News & Events

Great Minds Think Alike! ChemExpress and BMS have each achieved significant breakthroughs in the scalable synthesis of ((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol and its derivatives. These innovations offer a robust and efficient synthetic platform—poised to support broader drug development efforts and the next generation of KRAS inhibitors.

Figure 1 Background and Current Breakthrough

KRAS gene mutations are among the most common activating mutations in human cancers. KRAS has long been considered as undruggable targets in drug development. The G12D mutation refers to the substitution of glycine (G) at codon 12 with aspartic acid (D), introducing a terminal carboxylic acid group. Most of publicly disclosed small molecules targeting this mutation often share a key structural motif: ((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (Fig 1A,Compound 1, CAS No. 2097518-76-6). However, existing synthetic routes for this scaffold often suffered from low overall yields and required challenging operations such as ozonolysis and costly chiral chromatographic separation, making them difficult and expensive to scale for industrial production. There was an urgent need for a more efficient, scalable, and cost-effective synthetic process.

As early as 2021, our team began focusing on developing a scalable process for synthesizing ((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol and its derivatives, laying the groundwork for patent protection. In 2022, ChemExpress successfully filed a PCT international patent application for this process (Publication No. WO2024092420A1). Our patented route starts from low-cost, commercially available proline. It leveraged chiral epoxide ring-opening followed by base-induced intramolecular alkylation to construct the bridged bicyclic core with excellent stereocontrol. Note that the TMS ether can be isolated which can subject directly to the subsequent deoxy-fluorination and reduction to furnish the final product in 4 steps with >99% ee (Fig 1B).

Coincidentally, researchers from Bristol Myers Squibb independently discovered a similar route employing the same strategy as us with slight variations. Recently, they published their results on optimizing and improving the synthetic route for the same core structure (OPRD, 2025, 29, 704.). The key feature of the BMS route is the intramolecular nucleophilic cyclization to form the enantiopure bicyclic scaffold from proline. Like ChemExpress’ patented approach, BMS’ route eliminates the need for chiral separation, enables cost-efficient synthesis, and demonstrates strong potential for industrial scalability (Fig 1C).

Overall, we are happy to see two teams are so creative to figure out the same strategy and developed robust process to deliver the important building block in a large scale. The dedication of chemists from ChemExpress and BMS enabled a rapid access to the important building block in the KRAS therapeutics, which will surely benefit the patient in need.

Company introduction:

Founded in 2006, ChemExpress is dedicated to providing end-to-end CDMO services in small molecules and emerging modalities for both pharmaceutical and biotech clients. Our integrated CRO & CDMO platform offers R&D, manufacturing, and supply capabilities spanning RSMs, building blocks, intermediates, reference standards, APIs, and finished drug products—supporting programs from early discovery to commercialization. ChemExpress adheres to our vision, our mission, and our value, keeping abreast of the current trend and state-of-the-art science and technologies of the global biopharmaceutical industry to serve our clients to the utmost satisfaction.