1,2-Dichloroethane → Formate

3-Nitrophenylacetic acid (136 mg, 0.75 mmol), EDC (240 mg, 1.25 mmol) and HOBt (135 mg, 1 mmol) were combined in a reaction vial, and DMF (1 mL) was added, followed by N-methylmorpholine (0.137 mL, 1.25 mmol). The resulting solution was agitated for 1 h, after which time 3,4-dimethoxyaniline (115 mg, 0.75 mmol) was added and the reaction mixture was agitated overnight. The reaction mixture was then diluted with 6 mL dichloromethane, and the resulting mixture was washed with 1 N HCl (2×2 mL), NaHCO3 (satd. aq., 2×2 mL), and brine (1×2 mL), dried, and the solvents were evaporated to 216 mg of a dark oil. The product was purified by preparative HPLC using an acetonitrile/water/formic acid gradient to provide 36 mg (15% yield) of the intermediate N-(3,4-dimethoxy-phenyl)-2-(3-nitro-phenyl)-acetamide. This intermediate (36 mg, 0.114 mmol) was dissolved in methanol (1 mL) and ammonium formate (69 mg, 1.1 mmol) and then Pd/C (5 mg) was added. The reaction vial was sealed and heated to 45° C. overnight. The reaction mixture was filtered, and the mother liquors were diluted with ethyl acetate (10 mL). This mixture was washed with water (2×5 mL) and brine (1×5 mL), dried and concentrated to provide 10 mg (31% yield) of the desired intermediate 2-(3-amino-phenyl)-N-(3,4-dimethoxy-phenyl)-acetamide, which was used directly. Subsequently, 3-(2-carboxy-ethyl)-piperidine-1-carboxylic acid tert-butyl ester (12.9 mg, 0.05 mmol), EDC (11.5 mg, 0.06 mmol) and HOBt (8.1 mg, 0.06 mmol) were combined in a reaction vial, and DMF (1 mL) was added, followed by N-methylmorpholine (0.007 mL, 0.06 mmol). The resulting solution was agitated for 30 minutes, after which time the intermediate prepared above, 2-(3-amino-phenyl)-N-(3,4-dimethoxy-phenyl)-acetamide (10 mg, 0.035 mmol) was added. The reaction mixture was agitated overnight, then diluted with 5 mL dichloromethane, and the resulting mixture was washed with 1N HCl (2×2 mL), NaHCO3 (saturated aqueous, 1×2 mL), and brine (1×2 mL), dried, and concentrated to 19 mg (72%) of an amber oil, which was dissolved in dichloromethane (1 mL) and treated with SCX (136 mg, 0.12 mmol). The resulting mixture was agitated overnight. The reaction mixture was then filtered and the solids were washed with dichloromethane (2×2 mL) and methanol (2×2 mL). The product was eluted with NH3 in methanol (7 N, 2×2 mL), and the solvents were evaporated. The resulting residue was purified by preparative HPLC using an acetonitrile/water/formic acid gradient providing the title compound as a formate salt (6.5 mg, 38% yield), MS analysis electrospray, 426 (M+H).

1. additionwas added
2. customafter which time the intermediate prepared above
3. stirringThe reaction mixture was agitated overnight
4. washthe resulting mixture was washed with 1N HCl (2×2 mL), NaHCO3 (saturated aqueous, 1×2 mL), and brine (1×2 mL)
5. customdried
6. concentrationconcentrated to 19 mg (72%) of an amber oil, which
7. dissolutionwas dissolved in dichloromethane (1 mL)
8. additiontreated with SCX (136 mg, 0.12 mmol)
9. stirringThe resulting mixture was agitated overnight
10. filtrationThe reaction mixture was then filtered
11. washthe solids were washed with dichloromethane (2×2 mL) and methanol (2×2 mL)
12. washThe product was eluted with NH3 in methanol (7 N, 2×2 mL)
13. customthe solvents were evaporated
14. customThe resulting residue was purified by preparative HPLC

ORD record

ord-4c6a35b954a2488597e90d156f578688

Source dataset

uspto-grants-2012_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08093266B2