Diisopropylethylamine → (1R,2S)-ethyl 1-((2S,4R)-4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)-3,3-dimethylnon-8-enoyl)-4-(butylthio)pyrrolidine-2-carboxamido)-2-vinylcyclopropanecarboxylate

HRID 1666531Notes

Reaction equation

HRID 1666531 reaction equation
[C:1]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:6]=[CH:5][C:4]([C@@:7]2([S:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:11][N:10]([C:12](=[O:31])[C@@H:13]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:14]([CH3:22])([CH3:21])[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20])[C@H:9]([C:32]([OH:34])=O)[CH2:8]2)=[CH:3][CH:2]=1.[NH2:46][C@:47]1([C:52]([O:54][CH2:55][CH3:56])=[O:53])[CH2:49][C@H:48]1[CH:50]=[CH2:51].P([O-])([O-])([O-])=O.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>ClCCl.C(OCC)(=O)C>[C:1]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:6]=[CH:5][C:4]([C@@:7]2([S:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:11][N:10]([C:12](=[O:31])[C@@H:13]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:14]([CH3:21])([CH3:22])[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20])[C@H:9]([C:32]([NH:46][C@:47]3([C:52]([O:54][CH2:55][CH3:56])=[O:53])[CH2:49][C@H:48]3[CH:50]=[CH2:51])=[O:34])[CH2:8]2)=[CH:3][CH:2]=1

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 10820795rac-ethyl (1R,2S)-1-amino-2-ethenylcyclopropane-1-carboxylateHCID 67443406(2S,4R)-4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)-3,3-dimethylnon-8-enoyl)-4-(butylthio)pyrrolidine-2-carboxylic acidHCID 86636557O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium phosphate

Product 1

HCID 86636556(1R,2S)-ethyl 1-((2S,4R)-4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)-3,3-dimethylnon-8-enoyl)-4-(butylthio)pyrrolidine-2-carboxamido)-2-vinylcyclopropanecarboxylateYield 49%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

To an iced slurry of (2S,4R)-4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)-3,3-dimethylnon-8-enoyl)-4-(butylthio)pyrrolidine-2-carboxylic acid (126 mg, 0.198 mmol), (1R,2S)-ethyl 1-amino-2-vinylcyclopropanecarboxylate (36.8 mg, 0.237 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium phosphate (HATU, 113 mg, 0.297 mmol) in dichloromethane (4 mL) was added N,N-diisopropylethylamine (0. 104 mL, 0.594 mmol). The formed light brown solution was stirred at room temperature overnight. Diluted with ethyl acetate, washed it with 5% citric acid, 0.1 M NaOH, and brine, dried over MgSO4, filtered, and concentrated. The resulting brown residue was purified by BIOTAGE® column, eluted with gradient 5˜45% ethyl acetate-hexane to afford the desired product (1R,2S)-ethyl 1-((2S,4R)-4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)-3,3-dimethylnon-8-enoyl)-4-(butylthio)pyrrolidine-2-carboxamido)-2-vinylcyclopropanecarboxylate (75 mg, 0.097 mmol, 49.0% yield) as a white film. 1H NMR (500 MHz, MeOD) δ ppm 0.75-0.90 (m, 3 H) 1.24-1.54 (m, 24 H) 1.61 (tt, J=9.00, 4.27 Hz, 1 H) 1.65-1.77 (m, 2 H) 1.86 (d, J=7.32 Hz, 1 H) 1.94-2.11 (m, 2 H) 2.19-2.41 (m, 3 H) 2.41-2.51 (m, 1 H) 2.77 (dd, J=13.12, 7.02 Hz, 1 H) 3.03 (dd, J=12.51, 7.63 Hz, 1 H) 3.94-4.04 (m, 1 H) 4.09-4.24 (m, 3 H) 4.35 (t, J=7.48 Hz, 1 H) 5.07-5.18 (m, 1 H) 5.24-5.36 (m, 1 H) 5.70-5.86 (m, 2 H) 7.30-7.41 (m, 1 H) 7.46 (t, J=7.63 Hz, 2 H) 7.58-7.75 (m, 6 H). LC-MS (retention time: 3.72 min, method C), MS m/z 774 (M-C2 H4).

Workup

  1. washwashed it with 5% citric acid, 0.1 M NaOH, and brine
  2. dry with materialdried over MgSO4
  3. filtrationfiltered
  4. concentrationconcentrated
  5. customThe resulting brown residue was purified by BIOTAGE® column
  6. washeluted with gradient 5˜45% ethyl acetate-hexane

Sources & evidence

ORD record
ord-ff4d96ff8f814493a06873fb3cf5f16d
Source dataset
uspto-grants-2011_10
Patent number
US08044023B2

Reaction notes

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