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Trilaciclib: Synthesis and Introduction

Jan 25，2024

Synthesis of Trilaciclib

Trilaciclib is synthesised using 2-thiomethyl-4- chloropyrimidine as a raw material by chemical reaction. The specific synthesis steps are as follows:

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The first step was a nucleophilic substitution reaction between 2-thiomethyl-4- chloropyrimidine (25.1) and piperazin-2-one 25.2. High temperatures and long reaction times (60 h) were required due to the low reactivity, but an effective crystallization purged leftover starting material and generated high[purity product 25.3 in 53% yield. After subsequent Boc protection, a Dieckmann condensation produced tricyclic 25.5 in quantitative yield without appreciable impurity formation. Next, the hydroxyl group on the pyrrole ring was removed in a 2-step process by formation of triflate intermediate 25.6, which had limited stability, followed by reduction with diethylsilane and tetrakis(triphenylphosphine)palladium to form 25.7. Next, Boc deprotection followed by thioether oxidation to the corresponding sulfone using an oxone afforded 25.8 in 95% yield. Finally, treatment of aniline 25.9 with lithium bis(trimethylsilyl)amide (LiHMDS) followed by addition to 25.8 generated trilaciclib (25) in a nucleophilic substitution reaction. This route was chosen over a similar synthetic route using an aryl aldehyde in place of 25.1 because the process did not require chromatography for the purification of intermediates, avoided a major bis-condensation impurity, and did not rely on an aldehyde-substituted pyrimidine starting material, which is not commercially available.

Introduction of Trilaciclib

Trilaciclib is an intravenously administered, short-acting inhibitor of cyclin-dependent kinases (CDKs) 4 and 6 used in combination with small-cell lung cancer and other cancer chemotherapy treatments. Because the current standard of care for small cell lung cancer is cytotoxic chemotherapy, patients experience myelosuppression as a result of damage to hematopoietic stem and progenitor cells in the bone marrow. Chemotherapy-induced myelosuppression is commonly managed with supportive treatments, such as trilaciclib. By inhibiting CDKs that regulate cell lifecycles, trilaciclib reversibly halts lifecycle progression, protecting cells from damage during chemotherapy.

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