Trifluoroacetic acid → (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

HRID 2285408Notes

Reaction equation

HRID 2285408 reaction equation
[Cl:1][C:2]([Cl:31])([Cl:30])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:29])[C@@H:14](NC(OC(C)(C)C)=O)[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([N:42](CC)C(C)C)(C)C.[C:48]([O:52][C:53]([NH:55][C@H:56]([C:60]([OH:62])=O)[CH:57]([CH3:59])[CH3:58])=[O:54])([CH3:51])([CH3:50])[CH3:49].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:31][C:2]([Cl:30])([Cl:1])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:29])[C@@H:14]([NH:42][C:60](=[O:62])[C@@H:56]([NH:55][C:53]([O:52][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:54])[CH:57]([CH3:59])[CH3:58])[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 83693Boc-L-ValineHCID 866211442-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate MethanaminiumHCID 89945073(S)-1-((S)-2-tert-Butoxycarbonylamino-3-pyrazol-1-yl-propionyl)-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester

Product 1

HCID 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 esterYield 52.3%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

To (S)-1-((S)-2-tert-butoxycarbonylamino-3-pyrazol-1-yl-propionyl)-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (730 mg, 1.47 mmol) in anhydrous dichloromethane (3 mL) at 0° C. and under an atmosphere of nitrogen was added trifluoroacetic acid (1.1 mL, 14.7 mmol). The reaction mixture was warmed to room temperature and stirred for 3 h before concentrating in vacuo. The residue was dissolved in anhydrous acetonitrile (7 mL) at room temperature and under an atmosphere of nitrogen was added N,N-diisopropylethylamine (1.3 mL, 7.3 mmol), N-(tert-Butoxycarbonyl)-L-valine (319 mg, 1.5 mmol) and 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (782 mg, 2.1 mmol). Following 16 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 1:2 then 1:3 to give the title compound (460 mg, 52%) as a viscous clear oil, as a 2:1 mixture of diastereoisomers. LCMS (m/z) 599.1 [M+H], Tr=2.83 min.

Workup

  1. concentrationbefore concentrating in vacuo
  2. dissolutionThe residue was dissolved in anhydrous acetonitrile (7 mL) at room temperature and under an atmosphere of nitrogen
  3. waitFollowing 16 h at room temperature
  4. temperaturethe reaction was cooled to 0° C.
  5. customquenched with 1 M hydrochloric acid
  6. customThe organic layer was separated
  7. washwashed with a saturated aqueous solution of sodium bicarbonate (2×) and brine (1×)
  8. customThe organic layer was then dried through a hydrophobic frit
  9. concentrationconcentrated in vacuo
  10. customThe residue was purified by silica gel chromatography

Sources & evidence

ORD record
ord-f885e4de496f4f3c9d65d61e23af3b4f
Source dataset
uspto-grants-2015_09
Patent number
US09145441B2

Reaction notes

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