Acetic Acid → 3-Ethynyl-6-methylpyridin-2-amine

HRID 1694133Notes

Reaction equation

HRID 1694133 reaction equation
[CH:1](NC(C)C)(C)C.C([Li])CCC.C[Si](C=[N+]=[N-])(C)C.[NH2:20][C:21]1[C:26]([CH:27]=O)=[CH:25][CH:24]=[C:23]([CH3:29])[N:22]=1.C(O)(=O)C>O.O1CCCC1>[C:27]([C:26]1[C:21]([NH2:20])=[N:22][C:23]([CH3:29])=[CH:24][CH:25]=1)#[CH:1]

Participants

8

Reactant 5

HCID 176Acetic AcidHCID 7912DiisopropylamineHCID 167693TrimethylsilyldiazomethaneHCID 534010302-Amino-6-methylnicotinaldehydeHCID 178418339Butyllithium

Product 1

HCID 552859393-Ethynyl-6-methylpyridin-2-amineYield 76.3%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

To a tetrahydrofuran (5 mL) solution of diisopropylamine (439 μL, 3.13 mmol) was added n-butyl lithium (1.81 mL, 1.6 M hexane solution, 2.89 mmol) under nitrogen atmosphere at −78° C., which was stirred for 15 minutes at 0° C. Then, trimethylsilyldiazomethane (1.81 mL, 2 M tetrahydrofuran solution, 3.62 mmol) was added to the reaction mixture at −78° C., which was stirred for 30 minutes at −78° C. To the reaction mixture was added a tetrahydrofuran (2 mL) solution of 2-amino-6-methyl-pyridine-3-carbaldehyde (328 mg, 2.41 mmol) described in Manufacturing Example 170-1-4 at −78° C., which was stirred for 25 minutes while the temperature was slowly raised to −30° C. Acetic acid (414 mL, 7.23 mmol) was added to the reaction mixture at −78° C., and the temperature was slowly raised, after which water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=2:1) to obtain the title compound (243 mg, 76%).

Workup

  1. stirringwhich was stirred for 30 minutes at −78° C
  2. customdescribed in Manufacturing Example 170-1-4 at −78° C.
  3. stirringwhich was stirred for 25 minutes while the temperature
  4. temperaturewas slowly raised to −30° C
  5. temperaturethe temperature was slowly raised
  6. extractionthe mixture was extracted with ethyl acetate
  7. washThe organic layer was washed with saturated aqueous sodium chloride
  8. dry with materialdried over anhydrous magnesium sulfate
  9. filtrationfiltered
  10. concentrationThe filtrate was concentrated under a reduced pressure
  11. customThe residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=2:1)

Sources & evidence

ORD record
ord-656e357d55924e808637dce7e7e033db
Source dataset
uspto-grants-2012_04
Patent number
US08158657B2

Reaction notes

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