c]pyrazol-3-yl]-5-methoxy-N-pyridin-4-ylpyrimidin-4-amine

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
100 °C

Procedure

1.74 g of 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[c]-pyrazol-3-yl]-5-methoxypyrimidin-4-amine 1-4-1 (4.34 mmol, 1.00 eq.), 1.26 g of 4-bromopyridine hydrochloride (1:1) (6.50 mmol, 1.50 eq.), 540 mg of (R)-(+)-2,2′-Bis(diphenylphosphino)-1,1′-binaphtyl (0.867 mmol, 0.20 eq.), 1.66 g of sodium-tert-buylat (17.3 mmol, 4.00 eq.) and 198 mg of tris(dibenzylideneacetone)dipalladium(0) (0.867 mmol, 0.20 eq.) were suspended in 23 mL of dry DMF and stirred under nitrogen atmosphere at 100° C. bath temperature for 24 h. The reaction mixture was partitioned between half saturated aqueous ammonium chloride solution and DCM/isopropanol (4:1). The separated aqueous layer was extracted twice with DCM/isopropanol (4:1). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. Toluene was added and concentrated in vacuo. The residue was purified by flash chromatography (hexane (50-100%)/ethyl acetate and ethyl acetate (0-100%)/methanole): 655 mg (1.29 mmol, 30%) of analytically pure target compound.

Workup

  1. customThe reaction mixture was partitioned between half saturated aqueous ammonium chloride solution and DCM/isopropanol (4:1)
  2. extractionThe separated aqueous layer was extracted twice with DCM/isopropanol (4:1)
  3. washThe combined organic layers were washed with brine
  4. dry with materialdried over sodium sulfate
  5. concentrationconcentrated in vacuo
  6. additionToluene was added
  7. concentrationconcentrated in vacuo
  8. customThe residue was purified by flash chromatography (hexane (50-100%)/ethyl acetate and ethyl acetate (0-100%)/methanole)

Sources & evidence

ORD record
ord-23e445e46a0144aa8b06b48c163eb9f4
Source dataset
uspto-grants-2016_08
Patent number
US09416125B2

Reaction notes

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