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-hydroxypyrrolidin-2-yl)propan-2-yl)-4-phenylbutanamide

HRID 132967노트

반응식

HRID 132967 반응식
[C:1]([NH:4][C@:5]1([C@@H:54]([CH2:56][CH3:57])[CH3:55])[CH2:9][CH2:8][N:7]([C@@H:10]([CH2:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:11]([NH:13][C@@H:14]([CH2:36][C:37]2[CH:42]=[C:41]([F:43])[CH:40]=[C:39]([F:44])[CH:38]=2)[C@@H:15]([C@H:17]2[CH2:21][C@@H:20]([OH:22])[CH2:19][N:18]2C(C2C=CC=CC=2)C2C=CC=CC=2)[OH:16])=[O:12])[C:6]1=[O:53])(=[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)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.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:1]([NH:4][C@:5]1([C@@H:54]([CH2:56][CH3:57])[CH3:55])[CH2:9][CH2:8][N:7]([C@@H:10]([CH2:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:11]([NH:13][C@@H:14]([CH2:36][C:37]2[CH:42]=[C:41]([F:43])[CH:40]=[C:39]([F:44])[CH:38]=2)[C@H:15]([OH:16])[C@H:17]2[CH2:21][C@H:20]([OH:22])[CH2:19][NH:18]2)=[O:12])[C:6]1=[O:53])(=[O:3])[CH3:2]

참가 물질

8

반응물 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 69194216(S)-2-((S)-3-acetamido-3-((R)-sec-butyl)-2-oxopyrrolidin 1-yl)-N-((1S,2S)-1-((2R,4S)-1-benzhydryl-4-hydroxypyrrolidin-2-yl)-3-(3,5-difluorophenyl)-1-hydroxypropan-2-yl)-4-phenylbutanamideHCID 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

생성물 1

HCID 69195085(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-hydroxypyrrolidin-2-yl)propan-2-yl)-4-phenylbutanamide수율 72%

시약·촉매·용매 1

HCID 6228Dimethylformamide용매2회

실험 절차

Step 15 (B): (S)-2-((S)-3-acetamido-3-((R)-sec-butyl)-2-oxopyrrolidin 1-yl)-N-((1S,2S)-1-((2R,4S)-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, 38.9 mg, 0.108 mmol) in DMF (2 mL) was added HATU (49.43 mg, 0.130 mmol). A solution of (3S,5R)-5-((1S,2S)-2-amino-3-(3,5-difluorophenyl)-1-hydroxypropyl)-1-benzhydrylpyrrolidin-3-ol (Step 15 (A), 47.3 mg, 0.108 mmol) in DMF (2 mL) was then added, followed by N-methylmorpholine (42 μl, 0.378 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 (60.5 mg, 72% yield) as a clear oil:

후처리

  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

출처 및 근거

ORD 기록
ord-881625e4ab484333b0be3393aa3b88d3
출처 데이터셋
uspto-grants-2008_06
특허 번호
US07388007B2

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