Reaktion #172045

Reaktionsgleichung

cesium carbonate

tert-butyl (1S,2R)-2-(6-chloro-5-cyano-3-fluoropyridin-2-ylamino)cyclohexylcarbamate

3-aminopyridine

→

desired product

6-((1R,2S)-2-aminocyclohexylamino)-5-fluoro-2-(pyridin-3-ylamino)nicotinamide

tert-butyl (1S,2R)-2-(5-cyano-3-fluoro-6-(pyridin-3-ylamino)pyridin-2-ylamino)cyclohexylcarbamate

Lösungsmittel

toluene

Reaktionsbedingungen

Aufarbeitung

1. 1
   workup.ADDITIONTo a clean 100 mL flask were added
2. 2
   SonstigeThe resulting slurry was degassed
3. 3
   Sonstigewas then sent to 110° C.
4. 4
   Einengenconcentrated on rotovap
5. 5
   Sonstigeto remove all the solvent
6. 6
   workup.ADDITIONTo the residue were added 300 mL EtOAc and 100 mL water
7. 7
   workup.STIRRINGAfter vigorously stirring for 15-30 min
8. 8
   Sonstigethe organic phase was separated
9. 9
   WaschenThe EtOAc phase was then washed with brine twice
10. 10
    TrocknenThe organic phase was dried over MgSO4
11. 11
    Einengenconcentrated

Vorschrift

To a clean 100 mL flask were added to following reagents: (tert-butyl (1S,2R)-2-(6-chloro-5-cyano-3-fluoropyridin-2-ylamino)cyclohexylcarbamate (100 mg, 0.27 mmol), 3-aminopyridine (68 mg, 0.54 mmol), fine-powder cesium carbonate (264 mg, 0.81 mmol), Q-Phos (1,2,3,4,5-pentaphenyl-1′-(di-tert-butylphosphino)ferrocene) (19 mg, 0.03 mmol; Aldrich #675784) and Pd(dba)2 (bis(dibenzylideneacetone)palladium(0)) (16 mg, 0.03 mmol; Aldrich #227994). To the mixture was then added 15 mL toluene. The resulting slurry was degassed using argon stream gently for 3 min. It was then sent to 110° C. bath with an air-cooled condenser on top and stirred under argon for overnight. The mixture was then cooled to RT and concentrated on rotovap to remove all the solvent. To the residue were added 300 mL EtOAc and 100 mL water. After vigorously stirring for 15-30 min, the organic phase was separated, and the aq phase and the black junks between org and aq phases were all discarded. The EtOAc phase was then washed with brine twice. The organic phase was dried over MgSO4, concentrated and subjected to flash column with 0%-40% EtOAc in DCM to isolate the desired product, tert-butyl (1S,2R)-2-(5-cyano-3-fluoro-6-(pyridin-3-ylamino)pyridin-2-ylamino)cyclohexylcarbamate. It was added 5 mL TFA at RT. After stirring for 3 min, 1 mL conc. H2SO4 was added. The mixture was then sent to pre-heated 80° C. bath and stirred for 60 min. It was then cooled to RT. To it was added 10 mL water. The mixture was stirred for 10 min, filtered and directly subjected to prep HPLC (running with 3 mM HCl in water as solvent A and neat acetonitrile as solvent B) in two injections to isolate the title compound as HCl salt (lyophilized). Yield: 62 mg, 67% yield for Step 2. UV: 259, 325 nm. M+H found for C17H21FN6O: 345.3. NMR (CD3OD): 9.32 (1H, s), 8.43 (1H, m), 8.33 (1H, m), 7.90-7.82 (2H, m), 4.52 (1H, m), 3.79 (1H, m), 1.93-1.64 (8H, m) ppm.

Quelle