Potassium Phosphate, Tribasic → Dasabuvir

HRID 58405

Reaction equation

HRID 58405 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 167.8%

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 600-mL, stainless steel Parr® pressure reactor equipped with an overhead stirrer was charged with tris(dibenzylideneacetone)dipalladium(0) (0.229 g, 0.251 mmol), di-tert-butyl(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine (0.291 g, 0.601 mmol) and milled potassium phosphate tribasic (11.70 g, 55.1 mmol). The flask was purged with argon for not less than 90 minutes. Ethyl acetate (140 mL) was taken in a 250-mL, round bottom flask, purged with argon for not less than 30 minutes and was transferred to the 600-mL reactor using a cannula under argon atmosphere. The contents of the 600-mL reactor were heated to 80° C. and stirred at this temperature for 30 minutes. A 500-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 (35.0 g, 50.1 mmol), methanesulfonamide (5.72 g, 60.1 mmol) and ethyl acetate (280 mL), purged with argon for not less than 60 minutes while stirring at 50° C. This solution was transferred to the 600-mL reactor that had been cooled to room temperature using a cannula under argon atmosphere. The temperature of the 600-mL flask was raised to 90° C., and the contents were stirred for 18 hours. The reaction mixture was allowed to cool down to 40° C., filtered and rinsed with ethyl acetate (140 mL). Solid (41.50 g) was obtained after drying for 2 hours on high vacuum. This solid contained the titled product (23.06 g, 93%).

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 500-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. temperaturehad been cooled to room temperature
  7. temperatureThe temperature of the 600-mL flask was raised to 90° C.
  8. stirringthe contents were stirred for 18 hours
  9. temperatureto cool down to 40° C.
  10. filtrationfiltered
  11. washrinsed with ethyl acetate (140 mL)

Sources & evidence

ORD record
ord-788773e4277e4723a64b3f7ceea140f5
Source dataset
uspto-grants-2016_09
Patent number
US09434698B2

Linked notes

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