Breakthrough therapy mobocertinib synthesis process analysis

On April 27, 2020, the FDA awarded mobocertinib (TAK-788) breakthrough therapy, not only to advance after platinum chemotherapy, EGFR exon 20 insertion of mutant non-small cell lung cancer patients with new treatment options, the drug is also an innovative breakthrough in eGFR exon 20 insertion of mutant non-small cell lung cancer specific targeted therapy! EGFR exon 20 insertion of mutant non-small cell lung cancer has been lack of effective targeted chemotherapy program, the current lyse-listed EGFR targeted chemotherapy can not bring positive clinical benefits to such patients, mobocertinib is expected to be the first EGFR exon 20 insertion mutation mutant non-small cell lung cancer specific targeted chemotherapy programoneNon-small cell lung cancer: EGFR exon 20 insertion mutations account for about 2%Cancer Clinical Journal data show that in 2018, there were about 2.1 million new cases of lung cancer worldwide and about 1.8 million deaths, with lung cancer in Eastern Europe, East Asia, Western Europe, Southern Europe and North America particularly burdenedLung cancer is divided into small cell lung cancer and non-small cell lung cancer according to its cell morphology characteristics and biological behavior, in general, 85% of patients are non-small cell lung cancer, and lung squamous cancer and lung adenocarcinoma are the two most common non-small cell lung cancer subtypeslung cancer is a molecular heterogeneous disease, with the development of biotechnology, the basic theory of non-small cell lung cancer is constantly breaking throughEGFR, KRAS, c-Met, ALK and other related driving gene mutations are very closely related to lung cancer, of which EGFR-mutant is one of the main driving gene mutations, statistics show that it accounts for about 27% of lung adenocarcinoma patients, lung squamous cancer patients about 9%the mutation of various driving genes in patients with lung squamous and pulmonary adenocarcinoma
DOI: https://doi.org/10.1038/nature25183epidermal growth factor receptor (EGFR) is a cross-membrane protein belonging to the tyrosine kinase receptor family (RTK), which plays an important role in cell proliferation, survival, differentiation, and migrationEGFR-driven gene mutations are diverse and are more common in EGFR 18-21 exons, with classic mutations such as EGFR exon 19DEL or EGFR exon21 L858R mutations (approximately 80-90%)Takeda
EGFR configuration change and signal activationdoi:10.1038/s41392-019-0038-9physiological state, EGFR can be changed by conformation to control signal conduction, where in which EGFR exon 19DEL or EGFR exon 20 insertion mutation sepsis can lead to continuous exposure of the active point of the EGFR pathwayEGFR exon 20 inserts mutation position:V769-D 770-N 771, H 773 - V 774 Most Common doi:10.1038/s41392-019-0038-9 EGFR exon 20 insertion mutation sepsis ratio in all types of cancer WCLC 2018, Spectrum Pharmaceuticals 2 EGFR exon 20 insertion of mutant non-small cell lung cancer patients still lack effective treatment plan DOI: https://doi.org/10.1038/nature25183 o 2002, the approval of Irisa (Gifitinib) opened a new era of non-small cell lung cancer targeted chemotherapy, all kinds of targeted chemotherapy followed, non-small cell lung cancer patients layering more and more fine, more and more precise treatment small and beautiful; 2015, Corida Odivo has been approved for non-small cell lung cancer treatment without drive gene mutation, opened the curtain on the treatment of lung cancer tumor immunotherapy, tumor immunity innovated non-small cell lung cancer treatment without drive gene mutation, tumor immunity greatly increased the 5-year survival rate of patients with stage IV small cell lung cancer ; , MET, BRAF, RET and NTRK testing are necessary However, it is very regrettable that the currently approved eGFR targeted chemotherapy for EGFR exon 20 insertion mutation non-small patients has poor efficacy, clinical benefits are extremely limited, platinum chemotherapy, patients are not available WCLC 2018 Mobocertinib: PR 54% (14/26) NCT02716116, https://ascopubs.org/doi/abs/10.1200/JCO.2019.37.15_suppl.9007 III Mobocertinib's rational design: Insertion from Ochitinib to mobocertinib EGFR exon 20 significantly increases the difficulty of the drug entering the active ATP binding pocket, which is an important reason why current EGFR targeted chemotherapy drugs do not deliver significant clinical benefits to such patients Takeda
Mobocertinib is based on Oxitinib's rational design, which gradually reduces molecularly induced theinics, improves binding capability and selectivity with EGFR-WT, and improves pharmacokinetics The patent information for pharmaceutical compounds is as follows: 1 ARIAD Pharmaceuticals has a PCT application WO2015195228 (A1); China CN106559991 (B) searched Mobocertinib's structure in Reaxys or SciFinder and found no literature on its synthesis process Given that Mobocertinib's structure is highly similar to that of Osimertinib, we can make a reasonable guess about the synthetic route of Mobocertinib from Osimertinib (AZD9291) AstraZeneca (J Med Chem 2014, 57, 8249?8267.) The published original route can produce a series of Osimertinib derivatives With 5 bits with a replacement base (R2-H, Me, Cl) 2,4-dichloroquine1 as the starting raw material, in the same amount of methylglycinret reagent as alkali conditions, with the sNAr of the snAr of the sinium 2 to obtain 3, further obtainN-methylation of the product 4 (R1-H-Me); The conditions for the modification of the benzene ring can be more demanding: first of all, it is necessary to use trifluoroethanol as a solvent, DIPEA as alkali, 140 degrees C microwave conditions, so that N, N, N'-trimethylethyamine 7 (preparation of other derivatives can also be introduced, etc.) and benzene ring f replacement, purified by SCX column purification Over the silicone column, obtain compound 8, then in ethanol / water (3:1 v/v) as a solvent, co-boiling conditions with Fe and NH4Cl reduction nitro 9, and finally in an ice water bath drips with acrylolchloride DCM solution, introduced Micheal into the receptor officer group, complete the synthesis of Osimertinib it is worth noting that, in the penultimate step of the original route, the 5-bit R2 can be further modified, with Zn (CN)2 as the source of cyanide, and under the catalysis of Pd(0) to convert Cl to CN at a medium yield We speculate that CN in compound 12 can cause alcohol solutions (Synthetic Commun 2003, 33 (19), 3461-3466., or hydrolysis re-esterification, and then introduce acrylonyltol, which can be produced by Mobocertinib reference to Liu (J Chem Res 2015, 39, 318?320.) To change the sequence of links in key fragments, the author theoretically analyzed and brick-throwing jade designed a convergent Mobocertinib synthesis route: modified aniline 16 and compound 4' were replaced directly under TsOH catalysis, and then R2 was converted into cyanide, alcohol solution, nitro-catalytic hydrogen, propylene propylene modified to replace the bocicification (and purification structure) to obtain the final Moert The compound 16 can be aniline 5 as raw material, in turn, Boc protection, SNAr replacement, de-protection, 4' can be directly N-methyl pyridine as the starting raw material, with 2,4,5-triclosan replacement reaction given the mechanism of drug-resistant mutations in EGFR and the uncertainty of the target spatial structure caused by the diversity of EGFR exon 20 insertion mutations, the future demand for next-generation EGFR inhibitors may be accompanied by new mutation types As with molecular optimization from Osimertinib to Mobocertinib, a change in the power group has the potential to provide a completely new treatment for specific drug-resistant mutations;