Trimethylsilyl triflate → (S)-1-[(S)-2-((S)-2-tert-Butoxycarbonylamino-3-methyl-butyrylamino)-3-difluoromethoxy-propionyl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester

HRID 2285402Notes

Reaction equation

HRID 2285402 reaction equation
[Cl:1][C:2]([Cl:30])([Cl:29])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:28])[C@@H:14]([NH:20][C:21]([O:23]C(C)(C)C)=O)[CH2:15][O:16][CH:17]([F:19])[F:18])[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:52]([O:56][C:57]([NH:59][C@H:60](C(O)=O)[CH:61]([CH3:63])[CH3:62])=[O:58])([CH3:55])([CH3:54])[CH3:53].F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C>ClCCl.C(#N)C>[Cl:30][C:2]([Cl:1])([Cl:29])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:28])[C@@H:14]([NH:20][C:21](=[O:23])[C@@H:60]([NH:59][C:57]([O:56][C:52]([CH3:54])([CH3:53])[CH3:55])=[O:58])[CH:61]([CH3:63])[CH3:62])[CH2:15][O:16][CH:17]([F:18])[F:19])[NH:8]1)=[O:6]

Participants

8

Reactant 5

HCID 65367Trimethylsilyl triflateHCID 81531Diisopropylethylamine2×HCID 83693Boc-L-ValineHCID 86709696(S)-1-((S)-2-tert-Butoxycarbonylamino-3-difluoromethoxy-propionyl)-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl esterHCID 178484293HCID 178484293, compound

Product 1

HCID 86709697(S)-1-[(S)-2-((S)-2-tert-Butoxycarbonylamino-3-methyl-butyrylamino)-3-difluoromethoxy-propionyl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl esterYield 61.2%

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

A cooled (0° C.) solution of (S)-1-((S)-2-tert-butoxycarbonylamino-3-difluoromethoxy-propionyl)-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (143 mg, 0.287 mmol) in dichloromethane (5 mL) was treated with trimethylsilyl trifluoromethanesulfonate (72 μL, 0.431 mmol). After stirring at 0° C. for 30 minutes the reaction mixture was treated with N,N-diisopropylethylamine (0.2 mL, 1.15 mmol) and the volatiles were removed in vacuo to provide a brown solid which was then dissolved in anhydrous acetonitrile (5 mL) and this mixture was subsequently treated with N-(tert-butoxycarbonyl)-L-valine (75 mg, 0.344 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (153 mg, 0.402 mmol) and N,N-diisopropylethylamine. After stirring at room temperature for 16 h, the volatiles were removed in vacuo and the residue was partitioned between ethyl acetate and water. The organics were dried over anhydrous sodium sulfate, filtered and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography eluting with a stepwise gradient of iso-hexanes/ethyl acetate 1:0 to 1:1 to provide the title compound (105 mg, 61%) as a pale yellow gum and as a complex mixture of rotamers. LCMS (m/z) 597.0, 599.0 [M+H], Tr=3.18 min.

Workup

  1. customthe volatiles were removed in vacuo
  2. customto provide a brown solid which
  3. stirringAfter stirring at room temperature for 16 h
  4. customthe volatiles were removed in vacuo
  5. customthe residue was partitioned between ethyl acetate and water
  6. dry with materialThe organics were dried over anhydrous sodium sulfate
  7. filtrationfiltered
  8. customthe volatiles were removed in vacuo
  9. customThe residue was purified by silica gel chromatography
  10. washeluting with a stepwise gradient of iso-hexanes/ethyl acetate 1:0 to 1:1

Sources & evidence

ORD record
ord-68a9f174d1814b31a604e1579dabf2b8
Source dataset
uspto-grants-2015_09
Patent number
US09145441B2

Reaction notes

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