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 132957ノート

反応式

HRID 132957 の反応式
[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]

参加物

8

反応物 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

生成物 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-phenylbutanamide収率 56%

試薬・触媒・溶媒 1

HCID 6228Dimethylformamide溶媒2 回

実験手順

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.

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-fb9bcdf762514f1a8ea20a6763af82ea
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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