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

HRID 391837Notes

Reaction equation

HRID 391837 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:12]=[CH:11][C:10]([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:9][CH:8]=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:12]=[CH:11][C:10]([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:9][CH:8]=1

Participants

4

Reactant 2

HCID 24758Sodium hydrideHCID 583270913-{(R)-2-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2-hydroxy-ethoxy}-4-fluoro-benzonitrile

Product 1

HCID 58327239(R)-2-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxine-6-carbonitrileYield 53.5%

Reagents, catalysts & solvents 1

HCID 67898654NMP diglymeSolvent2×

Conditions

Temperature
150 °C

Procedure

3-{(R)-2-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2-hydroxy-ethoxy}-4-fluoro-benzonitrile (10.2 g) was dissolved in 108 mL NMP-diglyme (1:9) under nitrogen and heated to 150° C. internal temperature. A suspension of sodium hydride (1130 mg of 60% NaH in mineral oil) in 10 mL NMP-diglyme (1:9) was added all at once via syringe while stirring. After 2 minutes, the reaction was removed from heating and cooled, then poured onto saturated ammonium chloride and EtOAc. The layers were separated and the organic layer washed 3 times with 1 N HCl and dried over Na2SO4. The residue was purified by silica gel flash chromatography (DCM-hexanes 1:1 to DCM). The residue was crystallized from refluxing MeOH/DCM (about 3:1), to give 5.2 g of desired product. 1H NMR (400 MHz, CDCl3): 7.53 (d, 1H), 7.45 (d, 1H), 7.34 (m, 2H), 7.27-7.24 (m, 1H), 7.22 (d, 1H) 7.18 (m, 1H), 7.0 (m, 3H), 5.12 (m, 1H), 5.04 (s, 2H), 4.37 (m, 1H), 4.03 (m, 1H).

Workup

  1. additionwas added all at once via syringe
  2. customthe reaction was removed
  3. temperaturefrom heating
  4. temperaturecooled
  5. additionpoured onto saturated ammonium chloride and EtOAc
  6. customThe layers were separated
  7. washthe organic layer washed 3 times with 1 N HCl
  8. dry with materialdried over Na2SO4
  9. customThe residue was purified by silica gel flash chromatography (DCM-hexanes 1:1 to DCM)
  10. customThe residue was crystallized
  11. temperaturefrom refluxing MeOH/DCM (about 3:1)

Sources & evidence

ORD record
ord-7ad222d3ddda43c19a63a3c9940a4622
Source dataset
uspto-grants-2013_02
Patent number
US08383644B2

Reaction notes

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