2-Methyltetrahydrofuran → Dasabuvir

HRID 58410

Reaction equation

HRID 58410 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)C(F)(S(O[C:60]1[CH:69]=[CH:68][C:67]2[C:62](=[CH:63][CH:64]=[C:65]([C:70]3[CH:75]=[C:74]([N:76]4[CH:81]=[CH:80][C:79](=[O:82])[NH:78][C:77]4=[O:83])[CH:73]=[C:72]([C:84]([CH3:87])([CH3:86])[CH3:85])[C:71]=3[O:88][CH3:89])[CH:66]=2)[CH:61]=1)(=O)=O)C(F)(F)F.[CH3:93][S:94]([NH2:97])(=[O:96])=[O:95]>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:84]([C:72]1[C:71]([O:88][CH3:89])=[C:70]([C:65]2[CH:66]=[C:67]3[C:62](=[CH:63][CH:64]=2)[CH:61]=[C:60]([NH:97][S:94]([CH3:93])(=[O:96])=[O:95])[CH:69]=[CH:68]3)[CH:75]=[C:74]([N:76]2[CH:81]=[CH:80][C:79](=[O:82])[NH:78][C:77]2=[O:83])[CH:73]=1)([CH3:86])([CH3:87])[CH3:85]

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 866938686-(3-tert-Butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl 1,1,1,2,3,3,3-heptafluoropropane-2-sulfonate2×

Product 1

HCID 56640146Dasabuvir

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
80 °C

Procedure

Tris(dibenzylideneacetone)dipalladium(0) (0.0071 g, 7.71 μmol), di-tert-butyl(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine (0.0089 g, 19.0 μmol) and milled potassium phosphate tribasic (0.360 g, 1.696 mmol) were charged to a 40-mL reaction vial inside an inert atmosphere glove box. 2-Methyltetrahydrofuran (4 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 1,1,1,2,3,3,3-heptafluoropropane-2-sulfonate (1.0 g, 1.542 mmol, Example 3-4, compound (5c)), methanesulfonamide (0.176 g, 1.850 mmol) and ethyl acetate (8 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 20 hours. HPLC analysis of the reaction mixture showed that the product was formed in 95 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 20 hours
  5. customwas formed in 95 area % at 210 nm

Sources & evidence

ORD record
ord-37110502d7ba4f61b00dde3d85b882c1
Source dataset
uspto-grants-2016_09
Patent number
US09434698B2

Linked notes

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