N-methyl-2-pyrrolidone → 2-Ethyl-6-methylisonicotinic acid tert-butyl ester

HRID 2040766Notes

Reaction equation

HRID 2040766 reaction equation
[C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9](Cl)[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].CN1C(=O)C[CH2:19][CH2:18]1.C([Mg]Br)C>C1COCC1>[C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([CH2:18][CH3:19])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2]

Participants

5

Reactant 3

HCID 13387N-methyl-2-pyrrolidoneHCID 860403662-Chloro-6-methyl-isonicotinic acid tert-butyl esterHCID 178418443HCID 178418443, compound

Product 1

HCID 670269672-Ethyl-6-methylisonicotinic acid tert-butyl ester

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

To a red solution of 2-chloro-6-methyl-isonicotinic acid tert.-butyl ester (2.95 g, 13.0 mmol), Fe(acac)3 (512 mg, 1.45 mmol) and NMP (1.58 g, 16.0 mmol) in THF (400 mL), a solution of ethylmagnesium bromide (1.81 g, 13.6 mmol) in THF is slowly added at −77° C. The brown solution turns green-grey. The suspension is warmed to rt, stirred for 30 min before the yellow solution is again cooled to −70° C. and another portion of the Grignard reagent (1.38 g, 10.4 mmol) is added. The reaction mixture is warmed to rt, stirred for 16 h and then carefully quenched with 1 N aq. HCl (100 mL) and diluted with ether. The org. layer is separated and the aq. phase is extracted with ether. The combined org. extracts are dried over MgSO4, filtered and evaporated. The crude product is purified by MPLC on silica gel to give 2-ethyl-6-methyl-isonicotinic acid tert.-butyl ester as a yellow oil which is dissolved in 4 N HCl in dioxane (50 mL). The solution is stirred at 50° C. for 16 h before the solvent is evaporated to give 2-ethyl-6-methylisonicotinic acid hydrochloride as a beige powder; LC-MS: tR=0.28 min, [M+1]+=166.25; 1H NMR (CDCl3): δ 8.19 (s, 2H), 3.12 (q; J=7.6 Hz, 2H), 2.84 (s, 3H), 1.43 (t, J=7.6 Hz, 3H).

Workup

  1. temperatureis again cooled to −70° C.
  2. temperatureThe reaction mixture is warmed to rt
  3. stirringstirred for 16 h
  4. customcarefully quenched with 1 N aq. HCl (100 mL)
  5. additiondiluted with ether
  6. customlayer is separated
  7. extractionthe aq. phase is extracted with ether
  8. dry with materialextracts are dried over MgSO4
  9. filtrationfiltered
  10. customevaporated
  11. customThe crude product is purified by MPLC on silica gel

Sources & evidence

ORD record
ord-6197ea0be1b74e16bb394a21ced2a5f6
Source dataset
uspto-grants-2013_11
Patent number
US08580824B2

Reaction notes

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