Cesium carbonate → Tert-butyl {3-[(6-{[bis(4-methoxyphenyl)methyl]carbamoyl}-5-[(4,6-dimethylpyridin-2-yl)amino]pyridin-3-yl)amino]propyl}carbamate

HRID 1504880Notes

Reaction equation

HRID 1504880 reaction equation
[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[NH:10][C:11]([C:13]2[C:18]([NH:19][C:20]3[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[N:21]=3)=[CH:17][C:16](Br)=[CH:15][N:14]=2)=[O:12])=[CH:5][CH:4]=1.[NH2:37][CH2:38][CH2:39][CH2:40][NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>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]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:10][C:11]([C:13]2[N:14]=[CH:15][C:16]([NH:37][CH2:38][CH2:39][CH2:40][NH:41][C:42](=[O:48])[O:43][C:44]([CH3:46])([CH3:45])[CH3:47])=[CH:17][C:18]=2[NH:19][C:20]2[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[N:21]=2)=[O:12])[C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)=[CH:5][CH:4]=1

Participants

6

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 2735700tert-Butyl (3-aminopropyl)carbamateHCID 86731658N-[bis(4-methoxyphenyl)methyl]-5-bromo-3-[(4,6-dimethylpyridin-2-yl)amino]pyridine-2-carboxamide

Product 1

HCID 86731751Tert-butyl {3-[(6-{[bis(4-methoxyphenyl)methyl]carbamoyl}-5-[(4,6-dimethylpyridin-2-yl)amino]pyridin-3-yl)amino]propyl}carbamate

Reagents, catalysts & solvents 1

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst

Conditions

Temperature
95 °C

Procedure

N-[bis(4-methoxyphenyl)methyl]-5-bromo-3-[(4,6-dimethylpyridin-2-yl)amino]pyridine-2-carboxamide (PrepEx 1.11) (50 mg, 0.091 mmol), tert-butyl (3-aminopropyl)carbamate (32 mg, 0.18 mmol), tris(dibenzylideneacetone)dipalladium(0) (8 mg, 0.01 mmol), Xantphos (11 mg, 0.018 mmol), and cesium carbonate (66 mg, 0.20 mmol) were combined in a dry flask and purged with argon for 5 minutes. To this mixture was added 1,4-dioxane (0.75 mL), and the reaction mixture was deoxygenated by flushing it with argon for 5 minutes. The reaction mixture was heated to 95° C. After 6 hours, the reaction mixture was cooled, diluted with ethyl acetate (50 mL), filtered through CELITE, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0-60% ethyl acetate/hexanes, linear gradient) to afford tert-butyl {3-[(6-{[bis(4-methoxyphenyl)methyl]carbamoyl}-5-[(4,6-dimethylpyridin-2-yl)amino]pyridin-3-yl)amino}propyl]carbamate. MS ESI calc'd. for C36H45N6O5 [M+H]+ 641. found 641. 1H NMR (500 MHz, DMSO-d6) δ 11.48 (s, 1H), 8.70 (d, J=8.5 Hz, 1H), 8.51 (d, J=2.5 Hz, 1H), 7.53 (d, J=2.0 Hz, 1H), 7.22 (d, J=8.5 Hz, 4H), 6.92-6.84 (m, 5H), 6.64-6.60 (m, 1H), 6.57 (s, 1H), 6.45 (s, 1H), 6.11 (d, J=8.5 Hz, 1H), 3.71 (s, 6H), 3.12-3.05 (m, 2H), 3.04-2.97 (m, 2H), 2.35 (s, 3H), 2.18 (s, 3H), 1.74-1.66 (m, 2H), 1.32 (s, 9H).

Workup

  1. custompurged with argon for 5 minutes
  2. additionTo this mixture was added 1,4-dioxane (0.75 mL)
  3. customthe reaction mixture was deoxygenated
  4. customby flushing it with argon for 5 minutes
  5. temperaturethe reaction mixture was cooled
  6. additiondiluted with ethyl acetate (50 mL)
  7. filtrationfiltered through CELITE
  8. concentrationconcentrated under reduced pressure
  9. customThe residue was purified by chromatography on silica gel (0-60% ethyl acetate/hexanes, linear gradient)

Sources & evidence

ORD record
ord-8eb519abeaf54f53baea8eeb5c278ebe
Source dataset
uspto-grants-2015_12
Patent number
US09216173B2

Reaction notes

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