Lithium diisopropylamide → 4-[1-(2-aminopyrimidin-4-yl)-2-(2-fluoroethoxy)-1H-1,3-benzodiazol-6-yl]-2-(pyrimidin-2-yl)but-3-yn-2-ol

HRID 1398690Notes

Reaction equation

HRID 1398690 reaction equation
[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([O:11][CH2:12][CH2:13][F:14])[N:8]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[N:16]=3)[C:7]=2[CH:22]=1)#[CH:2].C([N-]C(C)C)(C)C.[Li+].[N:31]1[CH:36]=[CH:35][CH:34]=[N:33][C:32]=1[C:37](=[O:39])[CH3:38]>O1CCCC1>[NH2:21][C:17]1[N:16]=[C:15]([N:8]2[C:7]3[CH:22]=[C:3]([C:1]#[C:2][C:37]([C:32]4[N:33]=[CH:34][CH:35]=[CH:36][N:31]=4)([OH:39])[CH3:38])[CH:4]=[CH:5][C:6]=3[N:10]=[C:9]2[O:11][CH2:12][CH2:13][F:14])[CH:20]=[CH:19][N:18]=1

Participants

5

Reactant 3

HCID 2724682Lithium diisopropylamideHCID 116079091-(Pyrimidin-2-yl)ethan-1-oneHCID 866696154-[6-ethynyl-2-(2-fluoroethoxy)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine

Product 1

HCID 866696164-[1-(2-aminopyrimidin-4-yl)-2-(2-fluoroethoxy)-1H-1,3-benzodiazol-6-yl]-2-(pyrimidin-2-yl)but-3-yn-2-olYield 9%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

To a solution of 4-[6-ethynyl-2-(2-fluoroethoxy)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine (30 mg, 0.10 mmol) in tetrahydrofuran (0.5 mL) under a nitrogen atmosphere at −78° C. was added a lithium diisopropylamide solution (0.3 mL, 3.00 equiv) dropwise with stirring. The reaction mixture was stirred at −78° C. for 15 min. A solution of 1-(pyrimidin-2-yl)ethan-1-one (48.8 mg, 0.40 mmol) in tetrahydrofuran (0.5 mL) was then added and the mixture was stirred at −78° C. for another 20 min. The resulting solution was then stirred at room temperature for 13 h. The reaction was then quenched by the addition of saturated ammonium chloride solution (1 mL) and the mixture was extracted with 10 mL of ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column (ethyl acetate/petroleum ether, 1:3) to give 3.7 mg (9%) of 4-[1-(2-aminopyrimidin-4-yl)-2-(2-fluoroethoxy)-1H-1,3-benzodiazol-6-yl]-2-(pyrimidin-2-yl)but-3-yn-2-ol as an off-white solid: 1H NMR (400 MHz, DMSO) delta 8.89 (d, J=4.8 Hz, 2H), 8.40 (d, J=5.6 Hz, 1H), 8.13 (d, J=1.2 Hz, 1H), 7.51-7.44 (m, 2H), 7.25-7.22 (m, 1H), 7.10 (s, 1H), 6.96 (d, J=5.2 Hz, 1H), 6.12 (s, 1H), 4.93-4.88 (m, 2H), 4.80 (s, 2H), 1.88 (s, 3H); LC-MS: m/z=+420 (M+H)+.

Workup

  1. stirringThe reaction mixture was stirred at −78° C. for 15 min
  2. stirringthe mixture was stirred at −78° C. for another 20 min
  3. stirringThe resulting solution was then stirred at room temperature for 13 h
  4. customThe reaction was then quenched by the addition of saturated ammonium chloride solution (1 mL)
  5. extractionthe mixture was extracted with 10 mL of ethyl acetate
  6. dry with materialThe organic layer was dried over anhydrous sodium sulfate
  7. concentrationconcentrated under vacuum
  8. customThe residue was purified on a silica gel column (ethyl acetate/petroleum ether, 1:3)

Sources & evidence

ORD record
ord-70b08550ee0c4a728c5bdb56b00e350c
Source dataset
uspto-grants-2014_12
Patent number
US08901313B2

Reaction notes

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