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

HRID 1047453Notes

Reaction equation

HRID 1047453 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+].Cl[C:17]1[CH:22]=[CH:21][N:20]=[C:19]2[CH:23]=[C:24]([C:26]3[N:31]=[CH:30][C:29]([CH2:32][N:33]([CH2:41][CH2:42][O:43][CH3:44])[C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:28][CH:27]=3)[S:25][C:18]=12.O>CS(C)=O.NC1C=CC(O)=C(F)C=1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:17]2[CH:22]=[CH:21][N:20]=[C:19]3[CH:23]=[C:24]([C:26]4[N:31]=[CH:30][C:29]([CH2:32][N:33]([CH2:41][CH2:42][O:43][CH3:44])[C:34](=[O:40])[O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[CH:28][CH:27]=4)[S:25][C:18]=23)=[C:4]([F:9])[CH:3]=1

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-79e0f9e5bb6148ad92650ef7dbb9ba17
Source dataset
uspto-grants-2013_10
Patent number
US08569503B2

Reaction notes

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