Route evaluation and development of a practical synthesis of methyl (S)-2-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-7-carboxylate

A rapid and reliable route to methyl (S)-2-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-7-carboxylate moiety that is useful as a synthetic scaffold is described. Previously, this Boc-protected entity was prepared in 10 chemical steps starting with l-hydroxyproline with an overall yield of 0.67%. The newly developed synthetic route provided the desired target in seven chemical steps with an overall yield up to 38%. Three main issues that needed to be addressed with the previous route were; first, the ring expansion of the l-hydroxyproline that generated an inseparable regioisomeric mixture (1.5:1) by flash chromatography; secondly, the low yielding condensation step between the keto ester and urea; thirdly, the low yielding chlorination of the desired isomer. Starting with commercially available (2-chloropyrimidin-5-yl)methanol, the new route incorporates a Knochel iodination, a Negishi cross-coupling, and a ring closure as the key steps. This new route afforded us the opportunity to deliver enantiomerically pure intermediate in support of drug discovery efforts. [Display omitted]