Page 204 - CW E-Magazine (3-12-2024)

Special Report

Orru, Hantzsch, Petasis, Groebke-Black- developed a new green synthesis method its HCl salt by fractional crystallization
burn-Bienayme, Kabachnik-Fields, from the same starting material using and was subsequently resolved with
Willgerodt-Kindler, Bucherer-Bergs, only three steps instead of six. As D-(-)mandelic acid to produce the de-
Gewald reactions, etc. The mentioned BHC recycles and recovers the waste sired (-)-(1S,4S)-sertraline. To recover
MCRs are used directly to synthesize byproduct from the synthesis process, these solvents, energy-intensive proce-
many pharmaceuticals and key inter- a bulky amount of aqueous salt wastes dures such as distillation were required,
mediates following the major principles is eliminated. For this green synthesis, and even after that, 100% recovery
of GC. BHC received the Presidential Green was not possible. Moreover, the workers
Chemistry Challenge Award in 1997 may have been exposed to solvents like
Examples of Green Chemistry in APIs and was recognized by the US EPA toluene and THF. Again, titanium tetra-
There are several examples where- as a model for green synthesis. Like chloride employed in the imination
in pharmaceutical companies and the Boots synthesis, the Friedel-Crafts reaction is an air-sensitive corrosive
researchers used the majority of GC acetylation of 2-methylpropylbenzene liquid that produces dense HCl fumes
principles through redesigning the entire produced 1-(4-isobutylphenyl)ethenone when exposed to moist air.
reaction scheme of many established in the presence of anhydrous hydro
APIs. The obtained synthesis schemes gen fl uoride as a catalysis instead of Later in 1998, Pfi zer designed and
are further scrutinized based on green AlCl . In the following steps, hydro- implemented a combined process for
3
principles, cost-effectiveness, percen- genation with Raney nickel gave the the synthesis of sertraline, employing
tage of yield, and amount of waste alcohol 1-(4-isobutylphenyl)ethanol, only two solvents, ethyl acetate and
generated. Many of have received the followed by carbonylation to generate ethanol, requiring over 24-kl of both
American Chemical Society (ACS) ibuprofen, using cobalt and palladium to produce 1,000-kg of sertraline that
Green Chemistry Awards and/or the US for catalysis. directly saved around 76-kl of solvents,
EPA’s Presidential Green Chemistry and interestingly, both solvents are rela-
Challenge Award. In the case of the Boots synthesis, tively safer for both the environment
the overall used atoms were around and the workers.
Ibuprofen 40%, which suggested that 60% of the
Ibuprofen, an NSAID, commonly materials were waste products. On the The condensation reaction between
used as a pain killer, was fi rst paten- contrary, the new three-catalytic-step tetralone and monomethylamine was
ted by the Boots Company in the green synthesis results in 77% atom carried out in ethanol without the need
1960s. The Boots synthesis comprises utilisation (if we consider recovered for a classical dehydrating agent, such
six steps. According to their patent, acetic acid as byproducts, then it is as titanium tetrachloride (TiCl ), which
4
the starting material 2-methylpropyl- 99%). produces hazardous byproducts and
benzene went through the Friedel- solid wastes. The obtained imine was
Crafts acetylation in the presence of Sertraline catalytically reduced with Pd/CaCO 3
AlCl and acetic anhydride to produce Sertraline is the active ingredient in as a catalyst in ethanol as the reaction
3
1-(4-isobutylphenyl)-ethenone, which the drug Zoloft, prescribed as an anti- solvent to generate racemic mixtures of
reacted with ethyl chloroacetate to depressant. Since its introduction, from cis and trans isomers (20:1), followed
give the α,β-epoxy ester following the 1992 to 1997, the commercial synthe- by the resolution of the racemic cis iso-
Darzens reaction. In the next step, the sis of sertraline by Pfi zer involved fi ve mer with D-(-)-mandelic acid, resulting
α,β-epoxy ester was decarboxylated volatile solvents such as hexane, toluene, in a more effi cient sertraline mandelate.
and hydrolysed to 2-(4-isobutylphenyl) THF, ethyl acetate, and ethanol, and Finally, it was purifi ed as a HCl salt of
propanal. Subsequently, the reaction in total around 100-kl of solvents was sertraline.
with hydroxylamine gave the 2-(4-iso- needed to get a yield of 1,000-kg of
butylphenyl)propanal oxime, followed sertraline. The green synthesis abolishes the
by a two-step hydrolysis to produce requirement for TiCl , and the main
4
the penultimate product 2-(4 isobutyl- Condensation of tetralone with hydrogenation step has been redesigned
phenyl)propanenitrileand the fi nal methylamine in the presence of titanium through the use of selective catalysis,
product ibuprofen, respectively. tetrachloride prepared an imine inter- resulting in much smaller quantities of
mediate, which gave a mixture of cis and wastes and a higher amount of yield.
After the patent ran out, the Boots- trans amines (6:1) through a catalytic Until today, Pfi zer has produced around
Hoechst-Celanese (BHC) company reduction. The cis form was purifi ed as 1,500-tonnes of sertraline, employing

204 Chemical Weekly December 3, 2024

Contents Index to Advertisers Index to Products Advertised