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 2425799Notes

Reaction equation

HRID 2425799 reaction equation
[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]

Participants

8

Reactant 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

Product 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-ylcarbamateYield 55.2%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

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).

Workup

  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

Sources & evidence

ORD record
ord-c8cbcad1810549d59e223f617bcde401
Source dataset
uspto-grants-2011_06
Patent number
US07964560B2

Reaction notes

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