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

HRID 132952ノート

反応式

HRID 132952 の反応式
[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][CH: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(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=CC=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: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:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:19][NH:18]2)=[O:12])[C:6]1=[O:59])(=[O:3])[CH3:2]

参加物

7

反応物 5

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 69193948(S)-2-((S)-3-acetamido-3-((R)-sec-butyl)-2-oxopyrrolidin-1-yl)-N-((1S,2S)-1-((2R,4S)-1-benzhydryl-4-phenoxypyrrolidin-2-yl)-3-(3,5-difluorophenyl) 1-hydroxypropan-2-yl)-4-phenylbutanamideHCID 69195486(1S,2S)-2-amino-1-((2R,4S)-1-benzhydryl-4-phenoxypyrrolidin-2-yl)-3-(3,5-difluorophenyl)propan-1-ol

生成物 1

HCID 69196467(S)-2-((S)-3-acetamido-3-((R)-sec-butyl)-2-oxopyrrolidin-1-yl)-N-((1R,2S)-3-(3,5-difluorophenyl)-1-hydroxy-1-((2R,4S)-4-phenoxypyrrolidin-2-yl)propan-2-yl)-4-phenylbutanamide

試薬・触媒・溶媒 1

HCID 6228Dimethylformamide溶媒2 回

実験手順

Step 9 (C): (S)-2-((S)-3-acetamido-3-((R)-sec-butyl)-2-oxopyrrolidin-1-yl)-N-((1S,2S)-1-((2R,4S)-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, 29 mg, 0.080 mmol) in DMF (2 mL) was added HATU (36.5 mg, 0.096 mmol). A solution of (1S,2S)-2-amino-1-((2R,4S)-1-benzhydryl-4-phenoxypyrrolidin-2-yl)-3-(3,5-difluorophenyl)propan-1-ol (Step 9 (B), 41.1 mg, 0.080 mmol) in DMF (2 mL) was then added, followed by N-methylmorpholine (37 μl, 0.336 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 (34 mg): 1H NMR (CDCl3, 300 MHz) δ 0.82 (3H, d, J=6 Hz), 0.98 (3H, m), 1.07-1.15 (1H, m), 1.51-1.61 (1H, m), 1.68-1.74 (1H, m), 1.85-2.08 (5H, m), 2.17-2.30 (1H, m), 2.41-2.57 (2H, m), 2.63-2.76 (2H, m), 2.80-2.95 (3H, m), 3.09 (1H, dd, J=3, 15 Hz), 3.47-3.54 (3H, m), 3.67-4.05 (6H, m), 5.08 (1H, m), 5.39 (1H, s), 5.99 (1H, s), 6.56-6.69 (4H, m), 6.86 (2H, d, J=9 Hz), 7.03 (1H, m), 7.14-7.34 (12H, m), 7.68 (2H, m), 7.63-7.66 (2H, m). HPLC retention time: 1.99 min (method C). MS (ESI) (M+H)+ 857.45.

後処理

  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

出典と根拠

ORDレコード
ord-41d088f1b94c43db9e0c44bbd42f04f5
出典データセット
uspto-grants-2008_06
特許番号
US07388007B2

反応ノート

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