Sitagliptin Manufacture: A Compelling Tale of Green Chemistry, Process Intensification, and Industrial Asymmetric Catalysis

Desai, Aman A.

doi:10.1002/anie.201007051

Cited by 188 publications

(73 citation statements)

References 12 publications

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“…Such a large value makes it economically impractical for a company to bring this process to a commercial scale. Consequently, researchers at Merck began to work with scientists at Solvias and Codexis (companies specializing in homogeneous catalysis and biocatalysis respectively) in order to develop a more efficient process [41]. The 2006 secondgeneration synthesis (an asymmetric hydrogenation route) succeeded in lowering the E factor to 67 (65 kg organic waste and 2 kg aqueous waste) [47].…”

Section: Comentioning

confidence: 99%

“…A well-established example of this approach is the redesigned synthesis of sitagliptin phosphate ( Fig. 1.3) [41]. Sitagliptin is the active ingredient in Januvia ® , a drug marketed by Merck for the treatment of type II diabetes [42].…”

Section: Merck's Synthesis Of Januvia: Highlights and Global Efficiencymentioning

confidence: 99%

“…In terms of global efficiency, the initial process developed by Merck (called the β-lactam route) [41] consisted of nine steps with an overall yield of 45 % [46]. This process generated large amounts of waste due to many factors, including the use of a 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) coupling and Mitsunobu sequence to convert a hydroxyl group into an amine.…”

Section: Comentioning

confidence: 99%

“…With each new stage, the process has become increasingly more efficient in the context of global waste reduction. For detailed comparisons of the three routes as well as a discussion of the development process, the reader is referred to several excellent reviews [41,46,47].…”

Section: Merck's Synthesis Of Januvia: Highlights and Global Efficiencymentioning

confidence: 99%

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Green Chemistry and Associated Metrics

Dicks

Hent

2014

SpringerBriefs in Molecular Science

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This chapter provides an overview of green metrics and their historical role in promoting the development of green chemistry. Starting with the history of the field, the Twelve Principles of Green Chemistry are introduced and discussed in conjunction with a "green-by-design" approach recently applied to the synthesis of Lipitor ® . Various perspectives on synthetic efficiency are briefly outlined with reference to atom economy and E factor. These ideas are further explored in the context of three industrial processes which have received Presidential Green Chemistry Challenge Awards. The synthesis of ibuprofen is examined from the point of view of intrinsic efficiency. Using the BHC process as an example, several benefits associated with the use of catalysis are discussed, with an emphasis placed on designing atom-efficient reactions. A global perspective centered around the production of chemical waste is also outlined with reference to Merck's commercial synthesis of Januvia ® , a medication for the treatment of type II diabetes. Finally, Pfizer's new sertraline process is used to describe ways of improving both quantitative as well as qualitative aspects of an industrial synthesis. The chapter concludes with a brief outline of the future directions of green metrics.

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Section: Comentioning

confidence: 99%

Section: Merck's Synthesis Of Januvia: Highlights and Global Efficiencymentioning

confidence: 99%

Section: Comentioning

confidence: 99%

Section: Merck's Synthesis Of Januvia: Highlights and Global Efficiencymentioning

confidence: 99%

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Green Chemistry and Associated Metrics

Dicks

Hent

2014

SpringerBriefs in Molecular Science

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“…To date, ω-transaminase (ω-TA) is the only naturally occurring enzyme that can mediate the asymmetric reductive amination of ketones, which renders the enzyme attractive for the industrial production of chiral amines. 3,4) One of the challenges for the ω-TA-catalyzed amination of ketones is unfavorable reaction equilibrium. 5,6) For example, the equilibrium constant (K eq ) of the transamination between acetophenone and alanine was determined to be 8.8 × 10 −4 .…”

mentioning

confidence: 99%

Metabolically driven equilibrium shift of asymmetric amination of ketones by ω-transaminase using alanine as an amino donor

Han

Shin

2014

Bioscience, Biotechnology, and Biochemistry

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Removal of a side product to overcome unfavorable equilibrium is a prerequisite for the asymmetric amination of ketones using ω-transaminase (ω-TA). Alanine has been preferred as an amino donor because its deamination product (i.e. pyruvate) is easily removable by several enzymatic methods. Here, we demonstrated that the removal of pyruvate by an innate metabolic pathway could afford equilibrium shift of the ω-TA reactions.

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Survey of Protein Engineering Strategies

Bornscheuer

Kazlauskas

2011

CP Protein Science

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Protein engineering is altering the structure of a protein to improve or change its properties. This unit summarizes concepts for protein engineering using rational design, directed evolution, and combinations of them. Different strategies are presented for identifying the best mutagenesis method, how to identify desired variants by screening or selection, and examples for successful applications are given. This should enable researchers to choose the most promising tools to solve their protein engineering challenges.

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Sitagliptin Manufacture: A Compelling Tale of Green Chemistry, Process Intensification, and Industrial Asymmetric Catalysis

Cited by 188 publications

References 12 publications

Green Chemistry and Associated Metrics

Green Chemistry and Associated Metrics

Metabolically driven equilibrium shift of asymmetric amination of ketones by ω-transaminase using alanine as an amino donor

Survey of Protein Engineering Strategies

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