Sodium t-butoxide → Tert-butyl 4-(4-((6-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methyl-3-((2-(trimethylsilyl)ethoxy)methyl)ureido)pyrimidin-4-yl)amino)-3-nitrophenyl)piperazine-1-carboxylate

HRID 58202Notes

Reaction equation

HRID 58202 reaction equation
Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]([CH3:32])[C:9]([N:11]([C:20]2[C:25]([Cl:26])=[C:24]([O:27][CH3:28])[CH:23]=[C:22]([O:29][CH3:30])[C:21]=2[Cl:31])[CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])=[O:10])[CH:3]=1.[NH2:33][C:34]1[CH:39]=[CH:38][C:37]([N:40]2[CH2:45][CH2:44][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:42][CH2:41]2)=[CH:36][C:35]=1[N+:53]([O-:55])=[O:54].CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.CC(C)([O-])C.[Na+]>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]>[Cl:31][C:21]1[C:22]([O:29][CH3:30])=[CH:23][C:24]([O:27][CH3:28])=[C:25]([Cl:26])[C:20]=1[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:17])([CH3:19])[CH3:18])[C:9](=[O:10])[N:8]([C:4]1[N:5]=[CH:6][N:7]=[C:2]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([N:40]3[CH2:41][CH2:42][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:50])[CH3:51])=[O:47])[CH2:44][CH2:45]3)=[CH:36][C:35]=2[N+:53]([O-:55])=[O:54])[CH:3]=1)[CH3:32]

Participants

6

Reactant 4

HCID 23676156Sodium t-butoxideHCID 25112535BrettphosHCID 117722366Tert-butyl 4-(4-amino-3-nitrophenyl)piperazine-1-carboxylateHCID 1317369691-(6-Chloropyrimidin-4-yl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methyl-3-((2-(trimethylsilyl)ethoxy)methyl)urea

Product 1

HCID 131736984Tert-butyl 4-(4-((6-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methyl-3-((2-(trimethylsilyl)ethoxy)methyl)ureido)pyrimidin-4-yl)amino)-3-nitrophenyl)piperazine-1-carboxylateYield 45.3%

Reagents, catalysts & solvents 1

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst

Conditions

Temperature
100 °C

Procedure

1-(6-chloropyrimidin-4-yl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methyl-3-((2-(trimethylsilyl)ethoxy)methyl)urea (175 g, 0.34 mmol), tert-butyl 4-(4-amino-3-nitrophenyl)piperazine-1-carboxylate (90 g, 0.28 mmol), Pd2(dba)3 (13 g, 0.014 mmol), Brettphos (13 g, 0.028 mmol) and sodium tert-butoxide (54 g, 0.56 mmol) were placed in a reaction vial (2 to 5 ml) and purged with nitrogen. Toluene (1.0 ml) was added and nitrogen was bubbled for 5 min then the reaction mixture was heated at 100° C. overnight. Heating was stopped and cooled to room temperature. The reaction mixture was filtered through pad of Celite®. The filtrate was evaporated and resulting material was purified by flash chromatography on silica eluting with 20% to 70% EtOAc/Hexane to afford the title compound (102.4 mg, yield: 45%). 1H-NMR (400 MHz, CDCl3) δ 0.01 (s, 9H) 0.85-0.98 (m, 2H) 1.50 (s, 9H) 3.03 (s, 3H) 3.17 (br. s., 4H) 3.56-3.66 (m, 4H) 3.75-3.97 (m, 8H) 5.22 (s, 2H) 6.50 (s, 1H) 6.95 (s, 1H) 7.65 (s, 1H) 8.46 (s, 1H)

Workup

  1. custompurged with nitrogen
  2. additionToluene (1.0 ml) was added
  3. customnitrogen was bubbled for 5 min
  4. temperatureHeating
  5. temperaturecooled to room temperature
  6. filtrationThe reaction mixture was filtered through pad of Celite®
  7. customThe filtrate was evaporated
  8. customresulting material
  9. customwas purified by flash chromatography on silica eluting with 20% to 70% EtOAc/Hexane

Sources & evidence

ORD record
ord-71807351406746c08bb71e860684051c
Source dataset
uspto-grants-2016_09
Patent number
US09434697B2

Reaction notes

Loading…