Chemistry Reference
In-Depth Information
2.9 Reagents
imising heavy metal pollution. Immobilising homo-
geneous catalysts onto a solid support holds much
promise in this area because normally tedious sepa-
ration processes can be reduced to a simple filtration
when the reaction is done and the recovered cata-
lysts can be reused. This also makes strong econom-
ical sense, because the price of palladium has nearly
quadrupled in the last decade. The use of some
highly toxic metals, such as mercury and thallium,
even in catalytic amounts, should be avoided alto-
gether at scale. Fortunately, there are usually alter-
natives to applications involving such metals.
For intermolecular reactions, excess reagents often
are used to drive the reactions to completion because
the reaction rate diminishes at higher conversion
when the stoichiometry is 1 : 1. However, unspent
reagents can cause separation problems and deci-
sions must be made on whether to have residual
starting material or excess reagent in the crude reac-
tion mixture. The choice should be the cheaper and
the one that displays the greatest difference com-
pared with the desired product for purification fea-
sibility. Judicious choice must be made on peripheral
reagents, such as oxidants, reducing agents and
hydroxyl and carboxyl activating agents. These
reagents themselves do not contribute to the product
skeleton and can have a profound impact on the
overall E value of the process. Change of oxidation
states often can be avoided by juxtaposing steps in
a reaction sequence, and greener agents (H
2
, O
2
, O
3
and H
2
O
2
) should be given priority consideration
when feasible. Utilising enzymatic hydrolysis often
has provided a vastly improved E factor over con-
ventional caustic conditions. Unlike synthetic strat-
egy, changes in reagents and reaction conditions
(indicated above and below the arrows in a synthetic
scheme) often can be made in the later stage of
product development and are always targets for per-
petual improvement.
2.12 Endurance
New reactions and catalysts with better selectivities
are continuously being discovered and refined.
Advances in organometallic chemistry in the last two
decades have expanded significantly the repertoire
of tools for organic chemists. Although it is not
acceptable to rely on the emergence of a future
miracle to cure the ills of a problematic step, a
process should be designed with vision and diligent
efforts so that it will not become obsolete during the
product's lifetime. When a short-term fix is applied
to a particular process to produce enough material
quickly for a pivotal study, one should also keep an
eye on the long-term solutions to the problem when
the drug candidate proceeds forward and a more
practical route is needed.
Getting it right the first time
would obviate all the troubles associated with
switching a manufacturing process for active phar-
maceutical ingredients. The staying power of a
process relies on its safety, environmental impact,
economy and reproducibility. Aesthetic elegance of
the synthetic scheme is an added bonus when all
these are factored in.
2.10 Reaction temperature
Increasing temperature can often bring about a vast
improvement in reaction kinetics. This must be
balanced by considering the effect of temperature
on side reactions, thermal hazards and solvent losses.
Although cryogenic conditions often afford better
selectivity for some anionic chemistry, energy con-
sumption is high for such operations and more
solvent usually is needed to compensate for the
decreased solubility at lower temperature.
3 Example 1
An example [15] of the global approach to the design
of a green process is the synthesis of 2-chloronico-
tinic acid (
9
), a versatile intermediate for a number
of agrochemical and pharmaceuticals, including
the anti-HIV drug nevarapine [16,17]. There have
been several reported synthetic routes to this rather
simple compound. The most notable one involves
chlorination of nicotinic acid
N
-oxide (
8
) using
POCl
3
[18]. This route is quite competitive in that
nicotinic acid (
7
) is a large-volume chemical pro-
2.11 Heavy metals
Transition metals such as palladium and rhodium
play a major role in reducing waste by improving the
atom economy through catalysis, but effective mea-
sures must be installed to prevent these heavy metals
from contaminating the product stream and the
environment. Recycling is the best means for min-
