p-Toluenesulfonic acid → tert-butyl (3S,14R,16S,E)-14-(biphenyl-4-yl)-16-((1R,2S)-1-(cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropylcarbamoyl)-2-oxo-13-thia-1-azabicyclo[12.2.1]heptadec-10-en-3-ylcarbamate

HRID 1666977Notes

Reaction equation

HRID 1666977 reaction equation
[C:1]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:6]=[CH:5][C:4]([C@@:7]23[CH2:26][N:20]([C@H:21]([C:23](O)=[O:24])[CH2:22]2)[C:19](=[O:27])[C@@H:18]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH:11]=[CH:10][CH2:9][S:8]3)=[CH:3][CH:2]=1.[NH2:42][C@:43]1([C:48]([NH:50][S:51]([CH:54]2[CH2:56][CH2:55]2)(=[O:53])=[O:52])=[O:49])[CH2:45][C@H:44]1[CH:46]=[CH2:47].CC1C=CC(S(O)(=O)=O)=CC=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C(Cl)Cl.CCOC(C)=O>[C:1]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:6]=[CH:5][C:4]([C@@:7]23[CH2:26][N:20]([C@H:21]([C:23](=[O:24])[NH:42][C@:43]4([C:48](=[O:49])[NH:50][S:51]([CH:54]5[CH2:56][CH2:55]5)(=[O:53])=[O:52])[CH2:45][C@H:44]4[CH:46]=[CH2:47])[CH2:22]2)[C:19](=[O:27])[C@@H:18]([NH:28][C:29](=[O:30])[O:31][C:32]([CH3:33])([CH3:35])[CH3:34])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH:11]=[CH:10][CH2:9][S:8]3)=[CH:3][CH:2]=1

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 59269832(3S,14R,16S,E)-14-(biphenyl-4-yl)-3-(tert-butoxycarbonylamino)-2-oxo-13-thia-1-azabicyclo[12.2.1]heptadec-10-ene-16-carboxylic acid

Product 1

HCID 59269831tert-butyl (3S,14R,16S,E)-14-(biphenyl-4-yl)-16-((1R,2S)-1-(cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropylcarbamoyl)-2-oxo-13-thia-1-azabicyclo[12.2.1]heptadec-10-en-3-ylcarbamateYield 66%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

To an iced slurry of (3S,14R,16S,E)-14-(biphenyl-4-yl)-3-(tert-butoxycarbonylamino)-2-oxo-13-thia-1-azabicyclo[12.2.1]heptadec-10-ene-16-carboxylic acid, (1R,2S)-1-amino-N-(cyclopropylsulfonyl)-2-vinylcyclopropanecarboxamide, pTSA, 0.68H2O (29.6 mg, 0.071 mmol), and HATU (32.5 mg, 0.0855 mmol) in DCM (2 mL) was added N,N-Diisopropylethylamine (0.050 mL, 0.285 mmol). The formed light brown solution was stirred at room temperature overnight. Diluted with EtOAc, washed it with 5% citric acid, and brine, dried over MgSO4, filtered, evaporated. The formed residue was purified by Biotage column, eluted with gradient 5%˜40% Acetone-Hexane to afford the desired product tert-butyl (3S,14R,16S,E)-14-(biphenyl-4-yl)-16-((1R,2S)-1-(cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropylcarbamoyl)-2-oxo-13-thia-1-azabicyclo[12.2.1]heptadec-10-en-3-ylcarbamate (31 mg, 0.038 mmol, 66.0% yield) as a white foam. 1H NMR (500 MHz, MeOD) δ ppm 1.09 (s, 1 H) 1.16-1.32 (m, 3 H) 1.33-1.40 (m, 2 H) 1.41-1.63 (m, 16 H) 1.64-1.83 (m, 4 H) 1.87-1.99 (m, 2 H) 2.00-2.11 (m, 1 H) 2.13-2.24 (m, 1 H) 2.24-2.34 (m, 1 H) 2.40 (t, J=11.29 Hz, 1 H) 2.62-2.75 (m, 2 H) 2.87-3.01 (m, 1 H) 3.08 (d, J=14.95 Hz, 1 H) 3.87 (dd, J=10.38, 6.41 Hz, 1 H) 4.01 (d, J=10.68 Hz, 1 H) 4.59-4.80 (m, 2 H) 5.12 (d, J=10.07 Hz, 1 H) 5.29 (d, J=17.09 Hz, 1 H) 5.53-5.63 (m, 2 H) 5.64-5.80 (m, 1 H) 7.37 (t, J=7.48 Hz, 1 H) 7.47 (t, J=7.48 Hz, 2 H) 7.57-7.64 (m, 2 H), 7.68-7.82 (m, 4 H). LC-MS (retention time: 3.48 min, method C), MS ink 792 (M+H), 735 (M-t-Bu), 691 (M-BOC).

Workup

  1. washwashed it with 5% citric acid, and brine
  2. dry with materialdried over MgSO4
  3. filtrationfiltered
  4. customevaporated
  5. customThe formed residue was purified by Biotage column
  6. washeluted with gradient 5%˜40% Acetone-Hexane

Sources & evidence

ORD record
ord-f7f0f452acc2484f928795ce03a3d57f
Source dataset
uspto-grants-2011_10
Patent number
US08044087B2

Reaction notes

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