Sulfuric Acid → 5-Chloro-2-[((2S)-2-fluoro-3-hydroxypropyl)oxy]benzonitrile

HRID 1160477Notes

Reaction equation

HRID 1160477 reaction equation
[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C@@H:12]([F:34])[CH2:13][O:14]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:6]([CH:9]=1)[C:7]#[N:8].C1(C)C(CO)=CC=CC=1.S(=O)(=O)(O)O.[OH-].[Na+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C@@H:12]([F:34])[CH2:13][OH:14])=[C:6]([CH:9]=1)[C:7]#[N:8]

Participants

5

Reactant 4

HCID 1118Sulfuric AcidHCID 69942-Methylbenzyl alcoholHCID 14798Sodium HydroxideHCID 684199965-Chloro-2-[[(2R)-2-fluoro-3-(trityloxy)propyl]oxy]benzonitrile

Product 1

HCID 595164255-Chloro-2-[((2S)-2-fluoro-3-hydroxypropyl)oxy]benzonitrileYield 88%

Conditions

Temperature
60 °C

Procedure

5-Chloro-2-[[(2R)-2-fluoro-3-(trityloxy)propyl]oxy]benzonitrile (460 g, 0.97 mol) was suspended in a toluene-methanol mixture (4.8 L/3.22 L) at room temperature and then concentrated sulfuric acid (3.1 mL, 0.06 mol) was added to the reaction mixture, followed by stirring the reaction mixture at the same temperature for 18.5 hours. A 1N sodium hydroxide aqueous solution was added to the reaction mixture at room temperature to adjust the pH to 14 or more, followed by subjecting the reaction mixture to vacuum concentration. Ethyl acetate (2.1 L) and water (1.2 L) were added to the residue to separate an organic layer, followed by washing the organic layer twice with water (1.2 L) before vacuum concentration. Ethyl acetate (0.7 L) was added to the resultant crude crystal, which was then heated to 60° C. for complete dissolution. Heptane (3.8 L) was then added to the reaction mixture, followed by cooling and the filtration of the precipitated crystal to obtain 196 g of the title compound (yield: 88%).

Workup

  1. concentrationto vacuum concentration
  2. additionEthyl acetate (2.1 L) and water (1.2 L) were added to the residue
  3. customto separate an organic layer
  4. washby washing the organic layer twice with water (1.2 L)
  5. concentrationbefore vacuum concentration
  6. additionEthyl acetate (0.7 L) was added to the resultant crude crystal, which
  7. additionHeptane (3.8 L) was then added to the reaction mixture
  8. temperatureby cooling
  9. filtrationthe filtration of the precipitated crystal

Sources & evidence

ORD record
ord-99d0848b76d2419285b2f6c405cd6aea
Source dataset
uspto-grants-2010_10
Patent number
US07816405B2

Reaction notes

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