Recently, the raw material process research and development team of Hequan Pharmaceutical and AstraZeneca published an online publication entitled "Exploration of a Nitromethane-Carbonylation Strategy during Route Design of an ACS) in The Journal of Organic Chemistry (JOC). Atropisomeric KRASG12C inhibitor" paper. JOC is one of the authoritative publications in the field of organic synthesis.

KRASG12C mutation is closely related to lung cancer. The compound 1 introduced in this article can specifically bind to the cysteine residues on the GTPase domain of KRAS protein and inhibit the activity of KRASG12C. Because the KRAS protein acts like a molecular switch in the human body, it can activate or inhibit a series of downstream signaling pathways related to the growth and reproduction of cancer cells. As a specific inhibitor of KRASG12C, compound 1 has a potential role in the treatment of cancer.

The original route of compound 1 can be used for gram-scale API synthesis, but when applied to large-scale production, it will face: large number of reaction steps, low yield, Gould-Jacobs high temperature (200℃) closed loop causing safety problems, and the need for supercritical fluids Chromatographic separation, etc. Based on this, the Hequan API process research and development team cooperated with AstraZeneca to optimize the original route of the key intermediates piperazine 2 and quinoline 3, and finally realized kilogram-level production. The following will briefly introduce how the research team solved these two pain points.

1. Reduce functional group protection, optimize oxidation reaction, realize safe amplification and increase yield

In the original route, the key intermediate piperazine 2 needs to be synthesized through 10 steps with a total yield of 10-15%. However, in kilo-level synthesis, challenges such as poor reproducibility of selective de-Boc, difficulty in separation and purification of some intermediates, and low yield are encountered.

By replacing BH3 with I2/NaBH4 to reduce the amide, the yield is significantly improved and the post-processing is easy. The obtained intermediate 7 can be directly cast to the next step for Boc protection to obtain intermediate 11. In order to reduce the number of reaction steps, the researchers preferentially TEMPO oxidizes alcohol to obtain carboxylic acid, and then obtains an N-acid anhydride structure based on the conditions of SOCl2/DMF. This design scheme reduces the number of reaction steps and makes full and effective use of Boc functional group. Finally, the structure of N-acid anhydride was ring-opened in methanol to obtain the key intermediate piperazine 2. Compared with the original route, the number of reaction steps in the new route is optimized to 7 steps, and at the same time it has the advantages of high atom utilization, simple purification and separation.

2. Avoid safety hazards caused by high temperature reactions and supercritical fluid chromatographic separation steps

In the original synthetic route, the key intermediate quinoline 3 needs to undergo ring closure at high temperature (200°C) by Gould-Jacobs, and then undergo a Suzuki coupling reaction to obtain atropisomers, which are finally separated by SFC. For safety and economic considerations, the researchers first introduced the Suzuki coupling step to obtain the intermediate 14 aniline, and then screened through a series of chiral acids to confirm the resolution of ((+)-3-Br-10-CSA) The effect is good. The key intermediate quinoline 3 is obtained through a series of reactions such as the introduction of iodine atoms into aniline by iodine and the intercalation of carbonyl. This new route effectively avoids the potential safety hazards caused by high-temperature reactions, and at the same time avoids the costly and time-consuming SFC separation step.