Ammonium Chloride → HCID 178441114, compound

HRID 2042004Notes

Reaction equation

HRID 2042004 reaction equation
[C:1]([C:5]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:6]=1[O:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:18])[CH2:15][C:16]#[N:17])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+].[N-:26]=[N+:27]=[N-:28].[Na+]>CN(C=O)C>[C:1]([C:5]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:6]=1[O:7][CH:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:18])[CH2:15][C:16]2[NH:28][N:27]=[N:26][N:17]=2)[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]

Participants

5

Reactant 3

HCID 25517Ammonium ChlorideHCID 33557Sodium AzideHCID 59577307HCID 59577307, compound

Product 1

HCID 178441114HCID 178441114, compoundYield 15.2%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

3-[4-(2-tert-Butyl-4-fluorophenoxy)piperidin-1-yl]-3-oxopropanenitrile (400 mg, 1.26 mmol) obtained in Example 237, ammonium chloride (101 mg, 1.89 mmol) and sodium azide (123 mg, 1.89 mmol) were stirred in DMF (15 mL) at 120° C. for 16 hr. The reaction mixture was cooled to room temperature, and partitioned between ethyl acetate and water. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate 40:60-0:100) and by preparative HPLC (device: Gilson Inc., High Throughput Purification system; column: YMC Combiprep ODS-A, S-5 μm, 50×20 mm; solvent: SOLUTION A; 0.1% trifluoroacetic acid-containing water, SOLUTION B; 0.1% trifluoroacetic acid-containing acetonitrile; gradient cycle: 0.00 min (SOLUTION A/SOLUTION B=90/10), 1.00 min (SOLUTION A/SOLUTION B=90/10), 4.20 min (SOLUTION A/SOLUTION B=10/90), 5.40 min (SOLUTION A/SOLUTION B=10/90), 5.50 min (SOLUTION A/SOLUTION B=90/10), 5.60 min (SOLUTION A/SOLUTION B=90/10); flow rate: 25 mL/min; detection method: UV 220 nm) to give the title compound (69 mg, 15%).

Workup

  1. custompartitioned between ethyl acetate and water
  2. washThe ethyl acetate layer was washed with saturated brine
  3. dry with materialdried over anhydrous magnesium sulfate
  4. filtrationfiltered
  5. concentrationThe filtrate was concentrated under reduced pressure
  6. customthe obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate 40:60-0:100) and by preparative HPLC (device: Gilson Inc., High Throughput Purification system; column: YMC Combiprep ODS-A, S-5 μm, 50×20 mm; solvent: SOLUTION A; 0.1% trifluoroacetic acid-containing water, SOLUTION B; 0.1% trifluoroacetic acid-containing acetonitrile; gradient cycle: 0.00 min (SOLUTION A/SOLUTION B=90/10), 1.00 min (SOLUTION A/SOLUTION B=90/10), 4.20 min (SOLUTION A/SOLUTION B=10/90), 5.40 min (SOLUTION A/SOLUTION B=10/90), 5.50 min (SOLUTION A/SOLUTION B=90/10), 5.60 min (SOLUTION A/SOLUTION B=90/10); flow rate: 25 mL/min; detection method: UV 220 nm)

Sources & evidence

ORD record
ord-f39acd8db4b94cd0ac71ce9e1d984467
Source dataset
uspto-grants-2013_11
Patent number
US08586571B2

Reaction notes

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