Triethylamine → HCID 59255279, compound

HRID 78131Notes

Reaction equation

HRID 78131 reaction equation
[N+:1]([CH2:4][CH2:5][C:6]1[CH:18]=[CH:17][C:9]([O:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:8][CH:7]=1)([O-:3])=O.C[O-].[Li+].C(=O)(O)[O-].[Na+].[C:27]([C:29]1[C:30]([NH2:36])=[N:31][C:32]([NH2:35])=[CH:33][CH:34]=1)#[CH:28].C(N(CC)CC)C>[Ti](Cl)(Cl)(Cl)Cl.O.O1CCCC1.C(OCC)(=O)C.CO>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([O:10][C:9]2[CH:17]=[CH:18][C:6]([CH2:5][C:4]3[CH:28]=[C:27]([C:29]4[C:30]([NH2:36])=[N:31][C:32]([NH2:35])=[CH:33][CH:34]=4)[O:3][N:1]=3)=[CH:7][CH:8]=2)[CH:12]=1

Participants

11

Reactant 5

HCID 8471TriethylamineHCID 516892Sodium BicarbonateHCID 4177230Lithium methanolateHCID 552816763-Ethynylpyridine-2,6-diamineHCID 592552763-(4-(2-Nitro-ethyl)-phenoxy)-pyridine

Product 1

HCID 59255279HCID 59255279, compoundYield 15.8%

Reagents, catalysts & solvents 5

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

Procedure

To a methanol (10.0 mL) solution of 3-(4-(2-nitro-ethyl)-phenoxy)-pyridine (819 mg, 3.35 mmol) described in Manufacturing Example 76-1-3 was added lithium methoxide (254 mg, 6.70 mmol), which was stirred for 30 minutes at room temperature. The reaction mixture was concentrated under a reduced pressure, and anhydrous dichloromethane (15.0 mL) and anhydrous tetrahydrofuran (7.00 mL) were added to the residue. Titanium (IV) chloride (1.18 mL, 10.7 mmol) was added dropwise to the reaction mixture on a dry ice-ethanol bath (−78° C.), after which the system 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.), and the mixture 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 the filtrate was concentrated under a reduced pressure, which gave a crude product (400 mg). To a tetrahydrofuran (5.00 mL) solution of 3-ethynyl-pyridin-2,6-diamine (40.0 mg, 0.300 mmol) described in Manufacturing Example 13-1-3 and this crude product (150 mg) was added triethylamine (125 μL, 0.900 mmol), which was stirred for 3 hours at 60° C. Water was added to the reaction solution at room temperature, 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=3:1→5:1) to obtain the title compound (17.0 mg, 15.8%).

Workup

  1. concentrationThe reaction mixture was concentrated under a reduced pressure, and anhydrous dichloromethane (15.0 mL) and anhydrous tetrahydrofuran (7.00 mL)
  2. additionwere added to the residue
  3. stirringafter which the system was stirred for 30 minutes at room temperature
  4. filtrationthe mixture was 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. concentrationthe filtrate was concentrated under a reduced pressure, which
  9. customgave a crude product (400 mg)
  10. stirringwas stirred for 3 hours at 60° C
  11. extractionwhich was extracted with ethyl acetate
  12. washThe organic layer was washed with saturated aqueous sodium chloride
  13. dry with materialdried over anhydrous magnesium sulfate
  14. customthe solvent was evaporated under a reduced pressure
  15. customThe residue was purified by NH silica gel column chromatography (ethyl acetate: heptane=3:1→5:1)

Sources & evidence

ORD record
ord-9bc3b7d04da442c4b77a6745b9099c36
Source dataset
uspto-grants-2014_09
Patent number
US08841327B2

Reaction notes

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