Dichloromethane → Ethyl 3-{[3-(ethyloxy)-3-oxopropanoyl][2-(2-oxo-1-pyrrolidinyl)ethyl]amino}-5-[(4-fluorophenyl)methyl]-2-pyridinecarboxylate

HRID 2364428Notes

Reaction equation

HRID 2364428 reaction equation
[F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][C:7]2[CH:8]=[C:9]([NH:18][CH2:19][CH2:20][N:21]3[CH2:25][CH2:24][CH2:23][C:22]3=[O:26])[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:11][CH:12]=2)=[CH:4][CH:3]=1.C([CH:31]([C:35](Cl)=[O:36])[C:32](Cl)=[O:33])C.[C:38]([O-:41])(O)=O.[Na+].[CH2:43](Cl)Cl>>[CH2:38]([O:41][C:35](=[O:36])[CH2:31][C:32]([N:18]([CH2:19][CH2:20][N:21]1[CH2:25][CH2:24][CH2:23][C:22]1=[O:26])[C:9]1[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:11][CH:12]=[C:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:28][CH:27]=2)[CH:8]=1)=[O:33])[CH3:43]

Participants

5

Reactant 4

HCID 6344DichloromethaneHCID 516892Sodium BicarbonateHCID 109209242-Ethylpropanedioyl dichloride2×HCID 58882948Ethyl 5-(4-fluorobenzyl)-3-{[2-(2-oxopyrrolidin-1-yl)ethyl]amino}pyridine-2-carboxylate

Product 1

HCID 69482032Ethyl 3-{[3-(ethyloxy)-3-oxopropanoyl][2-(2-oxo-1-pyrrolidinyl)ethyl]amino}-5-[(4-fluorophenyl)methyl]-2-pyridinecarboxylate

Procedure

A solution of ethyl 5-(4-fluorobenzyl)-3-{[2-(2-oxopyrrolidin-1-yl)ethyl]amino}pyridine-2-carboxylate (2.445 g, 6.34 mmol) and ethyl malonyl chloride (1.25 mL, 9.5 mmol) was heated under nitrogen at reflux for 1 hour. Additional ethyl malonyl chloride (0.25 mL, 1.9 mmol) was added and the reaction was maintained for another hour at reflux. The reaction mixture was cooled, diluted with CH2Cl2, and treat with saturated aqueous NaHCO3. After phase separation, the aqueous phase was extracted twice with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, evaporated in vacuo and purified on silica gel eluting with 3% MeOH in CH2Cl2 to provide an oil: 1H NMR (CDCl3) δ 8.57 (1H, d, J=2 Hz), 8.23 (1H, d, J=2 Hz), 7.23 (2H, dd, J=6, 8 Hz), 7.00 (2H, t, J=8 Hz), 4.66-4.76 (1H, m), 4.41 (2H, q, J=7 Hz), 3.98-4.08 (4H, m), 3.80-3.90 (2H, m), 3.24-3.31 (1H, m), 3.02 (2H, dd, J=16, 32 Hz), 2.86-2.96 (2H, m), 2.30-2.48 (2H, m), 1.92-2.11 (2H, m), 1.38 (3H, t, J=7 Hz), 1.17 (3H, t, J=Hz); ES+ MS: 500 (M+H+).

Workup

  1. temperatureat reflux for 1 hour
  2. temperaturethe reaction was maintained for another hour
  3. temperatureat reflux
  4. temperatureThe reaction mixture was cooled
  5. customAfter phase separation
  6. extractionthe aqueous phase was extracted twice with CH2Cl2
  7. dry with materialThe combined organic layers were dried over MgSO4
  8. filtrationfiltered
  9. customevaporated in vacuo
  10. custompurified on silica gel eluting with 3% MeOH in CH2Cl2
  11. customto provide an oil

Sources & evidence

ORD record
ord-53fe8bab4161409bad43727c9125a4ae
Source dataset
uspto-grants-2014_04
Patent number
US08691991B2

Reaction notes

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