Trifluoroacetic acid → N-[4-(2-amino-4,4,4-trifluoro-butoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-2-fluoro-4-methoxy-benzamide trifluoroacetate

HRID 1685941Notes

Reaction equation

HRID 1685941 reaction equation
[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:26])[C:6]=1[C:7]1[CH:8]=[C:9]([NH:14][C:15](=[O:25])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=2[F:24])[CH:10]=[CH:11][C:12]=1[OH:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClC1C=NN(C)C=1C1C=C(NC(=O)C2C=CC(OC)=CC=2F)C=CC=1O.C1COCC1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[F:91][C:92]([F:106])([F:105])[CH2:93][CH:94]([NH:97]C(=O)OC(C)(C)C)[CH2:95]O.[C:107]([OH:113])([C:109]([F:112])([F:111])[F:110])=[O:108]>C1COCC1>[F:110][C:109]([F:112])([F:111])[C:107]([OH:113])=[O:108].[NH2:97][CH:94]([CH2:93][C:92]([F:106])([F:105])[F:91])[CH2:95][O:13][C:12]1[CH:11]=[CH:10][C:9]([NH:14][C:15](=[O:25])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=2[F:24])=[CH:8][C:7]=1[C:6]1[N:5]([CH3:26])[N:4]=[CH:3][C:2]=1[Cl:1]

Participants

8

Reactant 6

HCID 6422Trifluoroacetic acidHCID 11776TriphenylphosphineHCID 5363146Diisopropyl azodicarboxylateHCID 23237059Tert-butyl (4,4,4-trifluoro-1-hydroxybutan-2-yl)carbamateHCID 136388017N-(3-(4-chloro-1-methyl-1H-pyrazol-5-yl)-4-hydroxyphenyl)-2-fluoro-4-methoxybenzamideHCID 136388019N-(3-(4-chloro-1-methyl-1H-pyrazol-5-yl)-4-hydroxyphenyl)-2-fluoro-4-methoxybenzamide THF

Product 1

HCID 86633181N-[4-(2-amino-4,4,4-trifluoro-butoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-2-fluoro-4-methoxy-benzamide trifluoroacetateYield 24.5%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent4×

Procedure

N-(3-(4-chloro-1-methyl-1H-pyrazol-5-yl)-4-hydroxyphenyl)-2-fluoro-4-methoxybenzamide (20.0 mg, 53.2 μmol) was dissolved in anhydrous THF (0.3 mL). Triphenylphosphine (15.4 mg, 58.5 μmol), pre-dissolved in anhydrous THF (0.1 mL) was added to the N-(3-(4-chloro-1-methyl-1H-pyrazol-5-yl)-4-hydroxyphenyl)-2-fluoro-4-methoxybenzamide/THF solution. The reaction was stirred for 5 minutes and then DIAD (16.6 μl, 85.2 μmol), pre-dissolved in anhydrous THF (0.1 mL) was added to the reaction. The mixture was stirred at r.t. for 5 more minutes and then tert-butyl 4,4,4-trifluoro-1-hydroxybutan-2-ylcarbamate (16.2 mg, 66.5 μmol), pre-dissolved in anhydrous THF (0.1 mL) was added. The reaction was then stirred for 4 hours and checked by LC/MS. While the reaction had not gone to completion, pushing the reaction by heating or extending the reaction time did not seem to improve the yield. Thus, the solvent was evaporated, the resulting oil re-suspended in CH2Cl2 (0.5 mL) and TFA (20.5 μl, 266 μmol) was added (to remove the Boc-protecting group from the amine). The reaction was stirred overnight at room temperature. The next day, the solvent was removed and the resulting oil was re-dissolved in DMSO (1 mL). The product was purified by Prep LC/MS (0-50% B, 30 min) to yield N-[4-(2-amino-4,4,4-trifluoro-butoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-2-fluoro-4-methoxy-benzamide trifluoroacetate (8.1 mg, 13.0 μmol, 24.5%) as a colorless oil. LCMS m/z 501.3 (M+H); 1H NMR (400 MHz, MeOH-d4) δ ppm 2.48-2.86 (m, 2 H), 3.75 (d, J=2.78 Hz, 3 H), 3.87-3.97 (m, 1 H), 3.89 (s, 3 H), 4.10-4.43 (m, 2 H), 6.85 (dd, J=12.88, 2.27 Hz, t H), 6.91 (dd, J=8.72, 2.40 Hz, 1 H), 7.30 (dd, J=9.09, 2.27 Hz, 1 H), 7.61 (d, J=2.53 Hz, 1 H), 7.65-7.69 (m, 1 H), 7.76 (t, J=8.59 Hz, 1 H), 7.90 (dd, J=8.97, 2.65 Hz, 1 H).

Workup

  1. additionwas added to the reaction
  2. stirringThe mixture was stirred at r.t. for 5 more minutes
  3. additionwas added
  4. stirringThe reaction was then stirred for 4 hours
  5. customthe reaction
  6. temperatureby heating
  7. customThus, the solvent was evaporated
  8. customto remove the Boc-
  9. stirringThe reaction was stirred overnight at room temperature
  10. customThe next day, the solvent was removed
  11. dissolutionthe resulting oil was re-dissolved in DMSO (1 mL)
  12. customThe product was purified by Prep LC/MS (0-50% B, 30 min)

Sources & evidence

ORD record
ord-9c80ebff6b5c46109390ee70ba716799
Source dataset
uspto-grants-2012_04
Patent number
US08148417B2

Reaction notes

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