3-Aminopyridine → 3-[1-(N-cyclopentylglycyl)-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl]-5,5-dimethyl-1-{[2-(pyridin-3-ylamino)pyridin-4-yl]methyl}imidazolidine-2,4-dione

HRID 546569

Reaction equation

HRID 546569 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.[NH2:45][C:46]1[CH:47]=[N:48][CH:49]=[CH:50][CH:51]=1.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:45][C:46]6[CH:47]=[N:48][CH:49]=[CH:50][CH:51]=6)[CH:7]=5)[C:10]4=[O:44])[CH:25]=3)[C:21]([CH3:43])([CH3:42])[CH2:22]2)=[O:41])[CH2:37][CH2:38][CH2:39][CH2:40]1

Participants

7

Reactant 4

HCID 100093-AminopyridineHCID 10796Cesium carbonateHCID 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 576259853-[1-(N-cyclopentylglycyl)-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl]-5,5-dimethyl-1-{[2-(pyridin-3-ylamino)pyridin-4-yl]methyl}imidazolidine-2,4-dioneYield 41.3%

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 1) of Example 3 in 12 mL of dioxane are successively added, under argon, 0.094 g of 3-aminopyridine, 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 the filtrate is concentrated under reduced pressure. The residue is taken up in 10 mL of dioxane, 12 mL of a 4N solution of hydrogen chloride in dioxane are then 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 25 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 triturated with diethyl ether and the solid obtained is filtered off and dried to give 0.12 g of 3-[1-(N-cyclopentylglycyl)-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl]-5,5-dimethyl-1-{[2-(pyridin-3-ylamino)pyridin-4-yl]methyl}imidazolidine-2,4-dione, the characteristics of which are as follows:

Workup

  1. temperatureThe reaction mixture is refluxed for 4 hours
  2. filtrationfiltered
  3. concentrationthe filtrate is concentrated under reduced pressure
  4. addition12 mL of a 4N solution of hydrogen chloride in dioxane are then added
  5. concentrationAfter concentrating under reduced pressure
  6. additionneutralized by addition of sodium hydrogen carbonate
  7. extractionextracted with three times 25 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 triturated with diethyl ether
  13. customthe solid obtained
  14. filtrationis filtered off
  15. customdried

Sources & evidence

ORD record
ord-50823883cdcc40d1a60b80f8ad9058dc
Source dataset
uspto-grants-2011_05
Patent number
US07935819B2

Linked notes

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