Acetaldehyde → 1-(3,5-Dichloropyridin-4-yl)ethanol

HRID 41508

Reaction equation

HRID 41508 reaction equation
C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([Cl:20])[CH:19]=1.[CH:21](=[O:23])[CH3:22]>O1CCCC1.COC(C)(C)C.[Cl-].[NH4+].O>[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([Cl:20])[C:19]=1[CH:21]([OH:23])[CH3:22]

Participants

9

Reactant 4

HCID 177AcetaldehydeHCID 7912DiisopropylamineHCID 171533,5-DichloropyridineHCID 178418339Butyllithium

Product 1

HCID 666447221-(3,5-Dichloropyridin-4-yl)ethanol

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×HCID 15413tert-Butyl methyl etherSolventHCID 25517Ammonium ChlorideSolvent2×

Conditions

Temperature
-78 °C

Procedure

To a 3-neck 12 L round bottom flask add tetrahydrofuran (THF, 3 L) and diisopropylamine (DIPA, 315 mL, 2.24 mol) and cool to −78° C. Add slowly n-butyllithium (1.6 M in hexanes, 1400 mL, 2.24 mol). After the addition is complete and the temperature has settled at −78° C. slowly add a solution of 3,5-dichloropyridine (296.7 g, 2.00 mol) which immediately forms a yellow solution that changes to a rust colored suspension. After the addition is complete and the temperature has settled at −78° C. slowly add acetaldehyde (230 mL, 4.05 mol) in THF (600 mL). Continue stirring at −78° C. After 3 hours, remove the dry ice bath and begin quenching the reaction by the dropwise addition of saturated aqueous ammonium chloride (1 L). Allow the reaction to warm to room temperature (RT) overnight with stirring. Dilute the mixture with methyl-tert-butylether (MTBE, 2 L), saturated aqueous ammonium chloride (1 L) and water (2 L). Partition and wash organics with saturated aqueous sodium chloride (brine). Extract the aqueous phase with MTBE (1.5 L). Combine the organic layers, dry over sodium sulfate, filter and concentrate in vacuo. Purify the residue by silica gel chromatography [25% ethylacetate (EA) in hexanes] to give the title compound as a red oil. Yield: 352 g (90%). MS (ES) m/z 192 [M+1]+.

Workup

  1. additionAfter the addition
  2. customhas settled at −78° C.
  3. additionAfter the addition
  4. customhas settled at −78° C.
  5. customremove the dry ice bath
  6. custombegin quenching
  7. customthe reaction
  8. customthe reaction
  9. temperatureto warm to room temperature (RT) overnight
  10. stirringwith stirring
  11. customPartition
  12. washwash organics with saturated aqueous sodium chloride (brine)
  13. extractionExtract the aqueous phase with MTBE (1.5 L)
  14. dry with materialCombine the organic layers, dry over sodium sulfate
  15. filtrationfilter
  16. concentrationconcentrate in vacuo
  17. customPurify the residue by silica gel chromatography [25% ethylacetate (EA) in hexanes]

Sources & evidence

ORD record
ord-db0e15b92da54061934686511d939227
Source dataset
uspto-grants-2013_09
Patent number
US08530665B2

Linked notes

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