Methanol → Trifluoroacetic acid

HRID 2246573Notes

Reaction equation

HRID 2246573 reaction equation
[C:1]([NH:4][C@@H:5]1[CH2:10][C@H:9]([N:11]([CH:13]([CH3:15])[CH3:14])C)[CH2:8][CH2:7][C@@H:6]1[N:16]1[CH2:20][CH2:19][C@H:18]([NH:21][C:22](=O)OCC2C=CC=CC=2)[C:17]1=[O:32])(=[O:3])[CH3:2].ClC1[C:43]2[C:38](=[CH:39][CH:40]=[C:41]([C:44]([F:47])([F:46])[F:45])[CH:42]=2)[N:37]=[CH:36][N:35]=1.C(N(C(C)C)CC)(C)C.[CH3:57][OH:58]>[Pd]>[CH:13]([NH:11][C@H:9]1[CH2:10][C@@H:5]([NH:4][C:1](=[O:3])[CH3:2])[C@@H:6]([N:16]2[CH2:20][CH2:19][C@H:18]([NH:21][C:22]3[C:39]4[C:38](=[CH:43][CH:42]=[C:41]([C:44]([F:45])([F:46])[F:47])[CH:40]=4)[N:37]=[CH:36][N:35]=3)[C:17]2=[O:32])[CH2:7][CH2:8]1)([CH3:14])[CH3:15].[C:57]([OH:3])([C:44]([F:47])([F:46])[F:45])=[O:58]

Participants

7

Reactant 4

HCID 887MethanolHCID 81531DiisopropylethylamineHCID 210750954-Chloro-6-(trifluoromethyl)quinazolineHCID 44185160benzyl (S)-1-((1S,2R,4R)-2-acetamido-4-(isopropyl(methyl)amino)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate

Product 2

HCID 6422Trifluoroacetic acidYield 93%HCID 24794624N-((1R,2S,5R)-5-(isopropylamino)-2-((3S)-2-oxo-3-((6-(trifluoromethyl)-4-quinazolinyl)amino)-1-pyrrolidinyl)cyclohexyl)acetamide

Reagents, catalysts & solvents 1

HCID 23938PalladiumCatalyst

Procedure

To a solution of benzyl (S)-1-((1S,2R,4R)-2-acetamido-4-(isopropylamino)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate (30 mg, 0.07 mmol; see Example 1, Step 8) in methanol (3 mL) was added 10% Pd/C (30 mg of 50% wet catalyst). The flask was evacuated and back-filled with hydrogen from a hydrogen balloon. The mixture was stirred at room temperature for 1.5 h under 1 atm hydrogen and then the catalyst was removed by filtration. The filtrate was concentrated in vacuo. The residue was dissolved in isopropanol (3 mL) and charged sequentially with 4-chloro-6-(trifluoromethyl)quinazoline (19.4 mg, 1.2 eq) and diisopropylethylamine (18 mg, 2 eq). The mixture was stirred at room temperature for 1 h. The solvent was removed under reduced pressure. The residue was purified by preparative reverse-phase HPLC to provide the title compound as its TFA salt (47 mg, 93%). LC/MS found [M+H]+=493. 1H-NMR (400 MHz, CD3OD), δ ppm: 8.90 (1H, s), 8.81 (1H, s), 8.25-8.29 (1H, m), 7.96 (1H, d, J=8.65 Hz), 5.44 (1H, t, J=9.92 Hz), 4.42 (1H, d, J=2.54 Hz), 4.15-4.24 (1H, m), 3.90 (1H, t, J=8.65 Hz), 3.70-3.79 (1H, m), 3.46-3.62 (2H, m), 2.56-2.67 (1H, m), 2.33-2.47 (1H, m), 1.70-2.23 (9H, m), 1.35 (6H, d, J=6.10 Hz).

Workup

  1. customThe flask was evacuated
  2. additionback-filled with hydrogen from a hydrogen balloon
  3. customthe catalyst was removed by filtration
  4. concentrationThe filtrate was concentrated in vacuo
  5. dissolutionThe residue was dissolved in isopropanol (3 mL)
  6. stirringThe mixture was stirred at room temperature for 1 h
  7. customThe solvent was removed under reduced pressure
  8. customThe residue was purified by preparative reverse-phase HPLC

Sources & evidence

ORD record
ord-d5fae43c797e48debaeb7d48f3db73d1
Source dataset
uspto-grants-2010_03
Patent number
US07687508B2

Reaction notes

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