Innovative use of ligands and palladium set to reduce drug production costs

The pharmaceutical industry is constantly working to produce more effective and affordable medications. One of the most promising areas of drug development in this regard is the use of catalysts in synthesising active substances. Catalysis can significantly increase the efficiency of synthesising complex molecules. New research conducted at the University of Missouri, USA represents a breakthrough in this field. The development of the AshPhos ligand in combination with palladium has led to the creation of a catalyst that paves the way for the cheaper production of a wide range of pharmaceutical compounds.

This approach reduces the cost of drugs and expands the possibilities of organic synthesis, solving several long-standing problems associated with the Buchwald–Hartwig reaction. Using a palladium-based catalyst and a new ligand overcomes the limitations associated with the low reactivity of certain classes of compounds. This opens up new prospects for creating the complex molecular structures needed in modern medicine, thereby reinforcing the importance of palladium catalysts in modern organic synthesis.

The AshPhos ligand was developed as an alternative to the highly reactive GPhos ligand, which requires significant synthesis costs. The starting material for AshPhos is 6,7-dibromo-2,3-dihydrobenzo[b][1,4]dioxin. Its structural features allow for the addition of a phosphine group in the para position relative to one ether group, and an electron-rich aryl ring in the para position relative to the second ether group and the ortho position relative to the phosphine group. These modifications significantly expand the potential applications of AshPhos in Buchwald–Hartwig amination reactions.

Using a palladium catalyst with an AshPhos ligand enhances chelation, simplifying the oxidative addition and transmetalation processes. This ensures effective amination, even of complex substrates that have previously demonstrated low reactivity. The study tested various palladium catalysts, including [Pd(crotyl)Cl]₂, Pd(OAc)₂, Pd₂dba₃, [Pd(allyl)Cl]₂ and Pd(cod)Cl₂. The best results were obtained with the [Pd(crotyl)Cl]₂ catalyst, which produced a target product yield of 90%. Using Pd2dba3 instead reduced the yield to 70%, while using Pd(OAc)2 reduced it further to 38%.
Thus, the development of AshPhos and its use in combination with palladium represents a significant step forward in organic synthesis and pharmaceutical production. This new technology reduces the cost of drug production and expands the possibilities for using palladium catalysts, which is important in the long term for both the scientific community and business.
Source:
https://medicalupdateonline.com/2025/02/mizzou-researchers-invent-a-new-tool-to-help-lower-the-cost-of-tomorrows-medicine/
https://pubs.acs.org/doi/10.1021/jacsau.4c00772