Diphosgene → Tert-butyl (6-(7-(2-fluoro-4-(3-phenyl-2-thioxoimidazolidine-1-carboxamido)phenoxy)thieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl(2-methoxyethyl)carbamate

HRID 84397Notes

Reaction equation

HRID 84397 reaction equation
O=C(Cl)[O:3][C:4](Cl)(Cl)Cl.[NH2:9][C:10]1[CH:44]=[CH:43][C:13]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[CH:21]=[C:22]([C:24]4[N:29]=[CH:28][C:27]([CH2:30][N:31]([CH2:39][CH2:40][O:41][CH3:42])[C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:26][CH:25]=4)[S:23][C:16]=23)=[C:12]([F:45])[CH:11]=1.[C:46]1([N:52]2[CH2:56][CH2:55][NH:54][C:53]2=[S:57])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.[H-].[Na+]>C1COCC1.CCOC(C)=O>[F:45][C:12]1[CH:11]=[C:10]([NH:9][C:4]([N:54]2[CH2:55][CH2:56][N:52]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:53]2=[S:57])=[O:3])[CH:44]=[CH:43][C:13]=1[O:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]2[CH:21]=[C:22]([C:24]3[N:29]=[CH:28][C:27]([CH2:30][N:31]([CH2:39][CH2:40][O:41][CH3:42])[C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:26][CH:25]=3)[S:23][C:16]=12

Participants

7

Reactant 4

HCID 10426DiphosgeneHCID 24758Sodium hydrideHCID 122691081-Phenylimidazolidine-2-thioneHCID 579194724-[[2-[5-[[Boc(2-methoxyethyl)amino]methyl]-2-pyridyl]-7-thieno[3,2-b]pyridyl]oxy]-3-fluoroaniline

Product 1

HCID 57919539Tert-butyl (6-(7-(2-fluoro-4-(3-phenyl-2-thioxoimidazolidine-1-carboxamido)phenoxy)thieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl(2-methoxyethyl)carbamateYield 48.7%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Procedure

Diphosgene (0.023 ml, 0.191 mmol) was added in one portion to a solution of 126 (schemes 6 or 9) (0.200 g, 0.381 mmol) in THF (3.81 ml) and the reaction mixture stirred vigorously for 2 h. 1-Phenylimidazolidine-2-thione (301, 0.102 g, 0.572 mmol) and sodium hydride (60% in mineral oil) (0.046 g, 1.143 mmol) were added sequentially and the mixture was stirred at room temperature for an additional 1 h. The crude mixture was then suspended in EtOAc, washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Luna C18 (2), 5.0 cm ID; gradient: 80% MeOH to 95% MeOH in water, 60 min) affording title compound 302 (0.068 g, 0.093 mmol, 24.5% yield) as creamy solid. m/z: (M+1)+ 729.4 (100%).

Workup

  1. stirringthe mixture was stirred at room temperature for an additional 1 h
  2. washwashed with water
  3. dry with materialdried over anhydrous sodium sulfate
  4. concentrationconcentrated under reduced pressure
  5. customThe residue was purified by preparative HPLC (column: Luna C18 (2), 5.0 cm ID; gradient: 80% MeOH to 95% MeOH in water, 60 min)

Sources & evidence

ORD record
ord-b3cd6e8e696b4ca1b2c46764c82bc879
Source dataset
uspto-grants-2014_09
Patent number
US08846927B2

Reaction notes

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