Choline, hydroxide → {(5-Chloro-benzo[b]thiophen-3-yl)-[2-(3,4-difluoro-phenyl)-vinylcarbamoyl]-methyl}-methyl-phosphinic acid choline salt

HRID 389334Notes

Reaction equation

HRID 389334 reaction equation
[Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[S:6][CH:7]=[C:8]([CH:9]([P:23]([CH3:26])(=[O:25])[OH:24])[C:10](=[O:22])[NH:11][CH:12]=[CH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=3)[C:4]=2[CH:3]=1.[OH-].[OH:30][CH2:31][CH2:32][N+:33]([CH3:36])([CH3:35])[CH3:34]>CO>[OH:30][CH2:31][CH2:32][N+:33]([CH3:36])([CH3:35])[CH3:34].[Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[S:6][CH:7]=[C:8]([CH:9]([P:23]([CH3:26])(=[O:24])[O-:25])[C:10](=[O:22])[NH:11][CH:12]=[CH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=3)[C:4]=2[CH:3]=1

Participants

4

Reactant 2

HCID 31255Choline, hydroxideHCID 66871866[(5-Chloro-benzo[b]thiophen-3-yl)-[2-(3,4-difluoro-phenyl)-vinylcarbamoyl]-methyl}-methyl-phosphinic acid

Product 1

HCID 131729941{(5-Chloro-benzo[b]thiophen-3-yl)-[2-(3,4-difluoro-phenyl)-vinylcarbamoyl]-methyl}-methyl-phosphinic acid choline salt

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent2×

Conditions

Temperature
64 °C

Procedure

A 250 mL three-necked round-bottomed flask was charged with {(5-chloro-benzo[b]thiophen-3-yl)-[2-(3,4-difluoro-phenyl)-vinylcarbamoyl]-methyl}-methyl-phosphinic acid (20.0 g, 42.2 mol) and methanol (150 mL), under nitrogen. To the resulting slurry was then added 45% by wt. of choline hydroxide in methanol (12.8 mL, 45.3 mol), in one portion. Shortly after the addition, a homogeneous clear solution was obtained. The solution was aged at room temperature for about 1 hour, then clarified by filtration through a medium sintered glass filter. The resulting filtered solution was concentrated by distillation (at a temperature of about 63-65° C.) to a residual volume of about 55-60 mL. While at the elevated temperature, EtOAc (140-150 mL) was added by an addition funnel over a period of about 40 minutes, while maintaining a temperature of about 63-65° C. The resulting clear solution was seeded, then cooled slowly under moderate agitation to ambient temperature. The resulting slurry was then aged overnight, cooled to about 5-10° C. and aged at this temperature for about 2 hours. The resulting solid was collected by filtration, rinsed with cold EtOAc (40 mL, 2C) and dried in a vacuum oven at 50° C., overnight to yield the title compound as a white crystalline solid.

Workup

  1. additionShortly after the addition
  2. customa homogeneous clear solution was obtained
  3. filtrationclarified by filtration through a medium sintered glass
  4. filtrationfilter
  5. filtrationThe resulting filtered solution
  6. concentrationwas concentrated by distillation (at a temperature of about 63-65° C.) to a residual volume of about 55-60 mL
  7. additionWhile at the elevated temperature, EtOAc (140-150 mL) was added by an addition funnel over a period of about 40 minutes
  8. temperaturecooled slowly under moderate agitation to ambient temperature
  9. waitThe resulting slurry was then aged overnight
  10. temperaturecooled to about 5-10° C.
  11. waitaged at this temperature for about 2 hours
  12. filtrationThe resulting solid was collected by filtration
  13. washrinsed with cold EtOAc (40 mL, 2C)
  14. customdried in a vacuum oven at 50° C., overnight

Sources & evidence

ORD record
ord-fda25eeb2bbb46478e2e2c53ce303336
Source dataset
uspto-grants-2013_02
Patent number
US08378122B2

Reaction notes

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