Ethanol → 2-(2-(O-tolylamino)benzo[d]oxazol-6-yl)acetic acid

HRID 49701Notes

Reaction equation

HRID 49701 reaction equation
C[C:2]1[C:7]2[N:8]=C(NC3C=CC=CC=3C)[O:10][C:6]=2[CH:5]=[C:4]([CH2:19][C:20](NC2C=CC(C(C)CC(O)=O)=NC=2)=[O:21])[CH:3]=1.[C:35]1([CH3:44])[C:36]([N:41]=[C:42]=S)=[CH:37][CH:38]=[CH:39][CH:40]=1.C1(N=C=NC2CCCCC2)CCCCC1.C([OH:62])C>>[C:35]1([CH3:44])[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[NH:41][C:42]1[O:10][C:6]2[CH:5]=[C:4]([CH2:19][C:20]([OH:21])=[O:62])[CH:3]=[CH:2][C:7]=2[N:8]=1

Participants

5

Reactant 4

HCID 702Ethanol2×HCID 10868DicyclohexylcarbodiimideHCID 691952-Methylphenyl isothiocyanateHCID 9955805(3RS)-3-{5-[2-(4-Methyl-2-o-tolylamino-benzoxazol-6-yl)acetylamino]pyrid-2-yl}butyric acid

Product 1

HCID 235083152-(2-(O-tolylamino)benzo[d]oxazol-6-yl)acetic acid

Procedure

A mixture of ethyl 4-amino-3-hydroxy-phenylacetate (3.3 g, Reference Example 3) and o-tolylisothiocyanate (2.5 mL) in ethanol (150 mL) was stirred at room temperature for about 2 hours. After standing at room temperature overnight the mixture was evaporated and the residue was subjected to flash chromatography on silica eluting with a mixture of pentane and ethyl acetate (7:3, v/v) to give a yellow foam. A solution of this material in ethanol (150 mL) was treated with dicyclohexylcarbodiimide (3.0 g) and the mixture was heated at reflux temperature for 2 hours. The mixture was evaporated and the residue subjected to short column chromatography on silica eluting with a mixture of 5-10% tert-butyl methyl ether in dichloromethane to remove dicyclohexylurea. The resulting light yellow oil was dissolved in ethanol (100 mL) and the solution was treated with sodium hydroxide solution (15 mL, 1M) then heated at reflux temperature for 2 hours. The reaction mixture was evaporated and the residue was dissolved in water. The solution was washed with ethyl acetate and the aqueous layer was acidified to pH 1 by addition of concentrated hydrochloric acid. The resulting white precipitate was collected by filtration, then washed thoroughly with water, and then dried to give the title compound (1.8 g) as a white solid.

Workup

  1. waitAfter standing at room temperature overnight
  2. customthe mixture was evaporated
  3. additionthe residue was subjected to flash chromatography on silica eluting with a mixture of pentane and ethyl acetate (7:3
  4. customv/v) to give a yellow foam
  5. temperaturethe mixture was heated
  6. temperatureat reflux temperature for 2 hours
  7. customThe mixture was evaporated
  8. additionthe residue subjected to short column chromatography on silica eluting with a mixture of 5-10% tert-butyl methyl ether in dichloromethane
  9. customto remove dicyclohexylurea
  10. dissolutionThe resulting light yellow oil was dissolved in ethanol (100 mL)
  11. additionthe solution was treated with sodium hydroxide solution (15 mL, 1M)
  12. temperaturethen heated
  13. temperatureat reflux temperature for 2 hours
  14. customThe reaction mixture was evaporated
  15. dissolutionthe residue was dissolved in water
  16. washThe solution was washed with ethyl acetate
  17. additionthe aqueous layer was acidified to pH 1 by addition of concentrated hydrochloric acid
  18. filtrationThe resulting white precipitate was collected by filtration
  19. washwashed thoroughly with water
  20. customdried

Sources & evidence

ORD record
ord-77ad59374b41438bb0b895c7dd2b255d
Source dataset
uspto-grants-2004_03
Patent number
US06706738B2

Reaction notes

Loading…