Acetic Acid → 1-(6-(3,3-Difluoroazetidin-1-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine

HRID 75309Notes

Reaction equation

HRID 75309 reaction equation
[F:1][C:2]1([F:18])[CH2:5][N:4]([C:6]2[CH:7]=[C:8]3[N:16]([CH3:17])[CH:15]=[CH:14][C:9]3=[N:10][C:11]=2[C:12]#[N:13])[CH2:3]1.[CH3:19][Mg]Cl.[BH4-].[Na+].C(O)(=O)C>C1(C)C=CC=CC=1.CO.C1COCC1>[F:18][C:2]1([F:1])[CH2:5][N:4]([C:6]2[CH:7]=[C:8]3[N:16]([CH3:17])[CH:15]=[CH:14][C:9]3=[N:10][C:11]=2[CH:12]([NH2:13])[CH3:19])[CH2:3]1

Participants

8

Reactant 4

HCID 176Acetic AcidHCID 4311764Sodium borohydrideHCID 867080076-(3,3-Difluoroazetidin-1-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridine-5-carbonitrileHCID 178418332HCID 178418332, compound2×

Product 1

HCID 867080081-(6-(3,3-Difluoroazetidin-1-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 1140TolueneSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

To a slurry of 6-(3,3-difluoroazetidin-1-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridine-5-carbonitrile (130 mg, 0.524 mmol) in toluene (3.0 mL) at −30° C. was added dropwise methylmagnesium chloride (0.262 mL, 0.786 mmol). The mixture was moved to an ice bath at 0° C. and stirred for 2 hours. The reaction mixture had lots of solid and was about 50% complete by LC/MS. THF (1 mL) was added at 0° C. followed by more methylmagnesium chloride (0.262 mL, 0.786 mmol) and the solution was allowed to sit in a refrigerator at −10° C. for 16 hours. The solution was subsequently warmed to 0° C. and the reaction was quenched with anhydrous methanol (1 mL). A solid formed which dissolved upon stirring. The mixture was added to a solution of sodium borohydride (99 mg, 2.62 mmol) in methanol (5 mL) at 0° C. The resulting mixture was stirred for 30 minutes at 0° C. Excess sodium borohydride was consumed by adding acetic acid (0.300 mL, 5.24 mmol). The solution was allowed to warm to 20° C. and was concentrated in vacuo. The concentrate was taken up in EtOAc (50 mL), washed with saturated aqueous sodium bicarbonate, dried over MgSO4, and concentrated in vacuo to give the title compound, which was used without further purification (84 mg, 60%). ESI-MS m/z [M+H]+ calc'd for C13H16F2N4, 267; found 267.

Workup

  1. customThe mixture was moved to an ice bath at 0° C.
  2. waitto sit in a refrigerator at −10° C. for 16 hours
  3. customthe reaction was quenched with anhydrous methanol (1 mL)
  4. customA solid formed which
  5. dissolutiondissolved
  6. stirringupon stirring
  7. stirringThe resulting mixture was stirred for 30 minutes at 0° C
  8. customExcess sodium borohydride was consumed
  9. temperatureto warm to 20° C.
  10. concentrationwas concentrated in vacuo
  11. washwashed with saturated aqueous sodium bicarbonate
  12. dry with materialdried over MgSO4
  13. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-a3c67bd1efe64827963c965670d5231b
Source dataset
uspto-grants-2014_09
Patent number
US08835420B2

Reaction notes

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