2-Chloroaniline → 5-(2-Chlorophenyl)aminomethyl-4-amino-2-methylthiopyrimidine

HRID 1280576Notes

Reaction equation

HRID 1280576 reaction equation
[NH2:1][C:2]1[C:7]([CH:8]=S)=[CH:6][N:5]=[C:4](C)[N:3]=1.[Cl:11][C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14].O.C1(C)C=C[C:23]([S:26](O)(=O)=O)=CC=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>C1(C)C(C)=CC=CC=1.O>[Cl:11][C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH:14][CH2:8][C:7]1[C:2]([NH2:1])=[N:3][C:4]([S:26][CH3:23])=[N:5][CH:6]=1

Participants

8

Reactant 5

HCID 72402-ChloroanilineHCID 14798Sodium HydroxideHCID 521998p-Toluenesulfonic acid monohydrateHCID 21226445Aluminium lithium hydrideHCID 867560534-Amino-2-methylthiopyrimidine-5-carboxaldehyde

Product 1

HCID 184254535-(2-Chlorophenyl)aminomethyl-4-amino-2-methylthiopyrimidineYield 554%

Reagents, catalysts & solvents 2

HCID 962WaterSolvent3×HCID 7237O-XyleneSolvent

Conditions

Temperature
25 °C

Procedure

A mixture of 4-amino-2-methylthiopyrimidine-5-carboxaldehyde (9.5 g, 56.1 mmol), 2-chloroaniline (6.7 mL, 63.7 mmol) and 4-toluene-sulfonic acid monohydrate (0.85 g, 4.5 mmol) in 350 mL of xylene was heated under reflux with azeotropic removal of water for 6 hours. The mixture was cooled to 25° C. and the precipitate was collected by vacuum filtration and was washed with hexanes and air dried. This solid was then dissolved in 300 mL tetrahydrofuran. and the reaction cooled to 0° C. Lithium aluminium hydride (2.3 g, 60.6 mmol) was added in small portions over 45 minutes. Once the addition was complete, the mixture was stirred for a further 15 minutes and carefully treated sequentially with 4.5 mL water, 4.5 mL of 15% aqueous sodium hydroxide and then 20 mL of water. The mixture was stirred for 30 minutes, filtered through celite, and the filtrate concentrated in vacuo. The solid was purified with column chromatography on silica gel using 25% acetone/hexane. The fractions containing product were concentrated under reduced pressure to a solid which was recrystallized from ethyl to give 7.0 g of 5-(2-chlorophenyl)aminomethyl-4-amino-2-methylthiopyrimidine as a white solid.

Workup

  1. temperaturewas heated
  2. filtrationthe precipitate was collected by vacuum filtration
  3. washwas washed with hexanes and air
  4. customdried
  5. dissolutionThis solid was then dissolved in 300 mL tetrahydrofuran
  6. temperatureand the reaction cooled to 0° C
  7. additionOnce the addition
  8. stirringThe mixture was stirred for 30 minutes
  9. filtrationfiltered through celite
  10. concentrationthe filtrate concentrated in vacuo
  11. customThe solid was purified with column chromatography on silica gel using 25% acetone/hexane
  12. additionThe fractions containing product
  13. concentrationwere concentrated under reduced pressure to a solid which
  14. customwas recrystallized from ethyl

Sources & evidence

ORD record
ord-a732c0b93b9a444ca6a4f075481175d4
Source dataset
uspto-grants-2002_09
Patent number
US06451804B1

Reaction notes

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