4-Fluoroaniline → 2-Chloro-N-(4-fluorophenyl)pyrimidin-4-amine

HRID 269868Notes

Reaction equation

HRID 269868 reaction equation
[Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.C([O-])(O)=O.[Na+].[F:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>C1COCC1.CCO.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([NH:19][C:18]2[CH:20]=[CH:21][C:15]([F:14])=[CH:16][CH:17]=2)[CH:5]=[CH:4][N:3]=1

Participants

7

Reactant 3

HCID 97314-FluoroanilineHCID 775312,4-DichloropyrimidineHCID 516892Sodium Bicarbonate

Product 1

HCID 223096702-Chloro-N-(4-fluorophenyl)pyrimidin-4-amineYield 79.3%

Reagents, catalysts & solvents 3

HCID 702EthanolSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
65 °C

Procedure

To a solution of 2,4-dichloropyrimidine (260 g, 1.75 mol) in THF (780 mL) and EtOH (3100 mL) is added NaHCO3 (244 g, 2.91 mol). To the slurry which results is added 4-fluoroaniline (162 g, 1.46 mol) in one portion and the resulting mixture allowed to warm to 65° C. and held at this temperature for 10 hours. The reaction if not completed in a single day can be cooled over night. Re-heating the next day to 70° C. for an additional 10 hours is usually sufficient for completion of the reaction. The reaction solution is diluted with EtOAc (4.5 L) and washed with water (3×2 L). The combined aqueous layers are extracted with EtOAc (3 L). The combined organic layers are dried over MgSO4 and filtered. The filter cake is washed with acetone (2×1 L) then with 5% MeOH/acetone (2×500 mL). The filtrate is concentrated until a thick slurry is obtained (ca. 1 L volume), hexane (3.5 L) is added and the solution cooled to about 4° C. for 16 hours. The thick slurry is collected by filtration, washed with hexane (2×500 mL), and dried (20 mmHg, room temperature) to afford 99.43 g (79.3% yield) of the desired product as a white solid. 1H NMR (300 MHz, CD3OD) δ 8.06 (d, J=6.0 Hz, 1H), 7.59 (m, 2H), 7.11 (m, 2H), 6.64 (d, J=6.0 Hz, 1H); MS (ESI) m/z 224 (M+1).

Workup

  1. customTo the slurry which results
  2. customThe reaction if not
  3. waitcompleted in a single day
  4. temperaturecan be cooled over night
  5. customRe-heating the next day to 70° C. for an additional 10 hours is usually sufficient for completion of the reaction
  6. washwashed with water (3×2 L)
  7. extractionThe combined aqueous layers are extracted with EtOAc (3 L)
  8. dry with materialThe combined organic layers are dried over MgSO4
  9. filtrationfiltered
  10. washThe filter cake is washed with acetone (2×1 L)
  11. concentrationThe filtrate is concentrated until a thick slurry
  12. customis obtained (ca. 1 L volume), hexane (3.5 L)
  13. additionis added
  14. temperaturethe solution cooled to about 4° C. for 16 hours
  15. filtrationThe thick slurry is collected by filtration
  16. washwashed with hexane (2×500 mL)
  17. customdried (20 mmHg, room temperature)

Sources & evidence

ORD record
ord-beeefb0ee2dc436f9c7326ccf89f99ec
Source dataset
uspto-grants-2008_11
Patent number
US07449474B2

Reaction notes

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