4-Methylmorpholine → (S)-2-((S)-3-acetamido-3-((R)-sec-butyl)-2-oxopyrrolidin-1-yl)-N-((1R,2S)-3-(3,5-difluorophenyl)-1-hydroxy-1-((2R,4R)-4-hydroxypyrrolidin-2-yl)propan-2-yl)-4-phenylbutanamide

HRID 132965Notes

Reaction equation

HRID 132965 reaction equation
[NH2:1][C@@H:2]([CH2:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[C:33]([F:38])[CH:32]=1)[C@@H:3]([C@H:5]1[CH2:9][C@H:8]([O:10]C2C=CC=CN=2)[CH2:7][N:6]1C(C1C=CC=CC=1)C1C=CC=CC=1)[OH:4].[C:39]([NH:42][C@:43]1([C@@H:92]([CH2:94][CH3:95])[CH3:93])[CH2:47][CH2:46][N:45]([C@@H:48]([CH2:83][CH2:84][C:85]2[CH:90]=[CH:89][CH:88]=[CH:87][CH:86]=2)[C:49](N[C@@H](CC2C=C(F)C=C(F)C=2)[C@@H]([C@H]2C[C@@H](O)CN2C(C2C=CC=CC=2)C2C=CC=CC=2)O)=[O:50])[C:44]1=[O:91])(=[O:41])[CH3:40].C(N[C@]1([C@@H](CC)C)CCN([C@@H](CCC2C=CC=CC=2)C(O)=O)C1=O)(=O)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N[C@]1([C@@H](CC)C)CCN([C@@H](CCC2C=CC=CC=2)C(N[C@@H](CC2C=C(F)C=C(F)C=2)[C@@H]([C@H]2CCCCN2C(C2C=CC=CC=2)C2C=CC=CC=2)O)=O)C1=O)(=O)C.CN1CCOCC1>CN(C=O)C>[C:39]([NH:42][C@:43]1([C@@H:92]([CH2:94][CH3:95])[CH3:93])[CH2:47][CH2:46][N:45]([C@@H:48]([CH2:83][CH2:84][C:85]2[CH:86]=[CH:87][CH:88]=[CH:89][CH:90]=2)[C:49]([NH:1][C@@H:2]([CH2:30][C:31]2[CH:36]=[C:35]([F:37])[CH:34]=[C:33]([F:38])[CH:32]=2)[C@H:3]([OH:4])[C@H:5]2[CH2:9][C@@H:8]([OH:10])[CH2:7][NH:6]2)=[O:50])[C:44]1=[O:91])(=[O:41])[CH3:40]

Participants

8

Reactant 6

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 67270863(S)-2-((S)-3-acetamido-3-((R)-sec-butyl)-2-oxopyrrolidin-1-yl)-4-phenylbutanoic acidHCID 69194179(S)-2-((S)-3-acetamido-3-((R)-sec-butyl)-2-oxopyrrolidin-1-yl)-N-((1S,2S)-1-((R)-1-benzhydrylpiperidin-2-yl)-3-(3,5-difluorophenyl)-1-hydroxypropan-2-yl)-4-phenylbutanamideHCID 69195403(1S,2S)-2-amino-1-((2R,4S)-1-benzhydryl-4-(pyridin-2-yloxy)pyrrolidin-2-yl)-3-(3,5-difluorophenyl)propan-1-olHCID 69196374(S)-2-((S)-3-acetamido-3-((R)-sec-butyl)-2-oxopyrrolidin-1-yl)-N-((1S,2S)-1-((2R,4R)-1-benzhydryl-4-hydroxypyrrolidin-2-yl)-3-(3,5-difluorophenyl)-1-hydroxypropan-2-yl)-4-phenylbutanamide

Product 1

HCID 69196515(S)-2-((S)-3-acetamido-3-((R)-sec-butyl)-2-oxopyrrolidin-1-yl)-N-((1R,2S)-3-(3,5-difluorophenyl)-1-hydroxy-1-((2R,4R)-4-hydroxypyrrolidin-2-yl)propan-2-yl)-4-phenylbutanamideYield 65%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Procedure

Step 14 (B): (S)-2-((S)-3-acetamido-3-((R)-sec-butyl)-2-oxopyrrolidin-1-yl)-N-((1S,2S)-1-((2R,4R)-1-benzhydryl-4-hydroxypyrrolidin-2-yl)-3-(3,5-difluorophenyl)-1-hydroxypropan-2-yl)-4-phenylbutanamide. To a solution of (S)-2-((S)-3-acetamido-3-((R)-sec-butyl)-2-oxopyrrolidin-1-yl)-4-phenylbutanoic acid (Preparation A, 22.6 mg, 0.063 mmol) in DMF (1 mL) was added HATU (28.7 mg, 0.076 mmol). A solution of (3R,5R)-5-((1S,2S)-2-amino-3-(3,5-difluorophenyl)-1-hydroxypropyl)-1-benzhydrylpyrrolidin-3-ol (Step 14 (A), 27.5 mg, 0.063 mmol) in DMF (1 mL) was then added, followed by N-methylmorpholine (24.2 μl, 0.221 mmol). The reaction mixture was stirred at rt for 3 h. 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. The crude mixture was purified by reverse phase Prep HPLC to give the title compound (32 mg, 65% yield) as a slightly yellow oil: 1H NMR (CDCl3, 500 MHz) δ 0.88 (3H, d, J=10 Hz), 1.00 (3H, m), 1.07-1.18 (1H, m), 1.55-1.61 (1H, m), 1.72-1.78 (1H, m), 1.95-2.03 (4H, m), 2.05-2.11 (2H, m), 2.30 (2H, d, J=15 Hz), 2.38-2.47 (1H, m), 2.48-2.53 (1H, m), 2.64-2.70 (1H, m), 2.88 (1H, m), 3.03-3.08 (3H, m), 3.17-3.20 (1H, m), 3.49 (1H, s), 3.53-3.61 (3H, m), 3.91 (1H, d, J=10 Hz), 3.96 (3H, s), 4.11 (1H, m), 4.47 (1H, brd s), 4.96 (1H, brd s), 6.13 (1H, brd s), 6.58-6.67 (3H, m), 7.04-7.37 (10H, m), 7.49 (2H, m), 7.67 (2H, d, J=10 Hz). HPLC retention time: 1.67 min (method A). MS (ESI) (M+H)+ 781.35.

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
  7. customThe crude mixture was purified by reverse phase Prep HPLC

Sources & evidence

ORD record
ord-ae4f59e65419479dbad1a7a4543563c8
Source dataset
uspto-grants-2008_06
Patent number
US07388007B2

Reaction notes

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