Triethylamine → 3-(3-(3-Fluoro-4-(pyridin-2-ylmethoxy)-benzyl)-isoxazol-5-yl)-pyridin-2,6-diamine

HRID 78151Notes

Reaction equation

HRID 78151 reaction equation
[F:1][C:2]1[CH:15]=[C:14]([CH2:16][CH2:17][N+:18]([O-:20])=O)[CH:13]=[CH:12][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1.C[O-].[Li+].C(=O)(O)[O-].[Na+].[C:29]([C:31]1[C:32]([NH2:38])=[N:33][C:34]([NH2:37])=[CH:35][CH:36]=1)#[CH:30].C(N(CC)CC)C>[Ti](Cl)(Cl)(Cl)Cl.O.O1CCCC1.C(OCC)(=O)C.CO>[F:1][C:2]1[CH:15]=[C:14]([CH:13]=[CH:12][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)[CH2:16][C:17]1[CH:30]=[C:29]([C:31]2[C:32]([NH2:38])=[N:33][C:34]([NH2:37])=[CH:35][CH:36]=2)[O:20][N:18]=1

Participants

11

Reactant 5

HCID 8471TriethylamineHCID 516892Sodium BicarbonateHCID 4177230Lithium methanolateHCID 552816763-Ethynylpyridine-2,6-diamineHCID 592550802-(2-Fluoro4-(2-nitro-ethyl)-phenoxymethyl)pyridine

Product 1

HCID 592550683-(3-(3-Fluoro-4-(pyridin-2-ylmethoxy)-benzyl)-isoxazol-5-yl)-pyridin-2,6-diamineYield 39.7%

Reagents, catalysts & solvents 5

HCID 24193Titanium TetrachlorideCatalystHCID 887MethanolSolventHCID 962WaterSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a methanol (20.0 mL) solution of 2-(2-fluoro-4-(2-nitro-ethyl)-phenoxymethyl)-pyridine (500 mg, 1.81 mmol) described in Manufacturing Example 87-1-3 was added lithium methoxide (137 mg, 3.61 mmol) under nitrogen atmosphere, which was stirred for 30 minutes at room temperature. The reaction mixture was concentrated under a reduced pressure, and dichloromethane (15.0 mL) and anhydrous tetrahydrofuran (7.00 mL) were added to the residue. Titanium (IV) chloride (656 μL, 5.97 mmol) was added dropwise to the reaction mixture on a dry ice-ethanol bath (−78° C.), and which was stirred for 30 minutes at room temperature. Aqueous sodium bicarbonate and ethyl acetate were added to the reaction mixture on an ice bath (0° C.), which was filtered through a Celite pad. The organic layer of the filtrate was extracted with ethyl acetate, and this organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain a crude product (300 mg). To a tetrahydrofuran (5.00 mL) solution of this crude product (150 mg) and 3-ethynyl-pyridin-2,6-diamine (30.0 mg, 0.225 mmol) described in Manufacturing Example 13-1-3 was added triethylamine (94.1 μL, 0.675 mmol) at room temperature, which was stirred for 1 hour at room temperature. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane=2:1→10:1) to obtain the title compound (35.0 mg, 39.7%).

Workup

  1. concentrationThe reaction mixture was concentrated under a reduced pressure, and dichloromethane (15.0 mL) and anhydrous tetrahydrofuran (7.00 mL)
  2. additionwere added to the residue
  3. stirringwas stirred for 30 minutes at room temperature
  4. filtrationwas filtered through a Celite pad
  5. extractionThe organic layer of the filtrate was extracted with ethyl acetate
  6. washthis organic layer was washed with water and saturated aqueous sodium chloride
  7. dry with materialdried over anhydrous magnesium sulfate
  8. filtrationfiltered
  9. concentrationThe filtrate was concentrated under a reduced pressure
  10. customto obtain a crude product (300 mg)
  11. stirringwhich was stirred for 1 hour at room temperature
  12. extractionwas extracted with ethyl acetate
  13. washThe organic layer was washed with saturated aqueous sodium chloride
  14. dry with materialdried over anhydrous magnesium sulfate
  15. customthe solvent was evaporated under a reduced pressure
  16. customThe residue was purified by NH silica gel column chromatography (ethyl acetate: heptane=2:1→10:1)

Sources & evidence

ORD record
ord-efb2bca7269e44a0b5f713b91bb8a0d1
Source dataset
uspto-grants-2014_09
Patent number
US08841327B2

Reaction notes

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