Potassium Phosphate, Tribasic → Dasabuvir

HRID 341640Notes

Reaction equation

HRID 341640 reaction equation
[O-]P([O-])([O-])=O.[K+].[K+].[K+].FC(F)(S(O[C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[C:30]([C:35]3[CH:40]=[C:39]([N:41]4[CH:46]=[CH:45][C:44](=[O:47])[NH:43][C:42]4=[O:48])[CH:38]=[C:37]([C:49]([CH3:52])([CH3:51])[CH3:50])[C:36]=3[O:53][CH3:54])[CH:31]=2)[CH:26]=1)(=O)=O)C(F)(F)C(F)(F)C(F)(F)F.[CH3:56][S:57]([NH2:60])(=[O:59])=[O:58]>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(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.C(OCC)(=O)C>[C:49]([C:37]1[C:36]([O:53][CH3:54])=[C:35]([C:30]2[CH:31]=[C:32]3[C:27](=[CH:28][CH:29]=2)[CH:26]=[C:25]([NH:60][S:57]([CH3:56])(=[O:59])=[O:58])[CH:34]=[CH:33]3)[CH:40]=[C:39]([N:41]2[CH:46]=[CH:45][C:44](=[O:47])[NH:43][C:42]2=[O:48])[CH:38]=1)([CH3:51])([CH3:50])[CH3:52]

Participants

7

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 72879MethanesulfonamideHCID 566406691-Butanesulfonic acid, 1,1,2,2,3,3,4,4,4-nonafluoro-, 6-(5-(3,4-dihydro-2,4-dioxo-1(2H)-pyrimidinyl)-3-(1,1-dimethylethyl)-2-methoxyphenyl)-2-naphthalenyl ester

Product 1

HCID 56640146DasabuvirYield 236.8%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 44233348Di-tert-butyl(2',4',6'-triisopropyl-3,6-dimethoxy-(1,1'-biphenyl)-2-yl)phosphineCatalystHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
80 °C

Procedure

A 450-mL, stainless steel Parr pressure reactor equipped with an overhead stirrer was charged with tris(dibenzylideneacetone)dipalladium(0) (0.131 g, 0.143 mmol), di-tert-butyl(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine (0.167 g, 0.344 mmol) and milled potassium phosphate tribasic (6.69 g, 31.5 mmol). The flask was purged with argon for not less than 90 minutes. Ethyl acetate (80 mL) was taken in a 100-mL, round bottom flask, purged with argon for not less than 30 minutes and was transferred to the 450-mL reactor using a cannula under argon atmosphere. The contents of the 450-mL reactor were heated to 80° C. and stirred at this temperature for 30 minutes. A 250-mL round bottom flask equipped with a magnetic stir bar was charged with 6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (20.0 g, 22.9 mmol), methanesulfonamide (3.27 g, 34.4 mmol) and ethyl acetate (160 mL), purged with argon for not less than 60 minutes while stirring at 50° C. This solution was transferred to the 450-mL reactor that has been cooled to the room temperature using a cannula under argon atmosphere. The temperature of the 450-mL flask was raised to 90° C. and the contents were stirred for 15 hours. The reaction mixture was allowed to cool down to the room temperature, filtered and rinsed with ethyl acetate (120 mL). Solid (26.76 g) was obtained after drying the solid for 2 hours on high vacuum.

Workup

  1. customThe flask was purged with argon for not less than 90 minutes
  2. custompurged with argon for not less than 30 minutes
  3. customA 250-mL round bottom flask equipped with a magnetic stir bar
  4. custompurged with argon for not less than 60 minutes
  5. stirringwhile stirring at 50° C
  6. temperaturehas been cooled to the room temperature
  7. temperatureThe temperature of the 450-mL flask was raised to 90° C.
  8. stirringthe contents were stirred for 15 hours
  9. temperatureto cool down to the room temperature
  10. filtrationfiltered
  11. washrinsed with ethyl acetate (120 mL)

Sources & evidence

ORD record
ord-61792153fb6a45cba642653639200174
Source dataset
uspto-grants-2014_11
Patent number
US08895737B2

Reaction notes

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