4-Chloro-3-fluoroaniline Chemical Properties

Melting point:

61

Boiling point:

226°C(lit.)

Density 

1.349±0.06 g/cm3(Predicted)

Flash point:

60 - 62°C

storage temp. 

Keep in dark place,Inert atmosphere,Room temperature

solubility 

soluble in Methanol

form 

powder to crystal

pka

2.94±0.10(Predicted)

color 

White to Gray to Red

BRN 

2716278

InChI

InChI=1S/C6H5ClFN/c7-5-2-1-4(9)3-6(5)8/h1-3H,9H2

InChIKey

ACMJJQYSPUPMPN-UHFFFAOYSA-N

SMILES

C1(N)=CC=C(Cl)C(F)=C1

CAS DataBase Reference

367-22-6(CAS DataBase Reference)

Safety Information

Hazard Codes 

T,Xi

Risk Statements 

20/21/22-36/37/38

Safety Statements 

26-36/37/39-63-45-38

RIDADR 

UN2811

WGK Germany 

3

Hazard Note 

Toxic

HazardClass 

6.1

PackingGroup 

III

HS Code 

29214200

4-Chloro-3-fluoroaniline Usage And Synthesis

Uses

4-Chloro-3-fluoroaniline is used in the synthesis of Methyl 5-Chloro-4-fluoro-1H-indole-2-carboxylate; a key intermediate towards phosphoindole inhibitors of HIV non-nucleoside reverse transcriptase. 4-Chloro-3-fluoroaniline is also used in the synthesis of 3-Deschloro-4-desfluoro-4-chloro-3-fluoro Gefitinib (D289540) which is an impurity of the tyrosine kinase inhibitor Gefitinib.

Chemical Properties

White to light yellow solid

Uses

4-Chloro-3-fluoroaniline is used in the synthesis of Methyl 5-Chloro-4-fluoro-1H-indole-2-carboxylate

Synthesis

1. A CHCl3 (20.0 mL) solution of N-chlorosuccinimide (NCS) was added slowly and dropwise to a stirred CHCl3 (30.0 mL) solution of 3-fluoroaniline (1.11 g, 10.0 mmol) at 0 °C. 2. The reaction mixture was stirred continuously at 0 °C for 42 hours. 3. Upon completion of the reaction, the reaction mixture was concentrated under reduced pressure and the residue was dissolved in Et2O. 4. The mixture was washed with water and subsequently dried with MgSO4. 5. After concentration under reduced pressure, the mixture was purified by rapid chromatography on silica gel, using EtOAc/hexane as eluent, to afford 4-chloro-3-fluoroaniline (259.4 g, 18% yield) as a crystalline solid. 6. To a stirred solution of the above 4-chloro-3-fluoroaniline (259.4 mg, 1.78 mmol) in THF (8.9 mL) was added ethyl chloroacetate (237.3 μL, 2.14 mmol) and Et3N (296.6 μL, 2.14 mmol) sequentially at 0 °C. 7. The mixture was stirred at room temperature for 12 hours. 8. After filtration to remove the precipitate, the filtrate was concentrated under reduced pressure. 9. The residue was dissolved in EtOAc, washed sequentially with 1.0 M HCl, saturated NaHCO3 solution and brine, and then dried with MgSO4. 10. After concentration under pressure, 3-fluoro-4-chloroaniline 6a (435.2 mg, 99% yield) was obtained as brown crystals, which could be used without further purification.

References

[1] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 11, p. 3282 - 3285
[2] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 9, p. 2518 - 2526
[3] Patent: EP1342717, 2003, A1
[4] Patent: US2003/236267, 2003, A1. Location in patent: Page 30

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