Ethyl 2-aminopyridine-3-carboxylate → Ethyl 2-(3-Phenoxyphenylacetamido)nicotinate

HRID 2392724Notes

Reaction equation

HRID 2392724 reaction equation
[NH2:1][C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[O:13]([C:20]1[CH:21]=[C:22]([CH2:26][C:27](Cl)=[O:28])[CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>N1C=CC=CC=1>[O:13]([C:20]1[CH:21]=[C:22]([CH2:26][C:27]([NH:1][C:2]2[N:12]=[CH:11][CH:10]=[CH:9][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:28])[CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1

Participants

4

Reactant 2

HCID 12433260Ethyl 2-aminopyridine-3-carboxylateHCID 129401163-Phenoxyphenylacetyl chloride

Product 1

HCID 54186397Ethyl 2-(3-Phenoxyphenylacetamido)nicotinate

Reagents, catalysts & solvents 1

HCID 1049PyridineSolvent

Conditions

Temperature
130 °C

Procedure

Ethyl 2-aminonicotinate (121, Example 4) (367.3 mg, 2.238 mmol) was added to 3-phenoxyphenylacetyl chloride (1.0 g, 4.4 mmol) in a 10 mL round-bottom flask. A stir bar and pyridine (2.0 mL, distilled) were added and the mixture heated to reflux (130° C., oil bath) under nitrogen with stirring for 3 h, then cooled to room temperature. The reaction mixture was quenched with water (10 mL) and extracted with chloroform (3×15 mL). The combined organic extracts were washed with sat. NaHCO3 (3×10 mL) and water (3×10 mL), dried (MgSO4), and rota-evaporated to dryness, leaving a dark residue. This residue was chromatographed on silica gel (24 g, Mallinckrodt, grade 62; mesh 60-200) and eluted with hexanes-EtOAc (1:4, 300 mL). The desired fractions were collected (Rf =0.52) and rota-evaporated to dryness, leaving an orange oil. This oil eventually precipitated out as a wet orange mass. Crystallization from ethanol afforded the title compound as yellow flakes, 224 mg (26.5%), mp 90°-1° C.; 1H NMR (CDCl3): δ1.39 (t, J=6.8, 3, CH3CH2), 3.83 (s, 2, benzylic), 4.35 (q, J=6.8, 2, CH3CH2O), 7.10 (m, 9, phenyl), 8.29 (dd, J1 =1.5, J2 =7.8, 1, py), 8.59 (dd, J1 =1.5, J2 =4.8, 1, py), 10.81 (s, 1, NH); IR (KBr): 3441, 3168, 1723, 1668, 1660, 1549, 1490, 1436, 1409, 1307, 1246, 1211, 1143, 1027, 980, 775, 700; HPLC: 100%; LRMS: 377 (10), 376 (M+, 45), 211 (15), 210 (100), 183 (10), 167 (15), 166 (25), 147 (35), 121 (10), 94 (35), 89 (30), 77 (15), 51 (10), 39 (10); HRMS Calcd: 376.1423. Found: 376.1419.

Workup

  1. temperaturethe mixture heated
  2. temperaturecooled to room temperature
  3. customThe reaction mixture was quenched with water (10 mL)
  4. extractionextracted with chloroform (3×15 mL)
  5. washThe combined organic extracts were washed with sat. NaHCO3 (3×10 mL) and water (3×10 mL)
  6. dry with materialdried (MgSO4)
  7. customrota-evaporated to dryness
  8. customleaving a dark residue
  9. customThis residue was chromatographed on silica gel (24 g, Mallinckrodt, grade 62; mesh 60-200)
  10. washeluted with hexanes-EtOAc (1:4, 300 mL)
  11. customThe desired fractions were collected (Rf =0.52)
  12. customrota-evaporated to dryness
  13. customleaving an orange oil
  14. customThis oil eventually precipitated out as a wet orange mass
  15. customCrystallization from ethanol

Sources & evidence

ORD record
ord-2615e424fb344adf85ec95b6354101c1
Source dataset
uspto-grants-1998_09
Patent number
US05801183

Reaction notes

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