Cesium carbonate → 3-[4-({3-[1-(N-cyclopentylglycyl)-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl]-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl}methyl)pyridin-2-yl]-1,1-dimethylurea

HRID 546558

Reaction equation

HRID 546558 reaction equation
Cl[C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[C:13]([CH3:15])([CH3:14])[C:12](=[O:16])[N:11]([C:17]3[CH:25]=[C:24]4[C:20]([C:21]([CH3:43])([CH3:42])[CH2:22][N:23]4[C:26](=[O:41])[CH2:27][N:28]([CH:36]4[CH2:40][CH2:39][CH2:38][CH2:37]4)C(=O)OC(C)(C)C)=[CH:19][CH:18]=3)[C:10]2=[O:44])[CH:5]=[CH:4][N:3]=1.[CH3:45][N:46]([CH3:50])[C:47]([NH2:49])=[O:48].CC1(C)C2C=CC(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=2OC2C1=CC=C(P(C1C=CC=CC=1)C1C=CC=CC=1)C=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:36]1([NH:28][CH2:27][C:26]([N:23]2[C:24]3[C:20](=[CH:19][CH:18]=[C:17]([N:11]4[C:12](=[O:16])[C:13]([CH3:15])([CH3:14])[N:9]([CH2:8][C:6]5[CH:5]=[CH:4][N:3]=[C:2]([NH:49][C:47](=[O:48])[N:46]([CH3:50])[CH3:45])[CH:7]=5)[C:10]4=[O:44])[CH:25]=3)[C:21]([CH3:42])([CH3:43])[CH2:22]2)=[O:41])[CH2:37][CH2:38][CH2:39][CH2:40]1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 11737N,N-DimethylureaHCID 57626019tert-butyl [2-(6-{3-[(2-chloropyridin-4-yl)methyl]-4,4-dimethyl-2,5-dioxo-imidazolidin-1-yl}-3,3-dimethyl-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]cyclopentylcarbamateHCID 86628973(9,9-dimethyl-9H-xanthene-3,6-diyl)bis(diphenylphosphine)

Product 1

HCID 236303123-[4-({3-[1-(N-cyclopentylglycyl)-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl]-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl}methyl)pyridin-2-yl]-1,1-dimethylureaYield 27.8%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 312751,4-DioxaneSolvent

Procedure

To a solution of 0.312 g of tert-butyl [2-(6-{3-[(2-chloropyridin-4-yl)methyl]-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl}-3,3-dimethyl-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]cyclopentylcarbamate obtained in stage l) below in 12 mL of dioxane are successively added, under argon, 0.066 g of N,N-dimethylurea, 0.028 g of (9,9-dimethyl-9H-xanthene-3,6-diyl)bis(diphenylphosphine) (Xantphos), 0.022 g of palladium acetate and 0.65 g of caesium carbonate. The reaction mixture is refluxed for 4 hours and then filtered and concentrated under reduced pressure. The residue is taken up in 10 mL of dioxane and then 12 mL of a 4N solution of hydrogen chloride in dioxane are added and the reaction mixture is stirred at room temperature for 15 hours. After concentrating under reduced pressure, the residue is taken up in 40 mL of water, neutralized by addition of sodium hydrogen carbonate and extracted with three times 20 mL of dichloromethane. The combined organic phases are then washed with water, dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica, eluting with a mixture of dichloromethane and methanol (90/10 by volume) to give 0.08 g of 3-[4-({3-[1-(N-cyclopentylglycyl)-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl]-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl}methyl)pyridin-2-yl]-1,1-dimethylurea, the characteristics of which are as follows:

Workup

  1. temperatureThe reaction mixture is refluxed for 4 hours
  2. filtrationfiltered
  3. concentrationconcentrated under reduced pressure
  4. addition12 mL of a 4N solution of hydrogen chloride in dioxane are added
  5. concentrationAfter concentrating under reduced pressure
  6. additionneutralized by addition of sodium hydrogen carbonate
  7. extractionextracted with three times 20 mL of dichloromethane
  8. washThe combined organic phases are then washed with water
  9. dry with materialdried over magnesium sulphate
  10. filtrationfiltered
  11. concentrationconcentrated under reduced pressure
  12. customThe residue is purified by chromatography on a column of silica
  13. washeluting with a mixture of dichloromethane and methanol (90/10 by volume)

Sources & evidence

ORD record
ord-b4835569d3b5453d92f1e0cb06aaadb5
Source dataset
uspto-grants-2011_05
Patent number
US07935819B2

Linked notes

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