Sodium Hydroxide → (2-Chloro-5-fluoropyridin-3-yl)methanol

HRID 707224Notes

Reaction equation

HRID 707224 reaction equation
[Cl:1][C:2]1[N:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)(Cl)=O.[BH4-].[Na+].[OH-].[Na+]>ClCCl.O.C(OCC)(=O)C.CN(C)C=O>[Cl:1][C:2]1[C:3]([CH2:4][OH:5])=[CH:7][C:8]([F:11])=[CH:9][N:10]=1

Participants

9

Reactant 4

HCID 14798Sodium HydroxideHCID 24386Thionyl ChlorideHCID 4311764Sodium borohydrideHCID 114352432-Chloro-5-fluoronicotinic acid

Product 1

HCID 24229204(2-Chloro-5-fluoropyridin-3-yl)methanolYield 34.3%

Reagents, catalysts & solvents 4

HCID 962WaterSolvent2×HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

2-Chloro-5-fluoronicotinic acid (4.50 g, 25.6 mmol) was dissolved in dichloromethane (100 mL) and dry dimethylformamide (1 mL) and cooled in an ice bath. Thionyl chloride (20 ml, 274 mmol) was added slowly and the reaction stirred for 20 minutes then it was removed from the ice bath. After another 15 minutes the solution was evaporated to dryness under reduced pressure. The crude acid chloride was further dried under high vacuum then dissolved in dry tetrahydrofuran (20 mL) and slowly added to an ice cooled solution of sodium borohydride (2.5 g, 66.1 mmol) in water (100 mL with about 80 mL of ice) over 40 minutes. The reaction was stirred for an additional 15 minutes. Ethyl acetate (400 mL) and additional water (100 mL) were added and the phases stirred. Sodium hydroxide (5 N, 40 mL) was added to make the aqueous layer basic. The mixed phases were stirred for 2 hours then the layers were separated. The organic layer was dried with magnesium sulfate before evaporating to dryness under reduced pressure. Purification using silica chromatography (hexane to ethyl acetate gradient) gave the desired (2-chloro-5-fluoropyridin-3-yl)methanol (1.42 g, 8.79 mmol, 34.3% yield) as a brown oil that solidified on standing.

Workup

  1. customit was removed from the ice bath
  2. customAfter another 15 minutes the solution was evaporated to dryness under reduced pressure
  3. dry with materialThe crude acid chloride was further dried under high vacuum
  4. dissolutionthen dissolved in dry tetrahydrofuran (20 mL)
  5. stirringThe reaction was stirred for an additional 15 minutes
  6. stirringthe phases stirred
  7. stirringThe mixed phases were stirred for 2 hours
  8. customthe layers were separated
  9. dry with materialThe organic layer was dried with magnesium sulfate
  10. custombefore evaporating to dryness under reduced pressure
  11. customPurification

Sources & evidence

ORD record
ord-3608dac549b34c7aa355da85bb8760f8
Source dataset
uspto-grants-2015_11
Patent number
US09174992B2

Reaction notes

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