N-methyl-2-pyrrolidone → HCID 66935546, compound

HRID 1908790Notes

Reaction equation

HRID 1908790 reaction equation
[CH:1]([O:4][C:5](=[O:17])[C:6]1[CH:11]=[C:10](Cl)[C:9]([N:13]([CH2:15][CH3:16])[CH3:14])=[N:8][CH:7]=1)([CH3:3])[CH3:2].[CH3:18]N1C(=O)CCC1.C[Mg]Br>C1COCC1.CC(=O)OCC>[CH:1]([O:4][C:5](=[O:17])[C:6]1[CH:11]=[C:10]([CH3:18])[C:9]([N:13]([CH2:15][CH3:16])[CH3:14])=[N:8][CH:7]=1)([CH3:3])[CH3:2]

Participants

6

Reactant 3

HCID 13387N-methyl-2-pyrrolidone2×HCID 66935970HCID 66935970, compoundHCID 178418573HCID 178418573, compound3×

Product 1

HCID 66935546HCID 66935546, compoundYield 46.1%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Procedure

A solution of 5-chloro-6-(ethyl-methyl-amino)-nicotinic acid isopropyl ester (5.18 g, 20.1 mmol), NMP (3.0 g, 30.2 mmol) and Fe(acac)3 (498 mg, 1.41 mmol) in THF (150 mL) is put under argon before a methylmagnesium bromide (3.0 g, 25.2 mmol, solution in diethyl ether) is added dropwise. The dark red-brown solution turns yellow, then dark brown again. The mixture is stirred at rt for 2 h before another portion of methylmagnesium bromide (1.44 g, 12.1 mmol) is added. The dark mixture is stirred at rt for 16 h. Another portion of NMP (3.0 g, 30.2 mmol), Fe(acac)3 (498 mg, 1.41 mmol) and methylmagnesium bromide (1.44 g, 12.1 mmol) is added and stirring is continued at rt for one more hour. The reaction mixture is diluted with EA (200 mL) and carefully quenched with ice-water (100 mL). The suspension is basified by adding 1 N aq. NaOH solution (10 mL) and filtered over a small pad of Hyflo and silica gel. The org. phase of the filtrate is separated and collected and the aq. phase is extracted with DCM (3×100 mL). The org. extracts are combined, dried over MgSO4, filtered and concentrated. The crude product is purified by prep. MPLC on silica gel eluting with a gradient of EA in heptane to give 6-(ethyl-methyl-amino)-5-methyl-nicotinic acid isopropyl ester (2.19 g) as a beige oil; LC-MS: tR=0.76 min, [M+1]+=237.20.

Workup

  1. additionis added dropwise
  2. additionis added
  3. stirringstirring
  4. customis continued at rt for one more hour
  5. customcarefully quenched with ice-water (100 mL)
  6. additionby adding 1 N aq. NaOH solution (10 mL)
  7. filtrationfiltered over a small pad of Hyflo and silica gel
  8. customphase of the filtrate is separated
  9. customcollected
  10. extractionthe aq. phase is extracted with DCM (3×100 mL)
  11. dry with materialdried over MgSO4
  12. filtrationfiltered
  13. concentrationconcentrated
  14. customThe crude product is purified by prep

Sources & evidence

ORD record
ord-36b0c94cd72041c687ad2fdb95fbdb48
Source dataset
uspto-grants-2013_12
Patent number
US08598208B2

Reaction notes

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