Hydrochloric Acid → Palonosetron hydrochloride

HRID 419296Notes

Reaction equation

HRID 419296 reaction equation
[CH:1]1[CH:6]=[C:5]2[C:7]([N:9]([C@H:15]3[CH:20]4[CH2:21][CH2:22][N:17]([CH2:18][CH2:19]4)[CH2:16]3)[CH2:10][C@H:11]3[CH2:12][CH2:13][CH2:14][C:3](=[C:4]23)[CH:2]=1)=[O:8].[ClH:23].BrBr>CO.C(O)C>[CH:1]1[CH:6]=[C:5]2[C:7]([N:9]([C@H:15]3[CH:20]4[CH2:21][CH2:22][N:17]([CH2:18][CH2:19]4)[CH2:16]3)[CH2:10][C@H:11]3[CH2:12][CH2:13][CH2:14][C:3](=[C:4]23)[CH:2]=1)=[O:8].[ClH:23]

Participants

6

Reactant 3

HCID 313Hydrochloric AcidHCID 24408BromineHCID 6337614Palonosetron

Product 1

HCID 6918303Palonosetron hydrochloride

Reagents, catalysts & solvents 2

HCID 702EthanolSolvent2×HCID 887MethanolSolvent

Conditions

Temperature
72.5 °C

Procedure

The diastereomeric palonosetron (VIII) (5.0 g) showing 54.06% of the desired (S, S) isomer, 42.13% of the undesired (3aR, S) isomer (Ia) and 1.04% of unreacted compound (IIa) was dissolved in 5% methanol in ethanol mixture (4.2 volumes). To it hydrochloric acid in ethanol was added and was heated to 70-75° C. Then neat liquid bromine (100 mg) was added at reflux. The solution was then cooled to 0 to 5° C. and 2.2 g of the precipitated crude palonosetron hydrochloride (I) was isolated by filtration. This obtained crude palonosetron hydrochloride (I) showing 96.41% of the desired (3aS, S) isomer, 3.59% of the undesired (3aR, S) isomer (Ia) and no unreacted compound (IIa) on HPLC, was then crystallized twice from ethanol-methanol mixture to give 1.5 g of the title product (I) which was found to contain 99.62% of the titled compound (I) and 0.38% (3aR, S) isomer (Ia) while no unreacted intermediate (IIa) could be detected by HPLC analysis.

Workup

  1. temperatureat reflux
  2. temperatureThe solution was then cooled to 0 to 5° C.
  3. custom2.2 g of the precipitated crude palonosetron hydrochloride (I)
  4. customwas isolated by filtration
  5. customThis obtained crude palonosetron hydrochloride (I)
  6. customno unreacted compound (IIa) on HPLC, was then crystallized twice from ethanol-methanol mixture

Sources & evidence

ORD record
ord-f139e003afcf489ea25009e753bfc272
Source dataset
uspto-grants-2012_01
Patent number
US08093391B2

Reaction notes

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