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

HRID 879678Notes

Reaction equation

HRID 879678 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

5

Reactant 2

HCID 24758Sodium hydrideHCID 583274143-{(S)-2-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2-hydroxy-ethoxy}-4-fluoro-benzonitrile

Product 1

HCID 58327291(S)-2-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxine-6-carbonitrileYield 54.4%

Reagents, catalysts & solvents 2

HCID 8150DiglymeSolvent2×HCID 13387N-methyl-2-pyrrolidoneSolvent2×

Procedure

3-{(S)-2-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2-hydroxy-ethoxy}-4-fluoro-benzonitrile (28.9 g) was dissolved in 30 mL dry NMP and 270 mL dry diglyme under nitrogen and heated to 142° C. internal temperature. A suspension of sodium hydride (2.676 g of 60% NaH in mineral oil) in 6 mL of dry NMP and 54 mL of dry diglyme was added all at once via cannula while stirring. After 15 min the reaction was removed from heating and cooled 5 min, then poured into ice/1 L EtOAc/0.5 L 1 N HCl. The layers were separated and the organic layer washed twice with water, once with brine and dried over Na2SO4. The residue was purified by silica gel flash chromatography (DCM to 1:1 DCM/EtOAc) to provide 31 g of partially purified solid which was then crystallized from refluxing 3:1 MeOH/DCM, to give 15 g of desired product. 1H NMR (400 MHz, CDCl3): 7.54 (d, 1H), 7.46 (d, 1H), 7.33 (m, 2H), 7.28-7.24 (m, 1H), 7.23 (d, 1H) 7.19 (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 cannula
  2. customAfter 15 min the reaction was removed
  3. temperaturefrom heating
  4. temperaturecooled 5 min
  5. additionpoured into ice/1 L EtOAc/0.5 L 1 N HCl
  6. customThe layers were separated
  7. washthe organic layer washed twice with water, once with 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 31 g of partially purified solid which
  11. customwas then crystallized
  12. temperaturefrom refluxing 3:1 MeOH/DCM

Sources & evidence

ORD record
ord-5f64c58dbddd44179ee423704dbbfd94
Source dataset
uspto-grants-2015_03
Patent number
US08987295B2

Reaction notes

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