3-Fluoroaniline → Methyl 4-(1-(2-(3-((3-fluorophenyl)amino)azetidin-1-yl)-5-(trifluoromethyl)nicotinamido)cyclopropyl)benzoate

Temperature

200 °C

To a solution of 3-Fluoroaniline (0.032 ml, 0.34 mmol) in acetonitrile (0.5 ml), potassium carbonate (61 mg, 0.044 mmol) was added followed by the addition of methyl 2-(3-((methylsulfonyl)oxy)azetidin-1-yl)-5-(trifluoromethyl)nicotinate (D68) (120 mg, 0.374 mmol). The reaction mixture was stirred under microwave irradiation for 50 min at 200° C. (2 cycles of 25 min each). Lithium hydroxide monohydrate (14.26 mg, 0.34 mmol) and a mixture 1,4-dioxane/water (3/1 ml) was added and the mixture was stirred under microwave irradiation for 5 min at 150° C. The mixture was evaporated in vacuo, diluted with water (5 ml)/1M HCl (15 ml) and extracted with ethylacetate (3×20 ml). After solvent evaporation, the residue was dissolved in dimethylformamide (2.5 ml) then (Benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP) (307.55 mg, 0.59 mmol) and N,N-Disopropylethylamine (0.27 ml, 1.57 mmol) were added and the mixture stirred at room temperature for 1 h. Methyl 4-(1-aminocyclopropyl)benzoate hydrochloride (D7) (89.7 mg, 0.394 mmol) was added and the resulting mixture was stirred at room temperature overnight then poured into ice-water and extracted with diethylether (3×20 ml). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The crude residue obtained after solvent evaporation was loaded on SNAP-Si cartridge (10 g) and eluted with a mixture cyclohexane/dichloromethane from 30/70 to 0/100 then dichloromethane/ethylacetate from 100/0 to 80/20. Collected fractions, after solvent evaporation afforded the title compound (D183) (16 mg)

1. stirringthe mixture was stirred under microwave irradiation for 5 min at 150° C
2. customThe mixture was evaporated in vacuo
3. additiondiluted with water (5 ml)/1M HCl (15 ml)
4. extractionextracted with ethylacetate (3×20 ml)
5. customAfter solvent evaporation
6. dissolutionthe residue was dissolved in dimethylformamide (2.5 ml)
7. stirringthe mixture stirred at room temperature for 1 h
8. stirringthe resulting mixture was stirred at room temperature overnight
9. extractionextracted with diethylether (3×20 ml)
10. washThe combined organic layers were washed with brine
11. dry with materialdried over Na2SO4
12. filtrationfiltered
13. concentrationconcentrated
14. customThe crude residue obtained
15. customafter solvent evaporation
16. washeluted with a mixture cyclohexane/dichloromethane from 30/70 to 0/100
17. customCollected fractions, after solvent evaporation

ORD record

ord-2a221ddf721d4585bea1a1101e542429

Source dataset

uspto-grants-2014_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08828987B2