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

HRID 1666978Notes

Reaction equation

HRID 1666978 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][CH2:11][CH2:10][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:37]=[CH:38][CH:39]=[CH:40][CH:41]=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]([CH3:34])([CH3:35])[CH3:33])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][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 59269830(3S,14R,16S)-14-(biphenyl-4-yl)-3-(tert-butoxycarbonylamino)-2-oxo-13-thia-1-azabicyclo[12.2.1]heptadecane-16-carboxylic acid

Product 1

HCID 59269827tert-butyl (3S,14R,16S)-14-(biphenyl-4-yl)-16-((1R,2S)-1-(cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropylcarbamoyl)-2-oxo-13-thia-1-azabicyclo[12.2.1]heptadecan-3-ylcarbamateYield 25.1%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

To an iced slurry of (3S,14R,16S)-14-(biphenyl-4-yl)-3-(tert-butoxycarbonylamino)-2-oxo-13-thia-1-azabicyclo[12.2.1]heptadecane-16-carboxylic acid (20 mg, 0.034 mmol), (1R,2S)-1-amino-N-(cyclopropylsulfonyl)-2-vinylcyclopropanecarboxamide, pTSA, 0.68H2O (17.85 mg, 0.043 mmol), and HATU (32.5 mg, 0.0855 mmol) in DCM (1 mL) was added N,N-Diisopropylethylamine (0.030 mL, 0.172 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 prep-HPLC to afford the desired product tert-butyl (3S,14R,16S)-14-(biphenyl-4-yl)-16-((1R,2S)-1-(cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropylcarbamoyl)-2-oxo-13-thia-1-azabicyclo[12.2.1]heptadecan-3-ylcarbamate (7 mg, 8.65 mmol, 25.1% A yield) as a white foam. 1H NMR (400 MHz, MeOD) δ ppm 0.94-1.37 (m, 13 H) 1.35-1.63 (m, 12 H) 1.84 (dd, J=8.16, 5.40 Hz, 1 H) 1.91-2.08 (m, 4 H) 2.08-2.19 (m, 1 H) 2.19-2.45 (m, 4 H) 2.59 (dd, J=12.30, 6.53 Hz, 1 H) 2.82-2.99 (m, 1 H) 3.87 (dd, J=10.29, 6.53 Hz, 1 H) 4.00-4.22 (m, 2 H) 4.64 (t, J=8.53 Hz, 1 H) 5.07 (dd, J=10.29, 1.51 Hz, 1 H) 5.24 (dd, J=17.19, 1.38 Hz, 1 H) 5.60-5.78 (m, 1 H) 6.36 (d, J=8.53 Hz, 1 H) 7.32 (t, J=7.28 Hz, 1 H) 7.42 (t, J=7.53 Hz, 2 H) 7.53-7.74 (m, 6 H); LC-MS (retention time: 3.50 min, method C), MS m/z 793.5 (M+H), 737 (M-t-Bu), 693 (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 prep-HPLC

Sources & evidence

ORD record
ord-8c7542a97df74592ab662396e7643662
Source dataset
uspto-grants-2011_10
Patent number
US08044087B2

Reaction notes

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