3-(2-Chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one

Chemical Properties

White Solid

Uses

3-(2-Chloroethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (Risperidone EP Impurity L) is an intermediate in the synthesis of Risperidone (R525000), which is a combined serotonin (5-HT2) and dopamine (D2) receptor antagonist.

Synthesis

The general procedure for the synthesis of 3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one from 3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one is as follows: 28 g of 3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one obtained in step A) was dissolved in 90 mL 6N hydrochloric acid. -a]pyrimidin-4-one was dissolved in 90 mL of 6N hydrochloric acid, followed by the addition of 2.8 g of 10% palladium carbon catalyst to the solution. The reaction mixture was subjected to 35 psi hydrogen pressure and hydrogenated at room temperature with stirring for 8 hours. Upon completion of the reaction, the mixture was filtered through diatomaceous earth (Cellite) to remove the catalyst. The filtrate was concentrated under reduced pressure to give a residue. To the residue was added 200 mL of isopropanol and the mixture was stirred. The precipitated solid was collected by filtration and dried to give 25.1 g of the target product 3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one as white crystals in 90% yield.

References

[1] Patent: WO2004/35573, 2004, A1. Location in patent: Page 9
[2] Journal of the American Chemical Society, 2017, vol. 139, # 24, p. 8267 - 8276
[3] Letters in Drug Design and Discovery, 2011, vol. 8, # 10, p. 988 - 995
[4] Medicinal Chemistry, 2013, vol. 9, # 2, p. 240 - 248