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 132952노트

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HRID 132952 반응식
[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]

참가 물질

7

반응물 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

생성물 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

시약·촉매·용매 1

HCID 6228Dimethylformamide용매2회

실험 절차

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.

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-41d088f1b94c43db9e0c44bbd42f04f5
출처 데이터셋
uspto-grants-2008_06
특허 번호
US07388007B2

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