Route evaluation and development of a practical synthesis of methyl (S)-2-chloro-5, 6, 7, 8-tetrahydropyrido[4, 3-d]pyrimidine-7-carboxylate. Issue 49 (4th December 2020)

• Record Type: Journal Article
• Authors: Pawluczyk, Joseph M.; Kempson, James; Mathur, Arvind; Oderinde, Martins S.
• Is Part Of: Tetrahedron. Volume 76:Issue 49(2020)
• Publication Date: 2020-12-04
• Subjects: Pyrimidine -- Knochel iodination -- Negishi cross-coupling -- Photoredox -- Minisci reaction; Chemistry, Organic -- Periodicals; 547.005
• DOI: 10.1016/j.tet.2020.131624
• Languages: English
• ISSNs: 0040-4020

Abstract

Abstract: 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. Graphical abstract: Image 1