Methyl iodide → HCID 71727473, compound

HRID 1774202Notes

Reaction equation

HRID 1774202 reaction equation
[H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:32]2[CH:33]=[N:34][NH:35][CH:36]=2)[N:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:22]([F:23])=[CH:21][N:20]=[C:19]([NH:24][CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[N:18]=3)=[CH:13][C:12]2=[O:31])=[CH:6][C:5]=1[F:37].[CH3:38]I>CN(C=O)C>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:32]2[CH:36]=[N:35][N:34]([CH3:38])[CH:33]=2)[N:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:22]([F:23])=[CH:21][N:20]=[C:19]([NH:24][CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[N:18]=3)=[CH:13][C:12]2=[O:31])=[CH:6][C:5]=1[F:37]

Participants

5

Reactant 3

HCID 6328Methyl iodideHCID 24758Sodium hydrideHCID 86696702HCID 86696702, compound

Product 1

HCID 71727473HCID 71727473, compoundYield 23%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

NaH (3.05 mg, 0.0762 mmol; 60% oil dispersion) neat as a solid was added to a stirred solution of 1-((4-chloro-3-fluorophenyl)(1H-pyrazol-4-yl)methyl)-4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (38 mg, 0.0762 mmol) in DMF (1 mL) at room temperature under nitrogen. After 15 minutes, a red solution had formed. Methyl iodide (4.75 μL, 0.0762 mmol) was then added neat by syringe. After stirring overnight, the reaction was quenched by addition of saturated ammonium chloride solution (1 mL). The mixture was partitioned between ethyl acetate (15 mL) and saturated sodium bicarbonate (15 mL). The organics were isolated and washed with water (3×15 mL) and with brine (15 mL). TLC in 95/5 ethyl acetate/methanol showed complete consumption of starting material with two new major spots of higher rf. The organics were isolated, dried (MgSO4), filtered and concentrated. The crude product was loaded onto a 20 cm×20 cm×0.5 mm prep plate and eluted with 95/5 ethyl acetate/methanol. Three bands were scraped off the plate. Compound was freed from the silica gel by stirring for 15 minutes with ethyl acetate (50 mL) and filtration. The high rf material shows two methyl signals by 1H-NMR and is presumed to be dimethylated byproduct. The lower rf material was isolated as a clear oil, 1-((4-chloro-3-fluorophenyl)(1-methyl-1H-pyrazol-4-yl)methyl)-4-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (9 mg, 23%) and appears to be the desired product by comparison to the non-fluoro analog (see Example 35). 1H NMR (400 MHz, CDCl3) δ 8.27 (d, 1H), 7.36 (m, 3H), 7.30 (br s, 1H), 7.23 (s, 1H), 7.01 (m, 2H), 6.80 (d, 1H), 5.09 (d, 1H), 4.00 (m, 3H), 3.91 (s, 3H), 3.54 (m, 2H), 2.04 (m, 2H), 1.57 (m, 2H).

Workup

  1. customa red solution had formed
  2. customthe reaction was quenched by addition of saturated ammonium chloride solution (1 mL)
  3. customThe mixture was partitioned between ethyl acetate (15 mL) and saturated sodium bicarbonate (15 mL)
  4. customThe organics were isolated
  5. washwashed with water (3×15 mL) and with brine (15 mL)
  6. customTLC in 95/5 ethyl acetate/methanol showed complete consumption of starting material with two new major spots of higher rf
  7. customThe organics were isolated
  8. dry with materialdried (MgSO4)
  9. filtrationfiltered
  10. concentrationconcentrated
  11. washeluted with 95/5 ethyl acetate/methanol
  12. stirringby stirring for 15 minutes with ethyl acetate (50 mL) and filtration

Sources & evidence

ORD record
ord-45baa8993b5f471b8f2e5b9bc4c2d14b
Source dataset
uspto-grants-2016_02
Patent number
US09259470B2

Reaction notes

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