Intermediates
Organic compounds formed during the synthesis of APIs are termed as intermediates. The compound in the synthetic chain before
the production of the final desired compound is called the penultimate intermediate.
Impurities due to rearrangement.
Developing practical synthetic routes to render high-yield products in shorter stages or in a one- or two-pot reaction generally
involves formation of rearranged intermediates that ultimately give the required final product.
As an example, the cyclization of bromonitrostyrene in the API ropinirole involves the rearrangement of the intermediate cyclic
ion to give the indole ring with the formation of hydroxamic ester and chlorooxime acetate as impurities.
Impurities due to in situ reactions.
Advances in synthetic chemistry have enabled a number of stages in a reaction to be carried out in just one or two pots without
the need to isolate intermediates. The downside of such reactions is the unexpected and numerous impurities that form because
intermediates and reagents are not isolated.
Figure 3: Linezolid (e.g., oxazolidinones class) and pemetrexed disodium tautomer impurity. EP is the European Pharmacopoeia.
RRT is relative retention time.
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As an example, the alkylation of the key starting material (S)-2-amino butyramide for the API levetiracetam with chlorobutyrylchloride using potassium hydroxide in the presence of tetra-n-butylammonium bromide gives an intermediate that eventually cyclized into levetiracetam. This intermediate, however, is present
in the final product as an USP impurity A.
Nonreactive intermediates.
Nonreactive intermediates are impurities formed in some intermediate stage by the reaction of reagents used in the next stages
due to carryover. Such impurities remain nonactive in the later stages.
For example, 4-phenyl butanol is a key raw material for the synthesis of salmeterol Intermediates 1 and 2 (see Figure 2).
Intermediate 1 reacts with 4-phenyl butanol in the presence of sodium hydride and toluene to yield Compound 1, which is a
nonreactive impurity in further stages. Intermediate 2 reacts with the trace amounts of Intermediate 1 and in the same conditions
react to form Compound 2 (see Figure 2).
Reactive intermediates.
Reactive intermediates, as the name implies, are byproducts or impurities resulting from the intermediate stages of the reaction
that have the potential to react with the reagents or catalysts used in later stages. They are carried forwarded in every
stage up to the final API as a reactive intermediate.
During the process development of salmeterol, an unknown impurity was detected at 2.08 RRT at a level of 0.11% and later identified
after isolation to be Compound 3 (see Figure 2). The impurity formed in the final API due to presence of N-benzyl-6-(4-cyclohexylbutoxy)hexan-1-amine in Intermediate 2 leads to the salmeterol cyclohexyl impurity (12).
The reactive intermediate, N-benzyl-4-phenylbutan-1-amine is present in Intermediate 2 (see Figure 2). It is formed by the reaction of 4-phenyl butanol
with benzyl amine and competes in all reaction stages with Intermediate 2 to form Compound 4 (see Figure 2).
A main challenges faced in developing the olefination route of the API aprepitant was a subsequent reaction of the vinyl ether
intermediate with dimethyltitanocene to form an ethyl impurity (13).
Bis-compound impurities.
The formation of new or unknown impurities can occur when scaling up a process, even with successful runs at a smaller scale.
Examining the molecular weight of such impurities often reveals the compound is exactly double the weight of that being formed
in that reaction step. Such dimeric derivatives are called bis-compound impurities. Two bis-compound impurities were formed
in the intermediate and final stages in the synthesis of linezolid, to be discussed in Part III of this article.
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