A novel synthetic approach for the piperazynyl pyrimidine intermediate: focus on the cost cutting of buspirone drug at commercial level.

Background: Buspirone is a critical in treatment for generalized anxiety disorder (GAD), but the synthesis of its key intermediate, 2-(piperazin-1-yl) pyrimidine faces challenges in terms of cost, yield and purity. Traditional synthesis methods are hindered by high material costs and significant by-product formation, necessitating a more efficient and economical approach.

Objective: To develop a novel, cost-effective synthesis strategy for the 2-(piperazin-1-yl) pyrimidine intermediate that improves yield and purity while reducing production costs and environmental impact.

Methods: A four-step synthesis process was optimized as follows: First, piperazine reacts with sulfuric acid and cyanamide, followed by precipitation with cold methanol. Next, 1,1,3,3-tetramethoxypropane reacts with hydrochloric acid and amidine, and the mixture was extracted with dichloromethane (DCM). In the third step, the product was dissolved in isopropanol (IPA), treated with charcoal and converted to the oxalate salt using oxalic acid. Finally, the oxalate salt was converted to the freebase with ammonia, followed by a final extraction with DCM. Key variables such as reagent equivalents, reaction conditions and purification techniques were systematically optimized throughout the process.

Results: The optimized process achieved a purity level of over 99% and reduced production costs by 25-30%. Significant improvements included controlled bis-product formation with cyanamide, effective addition of 1,1,3,3-tetramethoxypropane and efficient removal of by-products through oxalate salt formation and charcoal treatment.

Conclusion: The developed synthesis method for 2-(piperazin-1-yl) pyrimidine was both cost-effective and efficient, significantly enhancing the yield and purity. This method is highly suitable for large-scale pharmaceutical production, aligning with industry goals of improved process efficiency, cost reduction and environmental sustainability.