Trifluoroacetic acid → (2S,4R)-methyl 4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoyl)-4-(isopropylthio)pyrrolidine-2-carboxylate

HRID 2425794Notes

Reaction equation

HRID 2425794 reaction equation
[C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([C@@:7]2([S:16][CH:17]([CH3:19])[CH3:18])[CH2:11][NH:10][C@H:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]2)=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O.[C:33]([O:37][C:38]([NH:40][C@@H:41]([C:45]([CH3:48])([CH3:47])[CH3:46])[C:42](O)=[O:43])=[O:39])([CH3:36])([CH3:35])[CH3:34].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>[C:1]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:2]=[CH:3][C:4]([C@@:7]2([S:16][CH:17]([CH3:19])[CH3:18])[CH2:11][N:10]([C:42](=[O:43])[C@@H:41]([NH:40][C:38]([O:37][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:39])[C:45]([CH3:48])([CH3:47])[CH3:46])[C@H:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]2)=[CH:5][CH:6]=1

Participants

7

Reactant 5

HCID 6422Trifluoroacetic acidHCID 81531DiisopropylethylamineHCID 2734668(S)-2-((tert-Butoxycarbonyl)amino)-3,3-dimethylbutanoic acidHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 57998019(2S,4R)-methyl 4-(biphenyl-4-yl)-4-(isopropylthio)pyrrolidine-2-carboxylate

Product 1

HCID 57998024(2S,4R)-methyl 4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoyl)-4-(isopropylthio)pyrrolidine-2-carboxylateYield 69.9%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

To an iced slurry of (2S,4R)-methyl 4-(biphenyl-4-yl)-4-(isopropylthio)pyrrolidine-2-carboxylate, TFA (255 mg, 0.543 mmol), (S)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoic acid (138 mg, 0.597 mmol), and HATU (309 mg, 0.814 mmol) in DCM (8 mL) was added N,N-diisopropylethylamine (0.285 mL, 1.629 mmol). The formed colorless slurry was stirred at room temperature overnight. Diluted with DCM, quenched with 5% citric acid. The organic layer was washed with 0.1 M NaOH and brine, dried over MgSO4, filtered, evaporated in vacuo. The residue was purified by BIOTAGE® column, eluted with 5˜35% EtOAc-hexane to yield the desired product (2S,4R)-methyl 4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoyl)-4-(isopropylthio)pyrrolidine-2-carboxylate (240 mg, 0.380 mmol, 69.9% yield) as a white foam. 1H NMR (500 MHz, MeOD) ppm 1.06 (d, 3H), 1.09-1.13 (m, 12H), 1.48 (s, 9H), 2.48 (dd, J=12.82, 8.24 Hz, 1H), 2.53-2.62 (m, 1H), 2.97 (dd, J=12.51, 7.63 Hz, 1H), 3.73 (s, 3H), 4.03 (d, J=11.29 Hz, 1H), 4.25 (t, J=7.93 Hz, 1H), 4.45 (s, 1H), 4.88-4.91 (m, 1H), 7.36 (t, J=7.32 Hz, 1H), 7.45 (t, J=7.78 Hz, 2H), 7.58-7.73 (m, 6H). LC-MS (retention time: 3.50 min, method B), MS m/z 569 (M+H).

Workup

  1. customquenched with 5% citric acid
  2. washThe organic layer was washed with 0.1 M NaOH and brine
  3. dry with materialdried over MgSO4
  4. filtrationfiltered
  5. customevaporated in vacuo
  6. customThe residue was purified by BIOTAGE® column
  7. washeluted with 5˜35% EtOAc-hexane

Sources & evidence

ORD record
ord-629c5da20c0a4190bf4222b084de3bf4
Source dataset
uspto-grants-2011_06
Patent number
US07964560B2

Reaction notes

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