Trifluoroacetic acid → Piperidine-2(R)-carboxylic acid {4-[3-(5-chloro-2-hydroxy-phenyl)-1-(2-hydroxy-ethyl)-1H-pyrazol-4-ylethynyl]-phenyl}-amide

HRID 2075758Notes

Reaction equation

HRID 2075758 reaction equation
C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[C:14](=[O:40])[NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]#[C:23][C:24]2[C:25]([C:32]3[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=3[OH:39])=[N:26][N:27]([CH2:29][CH2:30][OH:31])[CH:28]=2)=[CH:18][CH:17]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:38][C:36]1[CH:35]=[CH:34][C:33]([OH:39])=[C:32]([C:25]2[C:24]([C:23]#[C:22][C:19]3[CH:18]=[CH:17][C:16]([NH:15][C:14]([C@H:9]4[CH2:10][CH2:11][CH2:12][CH2:13][NH:8]4)=[O:40])=[CH:21][CH:20]=3)=[CH:28][N:27]([CH2:29][CH2:30][OH:31])[N:26]=2)[CH:37]=1

Participants

4

Reactant 2

HCID 6422Trifluoroacetic acidHCID 135974981HCID 135974981, compound

Product 1

HCID 135974922Piperidine-2(R)-carboxylic acid {4-[3-(5-chloro-2-hydroxy-phenyl)-1-(2-hydroxy-ethyl)-1H-pyrazol-4-ylethynyl]-phenyl}-amide

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

Compound 4A (8.2 g) was dissolved in dichloromethane (50 mL) and cooled to 0° C. with ice-water bath. TFA (50 mL) was added slowly to the above solution at 0° C. The mixture was stirred at 0° C. for 1.5 hour. LC-MS indicated the reaction was complete. Dichloromethane and TFA were removed with a rotavapor at rt. Dichloromethane (˜100 mL) was added to the residua and removed again. The process was repeated twice more. The resultant residua were suspended in ethyl acetate (˜50 mL). 5% Aqueous NaHCO3 and solid NaHCO3 were added slowly to neutralize any residual TFA. The mixture was filtered and the solid was washed with water and ethyl acetate. The solid was collected and dried under high vacuum in the presence of Drierite. The filtrate was collected and the organic layer was separated and dried over sodium sulfate. It was then filtered and the solvent was removed to give yellowish solid. The solid from filtration and the solid from filtrate were combined and the title compound 5A was obtained in quantitative yield. Using the same procedure for the preparation of 5A, the treatment of compound 16A (870 mg) with TFA (10 mL) in methylene chloride (10 mL) gives compound 17A in 74.0% yield. 1H NMR (DMSO-d6, 500 MHz) δ 10.68 (s, 1H), 9.95 (br s, 1H), 8.36 (s, 1H), 8.28 (s, 1H), 7.73 (d, 2H, J=8.5 Hz), 7.46 (d, 2H, J=8.5 Hz), 7.29 (d, 1H, J=9.0 Hz), 6.99 (d, 1H, J=9.0 Hz), 5.01 (s, 1H), 4.26 (s, 2H), 3.78 (d, 2H, J=4.0 Hz), 2.99 (d, 1H, J=12.0 Hz), 2.60 (t, 1H, J=11.0 Hz), 1.84 (s, 1H), 1.77 (s, 1H), 1.51 (d, 1H, J=11.0 Hz), 1.41 (m, 3H). LCMS (ESI) m/z 465.06 (MH+, 100); HPLC: tR=4.02 min.

Workup

  1. customDichloromethane and TFA were removed with a rotavapor at rt
  2. additionDichloromethane (˜100 mL) was added to the residua
  3. customremoved again
  4. addition5% Aqueous NaHCO3 and solid NaHCO3 were added slowly
  5. filtrationThe mixture was filtered
  6. washthe solid was washed with water and ethyl acetate
  7. customThe solid was collected
  8. dry with materialdried under high vacuum in the presence of Drierite
  9. customThe filtrate was collected
  10. customthe organic layer was separated
  11. dry with materialdried over sodium sulfate
  12. filtrationIt was then filtered
  13. customthe solvent was removed
  14. customto give yellowish solid
  15. filtrationThe solid from filtration

Sources & evidence

ORD record
ord-cdbdd3414cc243b493f2c68f2773e4cc
Source dataset
uspto-grants-2011_04
Patent number
US07923004B2

Reaction notes

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