Development of a programmable high volume manufacturing platform for fine chemicals via arene halogenation-lithiation & lithium-halogen exchange

Snapdragon proposes to develop a continuous manufacturing platform that is able to convert the commodity chemicals, benzene and chlorobenzene to highly functionalized fine chemicals of importance to the pharmaceutical industry.  The platform will perform two reaction types.  The first process is electrophilic aromatic halogenation reaction to produce the products bromobenzene, 1-bromo-2-chlorobenzene (1) and 1-bromo-4-chlorobenzene (2).  The di-functionalized 1 and 2 are themselves useful fine chemical building blocks.  The three products of the halogenation platform, 1, 2 and bromobenzene, will then be converted to nine fine chemical products in a connected reactor designed to perform lithium-halogen exchange followed by reaction with a range of electrophiles.  Isolation and purification of the nine final products to achieve >98% purity will be performed as connected processes.  The system proposed will include a supervisory control and data acquisition (SCADA) system through to interface with the highly automated platform.  The platform will be reconfigured to change between products, and perform clean-out operation, through the SCADA interface. No manual modifications to the platform, aside from changing the input materials, will be required to make the change between products.  The products selected for manufacture have been identified as intermediates to a majority of the top selling 200 small molecule pharmaceuticals and also to a number of the HHS – DoD list of medicines essential to the COVID-19 response.  The halogenation / lithiation chemistry proposed has greater energy efficiency, higher space-time productivity and improved environmentally sustainability compared to existing technology based on arene nitration and hydrogenolysis.  The lithium-halogen exchange platform is designed as a general-purpose system applicable to a broad range of mixing sensitive and exothermic reactions that are broadly applicable to fine chemical manufacture.  As such the platform is anticipated to be extensible to a broad range of fine chemicals.  The platform will be fully automated such that it can switch from one product to another without manual recofiguration of the platform hardware, but will instead rely on software alone to change from one product to another.  The product range possible through the proposed platform technology are potential key raw materials in the vast majority of pharmaceutical products used by the US population and also building blocks for other important products from materials to animal health.