Selective mono‐Boc Protection of Diamine Compounds Employing Acetamidine Hydrochloride as a Catalyst: A Potential Large‐Scale Approach

ABSTRACT A novel method for the selective mono‐Boc protection of diamines, utilizing acetamidine hydrochloride and its analogs as catalysts, has been investigated. Under the catalysis of 1% acetamidine hydrochloride hydrochloride, utilizing methanol and water as solvents in the presence of acetic acid, piperazine achieved a mono‐Boc selectivity exceeding 99%. A feasible process was established by introducing 3 moles of piperazine into the reaction; one mole reacted with (Boc) 2 O to produce the mono‐Boc protected product, while the remaining 2 moles entered into the subsequent cycle of mono‐Boc protection in the form of acetate salt. Then, the production of kilogram‐grade products was conducted in a 50‐liter reaction kettle, achieving a high yield. The research on substrate expansion was conducted. The findings revealed that aliphatic diazacyclo compounds, cyclic aliphatic diamines, linear aliphatic diamines, and aromatic diamines can all achieve over 98% mono‐Boc selectivity. The mechanism of the reaction shows that core issue is not merely an increase in choice, but rather a significant acceleration of the reaction rate. Due to the significant increase in reaction speed, (Boc) 2 O is rapidly consumed within the reaction system, resulting in no excess (Boc) 2 O being available to react with the target mono‐Boc protection production.