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Synthesis of Sitagliptin (PDF Download Available)

Merck and Codexis Honored with Presidential Green Chemistry Challenge Award for Novel Process for Sitagliptin Synthesis

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Highly Efficient Asymmetric Synthesis of Sitagliptin Karl B

A highly efficient synthesis of sitagliptin, a potent and selective DPP-4 inhibitor for the treatment of type 2 diabetes mellitus (T2DM), has been developed. The key dehydrositagliptin intermediate 9 is prepared in three steps in one pot and directly isolated in 82% yield and >99.6 wt % purity. Highly enantioselective hydrogenation of dehydrositagliptin 9, with as low as 0.15 mol % of Rh(I)/tBu JOSIPHOS, affords sitagliptin, which is finally isolated as its phosphate salt with nearly perfect optical and chemical purity. This environmentally friendly, ‘green’ synthesis significantly reduces the total waste generated per kilogram of sitagliptin produced in comparison with the first-generation route and completely eliminates aqueous waste streams. The efficiency of this cost-effective process, which has been implemented on manufacturing scale, results in up to 65% overall isolated yield.

The outcome has been to slash the number of reaction steps in the sitagliptin synthesis ..

and paired up to win the award in the Greener Reaction Conditions category for revising the synthesis of sitagliptin, a chiral β-amino acid derivative that serves as the active ingredient in Merck's type 2 diabetes drug Januvia. The synthetic improvements center on engineering a transaminase enzyme to catalyze conversion of a precursor ketone directly to the desired chiral amine, improving the yield while reducing the number of production operations and overall waste.

Green Synthesis of Sitagliptin" 10:15 am - 10:30 am: Discussion:

11 New synthesis of Sitagliptin.

Industrial biotechnology is seen by the authors as a contributor to green industrial chemistry. The criteria of green chemistry are met through the use of biocatalysis. There are admittedly significant limitations where these approaches are used in industry. Significant examples show the emerging prowess of biosynthesis with detailed applications to biologically active chemicals. Vitamin B12 is found in nearly all organisms as a biologically active compound. In humans, B12 is required for red blood cell formation, neurological function, and DNA synthesis in trace quantities of 2.4–3.0 μg each day at a purity of 96–98 %. Chemical synthetic pathways to B12 require 70-steps but two biosynthetic approaches can accomplish synthesis in 9 days or less utilizing selected microorganisms under fermentation conditions. Eco-efficiency analysis of different chemical or biotechnological B12 synthetic technologies show the biotechnology processes to have high eco-efficiency when compared with the chemical process.

News from a recent American Chemical Society (ACS) Green Chemistry and Engineering conference shows the investments made by many innovative companies in embracing green chemistry due to considerations of environmental sustainability, increased efficiency, and reduced costs. Green chemistry is gaining prominence through global expectations for sustainable use of resources, and responsive to the precautionary and risk adverse interests of stockholders. In the US, eighteen states have passed some 71 chemical control laws since 2003 focused on the implementation of green chemistry, data collection, and phased out and/or reduced industrial use of toxic chemicals. One contributor offered that “Green chemistry is good chemistry.” An example of the these principles is to be found in the Pfizer synthesis of the antidepressant sertraline (Zoloft®). An effort to streamline the original three-step process to produce the pure chiral sertraline was improve to enhance the product yield and selectivity. The optimized process was accomplished through raw material usage in the range of 20–60 % for each of the three chemicals employed. Solvent recovery was improved through the use of ethanol to replace four hazardous solvents. Waste control for the process has found means to double the product yield, eliminate 2 million lbs. of chemical wastes yearly, reduce energy consumption, and enhance safety and material handling.

a selected transaminase in the synthesis of sitagliptin.

Combining biological and chemical approaches for green synthesis of chemicals

The Presidential Green Chemistry Challenge Awards are presented annually by the Environmental Protection Agency to recognize new technologies that help prevent pollution by reducing or eliminating hazardous waste in industrial production. It provides recognition of outstanding chemical technologies that incorporate the principles of green chemistry into chemical design, manufacture, and use, and that have been or can be utilized by industry in achieving their pollution prevention goals. The award was launched in 1995 in partnership with the chemical industry, the American Chemical Society, the National Academies and other stakeholders. Both Merck and Codexis won awards individually in 2006.

“Codexis is honored to receive one of the U.S. government’s highest awards for environmental protection with Merck,” said Alan Shaw, Ph.D., Codexis President and CEO. “Our proven technology platform is in use around the world, enabling creation of cleaner, more efficient pharmaceutical manufacturing processes. We are committed, with our colleagues at Merck, to leveraging the power of green chemistry for a sustainable environment.”

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  • Greener Reaction Conditions Award | Merck & Co. and Codexis

    to develop a large-scale biocatalytic reductive amination for the final step of its sitagliptin synthesis.

  • Merck used a first-generation …


  • Presidential Green Chemistry Awards: Codexis/Merck …

    The Taxol Story-Development of a Green Synthesis Via Plant Cell Fermentation

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Toronto Research Chemicals - TRC Canada

WHITEHOUSE STATION, N.J. & REDWOOD CITY, Calif.--()--Merck and Codexis, Inc. (NASDAQ:CDXS) today announced that they have jointly been awarded the annual Presidential Green Chemistry Challenge Award from the U.S. Environmental Protection Agency (EPA) for the development of a novel biocatalytic method for the synthesis of sitagliptin. In addition, a paper co-authored by Merck and Codexis scientists and published online June 17 in the peer-reviewed journal , details how an enzyme was systematically customized using Codexis technology to perform the key chemical step in the sitagliptin synthesis process. This process showed improved efficiency and significantly decreased chemical waste byproducts.

Saxagliptin and Cardiovascular Outcomes in Patients …

The state of California has adopted policies and laws supporting the development of clean energy technology designed to reduce pollutant emissions. Next 10, has issued the 68 page 2012 California Green Innovation Index which the 4th edition of an annual analysis of key factors including energy productivity, active clean energy technology patents, emissions relative to economic growth, and venture capital investments to this technology area. The non-partisan group, NEXT 10 is focused on the enhancement of innovation addressing the solution of California’s environmental pollutant emissions and related issues. This year’s index tracks the relation of pollutant emissions on the economy, energy productivity, venture capital investments, and patents describing clean technology inventions and applications in this context. Clean technology patents increased by 41 % in the period from 2005–2007 to 2008–2010. Venture capital investment in clean technology increased to 24 % of the total US venture capital investment. California has 29 % of the US solar capacity due to recent utility-scale solar installations. California wind generation capacity grew 44 % in the period 2009–2010. The analysis asserts that California emitted 28 % less carbon for the latest reporting period than in 1990 for every dollar in 2009 gross domestic product. Energy productivity, ratio of consumed energy to GDP, is 64 % lower in California than in the other 49 states. This efficiency is comparable to Japan, Germany and the UK. The savings related to this enhanced efficiency can be reinvested into the state economy through a variety of investments. The report investigated California’s desire to enhance the use of renewable energy. The state has enunciated goals to derive 33 % of their electricity from solar, wind, and other renewable energy sources.

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The ecological risks associated with synthetic microbes have received strong comment from a group of interested parties. Global markets for synthetic biology are expected to expand aggressively with the success of current research efforts. The 2010 market was estimated to be $1.1 billion US/year with an expectation to reach $10.8 billion US by 2016 due mainly to chemical and energy applications. Four areas of risk valuation are recommended for consideration: organisms will react with the environmental surrounding through their physiology and differences between the synthetic and natural organisms will modulate the interaction with the environment, the survivability of the synthetic organisms will be important to long term concerns, the new synthetic organisms are expected to occupy different/new ecological niches, and gene transfer between the synthetic organism and the environment. Many of these concerns have been addressed during the vetting of similar concerns for genetically modified microorganisms in technologies such as bioremediation. This earlier review has shown the release of the GM microbes did not present a threat to the environment. The current direction of concern comes from the Synthetic Biology Project at the Woodrow Wilson International Center for Scholars in Washington DC. A workshop was held during 2011 to address the general concerns perceived for synthetic biology. Ecologists and synthetic biologists contributed at the meeting to help move the new research field forward while being attentive to ecological impacts. The new organisms are seen to be altered in more sophisticated ways thereby offering problems with monitoring, management, and regulation as the new technology is introduced to the environment.

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