4-Chloro-2-(methylthio)pyrimidine-5-carboxylic acid ethyl ester → 8-Cyclopentyl-2-methylsulfanyl-5-oxo-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester

Participants

Reaction Steps

3-Cyclopentylamino-propionic acid ethyl ester (1.0 g, 5.4 mmol) and 4-chloro-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (1.25 g, 5.4 mmol) were combined in DCM (10 mL) and diisopropylethylamine (0.83 g, 6.5 mmol) was added. After 16 h, the solution was partitioned between water and DCM and the organic layer was dried (MgSO4) and concentrated. Chromatography (0-20% EtOAc/hexanes gradient) provided the title compound that was directly carried on to the next step. Sodium (25 wt % dispersion in paraffin wax, 0.25 g, 6.0 mmol) was added to t-butanol (5.0 mL) at rt. After 10 minutes, a solution of 4-[cyclopentyl-(2-ethoxycarbonyl-ethyl)-amino]-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (2.0 g, 5.4 mmol) in 10 mL of toluene was added to the sodium t-butoxide solution and the resulting mixture was heated at 90° C. for 30 minutes. The reaction mixture was then cooled and the solution was adjusted to pH 7 using a 1N HCl solution. The solution was then extracted with EtOAc (2×20 mL) and the organic layer was dried (MgSO4) and concentrated to provide 0.26 g (14%). 1H-NMR (400 MHz, CDCl3:) 5 ppm 12.0 (br s, 1H), 8.20 (s, 1H), 5.10-5.18 (m, 1H), 4.26-4.31 (m, 3H), 3.72 (q, 2H, J=7.0 Hz), 2.50 (s, 3H), 1.63-1.86 (m, 5H), 1.20-1.35 (m, 5H).

Provenance & Evidence