Methyl iodide → 2-((6-Chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)benzonitrile

HRID 1921100Notes

Reaction equation

HRID 1921100 reaction equation
[Cl:1][C:2]1[N:7]([CH2:8][C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]#[N:12])[C:6](=[O:17])[NH:5][C:4](=[O:18])[CH:3]=1.[H-].[Na+].[Li+].[Br-].I[CH3:24]>CN(C=O)C.C1COCC1.C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:7]([CH2:8][C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]#[N:12])[C:6](=[O:17])[N:5]([CH3:24])[C:4](=[O:18])[CH:3]=1

Participants

7

Reactant 4

HCID 6328Methyl iodideHCID 24758Sodium hydrideHCID 82050Lithium BromideHCID 113574682-((6-Chloro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)benzonitrile

Product 1

HCID 113464162-((6-Chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)benzonitrileYield 72.5%

Reagents, catalysts & solvents 2

HCID 6212ChloroformSolventHCID 21974620tetrahydrofuran N,N-dimethylformamideSolvent

Procedure

To a cold (0° C.) solution of benzylated 6-chlorouracil 2 (10 g, 38 mmol) in DMF-THF (1:1, 300 mL) under nitrogen, was added NaH (60%, 1.6 g, 39.9 mmol) in portions, followed by adding LiBr (2 g). The mixture was stirred at r.t for 20 min. After adding iodomethane (5.4 mL, 76 mmol), the flask was sealed and stirred at this temperature for 10 min, rt for 2 h, and 35° C. overnight, and then concentrated in vacuo. It will be understood that alkylation of the amine may be performed under standard conditions known in the art, including the use of a base such as NaH, LiH or the like in an organic solvent or mixture of solvents. The solvent may include DMSO, THF, DMF and the like, or mixtures thereof. In addition, additives may be used, including LiBr, LiI, NaI and the like. For example, the alkylation can be performed using methyliodide and KsCO3 in acetone. The reaction may be performed at about 15-45° C., preferably at about 20-43° C., and more preferably at about 35-41° C. until the reaction is complete. The residue was dissolved in CHCl3 and washed with water and brine, dried (Na2SO4), and filtered then concentrated in vacuo. The crude product was crystallized from THF-Hexanes to give 7.6 g (72%) of the title compound 3. It will also be understood by those skilled in the art that the benzonitrile may be purified in a variety of organic solvents or solvent mixtures. For example, the benzonitrile can be purified by adding a mixture of dichloromethane and heptane. Optionally, the benzonitrile may be further purified in an organic solvent or mixture of solvents such as dichloromethane, chloroform, acetonitrile, THF, ethyl acetate, isopropyl acetate and the like. Preferably, the product is purified and washed with ethyl acetate. 1H NMR (400 MHz, DMSO): δ 7.87 (d, 1H, J=7.6 Hz), 7.70 (t, 1H, J=7.6 Hz), 7.51 (t, 1H, J=7.6 Hz), 7.40 (d, 1H, J=8 Hz), 6.21 (s, 1H), 5.38 (s, 2H), 3.28 (s, 3H). MS (ES) [m+H] calc'd for C13H11ClN3O2, 276.1; found 276.1.

Workup

  1. customthe flask was sealed
  2. stirringstirred at this temperature for 10 min, rt for 2 h
  3. concentration35° C. overnight, and then concentrated in vacuo
  4. additionthe like in an organic solvent or mixture of solvents
  5. customThe reaction
  6. custommay be performed at about 15-45° C., preferably at about 20-43° C.
  7. custommore preferably at about 35-41° C.
  8. washwashed with water and brine
  9. dry with materialdried (Na2SO4)
  10. filtrationfiltered
  11. concentrationthen concentrated in vacuo
  12. customThe crude product was crystallized from THF-Hexanes

Sources & evidence

ORD record
ord-783a01a3f9be4d36aee5c2ee72f0f9ef
Source dataset
uspto-grants-2012_05
Patent number
US08173663B2

Reaction notes

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