Pharmaceuticals - Fundamentals of Industrial Chemistry: Pharmaceuticals, Polymers, and Business - page 170

Of these, the best synthesis [26] involves four steps and gives an overall
yield of 11.4%. The synthesis also has a radical benzylic bromination step
using carbon tetrachloride as a solvent. There are industrial hygiene issues
with large scale use of carbon tetrachloride because of its health effects. Also
with an overall yield of 11.4%, there are many impurities and purification
can be a problem. Even without these problems, the starting carbonitrile itself
is not readily available, requiring either a low yield (11%) copper coupling
reaction or a higher yield synthesis employing a Grignard reagent. Grignard
reagents are difficult to handle in large scale because of the flammability
issues with the reagent and solvent.
Losartan K is a widely prescribed drug and the early synthetic routes are
problematic. Because of this, the inventing company has a motivation to
develop improved processes. An improved route can improve profitability
and in some instances can be patented, thereby extending the exclusivity
for the inventing company. When a drug goes generic, as Losartan K has,
the company with the best synthesis will often be in the best competitive
position to market the generic compound. For this reason, other companies
have a motivation to develop improved syntheses of large volume drugs.
They too have an opportunity to obtain patent coverage for new synthetic
processes. Because of these reasons new processes have been developed
by workers at Dupont-Merck, Abbott, Wyeth-Ayerst (now Pfizer), Roche,
Synthelabo, Johnson and Johnson, Zeneca, and Sanofi [27]. That so many
companies have worked in this area demonstrates the importance of having
the best synthesis.
Losartan K is an example of a drug that can exist in different crystalline
forms. The occurrence of different crystalline forms of the same drug is called
polymorphism. Polymorphs can have different chemical properties such as
dissolution rate, hygroscopicity, stability, and bioavailability. Therefore, it is
important for pharmaceutical companies to understand the possibility of poly-
morphism. Ignoring this could lead to possible quality problems. There have
been instances where a specific polymorph has been patented after a patent
had issued for the pharmaceutical active itself. This effectively extends the
patent protection of a drug.
An attractive synthesis is high yield, has few steps, results in good purity,
and avoids conditions or reagents that are problematic on a large scale. A
multi-step synthesis, even if all the steps are individually high, can have a
low overall yield. For example, a ten-step synthesis with each individual step
being 90% yield has an overall yield of 35% (0.90 10 ) and if each step were
80% yield, the overall yield would be about 11%. One low yield step can
be a problem. A ten-step synthesis with nine reactions having a 90% yield
and one being 10% yield has an overall yield of 3.9%. If faced with a situa-
tion like this, it is generally better if the low yield reactions take place early