benzyl (S)-1-((1S,2R,4R)-2-acetamido-4-(isopropyl(methyl)amino)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate → N-((1R,2S,5R)-2-((S)-3-amino-2-oxopyrrolidin-1-yl)-5-(isopropylamino)cyclohexyl)acetamide

HRID 2246584Notes

Reaction equation

HRID 2246584 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(=O)OCC2C=CC=CC=2)[C:17]1=[O:32])(=[O:3])[CH3:2]>CO.[Pd]>[NH2:21][C@H:18]1[CH2:19][CH2:20][N:16]([C@H:6]2[CH2:7][CH2:8][C@@H:9]([NH:11][CH:13]([CH3:15])[CH3:14])[CH2:10][C@H:5]2[NH:4][C:1](=[O:3])[CH3:2])[C:17]1=[O:32]

Participants

4

Reactant 1

HCID 44185160benzyl (S)-1-((1S,2R,4R)-2-acetamido-4-(isopropyl(methyl)amino)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate

Product 1

HCID 68692292N-((1R,2S,5R)-2-((S)-3-amino-2-oxopyrrolidin-1-yl)-5-(isopropylamino)cyclohexyl)acetamide

Reagents, catalysts & solvents 2

HCID 23938PalladiumCatalystHCID 887MethanolSolvent

Procedure

Example 6, Alternative Preparation, Step 1: To a solution of benzyl (S)-1-((1S,2R,4R)-2-acetamido-4-(isopropylamino)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate (0.090 g, 0.209 mmol; see Example 1, Step 8) in MeOH (10 mL) was added ˜100 mg of 10% Pd/C (50%, wet). The mixture was stirred under H2 (50 psi) for 14 h. The catalyst was filtered off and the solvent was evaporated to give N-((1R,2S,5R)-2-((S)-3-amino-2-oxopyrrolidin-1-yl)-5-(isopropylamino)cyclohexyl)acetamide as a foamy solid residue (50 mg, 0.169 mmol). This material was dissolved in i-PrOH (2 mL), and the resultant solution was charged with 4-phenoxy-6-(trifluoromethyl)quinazoline 1-oxide (103 mg, 0.169 mmol; see Example 5, Alternative Preparation, Step 2) and N,N-diisopropylethylamine (0.059 ml, 0.337 mmol). The vessel was sealed under argon atmosphere and heated in a microwave for 1 hr at 120° C. The reaction was evaporated to give an oily residue, which was purified by automated flash chromatography to give a yellow solid. This was re-crystallized from CH2Cl2-hexane to afford the desired 4-((S)-1-((1S,2R,4R)-2-acetamido-4-(isopropylamino)cyclohexyl)-2-oxopyrrolidin-3-ylamino)-6-(trifluoromethyl)quinazoline 1-oxide (1st crop, 43.5 mg and 2nd crop, 3.1 mg). LC/MS found: (M+H)+=509.32. 1H-NMR (400 MHz, CD3OD), δ ppm: 8.99 (s, 1H), 8.81 (s, 1H), 8.62 (d, J=9.0 Hz, 1H), 8.33 (dd, J=9.0, 1.6 Hz, 1H), 5.28 (t, J=8.3 Hz, 1H), 4.56 (brs, 1H), 4.02 (brd, 1H), 3.63 (m, 2H), 3.18 (brs, 1H), 2.55 (m, 1H), 2.27 (m, 1H), 2.03 (s, 3H), 1.97-1.67 (m, 7H), 1.16 (d, J=5.5 Hz, 3H), 1.15 (d, J=5.5 Hz, 3H).

Workup

  1. customExample 6, Alternative Preparation, Step 1
  2. filtrationThe catalyst was filtered off
  3. customthe solvent was evaporated

Sources & evidence

ORD record
ord-895f3e4d78a745ffa670caa7b90d6a9e
Source dataset
uspto-grants-2010_03
Patent number
US07687508B2

Reaction notes

Loading…