5,6-Dimethyluracil → HCID 178467469, compound

To dimethyl uracil (10.5 g, 75 mmol) in EtOH (75 mL) was added malonitrile (9.9 g, 150 mmol) and EtONa (2.5 M, 60 mL, 150 mmol). The mixture was refluxed for 2 h and the precipitates were collected and washed with EtOH. The solid was treated with 2N aqueous HCl and extracted with EtOAc to provide 2-ethoxy-6-hydroxy-nicotinonitrile (8.7 g, 71%). A portion of this material (8.2 g, 50 mmol) was dissolved in CH2Cl2 (75 mL) followed by addition of PhNTf2 (19.6 g, 55 mmol) and Et3N (6.06 g, 60 mmol). The mixture was allowed to stir at ambient temperature overnight and washed with water and purified by column chromatography to provide trifluoro-methanesulfonic acid 5-cyano-6-ethoxy-pyridin-2-yl ester (15.9 g, coeluted with PhNHTf). A portion of this material (9.5 g, impure) was dissolved in MeOH (40 mL) followed by addition of PdCl2CH2Cl2dppf (1.4 g, 1.7 mmol) and Et3N (6.5 g, 65 mmol). The mixture was heated at 50° C. under CO (100 psi) for 6 h. The mixture was purified by column chromatography to provide 5-cyano-6-ethoxy-pyridine-2-carboxylic acid methyl ester (2 g, 32% over 2 steps). A portion of this material (1.5 g, 7.3 mmol) was dissolved in EtOH/H2O (5:3, 15 mL) followed by addition of LiOH (640 mg, 15 mmol). The mixture was stirred for 30 min and 2N aqueous HCl was added to adjust the acidity to pH of 1. Precipitates were collected and washed to provide 5-cyano-6-ethoxy-pyridine-2-carboxylic acid (1.0 g, 71%).

1. temperatureThe mixture was refluxed for 2 h
2. customthe precipitates were collected
3. washwashed with EtOH
4. additionThe solid was treated with 2N aqueous HCl
5. extractionextracted with EtOAc

ORD record

ord-a3c3e536e6e34ef581c61898c8cee0de

Source dataset

uspto-grants-2011_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07888374B2