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SECTION C Group 1

The manufacture of pharmaceuticals is consistently shown to be amongst the top performing industrial sectors
worldwide. Sales exceeding 207 billion in 2000 illustrates the industrys contribution and importance to the global
economy [9]. The continued growth and success of the industry largely depends on the production of lucrative high
volume drugs. Analgesics (painkillers) are an important class of drug exemplifying bulk production within the
pharmaceutical industry. Ibuprofen is the active ingredient in many analgesics and current production is well in excess of
13,000 tonnes per annum [5]. Brand name products such as Nurofen, Brufen and Ibuleve, to name but a few,
incorporate Ibuprofen to provide their analgesic action. In addition, Ibuprofen is a member of the nonsteroidal anti-
inflammatory (NSAI) group of drugs, which combat swelling and inflammation.

Pharmacological Aspects of Ibuprofen

MODE OF ACTION
Ibuprofen has been available as a treatment for mild to moderate pain for almost 40 years [5]. The compound exerts its
action through reversible competitive inhibition of an enzyme found in the body called cyclo-oxygenase (COX), which is
active in the arachidonic acid cascade [10]. This C20 tetra-unsaturated fatty acid is an important precursor for a range of
biologically important molecules. Inhibition of COX by Ibuprofen purposely blocks the synthesis of cyclic endoperoxides
and, in sequence, prostaglandin derivatives, as shown in Scheme 3 below [10].

Prostaglandins belong to a diverse biochemical family with a wide range of physiological effects. Ibuprofen, as an
analgesic and anti-inflammatory, seeks to prevent prostaglandin formation for two main reasons. Firstly, certain basic
pain COX Cyclic endoperoxides Prostaglandins Ibuprofen Scheme 3. Inhibition of COX by Ibuprofen [10]. Arachidonic acid
mechanisms operational in the body are amplified by some prostaglandins [11]. Secondly, certain prostaglandins are
implicated in the inflammatory response to cell trauma (allergic reactions, sprains, etc.) [11]. Suppression of
prostaglandin synthesis, however, can cause unwanted side effects [11]. The general blockade of the COX enzyme also
inhibits the formation of beneficial prostaglandins that help to protect the gut lining. Consequently, complications such
as stomach ulceration and bleeding can arise. Importantly, in 1991 researchers showed that the cyclooxygenase enzyme
was present in two forms, COX-1 and COX-2 [12]. With the subsequent discovery that COX-2 is only present during the
inflammatory response, a number of pharmaceutical companies are now working to develop specific COX-2 inhibitors to
lower the risk of side effects. In fact, Meloxicam (COX-2 selective) is already being marketed in the UK as a treatment for
rheumatoid arthritis [12].

Stereochemical considerations Stereochemistry is an important field of chemistry dedicated to the structure

determination of molecules in three dimensions. Cyclo-oxygenase, as with all other enzymes, has a distinct three-
dimensional shape. Ibuprofens success as a COX inhibitor depends largely on its ability to fit into the enzymes active
site and, subsequently, to form compatible bonding interactions (mainly hydrophobic) [11]. The compound contains a
single chiral centre, i.e. a carbon bonded to four different substituents. As such, there are two non-superimposable
mirror image forms of Ibuprofen, that is, a pair of Ibuprofen enantiomers (Fig. 2).

During the 1950s, Cahn, Ingold and Prelog devised a set of arbitrary rules to distinguish between enantiomers [13a].
Using these rules, the absolute configuration of the enantiomers of Ibuprofen can be assigned accordingly as (R)-
Ibuprofen and (S)-Ibuprofen (shown in Fig. 2 above). Such notation is vital to modern chemists because although
enantiomers are said to be chemically identical, when placed in a chiral environment (e.g. living systems) their
properties can differ markedly [7c]. The devastating effect of the drug Thalidomide is perhaps the most famous example
of differing enantiomeric interactions in the body. Given that there is the scope for enantiomers to display very different
properties in vivo, it may be surprising to learn that Ibuprofen is widely marketed as a mixture of the (R)- and (S)- forms,
ie as the racemate [14]. Although only the (S)-enantiomer delivers the desired therapeutic action, the physiological
enzyme mandelate racemase readily converts inactive (R)- CH3 H3C H CH3 CO2H H3C H HO2C CH3 CH3 R S Fig. 2.
Enantiomers of Ibuprofen. Ibuprofen to the active enantiomorph [14]. Nevertheless, single (S)-enantiomer versions of
Ibuprofen are currently being developed, with the benefits cited as a reduction in the required dose and a shorter time
for therapeutic levels to be reached [15]. The current trend in the pharmaceutical industry is towards the production of
single enantiomer compounds. This is highlighted by 13% growth to 85 billion in worldwide sales of single enantiomer
drugs for the year 2000 [9]. Furthermore, they accounted for 40% of global drug sales in 2000, up 7% on the previous
year [9]. As well as significant advances in technology, regulatory bodies such as the US Food and Drug Administration
(FDA) are requiring the development of single enantiomer compounds by pharmaceutical manufacturers [15]. At
present the list of the top 100 drugs worldwide contains no fewer than 50 that are single enantiomers [9]. This figure is
set to rise significantly in the next few decades.
(A) USING SCHEME 3 ON THE ACETATE, SUMMARISE THE INHIBITORY MODE OF ACTION OF IBUPROFEN ON THE COX
ENZYME. ALSO ALLUDE TO THE DISCOVERY OF COX-2.

Ibuprofen competes with the natural substrate arachidonic acid (C20 tetraunsaturated fatty acid) for the active site of
the enzyme cyclo-oxygenase (COX).

Reversible competitive inhibition of COX by Ibuprofen ultimately blocks the synthesis of certain prostaglandins
(Scheme 3). This class of biochemical is associated with both the reception of pain and the inflammatory response to cell
trauma.

Ulceration and bleeding of the stomach/gut can occur as a consequence of preventing the formation of protective
prostaglandins. However, in 1991 researchers discovered a second distinct form of cyclo-oxygenase (COX-2), which is
only present during the inflammatory response. The race is on to develop COX-2 selective inhibitors that will not prevent
the synthesis of beneficial prostaglandins.

(B) REFERRING TO FIG. 2 ON THE ACETATE, EXPLAIN THE STEREOCHEMICAL REQUIREMENTS FOR IBUPROFENS
SUCCESS AS AN INHIBITOR OF COX.

COX, as with all other enzymes, has a distinct 3D shape. In its role as an inhibitor of COX, Ibuprofen must fit into the
enzymes active site to form the appropriate bonding interactions (lock and key analogy).

Ibuprofen has one chiral centre and so exists as a pair of enantiomers (Fig. 2). A set of arbitrary rules (Cahn-Ingold-
Prelog rules) is used to label the enantiomers as (R)- and (S)- Ibuprofen (Fig. 2).

The (S)- enantiomer delivers the therapeutic action, whereas (R)-Ibuprofen is virtually inactive. However, the drug is
currently given as an equal mixture of both enantiomers (racemate) as it is enzymatically converted to the active
enantiomorph in vivo.

Nevertheless, single enantiomer (S)-Ibuprofen is currently in development. Benefits over the racemate are cited as
lower dosage requirements and a shorter time period to reach therapeutic levels.

(C) DISCUSS THE CURRENT TREND TOWARDS THE DEVELOPMENT OF SINGLE ENANTIOMER DRUGS IN THE
PHARMACEUTICAL INDUSTRY.

The development and production of single enantiomer compounds is a progressive area in the pharmaceutical industry.
Global sales of single enantiomer compounds grew 13% to 85 billion during 2000 and, in the same year, accounted for
40% of total drug sales worldwide, up 7% on the previous year. At present, the list of the top 100 drugs contains no
fewer than 50 single enantiomer compounds. It is likely that this figure will rise in the near future.
The manufacture of pharmaceuticals is consistently shown to be amongst the top performing industrial sectors
worldwide. Sales exceeding 207 billion in 2000 illustrates the industrys contribution and importance to the global
economy [9]. The continued growth and success of the industry largely depends on the production of lucrative high
volume drugs. Analgesics (painkillers) are an important class of drug exemplifying bulk production within the
pharmaceutical industry. Ibuprofen is the active ingredient in many analgesics and current production is well in excess of
13,000 tonnes per annum [5]. Brand name products such as Nurofen, Brufen and Ibuleve, to name but a few,
incorporate Ibuprofen to provide their analgesic action. In addition, ibuprofen is a member of the nonsteroidal
antiinflammatory (NSAI) group of drugs, which combat swelling and inflammation. The traditional synthesis of Ibuprofen
was patented in the 1960s by the Boots Company PLC, Nottingham [5]. Until the early 1990s, industrial synthesis of the
drug was almost exclusively by the Boots methodology. The traditional six-step route to Ibuprofen is shown in Scheme 4
below [5].

Step 1. Friedel Crafts acylation. Acetic anhydride as the acylating agent, in the presence of stoichiometric quantities of
aluminium trichloride.

Step 2. Darzens condensation. The -chloroester (5) is treated with sodium ethoxide (6) base to yield the -
chloroenolate (ClHC=CO2C2H5) which reacts with 4, forming the epoxide, 7

Step 3. Glycidic acid rearrangement. Treatment of the epoxide species (7) with aqueous acid effects the rearrangement
of the carbon skeleton, resulting in the aldehyde (9
Step 4. Oxime formation. The conversion of the aldehyde (9) into the oxime (11) is carried out using hydroxylamine (10).

Step 5. Nitrile formation. The oxime species (11) readily loses water to form the corresponding nitrile.

Step 6. Nitrile hydrolysis. The nitrile species is slowly hydrolysed (two water equivalents) to yield the desired product,
Ibuprofen.

Considered key to the overall process, the first step in the new synthesis is a novel Friedel Crafts acylation of
isobutylbenzene (1). Acetic anhydride is employed as the acylating agent to introduce the ketone functionality onto the
aromatic ring. Although the first step in the traditional synthesis of Ibuprofen is an identical acylation, the major
distinction between it and the new process is the choice of acylation catalyst. Whereas the traditional synthesis of
Ibuprofen utilises aluminium trichloride (AlCl3), the BHC synthesis employs anhydrous hydrogen fluoride (HF). The
description of AlCl3 as a catalyst is somewhat misleading given that it is used in stoichiometric amounts and, ultimately,
forms large quantities of aluminium chloride hydrate waste [5]. In contrast, HF used in the new process is recovered and
reused with > 99.9 % efficiency [17]. Besides its role as a catalytic agent, HF also functions as a solvent for the acylation
step in the new synthesis [17]. This negates the need for a co-solvent, making product recovery simpler (vacuum
distillation). HF catalyses the conversion of 1 into 3 with >90% yield [17]. The second step in the BHC synthesis is a
catalytic hydrogenation reaction. Hydrogen gas and Raney nickel are employed to reduce 4-isobutylacetophenone (3) to
1-(4-isobutylphenyl) ethanol (5). Raney nickel is a highly active form of the metal produced by the action of sodium
hydroxide on a nickel-aluminium alloy (2NiAl + 2NaOH + 2H2O 2Ni + 2NaAlO2 + 3H2) [18]. The finely divided nickel
formed has a large surface area and is an extremely efficient hydrogenation catalyst, especially at room temperature.
Hydrogenation of 3 is a heterogeneous process, i.e. the catalyst phase (solid) is different to that of the reactants (liquid).
In its liquid state, 4-isobutylacetophenone (3) is charged into a reactor in the presence of hydrogen gas and catalytic
amounts of solid Raney nickel. One of the properties of the nickel catalyst is to lower the high-energy requirements
associated with the cleavage of molecular hydrogen (H-H 436 kJ/mol), otherwise it is thermally unfavourable to effect
a stepwise H addition process [13c]. Selective reduction of the ketone functionality occurs, as hydrogenations of
aromatic rings usually require high pressures. The separation of the liquid product (5) from the reaction mixture is by
simple filtration. At 98 %, the conversion of 3 into 5 is extremely efficient. CH3 H3C HFcat. H3C C O C O O CH3 CH3 H3C
CH3 O Raney Nickel cat. H2 CH3 H3C CH3 OH CO Palladium cat. CH3 H3C CH3 COOH Ibuprofen 1 2 3 4 6 5 Step 1 Step 2
Step 3 Scheme 5. BHC company synthesis of Ibuprofen [5]. H The final step in the BHC synthesis is the carbonylation of
1-(4-isobutylphenyl) ethanol (5) to give Ibuprofen. Carbonylation of 5 is carried out using carbon monoxide in the
presence of the soluble palladium catalyst complex, PdCl2(PPh3)2, in an acidic medium [17,19]. This is a homogeneous
process where the catalyst phase (liquid) is the same as that of the reactants. Homogeneous catalysts are generally used
when selectivity is critical and, importantly, when product-catalyst separation problems can be overcome. In this case,
Ibuprofen is removed from the reaction mixture by vacuum distillation [17]. The carbonylation of 1-(4- isobutylphenyl)
ethanol (5) proceeds with 98% efficiency to Ibuprofen. By cutting the number of steps to three, all catalytic, the BHC
synthesis has dramatically reduced waste quantities associated with Ibuprofen manufacture. Moreover, larger volumes
of the drug can be produced in less time and with less capital expenditure [5]. Therefore, as well as being
environmentally superior to the traditional synthesis, the BHC route also offers more favourable production economics.
The achievements of the BHC Company were recognised with the Kirpatrick Chemical Engineering Award in 1993 [20]
and, in 1997, a Presidential Green Chemistry Challenge Award [5].

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