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Water → Tert-butyl (s)-1-((2s,4r)-4-(biphenyl-4-yl)-4-(butylthio)-2-((1r,2s)-1-(cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropylcarbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-ylcarbamate

HRID 2425783
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HRID 2425783 반응식
C1(C2C=CC=CC=2)C=CC([C@@:7]2([S:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:11][N:10]([C:12](=[O:26])[C@@H:13]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:14]([CH3:17])([CH3:16])[CH3:15])[C@H:9]([C:27](O)=[O:28])[CH2:8]2)=CC=1.[C:41]1([CH3:51])[CH:46]=[CH:45][C:44](S(O)(=O)=O)=[CH:43][CH:42]=1.[NH2:52][C@:53]1([C:58]([NH:60][S:61]([CH:64]2[CH2:66][CH2:65]2)(=[O:63])=[O:62])=[O:59])[CH2:55][C@H:54]1[CH:56]=[CH2:57].O.CN(C(ON1N=N[C:78]2[CH:79]=[CH:80][CH:81]=N[C:77]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:51]1([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:81]=[CH:80][C:79]([C@@:7]2([S:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:11][N:10]([C:12](=[O:26])[C@@H:13]([NH:18][C:19](=[O:20])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[C:14]([CH3:15])([CH3:16])[CH3:17])[C@H:9]([C:27](=[O:28])[NH:52][C@:53]3([C:58](=[O:59])[NH:60][S:61]([CH:64]4[CH2:66][CH2:65]4)(=[O:63])=[O:62])[CH2:55][C@H:54]3[CH:56]=[CH2:57])[CH2:8]2)=[CH:78][CH:77]=1
참가 물질실험 절차후처리출처 및 근거반응 노트

참가 물질

7

반응물 5

HCID 962WaterHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 57998016(2S,4R)-4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoyl)-4-(butylthio)pyrrolidine-2-carboxylic acidHCID 72163227Cyclopropanecarboxamide, 1-amino-N-(cyclopropylsulfonyl)-2-ethenyl-, (1R,2S)-, 4-methylbenzenesulfonate (1:1)

생성물 1

HCID 44476536Tert-butyl (s)-1-((2s,4r)-4-(biphenyl-4-yl)-4-(butylthio)-2-((1r,2s)-1-(cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropylcarbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-ylcarbamate수율 78%

시약·촉매·용매 1

HCID 6344Dichloromethane용매2회

실험 절차

To an iced slurry of (2S,4R)-4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoyl)-4-(butylthio)pyrrolidine-2-carboxylic acid (60 mg, 0.105 mmol), (1R,2S)-1-amino-N-(cyclopropylsulfonyl)-2-vinylcyclopropanecarboxamide, p-toluenesulfonate salt, H2O (53.1 mg, 0.127 mmol), and HATU (60.1 mg, 0.158 mmol) in DCM (2 mL) was added N,N-diisopropylethylamine (0.055 mL, 0.316 mmol). The formed colorless slurry was stirred at room temperature for 5 h (it became light yellow solution). Diluted with DCM, quenched with 5% citric acid. The separated organic layer was washed with sat. sodium citrate and brine, dried over MgSO4, filtered, evaporated in vacuo. The residue was purified by BIOTAGE® column, eluted with gradient 5%-40% acetone-hexane to yield the desired product tert-butyl (S)-1-((2S,4R)-4-(biphenyl-4-yl)-4-(butylthio)-2-((1R,2S)-1-(cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropylcarbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-ylcarbamate (69 mg, 0.082 mmol, 78% yield) as a white solid. 1H NMR (500 MHz, MeOD) ppm 0.83 (t, J=7.32 Hz, 3H), 1.03-1.12 (m, 10H), 1.19-1.36 (m, 4H), 1.35-1.49 (m, 4H), 1.48 (s, 9H), 1.88 (s, J=7.93, 5.49 Hz, 3H), 2.14-2.24 (m, 1H), 2.23-2.30 (m, 1H), 2.35 (t, J=11.60 Hz, 1H), 2.39-2.53 (m, 1H), 2.76-2.87 (m, 1H), 2.89-3.00 (m, 1H), 3.93 (dd, J=10.68, 641 Hz, 1H), 3.99 (d, J=10.99 Hz, 1H), 4.51 (d, J=10.07 Hz, 1H), 5.06 (d, J=10.99 Hz, 1H), 5.10-5.19 (m, 1H), 5.29 (d, J=17.09 Hz, 1H), 5.69-5.83 (m, 1H), 7.37 (t, J=7.32 Hz, 1H), 7.46 (t, J=7.78 Hz, 2H), 7.55-7.63 (m, 4H) 7.64-7.77 (m, 2H). LC-MS (retention time: 3.48 min, method B), MS m/z 781 (M+H).

후처리

  1. customquenched with 5% citric acid
  2. washThe separated organic layer was washed with sat. sodium citrate and brine
  3. dry with materialdried over MgSO4
  4. filtrationfiltered
  5. customevaporated in vacuo
  6. customThe residue was purified by BIOTAGE® column
  7. washeluted with gradient 5%-40% acetone-hexane

출처 및 근거

ORD 기록
ord-4c1a5ba4a5f74eadac378df9924ef1a8
출처 데이터셋
uspto-grants-2011_06
DOI
10.6084/m9.figshare.5104873.v1
특허 번호
US07964560B2

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