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-(pyridin-2-yloxy)pyrrolidin-2-yl)propan-2-yl)-4-phenylbutanamide

HRID 132960Notes

Reaction equation

HRID 132960 reaction equation
[C:1]([NH:4][C@:5]1([C@@H:60]([CH2:62][CH3:63])[CH3:61])[CH2:9][CH2:8][N:7]([C@@H:10]([CH2:51][CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=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][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=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](OC3C=CC=CN=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](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.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:60]([CH2:62][CH3:63])[CH3:61])[CH2:9][CH2:8][N:7]([C@@H:10]([CH2:51][CH2:52][C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=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]([OH:16])[C@H:17]2[CH2:21][C@@H:20]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=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 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-olHCID 69196307(S)-2-((S)-3-acetamido-3-((R)-sec-butyl)-2-oxopyrrolidin-1-yl)-N-((1S,2S)-1-((2R,4R)-1-benzhydryl-4-(pyridin-2-yloxy)pyrrolidin-2-yl)-3-(3,5-difluorophenyl)-1-hydroxypropan-2-yl)-4-phenylbutanamide

Product 1

HCID 69195856(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-(pyridin-2-yloxy)pyrrolidin-2-yl)propan-2-yl)-4-phenylbutanamideYield 80%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Procedure

Step 12 (C): (S)-2-((S)-3-acetamido-3-((R)-sec-butyl)-2-oxopyrrolidin-1-yl)-N-((1S,2S)-1-((2R,4R)-1-benzhydryl-4-(pyridin-2-yloxy)pyrrolidin-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, 21.1 mg, 0.067 mmol) in DMF (1 mL) was added HATU (30.0 mg, 0.081 mmol). A solution of (1S,2S)-2-amino-1-((2R,4R)-1-benzhydryl-4-(pyridin-2-yloxy)pyrrolidin-2-yl)-3-(3,5-difluorophenyl)propan-1-ol (Step 12 (B), 34.5 mg, 0.067 mmol) in DMF (1 mL) was then added, followed by N-methylmorpholine (26 μl, 0.235 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 (46.1 mg, 80% yield) as a yellow oil: 1H NMR (CDCl3, 300 MHz) δ 0.88 (3H, d, J=6 Hz), 0.99 (3H, t, J=6 Hz), 1.10-1.17 (1H, m), 1.53-1.63 (1H, m), 1.74-1.80 (1H, m), 1.88-1.98 (3H, m), 2.08 (2H, m), 2.21-2.29 (1H, m), 2.38-2.51 (2H, m), 2.61-3.06 (5H, m), 3.47-3.61 (3H, m), 3.69-3.75 (1H, m), 3.90-3.96 (3H, m), 4.11 (1H, brd s), 5.20 (1H, s), 5.70 (1H, m), 6.15 (1H, s), 6.89-7.01 (3H, m), 7.11-7.22 (5H, m), 7.30-7.40 (5H, m), 7.60 (2H, m), 7.72 (3H, d, J=6 Hz), 8.08 (1H, m), 9.83 (3H, brd s). HPLC retention time: 1.87 min (method A). MS (ESI) (M+H)+ 858.30.

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-902f9d8df84f443b9a3390594dbe33bf
Source dataset
uspto-grants-2008_06
Patent number
US07388007B2

Reaction notes

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