Sodium Iodide → HCID 23069607, compound

HRID 2377755Notes

Reaction equation

HRID 2377755 reaction equation
[F:1][C:2]1[C:3](=[O:9])[NH:4][C:5]([Cl:8])=[N:6][CH:7]=1.[I-].[Na+].CN(C)C(N(C)C)=N.Br[CH2:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[C:24]#[N:25]>CN(C=O)C.COCCOC>[Cl:8][C:5]1[N:4]([CH2:21][C:22]2[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=2[C:24]#[N:25])[C:3](=[O:9])[C:2]([F:1])=[CH:7][N:6]=1

Participants

6

Reactant 4

HCID 5238Sodium IodideHCID 664601,1,3,3-TetramethylguanidineHCID 895992-(Bromomethyl)benzonitrileHCID 2553942-Chloro-5-fluoropyrimidin-4(3H)-one2×

Product 1

HCID 23069607HCID 23069607, compound

Reagents, catalysts & solvents 1

HCID 18463208dimethoxyethane N,N-dimethylformamideSolvent2×

Conditions

Temperature
0 °C

Procedure

Example 30B was also prepared from 5-fluoro-2-chloro-3H-pyrimidin-4-one as follows. To a solution of 5-fluoro-2-chloro-3H-pyrimidin-4-one (100.00 g, 0.67 mol) in 1:1 DMF/DME (440 mL) under a nitrogen atmosphere was added sodium iodide (10 g, 67 mmol) and the resulting slurry cooled to 0° C. While maintaining the internal temperature to ≦12° C., 1,1,3,3-tetramethylguanidine (94 mL, 0.74 mol) was added dropwise over 45 minutes to form a homogeneous solution. The ice bath was removed and a solution of 2-(bromomethyl)benzonitrile (145 g, 0.74 mol) in 1:1 DMF/DME (600 mL) was added all at once and the reaction mixture heated to 70° C. for 18 h. In-process assay (by HPLC analysis) showed complete consumption of the starting material. The reaction mixture was cooled to 30° C. and then MTBE (1.14 L) and DI water (2.29 L) were added to form a slurry which was stirred at ambient temperature for 1 h. The crude product was collected by filtration and washed with MTBE (1.14 L). The phases of the filtrate were separated and the organic layer was combined with the filter-cake and concentrated to a thick slurry which was subsequently reslurried with DME (1.00 L). Insoluble impurities were removed by vacuum filtration and washed with DME (500 mL). The filtrate was concentrated to a wet residue which was reslurried with 2-propanol (365 mL) and the solid product collected by vacuum filtration. After removal of residual IPA, the product was reslurried in ethyl acetate (6 vol) at 70° C. and heptane (6 vol) was added slowly while maintaining the internal temperature at 68-70° C. At the end of the addition of heptane, insoluble materials were still visible. The mixture was stirred for an additional 10 min after which insoluble impurities were removed by hot vacuum filtration. The filtrate was slowly cooled to room temperature and then cooled further to about 0° C. by means of a salt-ice bath. The crystallized product was collected by vacuum filtration and then reslurried in ethanol (6 vol) at 50° C., cooled to 40° C., and the product collected by vacuum filtration to give 80.62 g (45%, 95.6% AUC by HPLC) of 2-(2-chloro-5-fluoro-6-oxo-6H-pyrimidin-1-ylmethyl)-benzonitrile as an off-white solid.

Workup

  1. temperatureWhile maintaining the internal temperature to ≦12° C.
  2. customto form a homogeneous solution
  3. customThe ice bath was removed
  4. temperatureheated to 70° C. for 18 h
  5. customconsumption of the starting material
  6. temperatureThe reaction mixture was cooled to 30° C.
  7. additionMTBE (1.14 L) and DI water (2.29 L) were added
  8. customto form a slurry which
  9. filtrationThe crude product was collected by filtration
  10. washwashed with MTBE (1.14 L)
  11. customThe phases of the filtrate were separated
  12. filtrationfilter-cake
  13. concentrationconcentrated to a thick slurry which
  14. customInsoluble impurities were removed by vacuum filtration
  15. washwashed with DME (500 mL)
  16. concentrationThe filtrate was concentrated to a wet residue which
  17. filtrationthe solid product collected by vacuum filtration
  18. customAfter removal of residual IPA
  19. customwas reslurried in ethyl acetate (6 vol) at 70° C.
  20. additionheptane (6 vol) was added slowly
  21. temperaturewhile maintaining the internal temperature at 68-70° C
  22. additionAt the end of the addition of heptane, insoluble materials
  23. stirringThe mixture was stirred for an additional 10 min after which insoluble impurities
  24. customwere removed by hot vacuum filtration
  25. temperatureThe filtrate was slowly cooled to room temperature
  26. temperaturecooled further to about 0° C. by means of a salt-ice bath
  27. filtrationThe crystallized product was collected by vacuum filtration
  28. customreslurried in ethanol (6 vol) at 50° C.
  29. temperaturecooled to 40° C.
  30. filtrationthe product collected by vacuum filtration

Sources & evidence

ORD record
ord-34d92eb33ce247f5a435c12688d797c0
Source dataset
uspto-grants-2008_12
Patent number
US07470700B2

Reaction notes

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