p-Toluenesulfonic acid → tert-butyl (S)-1-((2S,4R)-4-(allylthio)-4-(biphenyl-4-yl)-2-((1R,2S)-1-(cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropylcarbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-ylcarbamate

HRID 2425799Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 2425799
[CH2:1]([S:4][C@:5]1(C2C=CC(C3C=CC=CC=3)=CC=2)[CH2:9][N:8]([C:10](=[O:24])[C@@H:11]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:12]([CH3:15])([CH3:14])[CH3:13])[C@H:7]([C:25](O)=[O:26])[CH2:6]1)[CH:2]=[CH2:3].[NH2:40][C@:41]1([C:46]([NH:48][S:49]([CH:52]2[CH2:54][CH2:53]2)(=[O:51])=[O:50])=[O:47])[CH2:43][C@H:42]1[CH:44]=[CH2:45].[CH3:55][C:56]1[CH:57]=[CH:58][C:59](S(O)(=O)=O)=[CH:60][CH:61]=1.CN(C(ON1N=N[C:76]2[CH:77]=[CH:78][CH:79]=N[C:75]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[OH2:18].[CH2:1]([S:4][C@:5]1([C:59]2[CH:58]=[CH:57][C:56]([C:55]3[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=3)=[CH:61][CH:60]=2)[CH2:9][N:8]([C:10](=[O:24])[C@@H:11]([NH:16][C:17](=[O:18])[O:19][C:20]([CH3:21])([CH3:23])[CH3:22])[C:12]([CH3:15])([CH3:14])[CH3:13])[C@H:7]([C:25](=[O:26])[NH:40][C@:41]2([C:46](=[O:47])[NH:48][S:49]([CH:52]3[CH2:54][CH2:53]3)(=[O:51])=[O:50])[CH2:43][C@H:42]2[CH:44]=[CH2:45])[CH2:6]1)[CH:2]=[CH2:3]

Komponenten

8

Edukt 5

HCID 6101p-Toluenesulfonic acidHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 23595125(1R,2S)-1-Amino-N-(cyclopropylsulfonyl)-2-vinylcyclopropanecarboxamideHCID 57998012(2S,4R)-4-(allylthio)-4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoyl)pyrrolidine-2-carboxylic acid

Produkt 2

HCID 962WaterHCID 44544709tert-butyl (S)-1-((2S,4R)-4-(allylthio)-4-(biphenyl-4-yl)-2-((1R,2S)-1-(cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropylcarbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-ylcarbamateAusbeute 55,2 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 6344DichloromethaneLösungsmittel2×

Versuchsvorschrift

To a slurry of (2S,4R)-4-(allylthio)-4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoyl)pyrrolidine-2-carboxylic acid (16 mg, 0.029 mmol), (1R,2S)-1-amino-N-(cyclopropylsulfonyl)-2-vinylcyclopropanecarboxamide, pTSA, 0.68H2O (15.01 mg, 0.036 mmol), and HATU (16.51 mg, 0.043 mmol) in DCM (1 mL) was added N,N-diisopropylethylamine (0.025 mL, 0.145 mmol). The formed solution was stirred at room temperature overnight. Diluted with DCM, washed with 1M HCl and brine, dried over MgSO4, filtered, evaporated. The residue was purified by BIOTAGE® column, eluted with gradient 5%˜50% acetone-hexane to afford the desired product tert-butyl (S)-1-((2S,4R)-4-(allylthio)-4-(biphenyl-4-yl)-2-((1R,2S)-1-(cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropylcarbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-ylcarbamate (13 mg, 0.016 mmol, 55.2% yield) as a white foam. 1H NMR (500 MHz, MeOD) ppm 0.99-1.15 (m, 10H) 1.24 (d, J=4.52 Hz, 2H) 1.42 (dd, J=9.41, 5.40 Hz, 1H) 1.49 (s, 9H) 1.86 (dd, J=8.03, 5.52 Hz, 1H) 2.19 (q, J=8.78 Hz, 1H) 2.34 (t, J=41.54 Hz, 1H) 2.81 (dd, J=12.17, 6.40 Hz, 1H) 2.87-3.07 (m, 3H) 3.89 (dd, J=10.54, 6.27 Hz, 1H) 3.97 (d, J=11.04 Hz, 1H) 4.48 (d, J=9.79 Hz, 1H) 4.97-5.15 (m, 4H) 5.27 (d, J=17.07 Hz, 1H) 5.64-5.88 (m, 2H) 6.75 (d, J=9.79 Hz, 1H) 7.30-7.40 (m, 1H) 7.45 (t, J=7.53 Hz, 2H) 7.54-7.63 (m, 4H) 7.64-7.74 (m, 2H). LC-MS (retention time: 3.00 mm, method B), MS m/z 765 (M+H).

Aufarbeitung

  1. washwashed with 1M HCl and brine
  2. dry with materialdried over MgSO4
  3. filtrationfiltered
  4. customevaporated
  5. customThe residue was purified by BIOTAGE® column
  6. washeluted with gradient 5%˜50% acetone-hexane

Quellen und Nachweise

ORD-Eintrag
ord-c8cbcad1810549d59e223f617bcde401
Quelldatensatz
uspto-grants-2011_06
Patentnummer
US07964560B2

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