Trifluoroacetic acid → (S)-1-[(S)-2-((S)-2-{(E)-4-[2-((R)-1-Acetoxy-ethyl)-quinolin-7-yl]-2,2-dimethyl-but-3-enoylamino}-3-methyl-butyrylamino)-3-pyrazol-1-yl-propionyl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester

HRID 2285409Notes

Reaction equation

HRID 2285409 reaction equation
[Cl:1][C:2]([Cl:38])([Cl:37])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:36])[C@@H:14]([NH:21][C:22](=[O:35])[C@@H:23]([NH:27][C:28](OC(C)(C)C)=[O:29])[CH:24]([CH3:26])[CH3:25])[CH2:15][N:16]2[CH:20]=[CH:19][CH:18]=[N:17]2)[NH:8]1)=[O:6].FC(F)(F)C(O)=O.[C:46]([O:49][C@@H:50]([C:52]1[CH:61]=[CH:60][C:59]2[C:54](=[CH:55][C:56](/[CH:62]=[CH:63]/[C:64](C)([CH3:68])[C:65](O)=O)=[CH:57][CH:58]=2)[N:53]=1)[CH3:51])(=[O:48])[CH3:47].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(OCC)(=O)C>[Cl:1][C:2]([Cl:37])([Cl:38])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:36])[C@@H:14]([NH:21][C:22](=[O:35])[C@@H:23]([NH:27][C:28](=[O:29])[C:64]([CH3:68])([CH3:65])/[CH:63]=[CH:62]/[C:56]2[CH:55]=[C:54]3[C:59]([CH:60]=[CH:61][C:52]([C@H:50]([O:49][C:46](=[O:48])[CH3:47])[CH3:51])=[N:53]3)=[CH:58][CH:57]=2)[CH:24]([CH3:25])[CH3:26])[CH2:15][N:16]2[CH:20]=[CH:19][CH:18]=[N:17]2)[NH:8]1)=[O:6]

Participants

8

Reactant 5

HCID 6422Trifluoroacetic acidHCID 81531DiisopropylethylamineHCID 866211442-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate MethanaminiumHCID 86709703(S)-1-[(S)-2-((S)-2-tert-butoxycarbonylamino-3-methyl-butyrylamino)-3-pyrazol-1-yl-propionyl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl esterHCID 86709704(E)-4-[2-((R)-1-acetoxy-ethyl)-quinolin-7-yl]-2,2-dimethyl-but-3-enoic acid

Product 1

HCID 86709702(S)-1-[(S)-2-((S)-2-{(E)-4-[2-((R)-1-Acetoxy-ethyl)-quinolin-7-yl]-2,2-dimethyl-but-3-enoylamino}-3-methyl-butyrylamino)-3-pyrazol-1-yl-propionyl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl esterYield 72%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

To (S)-1-[(S)-2-((S)-2-tert-butoxycarbonylamino-3-methyl-butyrylamino)-3-pyrazol-1-yl-propionyl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (450 mg, 0.75 mmol) in anhydrous dichloromethane (1 mL) at 0° C. and under an atmosphere of nitrogen was added trifluoroacetic acid (0.58 mL, 7.6 mmol). The reaction mixture was warmed to room temperature and stirred for 3 h before concentrating in vacuo and co-evaporating from toluene. This residue was dissolved in anhydrous acetonitrile (7.5 mL) and at 0° C. and under an atmosphere of nitrogen was added (E)-4-[2-((R)-1-acetoxy-ethyl)-quinolin-7-yl]-2,2-dimethyl-but-3-enoic acid (246 mg, 0.75 mmol), N,N-diisopropylethylamine (0.66 mL, 3.76 mmol) and 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (401 mg, 1.05 mmol). The solution was warmed to room temperature and stirred for 2 h. 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 0:1 to give the title compound (433 mg, 72%) as a viscous clear oil, as a 2:1 mixture of diastereoisomers. LCMS (m/z)=806.3 [M+H], Tr=2.91 min.

Workup

  1. concentrationbefore concentrating in vacuo and co-evaporating from toluene
  2. dissolutionThis residue was dissolved in anhydrous acetonitrile (7.5 mL) and at 0° C. and under an atmosphere of nitrogen
  3. temperatureThe solution was warmed to room temperature
  4. stirringstirred for 2 h
  5. temperatureThe reaction was cooled to 0° C.
  6. customquenched with 1 M hydrochloric acid
  7. customThe organic layer was separated
  8. washwashed with a saturated aqueous solution of sodium bicarbonate (2×) and brine (1×)
  9. customThe organic layer was then dried through a hydrophobic frit
  10. concentrationconcentrated in vacuo
  11. customThe residue was purified by silica gel chromatography

Sources & evidence

ORD record
ord-7e5780d5ebce4192b064d916d721b557
Source dataset
uspto-grants-2015_09
Patent number
US09145441B2

Reaction notes

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