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.

描述了一种快速和可靠的途径来制备可用作合成支架的甲基（S）-2-氯-5,6,7,8-四氢吡啶并[4,3 - d ]嘧啶-7-羧酸酯部分。以前，这种由Boc保护的实体是从1-羟基脯氨酸开始的10个化学步骤中制备的，总收率为0.67％。新开发的合成路线通过七个化学步骤提供了所需的目标，总收率高达38％。上一条路线需要解决的三个主要问题是：第一，的扩环升-羟基脯氨酸，通过快速色谱法产生不可分割的区域异构混合物（1.5：1）；其次，酮酯与尿素之间的低收率缩合步骤。第三，所需异构体的氯化产率低。从市售的（2-氯嘧啶-5-基）甲醇开始，新路线将Knochel碘化，Negishi交叉偶联和闭环作为关键步骤。这一新途径为我们提供了提供对映体纯净中间体以支持药物开发工作的机会。