Trimethylsilyl triflate → (S)-1-[(S)-2-((S)-2-tert-Butoxycarbonylamino-3-methyl-butyrylamino)-3-(tert-butyl-diphenyl-silanyloxy)-propionyl]-hexahydropyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester

HRID 2285357Notes

Reaction equation

[Cl:1][C:2]([Cl:44])([Cl:43])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:42])[C@@H:14]([NH:34][C:35](OC(C)(C)C)=[O:36])[CH2:15][O:16][Si:17]([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[NH:8]1)=[O:6].FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C(N(CC)C(C)C)(C)C.[C:66]([O:70][C:71]([NH:73][C@H:74](C(O)=O)[CH:75]([CH3:77])[CH3:76])=[O:72])([CH3:69])([CH3:68])[CH3:67].C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F>ClCCl>[Cl:1][C:2]([Cl:44])([Cl:43])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:42])[C@@H:14]([NH:34][C:35](=[O:36])[C@@H:74]([NH:73][C:71]([O:70][C:66]([CH3:68])([CH3:67])[CH3:69])=[O:72])[CH:75]([CH3:77])[CH3:76])[CH2:15][O:16][Si:17]([C:30]([CH3:32])([CH3:31])[CH3:33])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:8]1)=[O:6]

Participants

Conditions

Temperature: 0 °C

Procedure

To (S)-1-[(S)-2-tert-butoxycarbonylamino-3-(tert-butyl-diphenyl-silanyloxy)-propionyl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (1.0 g, 1.46 mmol) in anhydrous dichloromethane (25 mL) at 0° C. and under an atmosphere of nitrogen was added trimethylsilyl trifluoromethanesulfonate (400 μL, 2.19 mmol). The reaction mixture was stirred at 0° C. for 2 h before adding N,N-diisopropylethylamine (1.0 mL, 5.84 mmol) and concentrating in vacuo. The residue was dissolved in anhydrous acetonitrile (15 mL) at room temperature and under an atmosphere of nitrogen was added N,N-diisopropylethylamine (763 μL, 4.38 mmol), N-(tert-butoxycarbonyl)-L-valine, (317 mg, 1.46 mmol) and 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (777 mg, 2.04 mmol). Following 2 h at room temperature the reaction was quenched with water and extracted with ethyl acetate (2×). The combined organic layers were dried through a hydrophobic frit and concentrated in vacuo. The residue was purified by silica gel chromatography using iso-hexanes/ethyl acetate 2:1 to give the title compound (500 mg, 44%) as a white foam. 1H NMR (300 MHz, CDCl3) δ 0.88-1.00 (m, 6H), 1.07 (s, 9H), 1.48 (s, 9H), 1.50-1.70 (m, 2H), 1.78-1.89 (m, 1H), 1.92-2.02 (m, 1H), 2.10-2.25 (m, 1H), 2.81-3.02 (m, 1H), 3.15-3.30 (m, 1H), 3.60 (d, J=10.7 Hz, 1H), 3.95 (br d, J=3.6 Hz, 2H), 3.98-4.06 (m, 1H), 4.19-4.30 (m, 1H), 4.59 (d, J=12.0 Hz, 1H), 4.90 (d, J=12.0 Hz, 1H), 5.10-5.20 (m, 1H), 5.36-5.47 (m, 1H), 6.77-6.88 (m, 1H), 7.36-7.50 (m, 6H), 7.56-7.70 (m, 4H). LCMS (m/z)=785.3 [M+H], Tr=4.25 min.

Workup

concentrationconcentrating in vacuo
dissolutionThe residue was dissolved in anhydrous acetonitrile (15 mL) at room temperature and under an atmosphere of nitrogen
waitFollowing 2 h at room temperature
customthe reaction was quenched with water
extractionextracted with ethyl acetate (2×)
customThe combined organic layers were dried through a hydrophobic frit
concentrationconcentrated in vacuo
customThe residue was purified by silica gel chromatography

Sources & evidence

ORD record: ord-7190efd0798c443eba6f0f687a62aa3b
Source dataset: uspto-grants-2015_09
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09145441B2

Reaction notes

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