beta-Alanine, ethyl ester, hydrochloride → HCID 59497292, compound

Temperature

130 °C

1-Methyl-2-fluoro-3-nitro-benzene (465 mg, 3 mmol) was dissolved in DMF (6 mL) and 3-aminopropionic acid ethyl ester hydrochloride salt (735 mg, 4.6 mmol) was added followed by TEA (1.5 mL, 10.7 mmol). The reaction mixture was heated in the microwave at 130° C. for 1 h, cooled, diluted with water (100 mL) and extracted with dichloromethane (2×50 mL). The combined organic fractions were washed with 1 N HCl (30 mL), water (30 mL) and brine (30 mL), dried and evaporated to provide 3-(2-methyl-6-nitrophenylamino)-propionic acid ethyl ester (580 mg, 77% yield) which was used directly. This intermediate (101 mg, 0.4 mmol), ammonium formate (252 mg, 4 mmol) and Pd/C (5%, 5 mg) were combined in a reaction vial and methanol (1 mL) was added. The mixture was agitated at room temperature for 4 h, diluted with dichloromethane (5 mL) and filtered, and the mother liquors were concentrated to provide the crude product 3-(2-amino-6-methylphenylamino)-propionic acid ethyl ester which was used directly. This intermediate (37 mg, 0.17 mmol) was dissolved in dichoromethane (1 mL) and carbonyldiimidazole (34 mg, 0.21 mmol) was added. The resulting mixture was agitated at room temperature overnight then purified directly by preparative HPLC using an acetonitrile/water/formic acid gradient providing the intermediate 3-(7-methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-propionic acid ethyl ester (21 mg, 51% yield) which was used directly. This intermediate was dissolved in DMF (1 mL), and K2CO3 (69 mg, 0.5 mmol) was added followed by (1,4-dimethyl-1H-indol-3-ylmethyl)-trimethyl-ammonium iodide (137.7 mg, 0.4 mmol), prepared as described previously. The resulting mixture was heated at 65° C. overnight, cooled, filtered and the solution was treated directly with Amberlyst® A26 (OH—) (650 mg, 0.87 mmol). This reaction mixture was agitated overnight and the resin was filtered and washed with several portions of methanol. The product was eluted by treating the resin with a 20% solution of formic acid in methanol (2×2 mL) and washing with methanol (2 mL). The combined eluant and final wash was evaporated and the residue was purified by preparative HPLC using an acetonitrile/water/formic acid gradient providing the title compound (9 mg, 15% yield). LCMS (ESMS): m/z 378 (M+H).

1. temperaturecooled
2. extractionextracted with dichloromethane (2×50 mL)
3. washThe combined organic fractions were washed with 1 N HCl (30 mL), water (30 mL) and brine (30 mL)
4. customdried
5. customevaporated

ORD record

ord-77e6cce9079c4d16b870ae6df0ef7626

Source dataset

uspto-grants-2015_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09150556B2