An Improved Integrated Batch‐Flow Synthesis for 4‐Amino‐2‐Methyl Pyrimidine‐5‐Carbonitrile, a Vitamin B1 Intermediate Assisted by Reaction Calorimetry

ABSTRACT Synthesizing intermediates for vitamin B1 is crucial for producing this essential nutrient, which plays a key role in various metabolic processes, particularly in energy metabolism and nervous system function. The synthesis of these intermediates involves several steps, each contributing to the overall production process. This study developed a reliable, efficient two‐step synthetic process for manufacturing a key vitamin B1 intermediate. The process uses malononitrile and N,N ‐dimethylformamide dimethyl acetal (DMF‐DMA), followed by condensation with acetamidine in methanol to yield 4‐amino‐2‐methylpyrimidine‐5‐carbonitrile. In situ reaction monitoring and analysis were performed using ReactIR, providing insights into the intermediates and the conversion in both steps, resulting in an isolated yield of approximately 97% for the batch synthesis. Additionally, RC1mx was employed to study the exothermicity and thermal behavior, allowing precise control of the reaction conditions and avoiding runaway reactions, thereby enhancing product yield and purity. A similar chemistry in stage 1 was run in flow to make it available to readers and industrial researchers. Combining these advanced monitoring techniques and process chemistry, both in batch and in flow, facilitated the development of a highly efficient and reproducible synthesis protocol. This demonstrates the potential for real‐time process optimization and characterization.