In synthetic organic chemistry, getting a single end product, 100% pure, seldom occurs because of the change into byproducts,
which can be formed through a variety of side reactions, such as incomplete reactions, overreactions, isomerization, or unwanted
reactions between starting materials, intermediates, chemical reagents, or catalysts. For example, in the bulk production
of paracetamol, diacetylated paracetamol may form as a byproduct (14).
In the Claisen rearrangement of the aryl propargyl ether in diethylaniline at elevated temperatures, formation of the desired
chroman product is accompanied by the generation of a furan byproduct in success sively increasing amounts (15).
In the ropinirole synthesis, a somewhat similar case is observed in the final step. The reaction between the ropinirole precursor
4-(2-bromoethyl)-13-dihydro-2H-indol-2-one and di-n-propyl amine in water produces ropinirole in modest yield (57%), together with styrene as the major byproduct (38%) (16).
Figure 4. Propionaldehyde with malanonitrile reactions. CAS refers to Chemical Abstracts Service, No. is number, and NA is
not available. Conditions: (a) with piperidine in pyridine, heating (Ref. 27); (b) with piperidine in pyridine, heating, cyclization
(Ref. 28); (c) with piperidine, 1,4-dioxane (Ref. 29–30); (d) With [C4DABCO][BF4] in water, Time = 0.0166667 h, T = 20 °C, Knoevenagel condensation or with aluminum oxide in dichloromethane, T= 20 °C, Knoevenagel
condensation aldol-condensation (Ref. 31–33).; and with morpholine in ethanol, T = 20 °C, Knoevenagel condensation (Ref. 34–37).
In another example, thiophenes are important heterocyclic compounds that are widely used as building blocks in many agrochemicals
and pharmaceuticals (17). The synthesis of 2-amino-5-methylthiopene-3-carbonitrile is achieved by reacting a mixture of sulfur,
propionaldehyde, malononitrile, and dimethylformamide using triethylamine (18–26).
The reaction of propionaldehyde with malononitrile and sulfur resulted in formation of two unknown impurities up to 7%, which
were isolated and confirmed by 1 H NMR (nuclear magentic resonance spectroscopy), correlation spectroscopy, nuclear Overhauser effect spectroscopy, and single
X-ray crystallography to be Impurity 1 (see Figures 4 and 5). These impurities are further found to react with 2-fluoro nitrobenzene
to give next-stage impurities and which are controlled by purification in the respective stages.
Impurity 1 (see Figure 5) is a novel tricarbonitrile bicyclic compound, and as of the writing of this article, it is not known
in the literature. Prediction of cLogP is 0.65, drug linkness is 4.04, and the drug score is 0.45 as determined by OSIRIS
Property Explorer, software used to calculate various drug-relevant properties of chemical structures. Structure–activity
relationship, quantitative structure–activity relationship, and drug design with other modified organic/inorganic hetrocyclic
moieties could give some biological activity. The molecular designing of Impurity 1 for specific and unspecific purposes (e.g.,
DNA-binding, enzyme inhibition, anticancer efficacy) is based on the knowledge of molecular properties, such as the activity
of functional groups, molecular geometry, and electronic structure, and on information cataloged on analogous molecules. The
compound 2,6-diamino-7-ethyl-8-methylbicyclo[2.2.2]octa-2,5-diene-1,3,5-tricarbonitrile could be coupled with an active or
nonactive peptide to check the biological activity as a prodrug or drug. The potential therapeutic and prophylactic activities
of antimalarials, antimitotics, and antitumor agents could also be performed. This bicyclic compound may be used alone as
a single agent or in combination with any organic or inorganic salts in chemotherapy or in combination with other chemotherapeutic
agents after in vivo and in vitro testing.
Figure 5: Reaction scheme of olanzapine impurities. DMF is dimethylformamide. TEA is triethylamine. Addn is addition. RT is
room temperature. CAS is Chemical Abstracts Service, No. is number, and NA is not available.