4/13/2015 GEN | Magazine Articles: Green Chemistry Initiatives Take Shape

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Gail Dutton

Medicinal Chemistry

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Many innovative companies are embracing green chemistry, citing environmental sustainability,

increased efficiency, and lowered costs, as they develop the tools and measurements that inform the

choices of solvents and reagents throughout a compound’s development and manufacturing,

according to speakers at the American Chemical Society’s (ACS) recent “Green Chemistry and

Engineering” conference.

“Green chemistry is gaining prominence, paralleling regulatory and economic movements. There is a

global expectation for sustainable resource use, chemical safety, and transparency as stakeholders

are becoming more precautionary and risk adverse,” Richard Williams, Ph.D., president and founder

of Environmental Science & Green Chemistry Consulting, said.

“Since 2003, 18 U.S. states have collectively passed 71 chemical control laws calling for the use of

green chemistry, phaseout of specific substances, data collection, or the reduced industrial use of

toxic chemicals.

“Green chemistry is just good chemistry,” Dr. Williams said. “As new science develops, it delivers

economic and environmental benefits. For example, Pfizer improved the manufacturing process for

sertraline, the active ingredient in Zoloft®.”

The original threestep sequence was streamlined to one step, producing chirally pure sertraline in

much higher yield and with greater selectively. Raw material usage for three materials declined by

60%, 45%, and 20%, respectively.

Employing ethanol as a solvent eliminated the use, distillation, and recovery of four more hazardous

solvents. The green approach has eliminated nearly 2 million pounds of chemical waste per year,

improved safety and material handling, reduced energy and water use, and doubled overall product

yield, Dr. Williams reported.

One aspect of Amgen’s sustainability initiative focuses on

medicinal chemistry. “Although the scale of reaction is

small, the cumulative footprint is significant,” noted Emily

Peterson, Ph.D., scientist and green chemistry team lead

Nov 1, 2011 (Vol. 31, No. 19)

Green Chemistry Initiatives Take ShapeEmbracing More Environmentally Friendly Practices Also Has EconomicBenefits

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4/13/2015 GEN | Magazine Articles: Green Chemistry Initiatives Take Shape

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Emily Peterson, Ph.D., Amgen scientist and greenchemistry team lead, applies green chemistryprinciples in her lab at Amgen’s Cambridge Researchfacility.

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Merck and Codexis developed a more efficientprocess for the synthesis of sitagliptin, the activepharmaceutical ingredient in Januvia, enabled by atransaminase developed using Codexis’ platformtechnology to customize biocatalysts derived fromliving organisms. Natural transaminases are inactiveon the prositagliptin ketone due to steric constraintsin the active site. In contrast, the custom biocatalystprovided the desired activity and productivity. Theillustrations show the chiral aldimine intermediatebound in the active site of an in silico model of thecatalyst. The large binding pocket is orange; the smallbinding pocket is blue; the catalytic residues and cofactor are green. Top: processes based on candidatenatural enzymes did not yield the desired molecule.Bottom: The Codexis custom biocatalyst developedwith Merck catalyzed a more efficient process.

for Amgen Massachusetts (AMA) medicinal chemistry.

The goal at Amgen, then, is to “equip medicinal chemists

with working knowledge of green chemistry, provide

access to tools to guide green solvent and reagent

selection, and apply restraint rather than constraint,” to

chemists’ choices. Immediate challenges include

reducing chlorinated solvent usage, phasing out toxic and

noneconomical reagents, modifying wasteful ordering

and disposal habits, and encouraging use of green

conditions.

These changes are seeing results. For example, since

November 2010, the use of dichloromethane at the AMA site has declined 40%. “Ten percent was

achieved just by picking up a different squirt bottle when chemists rinsed their tubes,” Dr. Peterson

explained.

Much of the rest was achieved by education and replacing dichloromethane chromatography with

greener solvent systems (like heptanes, ethyl acetate, and ethanol) and by replacing normalphase

chromatography with reversephase mediumpressure liquid chromatography, which allows

purification of highly polar compounds using aqueous media.

“You can load large amounts onto the column, including crude reaction mixtures, and you can reuse

the columns, which gives nice flexibility,” Dr. Peterson added.

At Amgen, “we also crafted our own green chemistry solvent selection guide. We made it into

magnets and put them on all the hoods, so chemists are reminded daily of greener options.”

At Dr. Peterson’s site, the T3P amide coupling reagent has become a popular reagent in medicinal

chemistry, she said. “You can work it up with water, and the product is often pure enough to go to the

next step without contamination with other reagents.”

To reduce waste, Amgen partners with ASDI to store its chemicals. Therefore, research sites can

order just the quantities they need from among Amgen’s own supplies. The company also changed its

chemical disposal policy, retaining chemicals with longterm stability rather than discarding all

chemicals after three years. In shipping 500 compounds to ASDI, “we saved $3,000 on disposal

alone.”

Chemists contemplating green chemistry cite concerns about reoptimization timeframes, costs,

access to established chemicals, or methods and regulatory issues. “The key to adoption is to use

green technologies that are superior to current methods.” Amgen also operates a green chemistry

awards program for labs that make the greatest green chemistry gains. “Cash talks,” she said.

Ingrid Mergelsberg, Ph.D., director of process chemistry

at Merck and immediate past cochair of the ACS Green

Chemistry Institute Pharmaceutical Roundtable (GCIPR),

agreed. “Since 2007, the Roundtable has awarded

$950,000 in research grants based on green principles

and formed academic liaisons with industry.”

Roundtable members lead by example. “Merck has

pioneered advances in areas such as asymmetric and

enzymatic catalysis, highthroughput screening in

catalysis, and supercritical fluid chromatography for chiral

and achiral separations, which avoid the creation of

significant amounts of solvent waste,” Dr. Mergelsberg

said.

To create a green chemistry environment, “it’s essential

to have routine demonstrations of commitment to green

chemistry and engineering from senior management.

We’ve implemented a crossfunctional green chemistry

team with measurable goals and objectives supported by

senior management. Merck has also created a green

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4/13/2015 GEN | Magazine Articles: Green Chemistry Initiatives Take Shape

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chemistry elearning course that will be available in the next few months, and a green chemistry

toolbox.

“Tools are very powerful to facilitate chemists getting greener,” Dr. Mergelsberg continued. Merck’s

own green chemistry toolbox includes a process mass intensity (PMI) and analytical method volume

intensity total solvent consumption calculator, solvent selection guide, pathway to greener solvents,

and a reagent selection guide tool kit for enzymatic and catalytic reactions.

By 2020, the Roundtable plans to have a database of highly efficient transformations, a predictive tool

for greener route design, and standard quantitative key performance indicators and measures of

greenness.”

Merck has developed its own green chemistry electronic notebook templates based on the reagent

selection guide. The Roundtable has initiated discussions with enotebook suppliers.

She also aims to influence the research agenda. “Most chemistry journals haven’t embraced green

chemistry policies and principles yet. In many broadly referenced articles, chloroform, benzene, and

other absolutely nongreen solvents and reagents are still used. Thus, medicinal chemists naturally

start with nongreen reagents because they are following established protocols.”

Dr. Mergelsberg sees progress, however. “Organic Process Research and Development has

accepted some of the Roundtable’s wishes, by not accepting papers with solvents of benzene or of

chloroform.”

The Roundtable is also preparing a reagent selection guide. Its goal is to identify the most

environmentally benign conditions for chemical transformations and analyze reactions for five green

criteria: the environmental degradation of reagent and degradation products, solvent compatibility to

green solvents, availability from natural feedstocks, atom efficiency of transformation, and toxicity and

process safety hazards.

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