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

HRID 1672522Notes

Reaction equation

HRID 1672522 reaction equation
[CH3:1][C:2]([NH:14]C(=O)C)([C:4]1[CH:5]=[N:6][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:9]=1)[CH3:3].Cl.O.[OH-].[Na+]>COC(C)(C)C>[CH3:3][C:2]([NH2:14])([C:4]1[CH:5]=[N:6][C:7]([C:10]([F:12])([F:13])[F:11])=[CH:8][CH:9]=1)[CH3:1]

Participants

6

Reactant 4

HCID 313Hydrochloric AcidHCID 962WaterHCID 14798Sodium HydroxideHCID 57951127N-[1-Methyl-1-[6-(trifluoromethyl)-3-pyridinyl]ethyl]acetamide

Product 1

HCID 545799022-[6-(Trifluoromethyl)pyridin-3-yl]propan-2-amineYield 74.3%

Reagents, catalysts & solvents 1

HCID 15413tert-Butyl methyl etherSolvent

Conditions

Temperature
27.5 °C

Procedure

Heat a mixture of N-[1-Methyl-1-(6-trifluoromethyl-pyridin-3-yl)-ethyl]-acetamide (93.5 moles, 19.1 kg), concentrated hydrochloric acid (805.9 moles; 66.2 L; 79.4 kg), and water (79.4 L; 79.4 kg) to 95-100° C. with stirring under nitrogen for 24 hours. Cool the reaction mixture to 20-35° C. and observe completion of the reaction by HPLC. Cool the reaction vessel to 10-20° C. and add tert-butyl methyl ether (105.4 L; 78.0 kg). Separate the phases, and discard the organic layer. Add 15% sodium hydroxide (910.9 moles; 205 L; 242.9 kg) to the aqueous phase and observe a pH of 9.5-10.5. Extract the aqueous layer with ethyl acetate (3×89 mL; 3×80.0 kg), combine the organic layers, and discard the aqueous phase. Concentrate the solution to approximately 2 volumes, add tert-butyl methyl ether (174 L; 129.1 kg), and concentrate the solution to approximately 2 volumes. Dilute the reaction vessel with n-heptane (168 L; 115.0 kg), concentrate the solution to approximately 2 volumes, and dilute with additional n-heptane (30 L, 20.7 kg). Cool the contents of the reaction mixture to 0-5° C. and stir the mixture for 2 hours at 0-5° C. Filter and dry the resultant solids under vacuum at 35-45° C. to afford the titled compound (14.19 kg; 74.3%, based on HPLC) as a 97.9% pure tan powder.

Workup

  1. temperatureHeat
  2. customcompletion of the reaction by HPLC
  3. temperatureCool the reaction vessel to 10-20° C.
  4. customSeparate the phases
  5. extractionExtract the aqueous layer with ethyl acetate (3×89 mL; 3×80.0 kg)
  6. concentrationConcentrate the solution to approximately 2 volumes
  7. additionadd tert-butyl methyl ether (174 L; 129.1 kg)
  8. concentrationconcentrate the solution to approximately 2 volumes
  9. additionDilute the reaction vessel with n-heptane (168 L; 115.0 kg)
  10. concentrationconcentrate the solution to approximately 2 volumes
  11. additiondilute with additional n-heptane (30 L, 20.7 kg)
  12. temperatureCool the contents of the reaction mixture to 0-5° C.
  13. stirringstir the mixture for 2 hours at 0-5° C
  14. filtrationFilter
  15. customdry the resultant solids under vacuum at 35-45° C.

Sources & evidence

ORD record
ord-664a716420d8463c96b25041578f4d38
Source dataset
uspto-grants-2011_08
Patent number
US07998985B2

Reaction notes

Loading…