Reaction #172018

Reaction equation

tert-butyl (1S,2R)-2-(5-bromo-4-cyano-2-fluorophenylamino)cyclohexylcarbamate

5-amino-3-methylisothiazole hydrochloride

BINAP

K2CO3

→

titled compound

Yield 74.2%

4-((1R,2S)-2-aminocyclohexylamino)-5-fluoro-2-(3-methylisothiazol-5-ylamino)benzamide

Yield 74.2%

Solvents

dioxane

Conditions

Workup

1. 1
   Otherwas degassed with Ar
2. 2
   FiltrationAfter the mixture was filtered
3. 3
   Concentrationthe filtrate was concentrated in vacuo
4. 4
   workup.ADDITIONTo a solution of the residue in EtOH (2 mL) and DMSO (0.5 mL), 1N aq. NaOH (0.5 mL) and H2O2 (50% aq., 0.5 mL) were added
5. 5
   workup.STIRRINGAfter being stirred at room temperature for 3 h
6. 6
   workup.ADDITIONwater and EtOAc were added
7. 7
   OtherThe organic phase was separated
8. 8
   Dryingdried over Na2SO4
9. 9
   Concentrationconcentrated in vacuo
10. 10
    workup.DISSOLUTIONThe residue was dissolved in TFA (5 mL)
11. 11
    workup.WAITAfter 30 min of standing
12. 12
    OtherTFA was removed in vacuo
13. 13
    OtherThe residue was purified by HPLC

Procedure

A mixture of tert-butyl (1S,2R)-2-(5-bromo-4-cyano-2-fluorophenylamino)cyclohexylcarbamate (220 mg, 0.534 mmol), 5-amino-3-methylisothiazole hydrochloride (97 mg, 0.644 mmol), BINAP (50 mg, 0.080 mmol), Pd(OAc)2 (35 mg, 0.156 mmol) and K2CO3 (250 mg, 1.81 mmol) in dioxane (4 mL) was degassed with Ar, then was stirred at 120 C for 18 h. After the mixture was filtered, the filtrate was concentrated in vacuo. To a solution of the residue in EtOH (2 mL) and DMSO (0.5 mL), 1N aq. NaOH (0.5 mL) and H2O2 (50% aq., 0.5 mL) were added. After being stirred at room temperature for 3 h, water and EtOAc were added. The organic phase was separated, dried over Na2SO4, concentrated in vacuo. The residue was dissolved in TFA (5 mL). After 30 min of standing, TFA was removed in vacuo. The residue was purified by HPLC to give the titled compound (144 mg). MS 364.4 (M+H); UV 204.7, 292.8 nm

Source