Hydrochloric Acid → Fosnetupitant Chloride Hydrochloride

HRID 1477277Notes

Reaction equation

HRID 1477277 reaction equation
[P:1]([O:11][C:12](C)(C)C)([O:6]C(C)(C)C)([O:3]C[Cl:5])=[O:2].[I-].[Na+].[CH3:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=1[C:25]1[CH:26]=[C:27]([N:52]2[CH2:57][CH2:56][N:55]([CH3:58])[CH2:54][CH2:53]2)[N:28]=[CH:29][C:30]=1[N:31]([C:33]([C:35]([C:38]1[CH:39]=[C:40]([C:48]([F:51])([F:50])[F:49])[CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)([CH3:37])[CH3:36])=[O:34])[CH3:32].[ClH:59].O1CCOCC1>CC(C)=O>[ClH:5].[Cl-:59].[F:47][C:44]([F:45])([F:46])[C:42]1[CH:43]=[C:38]([C:35]([CH3:36])([CH3:37])[C:33]([N:31]([C:30]2[C:25]([C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH3:18])=[CH:26][C:27]([N:52]3[CH2:53][CH2:54][N+:55]([CH3:58])([CH2:12][O:11][P:1]([OH:6])([OH:3])=[O:2])[CH2:56][CH2:57]3)=[N:28][CH:29]=2)[CH3:32])=[O:34])[CH:39]=[C:40]([C:48]([F:49])([F:51])[F:50])[CH:41]=1

Participants

7

Reactant 5

HCID 313Hydrochloric AcidHCID 5238Sodium IodideHCID 312751,4-DioxaneHCID 6451149NetupitantHCID 11701630Di-tert-butyl (chloromethyl) phosphate

Product 1

HCID 86764535Fosnetupitant Chloride Hydrochloride

Reagents, catalysts & solvents 1

HCID 180AcetoneSolvent

Conditions

Temperature
50 °C

Procedure

To the solution of chloromethyl di-tert-butyl phosphate in Acetone (22.1 g from a 10% solution, 85.58 mmole), 15.5 g (103.24 mmole) of sodium iodide and 33.0 g (57.00 mmole) of netupitant were added and the solution heated at 50° C. for at 6-16 h. The precipitated salts were filtered off, the acetone distilled under reduced pressure and the crude product dissolved in 43.0 g of methanol and 43.0 g 1,4-dioxane. 12.6 g of HCl 4M in dioxane (113.85 mmole) were added, and then methanol is distilled off at 40° C. under reduced pressure. The solution is cooled at 5° C. and stirred at 5° C. for at least 2 h at 5° C. The product was isolated by filtration, purified by additional slurry in acetone (238 g), and filtered and washed with acetone (47 g) and pentane (2×72 g).

Workup

  1. filtrationThe precipitated salts were filtered off
  2. distillationthe acetone distilled under reduced pressure
  3. dissolutionthe crude product dissolved in 43.0 g of methanol
  4. distillationmethanol is distilled off at 40° C. under reduced pressure
  5. temperatureThe solution is cooled at 5° C.
  6. customThe product was isolated by filtration
  7. custompurified by additional slurry in acetone (238 g)
  8. filtrationfiltered
  9. washwashed with acetone (47 g) and pentane (2×72 g)

Sources & evidence

ORD record
ord-32bb8003336342a290f1b5e83e78c583
Source dataset
uspto-grants-2016_08
Patent number
US09403772B2

Reaction notes

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