Propiolic Acid → tert-Butyl ((S)-1-(((S)-3,3-dimethyl-1-oxo-1-((2S,4S)-4-propiolamido-2-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-1-yl)butan-2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

HRID 527756Notes

Reaction equation

HRID 527756 reaction equation
[C:1](O)(=[O:4])[C:2]#[CH:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:30][C@@H:31]1[CH2:35][N:34]([C:36](=[O:56])[C@@H:37]([NH:42][C:43](=[O:55])[C@@H:44]([N:46]([CH3:54])[C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50])[CH3:45])[C:38]([CH3:41])([CH3:40])[CH3:39])[C@H:33]([C:57](=[O:69])[NH:58][C@H:59]2[C:68]3[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=3)[CH2:62][CH2:61][CH2:60]2)[CH2:32]1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C.[Cl-].[Na+].O>[CH3:39][C:38]([CH3:40])([CH3:41])[C@H:37]([NH:42][C:43](=[O:55])[C@@H:44]([N:46]([CH3:54])[C:47](=[O:53])[O:48][C:49]([CH3:50])([CH3:51])[CH3:52])[CH3:45])[C:36](=[O:56])[N:34]1[CH2:35][C@@H:31]([NH:30][C:1](=[O:4])[C:2]#[CH:3])[CH2:32][C@H:33]1[C:57](=[O:69])[NH:58][C@H:59]1[C:68]2[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=2)[CH2:62][CH2:61][CH2:60]1

Participants

8

Reactant 4

HCID 10110Propiolic AcidHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 57806830Tert-butyl (s)-1-((s)-1-((2s,4s)-4-amino-2-((r)-1,2,3,4-tetrahydronaphthalen-1-ylcarbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-ylamino)-1-oxopropan-2-yl(methyl)carbamate

Product 1

HCID 89930884tert-Butyl ((S)-1-(((S)-3,3-dimethyl-1-oxo-1-((2S,4S)-4-propiolamido-2-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-1-yl)butan-2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamateYield 70%

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolventHCID 57417360Sodium chloride; waterSolvent

Procedure

To a solution of propiolic acid (0.06 mL, 0.90 mmol) in DMF (2 mL) at 0° C. was added HATU (123 mg, 0.32 mmol) followed by tert-butyl ((S)-1-(((S)-1-((2S,4S)-4-amino-2-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate (100 mg, 0.18 mmol) and DIEA (0.06 mL, 0.36 mmol). The reaction mixture was stirred at rt for 1 h and diluted with ethyl acetate and brine. The organic layer was separated, washed with aq. NaHCO3 solution, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography (eluting with 90% EtOAc/hexane) to afford the title compound as a white solid (76 mg, 70%). 1H NMR (CDCl3) δ 8.60 (d, J=6.6 Hz, 1H), 7.85 (d, J=8.6 Hz, 1H), 7.25 (m, 1H), 7.16-6.98 (m, 3H), 5.23-5.08 (m, 1H), 4.73 (d, J=8.8 Hz, 1H), 4.63-4.48 (m, 1H), 4.32 (d, J=8.6 Hz, 1H), 3.96 (dd, J=10.9, 5.0 Hz, 1H), 3.75 (d, J=11.0 Hz, 1H), 2.80-2.70 (m, 5H), 2.43 (d, J=13.9 Hz, 1H), 2.18 (ddd, J=14.0, 8.9, 6.4 Hz, 1H), 2.06-1.94 (m, 1H), 1.91-1.80 (m, 4H), 1.46 (s, 10H), 1.30-1.25 (m, 3H), 0.76 (s, 9H); MS(ESI+) m/z 610.4 (M+H)+.

Workup

  1. customThe organic layer was separated
  2. washwashed with aq. NaHCO3 solution
  3. dry with materialdried over MgSO4
  4. concentrationconcentrated in vacuo
  5. customThe residue was purified by flash column chromatography (eluting with 90% EtOAc/hexane)

Sources & evidence

ORD record
ord-23f5e9d6c8ad4e8da92f9df666047c72
Source dataset
uspto-grants-2016_05
Patent number
US09345740B2

Reaction notes

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