Beyond organic solvents: synthesis of a 5-HT4 receptor agonist in water

J. Daniel Bailey; Edward Helbling; Amey Mankar; Matthew Stirling; Fred Hicks; David K. Leahy

doi:10.1039/D0GC03316B

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Beyond organic solvents: synthesis of a 5-HT₄ receptor agonist in water†

J. Daniel Bailey,

*^a Edward Helbling,^b Amey Mankar,^b Matthew Stirling,^a Fred Hicks^a and David K. Leahy^a

Author affiliations

* Corresponding authors

^a Process Chemistry Development, Takeda Pharmaceuticals, 35 Landsdowne St., Cambridge, MA 02139, USA
E-mail: Dan.Bailey@Takeda.com

^b Work carried out while at Process Chemistry Development, Takeda Pharmaceuticals, 35 Landsdowne St., Cambridge, MA 02139, USA

Abstract

Reducing or eliminating organic solvent use in pharmaceutical manufacturing is perhaps the most effective way to reduce the environmental, health, and safety impacts of drug substance manufacturing. With this in mind, we have developed a process to manufacture an investigational 5-HT₄ receptor agonist that is conducted almost entirely in water, including multiple controlled isolations. Key transformations carried out in aqueous media include a benzimidazole cyclization, amide bond formation, reductive amination, and a selective oxidation of an aliphatic alcohol. Compared to the first-generation manufacturing process using organic solvents, the aqueous process described here uses 77% less material inputs, 94% less organic solvent, and, surprisingly, 48% less water, while improving overall yield from 35% to 56%.

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Article information

DOI: https://doi.org/10.1039/D0GC03316B
Article type: Paper
Submitted: 01 Oct 2020
Accepted: 03 Nov 2020
First published: 03 Nov 2020

Download Citation

Green Chem., 2021,23, 788-795

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Beyond organic solvents: synthesis of a 5-HT₄ receptor agonist in water

J. D. Bailey, E. Helbling, A. Mankar, M. Stirling, F. Hicks and D. K. Leahy, Green Chem., 2021, 23, 788 DOI: 10.1039/D0GC03316B

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