Carl J. Mallia*, Peter R. Moore, Simon Hardy, Christopher D. Parsons, Paul A. J. Cronin, Andrew Ikin, Carl-Johan Aurell, Kuangchu Dai and Baoquan Sun,
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引用次数: 0
Abstract
A large-scale enantioselective manufacturing route to an unusual piperazine-substituted amino acid is described. Previous synthetic routes to this amino acid relied on the resolution of racemic mixtures using l-tartaric acid that was demonstrated on a 6 kg scale, but this resulted in a reduced overall yield and efficiency. The new enantioselective route to this amino acid uses the SN2 displacement of a chiral triflate with N-methylpiperazine that proceeds with very high levels of stereocontrol. The key chiral triflate is prepared in five synthetic steps in 38% overall yield and >99% enantiomeric purity (e.p.), starting from cheap and readily available d-serine. Subsequent reaction with N-methylpiperazine was initially demonstrated in batch, providing the benzyl-protected amino acid in 83% e.p. on a 3 kg scale. This transformation was further improved by the application of continuous manufacture to provide the benzyl-protected ester in >99% e.p. on an 80 kg scale. Simple deprotection of the benzyl ester group by hydrogenolysis, followed by isolation of the amino acid as the corresponding dihydrochloride salt, provided a scalable and efficient synthesis of (R)-3-methoxy-2-(4-methylpiperazin-1-yl)propanoic acid in good overall yield (33%) and very high optical purity (>99.5% e.p.).
期刊介绍:
The journal Organic Process Research & Development serves as a communication tool between industrial chemists and chemists working in universities and research institutes. As such, it reports original work from the broad field of industrial process chemistry but also presents academic results that are relevant, or potentially relevant, to industrial applications. Process chemistry is the science that enables the safe, environmentally benign and ultimately economical manufacturing of organic compounds that are required in larger amounts to help address the needs of society. Consequently, the Journal encompasses every aspect of organic chemistry, including all aspects of catalysis, synthetic methodology development and synthetic strategy exploration, but also includes aspects from analytical and solid-state chemistry and chemical engineering, such as work-up tools,process safety, or flow-chemistry. The goal of development and optimization of chemical reactions and processes is their transfer to a larger scale; original work describing such studies and the actual implementation on scale is highly relevant to the journal. However, studies on new developments from either industry, research institutes or academia that have not yet been demonstrated on scale, but where an industrial utility can be expected and where the study has addressed important prerequisites for a scale-up and has given confidence into the reliability and practicality of the chemistry, also serve the mission of OPR&D as a communication tool between the different contributors to the field.