Water → 4-[[2-[5-[[Boc(2-methoxyethyl)amino]methyl]-2-pyridyl]-7-thieno[3,2-b]pyridyl]oxy]-3-fluoroaniline

HRID 1475581Notes

Reaction equation

HRID 1475581 reaction equation
[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.CC(C)([O-])C.[K+].[C:16]([O:20][C:21](=[O:44])[N:22]([CH2:27][C:28]1[CH:29]=[N:30][C:31]([C:34]2[S:42][C:41]3[C:36](=[N:37][CH:38]=[CH:39][C:40]=3Cl)[CH:35]=2)=[CH:32][CH:33]=1)[CH2:23][CH2:24][O:25][CH3:26])([CH3:19])([CH3:18])[CH3:17].O>CS(C)=O.NC1C=CC(O)=C(F)C=1>[C:16]([O:20][C:21](=[O:44])[N:22]([CH2:27][C:28]1[CH:29]=[N:30][C:31]([C:34]2[S:42][C:41]3[C:36](=[N:37][CH:38]=[CH:39][C:40]=3[O:8][C:5]3[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][C:4]=3[F:9])[CH:35]=2)=[CH:32][CH:33]=1)[CH2:23][CH2:24][O:25][CH3:26])([CH3:19])([CH3:17])[CH3:18]

Participants

7

Reactant 4

HCID 962WaterHCID 2735918Phenol, 4-amino-2-fluoro-HCID 23665647Potassium tert-butoxide2×HCID 57919613tert-Butyl ((6-(7-chlorothieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl)(2-methoxyethyl)carbamate

Product 1

HCID 579194724-[[2-[5-[[Boc(2-methoxyethyl)amino]methyl]-2-pyridyl]-7-thieno[3,2-b]pyridyl]oxy]-3-fluoroanilineYield 90%

Reagents, catalysts & solvents 2

HCID 2735918Phenol, 4-amino-2-fluoro-CatalystHCID 679Dimethyl SulfoxideSolvent2×

Procedure

To a solution of 4-amino-2-fluorophenol (4, scheme 1) (14.29 g, 112 mmol 1.2 eq.) in DMSO (117 mL) was added potassium tert-butoxide (13.66 g, 122 mmol, 1.3 eq.) over 5 min. The reaction mixture was stirred at r.t. for 30 minutes. tert-Butyl(6-(7-chlorothieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl(2-methoxyethyl)carbamate (11) (40.65 g, 94 mmol, 1 eq) was added and the reaction mixture was heated at 100° C. for 1.5 h. Additional amounts of the phenol 4 (0.83 g, 6.53 mmol, 0.07 eq.) in DMSO (5 mL) and potassium tert-butoxide (1.05 g, 9.38 mmol, 0.1 eq.) were added to the reaction mixture which was heated at 100° C. for an additional 30 min. After cooling down to r.t., the reaction mixture was poured into water (900 mL) at 40° C. over 15 min. After stirring for 15 min at 40° C., the mixture was cooled to r.t. over 1 h. The solid was collected by filtration and the cake was washed with water (2×115 mL). The product was dried in vacuum for 16 h then triturated with MTBE (115 mL) for 1 h, collected by filtration and the cake was washed with MTBE (2×20 mL). The product was dried in a vacuum oven (45° C.) to afford title compound 13 as a beige solid (44.02 g, 84 mmol, 90% yield).

Workup

  1. temperaturethe reaction mixture was heated at 100° C. for 1.5 h
  2. temperaturewas heated at 100° C. for an additional 30 min
  3. temperatureAfter cooling down to r.t.
  4. stirringAfter stirring for 15 min at 40° C.
  5. temperaturethe mixture was cooled to r.t. over 1 h
  6. filtrationThe solid was collected by filtration
  7. washthe cake was washed with water (2×115 mL)
  8. customThe product was dried in vacuum for 16 h
  9. customthen triturated with MTBE (115 mL) for 1 h
  10. filtrationcollected by filtration
  11. washthe cake was washed with MTBE (2×20 mL)
  12. customThe product was dried in a vacuum oven (45° C.)

Sources & evidence

ORD record
ord-10ff58fc4cf44b8fa108571bee0fe8f9
Source dataset
uspto-grants-2015_04
Patent number
US09018378B2

Reaction notes

Loading…