Phosphorus oxychloride → 6-Chloro-2-methylpyrimidin-4-amine

HRID 2237415Notes

Reaction equation

HRID 2237415 reaction equation
[NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4](O)[CH:3]=1.P(Cl)(Cl)([Cl:12])=O>CN(C=O)C>[Cl:12][C:4]1[N:5]=[C:6]([CH3:8])[N:7]=[C:2]([NH2:1])[CH:3]=1

Participants

4

Reactant 2

HCID 24813Phosphorus oxychlorideHCID 178433178HCID 178433178, compound

Product 1

HCID 2867546-Chloro-2-methylpyrimidin-4-amine

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideCatalyst

Conditions

Temperature
80 °C

Procedure

6-Amino-2-methylpyrimidin-4-ol (5 g) was suspended in phosphorous oxychloride (50 ml) and heated at 80° C. for 1 hour. A few drops of DMF was added and the reaction heated to 105° C. for 3 hours to give an orange solution. The reaction was cooled, concentrated in vacuo and azeotroped with toluene. The residue was cautiously partitioned between ethyl acetate and ice-cold saturated aqueous sodium bicarbonate solution. The organic layer was separated, washed with water and brine, dried and concentrated in vacuo to afford 6-chloro-2-methylpyrimidin-4-amine as a yellow solid which was used without further purification (3 g, 68%); NMR Spectrum (300 MHz, CDCl3) 2.50 (s, 3H), 5.00 (br s, 2H), 6.30 (s, 1H); Mass Spectrum MH++CH3CN 185. 6-Chloro-2-methylpyrimidin-4-amine (2.45 g) was suspended in 1-methylpiperazine (24 ml) and the reaction heated at 140° C. for 20 minutes in a microwave reactor. The reaction was cooled and concentrated in vacuo. The residue was dissolved in methanol and neutralised with polymer-bound carbonate resin for 1 hour, then filtered and concentrated to give an orange solid that was triturated with ethyl acetate to give 2-methyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-amine as a cream solid (2.64 g, 81%); NMR Spectrum (300 MHz, CDCl3) 2.20 (s, 3H), 2.30 (s, 3H), 2.40 (m, 4H), 3.50 (m, 4H), 4.40 (br s, 2H), 5.40 (s, 1H); Mass Spectrum MH+ 208.

Workup

  1. temperaturethe reaction heated to 105° C. for 3 hours
  2. customto give an orange solution
  3. temperatureThe reaction was cooled
  4. concentrationconcentrated in vacuo
  5. customazeotroped with toluene
  6. customThe residue was cautiously partitioned between ethyl acetate and ice-cold saturated aqueous sodium bicarbonate solution
  7. customThe organic layer was separated
  8. washwashed with water and brine
  9. customdried
  10. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-287dda7296b948e592cc08bc0eac7157
Source dataset
uspto-grants-2010_05
Patent number
US07718653B2

Reaction notes

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