4-Methylmorpholine → (S)-N-((1S,2S)-1-((2R,4R)-1-(4-methoxybenzyl)-4-(allyloxy)pyrrolidin-2-yl)-3-(3,5-difluorophenyl)-1-hydroxypropan-2-yl)-2-((R)-3-acetamido-3-isobutyl-2-oxopyrrolidin-1-yl)-4-phenylbutanamide

HRID 132948Notes

Reaction equation

HRID 132948 reaction equation
[C:1]([NH:4][C@:5]1([CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:9][CH2:8][N:7]([C@@H:10]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11](O)=[O:12])[C:6]1=[O:22])(=[O:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:51][O:52][C:53]1[CH:81]=[CH:80][C:56]([CH2:57][N:58]2[CH2:62][C@H:61]([O:63][CH2:64][CH:65]=[CH2:66])[CH2:60][C@@H:59]2[C@@H:67]([OH:79])[C@@H:68]([NH2:78])[CH2:69][C:70]2[CH:75]=[C:74]([F:76])[CH:73]=[C:72]([F:77])[CH:71]=2)=[CH:55][CH:54]=1.CN1CCOCC1>CN(C=O)C>[CH3:51][O:52][C:53]1[CH:81]=[CH:80][C:56]([CH2:57][N:58]2[CH2:62][C@H:61]([O:63][CH2:64][CH:65]=[CH2:66])[CH2:60][C@@H:59]2[C@@H:67]([OH:79])[C@@H:68]([NH:78][C:11](=[O:12])[C@@H:10]([N:7]2[CH2:8][CH2:9][C@:5]([NH:4][C:1](=[O:3])[CH3:2])([CH2:23][CH:24]([CH3:25])[CH3:26])[C:6]2=[O:22])[CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:69][C:70]2[CH:71]=[C:72]([F:77])[CH:73]=[C:74]([F:76])[CH:75]=2)=[CH:55][CH:54]=1

Participants

6

Reactant 4

HCID 79724-MethylmorpholineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 58608197(1S,2S)-1-((2R,4R)-1-(4-methoxybenzyl)-4-(allyloxy)pyrrolidin-2-yl)-2-amino-3-(3,5-difluorophenyl)propan-1-olHCID 59733913(S)-2-((R)-3-acetamido-3-isobutyl-2-oxopyrrolidin-1-yl)-4-phenylbutanoic acid

Product 1

HCID 69195642(S)-N-((1S,2S)-1-((2R,4R)-1-(4-methoxybenzyl)-4-(allyloxy)pyrrolidin-2-yl)-3-(3,5-difluorophenyl)-1-hydroxypropan-2-yl)-2-((R)-3-acetamido-3-isobutyl-2-oxopyrrolidin-1-yl)-4-phenylbutanamideYield 55.3%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Procedure

Step 1 (A): To a solution of (S)-2-((R)-3-acetamido-3-isobutyl-2-oxopyrrolidin-1-yl)-4-phenylbutanoic acid (Preparation B, 96 mg, 0.266 mmol) in DMF (1.5 ml) was added HATU (121 mg, 0.319 mmol). A solution of (1S,2S)-1-((2R,4R)-1-(4-methoxybenzyl)-4-(allyloxy)pyrrolidin-2-yl)-2-amino-3-(3,5-difluorophenyl)propan-1-ol (Preparation C, 115 mg, 0.266 mmol) in DMF (1.0 ml) was then added, followed by N-methylmorpholine (102 μl, 0.931 mmol). The reaction mixture was stirred at rt for 30 min. pH 4 buffer was then added to quench. The mixture was extracted with ethyl acetate. The organic phase was washed with sat. aqueous NaCl, dried (MgSO4), and concentrated in vacuo. Flash chromatography (silica gel, 75-100% ethyl acetate/hexane) gave 114 mg (55%) of (S)-N-((1S,2S)-1-((2R,4R)-1-(4-methoxybenzyl)-4-(allyloxy)pyrrolidin-2-yl)-3-(3,5-difluorophenyl)-1-hydroxypropan-2-yl)-2-((R)-3-acetamido-3-isobutyl-2-oxopyrrolidin-1-yl)-4-phenylbutanamide as a clear, colorless oil:

Workup

  1. additionbuffer was then added
  2. customto quench
  3. extractionThe mixture was extracted with ethyl acetate
  4. washThe organic phase was washed with sat. aqueous NaCl
  5. dry with materialdried (MgSO4)
  6. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-68bf58505f86480bb1a54345dabf7314
Source dataset
uspto-grants-2008_06
Patent number
US07388007B2

Reaction notes

Loading…