2-Methyltetrahydrofuran → Dasabuvir

HRID 1049655Notes

Reaction equation

HRID 1049655 reaction equation
C(P(C(C)(C)C)C1C(OC)=CC=C(OC)C=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC1CCCO1.FC(F)(F)S(O[C:55]1[CH:64]=[CH:63][C:62]2[C:57](=[CH:58][CH:59]=[C:60]([C:65]3[CH:70]=[C:69]([N:71]4[CH:76]=[CH:75][C:74](=[O:77])[NH:73][C:72]4=[O:78])[CH:68]=[C:67]([C:79]([CH3:82])([CH3:81])[CH3:80])[C:66]=3[O:83][CH3:84])[CH:61]=2)[CH:56]=1)(=O)=O.[CH3:87][S:88]([NH2:91])(=[O:90])=[O:89]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C>[C:79]([C:67]1[C:66]([O:83][CH3:84])=[C:65]([C:60]2[CH:61]=[C:62]3[C:57](=[CH:58][CH:59]=2)[CH:56]=[C:55]([NH:91][S:88]([CH3:87])(=[O:90])=[O:89])[CH:64]=[CH:63]3)[CH:70]=[C:69]([N:71]2[CH:76]=[CH:75][C:74](=[O:77])[NH:73][C:72]2=[O:78])[CH:68]=1)([CH3:82])([CH3:81])[CH3:80]

Participants

8

Reactant 5

HCID 73012-MethyltetrahydrofuranHCID 62657Potassium Phosphate, TribasicHCID 72879MethanesulfonamideHCID 44233348Di-tert-butyl(2',4',6'-triisopropyl-3,6-dimethoxy-(1,1'-biphenyl)-2-yl)phosphineHCID 86693869HCID 86693869, compound2×

Product 1

HCID 56640146Dasabuvir

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
80 °C

Procedure

Tris(dibenzylideneacetone)dipalladium(0) (0.0042 g, 4.56 μmol), di-tert-butyl(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine (0.0053 g, 12.0 μmol) and milled potassium phosphate tribasic (0.213 g, 1.003 mmol) were charged to a 40-mL reaction vial inside an inert atmosphere glove box. 2-Methyltetrahydrofuran (1.9 mL) was added, and the closed vial and its contents were heated to 80° C. with magnetic stirring for 30 minutes. The reaction mixture was cooled down to room temperature. 6-(3-tert-Butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl trifluoromethanesulfonate (0.5 g, 0.912 mmol, Example 3-6, compound (5e)), methanesulfonamide (0.104 g, 1.094 mmol) and ethyl acetate (5.7 mL) were added to the 40-mL reaction vial. The temperature of the closed vial and its contents was raised to 90° C. and stirred for 14 hours. HPLC analysis of the reaction mixture showed that the product was formed in 91 area % at 210 nm.

Workup

  1. additionwere charged to a 40-mL reaction vial inside an inert atmosphere glove box
  2. temperatureThe reaction mixture was cooled down to room temperature
  3. temperatureThe temperature of the closed vial and its contents was raised to 90° C.
  4. stirringstirred for 14 hours
  5. customwas formed in 91 area % at 210 nm

Sources & evidence

ORD record
ord-a135c0d48d0c4dc998170e12afb41107
Source dataset
uspto-grants-2016_07
Patent number
US09381508B2

Reaction notes

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