Dimethylformamide → HCID 89692899, compound

In a 40 ml scintillation vial equipped with a magnetic stir bar and a fitted with a nitrogen inlet, the 5-amino-2-chloro-4-[4-(5-fluoro-2-methyl-phenyl)-piperazin-1-yl]-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-benzamide 16g (130 mg, 0.27 mmol) was taken up in clean, dry N,N-dimethylformamide (3.00 ml, 38.74 mmol) and the mixture was allowed to stir under nitrogen at room temperature until all solids were in solution. To this mixture was added the HATU (121.60 mg, 0.32 mmol) followed by the N,N-diisopropylethylamine (0.14 ml, 0.80 mmol) and the mixture was allowed to stir until all solids were taken into solution. The 2-cyclopropyl-oxazole-4-carboxylic acid 1h (56.80 mg, 0.37 mmol) was added to the reaction mixture and the reaction stirred at room temperature overnight. The reaction was diluted with 10 ml of water and 10 ml of ethyl acetate. The layers were separated and the product was extracted from the aqueous using ethyl acetate (3×15 ml). The organic phases were combined, washed with brine (1×25 ml) and with saturated aqueous lithium chloride solution (2×25 ml). The solution was then dried over Na2SO4; the solution was then decanted and the solvent was removed under reduced pressure. The product was purified from the resultant brown semi-solid using silica gel column chromatography, eluting a gradient of 100% dichloromethane to 10% MeOH in dichloromethane. A secondary purification was required and the compound was purified using reverse-phase prep HPLC, eluting a gradient of 30% MeOH in water to 100% MeOH over a 5 min period. The product, 2-cyclopropyl-oxazole-4-carboxylic acid {4-chloro-2-[4-(5-fluoro-2-methyl-phenyl)-piperazin-1-yl]-5-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-phenyl}-amide 16h (11.20 mg, 0.02 mmol), was isolated as a white solid.

1. customIn a 40 ml scintillation vial equipped with a magnetic stir bar
2. customa fitted with a nitrogen inlet
3. stirringto stir until all solids
4. stirringthe reaction stirred at room temperature overnight
5. customThe layers were separated
6. extractionthe product was extracted from the
7. washwashed with brine (1×25 ml) and with saturated aqueous lithium chloride solution (2×25 ml)
8. dry with materialThe solution was then dried over Na2SO4
9. customthe solution was then decanted
10. customthe solvent was removed under reduced pressure
11. customThe product was purified from the resultant brown semi-solid
12. washeluting a gradient of 100% dichloromethane to 10% MeOH in dichloromethane
13. customA secondary purification
14. customthe compound was purified
15. washeluting a gradient of 30% MeOH in water to 100% MeOH over a 5 min period

ORD record

ord-c517a5f3593f4470ab90658837d7bd50

Source dataset

uspto-grants-2016_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09409897B2