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4.2 Metrics for Green Chemistry 69
Table 4.3 Greener technologies.
Green technology Advantages
Biotechnology competence
fermentation/enzyme catalysis/
competence chemocatalysis/
biocatalysis
Greener, economical, fast, selective for specific
manufacturing processes
Combining biocatalysis and
homogeneous catalysis
Shortcut synthesis of a pharmaceutical intermediate
Microwave-assisted organic synthesis Requires minimal time and energy
Integrated approach of chemistry,
biology, and process technology
Reduction of the number of chemical steps to form the
final product
Solid phase synthesis Synthesis of multiple non-oligomeric organic molecules
at the same time
Multicomponent/convergent synthesis Saves time and energy
Hydrogenation technology An easy reduction technique without using harmful
reagents
Flow chemistry Micro-reactor technology
Successful multi-ton application with higher selectivity
and less waste
High productivity
Process intensification towards sustainable
manufacturing
High selectivity GMP production
Improved selectivity of particular isomers
Less consumption of raw materials and energy
(purification)
Energy integration
Intrinsic safety
Reduced DSP effort
Modular small units enable a switch from batch to
continuous processing
Avoidance of cryogenic cooling (energy), high heat, and
mass transfer
Microprocess technology Learning from nature
Enhanced transfer by increased transfer area
Enhanced transfer by decreased transfer distance
Eco-design toolkit Used for green processes that guide the company to
focus on the current vision and mission and reduce the
negative impact in the future
Life-cycle analysis (LCA) Many companies are diverting towards the
biotechnology route for synthesis of compounds by LCA
for sustainable development
‘LCA light’ tool for pharmaceutical
intermediates
Green ICT is a tool in which computer programs are
used for efficient and effective synthesis
(Continued)
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4 Impact of Green Approaches in Pharmaceutical Industries70
to the lifetime criteria of the patent. The overall objective of green synthesis is to develop
the process that is most cost-effective for commercial production of an API.
Cost-effective processes involve less waste generation, including disposal of the waste,
high yield, reagent/reactant utilisation factors, waste treatment, and cost of material to be
used. During development these factors lead to improvement of the process and ease of
operation, which makes the reaction process greener. In terms of metrics, reaction mass
efficacy (RME) is responsible for increasing yield and using reagents more economically.
This factor will also help to decrease waste over time, as waste is decreased with a more
efficient work-up process and mapping, and it also helps to reduce solvent uses. Processes
can be improved when green chemistry (methods, reagent/catalyst) is introduced.
Biocatalysis is one of these greener methods and the use of catalysts has become a valuable
technology for manufacturing sustainably in different chemical sectors, like pharma-
chemicals, fine chemicals, and other chemical divisions.
4.3 Case Studies of Active Pharmaceutical Ingredients
There are many examples related to green chemistry achievements, some of which are
described in this section. (The authors declare no competing financial interests.)
4.3.1 Ibuprofen
Ibuprofen is the basis of painkillers like Motrin®, Brufen®, Advil®, and Nurofen®. It has
had wide application since it was first synthesised by Boots Company in 1961. In the early
stages, iso-butylbenzene was acylated to give isobutyl acetophenone by Friedel–Crafts
acylation, followed by Darzens condensation, and oximate/hydrolysis or oxidation. This
older route was complicated with a six-step reaction, a low atom economy (atom efficiency
40%), and intensive energy consumption. More than 50% of the raw materials used were
wasted. Moreover, several other disadvantages were complicated purification, generation
of inorganic salts, high cost, and detrimental effects on pollution.
During the 1990s, BASF and Hoechst Celanesee Company (BHC copartnership) devel-
oped a new route for the synthesis of ibuprofen. In this route carbonylation of 1-(4-iso-
butylphenyl)ethanol improves ibuprofen synthesis, as shown in Figure 4.2 [23]. In the
traditional route, a stoichiometric amount of AlCl
3
is required for a high yield in the first
Green technology Advantages
Proactive management Telescoping and solvent recycling encourage innovation
while integrating green chemistry and engineering into
drug discovery, development, and manufacturing
Defines and delivers tools for innovation
DSP, dynamic solvent process; GMP, good manufacturing practice; ICT, information and communications
technologies. Source: Adapted from [4–22].
Table 4.3 (Continued)
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4.3 Case Studies of Active Pharmaceutical Ingredients 71
step, which generates a large amount of Al(OH)
3
simultaneously (Figure 4.2), while in the
BHC route a high yield is obtained by the hydrofluoric acid (HF) catalyst, and meanwhile
the catalyst can be recovered and reused so that no waste is generated. Thus, the target
product is acquired by only three steps in the new route, resulting in a great improvement
of the atom economy (atom efficiency 77.4%) with energy savings and a shorter period of
production. In addition to this, the other two steps in the new process use Raney nickel and
palladium catalysts, which also can be recovered and reused. Furthermore, the by-product
(acetic acid) is recovered, and thus the atom economy reaches 99% (Figure 4.3). Therefore,
this new synthetic process could lead to a remarkable reduction in detrimental effects on
pollution and production cost in comparison with the traditional route, thus representing
an improved process with both environmental and economic benefits. The BHC process
Figure 4.2 Traditional route of synthesis for ibuprofen.
Figure 4.3 Hoechst (BHC) synthesis of ibuprofen.
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4 Impact of Green Approaches in Pharmaceutical Industries72
for the synthesis of ibuprofen was awarded the ‘Presidential Green Chemistry Challenge
Award’ in 1997 [24].
The BHC synthetic route is much more easy and efficient compared to the traditional
route. In this route waste generation is less and the yield also improves by up to 77.40%
compared to the traditional route (Table 4.4). The advantages can be summarised as
follows:
● Waste generation is less.
● Yield is improved by up to 77.40%.
● Less reagent is used compared to the traditional route.
● The atom economy is higher than with the traditional route.
● There is recycling and reuse of by-products, catalyst, and reagent.
● There is a shorter route of synthesis.
4.3.2 Sildenafil Citrate (Viagra)
Sildenafil citrate (Viagra) is used for the treatment of male erectile dysfunction. The first
route of synthesis is shown in Figure 4.4. This route is not suitable for the environment. Later,
a new route was reported to remove the adverse effect of the old route on the environment.
The old and new green synthetic routes for sildenafil citrate are compared in this section.
Tin(II)chloride, which was used for the reduction of the nitro group in the old route, was
replaced by H
2
, Pd/C in the new green route, because tin chloride is a major environmental
polluter that it is difficult to decompose. In the greener route, thionyl chloride is used in stoi-
chiometric amounts as a solvent, which decreases the excess use of harmful thionyl chloride
that was used in the old route. Hydrogen peroxide was replaced by KO
t
Bu in
t
BuOH in a
greener route, because hydrogen peroxide causes skin irritation and can catch fire, especially
when it is in contact with organic materials. In the greener route, oxalyl chloride was replaced
by thionyl chloride for the synthesis of 2-ethoxybenzoyl chloride, because while using oxalyl
chloride carbon monoxide was emitted from the reaction, which was very harmful to human
health. The overall yield of sildenafil citrate increased to 75%, and the high yields minimised
the detrimental effect on the environment (Figure 4.5) [25, 26].
Table 4.4 Comparison of Boots and Hoechst (BHC) synthesis processes.
Starting materials/reagent Utilised in product Not utilised in product
Chemical formula Mol wt Chemical formula Mol wt Chemical formula Mol wt
Boots process
C
20
H
42
NO
10
ClNa 514.5 C
13
H
18
O
2
206 C
7
H
24
NO
8
ClNa 308.5
Atom economy = 206/(206 + 308.5) × 100% = 40%
Hoechst (BHC) process
C
15
H
22
NO
4
266 C
13
H
18
O
2
206 C
2
H
4
O
2
60
Atom economy = 206/(206 + 60) × 100% = 77.40%
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Figure 4.4 Traditional route of synthesis for sildenafil citrate.
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Figure 4.5 Greener route of synthesis for sildenafil citrate.
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4.3 Case Studies of Active Pharmaceutical Ingredients 75
Figure 4.6 Traditional route of synthesis for talampanel.
4.3.3 Talampanel (LY300164)
Talampanel (LY300164) is an oral drug for the treatment of seizure and it is a selective
α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor antagonist. Eli
Lilly’s greener process makes use of environmentally friendly processes such as a biocata-
lytic reduction and air oxidation. The old route of synthesis is a linear approach of eight
steps and gave a 22% overall yield. There are several environmental disadvantages of this
traditional route, like the use of chromium trioxide (it was the only acceptable oxidant for
making the diketone at that time), borane, perchloric acid, and hydrazine (Figure 4.6). The
disposal of 3 kg of chromium waste per kg of the product was a very difficult task because
disposal generates a large quantity of waste. Hydrazine was used in the last step, which
increases the chance of generating genotoxic impurities in the drug [27–31].
In the new route the required chirality was introduced at the beginning of the sequence.
The chiral alcohol was prepared enzymatically instead of by the late-stage borane imine
reduction. The resin-bound Zygosaccharomyces rouxii in water was used efficiently to pro-
vide the chiral alcohol in a remarkable 100% conversion, 99.9% enantiomeric excess (ee),
and 96% isolated yield (Figure 4.7) [32–34].
The chiral alcohol was used in the cyclisation step directly to form the chiral cyclic ether.
A new alternative route was developed to the oxonium salt route for oxidation that pre-
vented the hard-won chirality. In the new route, the oxidation of the benzylic centre was
carried out by air via base-mediated oxidation using NaOH in dimethyl sulfoxide to
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Figure 4.7 Greener route of synthesis for talampanel.
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4.3 Case Studies of Active Pharmaceutical Ingredients 77
generate the hemiketal. It reacted with acetylhydrazine and formed the compound, which
then reacted with triethylamine and mesylchloride. The crystalline mesylate salt was iso-
lated in a 75% overall yield in a three-step reaction. The beauty of the new greener route is
that hydrazine has been replaced by the less hazardous acetylhydrazine, chromium by air,
and the persistent environmental pollutant perchloric acid to form the oxonium salt is
totally avoided. The subsequent cyclisation formed the benzodiazepine in a 93% isolated
yield [32, 33].
The greener route tripled the overall yield, substituted heavy metal-induced oxidation by
air, reduced the number of steps, and developed a biocatalytic reduction for establishing
the chiral centre.
4.3.4 Saxagliptin
Saxagliptin is used to treat type 2 diabetes. It is synthesised via asymmetrical synthesis. Chiral
drugs can be synthesised using asymmetrical synthesis, hence application of the enzymes in
such reactions has advantages over traditional chemical synthesis. Most chemoenzymatic
reactions are stereoselective and can be carried out at atmospheric pressure and ambient
temperatures, which typically reduces hazards and cost, and minimises the chances of the
formation of undesired by-products. Generally enzymatic processes are carried out in water,
using chemicals that are less toxic, and thus waste generation is minimised.
(S)-N-BOC-3-hydroxy adamantyl glycine is an important key intermediate for the syn-
thesis of saxagliptin. It was prepared by an asymmetrical Strecker reaction in the tradi-
tional route and requires the highly toxic potassium cyanide (KCN) (Figure 4.8). The
Bristol–Myers Squibb enzyme technology research group successfully generates the chiral
centre by a modified phenylalanine dehydrogenase in the intermediate, which involves an
enzymatic reductive amination of a keto acid. This greener route is beneficial because of
the reduction of five steps to only one step, which ultimately reduces time, cost, and the
possibility of accidents. This process eliminates the use of KCN and the expensive chiral
reagent (R)-2-phenylglycinol, as well as poor oxidation using KMnO
4
in the final step, and
the reductive amination uses water as a solvent. It also increases the isolated yield up to
81% with minimal side product formation (Figure 4.9) [35, 36].
4.3.5 Pregabalin (Lyrica)
(S)-(+)-3-Aminomethyl-5-methylhexanoic acid (pregabalin) is used to treat pain caused by
fibromyalgia, or nerve pain in people with herpes zoster (post-herpetic neuralgia), diabetes
(diabetic neuropathy), or spinal cord injury [37, 38].
The old synthesis of pregabalin involved Knoevenagel condensation of diethyl malonate
and isovaleraldehyde, followed by cyanation that gives the intermediate. The intermediate
on hydrolysis, decarboxylation, and reduction gave a racemic mixture of 3-aminomethyl-
5-methylhexanoic acid. The resolution of the crude racemic pregabalin was carried out by
using (S)-(+)-mandelic acid. This was a three-step crystallisation process and the overall
yield of the reaction was about 20%. This synthetic route had several disadvantages, including
high PMI (raw material input/API output) and high manufacturing costs because the unde-
sired by-product (γ-amino acid enantiomer) could not be recycled (Figure 4.10) [39, 40].
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Figure 4.8 Traditional route of synthesis for saxagliptin.
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