Trifluoroacetic acid → 6-[(4-Fluorophenyl)oxy]-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamide

HRID 644767Notes

Reaction equation

HRID 644767 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[N:14]=[CH:13][C:12]([C:15]([N:17]([CH3:39])[C:18]3[CH:23]=[CH:22][C:21]([CH2:24][N:25]4[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[C@@H:27]([CH3:38])[CH2:26]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[N:14]=[CH:13][C:12]([C:15]([N:17]([CH3:39])[C:18]3[CH:23]=[CH:22][C:21]([CH2:24][N:25]4[CH2:30][CH2:29][NH:28][C@@H:27]([CH3:38])[CH2:26]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1

Participants

4

Reactant 2

HCID 6422Trifluoroacetic acidHCID 592621161,1-Dimethylethyl (2S)-4-({4-[({6-[(4-fluorophenyl)oxy]-3-pyridinyl}carbonyl) (methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate

Product 1

HCID 237290236-[(4-Fluorophenyl)oxy]-N-methyl-N-(4-{[(3S)-3-methyl-1-piperazinyl]methyl}phenyl)-3-pyridinecarboxamide

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

A solution of 1,1-dimethylethyl (2S)-4-({4-[({6-[(4-fluorophenyl)oxy]-3-pyridinyl}carbonyl)(methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate (D16) (32.39 g, 0.0606 mol) in DCM (150 mL) was cooled in an ice/water bath and TFA (80 mL) was added drop-wise over 10 minutes. The reaction mixture was stirred at room temperature overnight then concentrated to a yellow gum. The gum was dissolved in MeOH (100 mL) and loaded onto SCX resin (150 g, pre-washed with MeOH). Elution with MeOH (750 mL) gave unchanged TFA salt of the title compound, and elution with 2M NH3 in MeOH (750 mL) gave title compound free base. The recovered TFA salt was treated in a similar manner to that described above using further SCX resin (100 g) to give a further batch of title compound free base. The two batches of the free base were combined in DCM and concentrated to give the title compound as a pale yellow gum (26.78 g). δH (CDCl3, 400 MHz) 8.07 (1H, d), 7.65 (1H, dd), 7.22 (2H, d), 7.04 (6H, m), 6.70 (1H, d), 3.48 (3H, s), 3.42 (2H, s), 2.89 (3H, m), 2.68 (2H, d), 1.97 (1H, m), 1.64 (1H, t), 1.49 (1H bs), 1.00 (3H, d). MS (ES): MH+ 435.1.

Workup

  1. concentrationthen concentrated to a yellow gum
  2. dissolutionThe gum was dissolved in MeOH (100 mL)
  3. washloaded onto SCX resin (150 g, pre-washed with MeOH)
  4. washElution with MeOH (750 mL)
  5. customgave unchanged
  6. washTFA salt of the title compound, and elution with 2M NH3 in MeOH (750 mL)

Sources & evidence

ORD record
ord-b7e4a31d77534a0da9be370fcdfc5148
Source dataset
uspto-grants-2010_04
Patent number
US07700599B2

Reaction notes

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