Development of a Modeling-Based Strategy for the Safe and Effective Scale-up of Highly Energetic Hydrogenation Reactions

Abstract

A modeling-based strategy is disclosed for identifying reaction conditions for the safe and effective scale-up of highly energetic hydrogenation reactions. The model was developed within Scale-up Systems’s DynoChem 2011 and takes under consideration the kinetics of the reaction, the reactor heat transfer capabilities, and the degree of mass transfer. Fourier transform infrared spectroscopy (FT-IR), heat flow, and H2 uptake data were used to determine the reaction kinetics that were found to be most accurately described by a Langmuir–Hinshelwood type model. The scale-up model was validated within our kilo-laboratory using a 5 L reactor.

New Scale-Up Technologies for Multipurpose Pharmaceutical Production Plants: Use Case of a Heterogeneous Hydrogenation Process

“…This approach is described in the literature based on different optimization tools and software. 13,14 The final model describing the chemistry of the hydrogenation process includes 22 chemical reactions and 25 compounds. The binding of the hydrogen to the heavy-metal catalyst (palladium supported on charcoal) was described as an equilibrium reaction.…”

New Scale-Up Technologies for Hydrogenation Reactions in Multipurpose Pharmaceutical Production Plants

“…These models are usually based on reaction kinetics, reaction enthalpies and dynamic physical models for heat and mass transfer of production-scale reactors. [5][6][7] With information and knowledge gained from the development of a chemical process model the establishment of the design space can be strongly supported. [8,9] Product and process understanding is a key element of Quality by Design (QbD).…”

“…This approach is described in literature with different software and optimization tools. [5,19] At Siegfried AG the RC1 reaction calorimeter combined with an automatic sampling system, offline analytics and spectroscopic PAT tools are used to generate experimental data. The kinetic and thermodynamic parameters of the corresponding reactions and involved side reactions are then determined with Dynochem ® .…”

Regioselective Control of the SNAr Amination of 5-Substituted-2,4-Dichloropyrimidines Using Tertiary Amine Nucleophiles

“…2,4-Dichloropyrimidines that are further substituted at C-5 with an electron-withdrawing substituent (notably cyano, nitro, or trifluoromethyl) are particularly useful starting materials, yielding (upon further synthetic transformation) pyrimidine-containing structures with biological activity. The breadth of biologically active pyrimidine, and pyrimidine-derived, structures is expansive. , The synthetic objectives of several examples are cited herein: adenosine A 2A receptor antagonist; HIV non-nucleoside reverse transcriptase inhibitor; VLA-4 integrin antagonist; inhibitor of falcipain protease; inhibitor of stearoyl-CoA desaturase; and inhibitors of human kinases. − The S N Ar reactions of these pyrimidines (whether with carbon, nitrogen, or oxygen nucleophiles) invariably occur rapidly (often in minutes) at low temperatures (ambient and below), with excellent yields and outstanding regioselectivity for nucleophilic displacement of the C-4 halogen . Indeed, with many amine nucleophiles, this regioselectivity is so good that the accompanying experimentals often fail to acknowledge the possible presence of a minor product from competing substitution at C-2.…”

“…The value of this new strategy to control the S N Ar regioselectivity of reactive 5-substituted-2,4-dichloropyrimidines is illustrated. A common transformation following successive S N Ar reactions of 2,4-dichloro-5-nitropyrimidine is reduction of the nitro moiety . Pyrimidine 3c is a useful intermediate toward the synthesis of pyrrolo­[3,2- d ]­pyrimidine structures, a relatively unexplored class of biologically active heterocycles (Scheme A).…”