Highly flexible and efficient synthesis of the GABAB enhancer 4-(2-hexylsulfanyl-6-methyl-pyrimidin-4-ylmethyl)-morpholine

In the course of establishing a flexible synthesis of 2,4,6-substituted pyrimidines, we discovered that 2-hexyl-isothiourea hydrobromide reacts at ambient temperature and in a mildly exothermic fashion with 5,5-diethoxy-pent-3-yn-2-one upon treatment with 2 equiv of triethylamine in tetrahydrofuran to afford 4-diethoxymethyl-2-hexylsulfanyl-6-methyl-pyrimidine in 80% isolated yield. The methodology was developed in the search for an improved synthesis of the GABAB enhancer 4-(2-hexylsulfanyl-6-methyl-pyrimidin-4-ylmethyl)-morpholine.

Graphical abstractThe key step involved a cyclocondensation of a thiuronium salt with an acetylenic ketone harbouring an acetal protected aldehyde function.Download full-size image