Trifluoroacetic acid → (S)-1-[(S)-3-tert-Butoxycarbonyl-2-(9H-fluoren-9-ylmethoxy carbonylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester

HRID 2285384Notes

Reaction equation

HRID 2285384 reaction equation
[Cl:1][C:2]([Cl:28])([Cl:27])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15]C(C)(C)C)=O)[N:8]1C(OC(C)(C)C)=O)=[O:6].FC(F)(F)C(O)=O.[C:36]([O:40][C:41](=[O:65])[CH2:42][C@@H:43](C(O)=O)[NH:44][C:45]([O:47][CH2:48][CH:49]1[C:61]2[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=2)[C:55]2[C:50]1=[CH:51][CH:52]=[CH:53][CH:54]=2)=[O:46])([CH3:39])([CH3:38])[CH3:37].C(N(CC)C(C)C)(C)C.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.C(#N)C>[Cl:28][C:2]([Cl:1])([Cl:27])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:15])[C@@H:43]([NH:44][C:45]([O:47][CH2:48][CH:49]2[C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][C:55]=3[C:56]3[C:61]2=[CH:60][CH:59]=[CH:58][CH:57]=3)=[O:46])[CH2:42][C:41]([O:40][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:65])[NH:8]1)=[O:6]

Participants

8

Reactant 5

HCID 6422Trifluoroacetic acidHCID 81531DiisopropylethylamineHCID 2724635Fmoc-L-Asp(OtBu)-OHHCID 866211442-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate MethanaminiumHCID 86706063(S)-tetrahydro-pyridazine-1,2,3-tricarboxylic acid 1,2-di-tert-butyl ester 3-(2,2,2-trichloro-ethyl) ester

Product 1

HCID 86709674(S)-1-[(S)-3-tert-Butoxycarbonyl-2-(9H-fluoren-9-ylmethoxy carbonylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl esterYield 88.8%

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolventHCID 6344DichloromethaneSolvent

Procedure

To (S)-tetrahydro-pyridazine-1,2,3-tricarboxylic acid 1,2-di-tert-butyl ester 3-(2,2,2-trichloro-ethyl)ester (2.0 g, 4.3 mmol) in anhydrous dichloromethane (13 mL) at 0° C. and under an atmosphere of nitrogen was added trifluoroacetic acid (13 mL, 173 mmol). The solution was warmed to room temperature and stirred for 16 h. The reaction was concentrated in vacuo and the residue co-evaporated from toluene (3×). The resulting brown, viscous oil was dissolved in anhydrous acetonitrile (5 mL) and added to a solution of Fmoc-L-aspartic acid 4-tert-butyl ester (1.78 g, 4.3 mmol), N,N-diisopropylethylamine (3.0 mL, 17.3 mmol) and 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (1.60 g, 4.3 mmol) in anhydrous acetonitrile (25 mL) that had been previously stirred at 0° C. for 20 minutes. The reaction was warmed to room temperature and stirred for 16 h before being concentrated in vacuo. The residue was purified by silica gel chromatography using iso-hexanes/ethyl acetate 2:1 to give the title compound (2.5 g, 88%) as a clear, viscous oil. 1H NMR (300 MHz, CDCl3) δ 1.46 (s, 9H), 1.69-1.83 (m, 2H), 1.87-2.00 (m, 1H), 2.15-2.27 (m, 1H), 2.79-2.67 (m, 2H), 2.90-3.02 (m, 1H), 3.81-3.93 (m, 2H), 4.21-4.29 (m, 1H), 4.32-4.44 3H), 4.71 (d, J=12.0 Hz, 1H), 4.96 (d, J=12.0 Hz, 1H), 5.31-5.43 (m, 1H), 5.85 (d, J=8.5 Hz, 1H), 7.33 (app t, J=7.4 Hz, 2H), 7.41 (app t, J=7.4 Hz, 2H), 7.59-7.66 (m, 2H), 7.78 (d, J=7.6 Hz, 2H). LCMS (m/z)=654.2 [M+H], Tr=3.63 min.

Workup

  1. concentrationThe reaction was concentrated in vacuo
  2. dissolutionThe resulting brown, viscous oil was dissolved in anhydrous acetonitrile (5 mL)
  3. stirringhad been previously stirred at 0° C. for 20 minutes
  4. temperatureThe reaction was warmed to room temperature
  5. stirringstirred for 16 h
  6. concentrationbefore being concentrated in vacuo
  7. customThe residue was purified by silica gel chromatography

Sources & evidence

ORD record
ord-30cdd536c022494281067365e84a6dcd
Source dataset
uspto-grants-2015_09
Patent number
US09145441B2

Reaction notes

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