p-Toluenesulfonic acid → Isopropyl 2-(3-((5-(3-fluorophenyl)-2,3-dihydrobenzofuran-3-yl)amino)phenoxy)acetate

HRID 1051115Notes

Reaction equation

HRID 1051115 reaction equation
C1(C)C=CC(S(O)(=O)=O)=CC=1.[F:12][C:13]1[CH:14]=[C:15]([C:19]2[CH:20]=[CH:21][C:22]3[O:26][CH2:25][C:24](=O)[C:23]=3[CH:28]=2)[CH:16]=[CH:17][CH:18]=1.[NH2:29][C:30]1[CH:31]=[C:32]([CH:41]=[CH:42][CH:43]=1)[O:33][CH2:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36].C([BH3-])#N.[Na+]>CO>[F:12][C:13]1[CH:14]=[C:15]([C:19]2[CH:20]=[CH:21][C:22]3[O:26][CH2:25][CH:24]([NH:29][C:30]4[CH:31]=[C:32]([CH:41]=[CH:42][CH:43]=4)[O:33][CH2:34][C:35]([O:37][CH:38]([CH3:39])[CH3:40])=[O:36])[C:23]=3[CH:28]=2)[CH:16]=[CH:17][CH:18]=1

Participants

6

Reactant 4

HCID 6101p-Toluenesulfonic acidHCID 5003444Sodium cyanoborohydrideHCID 10608474Isopropyl 2-(3-aminophenoxy)acetateHCID 1181615575-(3-fluorophenyl)benzofuran-3(2H)-one

Product 1

HCID 118161554Isopropyl 2-(3-((5-(3-fluorophenyl)-2,3-dihydrobenzofuran-3-yl)amino)phenoxy)acetateYield 6%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Conditions

Temperature
80 °C

Procedure

Para-toluenesulfonic acid (76 mg, 0.43 mmol) was added to a solution of 5-(3-fluorophenyl)benzofuran-3(2H)-one (212 mg, 0.935 mmol) and isopropyl 2-(3-aminophenoxyl)acetate (202 mg, 0.964 mmol) in methanol (4 mL) at 25° C. The reaction was heated in an 80° C. oil bath and allowed to stir overnight for approximately 16 hours. The reaction was cooled to room temperature and concentrated in vacuo. The mixture was then dissolved in concentrated acetic acid (2 mL) and cooled to 0° C. Sodium cyanoborohydride (386 mg, 6.13 mmol) was added and the solution was stirred for 4 hours at room temperature. The reaction was quenched with saturated aqueous NaHCO3 (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The resulting crude residue was purified by combiflash (12 g column, hexanes→100% ethyl acetate/hexanes, gradient) to afford 22 mg (6%) of isopropyl 2-(3-((5-(3-fluorophenyl)-2,3-dihydrobenzofuran-3-yl)amino)phenoxy)acetate.

Workup

  1. temperatureThe reaction was cooled to room temperature
  2. concentrationconcentrated in vacuo
  3. dissolutionThe mixture was then dissolved in concentrated acetic acid (2 mL)
  4. temperaturecooled to 0° C
  5. stirringthe solution was stirred for 4 hours at room temperature
  6. customThe reaction was quenched with saturated aqueous NaHCO3 (50 mL)
  7. extractionextracted with ethyl acetate (3×50 mL)
  8. dry with materialThe combined organic extracts were dried (Na2SO4)
  9. filtrationfiltered
  10. concentrationconcentrated
  11. customThe resulting crude residue was purified by combiflash (12 g column, hexanes→100% ethyl acetate/hexanes, gradient)

Sources & evidence

ORD record
ord-cdac0c7090c04d0e9d6b2e5064ed3c23
Source dataset
uspto-grants-2016_07
Patent number
US09388153B2

Reaction notes

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