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-phenoxypyrrolidin-2-yl)propan-2-yl)-4-phenylbutanamide

HRID 132957Notes

Reaction equation

HRID 132957 reaction equation
[C:1]([NH:4][C@:5]1([C@@H](CC)C)[CH2:9][CH2:8][N:7]([C@@H:10]([CH2:51][CH2:52]C2C=CC=CC=2)[C:11]([NH:13][C@@H:14]([CH2:42][C:43]2[CH:48]=[C:47]([F:49])[CH:46]=[C:45]([F:50])[CH:44]=2)[C@@H:15]([C@H:17]2[CH2:21][C@H:20]([O:22]C3C=CC=CN=3)[CH2:19][N:18]2C(C2C=CC=CC=2)C2C=CC=CC=2)[OH:16])=[O:12])[C:6]1=[O:59])(=[O:3])[CH3:2].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]2C[C@@H](O[C:86]3[CH:91]=[CH:90][CH:89]=[CH:88][CH:87]=3)CN2C(C2C=CC=CC=2)C2C=CC=CC=2)O)=O)C1=O)(=O)C.C(N[C@]1([C@@H](CC)C)CCN([C@@H](CC[C:142]2[CH:147]=[CH:146][CH:145]=[CH:144][CH:143]=2)C(O)=O)C1=O)(=O)C.CN(C(ON1N=N[C:163]2[CH:164]=[CH:165]C=N[C:162]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N[C@@H](CC1C=C(F)C=C(F)C=1)[C@@H]([C@H]1C[C@H](OC2C=CC=CN=2)CN1C(C1C=CC=CC=1)C1C=CC=CC=1)O.CN1CCOCC1>CN(C=O)C>[C:1]([NH:4][C@:5]1([C@@H:163]([CH2:164][CH3:165])[CH3:162])[CH2:9][CH2:8][N:7]([C@@H:10]([CH2:51][CH2:52][C:142]2[CH:147]=[CH:146][CH:145]=[CH:144][CH:143]=2)[C:11]([NH:13][C@@H:14]([CH2:42][C:43]2[CH:44]=[C:45]([F:50])[CH:46]=[C:47]([F:49])[CH:48]=2)[C@H:15]([OH:16])[C@H:17]2[CH2:21][C@@H:20]([O:22][C:86]3[CH:91]=[CH:90][CH:89]=[CH:88][CH:87]=3)[CH2:19][NH:18]2)=[O:12])[C:6]1=[O:59])(=[O:3])[CH3:2]

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 69195116(S)-2-((S)-3-acetamido-3-((R)-sec-butyl)-2-oxopyrrolidin-1-yl)-N-((1S,2S)-1-((2R,4R)-1-benzhydryl-4-phenoxypyrrolidin-2-yl)-3-(3,5-difluorophenyl)-1-hydroxypropan-2-yl)-4-phenylbutanamideHCID 69195135(S)-2-((S)-3-acetamido-3-((R)-sec-butyl)-2-oxopyrrolidin-1-yl)-N-((1S,2S)-1-((2R,4S)-1-benzhydryl-4-(pyridin-2-yloxy)pyrrolidin-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-ol

Product 1

HCID 69195625(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-phenoxypyrrolidin-2-yl)propan-2-yl)-4-phenylbutanamideYield 56%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Procedure

Step 11 (C): (S)-2-((S)-3-acetamido-3-((R)-sec-butyl)-2-oxopyrrolidin-1-yl)-N-((1S,2S)-1-((2R,4R)-1-benzhydryl-4-phenoxypyrrolidin-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, 20.3 mg, 0.056 mmol) in DMF (1 mL) was added HATU (25.5 mg, 0.0672 mmol). A solution of (1S,2S)-2-amino-1-((2R,4R)-1-benzhydryl-4-phenoxypyrrolidin-2-yl)-3-(3,5-difluorophenyl)propan-1-ol (Step 11 (B), 29 mg, 0.056 mmol) in DMF (1 mL) was then added, followed by N-methylmorpholine (22 μl, 0.196 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 (27 mg, 56% yield) as a clear, slightly brown glass: 1H NMR (CDCl3, 300 MHz) δ 0.90 (3H, d, J=6 Hz), 1.01 (3H, m), 1.09-1.19 (1H, m), 1.51-1.61 (1H, m), 1.66-1.90 (5H, m), 2.00-2.08 (2H, m), 2.15-2.30 (1H, m), 2.40-2.49 (2H, m), 2.58-2.67 (2H, m), 2.89-3.14 (3H, m), 3.38-3.53 (3H, m), 3.71-3.96 (3H, m), 4.21-4.42 (1H, m), 5.02-5.14 (2H, m), 6.07 (1H, s), 6.53-6.63 (3H, m), 6.81 (2H, d, J=6 Hz), 6.97 (1H, m), 7.12-7.39 (13H, m), 7.56 (2H, m), 7.67 (2H, d, J=6 Hz), 9.14 (3H, brd s). HPLC retention time: 1.93 min (method A). MS (ESI) (M+H)+ 857.32.

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-fb9bcdf762514f1a8ea20a6763af82ea
Source dataset
uspto-grants-2008_06
Patent number
US07388007B2

Reaction notes

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