Trifluoroacetic acid → (S)-1-[(S)-2-[(S)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-methyl-butyrylamino]-3-(3-methyl-oxetan-3-ylmethoxy)-propionyl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester

HRID 2285416Notes

Reaction equation

[Cl:1][C:2]([Cl:33])([Cl:32])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:31])[C@@H:14]([NH:23][C:24]([O:26]C(C)(C)C)=O)[CH2:15][O:16][CH2:17][C:18]2([CH3:22])[CH2:21][O:20][CH2:19]2)[NH:8]1)=[O:6].FC(F)(F)[C:36]([OH:38])=[O:37].[CH:41](N(CC)C(C)C)(C)C.[CH:50]1[C:62]2[CH:61]([CH2:63]OC(N[C@H](C(O)=O)C(C)C)=O)[C:60]3[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=3)[C:54]=2[CH:53]=[CH:52][CH:51]=1.C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2[N:89]=[CH:90][CH:91]=[CH:92]C=2N=N1.F[P-](F)(F)(F)(F)F>ClCCl.C(OCC)(=O)C>[Cl:33][C:2]([Cl:32])([Cl:1])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:31])[C@@H:14]([NH:23][C:24](=[O:26])[C@@H:90]([NH:89][C:36]([O:38][CH2:63][CH:61]2[C:60]3[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=3[C:54]3[C:62]2=[CH:50][CH:51]=[CH:52][CH:53]=3)=[O:37])[CH:91]([CH3:92])[CH3:41])[CH2:15][O:16][CH2:17][C:18]2([CH3:22])[CH2:21][O:20][CH2:19]2)[NH:8]1)=[O:6]

Participants

Conditions

Temperature: 0 °C

Procedure

To (S)-1-[(S)-2-tert-butoxycarbonylamino-3-(3-methyl-oxetan-3-ylmethoxy)-propionyl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (1.2 g, 2.26 mmol) in anhydrous dichloromethane (10 mL) at 0° C. and under an atmosphere of nitrogen was added trifluoroacetic acid (1.7 mL, 22.6 mmol). The reaction mixture was stirred for 3 h before concentrating in vacuo and co-evaporating from toluene (1×). The residue was dissolved in anhydrous acetonitrile (24 mL) at room temperature and under an atmosphere of nitrogen was added N,N-diisopropylethylamine (2.0 mL, 11.3 mmol), N-(9-fluorenylmethoxycarbonyl)-L-valine (767 mg, 2.26 mmol) and 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (1.2 g, 3.2 mmol). Following 2 h at room temperature the reaction was cooled to 0° C., diluted with ethyl acetate and quenched with 1 M hydrochloric acid. The organic layer was separated and washed with a saturated aqueous solution of sodium bicarbonate (2×) and brine (1×). The organic layer was then dried through a hydrophobic frit and concentrated in vacuo. The residue was purified by silica gel chromatography using iso-hexanes/ethyl acetate 1:1 then 1:2 to give the title compound (1.4 g, 82%) as a viscous clear oil. 1H NMR (300 MHz, CDCl3) δ 0.89-1.07 (m, 6H), 1.23 (s, 3H), 1.54-1.95 (m, 5H), 2.10-2.23 (m, 1H), 3.29-3.48 (m, 3H), 3.52-3.62 (m, 1H), 3.72-4.00 (m, 3H), 4.20-4.30 (m, 2H), 4.31-4.44 (m, 4H), 4.48 (d, J=5.6 Hz, 1H), 4.54 (d, J=5.6 Hz, 1H), 4.69 (d, J=12.3 Hz, 1H), 4.94 (d, J=12.3 Hz, 1H), 5.44-5.54 (m, 1H), 5.71-5.82 (m, 1H), 6.76 (d, J=7.6 Hz, 1H), 7.30-7.37 (m, 2H), 7.38-7.46 (m, 2H), 7.57-7.67 (m, 2H), 7.75-7.82 (m, 2H). LCMS (m/z) 753.2 [M+H], Tr=3.34 min.

Workup

concentrationbefore concentrating in vacuo and co-evaporating from toluene (1×)
dissolutionThe residue was dissolved in anhydrous acetonitrile (24 mL) at room temperature and under an atmosphere of nitrogen
waitFollowing 2 h at room temperature
customquenched with 1 M hydrochloric acid
customThe organic layer was separated
washwashed with a saturated aqueous solution of sodium bicarbonate (2×) and brine (1×)
customThe organic layer was then dried through a hydrophobic frit
concentrationconcentrated in vacuo
customThe residue was purified by silica gel chromatography

Sources & evidence

ORD record: ord-2cd7045c27f048d4ad62f77578fb17ba
Source dataset: uspto-grants-2015_09
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09145441B2

Reaction notes

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