Hydrochloric Acid → 2-[6-(Trifluoromethyl)pyridin-3-yl]propan-2-ol

HRID 1672520Notes

Reaction equation

HRID 1672520 reaction equation
C(OC(=O)C1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][CH:6]=1)C.C[Mg]Cl.Cl.[Cl-].[Na+].C[O:23][C:24]([CH3:27])([CH3:26])[CH3:25]>O.O1CCCC1>[F:12][C:11]([F:14])([F:13])[C:8]1[N:7]=[CH:6][C:25]([C:24]([OH:23])([CH3:27])[CH3:26])=[CH:10][CH:9]=1

Participants

8

Reactant 5

HCID 313Hydrochloric AcidHCID 5234Sodium ChlorideHCID 15413tert-Butyl methyl etherHCID 11390362Ethyl 6-(trifluoromethyl)pyridine-3-carboxylateHCID 178418332HCID 178418332, compound

Product 1

HCID 534009962-[6-(Trifluoromethyl)pyridin-3-yl]propan-2-ol

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
8.5 °C

Procedure

Cool the contents of an inerted reaction vessel containing technical grade 6-trifluoromethyl-nicotinic acid ethyl ester (45.6 moles; 10.00 kg) and tert-butyl methyl ether (71.6 L; 53.0 kg) to 10-15° C., and add the solution into a separate inerted reaction vessel cooled to 5-12° C. containing 3 M methylmagnesium chloride (136.8 moles; 45.6 L; 46.2 kg) and tetrahydrofuran (76.5 L; 68.0 kg). Observe a moderate exotherm during the addition, and maintain the internal reaction temperature between 15-25° C. Confirm that the starting ester is completely consumed by HPLC, and cool the reactor contents to 0-3° C. Add the contents from the reaction vessel slowly to a separate reactor cooled to 0-5° C. containing hydrochloric acid (203 moles; 16.67 L; 20.0 kg) and water (81.0 L, 81.0 kg), and observe gas evolution. Separate the layers and extract the aqueous phase once with tert-butyl methyl ether (59.5 L; 44.0 kg). Combine the organic layers and wash with a 20% sodium chloride solution (189.3 moles; 46.5 L; 55.3 kg). Filter the organic solution, concentrate to approximately 1 volume, and dilute with acetonitrile (31.8 L; 25.0 kg). Concentrate the solution to approximately 1 volume to provide the titled compound as a technical grade oil (7.9 kg; 84.4%, based on HPLC) in acetonitrile. Use the crude material as a solution in acetonitrile without further purification. A pure sample of the product can be obtained by following the procedure given below.

Workup

  1. temperatureCool the contents of an inerted reaction vessel
  2. additionadd the solution into a separate inerted reaction vessel
  3. additionObserve a moderate exotherm during the addition
  4. temperaturemaintain the internal reaction temperature between 15-25° C
  5. customConfirm that the starting ester is completely consumed by HPLC
  6. temperaturecool the reactor contents to 0-3° C
  7. additionAdd the contents from the reaction vessel slowly to a separate reactor
  8. temperaturecooled to 0-5° C.
  9. customSeparate the layers
  10. extractionextract the aqueous phase once with tert-butyl methyl ether (59.5 L; 44.0 kg)
  11. filtrationFilter the organic solution
  12. concentrationconcentrate to approximately 1 volume
  13. additiondilute with acetonitrile (31.8 L; 25.0 kg)
  14. concentrationConcentrate the solution to approximately 1 volume

Sources & evidence

ORD record
ord-9cd8b7aabf824073b8e0f3f61a1c3bb8
Source dataset
uspto-grants-2011_08
Patent number
US07998985B2

Reaction notes

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