Sodium hydride → (S)-2-[3-(3,4-Dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxine-6-carbonitrile

HRID 391821Notes

Reaction equation

HRID 391821 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:5][O:6][C:7]1[CH:8]=[C:9]([C@H:13]([OH:25])[CH2:14][O:15][C:16]2[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=2F)[C:19]#[N:20])[CH:10]=[CH:11][CH:12]=1.[H-].[Na+]>CN1C(=O)CCC1.COCCOCCOC>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:5][O:6][C:7]1[CH:8]=[C:9]([C@@H:13]2[O:25][C:23]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][C:16]=3[O:15][CH2:14]2)[CH:10]=[CH:11][CH:12]=1

Participants

4

Reactant 2

HCID 24758Sodium hydrideHCID 583271373-{(S)-2-[3-(3,4-Dichloro-benzyloxy)-phenyl]-2-hydroxy-ethoxy}-4-fluoro-benzonitrile

Product 1

HCID 58327422(S)-2-[3-(3,4-Dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxine-6-carbonitrile

Reagents, catalysts & solvents 1

HCID 67898654NMP diglymeSolvent2×

Conditions

Temperature
150 °C

Procedure

3-{(S)-2-[3-(3,4-Dichloro-benzyloxy)-phenyl]-2-hydroxy-ethoxy}-4-fluoro-benzonitrile (13.0 g) was dissolved in 130 mL of anhydrous NMP:diglyme (1:9) solution under nitrogen and heated to 150° C. A suspension of sodium hydride (1.2 g of 60% NaH in mineral oil) in 26 mL of anhydrous NMP:diglyme (1:9) was added all at once via cannula while stirring. After 15 minutes, the reaction was removed from heating, cooled 5 minutes, and then poured into a mixture of ice, 0.5 L EtOAc, and 0.25 L 1 N HCl. The layers were separated and the organic layer was washed with water and brine, and dried over Na2SO4. The residue was purified by silica gel flash chromatography (DCM to 1:1 DCM/EtOAc) to provide 8.2 g of partially purified solid which was then purified by silica gel column (1:1 DCM:hex to DCM). 1H NMR (400 MHz, CDCl3): 7.54 (d, 1H), 7.46 (d, 1H), 7.36 (t, 1H), 7.18-7.28 (m, 3H), 6.95-7.06 (m, 4H) 5.16 (m, 1H), 5.04 (s, 2H), 4.42 (m, 1H), 4.02 (m, 1H).

Workup

  1. additionwas added all at once via cannula
  2. customthe reaction was removed
  3. temperaturefrom heating
  4. temperaturecooled 5 minutes
  5. additionpoured into a mixture of ice, 0.5 L EtOAc, and 0.25 L 1 N HCl
  6. customThe layers were separated
  7. washthe organic layer was washed with water and brine
  8. dry with materialdried over Na2SO4
  9. customThe residue was purified by silica gel flash chromatography (DCM to 1:1 DCM/EtOAc)
  10. customto provide 8.2 g of partially purified solid which
  11. customwas then purified by silica gel column (1:1 DCM:hex to DCM)

Sources & evidence

ORD record
ord-1890b3e02a7d45c980d1a6866250cfc6
Source dataset
uspto-grants-2013_02
Patent number
US08383644B2

Reaction notes

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