N1-methylisophthalamide → HCID 11848580, compound

HRID 1014883Notes

Reaction equation

HRID 1014883 reaction equation
[Si]([O:8][C@H:9]([C@H:33]1[CH2:37][C@@H:36](OCCC)[CH2:35][N:34]1C(OC(C)(C)C)=O)[C@@H:10]([NH:20][C:21](=[O:32])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([O:30]C)=O)[CH:23]=1)[CH2:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=1)(C(C)(C)C)(C)C.CNC(=O)[C:52]1[CH:60]=[CH:59][CH:58]=[C:54](C(N)=O)[CH:53]=1.[Si](O[C@H:70]([C@H:93]1[CH2:97][C@@H](OCCC)CN1C(OC(C)(C)C)=O)[C@@H:71]([NH:81][C:82](=O)C1C=CC=C(C(=O)N)C=1)CC1C=C(F)C=C(F)C=1)(C(C)(C)C)(C)C>CO.[Pd]>[CH2:71]([N:81]([CH3:82])[C:28](=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[C:22]([C:21]([NH:20][C@@H:10]([CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=2)[C@H:9]([OH:8])[C@H:33]2[CH2:37][CH:36]([C:52]3[CH:53]=[CH:54][CH:58]=[CH:59][CH:60]=3)[CH2:35][NH:34]2)=[O:32])[CH:23]=1)[CH2:70][CH2:93][CH3:97]

Participants

6

Reactant 3

HCID 22244017N1-methylisophthalamideHCID 67315032(2R,4R)-tert-butyl 2-((1S,2S)-1-(tert-butyldimethylsilyloxy)-2-(3-(carbamoyl)benzamido)-3-(3,5-difluorophenyl)propyl)-4-propoxypyrrolidine-1-carboxylateHCID 67316674(2R,4R)-tert-butyl 2-((1S,2S)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)-2-(3-(methoxycarbonyl)benzamido)propyl)-4-propoxypyrrolidine-1-carboxylate

Product 1

HCID 11848580HCID 11848580, compound

Reagents, catalysts & solvents 2

HCID 23938PalladiumCatalystHCID 887MethanolSolvent

Procedure

Step 7 (B): Preparation of N1-butyl-N3-((1R,2S)-3-(3,5-difluorophenyl)-1-hydroxy-1(2R)-4-phenylpyrrolidin-2-yl)propan-2-yl)-N1-methylisophthalamide. To a solution of (R)-tert-butyl 2-((1S,2S)-1-(tert-butyldimethylsilyloxy)-2-(3-(carbamoyl)benzamido)-3-(3,5-difluorophenyl)propyl)-4-phenyl-2,3-dihydropyrrole-1-carboxylate (Step 7 (A), 15 mg) in MeOH (1 mL) was added a catalytic amount of Pd on activated charcoal (10 wt %, 10 mg). The reaction mixture was put on hydrogenator at 50 psi for 3 h. The mixture was then filtered and concentrated in vacuo. To the above residue were added dioxane (0.5 mL) and 2 drops of H2O and the mixture was stirred at rt for 2 h. Solvent was removed and the mixture was purified by reverse phase HPLC to give the title compound (9 mg): 1H NMR (CDCl3, 500 MHz) δ 0.77 (2H, m), 1.03 (2H, m), 1.14 (1H, dd, J=10, 15 Hz), 1.45 (1H, dd, J=5, 15 Hz), 1.54 (1H, m), 1.69 (1H, m), 2.33 (1H, m), 2.58 (1H, m), 2.89 (1H, m), 2.94 (1H, s), 3.09 (1H, s), 3.23-3.29 (2H, m), 3.44 (1H, dd, J=5, 15 Hz), 3.57 (2H, m), 3.74 (1H, m), 4.00 (1H, m), 4.17 (1H, m), 4.26 (1H, m), 6.74 (1H, t, J=10 Hz), 6.89 (2H, d, J=10 Hz), 7.31 (1H, m), 7.36-7.40 (4H, m), 7.53-7.56 (2H, m), 7.67 (1H, s), 7.76-7.78 (1H, m). MS (ESI) (M+H)+ 550.31.

Workup

  1. filtrationThe mixture was then filtered
  2. concentrationconcentrated in vacuo
  3. additionTo the above residue were added dioxane (0.5 mL) and 2 drops of H2O
  4. customSolvent was removed
  5. customthe mixture was purified by reverse phase HPLC

Sources & evidence

ORD record
ord-bfa5b72e66274d2d844dd3b2f897699c
Source dataset
uspto-grants-2011_07
Patent number
US07981913B2

Reaction notes

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